Somatostatin Analogs in Cancer Management

Somatostatin Analogs in Cancer Management

Editor

C. Scarpignato, Parma/Nantes

17 figures, 1 in color, and 16 tables, 2001

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Vol. 46, Suppl. 2, 2000

Contents

V Foreword Lamberts, S.W.J. (Rotterdam) VIII Preface Scarpignato, C. (Parma/Nantes) 1 Somatostatin Analogs for Cancer Treatment and Diagnosis:

An Overview Scarpignato, C.; Pelosini, I. (Parma/Nantes) 30 Antiproliferative Effect of Somatostatin and Analogs Bousquet, C.; Puente, E.; Buscail, L.; Vaysse, N.; Susini, C. (Toulouse) 40 Established Clinical Use of Octreotide and Lanreotide in

Oncology Öberg, K. (Uppsala) 54 The Palliative Effects of Octreotide in Cancer Patients Dean, A. (Nedlands) 62 Management of Breast Cancer: Is There a Role for

Somatostatin and Its Analogs? Boccardo, F.; Amoroso, D. (Genoa) 78 Somatostatin, Its Receptors and Analogs, in Lung Cancer O’Byrne, K.J. (Leicester); Schally, A.V. (New Orleans, La.); Thomas, A. (Leicester); Carney, D.N. (Dublin); Steward, W.P. (Leicester) 109 Octreotide in the Management of Hormone-Refractory

Prostate Cancer Vainas, I.G. (Thessaloniki)

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127 Gastrointestinal Cancer Refractory to Chemotherapy:

A Role for Octreotide? Cascinu, S.; Catalano, V.; Giordani, P.; Baldelli, A.M.; Agostinelli, R.; Catalano, G. (Pesaro) 134 Pancreatic Cancer: Does Octreotide Offer Any Promise? Rosenberg, L. (Montreal) 150 Octreotide for Cancer of the Liver and Biliary Tree Kouroumalis, E.A. (Heraklion) 162 Somatostatin Analogs in Oncology: A Look to the Future Jenkins, S.A. (Swansea); Kynaston, H.G. (Cardiff); Davies, N. (London); Baxter, J.N. (Swansea); Nott, D.M. (London)

197 Author Index 198 Subject Index

IV

Contents

Foreword

Somatostatin plays an inhibitory role in the regulation of the function of a number of organs like the brain, the anterior pituitary gland, the gastrointestinal tract, the exocrine and endocrine pancreas, as well as lymphoid cells. It can be considered as an inhibitory (growth) factor in these organs, which mainly prevents local overreaction from a multitude of stimulatory factors. In addition to the negative role in controlling the physiological regulation of these organ systems, somatostatin also exerts inhibitory effects on the proliferation of normal and neoplastic cells. Somatostatin analogs inhibit tumor growth in a wide variety of experimental models in several species, like transplantable osteo- and chondrosarcomas, transplantable acinar and ductal pancreatic carcinomas, as well as different types of rat and mouse mammary and prostatic carcinomas. Also, a number of human pancreatic, colonic, gastric and small cell lung cancer lines xenografted in nude mice are inhibited in their growth during therapy with somatostatin analogs. While most of these experimental tumors and cell lines express a dense and homogeneous distribution of somatostatin receptors, some of these tumors seem to be inhibited in growth by somatostatin analog administra-

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tion via indirect mechanisms involving inhibitory effects on local or general growth factors (growth hormone, insulin-like growth factor 1, epidermal growth factor, gastrointestinal hormones) and/or angiogenesis. One should realize, however, that in most of the experimental models the inhibitory effects of somatostatin analogs on growth are most potent early after tumor implantation as well as early after the start of drug administration, and that complete growth curves of the (transplanted) tumors with and without somatostatin analog treatment often indicate a delay in growth only, while an escape of tumor growth from the inhibitory effects of somatostatin analogs is observed eventually. This indicates a decreased sensitivity of these tumors during long-term somatostatin analog therapy, which involves somatostatin receptor downregulation and/or the selection of somatostatin receptor-negative tumor cell clones. In clinical oncology prostate, breast and endometrial carcinomas are known to be ‘conditional’ cancers, which grow in certain specific hormonal environmental conditions. When these conditions are altered the tumors regress, but do not die. After a certain period of a persistent nonproliferating state, part of

V

the tumor cells resume active growth. This is the simple basis for the success of androgen, estrogen and progesterone depletion in the treatment of these cancers. The symptomatic relief of patients with metastatic prostatic, breast and endometrial cancers during treatment with antiandrogens, antiestrogens and progesterone receptor-blocking agents is highly appreciated and looked for by oncologists that otherwise mainly use intensive chemotherapy. The promising data demonstrating that many experimental tumor models also seem to be ‘conditionally’ dependent on somatostatin, growth hormone, insulin-like growth factor 1, prolactin and other hormones and growth factors has raised hopes that direct or indirect blockade of their activity and/or receptors on metastatic human cancers with well-tolerated drugs like somatostatin analogs, bromocriptine and retinoids would also induce a transient state of dormancy or even a slight temporary regression. Also, the somatostatin analog octreotide is widely and successfully used in patients with acromegaly, metastatic islet cell tumors and carcinoids. In these patients the quality of life improves and there is strong evidence for control of tumor growth as well as a clear prolongation of survival. Like most hormone-secreting tumors many human adenocarcinomas originating from the breast, colon, kidney, ovary as well as meningiomas and malignant lymphomas often express somatostatin receptors. Although somatostatin receptors are in many cases not distributed homogeneously over all tumor cells, and their numbers per tumor cell in general are lower than in hormone secreting tumors, most somatostatin receptor-bearing human cancers can be visualized by somatostatin receptor imaging. Only little evidence so far indicates that long-term therapy of patients with somatostatin receptor-positive tu-

VI

mors with somatostatin analogs induces a decrease or even control of tumor growth. More evidence points to a transient improvement in the quality of life in some of the patients treated. Human cancers differ in many respects from the experimental tumor models that respond so well to somatostatin analog therapy. (1) Most human cancers consist of a mixture of varying amounts of stromal tissue and different clones of epithelial tumor cells that do not uniformly express somatostatin receptors. This sharply contrasts with the monoclonal tumor models in animals, which in most instances express somatostatin receptors on all tumor cells. (2) Somatostatin receptor expression in human breast, prostate and colonic cancers often indicates loss of differentiation of the tumors, meaning that these undifferentiated tumors have a bad prognosis. (3) The nature of new clinical trials in oncology is often such that patients are mainly included ‘late’ in their disease, when tumors have already progressed considerably. Also, it remains uncertain whether somatostatin receptor subtype 2 (SSTR-2)-specific analogs like octreotide are the optimal compounds to be used in the treatment of human cancer. These analogs have little activity towards the SSTR-3 subtype, which is important in mediating apoptosis. In vitro studies have demonstrated that SSTR-2-expressing tumor cell lines as well as primary cultures of human tumors internalize radiolabeled somatostatin analogs like 111In-[DTPA0]octreotide and [90Y-DOTA0, Tyr3]octreotide. Preclinical studies using experimental tumor models have now demonstrated that tumor growth can be inhibited by administration of these two radiopharmaceutical compounds. Clinical trials already demonstrated promising effects using these radiopharmaceuticals on tumor size in patients with advanced somatostatin receptor-positive neuroendocrine tumors. Also, the concept of

Foreword

targeted chemotherapy to deliver chemotherapeutic compounds selectively to somatostatin receptor-positive tumor cells, thereby reducing their toxicity, has now been validated using newly developed cytotoxic somatostatin analogs in experimental mouse and rat models of human pancreatic, breast and prostate cancers. In this supplement to Chemotherapy Professor Scarpignato has succeeded in bringing together the most knowledgeable scientists in the field of oncology that have extensive personal experience with the use of somatostatin analogs in the treatment of cancer patients.

Foreword

They review the current status of their use in an admirable manner, while the perspectives of newer forms of therapy with the targeted somatostatin receptor-mediated approach are also discussed. I would like to congratulate the editor and the contributors on the exhaustive and balanced description of the current thoughts on the use of somatostatin analogs in patients with different forms of metastasized cancer. S.W.J. Lamberts, MD, PhD Professor of Medicine University Hospital Dijkzigt, Rotterdam

VII

Preface

Despite the enormous advances in science and medical technology in recent times, our knowledge of the pathophysiology and treatment of neoplasia is far from complete and, for the patients at least, the myths that surround cancer remain intact. Cancer remains the ‘bogy man’ of medicine as we enter the new millennium, and the very mention of the word strikes mortal fear in patients and their families in a way not generally seen with any other disease. Although chemotherapy is very effective in the management of certain neoplasms such as testicular cancer, the efficacy of this therapeutic modality in the treatment of many common malignancies such as those of the lung, breast, prostate, bowel, pancreas and kidney is limited. Cure of macroscopic metastatic disease is exceedingly rare, and palliation of symptoms of metastatic neoplasms by chemotherapy can be problematic since the toxicity of the treatment often outweighs any improvement in quality of life resulting from a temporary decrease in tumor burden. This situation has not only motivated attempts to develop novel cytotoxic agents and targeted chemotherapy, but has also stimulated research on innovative noncytotoxic therapies for cancer.

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Amongst the various hormonal agents, currently being evaluated for the management of neoplasia, considerable attention is directed to somatostatin analogs. This is largely due to the demonstration of antineoplastic activity of these compounds in a variety of experimental models in vitro and in vivo and to the elucidation of some aspects of the molecular mechanisms whereby they exert their cytostatic and cytotoxic effects. Furthermore, clinical experience with somatostatin analogs in the treatment of conditions such as acromegaly and GEP tumors has shown that they are well tolerated compared to other antineoplastic therapies currently in use. As a consequence, there is much ongoing clinical research to determine whether or not results from experimental studies will translate into clinically useful antineoplastic activity. In the recent years there has been extensive international media coverage of the allegedly successful treatment of a number of malignant neoplasms with the Di Bella multitherapy (DBM). This is a multidrug, individually tailored medical treatment (comprising a mixture of melatonin, bromocriptine, somatostatin, a solution of retinoids, and, depending on the kind of cancer, either cyclophosphamide or hydroxyurea) developed by Luigi

Di Bella, an Italian physician. Over the past 25 years Dr. Di Bella has consistently used it on an outpatient basis claiming its effectiveness in halting the progression or completely curing most cancers. Not surprisingly, in view of the public interest in cancer therapy, a number of associations have been formed to support this treatment. As a matter of fact, these associations mounted a campaign to request that DBM be included among those cancer treatments considered to be effective and that its cost be fully reimbursed by the Italian National Health Service. Despite some debate about the methodology of the different clinical trials [1–8], a phase II study, coordinated by the Italian National Institute of Health and the National Cancer Advisory Committee, did not show sufficient efficacy in patients with advanced cancer to warrant further clinical testing [9]. Furthermore, a follow-up of treated patients did not give any evidence that DBM improves the survival of cancer patients [10]. Since somatostatin or octreotide represent only one component of the DBM, the ineffectiveness of this approach does not necessarily translate into a lack of efficacy of peptide analogs in the management of neoplasia. A single component of a multidrug therapy could indeed be effective on its own [11]. However, as summarized by Jenkins et al. [12] in this issue, apart from some notable exceptions, somatostatin analog therapy has proven to be disappointing in the management of advanced malignancy. Should somatostatin analogs be abandoned? A thorough analysis of the available literature suggests that this is not the case. Indeed, besides being used in cancer treatment (alone or in combination with other cytotoxic or hormonal agents) and palliation, radiolabelled somatostatin analogs are employed for the localization of primary and metastatic tumors expressing somatostatin receptors. Indeed the so-called ‘somatostatin re-

Preface

ceptor scintigraphy’ is the most important clinical diagnostic investigation for patients with suspected neuroendocrine tumors. Targeted radiotherapy, which is being evaluated in clinical trials, represents an obvious extension of somatostatin scintigraphy. In addition, new receptor-selective and ‘universal’ analogs are being developed and new highdose regimens are being tested. Further, somatostatin receptor-targeted chemotherapy represents an appealing approach to treatment of SSTR-expressing tumors. Finally, the genetic transfer of hSSTR-2 and hSSTR-5 genes together with the genes that encode their membrane proteins to those neoplasms that do not express these receptor subtypes will translate the benefits of gene therapy to somatostatin analogue treatment of cancer. The final chapter on somatostatin and cancer has, therefore, not yet been written. Taking all the above considerations into account, we felt it timely and worthwhile to attempt a critical review of the recent developments in the field. To this end, the present issue of Chemotherapy was planned with the aim of synthesizing the massive body of evidence available on somatostatin analog therapy of cancer and the scientific basis for their antineoplastic effects, to enable oncologists to rationalize the use of these compounds in their clinical practice and to stimulate research on new therapeutic approaches. Unlike some other publications in the field, this supplement is not the result of any national or international symposium. It represents the collection of 11 commissioned monographic reviews generously offered by 30 international scientists, all of whom have significantly contributed to this new knowledge, in order to provide a glimpse of what may lie ahead. I am indebted to all the contributors for having accepted to share with us their experience of somatostatin analog therapy of cancer and for providing us with excel-

IX

lent manuscripts despite their many daily commitments. I would like to thank Mr. Peter Roth and Mrs. Andrea Brauns of S. Karger AG for their excellent cooperation during the publication of this supplement. Moreover, I am grateful to Novartis Pharma AG who backed the publication costs and to Voluntary Association for Cancer Research in Parma (A.VO.PRO.RI.T.) for financial help and for spreading this volume to Italian physicians. My sincere gratitude goes also to Dr. Viktor Boerlin, Mr. Gary Cheng and Dr. Susanne Schaffert at the Strategic Marketing Depart-

November 2000

ment, Novartis, who rendered this publication possible. They have shown great interest in the project from the very beginning and made huge efforts to make these proceedings available to the medical community. Last but not least, I am indebted to Dr. Spencer A. Jenkins (Departments of General Surgery & Urology, University Hospital of Wales, Cardiff, UK) for his invaluable help during my editorial work. He made constructive criticism and gave useful suggestions for every paper published in this supplement. We have had many discussions from which some ideas and concepts expressed in our papers emerged.

Carmelo Scarpignato MD, DSc (Hons), PharmD (h.c.), FCP, FACG Professor of Pharmacology and Therapeutics Associate Professor of Gastroenterology Universities of Parma and Nantes

References 1 Müllner M: Di Bella’s therapy: The last word? The evidence would be stronger if the researchers had randomised their studies. BMJ 1999; 318:208–209. 2 Reyes JL: Compared to what? eBMJ 1999; 22 January. 3 Liberati A, Magrini N, Patoia L, Pagliaro L: Randomised controlled trials may not always be absolutely needed. BMJ 1999;318:1073. 4 Raschetti R, Bruzzi P: Methodological and ethical difficulties in clinical oncology trials. Di Bella Multitreatment Italian Trial Coordinating Group. Lancet 1999;353:153–154.

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5 Raschetti R, Greco D, Menniti-Ippolito F, Spila-Alegiani S, Traversa G, Benagiano G, Bruzzi P: The Di Bella multitherapy trial. Criticisms ignores standard methodology of cancer treatments. BMJ 1999;318: 1074. 6 Müllner M, Evans SJW: Reply. BMJ 1999;318:1073. 7 Tirelli U, Di Filippo F: Debate on Di Bella therapy. Lancet 1999;354: 159. 8 Laderoute MP: Debate on Di Bella therapy. Lancet 1999;354:159. 9 Italian Study Group for the Di Bella Multitherapy Trials: Evaluation of an unconventional cancer treatment (the Di Bella multitherapy): Results of phase II trials in Italy. BMJ 1999; 318:224–228.

10 Buiatti E, Arniani S, Verdecchia A, Tomatis L: Results from a historical survey of the survival of cancer patients given Di Bella multitherapy. Cancer 1999;86:2143–2149. 11 Calabresi P: Medical alternatives to alternative medicine. Cancer 1999; 86:1887–1889. 12 Jenkins SA, Kynaston HG, Davies N, Baxter JN, Nott DM: Somatostatin analogues in oncology: A look to the future. Chemotherapy 2001;47 (suppl 2):162–196.

Preface

Chemotherapy 2001;47(suppl 2):1–29

Somatostatin Analogs for Cancer Treatment and Diagnosis: An Overview Carmelo Scarpignato a, b Iva Pelosini a a Department

of Internal Medicine, School of Medicine and Dentistry, University of Parma, Italy; bDepartment of Gastroenterology and Hepatology, Faculty of Medicine, University of Nantes, France

Key Words Somatostatin W Octreotide W Lanreotide W Vapreotide W Cancer treatment W Somatostatin receptor scintigraphy W Somatostatin receptor-targeted radiotherapy

Abstract Due to the limited efficacy and considerable toxicity of conventional chemotherapy, novel cytotoxic agents and innovative noncytotoxic approaches to cancer treatment are being developed. Amongst the various hormonal agents, increasing attention is being directed to somatostatin analogs. This is largely due to the demonstration of antineoplastic activity of these compounds in a variety of experimental models in vitro and in vivo and to the elucidation of some aspects of the molecular mechanisms underlying their antineoplastic activity. On the other hand, clinical experience with somatostatin analogs in the treatment of conditions like

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acromegaly and GEP tumors has shown that they are well tolerated compared to other antineoplastic therapies currently in use. As a consequence, there is much ongoing clinical research to determine whether or not results from experimental studies will translate into clinically useful antineoplastic activity. Besides being used in cancer treatment and palliation, radiolabelled somatostatin analogs are employed for the localization of primary and metastatic tumors expressing somatostatin receptors. The so-called ‘somatostatin receptor scintigraphy’ is indeed the most important clinical diagnostic investigation for patients with suspected neuroendocrine tumors. Targeted radiotherapy, which is being evaluated in clinical trials, represents an obvious extension of somatostatin scintigraphy. Since the short half-life of native somatostatin makes continuous intravenous infusion mandatory, several long-acting analogs have been synthesized. Amongst the hundreds of peptides synthesized, octreotide (which binds mainly to SSTR-2 and

Carmelo Scarpignato, MD, DSc, PharmD, FCP, FACG Laboratory of Clinical Pharmacology, Department of Internal Medicine Maggiore University Hospital, I–43100 Parma (Italy) Tel. +39 0521 903863, Fax +39 0521 292499, E-Mail [email protected]

SSTR-5 receptor subtypes) has been the most extensively investigated. A thorough analysis of the pharmacological activities and therapeutic efficacy of the native somatostatin and the synthetic analogs (octreotide, lanreotide and vapreotide) reveals that the biological actions of these peptides are not always identical. These differences appear to be related to the different affinities of the natural hormone and synthetic derivatives for the different receptor subtypes. For all the three peptides long-lasting formulations have been developed to provide patients with the convenience of once or twice a month administration and to ensure stable drug serum concentrations between injections. Radiolabelled derivatives of octreotide, lanreotide and vapreotide have been synthesized and used as radiopharmaceuticals for somatostatin receptor scintigraphy and somatostatin receptor-targeted radiotherapy. The safety profile of synthetic somatostatin analogs is well established. Most adverse reactions to these peptides are merely a consequence of their pharmacological activity and consist mainly of gastrointestinal complaints, cholelithiasis and effects on glucose metabolism. They are often of little clinical relevance, thus making somatostatin analogs safe drugs for long-term use. While immediate release preparations are the drugs of choice in the short term, long-acting formulations are better indicated, on an outpatient basis, for the long-term management of chronic conditions. New ‘receptor-selective’ and ‘universal’ somatostatin analogs are being developed and combinations of currently available derivatives with other (cytotoxic and/or hormonal) agents are being explored in the search for an efficacious and well-tolerated treatment of the various malignancies. Somatostatin receptor-targeted chemotherapy (with conjugates of somatostatin peptides with cytotoxic drugs) and gene therapy (e.g.

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Chemotherapy 2001;47(suppl 2):1–29

transferring the SSTR-2 gene into neoplastic cells), which have been successfully tested in experimental studies, should be applied to human beings in a not too distant future. Copyright © 2001 S. Karger AG, Basel

Introduction

Although cytotoxic chemotherapy is very effective in the management of certain neoplasms such as testicular cancer, the efficacy of this therapeutic modality in the treatment of many common neoplasms such as those of the lung, breast, prostate, bowel, pancreas and kidney is limited. Cure of macroscopic metastatic disease is exceedingly rare, and palliation of symptoms of metastatic neoplasms by chemotherapy can be problematic since the toxicity of the treatment often outweighs any improvement in quality of life resulting from the temporary decrease in tumor burden [1– 4]. Moreover, postsurgical adjuvant chemotherapy is frequently without beneficial effect (as in the case of renal cancer), or is associated with only small improvements in diseasefree survival (as in the case of colon cancer, for instance). This situation has not only motivated attempts to develop novel cytotoxic agents, but also has stimulated the research regarding innovative noncytotoxic approaches to cancer treatment [1–4]. Amongst the various hormonal agents, increasing attention is being directed to somatostatin analogs [5–12]. This is largely due to the demonstration of antineoplastic activity of these compounds in a variety of experimental models in vitro and in vivo [5, 7] and to the elucidation of some aspects of the molecular mechanisms underlying their antineoplastic activity [13–16]. On the other hand, clinical experience with somatostatin analogs in the treatment of conditions like acromegaly and GEP tumors has shown that they are well

Scarpignato/Pelosini

tolerated compared to other antineoplastic therapies currently in use [16, 17]. As a consequence, there is much ongoing clinical research to determine whether or not results from experimental studies will translate into clinically useful antineoplastic activity. Besides being used in cancer treatment and palliation, radiolabelled somatostatin analogs are employed for the localization of primary and metastatic tumors expressing somatostatin receptors [18–21]. The so-called ‘somatostatin receptor scintigraphy’ is indeed the most important clinical diagnostic investigation for patients with suspected neuroendocrine tumors [19]. Targeted radiotherapy, which is being evaluated in clinical trials [22, 23], represents an obvious extension of somatostatin scintigraphy. This paper will review the chemistry and pharmacokinetics of currently used synthetic peptides and summarize the rationale for their use in cancer treatment and diagnosis.

Somatostatin Analogs: Chemistry and Pharmacokinetics

Due to its central role in the regulation of growth hormone secretion, somatostatin is often referred to as somatotropin release-inhibiting factor (SRIF) or growth hormone (GH) release-inhibiting factor [24]. This peptide displays a wide range of biological actions that can make it an appropriate drug for the treatment of a variety of human diseases. Shortly after the isolation of somatostatin, protein chemists began to synthesize peptide analogs with a similar spectrum of action but with much longer biological half-life [25]. The short half-life of the native peptide [26] makes indeed continuous intravenous infusion mandatory. To design a more stable peptide derivative one needs to strengthen the metabolic resis-

Somatostatin Analogs for Cancer Treatment and Diagnosis

Fig. 1. Sites of enzymatic degradation of natural so-

matostatin.

tance of the cleavage sequences of the native peptide. In the case of somatostatin, at least 5 sites of enzymatic degradation are known (fig. 1) [27]. The most dangerous cleavage can occur after Trp8 because such a rupture leads to completely inactive fragments. Aminopeptidase attack at the N-terminal is less important since sequences which are 1 or 2 amino acids shorter are as potent as the native peptide. The usual trick to prevent or slow down enzymatic degradation of a peptide is the replacement of an L-amino acid by its D-isomer. Fortunately, the systematic replacement of L- by D-amino acids demonstrated that this exchange at position 8 is not only well tolerated but also leads to an enhanced GH-inhibitory potency [28]. Further important information on the active site can be deduced by systematic replacement of all amino acids in SRIF by a neutral amino acid such as Ala. The total inactivity of analogs with Ala in positions 6, 7, 8 or 9 indicates that these residues are essential for its biological activity. Similarly, yet more information can be gained by systematically deleting single amino acids from the natural sequence. Such studies showed that the first two amino acids, Ala-Gly, are not necessary for full biological activity [28].

Chemotherapy 2001;47(suppl 2):1–29

3

Fig. 2. Primary structure of octreotide and derived peptides.

Table 1. Synthetic analogs of somatostatin currently available

Cyclic octapeptide analogs

Linear peptide analogs

Hexapeptide analogs

SMS 201-995 (octreotide) RC-160 (vapreotide) NC-8-12 NC-4-28S DC 23-60 BIM 23014 (lanreotide) BIM 23023 BIM 23034 BIM 23059 BIM 23060

BIM 23049 BIM 23051 BIM 23052 BIM 23053 BIM 23055 BIM 23057 BIM 23065 BIM 23067 BIM 23068 BIM 23069

MK-678 BIM 23050 Linear octapeptide analogs EC5-21 BIM 23042 BIM 23056 BIM 23058

D-Trp8 somatostatin-14. Lcu8, D-Trp22, Tyr25 somatostatin-28.

Against this background, hundreds of somatostatin analogs have been synthesized in many research centers all over the world. Amongst the different peptides (table 1), the octapeptide SMS 201-995, called octreotide, has been the most extensively investigated [for reviews, see 29–32]. More recently, two

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Chemotherapy 2001;47(suppl 2):1–29

additional peptides [33], namely lanreotide (BIM 23014) [34] and vapreotide (RC-160) [35], have become available for clinical use. It is worthwhile to emphasize that all the three peptides share a common feature, namely the tetrapeptide X7-Trp8-Lys9-Y10 (where X could be either Phe or Tyr and Y either Thr or

Scarpignato/Pelosini

Fig. 3. Stability of octreotide (SMS

201-995) and SIRF against degradation by rat kidney homogenates [from 25]. Fig. 4. Plasma levels of unchanged peptides in the rat: intravenous application of [3H-Phe6]SRIF (o) and [4C-D-Trp4]octreotide ()). SRIF was injected at 1.6 mg/kg (12–16 mCi/mmol), octreotide at 1 mg/kg (35 ÌCi/mg). Unchanged peptides were recovered after highpressure liquid chromatography purification of plasma samples. Data are taken from Peters [42] for SRIF and from Lemaire et al. [38] for octreotide. Only the most relevant alpha phases of elimination are indicated.

3

4

Val, fig. 2), thus suggesting that this amino acid sequence is essential for receptor binding [36]. And indeed conformational analysis of the bioactive analogs of somatostatin that have conformational constraints revealed that the peptide backbone is not directly involved in binding, but serves mainly as a scaffold allowing the side chains to adopt the necessary pharmacophore spatial arrangement necessary for receptor binding [37]. Compared with native somatostatin, the synthetic derivatives show a remarkable stability. Indeed, introduction of a D-amino acid (DPhe or D-ßnal) at the N-terminus protects against exopeptidases, as does the amino-alcohol Thr(ol) at the C-terminus of octreotide and

lanreotide. The disulfide bridge itself offers some protection, and the D-Trp protects a position which would otherwise be cleaved by a specific endopeptidase. For instance, when incubated with kidney homogenate, a system known to degrade natural peptides within a few minutes, more than 90% of the biological activity of octreotide was still present after 20 h, whereas the natural peptide was almost completely destroyed in less than 1 h (fig. 3) [25]. The pharmacokinetics of octreotide was investigated in rats after administration of unlabelled and labelled (3H- and 14C-) peptides [38], and data were compared with those from a study with 3H-labelled SRIF [39] (fig. 4). The marked stability of octreotide

Somatostatin Analogs for Cancer Treatment and Diagnosis

Chemotherapy 2001;47(suppl 2):1–29

5

Fig. 5. Tissue levels of octreotide after subcutaneous administration of 1 mg/kg in the rat. Tissue levels were measured by means of a specific radioimmunoassay after extraction into a mixture of methanol-trifluoroacetic acid (80– 0.1%) and subsequent lyophilization and reconstitution in buffer. For each organ the columns represent (from left to right) concentrations measured 0.5, 4, 7 and 24 h after administration [from 39].

against proteolytic degradation together with a reduced hepatic clearance is responsible for the dramatically improved elimination halflife in rats [39, 40]. In both rats and monkeys, the peptide is well absorbed after subcutaneous administration, the elimination rate (based on plasma levels) being slower in the latter species [41]. Significant levels of octreotide can also be detected in the rat after oral administration of the peptide [41]. While extensive degradation into small fragments and amino acids is evident in all tissues within the first minutes after intravenous injection of 3H-SRIF in rats [42], octreotide proved to be quite stable in all the tissues examined [38]. Concentrations measured by quantitative whole body autoradiography, which determines total radioactivity, and by specific radioimmunoassay were quite comparable. Thirty minutes after intravenous administration the highest concentrations were detected in the kidney, skin and liver. By following the time course of organ distribution of total radioactivity and of unchanged octreotide (fig. 5) it became apparent that elimination from presumed target organs such as pituitary and pancreas was much slower when compared with nontarget tissues such as muscle, lung and heart. This indicates high-affini-

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Chemotherapy 2001;47(suppl 2):1–29

ty binding to target receptors characterized by slow off-kinetics. Pharmacokinetic investigations have also been performed in healthy subjects and patients with pituitary tumors and the review by Chanson et al. [40], to which the reader is referred, thoroughly summarizes all the available data. Studies in healthy volunteers [43] demonstrated that octreotide plasma levels are proportional to the dose administered both after intravenous and subcutaneous administration. Plasma peak concentration values, which were reached after 30 min, were approximately half those obtained after intravenous injection of the same dose. Systemic bioavailability after subcutaneous octreotide was reported to be almost complete [44]. Plotting the areas under concentration-time curves (AUCs) against the dose administered, gives a linear relationship and this suggests that the pharmacokinetic of octreotide is linear – at least in the dose range studied – irrespective of the route of administration [43]. The disposition half-life ranged from 80 to 100 min for both routes of administration, depending on the dose, that is more than 30 times the half-life of the natural peptide. In blood, octreotide is mainly distributed in the plasma, 65% of the drug being bound to

Scarpignato/Pelosini

lipoprotein and, to a lesser extent, albumin, while negligible amounts are taken up by red cells [38]. No conclusive data are available concerning the tissue distribution of octreotide in humans [45], although it has been shown that the drug concentrates in many tissues in the rat [38]. Pharmacokinetic data on the metabolism and elimination of octreotide are similar in acromegalic and healthy individuals [46, 47]. When compared with healthy volunteers, total body clearance of octreotide was reduced to 75 ml/min (4.5 liters/h) in patients with chronic renal failure [48]. Although biliary excretion and proteolysis are also important elimination pathways in the rat and the dog, they have not been thoroughly studied in humans. The pharmacokinetics of lanreotide in healthy volunteers [49, 50] has shown a pattern similar to that observed with octreotide, i.e. a Tmax of about 30 min and an elimination half-life of 90 min after single subcutaneous injection of the peptide. The pharmacokinetics of lanreotide proved to be linear either after subcutaneous or intravenous route. The significant negative correlation between plasma GH and peptide concentrations observed in the study does suggest a dose-dependent biological effect [49]. Conversely from octreotide, lanreotide in blood is mainly bound to albumin [51]. Given the very short half-life of SRIF, distribution and elimination studies become almost obsolete, and application is restricted to continuous infusion to maintain therapeutically relevant plasma concentrations. With octreotide and lanreotide, however, the highly improved metabolic stability, small volume of distribution and low clearance result in a long duration of exposure; consequently, longlasting biological activity after a single subcutaneous injection of the analogs is obtained.

Somatostatin Analogs for Cancer Treatment and Diagnosis

Receptor Selectivity of Somatostatin Analogs

The action of somatostatin is mediated through specific receptors that are functionally coupled to inhibition of adenylyl cyclase via pertussis toxin-sensitive GTP binding proteins [for reviews, see 15, 52–54]. Up to five cell-surface somatostatin receptors have been characterized. They have been termed SSTR1 through SSTR-5 according to the chronology of their discovery and because they all display the structural hallmark of the seventransmembrane-domain receptor (SSTR is indeed the acronym for somatostatin seventransmembrane-domain receptor). Their tissue distribution is depicted in figure 6. Human SSTRs (hSSTRs) are encoded by a family of 5 genes which map to separate chromosomes and which, with one exception, are intronless. SSTR-2 gives rise to spliced variants, SSTR-2A and 2B. hSSTR-1 to hSSTR-4 display weak selectivity for SST-14 binding whereas hSSTR-5 is SST-28-selective. Based on structural similarity and reactivity for octapeptide and hexapeptide SST analogs (table 2), hSSTR-2, 3 and 5 belong to a similar SSTR subclass. hSSTR-1 and 4 react poorly with these analogs and belong to a separate subclass [55, 56]. Somatostatin receptors have also been detected in a number of tumors such as pituitary adenomas, neuroendocrine and nonendocrine tumors [57–60]. Pituitary and islet tumors express several SSTR genes suggesting that multiple SSTR subtypes are coexpressed in the same cell [56]. However, there is variability in both the number and the distribution of somatostatin receptors between tumors and from site to site in a given tumor [61, 62]. Since a variable suppression of GH plasma levels following administration of somatostatin or octreotide has been demonstrated in an acromegalic patient, it has been

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7

Fig. 6. Localization of human somatostatin receptors. GI = Gastrointestinal.

Table 2. Agonist selectivity (Ki, nM) of cloned hSSTR

Compound

SSTR-1

SSTR-2

SSTR-3

SSTR-4

SSTR-5

Somatostatin-14 Somatostatin-28 Octreotide Lanreotide Vapreotide Seglitide

1.1 2.2 11,000 11,000 11,000 11,000

1.3 4.1 2.1 1.8 5.4 1.5

1.6 6.1 4.4 43 31 27

0.53 1.1 11,000 66 45 127

0.9 0.07 5.6 0.62 0.7 2

From Patel and Srikant [55].

Table 3. Receptor selectivity of some synthetic somatostatin analogs

Compound

SSTR-1

SSTR-2

SSTR-3

SSTR-4

SSTR-5

Somatostatin-14 Synthetic analogs Octreotide Lanreotide Vapreotide

+++

+++

+++

+++

+++

0 0 0

++ ++ +

+ 0 0

0 0 0

+ +++ +++

Derived from data in table 2 by using a cut-off value for agonist selectivity (Ki) of 6 nM.

hypothesized that the heterogeneity of both the number and distribution of somatostatin receptors might in part explain the individual variable sensitivity to treatment with somatostatin or its analogs [61, 62].

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Although the actions of synthetic analogs are similar to those of native somatostatin, some differences have emerged that probably relate to the different ligand affinities for SSTR subtypes (table 3). This may have sev-

Scarpignato/Pelosini

eral clinical consequences and the spectrum of the therapeutic efficacy of octreotide and its derivatives (i.e. lanreotide and vapreotide) may not be the same as somatostatin. Indeed, cells expressing SSTR-1 or SSTR-4 will respond poorly or not at all to somatostatin analogs.

Somatostatin Analogs: Mechanisms of the Antineoplastic Action

Besides having an important role in the symptomatic treatment of endocrine tumors through peptide suppression, somatostatin may also exert an antiproliferative effect, which is not limited to endocrine tumors. Nonendocrine tumors may also be affected, although some somatostatin influence may in part be hormonally mediated. Some authors have actually reported – after treatment with somatostatin and synthetic analogs – tumor regression either in patients or animals with experimentally induced neoplasms. More recent research has provided information regarding mechanisms underlying the antiproliferative and apoptosis-inducing actions of somatostatin analogs. These include both direct mechanisms that are sequelae of binding of somatostatin analogs to somatostatin receptors present on neoplastic cells [57–60] and indirect mechanisms related to effects of somatostatin analogs on the host [for reviews, see 7, 14, 15]. The indirect mechanism would operate through a suppression of the GH release from the pituitary and the resulting inhibition of the hepatic production of insulin-like growth factor-1 (IGF-1) [14, 15]. The fall in IGF-1 could inhibit the growth of various tumors since IGF-1 and IGF-2 as well as other growth factors, including EGF, appear to be involved in the proliferation of neoplastic cells. The potential importance of these mechanisms of

Somatostatin Analogs for Cancer Treatment and Diagnosis

action is emphasized by the in vivo antineoplastic activity of these compounds against somatostatin receptor-negative neoplasms. Another potential mechanism through which somatostatin may exert an antitumor effect is through its inhibition of tumor angiogenesis, which is essential for implantation and growth [63–65]. Several experimental pieces of evidence suggest that SSTR-2 preferring agonists such as octreotide do inhibit angiogenesis in vitro and in vivo [11]. Since peritumoral vessels express somatostatin receptors [66] and neovascularization is enhanced by IGF-1 [67], inhibition of angiogenesis itself might involve direct and/or indirect actions of somatostatin analogs on the nontransformed cells comprising the microvasculature of neoplastic tissue. Studies performed over the past 5 years have demonstrated that induction of apoptosis represents one of the mechanisms by which cytotoxic drugs exert their antineoplastic action [68]. Several lines of evidence suggest that somatostatin analogs can also induce apoptosis via interaction with SSTR-3 [14]. In this connection it is worth mentioning that IGF-1 is recognized as a potent antiapoptotic factor [69]. Thus, the inhibitory effects of somatostatin analogs on IGF-1 gene expression may enhance their direct apoptosis-inducing action and contribute to the apoptotic effect of these compounds. A recent investigation [70], performed in patients with gut neuroendocrine tumors, did show that treatment with high-dose somatostatin analogs induces apoptosis in tumor cells, which correlated with the biochemical response (i.e. decrease in tumor markers), while low-dose somatostatin analogs do not modify the apoptotic index. Finally, somatostatin analogs stimulate the activity of the reticuloendothelial and lymphopoietic systems in the rat [6]. Changes in natural killer cell activity were reported in man [6]. It is, therefore, possible that modula-

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Table 4. Possible mechanisms of the antineoplastic

action of somatostatin analogs 1 Direct antimitotic effects via somatostatin receptors on tumor cells 2 Suppression of the release of trophic hormones (e.g. GH, insulin, prolactin and gut peptides) 3 Direct or indirect inhibition of growth factors (e.g. IGF-1, EGF, PDGF) 4 Inhibition of angiogenesis 5 Induction of apoptosis 6 Modulation of the immune response

tion of immune defense mechanisms might contribute to the tumor growth inhibitory effects of these compounds. In summary, somatostatin and its analogs may have tumoricidal or antiproliferative effects mediated by suppressing promotor hormones, by inhibiting mitogens (directly suppressing cell division, protein synthesis, or translation), by inhibiting angiogenesis and inducing apoptosis or by stimulating the immune system (table 4). Although the clinical relevance of some experimental models is at present unknown, the prospects of such investigations are worthy of serious consideration. Octreotide and its derivatives may thus evolve towards an adjunctive, albeit limited role, in a direct chemotherapeutic management of endocrine and nonendocrine tumors. The key to this problem appears to be in the heterogeneity of somatostatin receptor subtype. There is no doubt that not all of the receptor subtypes are responsible for growth inhibition [58, 59]. Indeed, there is evidence that some may even promote cell growth. The future of somatostatin as a clinically useful anticancer drug thus lies in the characterization of the specific receptors that mediate growth inhibition and the synthesis of analogs that bind selectively to them.

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Long-Lasting Formulations of Somatostatin Analogs

Several studies [71–75] showed that Sandostatin® administered by continuous subcutaneous pump infusion produced better suppression of GH and IGF-1 serum concentrations, rapid clinical improvement, and shrinkage of GH-secreting adenomas in comparison to intermittent subcutaneous injections. Data on the very good efficacy of Sandostatin administered by pump infusion stimulated research to develop a new galenical formulation that could ensure long-lasting, sustained and consistent drug delivery. Nasal administration provides a satisfactory control of GH hypersecretion, but because of poor local tolerability, its chronic use is not feasible at present [76]. An extended-release formulation mimicking the continuous subcutaneous infusion of octreotide to be injected monthly would be an obvious improvement in the treatment of acromegalic patients requiring long-term Sandostatin therapy by twice daily or 3 times daily dosing. Sandostatin LAR®, obtained by incorporating octreotide into microspheres of a biodegradable polymer, poly(DL-lactide-co-glycolide glucose), was developed to provide patients with the convenience of a once-a-month administration and to ensure a stable serum octreotide concentration between injections, sustained GH and IGF-1 suppression, good clinical control of symptoms and signs of acromegaly, and improved acceptability and compliance for longterm treatment with Sandostatin [for a review, see 77]. The release characteristics and toxicology of Sandostatin LAR were studied in rats and rabbits [32, 78]. Single intramuscular injections of Sandostatin LAR resulted in an initial peak, attributed to drug adsorbed to the surface of microspheres, followed by low concentrations over 1–2 weeks and thereafter by sus-

Scarpignato/Pelosini

Fig. 7. Time course of serum oc-

treotide concentrations after administration of single doses of 10 mg (P, n = 16), 20 mg (d, n = 39) or 30 mg ($, n = 37) of Sandostatin LAR to acromegalic patients. Each point is the mean of 12-hour mean concentrations per patient. Vertical bars are standard errors [from 78].

tained octreotide plasma levels over a period of 4–6 weeks. After repeated injections at 4week intervals, consistent and stable plasma concentrations of octreotide were recorded. Toxicological studies performed in rabbits and rats revealed only a very limited, reversible granulomatous myositis at the injection site. The biodegradation of the microspheres is completed within 10–12 weeks, and toxicological studies showed that Sandostatin LAR has low toxicity and good local tolerability [32, 78]. Three different preparations (i.e. 10, 20 or 30 mg) are available for clinical use. Their pharmacokinetics has been studied in acromegalic patients [78]. A consistent pattern of octreotide release from the polymer matrix of

Sandostatin LAR was documented in all studies and for all dose levels investigated. A rapid increase in octreotide serum concentrations was noted after intramuscular injection of Sandostatin LAR, with a peak occurring within 1 h after the injection followed by a progressive decrease to low octreotide levels within 12 h. On days 2 through 7, after single doses of Sandostatin LAR, octreotide serum concentrations were at lowest levels. Thereafter, an increase in serum octreotide concentrations occurred, and dose-dependent plateau concentrations were observed between days 14 and 42 followed by a progressive decrease from day 42 on (fig. 7). In the plateau phase (days 14–42), the daily average plasma concentrations remained very stable over the

Somatostatin Analogs for Cancer Treatment and Diagnosis

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Table 5. Mean pharmacokinetic parameters of octreotide assessed over a period of 60 days

[from 78] Dose of Sandostatin LAR 10 mg (n = 16) tmax, days Cmax, ng/l Cmax/D, ng/l AUC0–60 days, ng/l AUC0–60 days/D, ng/l Plateau duration, days Relative bioavailability1, %

28B10 387B107 39B11 13,412B3,417 1,341B342 19.3B10.2 31

20 mg (n = 39) 28B11 1,126B749 56B38 35,737B16,243 1,787B812 18.5B10.1 39

30 mg (n = 37) 34B17 1,935B1,430 66B48 61,494B28,245 2,050B942 18.5B9.8 50

tmax = Time to maximum concentration; Cmax = maximum concentration; Cmax/D = maximum concentration normalized on dose; AUC0–60 days = area under the curve from day 0 to day 60; AUC0–60 days/D = AUC normalized on dose. Plateau duration is the duration during which the concentrations were above 80% of Cmax. 1 Relative bioavailability with respect to subcutaneous 3 times daily treatment; values are the geometric mean.

12-hour observation period, similar to those seen after subcutaneous continuous infusion. The height of the octreotide peak on day 1 for all doses tested was lower than the plateau concentrations, and the area under the peak on the day of injection of Sandostatin LAR was not larger than 0.5% of the total AUC (0–60 days). A dose-dependent increase of the maximum concentration and AUC of octreotide was recorded in the dose range between 10 and 30 mg. The computed key pharmacokinetic parameters are summarized in table 5. In agreement with animal data, human studies also showed good systemic and local tolerability as well as a lack of dose dumping (i.e. immediate release of significant quantities of drug). Preliminary results from studies performed in acromegalic subjects, responsive to subcutaneous octreotide, have shown that one single injection of 30 mg Sandostatin LAR is followed by 4- to 6-week GH suppression in 80% of patients [78–80]. It is likely,

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Chemotherapy 2001;47(suppl 2):1–29

therefore, that this long-lasting formulation can replace 3 times daily subcutaneous injections by an intramuscular injection at 4-week intervals to improve the acceptability of longterm therapy in acromegalics. In addition, by releasing consistent concentrations of serum octreotide and by producing a consistent suppression of GH secretion, Sandostatin LAR appears to be as effective as subcutaneous infusions of Sandostatin and more effective than intermittent subcutaneous administration. Indeed, in the patients switched from subcutaneous treatment to Sandostatin LAR, suppression of GH secretion and serum IGF-1 concentrations and the clinical improvement have been either as good as or better than with Sandostatin administered subcutaneously [78]. Indeed, a larger number of patients showed a normalization of serum IGF-1 concentrations and a clinical improvement. Beyond the improvement/disappearance of symptoms/signs of acromegaly, some patients actually become asymptomatic. The

Scarpignato/Pelosini

Fig. 8. Pharmacokinetics of lanreotide and GH pattern in 21 patients at the first intramuscular injection of the drug (Somatuline SR, 30 mg) [from 89].

usefulness of this octreotide formulation in the management of malignant carcinoid syndrome has been recently shown [81]. A slow-release formulation (SomatulineSR®) is also available for the other somatostatin analog, lanreotide. This formulation has been studied in healthy volunteers [82] and acromegalic patients [83]. The maximum lanreotide concentration (Cmax) in plasma (38.3 B 4.1 ng/ml) was obtained 2 h following injection. The levels then progressively decreased, remaining above 1.5 ng/ml until day 11 and reaching 0.92 B 0.28 ng/ml 2 weeks after injection. The apparent plasma half-life and mean residence time were 4.52 B 0.50 and 5.48 B 0.51 days, respectively [81]. Studies with Somatuline-SR have been carried out by several European centers [83– 88] on a few groups of acromegalic patients, often selected on the basis of their previous responsiveness to octreotide therapy. An Italian multicenter study [89] evaluated the tolerability and effectiveness of this formulation in a large number of acromegalic patients with active disease, unselected in terms of their

previous responsiveness to octreotide, and found that 30 mg of the compound, administered every 14 days, provided an effective treatment in the majority. After drug administration, an inverse correlation was found between lanreotide and GH plasma levels (fig. 8). Both octreotide and lanreotide slow-release formulations, administered monthly and every 10–14 days, respectively, proved to be effective in controlling symptoms associated with neuroendocrine gut tumors, providing – in addition – a substantial improvement in patient compliance [90–95]. A slow-release formulation of vapreotide was developed more than 10 years ago [96] whereas a long-term delivery system has been produced only recently [97]. This injectable, biodegradable depot formulation ensures satisfactory peptide blood levels in rats for over 250 days. No pharmacokinetic data with these formulations have yet been published in humans.

Somatostatin Analogs for Cancer Treatment and Diagnosis

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13

Radiolabelled Somatostatin Analogs

Radiopharmaceuticals for Somatostatin Receptor Scintigraphy The diagnosis and staging of neuroendocrine tumors is often difficult and time consuming. Blood levels of hormonal markers are frequently elevated and allow a presumptive diagnosis [98] but, since tumors are frequently small, standard imaging techniques such as ultrasonography or computed tomography cannot accurately localize the tumor [99]. Arteriography and selective venous sampling are more specific, but technically demanding and not always accurate [100]. Somatostatin receptor-expressing tumors and their respective metastases are attractive targets for diagnostic imaging with gamma emitter-labelled synthetic analogs. Indeed, somatostatin receptor detection can be accomplished by injecting a radiolabelled peptide analog and imaging tissue uptake of the compound via scintigraphy. Selective radioactive uptake will occur in proportion to the density and affinity of the receptor population. Octreotide binds with high affinity to the SSTR-2, while this analog has a relatively low affinity for SSTR-3 and SSTR-5 and shows no binding to SSTR-1 and SSTR-4 (see above). Octreotide scintigraphy (OctreoScan®) is, therefore, based on the visualization of (an) octreotide-binding somatostatin receptor(s), most probably SSTR2 and SSTR-5 [18–21]. Visualization of SSTR-positive tumors is widely used in tumor staging and may also predict therapeutic response to octreotide. A number of studies [101, 102] have suggested that somatostatin receptor scintigraphy can be used to select patients with malignant carcinoid tumors suitable for somatostatin analog treatment and exclude those that will not benefit from such medication since most hormone-secreting tumors react in vitro to octreotide with an inhibition of hormone release and possibly

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Chemotherapy 2001;47(suppl 2):1–29

inhibition of growth. It has been shown, for instance, that in patients with carcinoids, there was a complete agreement between the presence of mRNA for SSTR-2 detected by in situ hybridization and therapeutic response to octreotide [103]. In those patients with pathological tracer accumulation without expression of somatostatin SSTR-2 mRNA, other SSTRs may be present that can bind the somatostatin analog but not inhibit hormone secretion. However, octreotide scintigraphy alone may not be sufficient in determining the patients with neuroendocrine tumors who can benefit from chronic treatment with somatostatin analogs, because almost 20% of patients with pathological somatostatin scintigraphy fail to respond to such treatment and further, in rare cases, octreotide treatment results in clinical improvement in spite of octreotide scintigraphy failure to demonstrate any tumor localization [58, 59]. A radioiodinated analog of somatostatin, [123I-Tyr3]octreotide (fig. 9), was first used to detect somatostatin receptor-positive tumors [104]. However, despite the successful visualization with this radiopharmaceutical of a variety of somatostatin receptor-positive tumors in more than 100 patients, this method of in vivo imaging had several drawbacks, amongst which are the limited availability of chemically pure 123I and the high abdominal background of radioactivity, caused by clearance of this analog via the liver [104]. Therefore, an 111In-labelled somatostatin analog was developed. [Diethylenetriamine pentaacetic acid (DTPA)-D-Phe1]-octreotide was shown to bind 111In efficiently in a single step procedure. The binding as well as the biological activity of this new labelled peptide were shown to be similar to that of octreotide, making it a good radiopharmaceutical for in vivo imaging of somatostatin receptor-positive tumors [105]. The 111In-labelled octreotide is excreted mainly via the kidneys, 90% of the

Scarpignato/Pelosini

Fig. 9. Chemical structures of octreotide, [Tyr3]-octreotide, DTPA and DOTA.

dose being present in the urine 24 h after injection. Because of its relatively long effective half-life, [111In-DTPA-D-Phe1]-octreotide is a radiopharmaceutical which can be used to visualize somatostatin receptor-bearing tumors efficiently after 24 and 48 h, when interfering background radioactivity is minimized by renal clearance [104]. The synthesis and biological properties of 99mTc-hydrazinonicotinyl-Tyr3-octreotide (HYNIC-TOC) using different coligands for radiolabeling was reported quite recently by Decristoforo et al. [106]. HYNIC-TOC was radiolabelled at high specific activities using tricine, ethylenediaminediacetic acid, and tricine-nicotinic acid as coligand systems. All 99mTc-labelled HYNIC peptides showed retained somatostatin receptor binding affinities (Kd !2.65 nM). Protein binding and internalization rates were dependent on the coligand used. Specific tumor uptake between 5.8 and 9.6% of the injected dose/g was found for the 99mTclabelled peptides compared with 4.3% injected dose/g for [111In-DTPA-D-Phe1]-octreotide [106]. The high specific tumor uptake, rapid blood clearance, and predomi-

nantly renal excretion make [99mTc-EDDAHYNIC-TOC] a promising candidate as an alternative to [111In-DTPA-D-Phe1]-octreotide for tumor imaging. The major limitation of somatostatin receptor scintigraphy using radiolabelled ligands of octreotide is that the technique will only allow detection of those tumors expressing hSSTR-2 and hSSTR-5 and possibly those neoplasms expressing hSSTR-3 in sufficient density to allow visualization. Radioligands of lanreotide or vapreotide might be more useful than radiolabelled ligands of octreotide in visualizing those tumors that express hSSTR-4, but not hSSTR-2 and hSSTR-5. Visualization of tumors by lanreotide or vapreotide scintigraphy but not by octreotide scintigraphy may provide a rationale for the selection of patients that are likely to benefit from therapy with these analogs but this hypothesis requires confirmation in prospective controlled trials. Taking the above considerations into account, radiolabelled derivative of both lanreotide [111In-DOTA-lanreotide] and vapreotide [111In-DTPA-D-Phe1]-RC-160 have been de-

Somatostatin Analogs for Cancer Treatment and Diagnosis

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15

veloped [107–109]. However, while labelled lanreotide showed a high tumor uptake for a variety of different human tumor types and a favorable dosimetry over labelled octreotide [107], with [111In-DTPA-D-Phe1]-RC160 blood radioactivity (background) was higher, resulting in a lower tumor to blood (background) ratio [108]. This radiopharmaceutical should, therefore, have no advantage over [111In-DTPA-D-Phe1]-octreotide for the visualization of somatostatin receptors which bind both analogs. However, recent reports suggest the existence of different somatostatin receptor subtypes on some human cancers, which differentially bind the synthetic somatostatin analogs [60]. These tumors include cancers of the breast, ovary, exocrine pancreas, prostate and colon. Radiolabelled lanreotide or vapreotide might be of interest for future use in such cancer patients as a radiopharmaceutical for imaging somatostatin receptor-positive tumors, which do not bind octreotide. Compared with the parent peptide (i.e. lanreotide), DOTA-lanreotide seems to display a distinct binding pattern, since it binds all transfected hSSTR subtypes as well as a large variety of primary human tumors [107]. As a consequence, the radiopharmaceutical is claimed to be a ‘universal’ SSRT ligand. A multicenter study (called Multicentre Analysis of a Universal Receptor Imaging and Treatment Initiative: a European Study) was recently started, for which the acronym MAURITIUS has been coined. [DOTA]-lanreotide was then renamed MAURITIUS. In a preliminary report 111In-MAURITIUS was used in a series of 25 patients with advanced malignancies refractory to conventional antineoplastic treatment and in all of them at least one tumor site could be visualized at scintigraphy [110]. Interestingly enough, some neoplasms, which were repeatedly negative by the conventional OctreoScan, could be visualized by means of this

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new radiopharmaceutical, thus suggesting that somatostatin receptors other than hSSTR-2 and hSSTR-5 are responsible for binding. While single photon emission computed tomography seems to improve accuracy of somatostatin receptor scintigraphy [111], intraoperative gamma detection reveals abdominal endocrine turmors more efficiently than conventional OctreoScan [112–114] and may allow improvement in surgical management allowing radioimmunoguided surgery [115]. In vitro and in vivo studies [116] showed that a recently developed terbium161-labelled derivative, i.e. [161Tb-DTPA-DPhe1]-octreotide, represents a promising pharmaceutical for intraoperative scanning and radiotherapy. Octreotide has also been labelled with positron-emitting 67Ga [117], 64Cu [118, 119] or 18F [120]. Some of these radiolabelled derivatives ([2 - 18F - fluoropropionyl - D - Phe1]octreotide, [64Cu-TETA-D-Phe1]-octreotide and [67Ga]-DFO-B-succinyl-D-Phe1]-octreotide) have, therefore, been used for PET imaging [120]. However, the hepatobiliary excretion of these compounds complicates the interpretation of the images arising from abdominal tumors [120]. In contrast, [64CuTETA-D-Phe1]-octreotide binds to somatostatin receptor with five times the affinity of [111In-DTPA-D-Phe1]-octreotide, has desirable clearance properties (renal clearance with rapid excretion) and is a potential agent for PET imaging of somatostatin receptors. At present, however, other labelled compounds (e.g. 11C-5-HTP or 11C-labelled-L-DOPA) are preferred for PET scanning of neuroendocrine tumors [121]. The detection of heterogenous metastases (with regard to the expression of different peptide receptors or the accumulation of other radioligands) becomes possible if a combination of different radiolabelled peptides or

Scarpignato/Pelosini

of a radiolabelled peptide with other radioligands (all labelled with different radionuclides) can be used. Simultaneous use of 111Inoctreotide and 131I-MIBG (metaiodobenzylguanidine) scintigraphy in patients with metastasized pheochromocytoma [22] represents a successful example of such an approach. Radiopharmaceuticals for Somatostatin Receptor-Targeted Radiotherapy A new and fascinating application of radiolabelled peptides is represented by their use in the so-called peptide receptor radiotherapy [122]. The success of this therapeutic strategy relies upon the concentration of the radioligand within tumor cells which will depend on the rates of internalization, degradation and recycling of both ligand and receptor. Binding of several peptide hormones to specific surface receptors is generally followed by internalization of the ligand-receptor complex via invagination of the plasma membrane [123]. The resulting intracellular vesicles, termed endosomes, rapidly acidify, thus causing dissociation of the ligand from the receptor. The ligand may be delivered to lysosomes and the receptor recycles back to plasma membrane. The whole process takes approximately 15 min and a single receptor can deliver numerous ligand molecules to the lysosomes [124]. Receptor-mediated endocytosis of somatostatin analogs is especially important when radiotherapy of somatostatin-positive tumors using radiolabelled analogs is considered. Human neuroendocrine tumor cells internalize the radioligand [111In-DTPA-DPhe1]-octreotide. However, this radioligand may not be the most suitable compound to carry out radiotherapy because 111In, which emits Auger (as well as conversion) electrons, is probably not the optimal radionuclide. Moreover, since a stable coupling of ·- and ßemitting isotopes to [DTPA-D-Phe1]-octreo-

Somatostatin Analogs for Cancer Treatment and Diagnosis

tide has not been feasible, a novel compound [tetraazacyclododecane tetraacetic acid (DOTA), Tyr3]-octreotide (compound coded as SDZ-SMT 487, fig. 9) in which the DTPA molecule is replaced by another chelator, DOTA, allowing a stable bind with the ßemitter yttrium-90, has been synthesized [125]. It was recently shown that iodinated [DOTA, Tyr3]-octreotide is internalized in a large amount by mouse AtT20 pituitary tumor cells as well as by human insulinoma cells [126]. The high internalization rate of this ligand in vitro was also evident from the very high uptake of this radioligand in vivo by somatostatin receptor-positive organs in rats [126]. Along with the high internalization of the iodinated molecule, de Jong et al. [127] recently showed that the amount of [90YDOTA, Tyr3]-octreotide internalized by somatostatin receptor-positive pancreatic tumor cells was higher than that of [111InDOTA, Tyr3]-octreotide and of [111In-DTPAD-Phe1]-octreotide (1.8- and 3.5-fold, respectively). In vitro, SMT 487 binds selectively with nanomolar affinity to the somatostatin receptor subtype 2 (IC30 = 0.39 B 0.02 nM). In vivo, [90Y-DOTA, Tyr3]-octreotide shows a rapid blood clearance (t½· !5 min) and high accumulation in somatostatin subtype 2 receptor-expressing tumors [128]. The in vivo administration of this radiopharmaceutical induces a rapid tumor shrinkage in three different somatostatin receptor-positive tumor models, namely CA20948 rat pancreatic tumors grown in normal rats, AR42J rat pancreatic tumors and NCI-H69 human small cell lung cancer both grown in nude mice. The radiotherapeutic efficacy of 90Y-SMT 487 was enhanced when used in combination with standard anticancer drugs, such as mitomycin C, and resulted in a tumor decrease of 70% of the initial volume. In the CA20948 syngeneic rat tumor model, a single treatment with 10 ÌCi/kg [90Y-DOTA, Tyr3]-octreotide resulted

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17

in the disappearance of 5 out of 7 tumors. Thus the new radiotherapeutic agent showed its curative potential for the selective treatment of SRIF receptor-expression tumors [128]. According to these data, [90Y-DOTA, Tyr3]-octreotide would appear to be a suitable radiopharmaceutical for somatostatin receptor-targeted radiotherapy. To achieve an optimal radiotherapeutic effect, the radiopharmaceutical should also be retained within tumor cells to allow intracellular radioactivity exerting its antineoplastic activity. Therefore ‘trapping’ of radioligands into the tumor cells may be an additional important mechanism determining the amount of uptake of the radiopharmaceutical which is used for somatostatin receptor scintigraphy and/or targeted radiotherapy. While previous investigations [124] have shown that [111In-DTPA-D-Phe1]-octreotide is delivered in vivo to lysosomes of pancreatic tumor cells, the intracellular fate of [90Y-DOTA, Tyr3]octreotide is presently unknown. Although being not the ideal radioligand, [111In-DTPA-D-Phe1]-octreotide has been used for radionuclide therapy in patients with somatostatin receptor-positive tumors and proved the feasibility of the approach [129]. The trial did show a tendency towards better results in patients whose tumors had a higher accumulation of the radioligand. In a recent preliminary study, Otte et al. [130] reported encouraging results after treatment with [90YDOTA, Tyr3]-octreotide (OctreoTher®) in 10 patients with different somatostatin receptorpositive tumors. In addition, a case report [131] described a favorable response of a metastatic gastrinoma to treatment with another 90Y-labelled somatostatin analog, namely [90Y-DOTA]-lanreotide [132]. The concept of targeted radiotherapy of tumors using radioligands of somatostatin analogs remains a very attractive approach for the treatment of neoplasia. The very fact

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that it is over 12 years since the concept of octreotide targeted radiotherapy of neoplasia was first proposed and we are still awaiting good phase 2 clinical trials on the efficacy and tolerability of this appealing treatment highlights the practical difficulties involved in developing this technique.

Safety and Tolerability of Somatostatin Analogs

The safety profile of Sandostatin is well established [17]. Most adverse reactions to octreotide are merely a consequence of its pharmacological activity and consist mainly of gastrointestinal complaints, cholelithiasis and effects on glucose metabolism. The reported cases of toxicity unrelated to the drug’s pharmacological profile include reactions at the injection site, allergic reactions, and a few cases of reversible hepatic dysfunction. Although the kind of adverse events associated with Sandostatin is well known, their true frequency has not been accurately estimated. 34.4% of patients reported one or more side effects, most of which (93.2%) were of little clinical relevance [17]. For this reason, adverse events are only seldom mentioned in published series and are rarely reported to the manufacturer. In contrast, most reports received by the Novartis Pharmacosurveillance Unit pertained to events occurring in patients with severe underlying diseases and multiple drug treatment; therefore, a cause-effect relationship with octreotide could only seldom be established. The tolerability of octreotide LAR appears to be comparable to that of the subcutaneous formulation [77]. Here again, gastrointestinal adverse events predominate: abdominal pain, flatulence, diarrhea, constipation, steatorrhea, nausea and vomiting occurred in up to 50% of patients with acromegaly who re-

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Fig. 10. Adverse events observed in acromegalic patients (n = 93– 101) after a single intramuscular injection of Sandostatin LAR (10– 30 mg) or multiple injections (30 injections at 4-week intervals) of the same formulation (20–40 mg) [from 77].

ceived 1–3 intramuscular doses of octreotide LAR (10–30 mg). Representative results from the largest clinical trial are depicted in figure 10. Gastrointestinal symptoms tended to be mild to moderate and often disappeared

within 1–4 days of the injection. Furthermore, the incidence of these events decreased with long-term (up to 7 months) treatments. In addition, there was no evidence that tolerability worsened with increasing dose.

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Injection site events (pain, burning, redness and swelling at injection site) occurred in some patients receiving intramuscular octreotide LAR, but were generally mild and of short duration [77]. These phenomena are thought to be caused by the acidic vehicle of Sandostatin formulations and can be minimized by simple precautions, i.e. to allow refrigerator-cold vials to reach room temperature before administration, and to rotate the sites of injections. Although the risk of cholelithiasis increases in patients receiving octreotide [17], simultaneous bile acid administration strongly reduces its incidence [77]. Although diabetes mellitus may occur as a result of reduced glucose tolerance, the net effect of drug-induced changes is usually mild and not clinically relevant [17, 77]. Finally, few patients developed moderate to severe hair loss [77]. The spectrum and incidence of adverse events reported after lanreotide, either immediate and slow release formulations, are similar to those reported after octreotide [87, 88, 93, 94], the majority of poorly tolerant patients experiencing untoward reactions to both compounds [87]. Synthetic somatostatin analogs are, therefore, safe drugs for long-term use. While immediate release preparations are the drugs of choice in the short term, long-acting formulations are better indicated, on an outpatient basis, for the long-term management of chronic conditions.

Somatostatin Analogs for Cancer Diagnosis and Treatment: A Look into the Future

New Somatostatin Analogs and Regimens The principal challenge in somatostatin research derives from the fact that the five basic somatostatin receptor subtypes have high structural similarities and different tissue dis-

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tributions. The strong functional similarity among the five receptor types is exhibited in their common inhibitory effect on adenylyl cyclase activity. Therefore, it is understandable that somatostatin, which binds with high affinity to each receptor type, has multiple physiological actions. To explore the specific biological function of each subtype, receptorspecific synthetic analogs, agonists (as well as antagonists) are being developed. New compounds in the early phase of development include receptor-selective and ‘universal’ analogs. The receptor-selective analogs bind to one, possibly two somatostatin receptor subtypes [133, 134] while the universal analogs bind to most or all of the five known SSTRs. The elucidation of the 3-dimensional structures of receptor subtype-selective somatostatin agonists has aided and will considerably enhance the rational design of novel analogs including non-peptide compounds [135–137]. Development of potent non-peptide somatostatin analogs is important because they may display a good bioavailabilty [138] following oral administration. Continuing research on somatostatin receptors and somatostatin analogs will help to characterize better the functional somatostatin receptor models. Recent availability of the five transfected cell lines has enabled the use of more rational research methods. This will help to develop novel drug candidates beyond the clinically used octreotide-type analogs. Newly developed analogs (BIM 23190 and BIM 23197) show higher plasma levels, greater distribution to target tissues and longer in vivo stability [139]. They may prove to be superior to the currently available compounds for the treatment of acromegaly and some types of cancer. Future investigations should also be aimed at further exploring the use of long-acting somatostatin analogs as antineoplastic agents, either alone or in combination with other drugs. In this respect, it will be important to

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better define the dose-response relationship and to ascertain whether higher doses are associated with more disease stability or with greater response rate or survival [16]. Somatostatin Receptor-Targeted Chemotherapy It is now well established that chemotherapeutic compounds and toxins can be covalently attached to various carriers, including hormones, for which receptors are present on cancer cells or to antibodies that preferentially recognize tumor cells [140]. Such conjugates are designed to deliver cytotoxic agents more selectively to cancer cells. Ideally, tumor cells that bind these conjugates would be killed while normal cells that do not have the receptors would be spared [141]. Like targeted radiotherapy, somatostatin receptor-targeted chemotherapy represents an appealing approach to treatment of SSTR expressing tumors. By synthesizing conjugates of somatostatin analogs and cytotoxic drugs (such as methotrexate or doxirubicin) [142, 143], selective accumulation of cytotoxic radicals in somatosatin receptor-positive tumor cells would be possible. Obviously, with the currently available somatostatin analogs, targeted chemotherapy would be limited to the treatment of SSTR-2- and SSTR-5expressing tumors. Experimental studies [142, 143] have actually shown that these derivatives are less toxic and more effective than the parent cytotoxic drugs in inhibiting tumor growth in vivo. A recent study [144] demonstrated a high efficacy of SSTR-targeted chemotherapy in a model of disseminated human androgen-independent prostatic carcinoma. The use of cytotoxic somatostatin analog AN-238 (fig. 11) could provide an effective therapy for patients with advanced hormone-refractory prostatic carcinoma. Other studies in progress show that growth of various human pancreatic, colorectal and gas-

Somatostatin Analogs for Cancer Treatment and Diagnosis

Fig. 11. Molecular structure of the cytotoxic somato-

statin analog AN-238. The somatostatin analog RC121 is linked through the ·-aminogroup of it D-Phe moiety and a glutaric acid spacer to the 14-OH group of 2-pyrrolinodoxorubicin [from 142].

tric cancers in nude mice as well as glioblastomas and non-SCLC can be suppressed by cytotoxic somatostatin analogs [141]. Thus these somatostatin analogs might find applications for the therapy of different types of human malignancies. Gene Therapy Gene therapy is at an early phase, but represents an exciting opportunity to prolong life in some patients with advanced malignancies [145–149]. The key problems are getting the replacement gene to the appropriate cellular target and once there persuading it to make the normal gene product in sufficient quantities to correct the defect. With respect to somatostatin analog therapy there are a number of areas in which effective gene therapy may be used to potentiate the antineoplastic effects of these drugs. The most obvious application of gene therapy to somatostatin analog treatment of neoplasia is the delivery

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Fig. 12. Expression of the SSTR-2

in pancreatic tumor cells suppresses clonigenicity in vitro and tumorigenicity in nude mice by a feedback mechanism. According to the findings in vitro and in vivo, the expression of this receptor subtype leads to an increase in somatostatin ligand production and hence a constitutive receptor activation. Experimental data also suggest that the SSTR-2 expression is associated with an increase in the endoproteolytic processing of prosomatostatin [from 7].

of hSSTR-2 and hSSTR-5 genes together with the genes that encode their membrane proteins to those cancers such as pancreatic, gastric and colorectal carcinomas that do not express these receptor subtypes. The somatostatin analogs currently available for clinical use (i.e. octreotide, lanreotide and vapreotide) all exert the majority of their antineoplastic effects via hSSTR-2 and hSSTR-5 and it follows, therefore, that effective transfer of genes encoding for hSSTR-2 and hSSTR-5 and their membrane proteins to cancers which do not express these receptor subtypes may render them responsive to the direct antineoplastic effects of the current generation of somatostatin analogs. Human pancreatic adenocarcinomas lose the ability to express SSTR-2, the somatostatin receptor, which mediates the antiproliferative effect of currently available somatostatin analogs. Reintroducing SSTR-2 into human pancreatic cancer cells by stable expression evokes an autocrine negative feedback loop leading to a constitutive activation of the

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SSTR-2 gene and an inhibition of cell proliferation and tumorigenicity. In vivo studies [150], performed in athymic mice, confirmed the antitumor bystander effects resulting from the transfer of the SSTR-2 gene into human pancreatic cancer cell line BxPC-3. Mice were separately xenografted with control cells on one flank and with SSTR-2-expressing cells on the other flank. A distant antitumor effect was induced: growth of control tumors was delayed by 33 days, the Ki67 index decreased significantly, and apoptosis increased when compared with control tumors that grew alone [150]. The distant bystander effect may be explained in part by a significant increase in serum somatostatin-like immunoreactivity levels resulting from the autocrine feedback loop produced by SSTR-2 expressing cells (fig. 12) [151] and inducing an upregulation of the type 1 somatostatin receptor, SSTR-1, which also mediates the antiproliferative effect of somatostatin [150]. Limitations to peptide receptor radiotherapy are principally due to poor tumor pene-

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tration of the radioligand and insufficient accumulation of radioactivity within the neoplastic cell. In addition, low or variable expression of tumor-associated receptors may lead to poor tumor localization of radiolabelled peptide agonists. An attempt to overcome these problems consists in the use of biological response modifiers to increase target receptor expression [152]. In this connection, replication-deficient adenoviral vectors were constructed encoding the cDNA for the somatostatin receptor subtype (SSTR-2). In vitro binding and in vivo tumor localization were observed with radiolabelled octreotide analogs to cells infected with adenoviral vectors encoding the corresponding gene [152]. Provided it is successful in humans, this method could be useful for increasing the therapeutic efficacy of targeted radiotherapy in cancer patients.

Conclusions

Despite the explosion of knowledge in recent years in the somatostatin field, a great deal remains to be discovered. In particular, developing the potential of somatostatin analogs for cancer treatment will require a more complete understanding of their intracellular actions and interactions. Moreover, in spite of the ongoing clinical application of octreotide and its analogs in cancer management [153], the molecular mechanism and the beneficial effects of these drugs need to be elucidated. Twenty-seven years after its discovery, somatostatin is still the subject of continuing investigations by researchers in both the industry and the academia. In the future, the joint effort of many scientists from different fields will no doubt produce more specific therapeutic agents that are likely to result in major improvements in clinical management of various malignancies.

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129 Krenning EP, Valkema R, Kooij PPM, Breeman WAP, Bakker WH, deHerder WW, vanEijck CHJ, Kwekkeboom DJ, deJong M, Pauwels S: Scintigraphy and radionuclide therapy with [indium-111labelled-diethyl triamine pentaacetic acid-D-Phe1]-octreotide. Ital J Gastroenterol Hepatol 1999;31 (suppl 2):S219–S223. 130 Otte A, Müller-Brand J, Dellas S, Nitzsche EU, Hermann R, Mäcke HR: Yttrium-90-labelled somatostatin analogue for cancer treatment. Lancet 1998;351:417–418. 131 Leimer M, Kurtaran A, SmithJones P, Raderer M, Havlik E, Angelberger P, Vorbeck F, Niederle B, Herold C, Virgolini I: Response to treatment with yttrium-90DOTA-lanreotide of a patient with metastatic gastrinoma. J Nucl Med 1998;39:2090–2094. 132 Virgolini I, Szilvasi I, Kurtaran A, Angelberger P, Raderer M, Havlik E, Vorbeck F, Bischof C, Leimer M, Dorner G, Kletter K, Niederle B, Scheithauer W, Smith-Jones P: Indium-111-DOTA-lanreotide: Biodistribution, safety and radiation absorbed dose in tumor patients. J Nucl Med 1998;39:1928– 1936. 133 Reubi JC, Schaer JC, Waser B, Hoeger C, Rivier J: A selective analog for the somatostatin sst1receptor subtype expressed by human tumors. Eur J Pharmacol 1998;345:103–110. 134 Rohrer SP, Birzin ET, Mosley RT, Berk SC, Hutchins SM, Shen DM, Xiong Y, Hayes EC, Parmar RM, Foor F, Mitra SW, Degrado SJ, Shu M, Klopp JM, Cai SJ, Blake A, Chan WW, Pasternak A, Yang L, Patchett AA, Smith RG, Chapman KT, Schaeffer JM: Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry. Science 1998;282:737–740. 135 Hirschmann R, Nicolaou KC, Pietranico S, Leaby EM, Salvino J, Arison B, Clichy MA, Spoors PG, Shakespeare WC, Sprengeler PA, Hamley P, Smith AB III, Reisine T, Raynor K, Maechler L, Donaldson C, Vale W, Freidinger RM, Cascieri MR, Strader CD: Nonpeptidal peptidomimetics with a ßD-glucose scaffolding. A partial so-

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Antiproliferative Effect of Somatostatin and Analogs Corinne Bousquet Elena Puente Louis Buscail Nicole Vaysse Christiane Susini INSERM U 151, CHU Rangueil, IFR 31, Toulouse, France

Key Words Somatostatin receptor W Proliferation W Receptor signaling

Abstract Over the past decade, antiproliferative effects of somatostatin and analogs have been reported in many somatostatin receptor-positive normal and tumor cell types. Regarding the molecular mechanisms involved, somatostatin or analogs mediate their action through both indirect and direct effects. Somatostatin acts through five somatostatin receptors (SSTR1–5) which are variably expressed in normal and tumor cells. These receptors regulate a variety of signal transduction pathways including inhibition of adenylate cyclase, regulation of ion channels, regulation of serine/threonine and tyrosine kinases and phosphatases. This review focuses on recent advances in biological mechanisms involved in the antineoplastic activity of somatostatin and analogs. Copyright © 2001 S. Karger AG, Basel

ABC

© 2001 S. Karger AG, Basel 0009–3157/01/0478–0030$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/che

Introduction

Somatostatin (somatotroph release-inhibiting factor) was originally discovered as a hypothalamic neurohormone that inhibited growth hormone secretion. It was subsequently demonstrated that somatostatin is a widely distributed peptide both in the central and peripheral nervous systems and in peripheral tissues including the endocrine pancreas, gut, adrenals, kidney and immune cells. In mammals, two forms of bioactive peptides, somatostatin 14 and a C-terminally extended form, somatostatin 28 are produced by tissue-specific proteolytic processing of a common precursor. Somatostatin acts on various targets including the brain, pituitary, pancreas, gut, adrenals, thyroid, kidney and on the immune system to regulate a variety of physiological functions. Its actions include inhibition of endocrine and exocrine secretions, modulation of neurotransmission, motor and cognitive functions, inhibition of intestinal motility, absorption of nutrients and ions, vascular contractility and cell proliferation. Due to the short half-life of natural somatostatin peptides (F1 min), many somato-

Dr. Christiane Susini INSERM U151, Institut Louis Bugnard, IFR 31 CHU Rangueil, F–31403 Toulouse Cedex 4 (France) Tel. +33 5 61 32 24 07, Fax +33 5 61 32 24 03 E-Mail [email protected]

statin peptide analogs have been synthesized. Among them, octreotide (SMS 201-995), lanreotide (BIM 23014) and vapreotide have been intensively investigated and are in clinical use for the medical treatment of acromegaly and neuroendocrine tumors. All of these cyclic octapeptides retain amino acid residues (or substitutes) within a cyclic peptide backbone involved in the biological effect of the peptide (Phe7 or Tyr7, DTrp8, Lys9 and Thr10 or Val10 ) and display markedly increased stability (half-life 190 min). The biological effects of somatostatin are mediated via high affinity plasma membrane receptors which are coupled to various signal transduction pathways including inhibition of adenylate cyclase and Ca2+ channels and stimulation of several K+ channels and protein phosphatases. Somatostatin receptors are widely distributed throughout many tissues ranging from the central nervous system to the pancreas and gut, and also in pituitary, kidney, thyroid, lung and immune cells [for a review, see 1, 2]. Compelling evidence has implicated somatostatin in the inhibition of the growth and development of various normal and tumor cells. Thus, somatostatin analogs show antineoplastic activity in a variety of experimental models in vivo and in vitro [for a review, see 3, 4]. Somatostatin receptors are expressed in a large variety of human tumors. Octreotide treatment induces the shrinkage of the pituitary [5] and the stabilization of neuroendocrine tumor progression [6]. However, the clinical implications of the presence of somatostatin receptors in tumors for diagnostic and therapeutic purposes will need to define the physiological role of each receptor subtype expressed in the tumors with respect to its antisecretory and antiproliferative properties. Somatostatin or its analogs may influence tumor cell growth via indirect and direct mechanisms and this review focuses on

Antiproliferative Effect of Somatostatin and Analogs

recent advances in the molecular mechanisms involved in the antiproliferative effect of somatostatin and analogs.

Somatostatin Receptor Family

To date, five receptor subtypes, SSTR-1– SSTR-5, have been cloned. Human SSTRs are encoded by 5 genes localized on separate chromosomes. Four of these genes are intronless, the exception being SSTR-2 which is alternatively spliced in rodents to generate two isoforms named SSTR-2A and SSTR-2B which diverge in their C-terminal sequence. The SSTRs subtypes belong to the family of G-protein-coupled receptors with seven transmembrane spanning domains and present a high degree of sequence identity (39–57%). They all bind somatostatin 14 and somatostatin 28 natural peptides with similar affinity (nM range) although with a slightly higher affinity for somatostatin 14. Only SSTR-5 displays a 10-fold higher affinity for somatostatin 28. However, they show major differences in their affinities for analogs. Analogs exhibit a low affinity for SSTR-1 and SSTR-4 (61 ÌM) whereas they bind SSTR-2, SSTR-5 with a high affinity, comparable to that of somatostatin 14 (nM range) and bind SSTR-3 with moderate affinity (65–10 nM) [7, 8]. Using recombinant SSTRs transiently or stably expressed in various eukaryote cells, the intracellular signaling pathways coupled to SSTRs have been extensively studied. Each receptor subtype is coupled to multiple intracellular transduction pathways via pertussis toxin-sensitive heterotrimeric GTP binding proteins. Inhibition of the adenylate cyclase system leading to reduction of intracellular cAMP was one of the first signaling pathways identified to be associated with the occupation of somatostatin receptors. All five SSTRs are functionnally coupled to inhibition of ade-

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nylate cyclase via a pertussis toxin-sensitive protein, G·i1 or G·i2, or G·i3 being involved in mediating this coupling [7, 8]. A second key plasma membrane signaling pathway involved in somatostatin action concerns K+ and Ca2+ channels. In neuronal and neuroendocrine cells, somatostatin and analogs regulate several subsets of K+ channels including inward rectifying (GIRK1; via G protein G·i3), transient outward, delayed rectifying, voltage-dependent M current and ATP-sensitive K+ channels as well as large conductance Ca2+-activated BK channels. Activation of K+ channels by somatostatin causes hyperpolarization of the plasma membrane and leads to decreased Ca2+ influx through voltage-gated Ca2+ channels and consequently to reduction of intracellular Ca2+. Expression of GIRK1 channels together with each somatostatin receptor in Xenopus oocytes demonstrate that SSTR-2, SSTR-3, SSTR-4 and SSTR-5 can couple to inward rectifying K+ channels, SSTR-2 being the most efficiently coupled [9]. The SSTR subtypes coupled to other K2+ channels remain to be elucidated. Somatostatin can also decrease Ca2+ influx by directly inhibiting high voltage-dependent Ca2+ channels via G0·2. Somatostatin receptors couple to Ntype and L-type voltage-dependent calcium channels in several cell types including mouse pituitary AtT-20 cells and rat insulinoma RINm5F cells [7, 8]. Using receptor subtype-specific analogs, it has been demonstrated that SSTR-2 and SSTR-5 can negatively couple to voltage-dependent calcium channel (L-type) in mouse pituitary cells [10]. SSTR-1 is also implicated in the inhibition of Ca2+ influx since it has been shown to mediate the inhibition of voltage-dependent Ca2+ channels in rat insulinoma 1046-38 cells [11]. Both of these two signal transduction pathways, inhibition of Ca2+ and to a lesser extent inhibition of cAMP, mediate

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the negative regulation of hormone and neurotransmitter secretions induced by somatostatin. A third important membrane signaling a pathway linked to somatostatin receptors involves the regulation of protein phosphatases. Somatostatin and analogs activate a number of protein phosphatases including serine/threonine phosphatases, tyrosine phosphatases and Ca2+-dependent phosphatase [12–15]. SSTR-1, SSTR-2, SSTR-3 and SSTR-4 have been reported to stimulate tyrosine phosphatase activity when expressed in NIH 3T3 fibroblast or CHO cells [16–18]. Somatostatin receptor subtypes involved in the regulation of serine/threonine phosphatase have not yet been identified. Concerning the coupling of SSTRs with phospholipase C pathway, the results are controversial. In COS-7 cells expressing each receptor subtype, all five receptors are able to stimulate phospholipase C and increase Ca2+ mobilization via a pertussis toxin-dependent G protein, albeit at agonist concentration higher than 1 nM. However, the coupling of SSTR2, SSTR-5 and SSTR-3 to phospholipase C is more efficient. For SSTR-3, this coupling is involved in the stimulatory effect of somatostatin on guinea pig intestinal smooth muscle cell contraction and is mediated by phospholipase C-ß3 [19]. In contrast, in transfected CHO-K1 cells, SSTR-5 inhibits phospholipase C-mediated intracellular Ca2+ mobilization whereas SSTR-4 is without effect [20]. The MAP kinase pathway is also involved in signal transduction coupled to SSTR but the modulation differs according to the receptor subtype. When expressed in CHOK1 cells, SSTR-4 activates MAP kinases Erk1/2 leading to phosphorylation and activation of phospholipase A2 and release of arachidonic acid whereas SSTR-5 inhibits MAP kinases ERK1/2 by a mechanism involving a dephosphorylation cascade including inhibition of guanylate cyclase and thus decreasing cGMP

Bousquet/Puente/Buscail/Vaysse/Susini

formation and inhibition of cGMP-dependent protein kinase G [21]. Finally, another signal transduction pathway coupled to SSTR-1 has also been reported. Indeed, in transfected mouse fibroblast Ltk– cells, SSTR-1 has been reported to be negatively coupled to Na+/H+ exchanger by a mechanism independent of G protein. In the same cells, transfected SSTR-2 has no effect [22].

Indirect Effects of Somatostatin on Cell Growth

Indirect effects of somatostatin on tumor growth may be the result of inhibition of secretion of growth-promoting hormones and growth factors which stimulate the growth of various types of cancer. It is known that tumors depend on specific growth factors for their growth. For example, insulin-like growth factor-1 (IGF-1) which is produced by hepatocytes through GH-dependent and GH-independent mechanisms is an important modulator of many neoplasms that express IGF-1 receptors and respond to this mitogenic factor [23]. Octreotide has been demonstrated to negatively control the serum IGF-1 level as a result of an effect on GH secretion and SSTR2 and SSTR-5 have been demonstrated to be implicated in this effect [24]. In addition, a direct effect on IGF gene expression has also been reported [25]. The suppressive action of somatostatin analogs on the GH-IGF-1 axis has been proven effective in the treatment of GH-secreting pituitary adenomas [26]. Clinical studies have demonstrated a reduction of IGF-1 gene expression and serum levels of IGF-1 after treatment of breast cancers with octreotide and these effects are increased when combined with the antiestrogen tamoxifen [27]. Somatostatin and analogs also increase the expression and the secretion of

Antiproliferative Effect of Somatostatin and Analogs

IGF-binding protein-1, which specifically binds IGF-1 and negatively regulates plasma IGF-1 [28]. Somatostatin and analogs may also inhibit the secretion of gastrointestinal and pancreatic hormones involved in the regulation of tumor growth such as cholecystokinin, gastrin, insulin and glucagon and growth factors such as the epidermal growth factortransforming growth factor · family. In somatostatin SSTR-2 knockout mice, the use of new selective subtype analogs has enabled investigators to demonstrate the role of SSTR-2 in inhibiting glucagon and gastrin release from mouse pancreatic · and gastric cells, respectively, and the role of SSTR-5 as a mediator of insulin secretion from mouse pancreatic ß cells has recently been reported [24, 29]. In addition, the detection of SSTR-2 receptors with specific anti-SSTR-2 antibodies in human A and B pancreatic islet cells suggests that this receptor subtype is involved in the regulation of human pancreatic hormones [30]. The role of other receptor subtypes in the regulation of hormone secretion remains to be defined. Somatostatin or its analogs can also indirectly control tumor development and metastasis by inhibition of angiogenesis. Somatostatin analogs inhibit angiogenesis in vitro and in vivo [31]. Overexpression of peritumoral vascular somatostatin receptors with a highaffinity for somatostatin 14, somatostatin 28 and octreotide (suggesting a preferential expression of SSTR-2 subtype) has been reported in human primary colorectal carcinomas, small cell lung carcinoma of the lung, breast cancer, renal cell carcinoma and malignant lymphoma. Furthermore, the expression of somatostatin receptors in tumor vessels appears to be independent of receptor expression in the tumor [32]. This suggests that somatostatin and its receptors may play a regulatory role in hemodynamic tumor-host interactions, angiogenesis and vascular drainage.

Chemotherapy 2001;47(suppl 2):30–39

33

Evidence suggests that somatostatin may influence the immune system. Somatostatin and receptors are expressed in human lymphoid organs and can regulate various immune functions including lymphocyte proliferation, immunoglobulin synthesis, and cytokine production [33]. It has recently been reported that SSTR-2, SSTR-3, SSTR-4 and SSTR-5 are expressed in human lymphoid cell lines and expression of SSTR-2 is upregulated following lymphocyte activation [34]. It has been well demonstrated that somatostatin and octreotide inhibit the proliferation of human and rat T lymphocytes in vitro [33, 35] and that somatostatin inhibits IFN-Á release from T lymphocytes probably via the SSTR-2 subtype leading to a decrease of Ig2a levels [36]. However, no information is available on the effect of somatostatin in vivo on the immune system.

Direct Effect of Somatostatin on Tumor Cells

Somatostatin may also directly inhibit tumor cell growth by interacting with specific somatostatin receptors located on tumor cells. Using either radiolabeled somatostatin or its analogs, somatostatin receptors have been described in a large variety of human cancer cells (including pituitary adenomas, islet tumors, carcinoids, adenocarcinomas of breast, prostate, ovary, kidney and colon origin, lymphomas as well as astrocytomas and neuroblastomas and medulloblastomas). Most tumors express the SRIF1 subtype characterized by a high affinity for natural peptides and hexapeptide-stable analogs but a number of tumors express the SRIF2 subtype characterized by a low affinity for analogs. More recent analyses of SSTR mRNAs demonstrate that various human tumors from neuroendocrine and gastroenteropancreatic origin, brain tu-

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mors (gliomas and meningiomas), prostate, lung and breast tumors express various SSTR mRNA, each tumor expressing more than one subtype, SSTR-2 being the most frequently expressed [for a review, see 37, 38]. Indeed, in carcinoid tumors, of 87 tumors examined, approximately 85% are positive for SSTR-2. The majority of these tumors also express SSTR-5, with SSTR-1, SSTR-3 and SSTR-4 being less abundant. The high frequency of SSTR-2 mRNA (and probably also the presence of SSTR-5 mRNA) found in neuroendocrine tumors allows the localization of various human tumors and metastases by somatostatin receptor scintigraphy following injection of indium-111-labeled octreotide. However, the detection of specific SSTR mRNA in tumors does not necessarily reflect the presence of the protein. The recent availability of polyclonal antibodies has enabled different groups to identify the SSTR proteins. Indeed, using SSTR-2 antibodies, Dutour et al. [39] report the expression of SSTR-2 in human gliomas and meningiomas with a rich expression in both human brain tumor and peritumoral tissue, and a prominent expression in blood vessels. Immunohistochemical detection of somatostatin receptors SSTR-1, SSTR-2 and SSTR-3 using specific antibodies in 33 breast tumors allows the detection of the receptors on tumor cells but the level and the pattern of the expression of SSTR vary greatly between individual carcinomas: SSTR-2 detected at a high level in 28 tumors (85%), SSTR-1 in 17 tumors (52%) and SSTR-3 in 16 tumors (48%) [40]. Of 35 patients with carcinoid tumors, the presence of SSTR-2 protein has been detected in 25 patients and there was a correlation with the presence of SSTR-2 mRNA, the tracer uptake using somatostatin receptor autoradiography and the therapeutic response to somatostatin analog treatment [41]. In contrast to that observed in neuroendocrine tumors, in advanced pancreatic and

Bousquet/Puente/Buscail/Vaysse/Susini

prostatic as well as colorectal adenocarcinoma, SSTR-2 expression is lost. This may have a growth advantage in these tumors and provide one explanation for the lack of therapeutic effect of somatostatin analogs in such tumors [42, 43]. The presence of somatostatin receptors in tumors argues in favor of a direct role for somatostatin in the regulation of tumor growth. A direct inhibitory effect of somatostatin or analogs on cell growth has been demonstrated on various cancer cell lines which express endogenous somatostatin receptors (cells of mammary, pancreatic, gastric, lung, colorectal or thyroid origin) [for a review, see 4]. However, the mechanisms of cell growth arrest induced by somatostatin are still poorly understood. The fact that these tumor cells express multiple somatostatin receptors raises the questions of whether different somatostatin receptor(s) may account for these effects and which mechanisms are involved. The direct inhibitory action of somatostatin on cell growth may result from the blockade of mitogenic growth factor signal. In NIH 3T3 or CHO cells expressing SSTR-1 or SSTR-2, octreotide and vapreotide inhibit cell proliferation induced by serum or insulin with an affinity which correlates with the binding affinity of analogs to each receptor subtype. This effect involves the stimulation of a tyrosine phosphatase [16, 19]. The somatostatin-sensitive tyrosine phosphatase has recently been identified as SHP-1. This tyrosine phosphatase contains two SH2 domains which are involved in protein-protein interactions. SHP-1 associates in vivo with various activated tyrosylated growth factor tyrosine kinase receptors and cytokine receptors. Recent studies have suggested a role of SHP-1 in terminating growth factor and cytokine mitogenic signals by dephosphorylating critical molecules [44]. In CHO cells expressing SSTR-2, SHP-1 is weakly associated with the

SSTR-2 receptor via the protein Gi·3 at the resting level and occupation of SSTR-2 by analogs transiently increases the formation of SSTR-2-SHP-1-Gi·3 complexes leading to the activation of the enzyme. The activated enzyme rapidly dissociates from the SSTR-2 subtype, associates with the activated and tyrosylated insulin receptor, dephosphorylates it and its substrates, thus leading to a negative regulation of the insulin mitogenic signaling [45] due to G1 cell cycle arrest and inhibition of insulin-induced S phase entry [Pages, pers. results]. A somatostatin-induced increase of SHP-1 translocation to the membrane is also observed in MCF-7 mammary cancer cells [46]. The use of dominant negative SHP-1 reveals that SHP-1 is required for the antiproliferative signal initiated by SSTR-2 [47]. In addition, SSTR-4 could also mediate the antiproliferative effect of somatostatin via a tyrosine phosphatase since in the rat thyroid PC13 cell line which only expresses SSTR-4 mRNA, somatostatin inhibits insulin- and insulin-plus-TSH-dependent proliferation through the stimulation of a tyrosine phosphatase and induces a block in the G1/S progression in the cell cycle [48]. Concerning SSTR-5, its expression in CHOK1 cells leads to somatostatin analog-induced inhibition of cell proliferation stimulated by serum or cholecystokinin via a pertussis toxin-dependent Gi/0 protein [20]. The signaling pathway coupled to SSTR-5 and leading to inhibition of proliferation is selective for SSTR-5 and has been recently identified. It involves the inhibition of guanylate cyclase leading to a decrease of cGMP formation, inhibition of cGMP-dependent protein kinase G and inhibition of MAP kinase ERK1/2 [21]. The antiproliferative effect of somatostatin can also result from apoptosis. Apoptosis has been reported to be induced by the SSTR3 subtype via a G protein-dependent signaling

Antiproliferative Effect of Somatostatin and Analogs

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35

and to be associated with an intracellular acidification and activation of endonuclease and induction of p53 and Bax [49, 50]. In human pancreatic cancer cells expressing mutated p53 and devoid of endogenous SSTR-2, expression of SSTR-2 does not result in a G1 cell cycle arrest but induces an increase in cell death [Rochaix, pers. results]. This indicates that apoptosis can be signaled by other SSTR than SSTR-3 and somatostatin can induce apoptosis by p53-dependent and p53-independent mechanisms. Besides the antiproliferative effect of somatostatin due to cell growth arrest and/or apoptosis, somatostatin may directly control cell growth by inhibiting the synthesis and/or the secretion of autocrine growth factors, cytokines and hormones involved in the proliferation of tumor cells. It is well known that the aberrant expression of growth factors, cytokines or hormones and their receptors represent fundamental circuits that may spur and sustain uncontrolled growth and metastatic behavior of cancer cells. For example, EGF-related growth factors such as transforming growth factor-· and amphiregulin and/or their specific receptor, the EGF receptor as well as IGF-1 receptor and its ligand, have been detected in several types of human cancers, including breast, lung, pancreatic and colorectal cancers [51, 52]. Gastrin and CCK-B receptor isoforms are coexpressed in gastrointestinal cancer cells [53]. These growth factors may act by paracrine and autocrine mechanisms to exert growth promoting and metabolic effects. Somatostatin may influence the synthesis and/or the secretion of these factors and/or downregulate the expression of their receptors leading to disruption of proliferative autocrine loops. At the cellular level, blockade of secretion by somatostatin is mediated through inhibition of Ca2+ and cAMP production. Additionally, somatostatin can directly interfere with the exocytotic

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machinery by inhibiting the protein phosphatase calcineurin [14]. The specific SSTR subtypes involved in these processes and the mechanisms involved remain to be determined. Recent results using the patch-clamp technique indicate that in human neuroendocrine gut tumor cells, somatostatin and octreotide inhibit L-type voltage-dependent calcium channels with the same amplitude suggesting that at least SSTR-2 and SSTR-5 may be involved in the inhibition of Ca2+ influx and thereby inhibition of tumor-produced neurotransmitters and hormone [54]. The antiproliferative effects of somatostatin result from its actions via the endocrine pathway but evidence exists that somatostatin can also act via an autocrine/paracrine pathway. Indeed, immunoreactive somatostatin has been found in somatostatin receptor-positive normal and tumor cell types such as endocrine and lymphoid cells, breast cancer cells, colonic tumor cells and, additionally, somatostatin mRNA is detected in a wide variety of neuroendocrine tumors known to express somatostatin receptors [55–58]. Correction of the SSTR-2 deficit in human pancreatic cancer cells by SSTR-2 expression induces a negative autocrine loop in the absence of exogenous ligand, which is due to the SSTR-2-induced expression and secretion of endogenous SSTR-2 ligand (somatostatin 14 and somatostatin 28). This results in inhibition of cancer cell proliferation and reversion of cell tumorigenicity in vitro and in vivo after xenografts in nude mice [59]. SSTR-2 may function as a determinant factor in the negative control of cell growth and a loss of such an autocrine loop by the loss of expression of one component such as SSTR-2 or endogenous ligand contributes to the malignancy of cancers. As observed for other receptors coupled to G protein, somatostatin receptors are sensitive to agonist-induced desensitization and/or

Bousquet/Puente/Buscail/Vaysse/Susini

internalization and/or up- or down-regulation. Indeed, agonist-dependent internalization and upregulation of somatostatin receptors have been demonstrated in various cell lines expressing multiple SSTRs or transfected cells expressing individual subtype after prolonged agonist exposure. Although the molecular mechanisms involved in these effects are poorly understood, it appears that the response of somatostatin receptors to agonist application is agonist-, receptor- and cell type-specific. Indeed, a different pattern of internalization has been reported for the five SSTRs, in CHO-K1 cells and in human embryonic kidney (HEK) cells expressing individual subtypes. In CHO-K1 cells, SSTR-2–5 undergo rapid internalization following agonist activation but SSTR-1 is not internalized. In contrast, in HEK cells, SSTR-1, SSTR-2 and SSTR-3 are internalized in response to somatostatin 14 or somatostatin 28 whereas SSTR-5 is only internalized in response to somatostatin 28 and SSTR-4 is not internalized [for a review, see 8, 37]. In addition, somatostatin upregulates SSTRs in a receptor subtype-specific manner. Long-term exposure of CHO-K1 cells to somatostatin upregulates SSTR-1, SSTR-2 and SSTR-4 by 110, 26 and

22%, respectively, whereas the levels of SSTR3 and SSTR-5 are not modified [for a review, see 37]. These results suggest that these phenomena may be important for physiological and clinical indirect and/or direct response to somatostatin peptides. At the cellular level, one can expect that upregulation of somatostatin receptors transducing the antiproliferative effect of somatostatin by endogenous or exogenous somatostatin peptides can enhance the antiproliferative effect of the peptide. In conclusion, much progress has been made towards elucidation of the characterization, the molecular signal transduction, the expression and the regulation of SSTRs. However, the biological role as well as the cellular distribution of each receptor subtype is far from being completely understood. The development of specific antibodies, agonists and antagonists as well as gene knockout models will help to define the specific role of individual receptors in physiological and pathological conditions and the significance of multiple receptor subtypes in the same cell. Finally, the recent findings of antioncogenic properties of SSTR-2 for human pancreatic cancer cells suggest that SSTR-2 gene transfer may be a possible adjuvant gene therapy for pancreatic cancer.

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44 Neel BG, Tonks NK: Protein tyrosine phosphatases in signal transduction. Curr Opin Cell Biol 1997; 9/2:193–204. 45 Bousquet C, Delesque N, Lopez F, Saint-Laurent N, Esteve JP, Bedecs K, Buscail L, Vaysse N, Susini C: SSTR-2 somatostatin receptor mediates negative regulation of insulin receptor signaling through the tyrosine phosphatase Shp-1. J Biol Chem 1998;273:7099–7106. 46 Srikant CB, Shen SH: Octapeptide somatostatin analog SMS 201-995 induces translocation of intracellular PTP1C to membranes in MCF-7 human breast adenocarcinoma cells. Endocrinology 1996;137:3461– 3468. 47 Lopez F, Esteve JP, Buscail L, Delesque N, Saint-Laurent N, Theveniau M, Nahmias C, Vaysse N, Susini C: The tyrosine phosphatase SHP-1 associates with the SSTR-2 somatostatin receptor and is an essential component of SSTR-2-mediated inhibitory growth signaling. J Biol Chem 1997;272:24448–24454. 48 Florio T, Scorizello A, Fattore M, D’Alto V, Salzano S, Rossi G, et al: Somatostatin inhibits PC Cl3 thyroid cell proliferation through the modulation of phosphotyrosine activity. Impairment of the somatostatinergic effects by stable expression of E1A viral oncogene. J Biol Chem 1996;271:6129–6136. 49 Sharma K, Patel YC, Srikant CB: Subtype-selective induction of wildtype p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3. Mol Endocrinol 1996;10: 1688–1696. 50 Sharma K, Srikant CB: G protein coupled receptor signaled apoptosis is associated with activation of a cation insensitive acidic endonuclease and intracellular acidification Biochem Biophys Res Commun 1998; 242:134–140. 51 Quinn KA, Treston AM, Unsworth EJ, Miller MJ, Vos M, Grimley C, Battey J, Mulshine JL, Cuttitta F: Insulin-like growth factor expression in human cancer cell lines. J Biol Chem 1996;27/1:11477– 11483.

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Chemotherapy 2001;47(suppl 2):40–53

Established Clinical Use of Octreotide and Lanreotide in Oncology Kjell Öberg Department of Medical Sciences, Uppsala University, Uppsala, Sweden

Key Words Neuroendocrine tumors W Octreoscan W Octreotide W Lanreotide W Octastatin

Abstract The diagnosis and treatment of neuroendocrine tumors have been significantly improved during the last decades. Localization and staging of the disease by somatostatin receptor scintigraphy (Octreoscan) are now the ‘gold standard’ for the management of these tumors. Treatment with somatostatin analogs has improved quality of life and possibly also survival for patients with neuroendocrine tumors. New long-acting formulations of the somatostatin analogs are as effective as the old regular formulations but will further improve quality of life for the patients. Tumor-targeted therapy with 111In and 90Y coupled to somatostatin analogs show promising results but await further studies. Copyright © 2001 S. Karger AG, Basel

ABC

© 2001 S. Karger AG, Basel 0009–3157/01/0478–0040$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/che

Introduction

Octreotide and lanreotide are registered in most countries for the control of symptoms associated with metastatic carcinoid and VIPsecreting tumors. The clinical efficacy of somatostatin analogs has been established for many neuroendocrine tumors including acromegaly, although the latter will not be discussed in this paper. Neuroendocrine gut and pancreatic tumors constitute about 2% of all malignant gastrointestinal tumors. Carcinoids are the most common type of neuroendocrine tumors and may be classified according to the region in which they arise into foregut, midgut and hindgut carcinoids [1, 2]. Foregut tumors originate in the thymus, lung and gastroduodenal mucosa and represent about 15% of all carcinoids. Midgut carcinoids with the primary located in the jejunum, ileum and the proximal colon including the appendix comprise the most common (40–50%) of all clinically relevant carcinoids. Hindgut tumors lo-

Prof. Kjell Öberg Department of Medical Sciences, Uppsala University Uppsala (Sweden) Tel. +46 18 66 49 17, Fax +46 18 51 01 33 E-Mail [email protected]

cated in the rectum, sigmoid and the distal colon comprise approximately 20–25% of all carcinoids and are normally hormonally inactive (nonfunctioning). The hormones secreted by foregut carcinoids are varied giving rise to many clinical syndromes such as acromegaly, Cushing’s disease, SIADH, Zollinger-Ellison syndrome as well as the carcinoid syndrome per se. The above classification of carcinoid tumors has been questioned since it causes considerable confusion. Consequently the term carcinoid might in the future be reserved only for classical midgut carcinoids. Other neuroendocrine tumors in the gut should be assigned the term ‘neuroendocrine tumors’ followed by their primary location, e.g. neuroendocrine, lung, gastric, duodenal, pancreatic, colonic and rectal tumors. The dominant hormone produced by the tumors may also be included in the classification, e.g. gastrin-producing neuroendocrine tumor. Such a classification would certainly be helpful in communicating information about these tumors and also in evaluating potential therapies [1]. The carcinoid syndrome is a well-defined clinical syndrome which includes flushes, diarrhea, carcinoid heart disease with right heart failure and bronchial constriction accompanied by elevated levels of plasma serotonin and/or urinary 5-HIAA. The tumors also release tachykinins, bradykinins and prostaglandins. For some patients the syndrome is severe enough to be potentially lifethreatening with extensive flushing combined with hypotension or very frequent diarrhea, the so-called ‘carcinoid crisis’ [2, 3]. Another group of neuroendocrine tumors are the endocrine pancreatic tumors which are classified as funtioning if they are associated with a clinical syndrome related to the hormone they produce or which are considered nonfunctioning if they do not present with clinical

symptoms of excessive hormone release. The latter category constitutes around 30% of all endocrine pancreatic tumors and includes those which secrete pancreatic polypeptide, chromogranin A, peptide YY and neurotensin [4, 5]. The two most common clinical syndromes related to endocrine pancreatic tumors are the Zollinger-Ellison syndrome resulting from gastrin overproduction [6] and the hypoglycemic syndrome which is related to high insulin/proinsulin release [7]. The Zollinger-Ellison syndrome (gastrinoma) may also arise from hypersecretion of gastrin production by duodenal carcinoids (around 40%). More than 70% of the gastrin-producing tumors are malignant with early lymph node involvement. Most neuroendocrine pancreatic tumors are malignant except for insulin-producing tumors where 80% are benign solitary tumors in the pancreas [7]. Other functioning endocrine pancreatic tumors are the VIP-producing syndrome or WDHA syndrome which is characterized by extensive diarrhea, hypokalemia and achlorhydria [8]. In such patients the diarrhea volume might exceed more than 10 liters per day and they often require intensive care. Such tumors are mostly confined to the pancreas but sometimes may be located to the lung or sympathetic ganglia. Another rare tumor is the glucagonoma. The glucagonoma syndrome [9] is characterized by a typical necrolytic migratory erythema, diabetic glucose tolerance, anemia, weight loss and thromboembolism which may be related because of glucagon production and its endorgan effects. Both these rare tumors have been treated successfully with somatostatin analogs. Multiple endocrine neoplasia type 1 (MEN-1) is a familial disorder inherited as an autosomal dominant trait with variable penetrance patterns. In MEN-1 the pituitary, para-

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thyroids and endocrine pancreas are the most commonly affected organs but the adrenal cortex and the thyroid can also be involved [10]. A specific genetic deletion has been described for MEN-1, i.e. a loss of heterozygosity of the MEN-1 locus on chromosome 11q13 where the MEN-1 gene is deleted or mutated. About 80% of MEN-1 patients develop endocrine pancreatic tumors. Furthermore, about 30% of all gastrin-producing neuroendocrine gastrointestinal tumors are related to the MEN-1 syndrome. Some of these patients also develop lung, duodenal or gastric carcinoids. In fact, gastrinoma in MEN-1 patients is more often located in the duodenum than the pancreas itself and sometimes you can find the gastrinomas in both locations. The diagnosis of neuroendocrine tumors is based on histopathology, the cells showing the typical features of amine precursor uptakes and decarboxylation including positive silver staining (argyrophil, argentaffin) and positive staining for antibodies to chromogranin A, synaptophysin and NSE. The more sophisticated histopathology takes the tumor biology into account such as the proliferation markers (Ki-67, PCNA), angiogenetic factors (VEGF, b-FGF), adhesion molecules (CD-44, exon V6–V9) and finally deletions and mutations of the MEN-1 gene (menin). An essential component in the diagnosis of neuroendocrine tumors is the biochemical determination of the different peptide hormones they secrete. For example, determination of chromogranin A is the most important screening marker for the diagnosis of neuroendocrine tumors. Urinary 5-HIAA is important in diagnosing the carcinoid syndrome [1]. The localization and staging of neuroendocrine tumors may be significantly improved by somatostatin receptor scintigraphy (octreoscan), which will be discussed below in relation to treatment with somatostatin analogs. Somatostatin receptor scintigraphy is

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nowadays the procedure of choice for localizing neuroendocrine tumors and supported by computed tomography and ultrasonography to determine the tumor size follow-up during therapy. Endoscopic ultrasonography has recently come into clinical use and has been particularly useful for localizing endocrine pancreatic tumors located particularly in the head of the pancreas. The prognosis of neuroendocrine tumors, particularly carcinoids, has normally been assumed to be relatively good without treatment. Therefore, many physicians have been reluctant to administer medical treatment in the early stages of the disease. However, a critical analysis of the 5-year survival rates of patients with neuroendocrine tumors suggests that the prognosis of such patients is not as good as many physicians believe. Thus, the 5year survival rates of patients with neuroendocrine tumors is less than 20% when liver metastases are present. Furthermore, the median survival for patients with malignant carcinoid tumors with the carcinoid syndrome is less than 2 years from the time of diagnosis [1, 2]. The therapy for neuroendocrine tumors is aimed at providing symptomatic relief by suppression of hypersecreting hormones, inhibition of tumor growth and at improving and maintain a good quality of life. Surgery is the treatment of choice for malignant neuroendocrine tumors, and even if surgical resection is not possible, debulking and bypassing procedures should be considered [11]. To further reduce the tumor burden, embolization, with and without cytotoxic agents has been demonstrated to have beneficial effects [12]. External irradiation has been of limited value in most neuroendocrine tumors but may relieve pain in some patients [13]. Hitherto tumor-targeted treatment has been attempted using 131I-MIBG [14] but the technique has now been replaced by 111In-DTPA-

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octreotide. More recently 90Y label compounds have also been evaluated [15]. The medical treatment for neuroendocrine tumors include chemotherapy, somatostatin analogs and interferon-· [1, 16, 17]. Chemotherapy, particularly streptozotocin plus 5-fluorouracil, has demonstrated to be a valuable therapeutic regimen for endocrine pancreatic tumors with response rates of 50–70% being reported [1, 16, 17]; however, classical midgut carcinoids do not respond to chemotherapy, its response rates being less than 10% [1, 16, 18]. The therapeutic idea of somatostatin analogs in the management of neuroendocrine tumors will be discussed in detail below. Interferon-· has been shown to be of beneficial value, particularly in patients with midgut carcinoids with a reported subjective improvement in about 50% of the patients, a reduction in tumor size in 14% and biochemical responses in 40–50% of the patients [1, 19]. Patients who tolerate interferon-· therapy frequently exhibit significant long-term responses with a median survival from the diagnosis of the carcinoid syndrome of more than 60 months [20].

Somatostatin Receptors

Somatostatin receptors are expressed in somatostatin target tissues such as brain, pituitary, pancreas, gastrointestinal tract, blood vessels as well as in various types of tumors. At present five somatostatin receptor subtypes (SSTR-1–5) have been cloned and pharmacologically characterized [21–23]. All the somatostatin receptors are coupled to G proteins and belong to the seven-transmembranespanning receptor family. All the somatostatin receptor subtypes bind to their native hormones (SRIF-28 and SRIF-14) with high affinity. In contrast, short synthetic somatostatin (SRIF) analogs used clinically such as

Established Clinical Use of Octreotide and Lanreotide in Oncology

octreotide, lanreotide and octreostatin display high affinity binding only for SSTR-2 and SSTR-5 receptors, intermediate binding affinity for SSTR-3 subtype and very low or no affinity for SSTR-1 and SSTR-4 subtypes. The five somatostatin receptor subtypes cloned to date show very poor homology (40–50%) which may account, at least in part for the different binding affinities [23]. Although a number of studies have been performed over the past years to determine the distribution of the five somatostatin receptor subtypes, their physiological role is still poorly understood. This is partly due to the fact that there is no set of agonists and antagonists available with sufficient receptor selectivity for a single receptor subtype and because of coexpression of two or more SRIF receptor subtypes in a particular organ. All five somatostatin receptors are functionally coupled to inhibition of adenylyl cyclase. Likewise, the five subtypes induce phosphotyrosine phosphatase-1c in each case via pertussis toxin-sensitive GTP binding proteins. Some of the receptor subtypes are also coupled to K+ and Ca2+ channels, the Na2+/K+ hydrogen exchanges and to phospholipase C and MAP kinases. Neuroendocrine tumors express a variety of somatostatin receptors but particularly receptor subtype 2 [22, 24, 25]. Thus the SSTR-2 receptor subtype is expressed in 90% of carcinoid tumors and in 80% of endocrine pancreatic tumors. An exception are insulin-producing pancreatic tumors where less than 50% express the somatostatin receptor 2 subtype. However, neuroendocrine tumors also express SSTR-5, SSTR-3 and SSTR1 subtypes. Further, it is demonstrated that different somatostatin receptor subtypes are expressed in various patterns on different tumors [22]. This demonstration may explain the conflicting results of the therapeutic efficacy of reported somatostatin analogs in the management of neuroendocrine tumors. Activation of somatostatin receptor subtypes 1 and 2 results

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in the activation of tyrosine phosphatase, the activity of which has been correlated with the antimitotic effect of somatostatin and its analogs in some types of cells [26]. In addition, inhibition of cell proliferation is mediated by the somatostatin receptor subtype 5, but via a different mechanism, which probably involves changes in the intracellular calcium fluxes [23, 27]. Somatostatin receptor type 3 (SSTR-3) has been reported to mediate apoptosis. Thus, high dose treatment with octreotide, which only has a low binding affinity for the SSTR-3 subtype induces apoptosis both in carcinoid tumors and BON-1 cells xenotransplanted to nude mice [28]. Octreotide and other somatostatin analogs significantly inhibit the growth of the neuroendocrine-differentiated cell line BON-1, the pancreatic cancer cell line AR42J and the human breast cancer line MCF-7 in experimental animals [28, 29]. Tumors treated with somatostatin analogs are less vascular than those in untreated mice suggesting that the peptide inhibits angiogenesis. This suggestion is supported in a chorioalantoic membrane model of the chick embryo where octreotide inhibits angiogenesis in a dose-related manner [26]. Furthermore, octreotide in combination with endothelial growth factor inhibits blood vessel growth. Reubi et al. [30] demonstrated a high concentration of somatostatin receptors in the veins draining some human tumors. However, the expression of somatostatin receptors in the veins was not different from that in the tumour per se. Weckbecker et al. [29] studied the effects of octreotide in combination with doxorubicin, mitomycin C and Taxol or 5-FU on the growth of the pancreatic cancer cell line AR42J in vitro. Octreotide potentiated the antiproliferative effect of three of four cytotoxic agents (mitomycin C, doxorubicin and taxol) and was additive to 5-FU. The authors also investigated the temporal effects of a

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combination of octreotide and doxorubicin. They observed that the antiproliferative effect was greater if the doxorubicin therapy was administered initially with the octreotide therapy added 24 h later. The in vitro data was further confirmed in vivo using nude mice bearing AR42J tumors.

Somatostatin Receptor Scintigraphy

Somatostatin receptor scintigraphy is the most important clinical diagnostic investigation for patients with suspected neuroendocrine tumors [31, 32]. Dynamic scintigraphy detected more than 90% of all patients with carcinoid tumors, particularly liver metastases, regional lymph node metastases, bone metastases and sometimes also the primary tumor. In patients with endocrine pancreatic tumors, the clinical use of scintigraphy in the detection of such tumors has not been as fruitful as in carcinoid tumors. However, in a recent study 122 patients with a diagnosis of the Zollinger-Ellison syndrome were evaluated with upper gastrointestinal endoscopy, computerized tomography (CT), magnetic resonance imaging (MRI), angiography and bone scanning, to attempt to design a treatment plan [33]. Patients then underwent somatostatin receptor scintigraphy with 111InDTPA-D-Phe-octreotide. The somatostatin scintigraphy (62%) was superior to both CT (39%) and MRI (50%) in localizing primary tumors and was equal to all conventional imaging studies in combination. For metastatic disease scintigraphy (100%) was again superior to CT and MRI (64 and 80%, respectively) and equal to all conventional studies combined (96%). In 14% of the tumors, scintigraphy was the only technique which was positive. The scintigraphic results changed the clinical management in 47% of patients with gastrinoma. Therefore in patients with

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Table 1. Meta-analysis of

symptomatic (subjective), biochemical and radiological responses to different treatments with somatostatin analogs in studies conducted over the last 10 years in patients with metastatic neuroendocrine tumors

Response

Symptomatic Biochemical CR PR SD PD Radiological CR PR SD PD

Standard doses of octreotide

Slow release lanreotide

High dose lanreotide

(100–1,500 Ìg/day)

(30 mg/14 day i.m.)

(9–15 mg/day)

146/228 (64)

34/66 (52)

11/26 (42)

6/54 (11) 116/211 (55) NS NS

2/80 (2.5) 35/80 (44) 32/80 (40) 11/80 (13.5)

1/33 (3) 24/33 (72) 7/33 (21) 1/33 (3)

– 7/131 (5) 50/131 (38) 74/131 (56)

– 2/42 (5) 32/42 (76) 8/42 (19)

1/53 (2) 6/53 (11) 25/53 (47) 21/53 (39)

Figures represent numbers with the percentage in parentheses. CR = Complete response; PR = partial response; SD = stable disease; PD = progressive disease; NS = not indicated.

the Zollinger-Ellison syndrome the investigators suggested that somatostatin receptor scintigraphy should be regarded as the imaging modality of choice. In a prospective study evaluating somatostatin receptor imaging in 160 patients with confirmed gastroenteropancreatic tumors, somatostatin receptor scintigraphy was positive in 68% of patients. More interesting was the observation that in 46 patients, negative by conventional imaging, somatostatin receptor scintigraphy detected 47 previously undiagnosed lesions in 36 patients. Furthermore, somatostatin receptor scintigraphy modified the tumor staging in 38 patients and changed the surgical strategy in 40 patients [34]. On the basis of these findings, somatostatin receptor scintigraphy should be performed routinely in patients with neuroendocrine tumors both for the staging and for therapeutic decisions. Small tumors, less than 1 cm in diameter, such as in patients with MEN-1 still represent a diagnostic problem. Furthermore, in all primary tumors or metastases, even in the same patient, the ex-

pression of somatostatin receptor subtypes is not identical and they may not express the SSTR-2 or SSTR-5 subtypes. Since octreoscans are dependent as the expression of the SSTR-2 and SSTR-5 subtypes, positive somatostatin receptor scintigraphy has a predictive value for treatment with somatostatin analogs [35, 36]. Conversely, tumors not expressing the SSTR-2 and SSTR-5 subtypes will not be detectable by scintigraphy and are unlikely to respond to somatostatin analog therapy.

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Treatment with Somatostatin Analogs (table 1)

Somatostatin analogs, octreotide being the first available for clinical use [37], have become increasingly important in the management of patients with neuroendocrine tumors of the gut and pancreas. The rationale for the clinical efficacy of somatostatin analogs in the management of neuroendocrine tumors is related to the expression of somatostatin

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receptors in 80–90% of all such cases. All of the somatostatin analogs presently available for clinical use (octreotide, lanreotide, octastatin) bind with high affinity to the SSTR-2 and SSTR-5 subtypes and with lower affinity to SSTR-3 subtype. Although somatostatin analogs have been available for more than 15 years, we are still lacking randomized controlled trials, probably because neuroendocrine tumors represent rare diseases. Furthermore, the inclusion of different types of neuroendocrine tumors in multicenter trials is not appropriate for studying the efficacy of somatostatin analogs on these indications since there are large differences between ‘classical’ midgut carcinoids with a low proliferative capacity and several forms of endocrine pancreatic tumors or other foregut tumors which progress rapidly and show a high proliferative capacity. The efficacy of somatostatin analog therapy could be divided into subjective, biochemical and tumor responses (tumor size reduction). A complete remission is rarely obtained but partial remission is more than 50% reduction of clinical symptoms, biochemical markers or tumor size; stable disease is less than 50% reduction of these parameters but also less than 25% increase of the same parameters. Progressive disease is more than 25% increase of clinical symptoms, biochemical markers or tumor size. In the first trial reported by Kvols et al. [37], octreotide subcutaneously (150 Ìg t.i.d.) was observed to present symptomatic responses in 88% and biochemical responses in 72% of patients with carcinoid tumors. The median duration of the biochemical response was 12 months. In 1989 Gorden et al. [38] performed a meta-analysis of all reported cases of neuroendocrine tumors treated with somatostatin analogs. The meta-analysis indicated symptomatic improvement in 92% and a biochemical response in 66% of the

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patients. A reduction of the tumor size was, however, only noted in 8% of octreotidetreated patients, whereas tumor size was unchanged in 85%. In that study tachyphylaxis was observed in 40% of the patients but a proportion did respond to increased doses of octreotide. The median dose of octreotide used in these studies was 300 Ìg/day s.c. Low dose octreotide therapy (50 Ìg b.i.d.) resulted in significantly lower biochemical response rates (30%) compared to the regular dose analog therapy [39]. More than 50 patients with gastrinomas have been treated with doses of 100–1,500 Ìg octreotide/day, most of them in the short term [40, 41]. A clinical response defined as control of gastric hypersecretion, pain and diarrhea was observed in 90% of the patients and was accompanied by a significant reduction in serum gastrin and basal acid secretion. In a long-term study by Ruszniewski et al. [42], the maximal acid output decreased during 9–12 months of octreotide treatment suggesting an antitrophic effect of the analog (i.e. reduction of parietal cell mass). Such an effect has also been reported by an Italian group who demonstrated that octreotide, 500 Ìg once a day, elicited a significant decrease in its ECL cell population, which was paralleled by progressive reduction in serum gastrin levels in patients with chronic atrophic gastritis [43]. However, although somatostatin analog therapy is not the primary treatment for gastrinomas, many patients being initially treated with H2 receptor blockers or proton pump inhibitors combined with surgery, long-acting somatostatin analogs (Sandostatin-LAR®, Lanreotide PR®) may be beneficial for a subgroup of patients with malignant gastrinomas. Patients with insulin-producing tumors treated with somatostatin analogs should be very carefully monitored for escalation of their hypoglycemia. In some patients counterregulatory mechanisms, such as the growth

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hormone, IGF-1 and glucagon may be more suppressed than the insulin secretion by the tumor [41, 44, 45]. About 50% of insulin-producing tumors do not express somatostatin receptor 2 and 5 subtypes. However, there is a subgroup of insulin-producing tumors that might benefit from somatostatin analog therapy and these are the predominantly malignant insulinomas which concomitantly hypersecrete gastrin and/or glucagon. In patients with the WDHA syndrome and VIP-producing tumors which are unoperable and in whom chemotherapy has only been transiently effective, octreotide has been suggested to be the treatment of choice [41, 45, 46]. Symptomatic improvement has been reported in more than 80% of such patients treated with octreotide at doses of 100–400 Ìg/day. However, in some patients the beneficial effect of octreotide lasted only a few days requiring progressive increases in doses. Biochemical responses have been reported in about 80% of VIPoma patients. Symptomatic relief was not always related to a reduction of plasma concentration of VIP suggesting that octreotide may have a direct effect on the gut. In some patients octreotide has also been shown to change the molecular forms of circulating VIP, possibly into less bioactive forms. In approximately 90% of patients with glucagonomas who present with a rash it disappears rapidly after octreotide therapy [41, 47]. Other symptoms characteristic of the syndrome such as weight loss and diarrhea may improve during octreotide therapy but the analog has a variable effect on diabetes. Plasma glucagon is reduced in approximately 60% of patients during octreotide therapy. The symptomatic response observed during octreotide therapy was independent of the plasma glucagon, the concentration suggesting a direct effect of the analog on the skin. Furthermore, in patients with glucagonomas, octreotide can change the circulating molecular forms of glucagon, indicating

that the analogs inhibit the posttranslational processing of preproglucagon, thereby reducing the circulating levels of bioactive glucagon. Somatostatin-producing tumors, the socalled somatostatinomas, have been regarded as resistant to treatment with somatostatin analogs. However, a symptomatic and biochemical response has been reported in a small number of patients during octreotide therapy which correlated with the presence of somatostatin receptor subtypes in the tumors [48]. The inhibition of tumor growth in patients with carcinoid and endocrine pancreatic tumors has been reported to be low in most studies (0–17%) [40, 41, 49]. In a study by Saltz et al. [50] in patients with neuroendocrine tumors treated with octreotide (150– 250 Ìg t.i.d.), no regression was documented. However, octreotide stabilized the size assessed by CT in 50% of the patients for a median duration of 5 months. In a German multicenter trial, 52 patients with different forms of neuroendocrine malignancies and CT-documented tumor progression were treated with octreotide 200 Ìg t.i.d. [51]. Stabilization of tumor growth was achieved in 19 of 52 patients (36%) for a median duration of 18 months. Even though a reduction in tumor size is rarely seen with standard octreotide treatment, stabilization of further tumor growth suggests that octreotide has an antiproliferative effect. Harris and Redfern [49] performed a meta-analysis of data compiled from 62 published studies on patients with carcinoids to examine the relationship between the dose of octreotide and the clinical efficacy evaluated by analyzing urinary 5-HIAA, flushing and diarrhea in patients. Six dose ranges of octreotide were assessed and ranged from 100 to 3,000 Ìg/day. The maximum clinical response to octreotide occurred in patients treated with 300–375 Ìg/day with some fur-

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ther improvement in doses up to 1,000 Ìg/ day. Doses of octreotide above 10,000 Ìg showed no additional clinical benefit. The authors’ conclusion from this study is that there was a significant patient-to-patient variation in the sensitivity to octreotide treatment and that it is important to titrate the dose of the analog in each patient until adequate symptoms and/or biochemical control are achieved.

High-Dose Somatostatin Analog Therapy

A few studies have addressed the potential value of high-dose somatostatin analog treatment in neuroendocrine gastrointestinal tumors [52–56]. A dose-related tumor response has been demonstrated in a variety of tumor models with increasing somatostatin analog treatment. In a trial of our group [53], 19 patients with advanced neuroendocrine gastrointestinal tumors (13 carcinoids and 6 EPT) were included in the study. The mean duration of disease prior to entry into the trial was 56 months and all except 4 patients had received a variety of treatments. Finally patients had failing standard dose octreotide therapy. Somatostatin receptor scintigraphy was positive in 17 of 18 patients before initiation of lanreotide administered in increasing doses up to 12 mg/day s.c., a dose which was maintained for 1 year or until tumor progression. High-dose lanreotide resulted in biochemical responses in 58% of the patients, stabilization of the disease was observed in 70% and 1 patient (5%) showed a partial tumor response. Furthermore, patients with both a biochemical response and stabilization of their disease exhibited a progressive increase in the number of apoptotic cells in the tumor, maximal apoptosis occurring 12 months following commencement of lanreo-

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tide therapy [28, 53]. Apoptosis may have been mediated via the binding of lanreotide to somatostatin receptor type 3, as suggested by Patel and Srikant [23]. Moreover, in this trial positron emission tomography using the tracer 11C-L-DOPA lanreotide inhibited exocytosis more strongly than the inhibition of its synthesis of the peptide [57]. Anthony et al. [54] treated 13 patients with neuroendocrine tumors, refractory to standard doses of octreotide, with a high dose of the analog (6 mg/day) and reported a partial tumor response in 4 patients (31%) and stabilization of the disease in 2 (15%). The same group reported on high-dose lanreotide (9 mg/day) in 13 patients with various neuroendocrine tumors finding a partial remission in 4 patients (31%) and stabilization of the disease in 2 (15%). Faiss and Wiedenmann [55] treated 30 patients with metastatic neuroendocrine gastrointestinal tumors with 15 mg/day of lanreotide for 1 year and reported one complete and one partial tumor response. These studies suggest that a high-dose therapy of octreotide/ lanreotide can produce additional antiproliferative effects in patients deteriorating on regular dose analog therapy. These observations form the basis for a currently ongoing study with ultrahigh doses (160 mg/month) of octreotide (Onco-LAR®).

Continuous Infusion of Somatostatin Analogs

Several studies of patients with acromegaly have indicated that a continuous infusion of octreotide has advantages over intermittent subcutaneous injections of the analog [58]. A more pronounced clinical and biochemical control can be achieved at lower intravenous doses of somatostatin analogs and the adverse effects may be less than with higher subcutaneous doses. To test this hypothesis we

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performed a European multicenter trial in 35 patients with carcinoid syndrome (19 of them had failed standard doses of octreotide) with octastatin (RC-160) at a dose of 1.5 mg/day given as a continuous subcutaneous infusion via micropump for 3–6 months [56]. This was the first clinical trial of octastatin of particular interest since in vitro studies have suggested that octastatin has a stronger antiproliferative effect than both octreotide and lanreotide [58, 59]. In this trial subjective improvement and disease stabilization were observed in 60% of the patients. However, the biochemical response rate was rather low (23%) and there was no tumor response.

Slow Release Formulations of Somatostatin Analogs

One of the most important improvements in somatostatin analog treatment is the development of a slow release formulation. Sandostatin-LAR and Lanreotide-PR in which octreotide and lanreotide have been incorporated into microspheres of a biodegradable polymer were available for clinical use. Sandostatin-LAR can be administered once every 4 weeks and Lanreotide-PR every 2 weeks [60]. Ruszniewski et al. [61] treated 39 patients with carcinoids with Lanreotide-PR (30 mg i.m. every 2 weeks) and reported subjective responses in approximately 55% of patients, biochemical responses in 42%. However, no tumor response was observed after 6 months of lanreotide treatment. We conducted a European multicenter trial and included 55 patients (48 carcinoids and 7 EPT) with Lanreotide-PR (30 mg i.m.) every 2 weeks for 6 months [62]. Symptomatic improvement was observed in 38% of carcinoids, 66% of gastrinomas and one VIPoma. Biochemical responses were obtained in 47% and tumor responses in 2 patients (7%). Sta-

Established Clinical Use of Octreotide and Lanreotide in Oncology

bilization of tumor growth was achieved in 80% of patients. In this trial quality of life was studied using a validated instrument (QLC 30) and assessment after 1 month showed a significant improvement of emotional and cognitive function, overall health as well as sleeping disorders and diarrhea. This was the first trial to demonstrate that long-acting somatostatin analog therapy improves the quality of life of patients with neuroendocrine tumors.

Combination Trial with Somatostatin Analogs

The combination of somatostatin analogs with other agents is an interesting area for future studies. We have previously reported that a combination of octreotide and interferon-· produced biochemical responses in 75% of patients resistant to either interferon-· alone or conventional doses of octreotide [63]. In vitro and in vivo studies of BON-1 tumors indicate that a combination of these two compounds has a stronger antiproliferative effect than interferon or octreotide alone [28]. An Italian trial reported on 58 patients with metastatic neuroendocrine tumors who were initially treated with octreotide at a dose of 500 Ìg t.i.d. [52]. The dose was increased to 1,000 Ìg t.i.d. and this regimen was continued until disease progression. Twenty-five patients with progressive disease during octreotide treatment received concomitant chemotherapy (dacarbazine 200 mg/m2, 5-FU 250 mg/m2, epidoxorubicin 25 mg/m2) administered intravenously daily for 3 days every 3 weeks. For the whole group of 58 patients the median duration of octreotide treatment was 5 months. In 27 patients the disease stabilized for at least 6 months. A partial remission was achieved in 2 patients which lasted 10 and 14 months, respectively. The median survival of

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the entire group was 22 months. In this trial no additive or synergistic effect was obtained by adding chemotherapy. Therefore, the interesting observation by Weckbecker et al. [29] that doxorubicin in combination with octreotide showed a significant synergistic effect in in vitro and in vivo studies remains to be proven in forthcoming randomized clinical trials.

Tumor-Targeted Radioactive Somatostatin Analog Treatment

Peptide receptor scintigraphy with a radioactive somatostatin analogue (111InDTPA-octreotide) is a sensitive and specific technique to identify in vivo the presence and abundance of somatostatin receptors in various tumors. The method has now been accepted as an important tool for the staging and localization of neuroendocrine tumors. However, the technique is currently being evaluated as a possible means of targeting neuroendocrine tumors with ‘tumor-targeted’ radiotherapy using a repeated administration of high doses of 111In-DTPA-octreotide. 111In emits Auger electrons having a tissue penetration of 0.02–10 Ìm. In a recent trial 30 endstage patients with progressive neuroendocrine tumors were treated with 111In-DTPAoctreotide up to a maximal cumulative dose of 74 GBq in a phase 1 trial. No major clinical side effects were observed after up to 2 years’ treatment, except that in a few patients there was a transient decline in platelets and lymphocytes. Of the 21 patients who received a cumulative dose of more than 20 GBq, 8 patients showed stabilization of disease and there was a reduction in tumor size in a further 6. Furthermore, there was a tendency towards better results in patients whose tumor cells showed higher accumulation of the radioligand. We treated 16 patients, also

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end-stage neuroendocrine tumor patients, at doses up to 60 GBq and observed 30% response rates and also a tendency towards better results with higher tracer accumulation of the radioligand. Theoretically depending on the homogeneity of the distribution of tumor cells expressing somatostatin receptor subtypes and the size of tumors, ß-emitting radionucleids, e.g. 90Y labelled to DOTA octreotide, may be more effective than 111In targeting radionuclear therapy. Such trials are now in progress. Recently a study of 10 patients treated with 90Y DOTA TOC has been reported [15]. Two patients showed a significant antitumor response and another 2 developed stable disease. In 9 of the 10 patients treated renal and bone marrow toxicity did not exceed grade 1. One patient developed a persisting grade 2 thrombocytopenia at a total dose of 180 mCi. Tumor-targeted radioactive somatostatin analog therapy awaits further evaluation in patients with less advanced disease.

Adverse Reaction to Somatostatin Analog Therapy

The most common side effects of somatostatin analog are generally mild and include nausea, transient abdominal cramps, flatulence, diarrhea and local reaction at the injection site [58]. Most of these minor side effects resolve with time. In 20–50% of patients gall stones are formed de novo, but these remain virtually always asymptomatic [64]. Rare, more severe adverse events of octreotide therapy include hypocalcemia, bradycardia, acute pancreatitis, hepatitis, jaundice, transitory, ischemic attacks, and a negative inotropic effect of the analogs.

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Future Aspects

Somatostatin analogs can relieve symptoms, reduce circulating hormone levels and stabilize tumor growth in more than 50% of patients, which makes them a good therapy for patients with neuroendocrine tumors. There is, however, as yet no published study that shows that therapy with somatostatin analogs improves survival. However, the majority of centers working with patients with neuroendocrine tumors use a multimodal therapeutic approach. Thus, it is very unlikely that a patient with a neuroendocrine tumor will receive a somatostatin analog as the only treatment during the clinical course of the disease. There is no doubt that somatostatin analog therapy has significantly improved the quality of life in patients with malignant neuroendocrine tumors and is very important for palliative treatment. The most promising future areas are the clinical usefulness of slow release formulations, possibly also high-dose, slow release formulations (Onco-LAR) and the ‘tumor targeted’

radioactive octreotide therapy. The combination of somatostatin analogs with interferons and cytotoxic agents in clinical trials is also worthy of investigation. Furthermore, since somatostatin analogs can be coupled to chemotherapeutic drugs, internalization of the receptor/ligand complex will deliver the chemotherapeutic agent directly into the tumor cells. Somatostatin receptor subtype 5 is the receptor type which is more effectively internalized and receptor subtype 5-specific analogs alone or coupled with cytotoxic drugs or radioactivity might be of therapeutic advantage. This subtype of the somatostatin receptor is expressed in pituitary and neuroendocrine tumor cells. Combination treatments with different receptor subtype-specific analogs (cocktails) might be of benefit [65] when the determination of somatostatin receptor expression is routinely examined in all tumors. Using this concept it may be possible to design specific combinations of somatostatin analogs to treat a particular tumor.

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Established Clinical Use of Octreotide and Lanreotide in Oncology

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9 Stacpoole PW: The glucagonoma syndrome; clinical features, diagnosis and treatment. Endocr Rev 1981; 2:347. 10 Skogseid B, Eriksson B, Lundqvist G, et al: Multiple endocrine neoplasia type 1: A ten year prospective screening study in four kindreds. J Clin Endocrinol Metab 1991;73: 281–287. 11 Makridis C, Öberg K, Juhlin C, et al: Surgical treatment of midgut carcinoid tumors. World J Surg 1990;14: 377. 12 Carrasco CH, Chuang V, Wallace S: Apudoma metastatic to the liver: Treatment by hepatic artery embolization. Radiology 1983;149:79–83.

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13 Schupak KP, Wallner KE: The role of radiation therapy in the treatment of locally unresectable or metastatic carcinoid tumors. Int J Radiat Oncol Biol Phys 1991;20:489. 14 Hoefnagel CA, den Hartog Jager FC, Taal BG, et al: The role of 125IMIBG in the diagnosis and therapy of carcinoids. Eur J Nucl Med 1987; 13:187. 15 Olte A, Mueller-Brand J, Dellas S, et al: Yttrium–90-labelled somatostatin analoague for cancer treatment. Lancet 1998;351:417–418. 16 Moertel CG, Johnson CM, McKusick MA, et al: The management of patients with advanced carcinoid tumours and islet cell carcinomas. Ann Intern Med 1994;120:302– 309. 17 Eriksson B, Öberg K: An update of the medical treatment of malignant endocrine pancreatic tumors. Acta Oncol 1993;32:203–208. 18 Öberg K, Norheim I, Lundqvist G, Wide L: Cytotoxic treatment in patients with malignant carcinoid tumours; response to streptozocin – alone or in combination with 5-FU. Acta Oncol 1987;26:429–432. 19 Öberg K, Norheim I, Lind E, et al: Treatment of malignant carcinoid tumors with human leukocyte interferon: Long-term results. Cancer Treat Rep 1986;70:1297–1304. 20 Öberg K, Eriksson B: The role of interferons in the management of carcinoid tumors. Acta Oncol 1991; 30:519–522. 21 Yamada Y, Reisine T, Law SF, et al: Cloning and functional characterization of a family of human and mouse somatostatin receptors expresssed in brain, gastrointestinal tract and kidney. Proc Natl Acad Sci USA 1992;89:251–255. 22 Schaer JC, Waser B, Mengod G, Reubi JC: Somatostatin receptor subtypes, SSTR-1, SSTR-2, SSTR-3 and SSTR-5 expression in human pituitary, gastroenteropancreatic and mammary tumors: Comparison of mRNA analysis with receptor autoradiography. Int J Cancer 1997; 70:530–537. 23 Patel YC, Srikant CB: Somatostatin receptors. Trends Endocrinol Metab 1997;8:398–405.

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24 Janson ET, Stridsberg M, Gobl M, et al: Determination of somatostatin receptor subtype 2 in carcinoid tumours by immunohistochemical investigation with somatostatin receptor subtype 2 antibodies. Cancer Res 1998;58:2375–2378. 25 Reubi JC, Koppeler A, Waser B, et al: Immunohistochemical localization of somatostatin receptors, SSTR-2A in human tumors. Am J Pathol 1998;153:233–245. 26 Fassler JE, Hughes JH, Cataland S, et al: Somatostatin analogue: An inhibitor of angiogenesis? Biomed Res 1988(suppl):181–185. 27 Buscail L, Estève J-P, Saint-Laurent N, et al: Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms. Proc Natl Acad Sci USA 1995;92:1580–1584. 28 Imam H, Eriksson B, Lukinius A, et al: Induction of apoptosis in neuroendocrine tumors of the digestive system during treatment with somatostatin analogs. Acta Oncol 1997; 36:607–614. 29 Weckbecker G, Raulf F, Tolcsvai L, Bruns C: Potentiation of the antiproliferative effects of anticancer drugs by octreotide in vitro and in vivo. Digestion 1996;57(suppl 1): 22–28. 30 Reubi JC, Horisberger K, Laissue J: High density of somatostatin receptors in veins surrounding human cancer tissue: Role in tumour-host interaction? Int J Cancer 1994;56: 681–688. 31 Krenning EP, Kwekkeboom DJ, Bakker WH, et al: Somatostatin receptor scintigraphy with (111InDTPA-D-Phe1) and (123Tyr3)-octreotide. The Rotterdam experience with more than 1,000 patients. Eur J Nucl Med 1993;20:716–731. 32 Tiensuu Janson E, Westlin JE, Eriksson B, et al: (111In-DTPA-DPhe1)-Octreotide scintigraphy in patients with carcinoid tumors: The predictive value for somatostatin analog treatment. Eur J Endocrinol 1994;131:577–581.

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33 Termanini B, Gibril F, Reynolds JC, et al: Value of somatostatin receptor scintigraphy: A prospective study in gastrinoma of its effect on clinical management. Gastroenterology 1997;112:335–347. 34 Lebtai R, Cadiot G, Sarda L, et al: Clinical impact of somatostatin receptor scintigraphy in the management of patients with neuroendocrine gastroenteropancreatic tumours. J Nucl Med 1997;38:853– 858. 35 Janson ET, Westlin JE, Eriksson B, et al: (111In-DTPA-D-Phe1)-Octreotide scintigraphy in patients with carcinoid tumors; the predictive value for somatostatin analogue treatment. Eur J Endocrinol 1994;131: 577–581. 36 Lamberts SW, van der Lely AJ, De Herder WW, Hofland LJ: Octreotide. N Engl J Med 1996;334:246– 254. 37 Kvols LK, Moertel CG, O’Connell MJ, et al: Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 1986;315: 663–666. 38 Gorden P, Comi RJ, Maton PN, Go VLW: Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormone-secreting tumors of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. Ann Intern Med 1989;110: 35–50. 39 Öberg K, Norheim I, Lundqvist G, Wide L: Treatment of the carcinoid syndrome with SMS 201-995, a somatostatin analogue. Scand J Gastroenterol 1986;119:191–192. 40 Maton PN, Gardner JD, Jensen RT: Use of long-acting somatostatin analogue SMS 201-995 in patients with pancreatic islet cell tumors. Dig Dis Sci 1989;34:285–291. 41 Scarpignato C: Somatostatin analogues in the management of endocrine tumors of the pancreas; in Mignon M, Jensen RT (eds): Endocrine tumors of the Pancreas. Basel, Karger, 1995, pp 385–414. 42 Ruszniewski P, Ramdani A, Cadiot G, et al: Long-term treatment with octreotide in patients with Zollinger-Ellison syndrome. Eur J Clin Invest 1993;23:296–301.

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43 Ferraro G, Annibale B, Mariquani M, et al: Effectiveness of octreotide in controlling fasting hypergastrinemia and related enterochromaffin-like cell growth. J Clin Endocrinol Metab 1996;81:677–683. 44 Lamberts SWJ, Krenning EP, Reubi JC: The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocrinol Rev 1991;12:450–482. 45 Wood SM, Kraenzlin ME, Adrian TE, Bloom SR: Treatment of patients with pancreatic endocrine tumours using a new long-acting somatostatin analogue: Symptomatic and peptide response. Gut 1985;26: 438–444. 46 Kvols LK, Buck M, Moertel CG, et al: Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 2011-995). Ann Intern Med 1987;107:162–168. 47 Jockenhovel S, Lederbogen S, Olbricht T, et al: The long-acting somatostatin analogue octreotide alleviates symptoms by reducing posttranslational conversion of preproglucagon to glucagon in a patient with malignant glucagonoma, but does not prevent tumor growth. Clin Invest 1994;72:127–133. 48 Angeletti S, Corletto D, Schillaci O: Use of somatostatin analogue octreotide to localize and manage somatostatin-producing tumors. Gut 1998;42:792–794. 49 Harris A, Redfern JS: Octreotide treatment of carcinoid syndrome: Analysis of published dose-titration data. Aliment Pharmacol Ther 1995;9:387–394. 50 Saltz L, Trochanowski B, Buckley M, et al: Octreotide as an anti-neoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors. Cancer 1993; 72:244–248.

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51 Arnold R, Trautmann ME, Creutzfeldt W, et al: Somatostatin analogue and inhibition of tumor growth in metastatic endocrine gastroentero-pancreatic tumors. Gut 1996;38:430–438. 52 Bartholomeo M, Bajetta E, Buzzoni R, et al: Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group. Cancer 1996;77:402– 408. 53 Eriksson B, Renstrup J, Imam H, Öberg K: High-dose treatment with lanreotide of patients with advanced neuroendocrine gastrointestinal tumours; clinical and biological effects. Ann Oncol 1997;8:1–4. 54 Anthony L, Johnson D, Hande K, et al: Somatostatin analogue phase I trials in neuroendocrine neoplasms. Acta Oncol 1993;32:217–223. 55 Faiss S, Wiedenmann B: Dose-dependent and antiproliferative effects of somatostatin. J Endocrinol Invest 1997;20:68–70. 56 Eriksson B, Janson ET, Bax NDS, et al: The use of new somatostatin analogues, lanreotide and octastatin, in neuroendocrine gastro-intestinal tumours. Digestion 1996;57:77–80. 57 Bergström M, Eriksson B, Öberg K, et al: Induction of apoptosis in neuroendocrine tumors of the digestive system during treatment with somatostatin analogs. Acta Oncol 1997; 36:32–37. 58 Harris A, Kokoris S, Ezzat S: Continuous versus intermittent subcutaneous infusion of octreotide in the treatment of acromegaly. J Clin Pharmacol 1995;35:59–71.

59 Hofland LJ, Koetsveld, Waaijers M, et al: Relative potencies of the somatostatin analogs octreotide, BIM– 23014, and RC-160 on the inhibition of hormone release by cultured human endocrine tumor cells and normal rat anterior pituitary cells. Endocrinology 1994;134:301–306. 60 Lancranjan I, Bruns C, Grass P, et al: Sandostatin-LAR: Pharmaco-kinetics, pharmacodynamics, efficacy, and tolerability in acromegalic patients. Metabolism 1995;44:18–26. 61 Ruszniewski P, Ducreux M, Chayvialle JA et al: Treatment of the carcinoid syndrome with the long-acting somatostatin analogue lanreotide: A prospective study in 39 patients. Gut 1996;39:279–283. 62 Wymenga ANM, Eriksson B, Salmela PI, et al: Efficacy and safety of lanreotide prolonged release in patients with gastrointestinal neuroendocrine tumors with hormone related symptoms. J Clin Oncol, in press. 63 Janson ET, Ahlström H, Andersson T, Öberg K: Octreotide and interferon alpha: A new combination for the treatment of malignant carcinoid tumours. Eur J Cancer 1992;28A: 1647–1650. 64 Trendle MC, Moertel CG, Kvols LK: Incidence and morbidity of cholelithiasis in patients receiving chronic octreotide for metastatic carcinoid and malignant islet cell tumours. Cancer 1997;79:830–834. 65 Shimon I, Taylor J, Weiss MH, et al: Somatostatin receptor (SSTR) subtype-selective analogs differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumours. J Clin Invest 1997;100:2386–2392.

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Chemotherapy 2001;47(suppl 2):54–61

The Palliative Effects of Octreotide in Cancer Patients Andrew Dean Palliative Care Service, Sir Charles Gairdner Hospital, Nedlands, Australia

Key Words Palliative care W Somatostatin W Opioids

Abstract Octreotide is an extremely useful compound for palliative care physicians. It appears to be active in a number of different pain states and may be given by the spinal and intraventricular route. Its actions in reducing gut motility and secretions make it a valuable adjunct in the management of inoperable bowel obstruction. The same actions make it a potent antidiarrheal agent. Octreotide will often succeed where other antidiarrheal agents fail. Its ability to reduce gut secretions has led to its use in the treatment of fistulae. It has also been proposed as a useful drug in the management of cachexia and ascites. Most of the existing evidence is based on small numbers of case reports and further larger trials are necessary. Copyright © 2001 S. Karger AG, Basel

ABC

© 2001 S. Karger AG, Basel 0009–3157/01/0478–0054$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/che

Introduction

Octreotide, a synthetic analog of somatostatin, is an interesting compound to many specialities. It has a number of properties which make it potentially useful in many different palliative care situations. This paper serves to address some of its applications. When considering the palliative uses of octreotide, the most pertinent quote to consider is ‘in most situations where the drug has been found to be useful, no controlled clinical trials have been performed. At least in part this has been due to the rarity of the conditions treated. It does make it difficult, however, to assess just how effective octreotide is in many circumstances’ [1].

Pain

The past 5 years have seen tremendous improvements in the understanding of pain and analgesic neurophysiology. A distinction is made between opioid-sensitive pain and the

Dr. Andrew Dean Palliative Care Service, Sir Charles Gairdner Hospital Nedlands, WA 6009 (Australia) Tel. +61 8 9346 2551, Fax +61 8 9346 1848 E-Mail [email protected]

pain that exhibits partial or no response to narcotic analgesics. There are now a vast array of opioids to choose from including morphine, hydromorphone, methadone, oxycodone, and fentanyl, each having a place in mainstream analgesic pharmacotherapy. Opioids, however, are not perfect analgesics. Pain from nerve damage (neuropathic pain, neurogenic pain) exhibits a variable degree of opioid resistance. There has been substantial work done in identifying some of the mechanisms of opioid resistance. Drugs with actions on sodium channels, NMDA receptors, calcium channels and inflammatory mediators are now abundant. Many new and old drugs are thus used by the pain practitioner. Innovative routes of drug delivery are now also more common. The use of epidural and intrathecal analgesia for acute, chronic and cancer pain is commonplace. The number of patients who fail these now standard analgesic approaches are becoming fewer. The controversy regarding the value of octreotide in pain medicine should be viewed in this context of a drug with potential therapeutic benefit for a relatively small number of patients, i.e. those who fail the traditional approach. In understanding the actions of octreotide in pain, it is first necessary to note that somatostatin receptors are found in dorsal horn afferent neurones, spinal interneurones, and ascending and descending pathways. Native somatostatin is found in the periaqueductal grey matter, substantia gelatinosa, the spinal cord and in descending pathways [2–7]. Somatostatin is produced in the hypothalamus, cortex, cerebellum and spinal cord as well as in multiple organs of the gastrointestinal tract (stomach, small bowel, colon and pancreas) [2, 8–11]. The effects of octreotide on pain can be considered to be a summation of its actions as a neurotransmitter and as an autocrine/paracrine regulator. These effects are mediated via

a family of (as yet) 5 identified somatostatin receptors [12]. Given the distribution of somatostatin receptors in those parts of the nervous system concerned with pain transmission and inhibition, somatostatin and its analogs would be expected to have an effect on pain. The cellular and molecular effects of somatostatin and its analogs are also interesting. The somatostatin receptors are G-coupled protein receptors which exhibit many different actions. The various somatostatin analogs also exhibit differential receptor binding. Some receptors cause hyperpolarization of the cell membrane [13] and also block calcium channels [14]. Binding to some receptors regulates glutamate currents at the AMPA receptor [15]. Interestingly, opposing effects are seen on the glutamate current depending on which receptor subtype is activated [15]. Further indirect evidence of a potential analgesic action is found in examining the effects of other drugs on somatostatin secretion. Opioids and GABA agonists inhibit somatostatin secretion, as do high dose steroids. Low dose steroids, however, encourage somatostatin release. These are essentially observational phenomena which do not in themselves prove that somatostatin or its analogs are directly analgesic but certainly provide circumstantial evidence that somatostatin may be involved in the pain process. What clinical evidence is there for analgesic activity? In 1990 and 1991 [16, 17] subcutaneous octreotide was reported to relieve headache in acromegaly which was not related to tumor size. Naloxone did not reverse analgesia, suggesting that the analgesic effect was not mediated by standard opioid mechanisms. The limitations of imaging techniques in assessing minute changes in intracranial tumor size should, however, be noted. No randomized controlled trials have proven subcutaneous octreotide to have a spe-

The Palliative Effects of Octreotide in Cancer Patients

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Table 1. Analgesic requirements before and after epidural or intrathecal somatostatin treatment for the 8 patients in the study of Mollenholt et al. [20, p. 537]

Patient number

Daily analgesic dose before somatostatin treatment

Daily concomitant analgesic dose during somatostatin treatment

Response to treatment

1

Ketobemidone, 60 mg orally Ketobemidone, 20 mg i.m. Paracetamol, 3 g orally

None

Excellent

2

Morphine, 500 mg i.v.

Morphine, 20 mg s.c.a

Good

3

Ketobemidone, 80 mg i.v. Methadone, 30 mg orally

None

Excellent

4

Morphine, 300 mg i.v.

Morphine, 20 mg s.c.b

Good

5

Morphine, 40–60 mg s.c. Morphine, 160 mg orally Paracetamol, 6 g orally

Unaltered

Poor

6

Morphine, 60 mg orally Paracetamol, 4 g orally

Morphine, 0–20 mg orally Paracetamol, 1 g rectally

Good

7

Morphine, 10–30 mg s.c. Morphine, 600 mg orally Paracetamol, 3 g orally

Morphine, 180 mg orally Paracetamol, 3 g orally

Good

8

Morphine, 1,500 mg orally Ketobemidone, 100 mg rectally

Morphine, 60 mg i.v.c

Fair

Ketobemidone is a synthetic opioid that is equipotent with morphine. This dose of morphine was used to treat withdrawal symptoms and not for pain relief. b Intravenous morphine, 300 mg daily after removal of dislodged intrathecal catheter. c Intravenous morphine, 200–1,200 mg daily after the unintentional removal of the epidural catheter. a

cific analgesic action. De Conno et al. [18] found pain relief in 1 of 10 patients treated with subcutaneous octreotide for pain from cancer. Although a chemical action was proposed by the authors, it should be noted that the only patient with analgesic effect received relief from severe postprandial pain complicating pancreatic carcinoma. Pancreatic carcinoma can produce mesenteric ischemia because of its proximity to the celiac axis. We have treated several patients with mesenteric ischemia complicating pancreatic cancer with subcutaneous octreotide. This appeared to be

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an effective analgesic in these circumstances. The most likely mechanism of action is a reduction in bowel motility and secretion, with consequent reduction in ischemic pain. Spinal octreotide and somatostatin have been used for analgesia. Epidural somatostatin was shown to be an effective analgesic in upper abdominal surgery [19]. Mollenholt et al. [20] reported in 1994 that of 8 patients with intractable cancer pain treated with spinal somatostatin, 6 patients reported excellent or good pain relief (table 1). Five of these were patients who were probably suffering from

Dean

neurogenic pain. Penn et al. [21] reported the results of a 6-patient pilot study on intrathecal octreotide infusion for cancer pain. The patients were suffering from a variety of different pain types but it would appear a significant component of them had neurogenic pain. Good analgesia was generally obtained. Interestingly, analgesia was achieved in patients who had demonstrated significant opioid resistance. There has been much controversy regarding the use of spinal somatostatin and octreotide because of reports of neurotoxicity in some animal species [22–24]. Intraventricular octreotide has also been used to provide effective analgesia [25]. This should potentially be useful in patients with head and neck cancer exhibiting local nonopioid-sensitive pain. Interestingly the study of Mollenholt et al. [20] in 1994 was able to perform autopsies on 5 patients who received spinal somatostatin. Three patients of the 5 studied showed some demyelination either of dorsal roots or dorsal columns. These effects could also be explained as being part of a paraneoplastic process. No patients had neurological deficits which could be correlated with this finding. The debate continues whether octreotide should be used by these routes but it is encouraging to read the report of Paice et al. [26] of octreotide being used for 5 years via the intrathecal route to successfully manage chronic pain. This occurred without neurotoxicity. Although there are no large randomized double-blinded controlled trials of octreotide in these situations, the large numbers of case reports indicating that octreotide has potent analgesic activity (especially in non-opioidsensitive pain) is encouraging. My own practice is to use octreotide via these routes as an adjunct to other analgesics when conventional approaches fail but ultimately the decision on whether or not to use octreotide in difficult pain scenarios is down to the individual clinician.

The Palliative Effects of Octreotide in Cancer Patients

Bowel Obstruction

Since Khoo et al. [27] reported the use of octreotide in bowel obstruction in 1992, there have been many publications about this subject. The effects of octreotide on the gut are to reduce gut motility and secretion. Native somatostatin has been shown to inhibit fluid secretion into the rat jejunum [28] and stimulate sodium and chloride absorption in the rabbit ileum [29]. Octreotide has been shown to prolong small intestinal transit time in humans [30]. As both gastric and pancreatic secretions are significantly decreased, there is less total fluid turnover in the gut. A consequence of reduction in gut distension is to delay the onset of edema and ischemia in the antimesenteric border of the intestine. The subsequent delay in necrosis and perforation in mice with proximal small bowel obstruction treated with octreotide was noted in 1992 [31]. If this effect is mirrored in humans, as might be expected, it raises interesting questions relating to potential improvement and survival of patients receiving octreotide for bowel obstruction. In one controlled study of jejunal ligation in rats, octreotide significantly reduced the diameter of obstructed bowel and reduced sodium and potassium losses. The histopathological ischemic changes were more prominent in the control group and anastomotic bursting pressures were higher in the treated group. In a palliative care perspective, the main benefit of octreotide use in this setting is a reduction in distressing symptoms. The original report of Khoo et al. [27] was of 5 patients with vomiting unresponsive to conventional antiemetics but who responded rapidly to octreotide 300 mg/24 h subcutaneously. A marked reduction in nasogastric tube aspirate was noted in 2 of these patients. In our own experience and that of others this observation

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has been consistent [32–35]. One patient of ours with inoperable bowel obstruction survived for 3 months being treated at home with subcutaneous octreotide and nightly subcutaneous fluid. The use of octreotide in palliative care in the home setting has also been reported by Mercadante [36].

suggest that loperamide is at least as effective as low dose octreotide (150 Ìg/day) [44]. In my experience doses from 300–600 Ìg daily are usually effective in controlling difficult diarrheal states. Although 600 Ìg is the usual ceiling dose we have used doses of up to 1,200 Ìg daily with good effect and without adverse consequence.

Diarrhea Fistulae

The actions of octreotide in reducing intestinal motility and water secretion plus the effects on sodium and potassium absorption [1] make octreotide an important agent in the treatment of diarrhea. Profuse diarrhea is an accompaniment of many illnesses. In the cancer field it complicates hormonally active intestinal tumors and is a feature of short bowel syndrome after multiple resections [37]. Diarrhea also complicates celiac plexus block, a technique used in cancer pain treatment [38]. Subcutaneous octreotide has successfully treated this symptom in these conditions where other treatments have failed. The diarrhea associated with AIDS can be particularly severe and when seemingly intractable, octreotide offers an excellent therapeutic solution [39]. Octreotide also has a role in supportive care of patients undergoing chemotherapy. Agents such as 5-fluorouracil can cause severe diarrhea unresponsive to conventional treatment. Octreotide may often work in this situation [40–42] but it does not seem to have a preventive action [43]. As with all diarrheas the etiology should be clearly established and treated specifically as appropriate. Long-term subcutaneous administration of octreotide is not a cost-effective means of symptom management. If conventional measures such as use of opioids and drugs such as loperamide fail, then it is my view that octreotide is certainly worth a trial. Some sources

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Many patients develop fistulae after abdominal surgery for recurrent malignancy. The intensity of fistula output can be particularly distressing as both a constant reminder of the unremitting nature of malignant disease and from practical aspects such as requirements for multiple stoma bags. Octreotide can certainly reduce the fistula output [45] in these situations with consequent improvement in quality of life. Although randomized control trials of octreotide on fistula closure have not demonstrated significant benefit, there has been some debate as to the reason for this [46–48]. In an interesting report by Jenkins et al. [49] the authors measured pancreatic enzyme concentration in fistula secretion and found that enzyme concentration increases between intermittent subcutaneous injections of octreotide; they postulate that a low-volume high-enzyme concentration fistula output may be detrimental to fistula closure. It is not known whether subcutaneous infusion of octreotide would prevent this observation. Hernandez-Aranda et al. [50] showed an improvement in fistula closure rate in a mixed group of patients with enterocutaneous fistulae. Interestingly the total parenteral nutritional time required in the treated group was shorter in the octreotide group than in the placebo group.

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Other Uses – Cachexia, Ascites and Carcinoid Syndrome

Some interesting laboratory data has appeared on the use of octreotide with insulin and with insulin plus growth hormone for the treatment of cancer cachexia. As increased glucagon levels are found in some situations of cancer cachexia, the experimental rationale was to reverse the low insulin/glucagon ratio. A study was carried out in rats and the combination of somatostatin plus insulin was shown to increase weight and muscle protein [51]. Combination of octreotide, insulin and growth was also investigated and found to have similar effects. Whether the growth hormone added anything to the regimen was not clear. Although seemingly physiologically effective, it remains to be seen whether this translates into a useful quality of life measure in human cancer-associated cachexia. Cairns and Malone [52] have recently published a report of 3 cases of patients with ascites who were treated with octreotide. For 2 of these patients, the quantity of ascites appeared to decrease significantly and the need for paracentesis ceased. One of these patients was suffering from adenocarcinoma of the colon and the other adenocarcinoma of the breast. The exact reason for these observations is unclear but an effect on somatostatin receptors on tumors has been postulated. Octreotide is exceptionally useful in the palliation of symptoms due to the carcinoid syndrome. It can succesfully control flushing as well as diarrhea. Patients with the metastatic carcinoid syndrome who experience bone pain also reported alleviation of this symptom when treated with octreotide [53]. One concern in long-term administration is dose tachyphylaxis. In a prospective study of octreotide’s effect on gastric function some of the physiological effects were noted to di-

The Palliative Effects of Octreotide in Cancer Patients

minish on day 6 and 7 of treatment [54]. Certainly it is not known whether this is of clinical importance in palliative care patients whose prognosis is often short. In our own experience, dose tachyphylaxis does not appear to be an important issue. As octreotide use in palliative situations becomes more commonplace, the literature may well answer some of these questions. Although the physiology and pharmacology of octreotide is well understood, there remains a shortage of randomized controlled trials which prospectively study its use in many conditions. Case reports and anecdotal evidence abound. For the palliative care practitioner I believe octreotide is an important compound with many potential uses. The recent development of a long-acting slow-release depot preparation of octreotide and other somatostatin analogs is certainly exciting. The potential uses of this preparation would not necessitate subcutaneous infusion pumps, which is clearly a great convenience to the palliative care patient. I look forward to more randomized control trials in the forthcoming years.

Acknowledgments I am indebted to Karen Mattioli and Joanne Blight for their assistance in the preparation of the manuscript and to Professor Carmelo Scarpignato (University of Parma, Italy) for his encouragement, constructive criticism and assistance with the bibliography.

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11 Patel YC, Reichlin S: Somatostatin in hypothalamus, extrahypothalamic brain and peripheral tissues of the rat. Endocrinology 1978;102: 523–530. 12 Patel YC: Somatostatin and its receptor family. Front Neuroendocrinol 1999;20:157–198. 13 Sims SM, Lussier BT, Kraicer J: Somatostatin activates an inwardly rectifying K+ conductance in freshly dispersed rat somatotrophs. J Physiol 1991;441:615–637. 14 Ikeda SR, Schofield GG: Somatostatin blocks a calcium current in rat sympathetic ganglion neurons. J Physiol 1989;409:221–240. 15 Lanneau C, Viollet C, Faivre-Bauman A, Loudes C, Kordon C, Epelbaum J, Gardette RS: Somatostatin receptor subtypes sst1 and sst2 elicit opposite effects on the response to glutamate of mouse hypothalamic neurones: An electrophysiological and single cell RT-PCR study. Eur J Neurosci 1998;10:204–212. 16 Musolino NR, Marino Junior R, Bronstein MD: Headache in acromegaly: Dramatic improvement with the somatostatin analogue SMS 201-995. Clin J Pain 1990;6/3:243– 245. 17 Pascal J, Freijanes J, Berciano J, Pesquerac C: Analgesic effect of octreotide in headache associated with acromegaly is not mediated by opioid mechanisms. Case report. Pain 1991;47:341–344. 18 De Conno F, Saita L, Ripamonti C, Ventafridda V: Subcutaneous octreotide in the treatment of pain in advanced cancer patients. J Pain Symptom Manage 1994;9:34–38. 19 Taura P, Planella V, Balust J, Anglada T, Carrero E, Brugues S: Epidural somatostatin as an analgesic in upper body surgery: A double blind study. Pain 1994;59/1:135–140. 20 Mollenholt P, Rawal N, Gordh T, Olsson Y: Intrathecal and epidural somatostatin for patients with cancer. Analgesic effects and postmortem neuropathologic investigations of spinal cord and nerve roots. Anesthesiology 1994;81:534–542.

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21 Penn RD, Paice JA, Kroin JS: Octreotide: A potent new non-opiate analgesic for intrathecal infusion. Pain 1992;49:13–19. 22 Gaumann DM, Yaksh TL: Intrathecal somatostatin in rats: Antinociception only in the presence of toxic effects. Anesthesiology 1988;69: 733–742. 23 Asai T: Use of epidural somatostatin for postoperative analgesia is not justifiable. Pain 1995;62:388. 24 Yaksh TL: Spinal somatostatin for patients with cancer: Risk-benefits assessment of an analgesic. Anesthesiology 1994;81:531–533. 25 Candrina R, Gallli G: Intraventricular octreotide for cancer pain. J Neurosurg 1992;76:336–337. 26 Paice JA, Penn RD, Croin JS: Intrathecal octreotide for relief of intractable nonmalignant pain: 5-year experience with two cases. Neurosurgery 1996;38/1:203–207. 27 Khoo D, Riley J, Waxman J: Control of emesis in bowel obstruction in terminally ill patients. Lancet 1992;339:375–376. 28 Dharmsathaphorn K, Sherwin RS, Dobbins JW: Somatostatin inhibits fluid secretion in the rat jejunum. Gastroenterology 1980;78:1554– 1558. 29 Dharmsathaphorn K, Binder HJ, Dobbins JW: Somatostatin stimulates sodium and chloride absorption in the rat ileum. Gastroenterology 1980;78:1559–1565. 30 Dueno MI, Bai JC, Santangelo WD, Krejs GJ: Effect of somatostatin analogue on water and electrolyte transport and transit time in human small bowel. Dig Dis Sci 1987;32: 1092–1096. 31 Gittes GK, Nelson MT, Debas HT, Mulvihill SJ: Improvement in survival of mice with proximal small bowel obstruction treated with octreotide. Am J Surg 1992;163:231– 233. 32 Mercadante S, Maddaloni S: Octreotide in the management of inoperable gastrointestinal obstruction in terminal cancer patients. J Pain Symptom Manage 1992;7:496–498.

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33 Mercandate S, Spoldi E, Caraceni A, Maddaloni S, Simonetti MT: Octreotide in relieving gastrointestinal symptoms due to bowel obstruction. Palliat Med 1993;7/4:295–299. 34 Mangili G, Franchi M, Mariani A, Zanaboni F, Rabaiotti E, Rigerio L, Bolis PF, Ferrari A: Octreotide in the management of bowel obstruction in terminal ovarian cancer. Gynecol Oncol 1996;61:345–348. 35 Fainsinger RL, Pisani A, Bruera E: Use of somatostatin analogues in terminal cancer patients. J Palliat Care 1993;9/1:56–57. 36 Mercadante S: Bowel obstruction in home-care cancer patients: 4 years’ experience. Support Care Cancer 1995;3/3:190–193. 37 Sharkey MF, Kadden ML, Stabile BE: Severe posthemicolectomy diarrhoea: Evaluation and treatment with SMS 201-995. Gastroenterology 1990;99:1144–1148. 38 Dean AP, Reed WD: Diarrhoea – An unrecognised hazard of coeliac plexus block. Aust NZ J Med 1991; 1:47–48. 39 Cello JP, Grendell JH, Basuk P, Simon P, Weiss L, Wittner M, Rood RP, Wilcox CM, Forsmark CE, Read AE, et al: Effect of octreotide on refractory AIDS associated with diarrhoea. A prospective multicentre clinical trial. Ann Intern Med 1991;155:705–710. 40 Cascinu S, Fedeli A, Fedeli SL, Catalano G: Control of chemotherapy induce diarrhoea with octreotide in patients receiving 5-fluorouracil. Eur J Cancer 1992;28:482–483. 41 Cascinu S, Fedeli A, Fedeli SL, Catalano G: Control of chemotherapyinduced diarrhoea with octreotide. A randomised trial with placebo in patients receiving cisplatin. Oncology 1994;51/1:70–73.

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42 Cascinu S, Fedeli A, Fedeli SL, Catalano G: Octreotide versus loperamide in the treatment of fluorouracil induced diarrhoea: A randomised trial. J Clin Oncol 1993;11/1: 148–151. 43 Meropol NJ, Blumenoson LE, Creaven PJ: Octreotide does not prevent diarrhoea in patients treated with weekly 5-fluorouracil plus high dose leucovorin. Am J Clin Oncol 1998;21/2:135–138. 44 Geller RB, Gilmore CE, Dix SP, Lin LS, Topping DL, Davidson TG, Holland HK, Wingard JR: Randomized trial of loperamide versus dose escalation of octreotide acetate for chemotherapy-induced diarrhoea in bone marrow transplant and leukaemia patients. Am J Hematol 1995;50/3:167–172. 45 Nubiola P, Badia JM, MartinexRodenas F, Gil MJ, Segura M, Sancho J, Sitges-Serra A: Treatment of 27 postoperative enterocutaneous fistulas with long half-life somatostatin analogue SMS 201-995. Ann Surg 1989;210/1:56–58. 46 Nubiola-Calonge P, Badia JM, Sancho J, Gil MJ, Segura M, Sitges-Serra A: Blind evaluation of the effect of octreotide (SMS 201-995) on small bowel fistulae output. Lancet 1987;ii:672–674. 47 Scott NA, Finnegan S, Irving MH: Octreotide and postoperative enterocutaneous fistulae: A controlled prospective study. Acta Gastroenterol Belg 1993;53/3–4:266–270.

48 Sancho JJ, di Costanzo J, Nubiola P, Larrad A, Beguiristain A, Roqueta F, Franch G, Oliva A, Gubern JM, Sitges-Serra A: Randomized doubleblind placebo-controlled trial of early octreotide in patients with postoperative enterocutaneous fistula. Br J Surg 1995;82:638–641. 49 Jenkins SA, Nott DM, Baxter JN: Fluctuations in the secretion of pancreatic enzymes between consecutive doses of octreotide: Implications for the management of fistulae. Eur J Gastroenterol Hepatol 1995;7/ 3:255–258. 50 Hernandez-Aranda JC, Gallo-Chico B, Fores-Ramirez LA, AvalosHuante R, Magos-Vazquez FJ, Ramirez-Barba EJ: Treatment of enterocutaneous fistula with or without octreotide and parenteral nutrition. Nutr Hosp 1996;11/4:226– 229. 51 Bartlett DL, Charland SL, Torosian MH: Reversal of tumor-associated hyperglucagonemia as treatment for cancer cachexia. Surgery 1995;118/ 1:87–97. 52 Cairns W, Malone R: Octreotide as an agent for the relief of malignant ascites in palliative care patients. Palliat Med 1999;13:429–430. 53 Smith S, Anthony L, Roberts LJ, Oates JA, Pincus T: Resolution of musculoskeletal symptoms in the carcinoid syndrome after treatment with the somatostatin analogue octreotide. Ann Intern Med 1990;112: 66–68. 54 Londong W, Angerer M, Kutz K, Landgraf R, Londong V: Diminishing efficacy of octreotide (SMS 201-995) on gastric functions of healthy subjects during one week administration. Gastroenterology 1989;96:713–722.

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Management of Breast Cancer: Is There a Role for Somatostatin and Its Analogs? Francesco Boccardo Domenico Amoroso Academic Unit of Medical Oncology, National Cancer Institute, Genoa, Italy

Key Words Somatostatin W Somatostatin analogs W Breast cancer

Abstract Somatostatin and related peptides are a family of peptides which are ubiquitous and function as endogenous growth inhibitors. Analogs have been developed through the introduction of a D-amino acid in the position 8 of somatostatin moiety which is more resistant to the action of endogenous peptidases than the parental moiety. Both somatostatin and its analogs interact with specific receptors on the cell surface. The five receptor subtypes, SSTR-1 to SSTR-5, which have been characterized so far, have a different affinity for somatostatin and its analogs. This and the fact that receptors are not homogeneously expressed in tissues account for the different activity of these compounds, all of which have demonstrated tumoristatic

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properties both in vitro and in vivo. The interaction of somatostatin and of somatostatin analogs with specific SSTR receptors is crucial to the antiproliferative mechanisms exerted by these compounds in vitro and in some animal models and the various pathways have been reviewed in detail. However, inhibition of angiogenesis and suppression of lactogenic hormones might represent alternative mechanisms, in particular in breast cancer. The rationale for the use of somatostatin and its analogs in breast cancer patients and to combine these peptides with antihormones, like antiestrogens or prolactin-lowering drugs, or cytotoxics has been reviewed together with the results obtained in phase II and comparative trials. The reasons for the limited efficacy shown by these compounds either when used alone or when used in combination with other drugs have also been critically reviewed in the perspective of new trials. Copyright © 2001 S. Karger AG, Basel

Prof. F. Boccardo, Cattedra e UO Universitaria di Oncologia Medica Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi, 10 I–16132 Genova (Italy) Tel. +39 010 5600503, Fax +39 010 352753 E-Mail [email protected]

Introduction

Breast cancer is still a leading health issue in women. In fact, this disease is the most common cancer affecting women in developed countries and a major cause of cancer death [1, 2]. The incidence of breast cancer has gradually increased during the past decades in parallel with an increase in the ageing of the population. It was estimated that in 1997 about 180,000 new cases of breast cancer were diagnosed in the USA and that about 44,000 women died of this disease [3]. However, in many countries incidence and mortality have recently levelled off or even decreased [4–7], as a consequence of both early diagnosis and the introduction of more effective treatments. Strategies to control breast cancer include: (1) primary prevention, to decrease the incidence of this disease, (2) early diagnosis, to ensure that more patients might be diagnosed with curable disease, and (3) improvement of treatment, to increase cure rates. Primary prevention is not possible at present due to the multifactorial etiopathogenesis of this disease. However, increasing knowledge of the genetic alterations which can trigger the neoplastic transformation of breast cells and the recognition of the molecular events which control the growth of transformed cells have provided new targets for therapeutic and chemopreventive approaches [8–10]. Tamoxifen has recently been proven to be effective in decreasing the incidence of breast cancer in one study [11]. However, the lack of effectiveness in two other studies [12, 13] and the side effects produced by the long-term administration of this antiestrogen, including endometrial cancer and thromboembolic events, still question its role as a chemopreventive agent in healthy women. It is now recognized that mammographic screening results in a 25– 30% decrease in the risk of women aged 50

years or over dying of breast cancer [14]. However, the role of mammographic screening in women between the ages of 40 and 50 years is still unclear. Treatment of patients with primary breast cancer involves multiple treatment modalities, including surgery, radiotherapy and systemic therapy with combination chemotherapy, hormonal agents or both. Based on the assumption that primary breast cancer is a systemic disease in which subclinical metastases are already present at diagnosis in most patients [15], systemic adjuvant therapy has been extensively studied in several individual randomized trials. To assess a reliable fallout from these trials, partially avoiding the biases intrinsic to each study, the statistical technique of metanalysis was employed to add value to observed or expected events from each trial and to provide an estimate of the overall effect of treatment [16]. Over the past decade there have been four metanalyses of data from prospective randomized trials, involving more than 75,000 women treated with different adjuvant therapies. Current knowledge comes from the results of these metanalyses and, in particular, from the most recent of them. These metanalyses showed: that combination chemotherapy is able to reduce the annual risk of death by about 20%, especially in women younger than 50 [17], that prolonged treatment with tamoxifen is able to reduce to a similar extent the annual risk of death in all age groups, especially in women with estrogen-receptor-positive tumors [18], and that ovarian ablation appears to produce results comparable to those obtained by tamoxifen or chemotherapy in younger women [19]. Because there was enough evidence to suggest that the combination of chemotherapy with tamoxifen (or ovarian ablation in premenopausal women) might be even more effective than either treatment modality alone, this treatment option was included among the rec-

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ommendations for women with a higher risk of relapse generated by a panel of experts at a conference on breast cancer held in St. Gallen in 1998 [20]. In spite of more recent results of adjuvant therapy, at least 50% of women with primary breast cancer ultimately develop distant metastases and die of their disease, the risk being strictly correlated with the pathological status of axillary lymph nodes [21]. Once metastatic disease becomes overt, treatment strategy should be realistically addressed to achieve the best palliative results, through a wise use of chemotherapy and endocrine therapy. Endocrine manipulations represent the oldest form of systemic therapy for advanced breast cancer. Overall, approximately one third of unselected patients with metastatic breast cancer respond to these manipulations [22]. However, the discovery of steroid receptors contributed a lot to the selection of patients most likely to benefit from endocrine maneuvers and 50–75% objective response rates are usually reported in estrogen- or progesterone receptor-positive patients [23]. Tamoxifen has become the most widely used hormone therapy for advanced breast cancer, particularly after the menopause. However, other types of endocrine therapies, such as gonadal ablation in premenopausal women and progestins and aromatase inhibitors in postmenopausal women, may also provide considerable disease remission [22], especially in patients who progress after first-line treatment with tamoxifen [24]. New hormonal compounds, including second generation steroidal and nonsteroidal aromatase inhibitors which are now the treatment of choice for patients who relapse following front-line or adjuvant treatment with antiestrogens, are now being evaluated as an alternative to tamoxifen and are candidates for becoming an alternative to this agent even in the adjuvant setting [24]. Finally, new steroidal antiestrogens are now being evaluated

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either in patients failing first-line tamoxifen treatment or as a first-line treatment option, in view of their non-cross-resistance with triphenylethylene derivatives and lack of the pure agonistic effects exerted by these compounds [25]. In spite of the availability of so many therapeutic choices, the search for new compounds is still crucial and is encouraged by the new insight into the molecular biology of the neoplastic cell, with special regard to the different types of receptors, which are expressed on the surface of breast cancer cells and which interact with many signalling pathways. Since most breast cancers express a variety of somatostatin receptors, the therapeutic potential of somatostatin and its analogs has been investigated in breast cancer patients. Preclinical and clinical findings accumulated so far are the objective of this review.

Structure and Function of Somatostatin and Its Analogs

Somatostatin and somatostatin-related peptides are a family of peptides that include two important products, somatostatin-14 (SS14) and somatostatin-28 (SS28), a number of species-specific variants and even more numerous prehormone forms. SS14 and SS28 are mainly found in the gut and in various exocrine and endocrine glands throughout the body. However, they are ubiquitous and can be found also in the nervous system, specifically in the hypothalamus, limbic system, brain stem and spinal cord [26]. Somatostatin has a broad spectrum of biological actions and exerts suppressive effects on a large variety of cells, functioning as an endogenous growth inhibitor [26]. Naturally occurring peptides have a plasma half-life of less than 3 min, since they are rapidly inactivated by endogenous peptidases

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[27]. Therapeutic application of the native peptide has, therefore, been limited to those conditions where the use through intravenous continuous infusion is appropriate. Therefore, many efforts have been made to develop more stable peptides. Incorporation of D-amino acids into the somatostatin backbone succeeded in slowing down enzymatic degradation [28]. In particular, the introduction of a D-amino acid after tryptophan in the position 8 of the moiety led to the development of analogs with an enhanced GH inhibitory potency [29]. Therefore, the three more extensively tested analogs, i.e. SMS 201–995 (octreotide), BIM 23014 (lanreotide) and RC160 (vapreotide), are octapeptides [29]. Octreotide is 45 times more potent in vitro than naive somatostatin in inhibiting the release of GH and 11 times more potent in inhibiting the release of glucagon. This analog is also more potent in inhibiting insulin secretion [30]. Attempts to develop an analog with minimal effects on insulin and glucagon secretion, but a more profound effect on the release of GH and of GH-dependent growth factors, such as insulin-like growth factors (IGF), resulted in the development of lanreotide. Both octreotide and lanreotide are available as slow-release formulations obtained through the microencapsulation of the active drug in a matrix of polylactide-glycolide microspheres. These polymers are completely biodegradable and are commonly administered at 2- to 4-week intervals [26].

Critical to somatostatin action is the presence of somatostatin receptors, which principally have two distinct functions: (1) to bind

the ligand with high affinity and (2) to produce a transmembrane signal evoking a biological response. Up to five somatostatin receptor subtypes, SSTR-1 to SSTR-5, have been cloned and functionally characterized [31–35]. They all bind SS14 and SS28 with similar affinity but show major differences in the affinity for different somatostatin analogs [31, 34, 35]. Octreotide and vapreotide have a low affinity for SSTR-1, but have a high affinity for SSTR-2. Both of them can inhibit the proliferation of cells expressing SSTR-2 [32, 34, 35]. Vapreotide and octreotide have also a moderate to high affinity for SSTR-3 and SSTR-5 [32, 34]. In addition, vapreotide has a moderate affinity for SSTR-4 [35]. Noteworthy, the specificity of these analogs depends on their different affinity for receptor subtypes and on receptor heterogeneity on the surface of target cells. Indeed, there is a considerable heterogeneity between tumors and within the same tumor with respect to the density of somatostatin binding sites, higher receptor levels having been found in more differentiated tumors [36]. This implies the possibility for somatostatin receptors to represent differentiation markers, at least in certain neoplastic lineages and for their loss to be implicated in tumor progression. After the chronic administration of somatostatin, downregulation of receptors can occur, as shown by studies performed in pituitary cell lines [37]. However, this effect is not the rule. In vivo studies indicate that continuous treatment of acromegalic patients with octreotide does not desensitize the cellular responsiveness. Moreover, there is evidence that changes in gene expression or mRNA stability, rather than in receptor affinity, can be involved in both up- and downregulation of somatostatin receptors [39]. This mechanism is common with other peptides, i.e. LHRH analogs, and results in the occupation of a high proportion of somatostatin receptors which are inter-

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Mode of Action of Somatostatin and Its Analogs: Overview of Receptor Functions

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nalized into the cell and maintained so until treatment with somatostatin is continued. However, an immediate rebound effect has been observed on somatostatin discontinuation, which is associated with a rapid rise in target hormones [40]. Slow release somatostatin analogs can also be ineffective in maintaining the tissue levels necessary to downregulate the receptors and GH escape can occur in some patients if dosages are not appropriate [26]. After binding with somatostatin, receptor activation occurs. This in turn is associated with several transmembrane signalling pathways via pertussis toxin-sensitive guanine nucleotide-binding proteins [41]. In particular, the activation of the receptors is associated with a prompt reduction in the intracellular level of mediators, like cAMP and Ca2+, due to the effects on membrane adenylyl cyclase and ion (K+, Ca2+) channels [42, 43]. However, this proximal effect can explain only in part the inhibitory action of somatostatin on hormone secretion and more distal effects of the peptide in this respect have also been documented [44–46]. Another effector system, i.e. tyrosine phosphatase, has recently been shown to be stimulated by somatostatin receptor activation, leading to dephosphorylation and inactivation of the EGF receptor [47]. Emerging information regarding signal transduction pathways related to somatostatin receptor activation is crucial to understanding the possible mechanisms of action of somatostatin and of its analogs as antiproliferative agents. The transfection of the five cloned human somatostatin receptors into somatostatin receptor-negative cell lines was shown to induce specific signal transduction pathways associated with individual somatostatin receptor subtypes. For instance, it has been demonstrated that SSTR-3-transfected CHO cells respond to octreotide with the upregulation of p53 and the subsequent in-

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duction of apoptosis [48]. However, the presence of a particular receptor subtype on the tumor cell does not guarantee that its binding with the ligand is followed by the activation of antiproliferative or apoptotic pathways. For instance, octreotide can be ineffective in inducing apoptosis through its binding with SSTR-3 in tumors with a mutation in the p53 gene [48]. In other experimental systems, a signal transduction pathway associated with SSTR-2 implying the upregulation of phosphoprotein phosphatase activity has been demonstrated [34, 47, 49]. The activation of this pathway is supposed to represent one of the possible mechanisms through which somatostatin analogs exert their antineoplastic effects. In fact, the blockade of phosphoprotein phosphatase stimulates cellular proliferation [50], enhancing the consequences of the binding of growth factors, like EGF or IGF-1, to their receptors.

Mechanisms of Antitumor Action in Breast Cancer of Somatostatin and Its Analogs

While estradiol is recognized as the predominant hormone stimulating the growth of human breast cancer, there is also evidence that lactotrophic hormones (GH and prolactin) are involved in the growth of breast tumors, particularly in murine models [51]. Indeed, prolactin receptors can be demonstrated in 20–50% of human breast cancer cells and at least some MCF-7 cell clones have been shown to be prolactin-dependent [52, 53]. Inhibition of the release of lactotrophic hormones may, therefore, be one of the mechanisms through which somatostatin and its analogs could inhibit breast cancer growth. There is a substantial literature demonstrating considerable antineoplastic activity of somatostatin and its analogs in many in

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vitro and in vivo experimental systems [54, 55] and increasing information concerning the antiproliferative effects of these compounds has emerged over the past decade. Several mechanisms have been proposed, and it is important to note that they are not mutually exclusive. The direct mechanisms refer to the inhibition of proliferation and/or the induction of apoptosis, as a consequence of the binding of somatostatin and of its analogs to specific receptors on the target neoplastic cell, as reported above. The presence of somatostatin receptors seems to be the major determinant of the antiproliferative activity of somatostatin analogs in animal models [34, 47–49, 56]. Thus, a strong antiproliferative effect of these analogs has been demonstrated in mice bearing both estrogendependent and estrogen-insensitive MXT transplantable tumors that express somatostatin receptors [27]. Conversely, no activity was shown on DMBA-induced mammary carcinoma of the rat that does not express somatostatin receptors [27]. It is worth noting that up to 60% of human breast cancers were found to express somatostatin receptors, although they may not always be homogeneously distributed in the whole tissue sample. The specificity of action of various analogs through their binding with specific type of receptor is a subject of ongoing investigation, although recent data suggest that the antiproliferative effects of somatostatin against breast cancer are mostly mediated by receptor subtypes 2 and 5 [58]. Somatostatin receptors are frequently expressed in tumors with a high estrogen and progesterone receptor content [59], while in contrast a negative relationship was found between their expression and EGF receptors [60], which are regarded as poor prognostic indicators [60]. The indirect mechanisms of action of somatostatin and of its analogs are a direct

consequence of the systemic effects of these compounds and even somatostatin receptornegative tumors might be inhibited through these mechanisms. The indirect mechanism that has received the greatest attention to date concerns the inhibitory effect of somatostatin analogs on the IGF family (IGF-1 and IGF-2). IGF-1 and IGF-2 are peptides with structural similarities to insulin. IGF-1 is involved in normal growth and development processes, while the physiological function of IGF-2 remains unclear, although it appears to be essential for normal fetal growth. IGFs induce mitogenesis in cultured fibroblasts, chondroblasts, osteoblasts, neuroglial cells and erythroid progenitor cells. These peptides also appear to be involved in the control of cell proliferation in various malignant phenotypes [61–64], including breast cancer. The proliferative effects of IGF-1 and IGF-2 are mediated by IGF-1 receptors, which have been detected in 67–93% of human breast tumors [65–68]. Modulation of IGF-1 and IGF-2 activity occurs through the interaction with circulating IGF-binding proteins. However, also the GHIGF-1 axis appears to have an important influence on the biological behavior of many common neoplasms. The suppressive effect of somatostatin analogs on serum IGF-1 levels might be related either to the direct inhibition of IGF-1 gene expression or to the suppression of GH-dependent IGF-1 synthesis in the liver [69, 70]. The direct suppressive action on IGF-1 gene expression remains incompletely characterized and it is possible that both mechanisms (i.e. the suppression of IGF1 gene expression and the suppression of IGF1 synthesis in the liver) might contribute to somatostatin antiproliferative activity. Moreover, somatostatin analogs have been found to stimulate the secretion of certain IGFbinding proteins, an action which has been proposed to attenuate IGF-1 bioactivity

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independently of the suppressive effect on IGF-1 levels [71, 72]. Since IGF-1 is recognized as a potent antiapoptotic factor [73, 74], the antiproliferative effects of somatostatin analogs could also be mediated by the suppressive effects on IGF-1 gene expression, which in turn could enhance the antiapoptotic effects exerted by these compounds in experimental models [75, 76]. The interference with blood flow and nutritional support to the tumor could be a third mechanism through which somatostatin and its analogs could exert their antitumor properties. In fact, somatostatin receptors, namely the SSTR-2 subtype, have been demonstrated in the peritumoral veins of various human cancers, including breast tumors [77] and it appears that the increased expression of somatostatin receptors in peritumoral vessels in comparison to normal, nontumoral, tissue, might be related to the neoplastic process itself [77].

Somatostatin and Its Analogs: In vitro and in vivo Studies

Inhibition of Tumor Growth with Somatostatin and Its Analogs in Combination with Antiestrogens Based on the data mentioned above, it can be argued that somatostatin and its analogs might have some effect on the proliferation of breast cancer. However, unopposed estrogen action can be greater than the growth inhibitory effects of somatostatin and its analogs [78]. The molecular basis for the attenuation of this antiproliferative effect has not been elucidated. However, consistent with this effect is the observation that antitumor activity of octreotide in the MXT breast tumor model was enhanced by the coadministration of an LHRH analog, which lowers estradiol levels [79]. Moreover, the activity of octreotide

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was maximized in the absence of estrogens [78]. Such considerations provided the rationale for the concomitant administration of somatostatin or of its analogs with other hormonal agents, namely antiestrogens. The capability of tamoxifen to suppress the GH-IGF axis through the suppression of IGF-1 gene expression and of serum IGF-1 levels [80–82] provided a further rationale for this combination therapy. Several preclinical and clinical observations have suggested an additive biological and antitumor effect by combining somatostatin analogs and tamoxifen. In short-term experiments in rats, the concomitant administration of octreotide with tamoxifen suppresses serum IGF-1 levels and IGF-1 gene expression more potently than either agent alone [83]. This combination has also been evaluated in the DMBA-induced rat mammary tumor model [84]. These experiments showed that the development and the volume of DMBA-induced tumors were significantly reduced in the animals treated with both agents as compared to the animals treated with either agent alone. In clinical studies, an enhanced suppression of serum IGF-1 levels in patients receiving a combination of octreotide or lanreotide with tamoxifen has also been demonstrated [85]. It is noteworthy that in all experimental systems, tumor response to the combination of octreotide and tamoxifen was greater in smaller than in larger tumors, i.e. at an earlier stage of the disease, when the angiogenetic response to specific peptides released by the cancer cells is higher [86–88]. Since it has been suggested that part of the antitumor activity of somatostatin might be related to its inhibition of angiogenesis, these experiments have anticipated that somatostatin and its analogs would be more effective at an earlier stage of the disease in humans as well, for instance by preventing the growth of micro-

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metastases following surgery, and that the therapeutic effect might be much more limited in patients with overt metastatic disease. Inhibition of Tumor Growth with Somatostatin and Its Analogs in Combination with Chemotherapeutic Agents In order to augment the effects of chemotherapy, a combination of hormonal therapy and cytotoxics has been proposed. Such combination therapies are aimed at achieving additive or synergistic antitumor effects while reducing the incidence and the severity of side effects. The biological rationale for this form of treatment is tumor cell heterogeneity, since breast cancer consists of various populations of cells with different sensitivities to cytotoxic and hormonal agents. The modulatory effect of somatostatin analogs in combination with different chemotherapeutic agents has been studied in different preclinical studies [89]. Among the agents tested, combinations of mitomycin C, doxorubicin, Taxol and 5-fluorouracil have been investigated more extensively than other cytotoxics in a number of models. Thus, in AR42J cells, which express the somatostatin receptor subtype 2 and whose growth has been shown to be inhibited by octreotide [90], both mitomycin C and Taxol exerted antiproliferative effects that appeared to be synergistically enhanced by octreotide [89]. Both additive and synergistic interactions between octreotide and 5-fluorouracil were shown, depending on the 5-fluorouracil concentration used. This type of interaction was also observed with other combinations of octreotide and cytotoxics [91]. The combination of doxorubicin and octreotide resulted in a clear dose-dependent synergistic interaction on AR42J cells [89]. Moreover, it has been demonstrated in vitro that doxorubicin accumulation in MCF-7 cells treated with octreotide was increased 3-

Somatostatin and Breast Cancer

to 4-fold [92]. This observation suggests that octreotide modulates the uptake of doxorubicin and/or interferes with the activity of P-170 glycoprotein responsible for multidrug resistance. The combination of chemotherapy with somatostatin analogs also received attention because of the demonstrated ability of octreotide to reduce gastrointestinal toxicity associated with some cytotoxic agents [93]. However, the evidence concerning the biological and clinical effects of combining somatostatin analogs and chemotherapeutic agents is still limited and does not make it possible to draw any conclusion about the potential role of such combinations in anticancer therapy.

Clinical Studies

The clinical experience with somatostatin or its analogs in advanced breast cancer is still limited, despite the promising findings observed in experimental studies which clearly indicate inhibition of tumor growth. The majority of clinical studies have been carried out in patients pretreated with a variety of therapies and combining somatostatin or somatostatin analogs with tamoxifen or with prolactin-lowering drugs such as bromocriptine (table 1). Vennin et al. [94] treated 16 postmenopausal patients with 200 Ìg octreotide daily for at least 30 days and observed a disease stabilization in 3, and a decrease of IGF-1 levels by 33% in 8. Manni et al. [95] treated 10 postmenopausal breast cancer patients with a combination of octreotide (200–400 Ìg daily) and bromocriptine (5 mg/day) and observed disease stabilization in 1 patient. Interestingly, the baseline levels of IGF-1 declined in 6 out of 9 women. Moreover, following provocative tests, GH levels were suppressed in 7

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69

Table 1. Phase II studies with somatostatin and its analogs alone or in combination with

other hormonal agents Authors

Treatment

Dose/schedule

Patients

OR

Vennin et al. [94] Manni et al. [95]

Octreotide Octreotide and bromocriptine Octreotide

200 Ìg/day 200–400 Ìg/day 5 mg/day 750 Ìg for 10 days, then 500 Ìg for 5 days 200–400 Ìg/day 2.5–5 mg/day 20–30 mg/2 weeks 30 mg/day 30 mg/2 weeks 3 mg/day, then 4.5 mg/day, then 6 mg/day

16 10

3 SD 1 SD

10

3 PR

6

4 SD

36

4 CR 12PR None None

Stolfi et al. [96] Anderson et al. [97] Canobbio et al. [98] Di Leo et al. [99] O’Byrne et al. [100]

Octreotide and bromocriptine Lanreotide and tamoxifen Lanreotide Vapreotide

10 14

OR = Objective response; SD = stable disease; PR = partial response; CR = complete response.

and prolactin levels in 8 of 9 patients in whom these assessments were possible. Three patients experienced nausea and 1 of them had to discontinue treatment. Stolfi et al. [96] treated 10 patients with octreotide given by intravenous infusion for 10 days at a dose of 750 Ìg t.i.d. and then intramuscularly for a further 5 days at the dose of 500 Ìg b.i.d. They obtained a partial response in 3 patients. Moreover, a marked reduction in edema, cyanosis and bleeding from ulcerated tumor lesions was noted in most of the treated patients. Anderson et al. [97] treated 6 patients with octreotide (200–400 Ìg daily) and bromocriptine (2.5–5 mg/day), and observed a disease stabilization in 4. Suppression of both prolactin and IGF-1 levels were observed in all patients during the entire treatment period. Canobbio et al. [98] treated 36 postmenopausal patients with locally advanced or metastatic breast cancer with lanreotide (one 20to 30-mg slow-release vial i.m. every 2 weeks) and tamoxifen (30 mg/day). None of them had received prior treatment with hormone or

70

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chemotherapy. In 4 patients a complete response was observed and a partial response in 12, with an overall response rate of 52% (95% confidence interval: 35–69%). Toxicity was generally mild and treatment was well tolerated, mild diarrhea being the most common side effect. No patient, however, had to discontinue the treatment because of toxicity. A significant decrease in IGF-1 levels was observed at 3 and 6 months in the majority of patients. Di Leo et al. [99] evaluated the activity of lanreotide (BIM 23014) in 10 women with advanced breast cancer. The drug was administered at a dose of 30 mg i.m. fortnightly. No objective response was observed, and GH and IGF-1 serum levels were not adequately suppressed over time. O’Byrne et al. [100] treated 14 women with advanced breast cancer with the somatostatin analog vapreotide (RC-160) at a dose of 3 mg/day in week 1 increasing to 4.5 mg/day during weeks 2– 4 and then to 6 mg/day thereafter by continuous subcutaneous infusion.

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Table 2. Phase III studies with

somatostatin analogs

Authors

Treatment

Ingle et al. [102]

Tamoxifen (20 mg/day) 135 Tamoxifen (20 mg/day plus octreotide (150 Ìg twice/day) Tamoxifen plus placebo 103 Tamoxifen plus octreotide Tamoxifen 22 Tamoxifen (40 mg/day) plus octreotide (0.6 mg/day) and CV 205-502 (75 Ìg/day)

Bajetta et al. [103] Bontenbal et al. [104]

Patients OR % 49 43 21 20 36 55

OR = Objective response.

No objective tumor response was observed. However, a significant reduction in serum IGF-1 and prolactin levels was observed. In 1998 in Italy, the Health Minister promoted the evaluation of the antitumor effects of a therapeutic regimen containing somatostatin or octreotide, melatonin, bromocriptine and a retinoid mixture in eleven phase II trials, involving 386 patients with various tumors, including breast cancer. Cyclophosphamide was added for the treatment of certain types of cancer. The conclusions were quite discouraging since no evidence of efficacy was observed in any the studies performed [101]. In particular, no substantial therapeutic activity was observed in breast cancer patients. The promising findings achieved by somatostatin analogs alone or in combination with tamoxifen or bromocriptine in experimental models have not been confirmed as yet even in controlled trials (table 2). One hundred and thirty-five postmenopausal patients with metastatic breast cancer were randomized to tamoxifen (20 mg/day) alone or combined with octreotide (150 Ìg s.c. twice daily) [102]. About 30% of the patients enrolled in this study were pretreated with chemotherapy and 7% of them had received prior

treatment with tamoxifen. Although a significantly greater decline in serum IGF-1 levels was observed in the group of patients treated with the combination therapy, no differences were observed with respect to either progression-free survival or overall survival. The objective response rate was 49% in patients treated with tamoxifen alone and 43% in patients treated with tamoxifen and octreotide. Most patients treated with octreotide and tamoxifen experienced side effects, such as nausea, diarrhea and steatorrhea. Bajetta et al. [103] carried out a randomized double-blind phase III trial in previously untreated metastatic breast cancer patients who were randomly allocated to tamoxifen combined either with placebo or with octreotide. Unfortunately, drugs dosages were not reported. Two hundred and three patients were included. An overall tumor response rate of 20% was observed in the octreotide and tamoxifen arm compared to 21% in the placebo and tamoxifen arm. No difference was observed between groups in median time to progression, while more patients in the octreotide group experienced adverse effects such as diarrhea and abdominal pain.

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Table 3. Toxicity of somatostatin and its analogs

[105] Local (at the site of injection) Pain Redness Abscess Systemic Gastrointestinal Nausea Abdominal cramps Diarrhea Steatorrhea Malabsorption of fat Flatulence Cholesterol gallstones Glucose metabolism Reduced glucose tolerance Hyperglycemia Hypoglycemia

route of administration is used, slight pain and redness at the site of injection have been reported. Mild diarrhea, abdominal cramps and malabsorption of fat have also been observed in 5–10% of patients. The severity of these symptoms appears to be dose-dependent and they usually decrease spontaneously. In insulin-dependent diabetics a 10–20% reduction of the daily dose of insulin may be required. However, severe hypoglycemia is not usually observed. Cholesterol gallstone formation has been observed in 20–30% of patients after prolonged treatment, but fortunately they remain asymptomatic in most cases.

Conclusions

The feasibility and the endocrine and antitumor effects of a combination of octreotide (3 ! 0.2 mg s.c.) with tamoxifen (40 mg/day) and an antiprolactin drug (CV 205–502: 75 Ìg/day) was studied by Bontenbal et al. [104]. They randomized 22 metastatic breast cancer patients who were given either 40 mg/ day of tamoxifen or the above-mentioned combination. An objective response was observed in 36% of the patients treated with tamoxifen alone and in 55% of the patients treated with the combination therapy. A significant decrease of plasma IGF-1 levels was observed in both treatment arms. However, the authors reported a more uniform suppression of IGF-1 in the combined treatment.

Toxicity

Treatment with somatostatin or with its analogs is usually well tolerated, the most commonly encountered side effects being listed in table 3 [105]. When the subcutaneous

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Somatostatin analogs are a novel class of compounds that have an established role in the management of patients with neuroendocrine tumors but only a potential role in the treatment of other solid tumors, including breast cancer. In this tumor type in particular, somatostatin analogs showed a limited activity either when used alone or when given in combination with tamoxifen or bromocriptine. Moreover, none of the randomized trials that compared the therapeutic value of the combination of octreotide and tamoxifen versus tamoxifen alone showed any advantage in favor of combined treatment. Therefore, although the great majority of trials failed to show major side effects attributable to somatostatin analogs, there is no place as yet for the use of these compounds outside of controlled trials. However, further studies need to be done in humans on the preclinical evidence of improved efficacy of somatostatin analogs, either when used alone or when given in combination with both tamoxifen and chemotherapeutic agents. Moreover, the fact that an adequate suppression of the GH-

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IGF-1 axis and of lactogenic hormone secretion was also demonstrated in clinical studies, but was not associated with a substantial antitumor activity, suggests that a more appropriate setting, dosing and scheduling should be established for further trials. The limited tumor response observed in clinical studies may have several explanations. The somatostatin receptors, when present in advanced breast tumors, are not homogeneously distributed. Therefore, it can be speculated that only receptor-positive cells could be inhibited in their growth by somatostatin analogs. The majority of patients included in clinical trials with somatostatin analogs had far advanced disease in which somatostatin receptors might be lacking or might be defective in their affinity for somatostatin analogs. In other cases it is possible that the tumors affecting the patients treated with such compounds did not express the receptor specifically capable of binding the analog used. This mechanism is suggested by the lack of a complete cross-resistance among the different analogs in neuroendocrine tumors. Another possible reason for the limited clinical efficacy observed in breast cancer patients treated with somatostatin or somatostatin analogs could be inadequate dosing or scheduling. In fact, the doses employed in animal models were usually higher than those employed in clinical trials. Again the possibility of achieving better symptom control with higher doses or more appropriate scheduling of the same somatostatin analog has been observed in patients affected by neuroendocrine tumors. While an adequate suppression of GH, prolactin and IGF-1 levels has been observed in most of the studies conducted in humans, there is no proof yet that circulating levels of lactogenic hormones and of insulinlike peptides can influence breast cancer growth. Rather the direct inhibitory effect on tumor growth mediated by the binding of

Somatostatin and Breast Cancer

somatostatin analogs to their specific receptors might be more crucial, as suggested by the experiments in vitro using human breast cancer cell lines. There is evidence that the concentrations which are needed at the target cell level can largely exceed those that can be produced by a dose which otherwise can adequately suppress lactogenic hormones and IGF-1-circulating levels. Therefore, although results of clinical trials have been quite discouraging so far, further testing of somatostatin analogs alone or in combination with other antiproliferative drugs, including cytotoxics, is warranted. Patients with tumors displaying neuroendocrine features or those with tumors positive on OctreoScan® might be those best suitable for such new trials, provided that higher doses and more appropriate regimens of somatostatin or its analogs be used within the frame of well-designed and controlled trials.

Acknowledgments The authors thank Mrs. A. Fossati for her skilful assistance.

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84 Weckbecker G, Tolcsvai L, Stolz B, Pollak M, Bruns S: Somatostatin analogue octreotide enhances the anti-neoplastic effects of tamoxifen and ovariectomy on 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas. Cancer Res 1994; 54:6334–6337. 85 Pollak M: Enhancement of the antineoplastic effects of tamoxifen by somatostatin analogues. Digestion 1996;57(suppl 1):29–33. 86 Fidler IJ, Ellis LM: The implication of angiogenesis for the biology and therapy of cancer metastasis. Cell 1994;79:185–188. 87 Rak JA, St Croix BD, Kerbel RS: Consequences of angiogenesis for tumor progression, metastasis and cancer therapy. Anticancer Drugs 1995;6:3–18. 88 Weinstat-Saslow D, Steeg SP: Angiogenesis and colonization in the tumor metastatic process: Basic and applied advances. FASEB J 1994;8: 401–407. 89 Weckbecker G, Raulf F, Tolcsvai L, Bruns C: Potentiation of the antiproliferative effects of anti-cancer drugs by octreotide in vitro and in vivo. Digestion 1996;57(suppl 1): 22–28. 90 Viguerie N, Tahiri-Jouti N, Ayral AM, Cambillau C, Scemama JL, Bastie MJ, Knuhtsen S, Esteve JP, Pradayrol L, Susini C, Vaysse N: Direct inhibitory effects of a somatostatin analog, SMS 201–995, on AR4–2J cell proliferation via pertussis toxin-sensitive guanosine triphosphate-binding protein-independent mechanism. Endocrinology 1989;124:1017–1025. 91 Berembaum MC: What is synergy? Pharmacol Rev 1989;41:93–141. 92 Lee JM, Erlich R, Bruckner HW, Roboz J, Beasley J, Ohnuma T: Octreotide acetate (Sandostatin, SMS) increases in vitro accumulation of doxorubicin (DOX). Proc Am Assoc Cancer Res 1993;34:285. 93 Cascinu S, Fedeli A, Fedeli SL, Catalano G: Octreotide versus loperamide in the treatment of fluorouracil-induced diarrhea: A randomized trial. J Clin Oncol 1993;11:148– 151.

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94 Vennin P, Peyrat JP, Bonneterre J, Louchez MM, Harris AG, Demaille A: Effect of the long-acting somatostatin analog SMS 201–995 (Sandostatin) in advanced breast cancer. Anticancer Res 1989;9:153–156. 95 Manni A, Boucher AE, Demers LM, Harvey HA, Lipton A, Simmonds MA, Bartholomew M: Endocrine effects of combined somatostatin analog and bromocriptine therapy in women with advanced breast cancer. Breast Cancer Res Treat 1989; 14:289–298. 96 Stolfi R, Parisi AM, Natoli C, Iacobelli S: Advanced breast cancer: Response to somatostatin. Anticancer Res 1990;10:203–204. 97 Anderson E, Ferguson JE, Morten H, Shalet SM, Robinson EL, Howell A: Serum immunoreactive and bioactive lactogenic hormones in advanced breast cancer patients treated with bromocriptine and octreotide. Eur J Cancer 1993; 29A:209–217. 98 Canobbio L, Cannata D, Miglietta L, Boccardo F: Somatuline (BIM 23014) and tamoxifen treatment of postmenopausal breast cancer patients: Clinical activity and effect on insulin-like growth factor-I (IGF-I) levels. Anticancer Res 1995;15: 2687–2690.

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99 Di Leo A, Ferrari L, Bajetta E, Bartoli C, Vicario G, Moglia D, Miceli R, Callegari M, Bono A: Biological and clinical evaluation of lanreotide (BIM 23014), a somatostatin analogue, in the treatment of advanced breast cancer. A pilot study by the I.T.M.O. Group. Italian Trials in Medical Oncology. Breast Cancer Res Treat 1995;34:237– 244. 100 O’Byrne KJ, Dobbs N, Propper DJ, Braybrooke JP, Koukourakis MI, Mitchell K, Woodhull J, Talbot DC, Schally AV, Harris AL: Phase II study of RC-160 (vapreotide), an octapeptide analogue of somatostatin, in the treatment of metastatic breast cancer. Br J Cancer 1999;79:1413–1418. 101 Italian Study Group for the Di Bella Multitherapy Trials: Evaluation of an unconventional cancer treatment (the Di Bella multitherapy): Results of phase II trials in Italy. Br J Cancer 1999;318:224–228. 102 Ingle JN, Suman VJ, Kardinal CG, Krook JE, Mailliard JA, Veeder MH, Loprinzi CL, Dalton RJ, Hartmann LC, Conover CA, Pollak M: A randomized trial of tamoxifen alone or combined with octreotide in the treatment of women with metastatic breast carcinoma. Cancer 1999;85:1284– 1292.

103 Bajetta E, Sommer H, Guastalla J, Szakoiczai I, Baltali E, Pinter T, Csepreghy M, Ottestad L, Boni C, Bryce C, Klijo J, Kiese B, Mietlowski W, Bone A, Kay A: Phase 3 trial of octreotide pamoate (OP LAR) and tamoxifen versus placebo and tamoxifen in metastatic breast cancer. Proc ASCO 1999; 18:110a. 104 Bontenbal M, Foekens JA, Lamberts SWJ, de Jong FH, van Putten WLJ, Braun HJ, Burghouts JTM, van der Linden GHM, Klijn JGM: Feasibility, andocrine and antitumour effects of a triple endocrine therapy with tamoxifen, a somatostatin anlogue and an prolactin lowering drug in postmenopausal metastatic breast cancer: A randomized study with long-term follow-up. Br J Cancer 1998;77: 115–122. 105 Lamberts SWJ, Van der Lely AJ, De Herder WW, Hofland LJ: Octreotide. N Engl J Med 1996;334: 246–254.

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Somatostatin, Its Receptors and Analogs, in Lung Cancer Kenneth J. O’Byrne a Andrew V. Schally b Ann Thomas a Desmond N. Carney c William P. Steward a a University

Department of Oncology, Leicester Royal Infirmary, UK; b Endocrine, Polypeptide and Cancer Institute, Tulane University Medical School and Veterans Affairs Medical Centre, New Orleans, La., USA; c Department of Medical Oncology, Mater Misericordiae Hospital, Dublin, Ireland

Key Words Somatostatin W Receptor W Lung cancer W [111In]pentetreotide W Chemotherapy

Abstract Despite developments in diagnosis and treatment, lung cancer is the commonest cause of cancer death in Europe and North America. Due to increasing cigarette consumption, the incidence of the disease and resultant mortality is rising dramatically in women. Novel approaches to the management of lung cancer are urgently required. Somatostatin is a tetradecapeptide first identified in the pituitary and subsequently throughout the body particularly in neuroendocrine cells of the pancreas and gastrointestinal tract and the nervous system. The peptide has numerous functions including inhibition of hormone release, immunomodulation and neurotransmission and is an endogenous inhibitor of cell proliferation and angiogenesis. Somatostatin and its analogs, including octreotide

(SMS 201–995), somatuline (BIM 23014) and vapreotide (RC-160), act by binding to specific somatostatin receptors (SSTR) of which there are 5 principal subtypes, SSTR-1–5. Although elevated plasma somatostatin levels may be detected in 14–15% of patients, tumor cell expression appears rare. SSTR may be expressed by lung tumors, particularly small cell lung cancer and bronchial carcinoid disease. [111In]pentetreotide scintigraphy may have a role to play in the localization and staging of lung cancers both before and following treatment, and in detecting relapsed disease. The potential role of radiolabelled somatostatin analogs as radiotherapeutic agents in the management of lung cancer is currently being explored. Somatostatin analog therapy results in significant growth inhibition of both SSTR-positive and SSTR-negative lung tumors in vivo. Recent work indicates that these agents may enhance the efficacy of chemotherapeutic agents in the treatment of solid tumors including lung cancer. Copyright © 2001 S. Karger AG, Basel

ABC

© 2001 S. Karger AG, Basel 0009–3157/01/0478–0078$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/che

K.J. O’Byrne University Department of Oncology, Leicester Royal Infirmary Leicester LE1 5WW (UK) Tel. +44 116 258 7602 E-Mail [email protected]

Introduction

At the turn of the century lung cancer was an extremely rare tumor. Since then its incidence has increased to such an extent that it is now the commonest cause of cancer death in Europe and North America. This dramatic change is largely attributable to cigarette smoking which is responsible for over 80% of all cases. A reduction in cigarette smoking in developed countries is beginning to produce an age-adjusted decrease in the incidence of lung cancer in men. However, smoking rates and the incidence of lung cancer are rising rapidly in women. The disease has now surpassed breast cancer as the commonest cause of cancer death in women. Of great concern is the fact that the peak of the lung cancer epidemic in women has not yet been reached [1, 2]. Despite improvements in the diagnostic, surgical, chemotherapeutic and radiotherapy management of lung cancer the overall results of treatment are poor. The 5-year survival rate for small cell lung cancer is approximately 3%, and for non-small cell lung cancer 8– 14%. Novel approaches to management are urgently required. The growth in our understanding of the molecular biology of lung cancer is leading to the development of new approaches to the treatment of this group of diseases including the use of growth factor antagonists, growth factor receptor antibodies and antiangiogenic agents [3–7].

Somatostatin

Somatostatin is a tetradecapeptide hormone first identified in the hypothalamus as an inhibitor of growth hormone release. The peptide has subsequently been found throughout the body, particularly in the pancreas, gastrointestinal tract and nervous system. Somatostatin inhibits the release of growth hor-

Somatostatin, Its Receptors and Analogs, in Lung Cancer

mone and thyroid-stimulating hormone from the anterior pituitary and hormone release from the pancreas and gastrointestinal tract. Somatostatin also functions as a neurotransmitter, immunomodulator and suppressor of angiogenesis and cell proliferation [8–14]. It acts by binding to specific receptors (SSTR) of which 5 principal subtypes have been identified: SSTR-1, SSTR-2, SSTR-3, SSTR-4 and SSTR-5 [15].

Growth Inhibitory Effects of Somatostatin and Somatostatin Analogs

Through the activation of SSTR, somatostatin and its analogs exert a number of direct growth inhibitory effects on normal and malignant cells. All 5 SSTR are functionally coupled to adenylyl cyclase. Activation of SSTR results in inhibition of the intracellular accumulation of cyclic adenosine monophosphate (cAMP). This may result in direct inhibition of the growth of cells in which accumulation of cAMP, and subsequent activation of the protein kinase A pathway, results in proliferation [14–16]. This is supported by observations in the SSTR-2-positive human pancreatic cancer cell line CFPAC-1 where in vitro growth inhibition by the octapeptide somatostatin analog RC-160 is associated with inhibition of cAMP accumulation [17]. Acting through SSTR-5, the somatostatin analog RC-160 has been demonstrated to suppress the proliferative effects of cholecystokinin on CHO cells by inhibiting the accumulation of cyclic guanosine monophosphate (cGMP) [18]. On binding to their extracellular receptor domains, many growth factors induce intracellular receptor tyrosine kinase activity. Likewise a number of oncogene products are truncated growth factor receptors, lacking an extracellular domain but having permanent

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Table 1. Antiproliferative activity of somatostatin

Direct effects Activation of phosphatase activity Inhibition of cAMP accumulation Inhibition of cGMP accumulation Inhibition of the mobilization of intracellular calcium through 1 Inhibition of cell membrane calcium channels 2 Interaction with phospholipase C and inositol/ phospholipid growth pathways Induction of programmed cell death (apoptosis) Indirect effects Inhibition of the release of trophic factors from elsewhere, e.g. EGF and IGF-1 Inhibition of angiogenesis Inhibition of cancer cell adhesion

endogenous intracellular tyrosine kinase activity. This activity results in phosphorylation of a number of tyrosine residues on the intracellular portion of the receptor. The phosphorylated tyrosine residues interact with guanine nucleotide-binding proteins and subsequently ras, inducing a phosphorylation cascade which activates transcription factors and ultimately results in cell proliferation [19]. Somatostatin stimulates the activity of phosphatases including phosphotyrosine phosphatases which have been demonstrated to dephosphorylate the tyrosine residues of activated type 1 growth factor receptors, such as the epidermal growth factor receptor (EGFR) [10, 11, 14, 20, 21]. Further evidence for activation of intracellular phosphatases comes from studies which have demonstrated that somatostatin analogs can inhibit insulinlike growth factor-1 (IGF-1) and serum-stimulated MAP kinase activation in vitro [22]. Activation of phosphatases is associated with inhibition of the proliferation of SSTR-positive normal and cancer cells in vitro [6, 10, 14, 20–22]. The activation of phosphotyrosine phosphatases is mediated through SSTR-1

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and SSTR-2 [10]. Somatostatin and somatostatin analogs also inhibit the accumulation of intracellular calcium from both extracellular and intracellular sources [11, 23]. Somatostatin analogs have been shown to inhibit the growth of SSTR-negative tumors in vivo demonstrating important indirect antiproliferative effects. Many tumors express IGF-1 receptors (R) and proliferate in response to exposure to IGF-1 [24, 25]. Therefore blocking the release of growth factors from normal and malignant tissues may inhibit autocrine-, paracrine- and endocrineinduced cancer cell proliferation [14]. Through the inhibition of the protein kinase A pathway, somatostatin and its analogs may not only modulate cell growth but also suppress the synthesis and release of hormones and trophic growth factors, including growth hormone and IGF-, from normal tissues [13, 14]. In keeping with these findings the growth inhibitory effects of RC-160 in SSTR-negative tumors are associated with a decrease in serum growth hormone (GH) and IGF-1 levels. Furthermore, the growth inhibition is associated with suppression of tumor cell IGF1R expression [14, 26–28]. Somatostatin analogs are also potent antiangiogenic agents having direct growth inhibitory effects on proliferating endothelial cells [12]. As angiogenesis is essential for the growth of a tumor greater than 1–2 mm in diameter, interference with this process may result in the inhibition of cancer growth [29]. Somatostatin also reduces the capacity of malignant cells to adhere to blood vessel walls thereby reducing the metastatic potential of malignant tumors [30]. In keeping with both the direct and indirect antiproliferative growth inhibitory effects described, somatostatin and its analogs have been shown to induce tumor cell apoptosis both in vitro and in vivo (table 1) [13, 14].

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Somatostatin Expression in Lung Cancer

Small cell lung cancer (SCLC) accounts for approximately 20% of all lung tumors. SCLC is a neuroendocrine tumor characterized by the expression of pan-neuroendocrine markers including neuron-specific enolase (NSE), creatine kinase BB and chromogranin, and specific hormones and their receptors including bombesin (GRP) and IGF-1 [5, 13, 25, 31]. Many of these substances may be elevated in the serum and/or plasma of patients with SCLC at presentation and, particularly in the case of NSE, may be of value as tumor markers, the levels falling if the disease responds to chemotherapy and rising if the disease progresses or relapses [13, 32, 33]. A number of studies have suggested that SCLC may synthesize and secrete somatostatin. The detection of elevated serum somatostatin-like immunoreactivity in lung cancer patients was first reported in 1980 [34]. Subsequent investigations revealed elevated somatostatin serum levels in 4 of 26 (15%) [35] and 3 of 21 (14%) patients [36] with SCLC compared to controls. Immunoreactive tissue somatostatin has been detected in 5 of 9 [35] and 2 of 6 SCLC tumor sample extracts [37]. Somatostatin has also been detected in 1 of 13 culture media of SCLC cell lines [38] and extracted from 5 of 13 cell lines [39]. Finally Chretien and coworkers [40] reported immunohistochemically detectable somatostatin in 75% of cytology-positive bronchial brushing smear samples obtained from 24 SCLC patients. They concluded that the presence of somatostatin immunoreactivity, along with other features, was highly suggestive of SCLC. However, some studies either failed to detect, or have shown a very low incidence of somatostatin-like immunoreactivity in SCLC tumor samples. In 2 studies employing indirect immunoperoxidase tech-

Somatostatin, Its Receptors and Analogs, in Lung Cancer

niques only 1 of 94 [41] and 1 of 10 [42] paraffin-embedded SCLC samples were found to express somatostatin. Furthermore, in a recent study of cryostat sections from 4 SCLC tumors, in situ hybridization failed to detect evidence of somatostatin mRNA expression [43]. The significance of somatostatin expression in SCLC has not been addressed in these studies. We evaluated somatostatin immunoreactivity in plasma samples and tissue sections of biopsy and surgically resected paraffin-embedded tumor specimens of patients with SCLC. Elevated fasting plasma somatostatin levels were seen in 6/44 (13.6%) of the patients studied. Elevated somatostatin levels were also seen in 2 SCLC patients who had associated diabetes mellitus, 1 insulin-dependent and the other non-insulin-dependent. Diabetes mellitus is associated with elevated fasting somatostatin levels [44, 45]. The degree of elevation in the serum levels was similar in both the diabetic and nondiabetic SCLC patients. This observation raises the possibility that elevated somatostatin levels in SCLC patients may be secondary to the release of other hormones/peptides released by, or because of, the tumor rather than being ectopic in nature. This contention is supported by the fact that we were unable to detect definite somatostatin immunoreactivity in tissue sections from paraffin-embedded tumor samples from 163 patients with SCLC using streptavidin-biotin immunohistochemistry (unpubl. data). Further evidence to support the argument that the elevated somatostatin plasma levels are often not ectopic in nature comes from the finding of a close association between somatostatin and calcitonin gene-related peptide (CGRP) expression in the SCLC patients in our study (p = 0.019; unpubl. data). Recent work has shown that CGRP and somatostatin modulate chronic hypoxic pulmonary hyper-

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tension. In in vivo experiments evaluating the role of CGRP in the regulation of pulmonary arterial pressure, infusion of this peptide into the pulmonary circulation of hypobaric hypoxic rats not only prevents pulmonary hypertension but also results in an increase in lung plasma somatostatin. Under these circumstances somatostatin has been shown to inhibit CGRP release [46]. Chronic hypoxic pulmonary hypertension may occur in patients with lung cancer and may explain, in part, the elevated CGRP and, as a result, somatostatin plasma levels observed in the SCLC patients [47]. Recent work has shown that a proportion of non-SCLC (NSCLC) tumors may also express pan-neuroendocrine markers including NSE and chromogranin and specific peptide hormones including calcitonin, CGRP and GRP [48–50]. The immunohistochemical expression of 2 or more neuroendocrine markers within a tumor and elevated serum NSE levels are observed in approximately 20% of patients with NSCLC and appear to define a subgroup of patients whose disease is more responsive to cytotoxic chemotherapy than neuroendocrine marker-negative disease [48, 51, 52]. The immunohistochemical detection or extraction of somatostatin from NSCLC tumor tissue samples has been described in a number of small studies [42, 53, 54]. In their study of NSCLC tumors which had been found to contain dense-core granules (a marker of neuroendocrine differentiation) by electron microscopy, Wilson et al. [42] detected somatostatin immunoreactivity in all 7 cases. All had associated expression of NSE, human chorionic gonadotropin, serotonin and keratin. Somatostatin expression has also been described in a range of atypical pulmonary tumors including an adenocarcinoma with endometrioid features [55], an adenocarcinoma resembling fetal lung [56], a chondroma [57] and a blastoma [58]. We have evaluated a

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number of endocrine markers in serum and plasma and paraffin-embedded tissue sections of patients with NSCLC. Although elevated serum NSE levels were seen in 7/25 (28%) patients, somatostatin immunoreactivity was absent in all plasma and paraffinembedded tissue sections examined (unpubl. data). Bronchial carcinoids are likewise neuroendocrine tumors and express both pan-neuroendocrine markers and specific hormones, including GRP, gastrin, glucagon, calcitonin and adrenocorticotropin (ACTH) [59, 60]. In a recent study of 57 carcinoid tumors, somatostatin immunoreactivity was detectable in 43% of 30 typical and 22% of 27 atypical tumors [59]. The balance of evidence of the aforementioned findings suggests that somatostatin expression in SCLC and NSCLC is rare. Elevated plasma/serum levels may, in many instances, be a secondary response to the disease and other ectopic hormones produced by these tumors rather than as a result of ectopic production of the hormone from the tumor itself. This suggestion is supported by the close correlation between elevated somatostatin and CGRP levels observed in SCLC patients.

Somatostatin Receptor (SSTR) Expression in Lung Cancer

The presence of SSTR on normal and malignant tumor cells has been the subject of considerable research since the early part of the last decade. SSTR are expressed by tumors derived from tissues known to be targets for somatostatin including somatotroph, thyrotroph and endocrine-inactive pituitary adenomas, central nervous system tumors including meningiomas, astrocytomas, oligodendrogliomas and medulloblastomas, gastrointesti-

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nal tract and pancreatic neuroendocrine (GEP) tumors, medullary thyroid carcinoma, and malignancies of the reticuloendothelial system including both Hodgkin’s and nonHodgkin’s lymphomas. SSTR have also been detected on a proportion of breast, renal, prostatic, ovarian, exocrine pancreatic and colorectal carcinomas and osteosarcomas [13, 14, 61, 62]. SCLC SSTR Expression The presence of SSTR on lung tumors was first demonstrated by Taylor et al. [63] in 1988 when they characterized the in vitro binding of [125I-Tyr11]somatostatin-14 to membranes prepared from cultured human SCLC tumor cells derived from the classical SCLC cell line NCI-H69. Binding was monophasic and of high affinity with an equilibrium dissociation constant (Kd) = 0.59 B 0.02 nM. The estimated maximum binding capacity (Bmax) was 173 B 2.4 fmol/mg protein. Specific binding sites were also detected on membrane preparations from solid NCIH69 xenografts grown in athymic nude mice. However, while the calculated equilibrium Kd was similar, the Bmax was only about 10% of that observed in cell culture. The binding was specific in that biologically active analogs of somatostatin were potent inhibitors of [125ITyr11]somatostatin-14 binding whilst biologically inactive somatostatin analogs and unrelated compounds such as bombesin and gastrin-17 were not. In subsequent experiments crude membrane preparations from xenografts of 2 other classic SCLC cell lines NCI-H345 and NCIH209 were reported to express high-affinity SSTR. However, SSTR expression was not observed in the variant SCLC cell line NCIH417 or the poorly differentiated solid SCLC tumor LX-1 [64, 65]. In vitro autoradiographic techniques have also been employed to study SSTR expression in SCLC tumor speci-

Somatostatin, Its Receptors and Analogs, in Lung Cancer

mens derived from cell lines and patients. SSTR have been demonstrated on fresh tumor specimens in 2 of 4 and 2 of 3 SCLC samples [66, 67]. The binding characteristics for somatostatin were characterized in 1 of the 2 SSTR-positive SCLC specimens in the study of Reubi et al. [66]. Specific high-affinity (Kd = 0.53 nM), low-capacity (Bmax = 189 fmol/mg protein) binding sites were detected, results consistent with the previous studies in cell lines. Macaulay et al. [68] demonstrated specific SSTR on 3 of 4 SCLC cell line xenografts. Strong expression was detected in SCLC tumors derived from the SCLC cell line NCI-H69 while weak, patchy expression was observed on tumors from the classic cell line HXI49 and the variant cell line ICR-SC17. Xenografts from the classic cell line HC12 were SSTR-negative. We evaluated the specific binding of radiolabelled RC-160 on membrane preparations from 9 SCLC cell lines. Specific binding sites for the octapeptide somatostatin analog were demonstrated on 6 of the 9 cell lines investigated (67%). Scatchard analysis of the displacement curve of the cell line NCI-H69 revealed evidence of 2 specific binding sites, 1 of high affinity and low capacity and the other of low affinity and high capacity [69]. The high-affinity binding site was in keeping with previous studies. The precise nature of the second binding site in our study was uncertain. As RC-160 binds with high affinity to SSTR-2 and SSTR-5, moderate affinity to SSTR-3 and low affinity to SSTR-1 and SSTR-4 [15], the results suggested that the high-affinity binding site represented SSTR-2 or SSTR-5 while the low-affinity site represented SSTR-1 or SSTR4 or, indeed, nonspecific protein binding. Evaluation of SSTR subtype expression by RT-PCR has confirmed that SCLC tumors may express more than one SSTR subtype. In the first reported study, the classic SCLC cell lines NCI-H69 and NCI-H345 were found to express SSTR-1 and SSTR-2 mRNA [70].

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This is entirely in keeping with the RC-160 results presented here. A further study analyzed the binding activity of [125I]somatuline and [125I-Tyr11]somatostatin-14 to crude homogenates of tumor xenografts from 3 SCLC cell lines, SCLC-6, SCLC-10 and SCLC-75. Employing cross-linking techniques 3 receptor proteins were identified. One major complex of 57 kD was bound by both radioligands in all 3 tumors. Two other minor complexes were only identified by the natural ligand [125ITyr11]somatostatin-14, 90 kD in all 3 tumors and 70 kD in 2 tumors. Subsequent analysis revealed the presence of SSTR-1 mRNA in all 3 tumors while SSTR-2 mRNA expression was observed in only 2. No SSTR-3 transcript was detected [71]. Finally RT-PCR analysis of the cell line COR-L103 revealed mRNA transcripts for SSTR-2, SSTR-3 and SSTR-4. Extra bands were obtained by PCR-single strand conformation polymorphism analysis of the SSTR-2 gene. Sequence analysis of the SSTR-2 gene demonstrated a point mutation in codon 188 of TGG for tryptophan to TGA for a stop codon causing loss of 182 C-terminal amino residues of the receptor. The nucleotide sequences of SSTR-3 and SSTR-4 were normal. Using the radiolabelled somatostatin analog [125I-Tyr11]somatostatin-14, affinity crosslinking studies revealed a lack of expression of a 72-kD protein compared to the pituitary cell line AtT-20, indicating that SSTR-2 is not expressed on cell membranes of COR-L103 cells due to this point mutation [72]. Regarding SSTR-2 expression in SCLC, Taylor et al. [73] also detected an mRNA transcript in NCI-H69 corresponding to a truncated isoform of SSTR-2. This was felt likely to represent a human homolog of the rodent receptor SSTR-2B. Immunoblotting analysis using the SSTR-2-specific antibody, 2e3, detected multiple immunoreactive protein species, including a predominant 150-kD molecule. The SSTR-2 identity was confirmed by blocking detection

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of the predominant 150-kD band by addition of the SSTR-2-derived 2e3 peptide. SSTR-2 mRNA expression has also been identified in resected, snap-frozen, SCLC tumor specimens through in situ hybridization [74]. In an RT-PCR study Fujita et al. [75] analyzed SSTR-1 and SSTR-2 expression in 9 SCLC cell lines, including 5 classic and 4 morphologically variant cell lines. Both receptor subtypes were detectable in all SCLC cell lines. Collectively these results indicate that SSTR are present in between 50 and 100%, and specific high-affinity binding sites for radiolabelled somatostatin analogs in 50–75% of SCLC tumor samples studied. NSCLC SSTR Expression In contrast to SCLC, initial studies suggested that NSCLC tumors do not express SSTR. Using autoradiography, no specific binding of the radiolabelled somatostatin analogs [125I-Tyr3]octreotide or [125I-Leu8, D-Trp22, Tyr125]somatostatin-28 was observed on cell pellets of the NSCLC tumors NCI-H23 or NCI-H226 [68], while only barely detectable levels of specific [125I-Tyr11]somatostatin-14 binding were detected in membrane preparations of the NSCLC cell line H-165 [64]. Similarly in 2 studies in 1990, SSTR were not detected in 17 NSCLC fresh-frozen tumor samples using autoradiography [66, 67]. Using the radiolabelled somatostatin analog [125I-Tyr11]somatostatin-14, we were unable to detect specific somatostatin binding sites on membrane preparations from xenografts of the adenocarcinoma NSCLC cell line NCI-H157 [26]. The results were in accord with the findings of previous NSCLC tumor sample studies [64–67]. However, we did detect a single class of specific binding sites for [125I]RC-160 in each of 3 NSCLC tumor samples [69]. All 3 were squamous cell tumors. The tissues examined were composed of a number of cell types including tumor

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cells, stroma, inflammatory cells and necrotic tissue. This observation raised the possibility that the NSCLC cells themselves were not expressing SSTR and that [125I]RC-160 was binding specifically to inflammatory cells within the tumor which are known to express SSTR [62]. Two recent studies support the suggestion that the [125I]RC-160 may bind specifically to NSCLC cancer cells. Employing RT-PCR, Fujita et al. [75] demonstrated SSTR-1 and SSTR-2 expression in a panel of squamous cell and adenocarcinoma NSCLC cell lines. The relative levels of SSTR-1 expression in the squamous cell tumors were similar to those seen in SCLC cell lines and were higher than those in adenocarcinomas. Indeed, in 2 of the 5 adenocarcinomas examined, expression of SSTR-1 mRNA was very weak. Unlike SCLC, there was a positive correlation between SSTR-1 and SSTR-2 subtypes in the NSCLC tumor cell lines. In another study specific somatostatin binding sites for the radiolabelled hexapeptide somatostatin analog [125I]MK-678 were found in 2 NSCLC cell lines, A 549 and H-165 [73]. This finding is of particular interest as previous studies with H165 had shown this cell line to have only barely detectable levels of specific [125I-Tyr11]somatostatin-14 binding [64]. As with the octapeptide somatostatin analog RC-160, MK678 binds with high affinity to SSTR-2. Subsequent RT-PCR confirmed SSTR-2 mRNA expression within both NSCLC tumors [73]. We have also evaluated somatostatin analog binding to bronchial carcinoid tissue [69]. A single class of high-affinity binding site for [1251]RC-160 was detected in the membrane preparations of both tumors assessed. These findings were not unexpected given that SSTR expression is common to similar tumors in the gastrointestinal tract [61, 76]. In summary, the available evidence indicates that the majority of SCLC tumors and

bronchial carcinoids express specific SSTR with high affinity for both hexa- and octapeptide somatostatin analogs. Although some controversy remains, recent results also indicate that a significant proportion of NSCLC tumors are SSTR-positive, SSTR-1 and SSTR-2 mRNA having been detected in both squamous and adenocarcinomas.

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Radiolabelled Somatostatin Analog Imaging in Lung Cancer: Therapeutic Implications

In 1989, Krenning et al. [77] reported the use of the radiolabelled somatostatin analog [123I-Tyr3]octreotide for the detection and localization of SSTR-positive tumors through scintigraphic imaging techniques. This agent was successfully applied in patients to visualize neuroendocrine GEP tumors, meningiomas and paragangliomas. Subsequent work led to the development of [111In]pentreotide which is easier to make up, remains longer in the circulation and has a longer imaging halflife and reduced hepatobiliary metabolism than the former agent improving the quality of the images obtained, particularly in the liver. The effectiveness of [111In]pentreotide has been established in the management of GEP tumors including carcinoid. The radiolabel often localizes primary GEP tumors that are undetectable by other methods including abdominal ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI), arteriography and venous sampling. [111In]pentreotide may also detect otherwise unsuspected metastatic deposits. The localization of both the primary and metastatic deposits using a single technique contributes to the patient’s comfort and convenience and may lead to changes in patient management in a significant proportion of cases [61]. [111In]pentreotide scintigraphy

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is of proven value in predicting the responsiveness of hormone-associated conditions, arising as a result of GEP tumors, to octreotide therapy [78]. SCLC [111In]Pentetreotide Imaging SCLC remains a disease with a poor prognosis despite being sensitive to both chemotherapy and radiotherapy. SCLC patients are staged as having either limited or extensive disease. Limited disease, corresponding to stage I to IIIB disease in the TNM classification, is confined to a hemithorax including the mediastinum and the ipsilateral and contralateral hilar and scalene lymph nodes. Consolidation radiotherapy to the primary tumor site and mediastinum may improve long-term survival in patients with limited stage disease who have a good partial or complete response to chemotherapy. The median survival for patients with limited disease is approximately 15 months and 7–20% survive for 5 years or more. Extensive stage SCLC refers to the spread of the tumor beyond these boundaries and includes patients with IIIB disease with an associated malignant pleural effusion. In patients with extensive disease the median survival is approximately 9–12 months with few long-term survivors. Therefore, stage has a significant impact on prognosis and, in some cases, on the management of patients [3, 79]. In keeping with the demonstration of SSTR in SCLC tumors, disease sites were visualized in 5 of 8 patients using [123ITyr3]octreotide [80]. On the basis of these observations we carried out a study to evaluate the efficacy of [111In]pentetreotide scintigraphy as a staging modality in SCLC patients prior to chemotherapy and in the assessment of disease response after treatment. Thirteen patients with newly diagnosed SCLC were studied prior to receiving chemotherapy. Following standard staging investiga-

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tions, 6 patients were found to have limited disease, and 7 extensive disease. Of the 7 patients with extensive disease, liver metastases were seen in 4, bony metastases in 4, a single large brain metastasis in 1 and an adrenal metastasis in 1. Scintigraphic imaging with [111In]pentetreotide led to the detection of all primary sites of disease. This included a patient whose primary tumor, detected at bronchoscopy, was not visualized with chest x-ray (CXR) or CT of the thorax. In the 7 patients with extensive disease metastatic disease was detected in 3 out of 4, and skeletal disease in 2 out of 4 patients. In 1 patient a previously undetected cerebellar metastasis was found, not suspected following routine staging. This was later confirmed with a CT brain scan. Therefore the imaging procedure correctly staged 9 out of 13 patients (69%), detecting 5 out of 10 known metastases and 1 previously unknown disease site (56%). Disease was downstaged in 4 out of 7 patients with extensive disease and upstaged in 1 patient with limited disease. In summary, [111In]pentetreotide detected secondaries in 4 or 50% of the 8 patients found to have metastases at the completion of all investigations [81]. We subsequently assessed a further 10 patients with SCLC. Eight of these were evaluated during chemotherapy. [111In]pentetreotide failed to localize the primary tumor in 1 patient and detected metastases in only 1 of 6 patients with extensive disease. Of the remaining 2 patients 1 was imaged at the time of disease relapse. The patient had extensive disease. All known tumor sites were localized. The other patient was imaged for what was thought to be NSCLC. Both standard and [111In]pentetreotide imaging indicated resectable disease. Histological evaluation of the resected specimen following surgery revealed a limited stage SCLC tumor (table 2) [82].

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Four patients imaged prior to treatment, 2 with limited disease and 2 with extensive disease, were reevaluated with [111In]pentetreotide. A further patient with extensive disease who was imaged with [111In]pentetreotide after completion of his first cycle of chemotherapy was also assessed after completion of treatment. Pathological uptake of the radiolabel was detected in the region of the original disease in 2 patients thought to be in complete remission following standard staging procedures. In 1 of these patients a subsequent MRI study demonstrated an abnormality away from the bronchus suggestive of residual disease. The patient subsequently relapsed at this site. Therefore the technique may allow a more accurate assessment of prognosis for the individual patient following completion of chemotherapy and aid subsequent management decisions [81]. Single photon emission computed tomography (SPET) imaging was performed in 9 patients and improved the anatomical localisation of disease in the thorax but contributed little to the overall assessment. The failure of [111In]pentreotide scintigraphy to visualize all disease sites in 9 of the 15 patients (60%) with metastases outside the thorax, despite detecting the primary tumor in 14 of these cases, is unclear. Nonspecific uptake of the radiolabel seen in the spleen, kidneys and urinary tract, liver and gastrointestinal tract, pituitary and thyroid gland may obscure visualization of metastases to these areas. However, the lack of uptake of radiolabel by bone and brain deposits cannot be explained in this way. This raises a number of possibilities. In a proportion of cases the metastatic disease may represent a dedifferentiated clone of the primary SCLC tumor not expressing SSTR. In individual cases local factors may downregulate SSTR expression. Furthermore, binding of the radioligand to the receptor may be blocked if high local lev-

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Table 2. Summary of results of SCLC patient imaging

studies (n = 23) Sites of disease

Primary Liver Adrenal Bone Brain

Number of disease sites detected standard staging

[111In]pentetreotide imaging

22 10 1 6 1

22a 5 0 3 1b

a

[111In]pentetreotide imaging detected an intrathoracic primary SCLC not seen on CXR or CT scan of the thorax. b An otherwise unsuspected cerebellar metastasis. On completion of the study metastases were not visualized in 9 out of 15 patients with proven metastatic disease. [111In]pentetreotide imaging failed to detect any site of disease in one patient with extensive SCLC.

els of endogenous somatostatin are being produced. Furthermore, in those patients imaged while receiving chemotherapy the primary tumor was seen in 7 of 8 patients but metastases were detected in only 1 of 6 patients with metastatic disease. This observation suggests that the chemotherapy itself may affect uptake of the radiolabel. This suggestion is supported by the results of a recent study in which the uptake of [111In]pentetreotide by primary SCLC tumors was significantly lower in patients imaged during chemotherapy compared to those evaluated before treatment (tumor to background ratios = 1.94 B 0.79 vs. 2.35 B 0.9; p ! 0.005) [83]. In image-negative metastatic disease the SCLC cells themselves may not be expressing SSTR-2 or SSTR-5, the subtypes known to bind octreotide with high affinity. Rather it may be that the primary tumor is being visualized due to uptake of the radiolabel by the local

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inflammatory response, as activated immune cells are known to express SSTR [62] and/or by SSTR expressed in high concentrations on peritumoral blood vessels [12, 84]. If this is so, then those tumors where the metastases are seen may represent the true proportion of metastatic SCLC tumors which express highaffinity binding sites for radiolabelled somatostatin analogs – 6 of 15 (40%) patients with extensive disease evaluated in this study. This would be in keeping with the proportion of SCLC tumors known to express specific high-affinity binding sites for radiolabelled somatostatin analogs in vitro as discussed earlier. The effectiveness of [111In]pentetreotide scintigraphy in the detection and localization of disease sites in SCLC patients has been evaluated and verified in a number of studies [83, 85–94]. Pretreatment of SCLC patients with cold somatostatin prior to administration of [111In]pentetreotide may enhance the visualization of metastases through increased uptake of the radiolabel by the tumor [91, 95]. However, the lack of visualization of all sites of disease indicates that the imaging technique has limited value as a single modality in the staging of SCLC prior to commencing chemotherapy. Nonetheless a recent cost-effectiveness analysis indicated that [111In]pentetreotide scintigraphy should be performed in patients with SCLC as it may alter the staging of the disease and localize otherwise undetected brain metastases. Under these circumstances the cost increase is outweighed by changes in patient management and the possibility of irradiating brain metastases at an early stage which may ultimately lead to improvements in symptom control [94]. Novel approaches to therapy in SCLC are currently being assessed and include inhibiting the action of autocrine growth factors such as GRP with GRP antagonists and GRP

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receptor antibodies [5]. Somatostatin analogs are currently being evaluated as possible therapeutic agents in SCLC with encouraging results in vitro and in vivo. In acromegaly and GEP tumors, the presence of SSTR has been shown to predict responsiveness to somatostatin analog therapy [78, 96, 97]. Imaging of SCLC tumors with [111In]pentetreotide may have a role to play in identifying those patients most likely to respond to somatostatin analog treatment. Of great significance in this respect is the efficacy of the radiolabel in detecting residual SCLC disease following chemotherapy, and relapsing disease, observations which suggest that treated SCLC tumors continue to express SSTR. This lays the groundwork for evaluation of somatostatin analogs as therapeutic agents in the treatment of chemotherapeutically debulked or relapsing SCLC in the future. NSCLC [111In]Pentetreotide Imaging In NSCLC the most important decisions to reach are whether the patient has resectable disease and, if so, is fit for surgery. If a patient is being considered for surgery extensive investigations are recommended including a full blood count, biochemistry profile, CXR and CT thorax, liver and adrenals. If mediastinal lymph nodes greater than 1.5 cm in the shortest transverse diameter are seen on the CT scan, mediastinoscopy and/or mediastinotomy should be performed to exclude inoperable disease prior to definitive surgery. Any symptoms the patient has which may be attributable to metastatic disease should be thoroughly investigated, e.g. an isotope bone scan for bone pain and a CT brain scan to assess headaches. Recent evidence suggests that stage III disease in patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 and possibly 2 may benefit from chemotherapy followed by radical radiotherapy. Furthermore, while still

O’Byrne/Schally/Thomas/Carney/ Steward

Fig. 1. Anterior and posterior views of the thorax and upper abdomen of 2 patients with NSCLC. A A stage IIIB tumor with abnormal uptake of [111In]pentetreotide throughout the right lung and mediastinum confirmed both radiologically and at surgery is clearly demonstrated. B Increased uptake in the right upper lobe consistent with a Pancoast tumor confirmed with CT imaging is shown.

largely investigational, there is accumulating evidence that preoperative, neoadjuvant chemotherapy may downstage the disease in a proportion of patients with stage IIIA, N2 disease making resection possible. These patients likewise require intensive staging to exclude disseminated disease. If the disease is inoperable due to the patient’s health and radical radiotherapy is not deemed appro-

priate, or if stage IV disease is established, then staging investigations may be kept to a minimum [4, 98]. We studied [111In]pentetreotide scintigraphy in 23 patients with NSCLC prior to treatment. The primary tumor was detected in all cases (fig. 1). Furthermore, the resectibility of the disease was correctly established in 20 cases. The value of the technique was best

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exemplified in 2 patients. In the first disease spread was seen with [111In]pentetreotide imaging which was not initially suspected. In the second patient a small primary squamous cell cancer found at bronchoscopy, but not visualized on CXR or CT thorax and upper abdomen, was localized. Of the 3 patients incorrectly staged, 2 were as the result of falsepositive uptake in benign lesions in the mediastinum, in a thyroid colloid cyst associated with intense lymphocytic infiltration in one case and in granulomatous lymph nodes in the other. These findings are readily explained by the fact that specific high-affinity SSTR may be expressed by immune cells, including those present in granulomas [61, 62]. In a third patient, mediastinal involvement and a malignant pleural effusion were missed. In a further patient the tumor, thought to be T2, N0/N1 disease, turned out on CT of the thorax and upper abdomen and at surgery to extend to and involve the chest wall pleura indicating T3 disease. As with CT scanning, it is difficult to distinguish between tumor and postobstructive atelectasis or consolidation as inflammatory cells may express high-affinity SSTR. Nonetheless, this did not affect staging of disease in our patient series (unpubl. data). [111In]pentetreotide SPET imaging was performed in 16 of the 23 NSCLC patients. Unlike SCLC, SPET imaging significantly affected staging in a number of cases by improving anatomical localization of the disease, indicating, in particular, spread of disease to the pleura/chest wall (unpubl. data). Although these results are encouraging, they also demonstrate some of the potential limitations of the technique. While the radiolabel is specific for SSTR-expressing tissues, it is not specific for individual pathological processes as demonstrated by the detection of benign disease in the mediastinum in 2 patients in this series. Likewise it is well established that not all tumors of a particular

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pathological subtype necessarily express highaffinity binding sites for radiolabelled somatostatin analogs [61, 99]. Furthermore, it is likely that in some cases individual tumors may not express SSTR in sufficient density to be visualized by [111In]pentetreotide scintigraphy. Therefore, false-negative results may occur. While the primary tumor may be localized, metastases may not necessarily contain SSTR-expressing cells. Also, although not a problem in the NSCLC studies reported here, nonspecific uptake of the radiolabel seen in the spleen, kidneys and urinary tract, liver and gastrointestinal tract, pituitary and thyroid gland may obscure visualization of metastases to these areas. Two further studies have confirmed that [111In]pentetreotide scintigraphy is effective in the localization of NSCLC tumors, detecting the primary tumor in 40 of 40 [86] and 10 of 13 patients, respectively [87]. However, metastatic sites of disease were not as frequently detected, thereby demonstrating the limitations of the technique. Of 15 patients with known metastases in the study of Kwekkeboom et al. [86], disease spread was detected in only 6, including 1 patient with a previously undetected brain metastasis – this was subsequently confirmed on CT brain scan. Spread to the mediastinum was detected in 5 of 15 cases and to the opposite lung in 1 of 3 cases. Hepatic, adrenal and bone metastases were also missed. In the second study, while metastatic disease was detected in 9 of 10 patients, spread to the liver was not detected in any of the 5 patients with known hepatic metastases [87]. The finding of uptake in NSCLC tumors was, to some extent, unexpected as the in vitro experimental data available prior to commencing the [111In]pentetreotide studies had failed to reveal specific binding sites for a number of radiolabelled somatostatin analogs [64, 66, 67]. As discussed earlier we

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demonstrated the presence of high-affinity binding sites for the radiolabelled somatostatin analog [125I]RC-160 in 3 squamous cell lung cancers. Two of these tumors had been localized with [111In]pentreotide prior to surgical resection. Histological assessment of the resected specimens carried out before conducting the binding assays showed them to be comprised of tumor cells, necrotic tissue, connective tissue and/or inflammatory cells. Therefore, the SSTR may have been expressed by activated immune cells [62] and/ or the cancer cells themselves. The imaging study of Kwekkeboom et al. [86] is of interest in this regard. They argued that the detection and localization of NSCLC tumors was due to uptake of the radiolabel in tissues surrounding the tumor rather than to uptake by the tumor cells. This suggestion was based on observations that in a number of cases in their series (1) a halo effect was seen around the tumor on planar imaging, (2) SPET imaging showed increased radioactivity at the periphery of the tumor and (3) the region of accumulation of radioactivity during scintigraphy was greater than the tumor as measured on CT. Following [111In]pentetreotide scintigraphy a number of these patients underwent surgery. Subsequent autoradiographic evaluation of the resected tumors using the radiolabelled octapeptide somatostatin analog [125I-Tyr3]octreotide failed to reveal SSTR on tumor cells. However, subsequent work demonstrated the presence of SSTR in NSCLC tumor cells [73, 75, 100]. As discussed earlier, in one of these studies moderate concentrations of specific binding sites for the radiolabelled hexapeptide somatostatin analog [125I]MK-678, which binds SSTR-2 with high affinity, were found in 2 NSCLC cell lines. Subsequent RTPCR confirmed SSTR-2 mRNA expression within both NSCLC tumors [73]. Therefore, it would appear likely that the localization of

some NSCLC tumors is due, at least in part, to specific uptake of [111In]pentetreotide by the malignant cells. The results of the present study suggest that [111In]pentetreotide imaging may have a role to play as an adjunct in the diagnostic evaluation of patients with NSCLC. The imaging studies in SCLC and those reported for other tumors [61, 81, 101, 102] demonstrate that [111In]pentetreotide scintigraphy may be of value in monitoring the response of SSTR-positive lung tumors to chemotherapy. As cytotoxic chemotherapy now plays an increasingly important role in the management of patients with NSCLC, [111In]pentetreotide scintigraphy may prove to be an effective radiological technique for assessing the response of image-positive NSCLC tumors to such therapy. Furthermore, [111In]pentetreotide scintigraphy may be of particular importance in the evaluation of the response of NSCLC tumors to novel treatments, including somatostatin analog treatment.

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Bronchial Carcinoid [111In]Pentetreotide Imaging Studies We have reported the localization of bronchial carcinoid in 2 of the 3 patients studied with [111In]pentetreotide scintigraphy [103]. As in the NSCLC patients SPET not only improved anatomical localization of the disease but also was necessary to detect the tumor in one case. In the patient where the primary tumor was not localized with [111In]pentetreotide scintigraphy, diffuse, low intensity uptake of the radioligand was noted in the opposite lung, an area of known bronchiectasis. This false-positive localization is in keeping with the findings in the NSCLC patients described earlier where 2 false-positive results were recorded. Following resection of the carcinoid tumor in one of the imagepositive cases, membrane-binding assays revealed the presence of a single class of high-

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affinity binding site for the radiolabelled somatostatin analog [125I]RC-160 [103]. Apart from presenting with respiratory symptoms, symptoms of metastatic disease, physical signs and associated abnormalities on CXR or CT scan, and, rarely, the carcinoid syndrome, patients with bronchial carcinoid tumors may present with ectopic hormone syndromes including Cushing’s syndrome and acromegaly. In many cases the tumor producing the ectopic-hormone-related syndrome cannot be localized on physical examination or with standard biochemical and radiological techniques. [111In]pentetreotide scintigraphy has now been evaluated in a series of patients with Cushing’s syndrome secondary to ectopic ACTH or corticotropinreleasing factor. In keeping with the results reported for neuroendocrine tumors in general, the primary tumor or its metastases were localized in 8 of 10 patients. The failure of [111In]pentetreotide scintigraphy to detect ACTH-secreting pituitary adenomas and an adrenal tumor in 9 patients is in accord with the ineffectiveness of somatostatin analog therapy in the management of Cushing’s disease [104]. Subsequent studies have confirmed these results and indicate that SSTR-2 is expressed by bronchial carcinoid tumors [104–113]. The results suggest SSTR imaging may be an important diagnostic investigation in the workup of patients with suspected ectopic hormonesecreting tumors and their metastases. Radiotherapeutics The possibility of employing a radiolabelled chelated somatostatin analog as a radiotherapeutic agent in treating SSTR-positive tumors, including those of the lung, is an exciting prospect for the future. Since somatostatin analogs are based on sequences of the native hormone, they rarely induce immunization.

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The accumulation of [111In]pentetreotide in gastrointestinal neuroendocrine tumors is between 0.0123 and 0.2% of the administered dose per gram of tumor tissue. The rapid clearance of the radiolabel from the blood, the relatively low accumulation in the liver (1.9 and 2.2% of the administered dose at 4 and 24 h, respectively) with resultant relatively low excretion into the gastrointestinal tract and the predominant renal clearance are advantageous in this regard. However, the amount of renal accumulation and the relatively long renal effective half-life may limit the maximally applicable radiation dose [61, 99]. Recent studies suggest that there are a number of approaches which may be useful in reducing the uptake of [111In]pentetreotide by normal tissues. Pretreatment of patients with SCLC and carcinoid disease with cold octreotide increases tumor uptake of [111In]pentetreotide, whereas uptake into the liver, spleen and kidneys is reduced [91, 109]. This in vivo observation has been supported in vitro in mouse AtT20/Dl6V pituitary tumor cells and primary cultures of human GH-secreting pituitary tumor cells. After 4 h of incubation up to 8% of the added [125I-Tyr3]octreotide had accumulated in AtT20/Dl6V cells and between 0.24 and 4.98% in 6 of the 7 human tumor cultures. This accumulation was specific and time-, temperature- and pertussis-toxin-sensitive G protein-dependent. Displacement of binding and internalization of [125I-Tyr3]octreotide in AtT20/Dl6V cells by the addition of unlabelled octreotide showed a bell-shaped curve. At low concentrations (0.1–1 nM) unlabelled octreotide enhanced the binding and internalization of [125I-Tyr3]octreotide whereas at higher concentrations saturation occurred. Furthermore, after 4 h of incubation, 88% of the radioactivity present in the cells was still peptide-bound suggesting slow intracellular breakdown of the radioligand [95].

O’Byrne/Schally/Thomas/Carney/ Steward

Infusion of amino acids, known to block renal tubular peptide reabsorption, significantly reduces renal parenchymal uptake of [111In]pentetreotide 4 h after administration when compared to controls. In this there was a nonsignificant increase in urinary clearance of the isotope over the 4 h consistent with reduced re-uptake of the radiolabel, and a lack of effect of the amino acids or radiolabelled peptide on glomerular filtration rate [114]. A number of new potential radiotherapeutic agents are currently under investigation. 188Re, a potential radiotherapeutic isotope, has been coupled to octreotide. [188Re]octreotide has been assessed for the in vivo localization of NCI-H69 SCLC tumor xenografts in athymic nude mice and proved as efficient as [111In]pentetreotide in this regard [115]. Likewise, l6lTb has been coupled to octreotide. In studies in the rat, l6lTb-DTPA-octreotide has similar distribution characteristics to [111In]pentetreotide but with less uptake in the liver and other SSTR-expressing tissues such as the pancreas and adrenals, and negligible excretion into the bile. The uptake of l6lTb-DTPAoctreotide by the renal tubules after glomerular filtration can be reduced by administration of lysine or sodium maleate [116]. The radiotherapeutic isotope 64Cu, a reactor-produced radionuclide, has been coupled to octreotide. Apart from its radiotherapeutic potential, 64Cu is also a suitable radioisotope for PET scanning. The resulting product, 64CuTETA-octreotide, binds to SSTR with 5 times the affinity of [111In]pentetreotide and, like [111In]pentetreotide, is excreted principally through the renal system [117]. Finally, [90Y] has been linked to DTPA-benzyl-acetamidoD-Phe1, Tyr3-octreotide and has proved effective in the treatment of SSTR-positive tumors in a nude mouse model [118]. Other somatostatin analogs are being linked to therapeutic radioisotopes with encouraging results. [188Re]RC-160 has been evaluated in vivo in

nude mice bearing xenografts of the SSTRpositive prostate cancer cell lines DU-145 and PC-3. In PC-3 xenografts, [188Re]RC-160 induced a dose-dependent therapeutic response, with disease stabilization or shrinkage, even in animals with relatively large tumor masses [119]. These results demonstrate that, in selected cases, radiolabelled somatostatin analogs may be employed as adjuncts to standard radiological techniques for the scintigraphic localization of primary lung tumors and their metastases. Radiotherapeutic somatostatin analogs may have a role to play in the treatment of lung tumors, in particular chemotherapeutically debulked SCLC, in the future.

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Somatostatin Analogs in the Treatment of Lung Cancer

Given the mode of action of somatostatin and the fact that between 50 and 100% of SCLC cell lines and fresh frozen tissue specimens express SSTR, the role of somatostatin and somatostatin analogs as possible therapeutic agents in SCLC has been investigated in a number of studies. Initial experiments with somatostatin-14 were not encouraging [120]. In 1988 Kee et al. [121] demonstrated that somatostatin could inhibit the secretion of bombesin-like peptides from SCLC cell lines. Subsequently in 1988 Taylor et al. [122] evaluated the somatostatin analog somatuline in the treatment of NCI-H69 in vitro. Significant inhibition of cell proliferation was demonstrated. The average cell concentration of treated samples was 59% of that observed in tumor controls after 72 h. Further work with NCI-H345 revealed that somatuline could not only inhibit the clonal growth of SCLC cell lines but could also inhibit VIPinduced cAMP formation within the tumor

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cells [123]. Somatuline inhibits serum-induced MAP kinase activation in SCLC cells at a dose range similar to that required to inhibit cell proliferation. This observation suggests that phosphatase activation is important for the antiproliferative effects of somatostatin analogs in SCLC as discussed earlier [10, 11, 14, 20, 21]. These results suggest that the SSTR on SCLC tumors are functional and interact with growth pathways within the cell. Following the promising results of the in vitro work, in vivo experiments in athymic nude mice were performed. Suspensions of NCI-H69 cells, containing 5 ! l06 cells, were injected into the flanks of athymic nude mice. These tumors were treated with somatuline 500 Ìg i.p. b.i.d. in one group and s.c. around the tumor in another. Both regimens resulted in delay of the mean tumor lag time compared to controls. Inhibition of tumor growth was dramatic with subcutaneous injection around the tumor site, with virtually no growth being seen at 48 days. Discontinuing treatment by any route resulted in an acceleration of tumor growth. The effects of somatuline treatment on NCI-H69 xenografts were also studied. The experiment was repeated as before but with a third group receiving subcutaneous somatostatin analog treatment at a site distant from the tumor. Again significant growth inhibition was seen in all treated groups [122]. Subsequent work with somatuline in SSTRpositive cell lines has confirmed the earlier findings [64, 124]. Furthermore, significant growth inhibition of the SSTR-negative variant SCLC cell line NCI-H417 and poorly differentiated SCLC cell line LX-1 by somatostatin analogs was seen suggesting that they may inhibit SCLC tumor growth by indirect as well as direct means [64]. The hexapeptide somatostatin analog, MK-678, has also been demonstrated to affect NCI-H69 tumor growth in vivo. Treatment with 300 Ìg/kg s.c.

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t.i.d. for 46 days resulted in a 51% decrease in tumor area, a 64% decrease in tumor DNA content and a 55% decrease in RNA content. Tumor protein and weight were not affected [125]. The effect of octreotide in the treatment of SCLC has also been assessed in vitro and in vivo. The SCLC lines NCI-H69, HX149, ICR-SC17 and HC12 were evaluated. The growth of the SCLC cell line HX149, found to have weak and patchy specific somatostatin binding sites at autoradiography, was significantly inhibited but that of the other cell lines, two of which were SSTR-positive, was unaltered [68]. We evaluated the efficacy of RC-160 in the treatment of SCLC. In NCI-H69 SCLC xenografts significant inhibition of tumor growth accrued from day 7 (p ! 0.05) through to the end of the experiment (p ! 0.01). The mean tumor weight was reduced significantly (p ! 0.01) by RC-160 compared to the control group. Tumor volume doubling time in mice receiving RC-160 was extended from 7.5 to 12.7 days. Histologically, the number of mitotic and apoptotic cells in treated tumors did not differ significantly from control. However, the ratio of apoptotic to mitotic indices was significantly higher in the group receiving RC-160 (p ! 0.05; table 3) [26]. Somatostatin analogs have also been evaluated in the treatment of NSCLC. Somatuline has been demonstrated to inhibit the in vivo growth of the SSTR-poor NSCLC cell line H165 supporting the contention that indirect growth inhibitory effects may be important in the antitumor activity of somatostatin analogs in solid tumors [64]. Regarding this study it is important to keep in mind the results of subsequent work which, using the radiolabelled somatostatin analog [125I]MK-678 as radioligand and RT-PCR techniques, demonstrated that H-165 is SSTR-positive [73].

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Table 3. Summary of RC-160 in vivo growth inhibition study data

SCLC NCI-H69

Tumor volume, mm3 Initial Final

NSCLC NCI-H157

control

RC-160

control

RC-160

10.5B1.6 249.7B182.3

9.8B1.8 66.0B26.5*

10.0B2.0 11.1B2.6 1,580.3B455.7 291.0B207.8*

Body weight, g

26.3B2.3

26.5B1.0

26.5B1.0

24.2B4.7

Tumor weight, g

0.27B0.19

0.058B0.04*

1.9B0.3

0.64B0.3*

Tumor doubling time, days Mitotic and apoptotic indices Mitotic index Apoptotic index Ratio of apoptotic to mitotic indices GH assay GH, ng/ml Receptors EGF Kd, nM EGF Bmax, fmol/mg protein IGF-1 Kd, nM IGF-1 Bmax, fmol/mg protein Bombesin/GRP Kd, nM Bombesin/GRP Bmax, fmol/mg protein Somatostatin Kd, nM Somatostatin Bmax, fmol/mg protein

7.5

12.7

37.9B2.9 35.4B2.6 0.96B0.1

23.0B4.6 42.3B3.2 2.27B0.5*

3.8B0.5

2.0B0.5*

1.3 278 1.0 294 1.1 420 3.5 450

1.6 174 0.9 176 1.3 435 5.5 570

3.88 17.3B4.0 2.87B0.5 0.19B0.04 6.8B0.8 0.7 249 0.5 257 ND ND ND ND

6.06 12.9B1.2 4.00B0.7 0.35B0.08 3.5B0.3* 0.5 100 0.7 129 ND ND ND ND

There were 10 animals in each group. GRP = Gastrin-releasing peptide; ND = not detected. Tumor and body weight values are means B standard deviation of the mean. Mitotic and apoptotic indices and GH values are means B standard error of the mean. * p ! 0.05 [26].

Nonetheless, our work supports the contention that indirect antiproliferative effects are important in the growth inhibition of lung tumors by somatostatin analogs. RC160, 100 Ìg s.c. once daily, significantly inhibited the growth of NCI-H157 tumors from day 14 of treatment (p ! 0.01). The final tumor volume and tumor weight were significantly reduced in animals receiving RC-160 compared with controls (table 3). Tumor volume doubling time was prolonged from 3.88 to 6.06 days. No significant difference in the extent of necrosis, mitoses or apoptosis or in

the ratio of apoptotic to mitotic indices between control and the RC-160-treated group was seen. No specific SSTR-binding sites were found on membranes prepared from the NSCLC tumor xenografts [26]. Similar in vivo growth inhibition has been observed in other SSTR-negative tumors [27]. In our studies GH levels in animals treated with RC-160 were significantly decreased [26], compared with controls (table 3), a finding confirmed in subsequent work [27]. GH induces the synthesis of IGF-1, an important growth factor for solid tumors including lung

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cancer [25]. In breast cancer patients RC-160 has been demonstrated to significantly reduce serum IGF-1 levels [28]. This may result in a reduced proliferative stimulus for tumors sensitive to the growth stimulatory effects of IGF-1 including lung cancers [5, 14, 28]. RC-160 also reduces elevated prolactin levels to within the normal range in patients with breast cancer. Prolactin is an autocrine growth factor for breast cancer. Somatostatin analogs have little or no effect on primary pituitary hyperprolactinemia. These findings suggest that the normalization of serum prolactin levels in breast cancer patients is due to a direct effect on hormone synthesis and release by the breast cancer cells themselves [28]. Somatostatin analogs inhibit the release of bombesin-like peptides from SCLC tumor cells [122] and gastrin from cultured human endocrine cells [126]. The results suggest that somatostatin analogs may downregulate autocrine feedback loops in SSTR-positive malignancies including lung tumors, in particular SCLC [5, 26]. Impact of Somatostatin Analogs on SCLC and NSCLC SSTR and Growth Factor Receptor Expression In accord with previous studies [5, 14, 61, 69, 127], and those mentioned above, we demonstrated specific binding sites for radiolabelled somatostatin, bombesin/GRP, IGF-1 and epidermal growth factor (EGF) on membrane preparations from treated and control xenografts of the SCLC cell line NCI-H69 [26]. Likewise, EGF [128] and IGF-1 [129] binding sites were found on the NSCLC xenografts, but no specific binding sites for radiolabelled somatostatin and bombesin/GRP receptors were detected [26]. The effects of RC-160 on SSTR, EGFR, luteinizing hormone-releasing hormone-R and IGF-1R expression have been evaluated in a number of tumors. RC-160 appears to

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upregulate SSTR [130, 131] while downregulating EGFR [130, 132–136], LHRH-R [130, 137] and IGF-1R [131, 137] expression. Although only performed on one occasion, the results of the membrane binding assays from our study are consistent with the previous findings. The EGF and IGF-1 Bmax were both reduced in RC-160-treated SCLC and NSCLC xenografts as compared to controls (table 3). EGFR levels in the RC-160-treated samples were 63 and 40%, and IGF-1R levels 60 and 50% of control in SCLC and NSCLC membranes, respectively. No change was observed in the Kd and Bmax values for bombesin/GRP in the SCLC tumor xenografts [26]. Both the Kd and Bmax for somatostatin increased with RC-160 treatment indicating reduced binding affinity but increased binding capacity. The Kd and Bmax values for [125I-Tyr11]somatostatin-14 were higher in membranes prepared from NCI-H69 xenografts than the Kd and Bmax for [125I]RC-160 high-affinity binding site in membranes prepared from NCI-H69 cell pellets grown in vitro [26, 69]. No low-affinity binding sites were detected [26]. Taken together these findings indicate that RC-160 therapy may affect the expression of a number of growth-stimulatory and potentially growth-inhibitory receptors as well as growth factors in lung cancer. These changes may result in a downregulation of autocrine, paracrine and endocrine proliferative stimuli in SCLC and NSCLC. Angiogenesis Angiogenesis is necessary for the growth of a primary tumor beyond 1–2 mm in diameter and plays an important role in tumor metastasis [29]. Recent work has demonstrated that in patients with resectable NSCLC, one of the most important prognostic factors is the degree of angiogenesis in the

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resected tumors as assessed by microvessel counts. Tumors with high microvessel counts are associated with spread of the tumor to locoregional lymph nodes and a significantly worse prognosis [138]. The potent antiangiogenic activity of somatostatin analogs [12] may be one of the principal mechanisms by which these agents inhibit lung cancer growth in vivo. This may be particularly so in tumors with negative or low levels of specific binding sites for radiolabelled somatostatin analogs as is the case for the NSCLC cell line NCI-H157.

Patient Studies

Treatment of SCLC A number of small studies have now been conducted in patients with SCLC. The first involved 20 patients including 6 newly diagnosed patients and 14 presenting with relapsed disease following first line treatment. Octreotide 250 Ìg s.c. t.i.d. resulted in a significant reduction of serum IGF-1 levels. The overall change in IGF-1 levels, with the lowest level while on treatment expressed as a percentage of the pretreatment baseline value, was median 53% and mean 62 B 7% (range 23–150%). Despite the reduction in IGF-1 levels, there was no evidence of antitumor activity as measured by tumor bulk or NSE levels. However, 2 of the 14 patients with relapsed SCLC had stabilization of their disease accompanied by improvements in respiratory symptoms for 8 and 15 weeks [68]. In a subsequent study, in which 13 patients with SCLC were treated with octreotide 200 Ìg s.c. t.i.d. for 1 week, a significant decrease in mean serum NSE levels from baseline values of 44.4 B 57.7 to 32.6 B 42 ng/ml was seen [139]. In a phase I dose-escalating study of octreotide and somatuline in the management

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of neuroendocrine tumors, 2 patients with SCLC were recruited to the somatuline arm. An objective tumor response was seen in 1 of these patients [140]. This was followed by a phase I dose escalation study in 18 patients with relapsing or resistant SCLC following treatment with standard cytotoxic chemotherapy. Patients received between 2 and 10.5 mg/ day of somatuline by continuous subcutaneous infusion. The agent was well tolerated with grade 1 or 2 diarrhea occurring in 8 patients and pain at the site of injection requiring a change in infusion site in 3 patients. A mean reduction of 17% in IGF-1 levels was seen. The relationship between the dose of somatuline administered and the reduction in IGF-1 levels was statistically significant, higher doses being more potent in this regard (p ! 0.01). By day 28 disease progression was seen in all 15 patients evaluable for tumor response and therefore treatment was discontinued [141]. Finally, the efficacy of octreotide has been studied in a number of SCLC patients with syndromes related to ectopic hormone secretion. Octreotide 100 Ìg s.c. was evaluated in 2 patients with SCLC tumors and Cushing’s syndrome secondary to ectopic ACTH release. In both cases a paradoxical increase in plasma ACTH and cortisol levels was seen. One patient went on to have treatment with a slow release preparation of somatuline. Following intramuscular depot injection of 30 mg of somatuline a rise in ACTH and cortisol levels similar to that seen with the octreotide challenge was found [142]. The cause for this remains unknown but raises the possibility that, in certain cases, somatostatin analogs may have a stimulatory rather than inhibitory effect on the tumor as suspected in one study in patients with prostate cancer [143]. Finally, as is the case for patients with neuroendocrine GEP and medullary thyroid tu-

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mors, somatostatin analogs may have a role to play in the management of SCLC-related paraneoplastic diarrhea [144]. Management of Bronchial Carcinoid As outlined earlier, [111In]pentetreotide imaging has an important role in the detection and staging of patients with bronchial carcinoid tumors including those presenting with ectopic hormone syndromes including Cushing’s syndrome and acromegaly [103–112]. In 1988, 2 patients with bronchial carcinoidassociated Cushing’s syndrome were treated with octreotide to see if this could induce a reduction in circulating ACTH levels and an improvement in symptoms. Octreotide 50 Ìg s.c. stat produced a 50% reduction of ACTH in 1 patient whilst the other was maintained in a clinical and biochemical remission for 10 weeks with octreotide 100 Ìg s.c. t.i.d. [145]. Subsequent reports indicate that, in the majority of cases, octreotide is an effective agent in the management of bronchial carcinoidrelated ectopic hormone syndromes providing palliation not only in Cushing’s syndrome but also for ectopic GHRH-related acromegaly [111, 113, 146, 147]. A recent case study reported the evaluation of octreotide in the treatment of a patient with multiple cerebral metastases from a bronchial carcinoid. Neurologically, the principal symptom was expressive dysphasia. Treatment with octreotide, initially in combination with a corticosteroid, resulted in disease stabilization for 6 months. During that time the patient’s symptoms resolved [148]. However, ACTH does not fall in response to octreotide in all cases [149, 150]. Therefore, an octreotide challenge may have a role to play in determining whether or not somatostatin analogs would be of value in controlling ectopic hormone syndromes in lung cancer [99, 151].

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There are now a number of case reports where ACTH-secreting bronchial carcinoid tumors have been localized leading to subsequent curative resection of the disease [105– 107]. Indeed radioguided surgery employing a peroperative probe may facilitate complete tumor excision whilst, at the same time, reducing the extent of resection by clearly separating involved from uninvolved tissues [113]. Somatostatin analogs are well tolerated, transient diarrhea, steatorrhea, colicky abdominal pain and borborygmi being the most commonly observed problems. Other side effects of somatostatin analog therapy include pain at the injection site, glucose intolerance and gallstone formation. Although very rare, severe complications may occur including allergic reactions varying from skin rashes to anaphylaxis, acute pancreatitis and hepatitis. Somatostatin may also have a negative inotropic effect on the heart [28, 152, 153].

Future Directions

Enhancing the Efficacy of Cytotoxic Agents Experimental evidence clearly demonstrates that somatostatin analogs may potentiate the cytotoxicity of a range of chemotherapeutic agents. Studies in vitro and in vivo in animal models and in patients have shown that somatostatin analogs may enhance the antitumor efficacy of 5-fluorouracil while reducing the incidence of known side effects such as neutropenia and diarrhea [154–159]. Using 19F nuclear magnetic resonance spectroscopy, octreotide has been shown to increase the formation of fluorouridinephosphates from 5-fluorouracil in human colon HT-29 adenocarcinoma cells. Furthermore, while 5-fluorouracil arrests cells in the S phase, cotreatment with octreotide al-

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most eliminates the S phase cells and induces the appearance of DNA fragments [160]. Perhaps of greater interest is the finding that the somatostatin analog octreotide has been shown to synergistically enhance the antitumor effects of mitomycin C, doxorubicin and paclitaxel in AR42J pancreatic cancer cells in vitro suggesting that somatostatin may have a role to play in overcoming multidrug resistance. Combination therapy with doxorubicin and octreotide has been studied in vivo for time dependency and efficacy. Pretreatment with octreotide for 24 h prior to addition of doxorubicin results in additive antitumor activity while pretreatment with doxorubicin is associated with clear synergy [159]. With specific reference to lung cancer, somatuline has been shown to enhance the cytotoxic activity of cyclophosphamide in SCLC both in vitro and in vivo [161]. These results raise the possibility that somatostatin analogs may enhance the antitumor activity of Adriamycin, mitomycin C, cyclophosphamide and paclitaxel-containing regimens in lung cancer [3, 4]. Evidence to support this observation comes from a phase II study in prostate cancer. A number of patients initially treated with octreotide received chemotherapy at disease progression. A high response rate above that normally expected for cytotoxic chemotherapy alone was seen [143]. The synergy between cytotoxic agents and somatostatin analogs in vivo may in part be due to the known antiangiogenic activity of somatostatin analogs. This suggestion is supported by a number of studies where the combination of known antiangiogenic drugs with cytotoxic chemotherapeutic agents has additive antitumor activity in solid tumors. For example, the antiangiogenic agent TNP-470, a derivative of fumagillin, and minocycline, an inhibitor of collagenase IV activity, potentiate the cytotoxic effects of cyclophosphamide in the treatment of Lewis lung carci-

noma and murine FSaIIC fibrosarcoma. The combination of both antiangiogenic agents with cyclophosphamide is additive [162]. As discussed earlier, tumor angiogenesis is an important prognostic factor in surgically resected, stage I and II, NSCLC [138]. Platelet-derived endothelial cell growth factor overexpression (PD-ECGF) is observed in approximately 20% of NSCLC tumors and correlates with increased tumor angiogenesis. PD-ECGF is thymidine phosphorylase, an important enzyme in the pathway leading to the conversion of 5-fluorouracil to its active metabolites including 5-fluoro-2)-deoxyuridine-5)-monophosphate [163]. Taken together, the growth inhibitory effects on NSCLC xenografts, the antiangiogenic activity and the modulation of 5-fluorouracil metabolism by somatostatin analogs suggest a role for the combination of 5-fluorouracil or other fluoropyrimidine analogs with RC-160 in the treatment of NSCLC. Early phase II studies suggest that the combination of octreotide with tamoxifen may be effective in the treatment of patients with pancreatic cancer [164]. Tamoxifen has been shown to enhance the antitumor activity of cisplatin [165]. Cisplatin is the principal cytotoxic agent in the management of NSCLC [166]. These data indicate that somatostatin analogs, with or without tamoxifen, should be evaluated in combination with cytotoxic regimens – platinum agents, the taxanes, ifosphamide, mitomycin C, vinca alkaloids, and antimetabolites, such as the fluoropyrimidines and gemcitabine – in the treatment of NSCLC [4, 166, 167]. A number of cytotoxic agents have been coupled to somatostatin analogs with encouraging results both in vitro and in vivo. Methotrexate has been linked, through the 7-carboxyl group of its glutamic acid moiety, to the free phenylalanine amino acid of the octapeptide somatostatin analog, RC-121. This analog,

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termed AN-51, has antitumor activity in vivo against the SSTR-expressing human pancreatic cancer cell line Mia PaCa-2 [168]. Cytotoxic analogs of somatostatin-containing potent anthracyclines have recently been developed. The superactive doxorubicin derivative, 2-pyrrolinodoxorubicin, has been linked to RC-121 and RC-160 yielding AN-238 and AN-258, respectively [169, 170]. These agents have shown promising antitumor activity in vitro and in vivo in a number of SSTR-positive solid tumors including breast, prostate, pancreatic, gastric and lung cancer. The possibility of specifically targeting such agents to SSTR-rich lung tumors in patients holds promise for the future. Adjuvant Therapy A recent overview meta-analysis indicates that adjuvant chemotherapy, established in the management of resected breast and Dukes’ C colorectal cancer, may have a role to play in NSCLC. Recent in vivo work indicates that wound healing following surgical wounding of normal tissues may stimulate the growth of malignant disease even if the primary has not been removed. This suggests that wound healing itself results in the induction and release of trophic factors that have systemic proliferative effects [171]. Application of a somatostatin analog to the wound within 1 h of surgery significantly reduces the induction of tumor growth seen otherwise [172]. As such somatostatin analogs may have a role to play in the adjuvant treatment of surgically resected lung tumors in the immediate postoperative period. Chemoprevention As discussed earlier, IGF-1 is a potent trophic and survival factor and plays an important role in cell transformation for many normal epithelial cells. IGF-1 acts through the IGF-1R. The central role of IGF-1R in the

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transformation of many cell types is best illustrated by the effects of disruption of the IGF1R signal transduction pathway. This reverses the transformed phenotype and/or inhibits tumorigenesis and/or induces loss of metastatic potential in human lung, breast, ovarian and melanoma tumor models amongst others [173]. Support for a central role for IGF-1 in the development of malignant disease comes from the observation that acromegalic patients are significantly more likely to develop malignant disease than the general population [174]. Furthermore, in two recently published prospective studies, high normal IGF-1 levels were associated with an increased relative risk for the development of prostate cancer in men (4.3) and breast cancer in premenopausal women (7.28 in premenopausal women aged !50 years, when adjusted for IGF-binding protein 3 levels) [175, 176]. The effects of somatostatin analogs on carcinogenesis have been evaluated in vivo. Fisher 344 female rats were initially exposed for 4 weeks to the initiator carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine in drinking water. They were then exposed to the promotor carcinogen mitomycin C intravesically for 12 weeks with or without concomitant subcutaneous somatostatin analog therapy. In the untreated group 34 rats developed transitional cell carcinoma. However, in the 20 rats treated with the octapeptide somatostatin analog RC-160 only 1 in situ carcinoma was observed [177]. Subsequent studies demonstrated that RC-160, infused at 2 Ìg/day for 14 days, significantly inhibited the progression of 0.5% 9,10-dimethyl-1,2-benzanthracene (DMBA)-initiated premalignant lesions in the buccal pouch of Syrian golden hamsters, as measured by Photofrin-induced fluorescence using in vivo photometry and histological evaluation of the lesions [178]. Groups of animals also had 0.5-cm incisions made in one cheek over the carcinogen-ini-

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tiated area by CO2 laser, a cancer promotor. The development of squamous cell carcinoma in these animals was likewise inhibited by RC-160 therapy. Further work analyzing kinase activity in DMBA-induced premalignant and malignant lesions demonstrated that phosphorylation increases continuously in a linear fashion from the first application of DMBA. This is independent of stimulation by growth factors such as EGF. RC-160 reduces phosphorylation in vitro at weeks 6–10 after DMBA application to the premalignant lesions and week 12 after DMBA application to the malignant tissues. The results suggest that one of the principal pathways of the inhibitory action of RC-160 on carcinogenesis is through activation of phosphotyrosine phosphatase activity and that this in turn is secondary to enhanced kinase activity [179]. These findings suggest that somatostatin analogs through the sustained suppression of IGF-1 levels [28, 180, 181] and through the inhibition of cell signal transduction pathways [10–18, 19–23] may have an important role to play in the chemoprevention of solid tumors including lung cancer.

Conclusion

Lung cancer is a plague of the late 20th century and will remain one of the prinicipal health issues well into the next century even if cigarette smoking stopped tomorrow. Despite progress in the diagnosis and treatment of lung cancer, with improvements in surgical techniques and the development of effective radiotherapeutic and chemotherapeutic regimens, the overall prognosis is appalling and novel approaches to treatment are urgently required if a significant impact is to be made on overall survival.

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The precise role for somatostatin analogs in the evaluation and treatment of lung cancer remains to be defined. SSTR may be expressed by lung tumors, particularly SCLC and bronchial carcinoid disease. Scintigraphic imaging with [111In]pentetreotide may play a role in the clinical evaluation of neoplastic lung disease both before and following treatment, and in detecting relapsed disease. The potential role of somatostatin analogs linked to radiotherapeutic isotopes in the management of SCLC is currently being explored. Cytotoxic somatostatin analogs containing 2-pyrrolinodoxorubicin have shown encouraging antitumor activity in a range of solid tumors including breast and prostate cancer. These analogs, including AN-238 and AN-258, hold promise as future therapeutic agents in the treatment of lung tumors. Somatostatin analog therapy inhibits the growth of SSTR-positive and SSTR-negative lung tumors in vivo. Furthermore, experimental evidence suggests that somatostatin analogs may enhance the efficacy of a range of chemotherapeutic agents in the treatment of solid tumors, including cisplatin, the anthracyclines and the taxanes. Based on the encouraging preclinical data we have set up a phase I/II study evaluating increasing doses of octreotide in combination with standard chemotherapy in the treatment of SCLC. Similar studies are indicated for NSCLC.

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Octreotide in the Management of Hormone-Refractory Prostate Cancer Iraklis G. Vainas Department of Endocrinological Oncology, Theagenion Cancer Center, Thessaloniki, Greece

Key Words Prostate cancer, hormone-refractory W Octreotide W Antiandrogen blockade, complete W Hormonal maneuvers, alternative

before the start of a selective SST analog, and finally the randomization in groups according to hormone resistance, dosage regimen and route of administration. Copyright © 2001 S. Karger AG, Basel

Abstract Patients with advanced or metastatic prostate cancer (PC), a partially hormone-resistant disease, will require some form of hormonal manipulations or some new therapeutic modalities. Octreotide, as somatostatin (SST) analogs, has been found to inhibit the growth of experimental PCs via several mechanisms, as indirect antihormonal and direct antimitogenic actions, mainly due to inhibition of SST receptor subtypes (SSTR-1– 5). Sporadic clinical trials with octreotide (alone or with a complete antiandrogen blockade) treatment of patients with advanced stage D2 PC demonstrated promising results. Unfortunately, at present these clinical trials have some disadvantages and leave some uncertainty with regard to the trial design, the SSTR subtype determination and tumor localization with SSTR scintigraphy

ABC

© 2001 S. Karger AG, Basel 0009–3157/01/0478–0109$17.50/0

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Epidemiology

Prostate cancer (PC) is the most common cancer in males and is secondary in incidence only to breast cancer as the most common type of hormone-dependent neoplasm in the USA. In Europe it accounted for 20% of all newly diagnosed cancers in 1990 and for 160,000 patients only in 1993 [1]. Furthermore, PC is the second most common cause of death due to cancer in men, with 35,000 deaths in 1993. Thus, it had been suggested that PC will become the leading cause of cancer death in men by the year 2000 [2]. In more than 50% of patients the disease is only diagnosed at a late stage, usually in men between the ages of 45 and 67, when it has already spread to distant sites, particularly to the bone, and at a time when most men have their

Dr. Iraklis Vainas Theagenion Cancer Center 2, Al. Simeonidis Street GR–54007 Thessaloniki (Greece) Tel. +30 31 82 92 12, Fax +30 31 84 55 14

highest level of social responsibilities [3]. Thus, advanced-stage PC is a significant health problem in the male population.

Natural History – Clinical Course of the Disease

The natural history of PC should be reflected by its stage, describing the burden and the extent of the tumor at the time of diagnosis [1]. All staging maneuvers (WhitemoreJewett or Tumor Node Metastasis system) determine if the disease is widespread or confined to the prostate, but understaging is a great problem clinically. The natural history of stage A1 PC remains unclear, because 16% of the patients will progress 3.5–8 years after the initial diagnosis, and 61% actually have stage A2 or diffuse disease. Stage A2 or B1–3 PC patients treated with radical prostatectomy may have an equivalent risk for disease spread and death from PC [4]. Advanced-stage disease (C, D1, D2) will be identified in more than 40% of these cases [5]. About 60% of the patients with untreated stage C PC will exhibit evidence of disease progression at 5 years, at rates of 10–20% annually [5–7]. 85% of the patients with stage D1 PC demonstrate a disease progression within 5 years of diagnosis [5, 8], although diploid tumors have a biologically indolent course [9]. Finally, stage D2 PC patients (with distant metastases) have a median survival of about 30 months with a 20% 5-year survival rate.

Endocrinological Aspects

The role of testicular androgens in the evolution of PC has been recognized since 1941 [10]. Since then surgical castration or treatment with estrogens has been reported to

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result in subjective-objective improvement in 60–80% of patients, due to neutralization of androgens, but for limited time intervals. The endocrine relationship between the testis, hypophysis and hypothalamus is shown in figure 1. Ninety percent of the circulating androgen pool in the normal male is derived from the testes and 10% from adrenal cortex sources, regulated by the hypothalamus (via CRF) and directly by the pituitary (via ACTH) [11]. The prostate gland has androgen receptors, so the circulating testosterone (T) is rapidly internalized into its cytosol and its receptors, and converted to dehydro-T (DHT) by the enzyme 5-reductase. DHT is 3 times more potent than T, with T being 5–10 times more potent than adrenal androgens [12]. DHT, from testicular or adrenal sources, is the primary (growth-promoting) intracellular messenger in androgen-responsive target cells and is internalized into the nucleus, where an mRNA clone is transcribed, which ultimately effects translation of androgen-dependent proteins, necessary for cellular existence [12, 13].

Current Therapeutic Approach in PC

General Therapeutic Considerations As a general therapeutic strategy, patients with localized stages A and B PC will be managed by local external radiotherapy (ER) or radical prostatectomy [4]. In contrast, stage D (T3N0–3M0–1) disease is associated with systemic spread and should be treated with systemic cytostatic therapy. Node-positive PC (D1) is also associated with systemic disease, and therefore does not respond to ER or radical prostatectomy treatment, but can be controlled, at least for some time, with systemic therapy, in particularly early androgen deprivation. The therapeutic strategy for stage C3 PC (large volume local disease) is similar,

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Fig. 1. Endocrine relationship between hypothalamus, pituitary, testis, adrenal and prostate

gland. Hormonal therapies in advanced PC. LHRH = Luteinizing hormone-releasing hormone; CRH = corticotropin-releasing hormone; LH, FSH = luteinizing and follicle-stimulating hormone; ¢4-dione = androstenedione; DHEA = dehydroepiandrosterone; T = testosterone; DHT = dihydrotestosterone; AR = androgen receptor.

which cannot be controlled by local therapies. The decision for stage C1–2 (local extension) is more complex, combining local radiotherapy and androgen deprivation [11]. Specific Therapeutic Modalities for Advanced PC Advanced or metastatic PC is a partially hormone-resistant disease, which needs systemic therapy from the outset. Adjuvant ER is attempted but is associated with undesirable side effects (13% bowel obstruction or severe cystitis or urethra strictures) and the longterm benefit of radiotherapy has yet to be demonstrated. Major surgical therapies (other than radical prostatectomy) such as cystoprostatectomy, total pelvic exenteration, or

salvage surgery do not achieve a complete resection of the tumor either, nor do they delay the progression of the cancer or prolong survival [14]. These procedures are also risky being associated with a high incidence of postoperative incontinence. Almost all stage C and D PC patients will require some form of hormonal manipulations, vitamin therapy, immune modulation, cytostatics or some new therapeutic modalities [11]. Surgical or chemical castration or estrogens are the first and main endocrine therapies for patients with advanced PC (table 1). These treatments have similar efficacies with respect to survival, relief of symptoms and the prevention of metastatic spread [12, 15]. However, androgen deprivation may result in

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Table 1. Conventional hormonal manipulations in

advanced PC Castration Surgical (orchidectomy, hypophysectomy) Chemical (LHRH analogs, estrogens) Antiandrogens Gestagenic compounds (cyproterone acetate) Pure nongestagenic compounds (flutamide, nilutamide, Casodex) Progesterone compounds (medroxyprogesterone, megestrol) Adrenal corticolytic agents Aminoglutethimide Ketoconazole Ablative hormonal manipulations Hypophysectomy Adrenalectomy CAB Castration + antiandrogens

Table 2. Recent hormonal therapies in advanced PC (under research)

Reductase inhibitors (finasteride) LHRH antagonists Specific SST analogs with high antitumor activities LHRH analogs with cytotoxic radicals Bombesin/GRP antagonists CAB + chemotherapy CAB + suramin CAB + synthetic retinoids Chemotherapy following androgen priming Specific radiolabeled (123I, 131I, 111In) SST analogs (with ß-emitting radiation)

unpleasant largely minor side effects (loss of libido, flushes, gynecomastia, impotence), but some are also serious (mainly due to estrogens), as the 7–11% incidence of thromboembolic and cardiovascular complications [14].

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Adrenal corticolytic agents (aminoglutethimide, ketoconazole), synthetic progesterone compounds (megestrol, medroxyprogesterone) and nonsteroidal pure antiandrogens (flutamide, nilutamide, Casodex) appear to be beneficial as palliative therapy in 20% of patients, but with a high percentage of side effects [12]. Complete androgen blockade (CAB) combines surgical or chemical castration with a pure antiandrogen, and eliminates both testicular and adrenal androgens in PC patients [11, 16]. Labrie et al. [16] found complete response rates of 29% at 22 months compared to the 5% response rate usually associated with monotherapies; similar results were reported by Navartil’s group in France with 70% response rates following surgical and chemical castration at 18 months versus 45% with monotherapies. In a large multicenter trial in the USA of 603 metastatic PC patients, CAB showed a longer disease-free survival than either drug alone and had a survival advantage of approximately 7 months, particularly among the 82 patients with a good performance status and with minimal disease [17]. Thus, the CAB has some advantage, the side effects are no more than with each drug alone, but the cost of the combined treatment is very high. Other Therapeutic Modalities PC is a biologically heterogeneous tumor, with an increasing number of hormone-resistant cell populations at late stages [18]. Thus, hormone treatment alone does not appear to be an effective long-term (or even curative) therapy. Unfortunately, the efficacy of several alternative modes of systemic drug treatment, including chemotherapy alone [19] or combined with hormone therapy or following androgen priming [20], suramin [21], or natural synthetic retinoids [22], has yet to be determined. Alternative endocrine treatment (table 2) with LHRH antagonists, bombesin an-

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tagonists or LHRH analogs with cytotoxic radicals, or recently with somatostatin (SST) analogs are still at the research stage [23, 24].

Introduction Natural or synthetic somatostatin (SST14) has numerous exocrine/endocrine antisecretory effects on a variety of systems [25– 27]. In addition SST-14 also acts as an endogenous growth inhibitor [28]. The growth inhibitory effects of the hormone have been documented in multiple experimental and human benign and malignant tumors [26], such as hypophyseal [25], endocrine pancreatic [29], ectopic and various solid tumors [30]. SST-14 has, therefore, nonselective, multiple actions, and a short duration of antisecretory or antitumor effects, because of its short biological half-life (1–2 min). Consequently SST analogs have been designed and synthesized, which are more resistant to metabolic degradation and have a more prolonged duration of actions [29, 30]. Due to substitutions and incorporation of Damino acids into the SST molecule, the resistance of SST analogs to digestion by tissue enzymes is increased [26, 31]. For example, 9 of the 14 amino acids were replaced with a single proline residue to produce a long-acting analog of somatostatin [32, 33]. Veber et al. [33] retained the sequence 7–10 of SST14 (Phe-Trp-Lys-Trp) as essential for the biological activity of native somatostatin, and incorporated the Trp residue into the D configuration (series of cystine-bridged SST analogs). Octreotide (SMS 201-995), an SST analog produced by Sandoz, has a longer duration of action (up to 113 min), is more potent than SST-14 (40–70 times) and is

more selective for hGH suppression than insulin or glucagon [33, 34]. Although the greater potency of SST analogs is only due to resistance to degradation by enzymes and to their prolonged half-lives, there is some doubt about the selectivity of the analogs, unless the tissues express the receptor subtypes, to which they bind with approximately equal efficacy as the native hormone. The five cell surface SST receptor (SSTR) subtypes have been characterized within the past 5 years and have been termed SSTR-1 through SSTR-5 according to the chronology of their discovery. The tissue distribution of the SSTRmRNAs (by Northern blotting, RT-PCR and in situ hybridization) showed that SSTR-1smRNA and SSTR-2smRNA occur in central as well as peripheral tissues (stomach, jejunum, colon and pancreatic islets), while SSTR-3smRNA and SSTR-4smRNA are limited to brain and endocrine pancreas [35–38]. The SSTR-5smRNA is present in the pituitary and a variety of peripheral tissues including the small intestine [39]. SST-14 (as SST-28) binds to all SSTRs with affinities ranging from 0.2 to 2.6 nM, but SST-28 shows a 10- to 20-fold higher affinity for SSTR-4 and SSTR-5. SMS 201-995 (Sandostatin) has 3- and 10fold higher affinities for SSTR-2 and SSTR-4, and a much lower affinity for the SSTR-1, SSTR-3 and SSTR-5 subtypes. Other SST analogs, such as MK-618, CGP-23996 and BIM-23014, bind mainly to SSTR-3, while CGP-23996 also binds to SSTR-5 with high affinity. These different affinities of SST-14 and SST-28 to the SSTR subtypes, which are consistent with tissue location of the SSTR subtypes and with their relative potency, suggest different functional properties for the various SSTRs [40]. However, the overlapping of the distribution of these five SSTR subtypes makes the ascription of a given physiological

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Somatostatin and Somatostatin Analogs in the Treatment of Metastatic PC

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Table 3. Antitumor effects of modern octapeptide

analogs in various animal or human cancers SCLC cell lines Dunning PC in rats Ductal pancreatic cancers in hamsters Human exocrine pancreas cancer Human PC Human breast cancer Human lung cancer Bladder cancer Carcinoma of the colon Primary brain tumors

function to a specific SSTR subtype difficult. In this respect, the availability of long-acting and relatively specific SST analogs would be of crucial interest. In particular, the SSTR-2 agonist octreotide and other modern SST analogs, besides their antisecretory effects on gastric, pancreatic and intestinal secretions, were reported (1) to inhibit in vitro and in vivo cultured tumor cell growth, (2) to enhance cell apoptosis, and (3) to activate cell cycle-regulated phosphatases at the cytoplasmic and nuclear levels [40]. Subsequently, Schally et al. [30] synthesized (1) nearly 300 octapeptide analogs with disulfide linkages, using also a C-terminal amide, (2) slow release preparations for intramuscular injections once monthly [27], and finally (3) new, modern SST analogs (RC-95-1, RC-121, RC160-II), by incorporation of Tyr and Val in position 3 and 6 (corresponding to residues 7 and 10), with high antitumor activities [41, 42]. The specific antitumor activities of the modern octapeptide analogs have been studied in various animal and human tumors (table 3). SST analogs, and especially octreotide, are well tolerated and have a favorable riskbenefit ratio, even in overdosage regimens with 3,000 Ìg/daily [43]. The observed main side effects were facial flushing, headache,

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nausea, vomiting, abdominal cramps, abdominal bloating and/or flatulence, steatorrhea and cholelithiasis [31, 43]. Although side effects of the octreotide treatment are usually mild, there is also the possibility of them being serious, fortunately in a minority of patients. Thus, occasionally steatorrhea may be serious enough to discontinue octreotide treatment, despite injecting octreotide between meals or giving pancreatic enzymes during the meals [24, 31, 43]. High-dose octreotide treatment may reduce gut motility and lead to more serious abdominal side effects mimicking gut obstruction and ileus [43]. Complications of the octreotide treatment, such as heavily symptomatic cholecystitis or acute pancreatitis, have been rare, but we observed them in 2 patients [24], which has also been observed by others [44–46]. Actual liver cell damage, pulmonary dysfunction and serious anaphylactoid reactions are some other very rare, worrying side effects of octreotide treatment [43]. Presence of SSTR in PC Cells Since 1986, low- and high-affinity SST-14 receptors have been identified and measured in various experimental and human tumors, such as brain, pituitary, endocrine gastrointestinal, prostate, pancreatic, colon and ovarian tumors, as well as in SCLC cell lines [30, 47–51]. The first studies have clearly shown the distribution of SSTRs in a wide variety of human tumors, but these SSTRs are localized in selected types of such tumors; for example, there is a very high incidence of high-affinity and specific SSTRs in meningiomas, in GRFproducing tumors, pituitary adenomas from acromegalics, but only in a small percentage of mammary cancers [48]. Interestingly, SSTRs are also present, often in high density, in tumors (e.g. meningiomas originating from tissue, arachnoidal cells of the human leptomeninx), without an established link to an

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SSTR mechanism. The same is also true for mammary tumors; therefore, only tumorously transformed cells of breast cancer bear SSTRs, although it has never been shown that SST-14 plays a functional role in normal mammary glands. Specific SST-14 receptors of low affinity (1.3 Nm) and very high capacity (Bmax 543 fmol/mg) were detected on Dunning R3327H rat PC cell membranes [52]. Modern SST analog RC-160 decreased the weight and volume of this prostate tumor, when given combined with the LHRH analog. This effect was due to a significant suppression of the SSTR capacity, as well as of the capacity and number of PRL receptors. In contrast, Fekete et al. [53] did not find a binding capacity to SST-14 on the Dunning rat or on normal and tumorous human prostate cell membranes. Reubi et al. [54] using 125I-(Tyr3)-octreotide, with in vitro receptor autoradiography techniques, suggested the presence of various SSTR subtypes on PC cells, expressing highaffinity receptors for SST-14 and SST-28, but low affinity for octreotide. Thus, human PC may be a target for SST therapy. However, SST analogues with different selectivities, particularly binding affinities, for SSTR subtypes cloned in PC would be required to achieve a response [55–57]. The cloning of 5 SSTR subtypes, using in situ hybridization, in a large variety of human tumors initiated a number of studies on SSTR subtypes in PC [55]. Reubi et al. [55] first detected, via in situ hybridization studies, that PC preferentially expressed the SSTR-1 subtype compared with the SSTR-2 or SSTR-3 subtypes. Furthermore, the presence of SSTR-2- or SSTR3mRNAs generally correlated with the presence of octreotide binding sites. It was pointed out that octreotide, which mainly binds to the SSTR-2 subtype, would not be the ideal SST analogue in the treatment of PC. In other words, octreotide will have no effect

on PC (or other tumors), which express the SSTR-1, SSTR-3 and SSTR-4 subtypes, because it has little or no binding affinities for these receptors. Thus, especially SSTR-2 represents an SSTR subtype target for the development of more specific SST analogues with higher affinities to these receptor subtypes [55]. In contrast, Prevost et al. [58] demonstrated a 57-kD SSTR-2 subtype in all prostatic normal and tumoral tissues; thus, the SSTR-2 subtype probably represents the SSTR subtype target for the specific SST analogs. Sinisi et al. [59] also demonstrated with the PCR technique that the SSTR-1 subtype was expressed only in the epithelial cells of PC, the SSTR-2 only in the epithelial cells of normal prostate, while the SSTR-3 subtype was undetectable in normal and tumor epithelial cells, but the SSTR-4 and SSTR-5 subtypes were expressed in the epithelial as well as in the stromal cells of PC. Thus, there are differences between normal and tumoral samples in the SSTR expression in the human prostate epithelial and stromal cells in vitro [57, 59]. Because some SSTR-2-selective SST analogs (e.g. Sandostatin) are probably ineffective in the treatment of PC, this observation would suggest that the absence of SSTR-2 could inhibit the growth and development of PC by analogs with a high binding for this receptor subtype. The three SSTRsmRNAs (1, 2 and 3) are expressed simultaneously not only in tumoral tissue but also in the host peritumoral vascular system; thus, some prostate tumor tissues bind octreotide due to a direct action on tumor cell SSTRs or through action on peritumoral vessels (due to SSTRs or growth factors), by altering the hemodynamics of the tumoral blood circulation [55]. The SSTR can be generally measured [60] using (1) biochemical techniques, i.e. binding assays on tissue homogenates in vitro, (2) autoradiography for visualization in tissue sections, (3) systemic injection of a radio-

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Fig. 2. Mechanisms of antiproliferative actions of SST-14 and SST analogs in advanced PC.

chemical-coupled SST analog into normal subjects, which specifically labels SST target tissue and localizes it by a subsequent in vitro autoradiography and (4) in vivo visualization of SST receptor-positive tumors, with the injection of [123I or 131I]-coupled Tyr3- or 111In[DTPA]-coupled octreotide. Radiolabeled with 123I, 131I or 111In SST analogs are synthesized for localization of prostate tumor and its metastases containing SST receptors, using scanning techniques [49]. In 8 of 31 biopsied patients with metastatic hormone-refractory PC, SST receptors were expressed both in vitro and in vivo, and visualized with the octreoscan technique [56]. SST analog RC160 labeled with 99mTc was shown to have a 400% higher 24-hour tumor uptake compared with 111In-DTPA-octreotide due to specific tumor binding sites in nude mice bearing experimental human PCs [61]. In contrast, 111In-DTPA-D-Phe1-octreotide scintigraphy identified only 3 of 7 patients with hormoneresistant PC who had the highest tumor to background ratio and responded to octreotide

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therapy [62]. The specific binding of a ß-emitting isotope-coupled SST analog to high-affinity membrane SSTR subtypes offers the opportunity to give brachytherapy to those tumors, which have the specific SSTR subtypes. Mechanisms of Antiproliferative Actions of SST-14 and SST Analogs in Advanced PC Five possible main antitumor actions of SST-14 and SST analogs have been discussed (fig. 2, 3). First, they inhibit secretory and hormonal effects on tumor growth. Prolactin acts as a cofactor on the growth of PC, alone as well as synergistically with GH [31, 32]. GH is of great importance for the suppression of various tumors, among them PC, in which GFs, such as IGF-1, are involved. Due to local production of IGF-1, GH directly promotes cell differentiation as well as indirectly clonal expansion [31]. Second, somatostatin and its analogs act as antimitogens synergistically with endogenous GFs (IGF-1

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Fig. 3. Molecular basis of the antiproliferative actions of octreotide in advanced PC.

and IGF-2, PDGF, FGF, TGF-· and TGF-ß), which are involved in proliferation and phenotypic transformation, or (directly) inhibit DNA synthesis and proliferation [63, 64]. Third, Sandostatin and its analogs have direct antiproliferative actions due to inhibition of SSTR, reversing the stimulatory effect of EGF (1) on phosphorylation of the tyrosine kinase portion of EGF receptors (EGF-R) and of tyrosine acceptor proteins, and (2) on cell growth [28]. EGF promotes phosphorylation of cell membrane proteins of 170 kD (as EGFR) and of 60 kD (as does LHRH-R). SST analogs (RC-160, RC-121) combined with LHRH analogs can increase the activity of tyrosine phosphatases, thus nullifying the EGF effects on the activation of dephosphorylation of such membrane peptides [65, 66]. Fourth, somatostatin and its analogs inhibit (fig. 3) the production of oncogene products

or the overexpression of protooncogenes, which act in the tyrosine kinase stimulatory pathway [61]. Oncogene products are similar to GFs or are aberrant GF receptors, which promote tumor cell growth. The protooncogene c-sis codes for the B chain of PDGF, while the viral oncogene erbB produces aberrant EGF-R [65]. Also, the EGF-R shares homology with erbB and c-erbB-2/new oncogenes [63, 67, 68]. Fifth, finally, SST-14 and some of its analogs have actions via specific SSTR on the peritumoral vessels [69], and are able to inhibit (due to FGF-related molecules) angiogenesis. Thus, another potentially therapeutic effect of somatostatin, octreotide and other analogs in vivo may partially depend on its suppressive action on tumor angiogenesis [70].

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In vitro and in vivo Studies of the Antitumor Actions of SST-14 and SST Analogs in PC: Animal and Human Models

Dunning R-3327H rats (with androgensensitive PC) were treated with modern SST analogs (Sandostatin, RC-160, RC-121) alone or combined with D-Trp6-LHRH analog or castration [71–74]. Final tumor volume, percentage change from initial tumor and final tumor weight were decreased due to the inhibitory effect of LHRH analog (or castration), effects which were potentiated by the superactive SST analogs, i.e. RC-98-I, RC160, RC-121 [71–73]. Schally’s group [50] demonstrated with the so-called superactive SST analogs higher and more specific binding to human and rat prostatic adenocarcinomas as well as to human ovarian and several human pancreatic cancers. Thus, different SST analogs had to be developed for diagnostic and clinical use other than octreotide, since octreotide is mainly effective in hormonehypersecreting endocrine tumors, or in those with the specific (for octreotide) SSTR-2 subtype. The combination of [D-Trp6]-LHRH and RC-160 in rats or in nude mice bearing xenografts of the hormone-dependent human prostate tumor PC-82 has shown a greater inhibition of tumor growth than [D-Trp6]LHRH or RC-160 alone [31, 75]. Sustained release formulations of SST analogs, such as Somatulin, also inhibited tumor growth after castration of male Copenhagen rats bearing Dunning R-3327H prostate tumors, but not in combination with LHRH analogs [73]. Male nude mice with PC-82 tumors, treated with slow-acting [D-Trp6]-LHRH agonist or LHRH antagonist (SB-75) or RC160, showed greater tumor inhibition after treatment with SB-75, than with LHRH agonist, but no significant inhibition with

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RC-160 [76]. Combination therapy with SB75 plus RC-160 achieved the best results, when it was started soon after the diagnosis of PC [77]. A decrease of IGF-1 and GH or a downregulation of EGF-R by RC-160 may improve the hormonal treatment of PC [75]. Androgen-independent human PC cell line (PC-3, DU-45, R3327-AT-1 PC) xenografts in nude mice treated with RC-160 plus a GRP antagonist (RC-3095) showed a significant growth inhibition, when the therapy was started at an early stage of tumor development [78–80]. SST-14 inhibited cell proliferation and protein secretion of the relatively indolent tumor LNCaP, probably mediated by the activation of phosphotyrosyl protein phosphatases [81]. Lanreotide, a slow-acting SST analog, applied topically to the surgical site on xenografts of human prostate tumors (PC-3, DU-145, H-1579) in athymic male rats, inhibited tumor proliferation [82]. Long-term exposure of cultured tumor cells (e.g. transplantable rat pituitary tumor 7315b or PRL-secreting cell line 7315c) to octreotide led to a loss of sensitivity with respect to its inhibitory effects on tumor cell growth, as well as to its hormone-inhibitory effects [60]. These desensitized tumor cells have lost their SST receptors, which reappeared after the withdrawal of octreotide. Thus, the gradual decrease of the growthinhibitory action of octreotide during the long-term treatment may be caused by the desensitization of SSTR, and is not due to selection of receptor-negative cell clones. 50% of all PCs have neuroendocrine (NE) cell populations with the presence of neurohormonal peptides (NSE, chromogranin, serotonin, ·-HCG, SST-14, calcitonin, ACTH, ß-endorphin, and others). The incidence of NE differentiation in PC cells is higher in fresh than in formalin-fixed biopsy specimens [83]. Certain NE peptides such as bombesin

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and VIP can increase the invasive potential of PC cells and may contribute to the rapid progression of PCs containing NE cell populations, and RC-160 did not alter the invasion of these PC-3 cells [84]. Thus, PCs appear to be more complex and heterogeneous than previously thought, exhibiting endocrine differentiation. PC cases with carcinoid tumor and hypercalcemia due to PTHrP [85, 86] and a case with Cushing’s syndrome due to CRHproducing PC [87] showed that these unusual PC cases with overexpression of NE differentiation may have major life-threatening effects, which are not significantly affected by octreotide treatment [86]. A review of the world’s literature on this topic suggested that PC cells with NE differentiation (1) allow screening for PC and/or monitoring for recurrence of PC, (2) are resistant to hormone therapy, and thus (3) show poorer prognosis and correlate directly with the tumor grade [75]. NE cells have a regulatory role in PC growth, and are prognostically useful in prostatic high-grade adenocarcinoma [1, 88, 89]. Only a partial correlation was observed between NE serum markers and immunohistochemical findings in 22 patients with PC [90]. Only chromogranin A showed a correlation (but not SST, NSE, chromogranin B, pancreastatin), being a useful serum marker in predicting the extent of NE differentiation in prostate tumors [91]. Certain PCs, which secrete somatostatin, are difficult to localize with the in vivo visualization technique with an isotope-labeled SST analog, because of a competition at their SST receptors. Two observations might in part explain this competition at the receptor levels with locally produced somatostatin: (1) the in vitro detection of SSTR could be improved after repeated additional wash procedures of the tumor samples, and (2) higher doses of octreotide are necessary in patients with such SST-producing PCs (with NE dif-

ferentiation) in order to suppress tumor growth [60]. In summary, many experimental findings suggest that both indirect and direct effects may play a role in the tumor growth-inhibitory action of SST analogs. In particular, the early tumor growth-inhibitory effects of SST analogs are probably due to the inhibition of the tumor angiogenesis. Finally, the decrease of the tumor growth-inhibitory action over time is mainly due to the desensitization and downregulation of the tumor SSTR.

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Clinical Trials of the Treatment of Advanced Hormone-Refractory PC

Introduction PC is often (60–80%) locally advanced or metastatic at diagnosis, making surgical removal and radiotherapy ineffective. Metastatic PC responds to normal hormonal manipulations, but once progression occurs new treatment modalities are required; at that time, specific and systemic antitumor therapy is better than local treatment, as ER. Alternative hormonal therapy involves androgen deprivation with surgical or chemical castration estrogens, antiandrogens, inhibitors of androgen metabolism or adrenal suppression. Complete androgen blockade may be a more superior hormonal treatment. PCs have initially androgen-dependent or androgen-sensitive and androgen-independent cell populations. Thus, in the later stages of PC a significant amount of tumor is androgen-independent, and needs alternative antiproliferative treatment. Additionally, advanced PCs have been noted to represent chemotherapeutically relatively nonresponsive tumors, with a median response rate of only 8.7% among 26 new drug trials during 1987–1991 [92]. Therefore, because of cytotoxic drug resistance, there is a need to develop new methods to overcome

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such resistance with new classes of antimitogen agents. Many SST analogs have been found to inhibit the growth of animal and human PC cells. Controlled Clinical Trials Sporadic clinical studies in patients with stage D2 PC (relapsed during treatment with flutamide plus castration) treated with SST analogs alone or combined with bromocriptine showed some advantage in tumor growth inhibition [93, 94]. Schally et al. [95] reviewed the hormone treatment of advanced PC with agonistic and antagonistic LHRH analogs or LHRH analogs linked to cytotoxic radicals, with very active SST analogs (SB-75, RC-160) or with bombesin/GRP antagonists. Thus, they tried to delay or prevent the relapse, and to improve the therapy of PC. Parmar et al. [96] treated 16 of 25 poor-risk patients with hormone refractory metastatic PC (failing to respond to total androgen blockade) with an SST analog BIM-23014. 2 of these 16 patients showed partial response and 3 no change of the disease, with only a few side effects, such as mild diarrhea and abdominal cramps. In contrast, Sandostatin treatment of 24 patients with hormone-resistant PC with a dose of 100 Ìg ! 3 times/day for 6 weeks did not give any objective evidence of tumor regression, but only of tumor progression [97]. The author concluded that Sandostatin eventually stimulates PC growth, but may have sensitized tumor cells to subsequent chemotherapy, because salvage chemotherapy resulted in an objective tumor regression in 5 of 6 patients treated after progression. In a small group of 5 PC patients relapsing during hormonal treatment with rapidly increasing PSA levels, octreotide administered as a subcutaneous infusion, at a dose of 400–1,000 Ìg/day for a period of 2–6 weeks offered only a moderate and temporary inhibition of PC growth [97, 98]. The author con-

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Table 4. Percentage and quality of response in 8

responding stage D2 PC patients after the combined treatment of CAB plus octreotide Previous treatment

Total Number Quality patients responding of response

No Yes CAB iHT

6 8 6 2

Total

3 (50) 3 (37.5) 1 (16.5) 2 (100)

14

3 (oPR + sCR) 1 (oNC + sPR) 1 (oPR + sPR)

6 (33)

Figures in parentheses represent percentage. iHT = Incomplete hormone treatment; CR = complete response; PR = partial response; NC = no change; o = objective; s = subjective.

cluded that more specific SST analogs may give better results possibly in higher doses, alone or in combination with LHRH agonists or antagonists. Slow-acting SST analog (Somatulin) in continuous intravenous infusion and in a dose escalation trial, administered to patients with advanced metastatic hormonerefractory PC, was well tolerated but no clinical responses were noted, even with the highest doses of 24 mg/day [99]. Somatulin treatment should be evaluated in less advanced PCs, or in combination with other antiproliferative agents. In the Theagenion Cancer Center my collaborators and I evaluated (in total) 18 carefully selected patients with advanced stage D2 PC and treated 14 of them with a combined treatment of CAB (castration or triptorelin plus flutamide) plus octreotide (Sandostatin), in doses of 0.2 mg ! 2 times/day, s.c. for at least 12 months [24]. 3 of 6 patients without previous hormone treatment (50%) showed the best response (objective partial plus subjective complete response). Among the 8 patients previously treated with hormone only 3

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Table 5. Natural history and follow-up of all 18 stage D2 PC patients after the treatment with CAB plus octreotide or CAB alone n

CAB R NR

Age years

Histology Diff.

Inv.

Duration of R months

Survival, months DFS

total

Deaths

Cause of death AHA

HF

Dis.

4 2 2

79 71

2 (high) 2 (low)

0 0

12 –

12 0

18 2

1 2

– 1

– 1

1 –

Octreotide + CAB 14 R 6 NR 8

68 68

5 (low) 8 (low)

1 3

17 –

17 –

18.5 4.5

5 8

1 2

– 2

4 4

R = Response; NR = no response; Diff. = differentiation; Inv. = invasive; DFS = disease-free survival; n = number; AHA = acute heart attack; HF = heart failure; Dis. = disease.

(37.5%) responded poorly to this treatment regimen (2 with no change and 1 with a partial objective response plus a partial subjective response) (table 4). The total response rate was 33% with a mean disease-free survival of 17 months compared to 12 months when CAB was given alone (table 5). Total mean survival was similar for the two therapy groups. IGF-1 and EGF serum levels during the combined treatment (with the addition of Sandostatin) decreased significantly in all responding patients, and corresponded to the drop in PSA levels, or eventually in prostatic acid phosphatase serum levels. These observations suggest that PSA and prostatic acid phosphatase levels as well as IGF-1 and EGF serum levels may be useful as a marker of SST analog therapy in advanced PC. Octreotide has a consistent and persistent suppressive effect on hormone release (for example in acromegaly), without the occurrence of therapy escapes. However, there are some escapes from the antineoplastic therapy of tumors. Thus, an escape from therapy occurs through the development of SSTR-negative tumor cell clones, or due to an early

insensitivity of hormonal secretion, related to downregulation of the SST receptors on these tumors. This downregulation can be restored after interruption of octreotide treatment. Additionally, a continuing sensitivity of hormone secretion to octreotide with a simultaneously progressive tumor growth may need an increase in the dose of octreotide, particularly if the somatostatin scintigraphy in vivo is positive [60]. IGF-1 serum levels do probably not remain consistently lowered during long-term octreotide treatment of patients with PC, because its suppressive effect is mostly transient; additionally, one would take into consideration that IGF-1 serum levels in cancer patients tend to decrease during tumor progression.

Octreotide and Prostatic Carcinoma

Chemotherapy 2001;47(suppl 2):109–126

Criticism of the Design of Clinical Trials Clinical trials with SST analog treatment of patients with metastatic hormone-refractory PC are based on multiple in vivo and in vitro studies in animal models and in patients with human PC. Unfortunately, at present the studies have major disadvantages, such as inclusion of only a small number of patients,

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inadequate trial design, in particular patient randomization in groups according to hormone resistance, and finally, the use of widely varying dosage regimens and routes of administration. Additionally, none of the trials hitherto reported has been based on SSTR determination before starting the SST analog therapy. In our clinical study octreotide was combined with CAB from the start [24], while in most other trials only the LHRH analog was added. We believe such a clinical trial should be planned at specific medical centers with extensive experience in this field. In summary, in planning clinical trials with SST analogs in patients with metastatic or advanced PC, it has to be decided (1) whether SSTR (based on scintigraphic results) should be included, (2) whether IGF-1 serum levels should be regularly measured during therapy, and (3) whether the dose of the SST analog used will be constant, increased, or even decreased according to the results of the in vivo scintigraphy measurements. Previous and recent clinical trials with octreotide in patients with PC leave uncertainty with regard to the optimal daily dose, the optimal route of administration, or the optimal duration of treatment.

Conclusions

Somatostatin seems to be an endogenous inhibitory GF in several organ systems, while exogenous SST analogs also have inhibitory effects on the growth of a variety of tumors; thus, one could speculate that the expression of SSTR on several PC cells might represent a general inhibitory control mechanism through which well-differentiated PC is inhibited in its growth. Thus SST analogs may have their place among the therapeutic antimitogen maneuvers in patients with metastatic and almost hormone-refractory PC.

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Chemotherapy 2001;47(suppl 2):109–126

Radiolabeled SST analogs with 123I, 131I or may detect the specific binding sites of these drugs, thus predicting their antiproliferative actions. PC could be partially visualized in vivo via an isotope-coupled SST analog and could be chronically treated with specific SST analogs according to a positive scan. Unfortunately, the value of the localization procedure with SSTR scintigraphy was lower in PCs than in other tumors. The detection of more than 2 SSTR subpopulations, of which 5 have been cloned, increases the possibility of using different SST analogs as selective antitumor agents for the treatment of disseminated hormone-resistant PC. Immunohistochemical NE differentiation of PC cells and serum NE hormonal markers may also predict the prognosis of such tumors or the usefulness of SST analog treatment in advanced PC.

111In

Projections for the Future

Multicenter, prospective, clinical, controlled trials are needed with a great number of patients randomized according to their status: with or without previous incomplete hormone treatment or refractory to hormone. Patients should be randomized to: (1) CAB only, (2) CAB plus appropriate SST analog, (3) SST analog only, (4) SST analog with systemic cytotoxic therapy, (5) SST analog with cytotoxic radicals, (6) SST analog with LHRH agonists/antagonists and finally (7) SST analog with GRP/bombesin-antagonists. Specific antimitogen-acting SST analogs should be controlled on the basis of SSTR subtype determination, thus predicting the specific analogs with the highest binding capacity and having the best antiproliferative actions on hormone-resistant PCs. New specific radiolabeled (with 123I, 131I, 111In) SST analogs, using scanning techniques, could

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demonstrate SSTR-positive PCs. Thus, they might be used to monitor the efficacy of therapy, and with the coupling of ß-emitting radionuclide should make a kind of brachytherapy possible. The development of slow-release SST analog preparations (subcutaneous, intramuscular or intranasal) may increase patient compliance with this long-term antitumor treatment.

Acknowledgments I am indebted to Dr. Frances Gillepsie, consultant anesthesiologist, for her skillful efforts in correcting the manuscript.

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Chemotherapy 2001;47(suppl 2):127–133

Gastrointestinal Cancer Refractory to Chemotherapy: A Role for Octreotide? Stefano Cascinu Vincenzo Catalano Paolo Giordani Anna Maria Baldelli Romina Agostinelli Giuseppina Catalano Section of Experimental Oncology, Division of Medical Oncology, Azienda Ospedaliera S. Salvatore, Pesaro, Italy

Key Words Octreotide W Gastrointestinal cancers W Chemotherapy

Abstract Although octreotide has been shown to inhibit the growth of gastrointestinal (GI) tumors in vitro and in vivo, preliminary clinical trials have reported disappointing results for this somatostatin analog in patients with GI cancers. The results of these trials probably reflect the difficulty in assessing the therapeutic potential of an agent such as octreotide in GI cancers. Thus, it is possible that treatment with octreotide could be useful in the stabilization of disease if it is associated with an improvement in survival. On the basis of these considerations five randomized trials were carried out to evaluate the therapeutic potential in patients with GI cancers.

ABC

© 2001 S. Karger AG, Basel 0009–3157/01/0478–0127$17.50/0

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Four trials (one in patients with colorectal carcinoma and three in patients with carcinoma of the pancreas) did not show any advantage of octreotide in untreated patients; in contrast, one trial reported that octreotide prolonged survival in patients with GI cancers refractory to chemotherapy. Some clinical features of the latter study (treatment with chemotherapy, different schedules) may explain these conflicting results. Although data from randomized trials suggest that octreotide is not effective in untreated asymptomatic advanced GI cancer patients, further studies are warranted to assess the efficacy of octreotide in chemotherapy refractory patients in order to clarify the impact of octreotide in terms of not only survival but also on the patients’ quality of life. Copyright © 2001 S. Karger AG, Basel

Stefano Cascinu, MD Division of Medical Oncology Maggiore University Hospital I–43100 Parma (Italy) Fax +39 521 995448

Gastrointestinal (GI) cancer accounts for a large proportion of all human tumors [1]. Although gastric cancer is declining in incidence, it remains the second most common malignancy in the world. Surgery is the only treatment which offers a chance of a complete cure for localized gastric cacarcinoma. However, at diagnosis 75% of all patients with gastric cancer have disseminated disease. Even among the subgroups of patients who undergo a potentially curative resection, relapse is common, consequently the 5-year survival ranges from 10 to 15% of all patients with newly diagnosed gastric cancer. Because of this poor outcome, the use of systemic treatment has been a subject of great interest. The currently available data indicate that with new combination cytotoxic regimens, approximately half of the patients with metastatized gastric cancer may benefit from chemotherapy by reduction of tumor-related symptoms and/or prolongation of survival [2]. In the western countries, colorectal carcinoma represents, after lung cancer, the second leading cause of deaths due to neoplasms. During the past decades, knowledge about this carcinoma has considerably increased, but in the advanced disease, little progress has been made in improving patient survival. In advanced colorectal cancer in fact (at least 40% of patients will have metastases sometime during the course of their illness) a standard treatment has not yet been established. For more than 30 years, fluorouracil has been the drug of choice even if tumor response rates are not more than 10–15%, with a median survival of about 1 year. Further innovative compounds (irinotecan, oxaliplatin) are now being evaluated in clinical trials producing promising results [3]. Carcinoma of the pancreas is the fourth cause of cancer-related death in the United States, with approximately 28,000 deaths recorded in 1997. Although there are worldwide

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variations, similar figures have been reported in other western countries, and about 30,000 deaths are reported in the European countries each year. Pancreatic cancer is an aggressive disease and only 5–22% of patients are eligible for a potentially curative resection at the time of diagnosis. Furthermore, the prognosis is unfavorable for this selected group of patients with only 10–30% 5-year survival rates. In patients with locally advanced or metastatic pancreatic cancer, conventional methods of treatment, including radiotherapy and chemotherapy, offer little benefit and their role in prolonging survival, ameliorating symptoms or improving quality of life still remains a matter of debate [4]. The outcome is even more dismal for patients with advanced gastrointestinal cancer nonresponsive to chemotherapy. Median survival for these patients is about 3–6 months, and symptoms are frequently difficult to control [5]. Consequently, there has been much interest in novel forms of therapy which may be more effective in patients with GI malignancies nonresponsive to chemotherapy. There is some evidence suggesting that GI tumors may be partly hormone-dependent and that hormonal manipulation may have a role to play in the management of these cancers [6]. In fact, previous studies have shown that the tumor growth and cellular proliferation are controlled by GI hormones and growth factors such as EGF and IGF-1 [7, 8]. One of the most important naturally occurring antiproliferative hormones is somatostatin. Somatostatin has been shown to inhibit proliferation of GI cancers both in vitro and in vivo [9]. However, the short halflife of native somatostatin (1–3 min) and the need for its intravenous administration makes long-term somatostatin therapy impractical [10]. Octreotide, a synthetic somatostatin analog, differs substantially from natural somatostatin in that it has a much longer half-life [11]. Octreotide inhibits the

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growth and development of tumor via one or more of the following mechanisms: a direct inhibitory effect on the tumor via specific somatostatin receptors, direct or indirect inhibition of the production of IGF-1 and/or other growth factors, inhibition of angiogenesis, reduction in tumor blood flow and stimulation of apoptosis. The possibility of a direct effect of octreotide on the tumor tissue implies that the tumor cells bear somatostatin receptors (SSTR). In recent years, it has been documented that many nonendocrine tumors bear somatostatin receptor subtypes. At present 5 somatostatin receptor subtypes have been cloned and characterized [12]. It was found that the antiproliferative effects of octreotide in vitro are mediated via the activation of the SSTR-2 subtype which is functionally a phosphotyrosine phosphatase [13]. The loss of SSTR-2 gene expression may provide a growth advantage for tumors which do not express this subtype and may explain, at least in part, the failure of somatostatin analogs to inhibit the growth and development of cancers. Furthermore, the restoration of SSTR-2 expression to human pancreatic cells resulted in a significant reduction in the growth of these cells [14]. Octreotide can also exert an antiproliferative effect by binding to SSTR-5 receptors and stimulate apoptosis by binding the SSTR-3 subtype. However, octreotide has little or no binding affinity to the somatostatin receptor subtypes expressed in gastric, pancreatic and colorectal cancers [12]. Nevertheless, octreotide has been demonstrated to inhibit their growth and development. These observations would suggest that octreotide can indirectly inhibit the growth and development in these tumors. Several studies have shown that EGF and IGF-1 may be implicated in the autocrine control of the growth and development of gastric and colorectal tumors. In vitro both EGF and IGF-1

promoted cell proliferation of gastric and colorectal cancer cell lines [15–17]. In addition, both growth factors enhanced the response of these cells to gastrin. Thus, the inhibition of the secretion of these trophic factors may have therapeutic potential in the management of GI cancers [18]. Recently, we have demonstrated that octreotide resulted in a significant decrease in serum IGF-1 levels in colorectal cancer patients which was associated with a decrease in the proliferative activity of the tumor cells [19]. Furthermore, we have demonstrated that there is no correlation between the dose of octreotide and the magnitude of serum IGF-1 levels [20]. Stewart et al. [21] and Iftikhar et al. [22] reported a similar interference in tumor cell kinetics after treatment with octreotide in patients with colonic and rectal cancer. According to data from Klijn et al. [23] no significant effects were observed in our patients on serum levels of HGH and EGF. The antiproliferative effects of octreotide may also be mediated by inhibition of angiogenesis. The inhibition of angiogenesis by octreotide in vivo could result indirectly from an inhibition of IGF-1 [24]. However, octreotide may also inhibit angiogenesis by suppression of paracrine angiogenic factors such as vascular endothelial growth factor. This suggestion is supported by the observation that octreotide significantly reduced serum and tissue vascular endothelial growth factor concentrations in patients with colorectal cancers [25]. Octreotide has been shown to inhibit the growth of GI tumors both in vitro and in experimental animal studies [15, 26, 27]. On the basis of these experimental data, pilot clinical trials with octreotide were carried out in GI tumors. In spite of the promising preclinical results, these initial studies in man were disappointing (table 1). Klijn et al. [23] treated 34 patients with gastric and colonic

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Table 1. Octreotide in GI cancers: pilot clinical trials

Authors, year

Reference Tumor No.

Number Clinical response of partial stable patients

Savage et al., 1987 Klijn et al., 1990

28 23

Friess et al., 1993 Rosenberg et al., 1995

31 33

10 16 14 4 22 12

Colon Colon Pancreas Stomach Pancreas Pancreas

0 0 0 0 0 0

4 4 3 1 3 3

Survival months

n.r. 8 2 n.r. 5 12

n.r. = Not reported.

cancers with octreotide. Although octreotide treatment stabilized the disease in 27% of these patients there was no benefit in terms of survival. However, interestingly most patients expressed a subjective improvement in the absence of serious side effects. Savage et al. [28] treated 10 patients without finding any indication that octreotide can alter the rate of growth of advanced GI tumors. In contrast, Smith et al. [29] found a modest increase in survival in 12 colorectal cancer patients treated with octreotide but no objective responses were observed. Similar results have been reported for patients with pancreatic cancer treated with octreotide, observing no benefit [30–32]. Conversely, Rosenberg et al. [33] reported an improvement in survival with a concomitant treatment of octreotide and tamoxifen compared to historical controls (12 vs. 3 months). Overall, these preliminary results in patients are disappointing but may reflect the difficulty in assessing the activity of an agent such as octreotide considering only the objective responses of tumors. It is possible in fact that treatment with octreotide could be useful even obtaining only a stabilization of disease if this is associated with an improvement in survival. These considerations were used to

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justify five randomized trials in which the major end points were survival and time to progression of disease. Three studies tested octreotide in untreated advanced pancreatic cancer and one in untreated advanced colorectal cancer [34–37]. However, none of the trials showed any benefit for octreotide treatment in terms of disease progression and survival (table 2). In 1995, we published the results of a randomized trial comparing octreotide with the best available supportive care in patients with advanced GI cancers refractory to conventional chemotherapy [38]. The primary outcome measure was duration of survival. Fiftyfive patients (15 stomach, 16 pancreas, 24 colorectal) received octreotide (200 Ìg 3 times a day for 5 days a week), while 52 (14 stomach, 16 pancreas, 22 colorectal) received the best supportive care only. The survival of patients treated with octreotide was significantly longer (median 20 weeks) than the 11 weeks of median survival observed in the control group (p ! 0.001) (table 3). This survival advantage of patients treated with octreotide was present in all three types of tumors. Furthermore, in 22 patients (40%) octreotide relieved pain and allowed discontinuation of analgesics.

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Table 2. Octreotide in GI cancers: randomized trials in untreated patients

Authors, year

Reference Treatment No.

Tumor

Number Survival of patients weeks

Goldberg et al., 1995

34

Octreotide Placebo

Colon

131 129

17 16.8

Burch et al., 1995

35

Octreotide Placebo

Pancreas

42 43

n.r. n.r.

Roy et al., 1998

36

Octreotide/5FU FU

Pancreas

284

22.6 21.6

Pederzoli et al., 1998

37

Octreotide Placebo

Pancreas

93 92

16 16.9

n.r. = Not reported.

Table 3. Octreotide in GI cancers: a randomized trial in refractory chemotherapy patients

Treatment

Octreotide Placebo

Number of patients

Survival, weeks

stomach

colorectal pancreas

stomach

colorectal pancreas

15 14

24 22

15 8

22 12

16 16

16 8

It is difficult to explain the disparity of our results and those of the other randomized trials. However, some clinical and methodological aspects could help to explain these different results. In our study, only patients with chemotherapy-refractory disease were entered, whereas other trials enrolled asymptomatic patients who had not been treated with chemotherapy. It is well known that chemotherapy can improve survival in patients with advanced GI cancer, so that cytotoxic drug administrations in some patients could have determined differences in survival. Unfortunately, in most of these trials the further treatments of patients failing octreotide therapy were not reported. Furthermore, there are

data suggesting that in the end stages of GI cancers, when bowel obstruction is present, octreotide may provide some symptomatic benefit, and may also be a determinant of survival [39]. Another problem arising from the studies cited above could be the continuous administration of octreotide for a prolonged period without interruptions. Preclinical data has shown that continuous administration of octreotide results in desensitization or tachyphylaxis of its inhibitory effects on somatostatin receptors and concomitant increase of plasma IGF-1 concentration within 6–10 days following initiation of therapy. Possibly, desensitization may be prevented or delayed

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if octreotide is administered intermittently as in our case [9]. Thus, although advanced GI cancer patients were included in these trials assessing the role of octreotide, there is a potential for the difference in activity due to the different subset of patients (untreated vs. refractory to chemotherapy, and so with ‘more advanced disease’) and to the variations in dose and schedule of octreotide.

In conclusion, the present data suggest that octreotide is not effective in the management of untreated asymptomatic GI cancer patients. Nevertheless, although we are aware that the interpretation of our results requires caution in view of other conflicting results in untreated patients, we believe that additional studies of octreotide are warranted to assess its efficacy in chemotherapy refractory GI cancer patients.

References 1 Ahlgren JD, Mac Donald JS: Gastrointestinal Oncology, ed 3. Philadelphia, Lippincott, 1992. 2 Schipper DL, Wagener DJT: Chemotherapy of gastric cancer. Anticancer Drugs 1996;7:137–149. 3 Labianca R, Pessi MA, Zamparelli G: Treatment of colorectal cancer. Drugs 1997;53:593–607. 4 Graziano F, Catalano G, Cascinu S: Chemotherapy for advanced pancreatic cancer: The history is changing. Tumori 1998;84:308–311. 5 Cascinu S, Fedeli A, Luzi Fedeli S, Catalano G: Salvage chemotherapy in colorectal cancer patients with good performance status and young age after failure of 5fluorouracil/leucovorin combination. J Chemother 1992;4:46–49 6 Townsend CM, Singh P, Thompson JC: Effects of gastrointestinal peptides on gastrointestinal cancer growth. Gastroenterol Clin 1989;18: 777–791. 7 Lahm H, Svardet L, Laurent PL, Fisher JR, Leyhan A, Givel JC, Odartchenko N: Growth regulation and co-stimulation of human colorectal cancer cell lines by insulin-like growth factors I, II and transforming growth factor ·. Br J Cancer 1992; 65:341–346. 8 Durrant LG, Watson SA, Hall A, Morris DL: Co-stimulation of gastrointestinal tumor growth by gastrin, transforming cell growth factor alpha and insulin like growth factors and cancer. Br J Cancer 1991;63: 67–70.

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9 Lamberts SWJ: Potential role of somatostatin analogues in the treatment of cancer. Eur J Clin Invest 1987;17:281–287. 10 Sheppard MC, Shapiro B, Pimstone B, Kronhein S, Berelowitz M, Gregory M: Metabolic clearance and plasma half disappearance time of exogenous somatostatin in man. J Clin Endocrinol Metab 1979;48:50– 53. 11 Lamberts SWJ, van der Lely AJ, de Herder WW, Hofland LJ: Octreotide. N Engl J Med 1996;334:246– 254. 12 Reubi JC: Octreotide and nonendocrine tumours: Basic knowledge and therapeutic potential, in Scarpignato C (ed): Octreotide: From Basic Science to Clinical Medicine. Prog Basic Clin Pharmacol. Basel, Karger, 1996, vol 10, pp 246–269. 13 Buscail L, Esteve JP, Saint-Laurent N: Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtype SSTR2 and SSTR5 through different mechanisms. Proc Natl Acad Sci USA 1995;92:1580– 1584. 14 Delesque N, Buscail L, Esteve JP, Saint-Laurent N, Muller C, Weckbecker G, Bruns C, Vaysse N, Susini C: SST2 somatostatin receptor expression reverses tumorigenicity of human pancreatic cancer cells. Cancer Res 1997;57:956–962. 15 Dy DY, Whitehead RH, Morris DL: SMS 201.995 inhibits in vitro and in vivo growth of human colon cancer. Cancer Res 1992;52:917–923.

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16 Pollak MN, Polychronakos C, Guyda H: Somatomedin analogue SMS 201–995 reduces serum IGF-I levels in patients with neoplasms potentially dependent on IGF-I. Anticancer Res 1989;9:889–892. 17 Baghdiguian S, Verrier B, Gerard C, Fantini J: Insulin like growth factor is an autocrine regulator of human colon cancer cell differentiation and growth. Cancer Lett 1992;62:23– 33. 18 Baserga R: The insulin-like growth factor I receptor: A key to tumor growth? Cancer Res 1995;55:249– 252. 19 Cascinu S, Del Ferro E, Grianti C, Ligi M, Ghiselli M, Foglietti G, Saba V, Lungarotti F, Catalano G: Inhibition of tumor cell kinetics and serum insulin growth factor I levels by octreotide in colorectal cancer patients. Gastroenterology 1997;113: 767–772. 20 Cascinu S, Del Ferro E, Ligi M, Rocchi MBL, Castellani A, Graziano F, Ghiandoni G, Catalano G: Lack of correlation between octreotide dose and decrease of serum insulin growth factor I in advanced colorectal cancer patients. GI Cancer 1997; 2:139–142. 21 Stewart GJ, Connor JL, Lawson JA, Preketes A, King J, Morris DL: Octreotide reduces the kinetic index, proliferating cell nuclear antigenmaximum proliferative index, in patients with colorectal cancer. Cancer 1995;76:572–578.

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22 Iftikhar SY, Watson SA, Morris DL: The effect of long acting somatostatin analogue SMS 201.995 therapy on tumor kinetic measurements and serum tumor marker concentrations in primary rectal cancer. Br J Cancer 1991;63:971–974. 23 Klijn JGM, Hoff AM, Planting ASTh, Verweij J, Kok T, Lamberts SWJ, Portengen H, Foekens JA: Treatment of patients with metastatic pancreatic and gastrointestinal tumors with the somatostatin analogue Sandostatin: A phase II study including endocrine effects. Br J Cancer 1990;62:627–630. 24 Mallet B, Vialettes B, Haroche S, Ecoffer P, Gastaut P, Taubert JP, Vague P: Stabilization of severe proliferative diabetic retinopathy by long-term treatment with SMS 201– 995. Diabète Métab 1992;18:438– 444. 25 Cascinu S, Del Ferro E, Ligi M, Staccioli MP, Giordani P, Catalano V, Agostinelli R, Muretto P, Catalano G: Inhibition of vascular endothelial growth factor by octreotide in colorectal cancer patients. Cancer Invest, in press. 26 Manni A: Somatostatin and growth hormone regulation in cancer. Biotherapy 1992;4:31–36. 27 Schally AV: Oncological applications of somatostatin analogues. Cancer Res 1988;48:6977–6985. 28 Savage AP, Calam J, Wood CB, Bloom SR: SM 201–995 treatment and advanced intestinal cancer: A pilot study. Aliment Pharmacol Ther 1987;1:133–139.

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29 Smith JP, Croitorou R, Townsend CM, Thompson JC: Effects of octreotide, a long-acting somatostatin analog, on advanced colon cancer. Gastroenterology 1992;102:399. 30 Ebert M, Friess H, Beger HG, Büchler MW: Role of octreotide in the treatment of pancreatic cancer. Digestion 1994;55:48–51. 31 Friess H, Büchler MW, Beglinger C, Weber A, Kunz J, Fritsch K, Dennler HJ, Beger HG: Low-dose octreotide treatment is not effective in patients with advanced pancreatic cancer. Pancreas 1993;8:540–555. 32 Friess H, Büchler MW, Ebert M, Malfertheiner P, Dennler HJ, Beger HG: Treatment of advanced pancreatic cancer with high-dose octreotide. Int J Pancreatol 1993;14:290– 291. 33 Rosenberg L, Barkun AN, Denis MH, Pollak M: Low-dose octreotide and tamoxifen in the treatment of adenocarcinoma of the pancreas. Cancer 1995;75:23–28. 34 Goldberg RM, Moertel CG, Wieand HJS, Krook JE, Schutt AJ, Veeder MH, Maillard JA, Dalton RJ: A phase III evaluation of a somatostatin analogue (octreotide) in the treatment of patients with asymptomatic advanced colon carcinoma. Cancer 1995;76:961–966.

35 Burch PA, Block M, Wieand HS, Veeder MH, Michalak JC, Hatfield AK, Wright K: A phase III evaluation of octreotide versus chemotherapy with 5FU or 5FU/leucovorin in advanced exocrine pancreatic cancer. Proc Am Soc Clin Oncol 1995; 14:488. 36 Roy A, Jacobs A, Bukowsky R, Cunningham D, Hamm J, Schlag PM, Rosen P, Francois E, Finley G, Lipton A, Bruckner H, Haller D, Conroy T, Goel R, Price P, Smith G, Mietlowski W, Linnart R, Russo D, Kay A: A phase III trial of SMS 201– 995 LAR and continuous infusion 5FU in unresectable stage II, III, IV pancreatic cancer. Proc Am Soc Clin Oncol 1998;17:987. 37 Pederzoli P, Maurer U, Vollmer K, Büchler MW, Kjaeve J, Van Cutsem E, Di Carlo V, Stauder H, Bergan A, Ebert M, Kiese B, Raymond MC, Kay A: Phase III trial of SMS 201– 995 LAR vs placebo in unresectable stage II, III, IV pancreatic cancer. Proc Am Soc Clin Oncol 1998;17: 988. 38 Cascinu S, Del Ferro E, Catalano G: A randomized trial of octreotide vs best supportive care only in advanced gastrointestinal cancer patients refractory to chemotherapy. Br J Cancer 1995;71:97–101. 39 Mercadante S, Spoldi E, Caraceni A, Maddaloni S, Simonetti MT: Octreotide in relieving gastrointestinal symptoms due to bowel obstruction. Palliat Med 1993;7:295–299.

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Pancreatic Cancer: Does Octreotide Offer Any Promise? Lawrence Rosenberg The Pancreatic Diseases Centre, McGill University Health Centre and Department of Surgery, McGill University, Montreal, Canada

Key Words Pancreatic cancer W Somatostatin W Somatostatin receptors W Somatostatin analogs W Octreotide W RC-160

Abstract The incidence of adenocarcinoma of the pancreas has risen steadily over the past 4 decades. Since pancreatic cancer is diagnosed at an advanced stage, and because of the lack of effective therapies the prognosis of such patients is extremely poor. Despite advances in our understanding of the molecular biology of pancreatic cancer, the systemic treatment of this disease remains unsatisfactory. Systemic chemotherapy and the administration of biologically active molecules such as tumor necrosis factor or interferons have not resulted in significant improvements in response rates or patient survival. New treatment strategies are obviously needed. This paper will discuss current advances in the use of somatostatin analogs in the management of pancreatic cancer. Copyright © 2001 S. Karger AG, Basel

ABC

© 2001 S. Karger AG, Basel 0009–3157/01/0478–0134$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/che

Introduction

The incidence of adenocarcinoma of the pancreas has risen steadily over the past 4 decades. It currently stands at approximately 29,000 new cases per year in North America [1], making it the second most common gastrointestinal malignancy and the fifth leading cause of adult deaths from cancer [2]. The disease is characterized by its aggressive nature. The diagnosis of pancreatic cancer is usually established at an advanced stage, and a lack of effective therapies leads to an extremely poor prognosis. A meta-analysis of 144 reported series including approximately 37,000 patients found the median survival time to be 3 months [3]. According to these findings, 65% of patients with pancreatic cancer will die within 6 months from the time of diagnosis, and about 90% within 1 year. Surgical resection, if performed early enough, is presently the only effective form of curative therapy [4]. However, fewer than 15% of patients with pancreatic cancer are potential candidates for a curative resection [5] due to spread of the cancer to adjacent tissues or beyond [6]. Only

Dr. Lawrence Rosenberg Montreal General Hospital, 1650 Cedar Ave., L9-424 Montreal, Que. H3G 1A4 (Canada) Tel. +1 514 937 6011, ext. 4346, Fax +1 514 934 8210 E-Mail [email protected]

1–4% of patients with adenocarcinoma of the pancreas will survive 5 years after diagnosis [7, 8]. Thus, the incidence rates are virtually identical to mortality rates. Approximately half of all patients with pancreatic cancer have metastatic disease at the time of diagnosis [9, 10], while most of the rest have locally advanced, unresectable disease [11, 12]. Metastatic pancreatic cancer is one of the most chemotherapy-resistant tumors, as evidenced by the fact that pancreatic cancer has the lowest 5-year survival rate (3%) of any cancer listed in the Surveillance, Epidemiology and End Results (SEER) data base of the NCI [13]. Computed tomography (CT) and magnetic resonance imaging have made it easier to determine the diagnosis and to define the stage of the disease. CT-guided needle biopsies and laparoscopy have resulted in fewer unnecessary laparotomies, while biliary stenting can reduce the need for an invasive operative procedure in patients with advanced tumors. Unfortunately, these advances have not resulted in disease detection at an earlier stage [14]. Reports of 5-year survival among patients managed with nonsurgical therapies remain anecdotal. Thus, of 150 patients who have survived for more than 10 years after their diagnosis of pancreatic cancer, only 12 have been cured by nonsurgical therapies [3]. Clearly more effective therapies need to be developed.

occupational exposure [15, 16]. Currently, cigarette smoking is the most firmly established risk factor associated with pancreatic cancer. Pancreatic malignancies can be induced in animals through long-term administration of tobacco-specific N-nitrosamines or by parenteral administration of other N-nitroso compounds [17–19]. Induction of pancreatic cancer in these experimental models can be influenced by additional factors, including changes in bile acid composition, cholecystokinin levels, diet and pancreatic duct obstruction [20–23]. Clinically, numerous case-control and cohort studies have reported an increased risk of pancreatic cancer for smokers in both the United States and Europe, and current estimates suggest that approximately 30% of pancreatic cancer cases may be attributed to cigarette smoking [24, 25].

Pathology

Most malignant pancreatic tumors (95%) are believed to arise from the exocrine portion of the gland and have light-microscopic features consistent with those of adenocarcinomas. Much more infrequent are tumors that arise from acinar cells or islet cells. Primary nonepithelial tumors of the pancreas (e.g. lymphomas or sarcomas) are exceedingly rare.

Natural History of Pancreatic Cancer

A number of factors that may contribute to the pathogenesis of pancreatic cancer have recently been identified. These have been classified as environmental factors, pathological factors (e.g. chronic pancreatitis), genetic factors (e.g. familial pancreatic cancer), and

Adenocarcinoma of the pancreas metastasizes to regional lymph nodes at an early stage of the disease, and subclinical liver metastases are present in the majority of patients at the time of diagnosis, even though findings from imaging studies may be otherwise normal. Patients who undergo surgical resection for localized nonmetastatic cancer of the head of

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Epidemiology and Etiologic Factors

135

the pancreas have a long-term survival rate of approximately 20% and a median survival of 15–19 months. However, disease recurrence following a potentially curative Whipple resection is the norm. Local recurrence occurs in up to 85% of patients who undergo surgery alone, and local-regional tumor control may be improved by combined modality therapy involving both chemoradiation and surgery. Liver metastases then become the dominant form of tumor recurrence and occur in 50–70% of patients following potential curative combined modality treatment. Patients with locally advanced, nonmetastatic disease have a median survival of 6–10 months, while those with metastatic disease have a short survival (3–6 months), the length of which depends on the extent of disease and performance status. Because of the prognosis and the patterns of treatment failure associated with adenocarcinoma of the pancreas, any proposed treatment must not be worse than the disease. The low cure rate and modest median survival following Whipple’s resection mandate that treament-related morbidity be low and treatmentrelated death be rare. A recent report of the experience from Johns Hopkins [26] demonstrates that this can be achieved by careful selection of patients who undergo therapy. In addition, however, the development of innovative treatment strategies directed at the known sites of tumor recurrence should be directed towards improvements in patient survival and quality of life.

A Brief History of Pancreatic Cancer Therapies

Phase II Trials Single-agent phase II trials in patients with advanced pancreatic cancer reported large variations in response rates [27, 28]. In evalu-

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ating these studies, it is important to recognize that the clinical trial methodology and the criteria for judging objective response have changed over time [27]. Phase II trials in the 1970s frequently included patients with a variety of different tumors in a single trial, and therefore the published response rates were often based on a small number of patients with a particular cancer. As a result, these studies were difficult to interpret from a statistical point of view. Prior to 1985, trials relied primarily on an estimation of tumor size by physical examination, and responses were defined as shrinkage of a palpable abdominal mass by 50% or more, or a reduction in the palpable liver span by 30% or more [28]. The inherent inaccuracy of these techniques, intraobserver and interobserver variability, and the influence of confounding factors on the size of the measured lesions all contributed to the initial reports of high response rates for drugs such as 5-fluorouracil (5-FU), chlorambucil, and mitomycin, as well as the failure to confirm these promising response rates in subsequent trials, especially when CT scans were used to determine tumor response [27]. Phase III Trials Two kinds of comparative studies have been carried out in patients with advanced pancreatic cancer: (1) those that compared active treatment to best supportive care (to determine whether chemotherapy made any difference in the outcome of these patients), and (2) those that compared multiple agent regimens to single-agent chemotherapy (to determine whether combinations of drugs with distinct mechanisms of action could improve outcome compared to that achieved by single agents) [27]. Of the three trials that compared active treatment to best supportive care, two demonstrated no significant difference [29, 30], and the third suggested a substantial sur-

Rosenberg

vival advantage in favor of a five-drug regimen [31]. However, subsequent trials of the regimen failed to duplicate the promising results of the original study [32]. Despite a number of potentially interesting preclinical findings and promising phase II studies, virtually no progress has been made in the chemotherapy for advanced pancreatic cancer during the past 30 years.

Gemcitabine Gemcitabine is a deoxycytidine analog with structural similarities to cytarabine. As a prodrug, gemicitabine must be phosphorylated to its active metabolites – gemcitabine diphosphate and gemcitabine triphosphate. In both preclinical and clinical testing, gemcitabine demonstrated greater activity against solid tumors than did cytarabine [42]. These observations have been explained by the following properties of gemcitabine: (1) it is 3–4 times more lipophilic than cytarabine, resulting in greater membrane permeability and cellular uptake; (2) it has higher affinity for

deoxycytidine kinase, and (3) the intracellular retention of gemcitabine triphosphate, an active metabolite, is prolonged [43]. Following a phase I study [44], gemcitabine was evaluated in a multicenter trial of 44 patients with advanced pancreatic cancer [45]. Although the objective response rate to this drug was only 11% and median survival was 5.6 months, a number of potentially important observations were made in this trial [45]. The 1-year survival rate was a remarkably high 23%, and the responses observed appeared to be somewhat prolonged, i.e. from 4 to more than 20 months. Perhaps the most unexpected outcome of this study, however, was the impact of gemcitabine on tumorrelated symptoms. Of the 5 patients who had an objective response to gemcitabine, 4 were able to resume normal daily activities. Three of the 5 patients were also able to reduce their daily requirement for analgesics. An additional 14 patients who did not meet the radiological criteria for an objective response experienced disease stabilization for 4 months or more, and, of these, 9 had an improvement in performance status. One hundred sixty patients with newly diagnosed, unresectable pancreatic cancer were recruited in a phase III trial [46]. A total of 126 patients completed a period during which pain was stabilized and then they were randomized to treatment with gemcitabine or 5-FU. Fifteen patients (23.8%) treated with gemcitabine achieved a clinical beneficial response compared with only 3 patients (4.8%) treated with 5-FU (p = 0.002). The median duration of the clinical beneficial response for gemcitabine-treated patients was 18 weeks compared to 13 weeks for the 5-FU-treated patients. Gemcitabine also proved superior to 5-FU in terms of the trial’s secondary endpoints. Median survival for gemcitabinetreated patients was 5.6 months compared to 4.4 months for 5-FU-treated patients. In addi-

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Current Approach to Single-Agent Chemotherapy The thymidylate synthase inhibitor 5-FU remains the most extensively evaluated chemotherapeutic agent for pancreatic cancer [33–35]. Despite numerous trials, however, its efficacy remains questionable. Between 1991 and 1994, 25 investigational new drugs were evaluated in phase II trials for the treatment of pancreatic cancer. The median response rate in these trials was 0% (range 0– 14%) and the median survival was 3 months [28]. Inactive drugs that have undergone evaluation over the past 5 years include iproplatin [36], trimetrexate [37], edatrexate [38], fazarabine [39], diaziquone [40], mitoguazone [40], and amonafide [41]. One trial conducted during this period focused on gemcitabine (2),2)-difluoro-2)-deoxycytidine).

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tion, the probability of survival at 1 year was 18% in the gemcitabine group, significantly greater than the 2% in the 5-FU group. Few objective responses, however, were observed in either treatment arm. A subsequent phase II study enrolled 63 patients with pancreatic cancer that had progressed despite treatment with 5-FU [47]. To be eligible for the trial, patients had to have a significant degree of tumor-related symptoms. In this study, 17 patients (27%) experienced a clinically beneficial response to gemcitabine, the median duration of which was 14 weeks. Median survival of all patients treated in this trial was 3.8 months. Objective responses were seen in 6 (10.5%) of the 57 patients with measurable disease. While these results could suggest that gemcitabine should become the accepted firstline therapy for patients with advanced pancreatic adenocarcinoma, the median survival for patients with metastatic disease was still less than 6 months, with few patients achieving long-term disease stabilization. Furthermore, some of the effects attributed to chemotherapy may not be substantially different from what can be achieved with aggressive supportive care alone. In fact the use of clinical benefit response as a valid means to determine the efficacy of gemcitabine has itself been questioned [48]. Thus the median survival was less than 4 months, and 85% did not survive 7 months. Eight patients had extension to regional organs or lymph nodes without distant metastases. One patient survived 4.4 years following the completion of a trial of 5-FU and the start of gemcitabine. Thus, there is no evidence from this study that gemcitabine improved the survival of patients with pancreatic cancer. The quality of life one seeks to evaluate by defining net patient benefit must take into account the duration of remaining survival available to the patient. Gelber [48] has sug-

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gested that performing treatment comparisons based on the amount of time patients spend in clinical health states characterized by relatively good quality of life might be a better indicator of net patient benefit than defining a percentage of patients who achieve some criteria of response. The fact that treatments which produce higher response rates do not always yield better survival also argues against putting too much emphasis in estimating response rates as a guide to net benefit. Seventeen patients had a clinically beneficial response in the phase II study, and the investigators claimed that the treatment was generally well tolerated [47]. However, although the toxicities were reported as moderate, more patients had some noticeable adverse experiences than achieved a clinical benefit response. The evidence for substantial benefit for gemcitabine is not overwhelming, and additional studies will be required to more fully define its role in the treatment of pancreatic cancer.

Other Approaches to Pancreatic Cancer

Despite advances in our understanding of the molecular biology of pancreatic cancer, the systemic treatment of metastatic disease remains unsatisfactory. Systemic chemotherapy and the administration of biologically active molecules such as tumor necrosis factor or interferons [49, 50] have not resulted in significant improvements in response rates or patient survival. New treatment strategies are obviously needed. A number of more general areas of investigation may yield more promising results. One of these involves interruption or modulation of growth factors and signal transduction pathways. One example is the successful treatment of carcinoma of the breast that has been achieved by endocrine

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manipulation. The presence of estrogen receptors on neoplastic breast tissue is correlated with response to ovarian ablation and/or antiestrogen treatment. A similar approach to the treatment of pancreatic cancer seems justified because of the presence of estrogen receptors in pancreatic carcinoma [51–54] as well as in normal pancreatic tissue [55, 56]. In fact, the use of tamoxifen in 80 patients with ductal adenocarcinoma of pancreas has been reported in a case-control study to increase the median survival time from 3 to 7 months [57, 58]. However, steroid hormones may not be the most important regulator of pancreatic cell proliferation. Other potential influences include the growth factor IGF-1 and the growth inhibitor somatostatin.

Somatostatin is a tetradecapeptide that elicits a variety of biological processes including inhibition of hormonal secretion and cell proliferation [59]. In some patients, analog therapy leads to an inhibition of tumor growth [60–62]. However, the use of native somatostatin is limited because of its very short plasma half-life and the need for continuous infusion. The recent development of long-acting somatostatin analogs, such as RC160 and octreotide, however, has made clinical trials possible. These properties of somatostatin form the basis for the treatment of hormone-producing pituitary or gastroenteropancreatic tumors by long-acting analogs of the native hormone [60]. Thus, hormonal suppression is produced in patients with acromegaly or with neuroendocrine tumors such as insulinoma, glucagonoma, gastrinoma, vipoma, or carcinoid syndrome by somatostatin analogs resulting in symptomatic relief [60].

Somatostatin can exert an antiproliferative activity by either indirectly inhibiting angiogenesis or hormone and growth factor release, or by acting directly on neoplastic cells [59, 60, 62]. For example, a number of gastrointestinal hormones, including gastrin and cholecystokinin, have trophic effects on pancreatic tissue [63] and can stimulate the growth of pancreatic tumors. Somatostatin suppresses the secretion and action of these peptides, and this may also contribute to its antiproliferative activity [64, 65]. In addition, somatostatin and its analogs may also act by reducing levels of growth factors such as EGF and IGF1 that are thought to be important in neoplastic processes [66–70]. This latter possibility is of considerable interest because both tamoxifen [70] and octreotide [71] have been shown to lower circulating levels of IGF-1 and the combination has recently been reported to lower IGF-1 levels more substantially than either agent alone [72]. This observation raises the possibility of therapeutic synergy if the two agents were used together, a suggestion which is supported by a report that tamoxifen and octrotide are an effective treatment for human pancreatic cancers growing in nude mice [73]. However, as appealing as this suggestion is, Klijn et al. [74] measured insulin, IGF-1, and EGF levels in a clinical study of the use of octreotide for pancreatic cancer. Chronic treatment with a octroetide had no effect on EGF levels. However, these investigators observed early significant decreases in insulin and IGF-1; the levels of both growth factors had returned to pretreatment values by 5 days and 4 weeks, respectively. This may have been due to the downregulation of the receptors responsible for inhibiting the release of these trophic factors. This is a well-recognized effect of even short-term treatment with octroetide, e.g. loss of initial potent inhibitory effects, which may be manifested clinically as tachyphylaxis. This study

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Scientific Background for the Use of Somatostatin-Based Therapies

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does not support suppression of trophic peptides as an important mechanism by which somatostatin inhibits pancreatic cancer, but it does not eliminate the possibility that these hormones may influence pancreatic tumor growth. The direct actions of somatostatin are mediated by specific receptors that have been detected using binding assay or autoradiography in various human normal and tumor tissues [59, 60]. Recently, five somatostatin receptor subtypes (SSTR-1–5) and one splice variant have been cloned from humans, mice and rats [75–80]. Buscail et al. [81, 82] have demonstrated a distinct profile for binding of clinically used somatostatin analogs, SMS 201-995 (octreotide), BIM 23014 (lanreotide), and RC-160 (vapreotide). These analogs bind with high affinity to SSTR-2, SSTR-3, and SSTR-5 and with low affinity to SSTR-1 and SSTR-4 [75– 85]. The biological functions mediated by the five SSTR(s) have not yet been completely established. Recently, after stable expression of SSTR(s), it was demonstrated that only SSTR-2 and SSTR-5 mediated the antiproliferative effect of the somatostatin analogs octreotide and vapreotide [82, 83]. The inhibition of tumor growth by somatostatin and its analogs is rather more complex than these studies would imply, and many gaps remain in our knowledge. For instance, it is difficult to measure the binding affinities of the somatostatin analogs and their selectivity, since most competitive studies use different SSTR receptor clones from different species expressed in different cell lines and tested with different radioligands [86–88]. The antiproliferative action of somatostatin and its analogs on pancreatic cancer has been demonstrated in vitro and in vivo. Schally [62] reported that the somatostatin analog RC-160 reduced the weight and volume of the tumor and prolonged host survival

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in nitrosoamine-induced pancreatic carcinoma in Syrian golden hamsters. Upp et al. [89] demonstrated that octreotide inhibited the growth and development of two human pancreatic cancers, SKI and CAV, in nude mouse xenografts. In keeping with these findings, recent experimental evidence has indicated that somatostatin analogs may act directly on neoplastic cells by upregulating activity of phosphotyrosine phosphatases [81, 90], an activity which would be expected to reduce proliferation stimulated by growth factors that act via tyrosine kinase signal transduction pathways. In fact, Fisher et al. [91, 92] have reported that when somatostatin receptors were present on pancreatic tumor cell lines, somatostatin analogs inhibited their proliferation both in vivo and in vitro. Eleven specimens of pancreatic adenocarcinoma tissue were harvested from patients undergoing surgery and nine human pancreatic carcinoma cell lines were maintained in vitro. All tumors were assayed for expression of mRNA of all five somatostatin receptors using RT-PCR. Their findings with the MIA PaCa-2 cell line are consistent with the results of previous studies [73, 90, 93–95] and support the hypothesis that high numbers of high affinity somatostatin receptors on the surface of pancreatic tumors render the tumor susceptible to inhibition by somatostatin. Their study indicated that seven of nine pancreatic cell lines showed expression of at least one subtype of somatostatin receptor mRNA, but only one cell line showed functional somatostatin receptors on the surface. In this regard, these findings are consistent with previous studies showing that somatostatin receptors are rarely detected on the surface of pancreatic adenocarcinomas [96]. Data also suggests that the presence of mRNA for the somatostatin receptor in the clinically acquired specimens cannot be taken as evidence of the pres-

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ence of cell surface somatostatin receptors in those tumors. Among the recently cloned somatostatin receptor subtypes, SSTR-2 displays the highest affinity for the somatostatin analogs [75, 79–83, 85]. It has been demonstrated that this subtype mediates the antiproliferative effect of the stable analogs octreotide and vapreotide through the stimulation of a tyrosine phosphatase activity, both in rat pancreatic cells that endogenously expressed SSTR-2 and in cells transfected with SSTR-2 cDNA [81, 82, 97, 98]. In contrast to that observed in normal tissue or benign lesions, there is a loss of gene expression of SSTR-2 in pancreatic adenocarcinoma, and metastases derived from these primaries. In addition, SSTR-2 was not expressed in the pancreatic cancer cell lines, except in the MIA PaCa-2 cells. Interestingly, RC-l60 inhibited growth of this latter cell line both in vitro and in vivo through binding of highaffinity sites and stimulation of a tyrosine phosphatase activity [90]. The molecular mechanism responsible for downregulation of SSR2 gene expression could occur at the transcriptional or translational level. Because expression of the SSR2 gene appears to predict the response of pancreatic cancer to octreotide, strategies to increase SSR2 gene expression in tumors lacking such receptors may prove beneficial. All of these observations argue in favor of the role of SSTR-2 in the negative regulation of pancreatic cell growth. The loss of expression of SSTR-2 in neoplastic pancreatic cells may provide a growth advantage for tumors and their metastases. Moreover, a direct antiproliferative effect of somatostatin and its analogs may thus be excluded in the absence of SSTR-2 receptors. The mRNAs of SSTR-1, SSTR-4 and SSTR-5 subtypes are present both in normal and cancerous tissues from exocrine pancreas.

We found previously that among these three subtypes, SSTR-5 also mediated the antiproliferative effect of somatostatin analogs [82]. However, the mechanism implicated in the mediation of cell growth inhibition does not involve activation of tyrosine phosphatase activity [82]. In these conditions, and contrary to SSTR-2, activation of SSTR-5 cannot counteract the effect of growth factors acting via tyrosine kinase-dependent receptors [82] such as epidermal growth factor, insulin-like growth factor, and insulin that are implicated in the growth of pancreatic and colon cancers [60, 90, 98, 99]. Only a few studies have so far addressed the potential benefit of combined treatment with octreotide and various chemotherapeutic agents. Lamberts et al. [100] combined octreotide with vincristine, methotrexate, 5FU or suramin and found an additive interaction. More recently, Weckbecker et al. [101] demonstrated the inhibitory effect of octreotide in combination with the chemotherapeutic agents Taxol, 5-FU, doxorubicin and mitomycin C on the growth of AR42J pancreatic cancer cells in vitro. The dose-dependent antiproliferative effects of mitomycin C, doxorubicin and Taxol were synergistically enhanced by octreotide. Combinations of octreotide and 5-FU resulted either in additive or, at high concentrations of the chemotherapeutic agent, in synergistic interactions. These experiments suggest a modulatory role for octreotide in combination with widely used anticancer drugs. The additive to synergistic interaction of octreotide with these chemotherapeutic agents in in vitro and in vivo models warrants clinical studies to explore the potential of such combinations in the treatment of pancreatic cancer.

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Clinical Studies: Somatostatin and Its Analogs

Preliminary results of somatostatin analog therapy in patients with tumors other than pancreatic have been encouraging [102–106]. The rationale for the use of somatostatin and its analogs can be briefly summarized as follows. Somatostatin decreases growth of the normal pancreas [107], and at least one somatostatin analog, SMS 201-995, inhibits the growth of human pancreatic adenocarcinoma in nude mice [89]. The demonstration of somatostatin receptors in exocrine pancreatic adenocarcinomas [107] and the large body of evidence [73, 108–114] demonstrating antiproliferative activity of somatostatin and somatostatin analogs on experimental pancreatic neoplasms in vitro and in vivo justify clinical studies on the potential therapeutic role of these drugs in pancreatic cancer. The first clinical study on somatostatin analog treatment was published by Klijn et al. [115]. This group [74] went on to treat 14 patients who had metastatic pancreatic cancer with three daily subcutaneous injections of octreotide (100–200 pg/injection) for an average of 7 weeks and observed no antitumor effect. Friess et al. [116, 117] and Ebert et al. [118], using octreotide at a low dose level [3 ! 100–200 Ìg/day) and a high dose level (3 ! 2000 Ìg/day), suggested that the effects of this somatostatin analog were dose-dependent. These observations are in accord with the dependent relationship of somatostatin analogs on the proliferation in breast cancer cell lines [119]. In the high-dose study of Friess et al. [117], the median survival increased from 4 to 6 months with symptomatic and clinical improvement. A positive impact on the course of disease was confirmed by a randomized trial of octreotide versus best supportive care [120] based on a low-dose

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therapy given 5 days/week. In this trial a significant advantage in duration of survival and in percentage of stable disease was observed for the octreotide-treated patients although no objective response was reached. The only objective response reported for somatostatin analogs in pancreatic cancer was observed by Canobbio et al. [121], who administered BIM 23014 in dosages between 250 and 1,000 Ìg/day to 18 evaluable patients. However, only one partial response was observed at the highest dose level. Huguier et al. [122] in a randomized prospective study of 86 patients who were given a similar treatment regimen demonstrated no significant increase in median survival rates using life table analysis. Weckbecker et al. [123] have demonstrated potentiation of the anticancer effect of tamoxifen by concomitant infusion of highdose octreotide in the rat DMBA mammary cancer model. In order to further define a possible beneficial role for combination hormonal therapy with octreotide and tamoxifen, Rosenberg et al. [124] studied the effect of chronic administration of these two inhibitory agents on survival of a prospective series of 12 consecutive patients with biopsy-proven ductal adenocarcinoma of the pancreas followed up from 1990 to 1993. Five of these patients had resectable disease and the remaining 7 were deemed unresectable. Treatment consisted of 100 Ìg of octreotide subcutaneously 3 times daily and 10 mg of tamoxifen orally twice daily. Patients had regular follow-up examinations at 4- to 6-week intervals until the time of death. The major outcome was the median duration of patient survival in months from the time of diagnosis. The outcome of this group of patients was compared to a cohort of 68 patients with a biopsy-documented diagnosis of ductal adenocarcinoma of the pancreas treated between 1985 and 1990. Data was collected on age, gender, stage

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at diagnosis (based on the TNM classification of the International Union against Cancer), type of treatment and duration of survival from the time of diagnosis. The median survival times of the octreotide/tamoxifen-treated group and the historical cohort were 12 and 3 months, respectively, and the 1-year actuarial survival was 59 and 16%, respectively. The median survival times of the resected (n = 5) and the unresected patients (n = 7) were 20 and 12 months, respectively, and the 1-year actuarial survival was 80 and 31%, respectively. The median survival times of the resected octreotide/tamoxifen-treated group and the resected historical cohort were 20 and 12 months, respectively, and the 1-year actuarial survival was 80 and 44%, respectively. The median survival times of the 7 unresected octreotide/tamoxifen-treated patients and the 59 unresected historical patients were 12 and 2.5 months, respectively, and the 1-year actuarial survival was 31 and 11%, respectively. Cox’s proportional hazard analysis confirmed that treatment and resection both independently predicted a longer survival (p ! 0.01). The significance of a possible interaction between both treatment and resection could not be fully determined due to the small sample size. Although an assessment of quality of life and pain control was not prospectively assessed in this study, a post hoc analysis demonstrated that morphine sulfate was not required until the final 4–6 weeks of illness in 9 of 12 patients that had already succumbed to their disease. CT scanning examinations of the twelve cases were performed at intervals of 6–8 weeks. No objective responses were seen in terms of tumor regression; rather the data was more consistent with a slowing of tumor progression. The 3 patients surviving at the time of publication had stable disease.

Possible explanations for the apparent benefit of octreotide/tamoxifen therapy in this study include (1) diagnosis of the historical cohort later in the course of the disease, (2) diagnosis of the cases earlier in the course of the disease, or (3) a change in the biological aggressiveness of the disease as a consequence of treatment. The first two explanations are unlikely as the data indicated that the stage at which the disease was diagnosed in cases and the cohort was similar. While it might appear that more patients in the octreotide/tamoxifen-treated group underwent resection, and were therefore ‘more curable’, the TNM stage at the time of diagnosis was similar in both groups. The most recent report is the phase II study by Fazeny et al. [125], which was designed to investigate the efficacy and toxicity of octreotide combined with goserelin in patients with advanced pancreatic cancer. Octreotide was injected subcutaneously in dosages increasing weekly, starting with 50 Ìg twice daily, until the level of maintenance therapy of 500 Ìg 3 times a day was reached. In addition, 3.8 mg goserelin acetate was administered subcutaneously at monthly intervals. A median of 7 cycles (range 1–27 cycles) was applied. In comparison to the 40% of patients who had no change in their disease while on high-dose octreotide [117], Fazeny et al. [125] demonstrated that 500 Ìg octreotide 3 times per day in combination with goserelin resulted in one partial response and no disease progression in 70% of participants. The observations suggest that combining octreotide with an LHRH analog might be of therapeutic benefit in patients with pancreatic cancer and could compensate for the potential advantage of a higher dose of octreotide. Overall, however, the regimen under investigation did not meet the criteria for sufficient antitumor effectiveness. Nevertheless, this study reinforces the concept that pancreatic cancer is principally re-

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sponsive to endocrine therapy and therefore the further investigation of hormonal manipulation seems worth while in the future.

Conclusions

In summary, while it is clear from the numerous studies conducted on experimental neoplasms in vitro and in vivo that somatostatin analogs inhibit growth of exocrine pancreatic cancers, clinical studies have demonstrated that somatostatin analog therapy probably does not produce an adequate clinical response in patients with advanced pancreatic cancer. An explanation for the discrepancy between the animal and human trials has not been elucidated. It is possible that a higher dose of somatostatin and its analogs should have been used in the human trials. Many of the animal studies used doses at least an order of magnitude greater than those used in the clinical trials. However, it is possible that the main reason for the failure of adjuvant treatment with somatostatin analogs is that most human pancreatic cancers lack receptors for somatostatin. Somatostatin binding sites were poorly expressed or not detected in many tumors from nonresponsive patients [60, 108, 126], and this could be one of the explanations for a lack of direct antiproliferative effect of analog therapy. Moreover, considering the differences in the pharmacological profile and the biological function mediated by somatostatin receptor subtypes, the therapeutic response may depend on the subtype expression for a given tumor. In contrast to that observed in normal tissue or benign lesions, there is a loss of gene expression of SSTR-2 in pancreatic adenocarcinomas, and metastases derived from these primaries [127]. The loss of expression of SSTR-2 in neoplastic pancreatic cells may provide a

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growth advantage for tumors and their metastases. Therefore, a direct antiproliferative effect of somatostatin and its analogs may thus partly be excluded in the absence of SSTR-2. Alternatively, the different results of animal and human studies with different analogs of somatostatin may reside in the fact that there are different binding affinities of the various somatostatin analogs to somatostatin receptors [107, 126, 128].

Future Directions

The management of pancreatic cancer has improved relatively little in the past few decades; the major advances have been better preoperative staging and a decrease in surgical morbidity and mortality. New cytotoxic drugs, novel biological agents or biological response modifiers, new surgical and radiotherapeutic techniques, or a combination of these modalities have all failed to have any appreciable impact on the final outcome of this disease. As local-regional treatment becomes more effective, the dominant site of failure has shifted to hepatic metastases. Therefore, future improvements in survival duration will result either from effective systemic or regional therapy directed at subclinical liver metastases or from strategies for screening and early diagnosis directed at increasing the number of patients eligible for potentially curative surgery. Further improvements in the quality of patient survival will result from the application of innovative multimodality therapy to carefully selected patients and the avoidance of unnecessary patient morbidity due to the inappropriate use of surgery, radiation, and/or chemotherapy in poorly selected patients with advanced disease. Although the indication for the use of somatostatin analogs in the treatment of pan-

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creatic cancer has yet to be decisively established, data from numerous in vitro and animal studies, as well as the results of several clinical trials reinforce the concept that pancreatic cancer is principally responsive to endocrine therapy. It has been suggested that improved methodology to assess the interaction of somatostatin (and its analogs) with its target at a cellular level may allow further development of this agent. A novel variation of this approach used an octapeptide analog of somatostatin that contained methotrexate attached to the ·amino group of D-phenylalanine in position 1. Subsequent experiments with the MIA PaCa-2 human pancreatic cell lines in nude mice demonstrated significant inhibition of tumor growth [102]. In addition, the attractive features of this therapeutic concept are the absence of severe

side effects, the frequently observed improvement of patients’ performance status and the advantage of treatment administered completely outside the hospital during the entire period of therapy. Furthermore, the definitive identification of different receptor subtype(s) mediating the antiproliferative effects, the expression of these receptor subtype(s) in this tumor and the development of subtype-specific analogs should lead to controlled trials of hormonal manipulation in this malignancy which is virtually untouched by any systemic therapy at present.

Acknowledgment L. Rosenberg is a Senior Clinician-Scientist supported by the Fonds de la Recherche en Santé du Québec (FRSQ).

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Octreotide for Cancer of the Liver and Biliary Tree Elias A. Kouroumalis Department of Gastroenterology, University Hospital, Heraklion, Greece

Key Words Octreotide W Hepatocellular carcinoma W Somatostatin receptors W Liver tumors

Abstract Inoperable liver tumors have an unfavorable natural course despite various therapeutic modalities. Octreotide, a somatostatin analog, has shown considerable antitumor activity on animal models of various hepatic tumors and on isolated cell culture lines. In this paper, a review of the experimental evidence is presented. Moreover clinical papers of case reports of uncontrolled studies of patients are also reviewed. The majority of clinical studies provide evidence of a clinical and biochemical response of liver endocrine tumors while regression of tumor size is a rare event. A randomized controlled trial of octreotide in the treatment of advanced hepatocellular carcinoma has shown a significant survival benefit in the treated patients. Literature reports indicate a stimulatory ef-

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fect of octreotide on Kupffer cells as a possible antitumor mechanism, but other antiproliferative actions of octreotide have been suggested but not proved. Finally the question of the presence and affinity of somatostatin receptors on liver tumor tissue is discussed. In conclusion, according to our experience, octreotide administration is the best available treatment for advanced inoperable hepatocellular carcinoma and future better patient selection, based on receptor subtypes, might further improve the results. Copyright © 2001 S. Karger AG, Basel

Introduction

Although octreotide appears to have considerable antimitotic activity in various nonendocrine tumors, its use in treating liver cancers is mostly limited to endocrine metastatic or primary liver neoplasms, with only limited experience in other hepatic primaries.

E.A. Kouroumalis, MD, PhD Associate Professor of Gastroenterology Head, Department of Gastroenterology University Hospital, PO Box 1352, Heraklion Crete (Greece) Fax +30 81 542085, E-Mail [email protected]

Epidemiology Liver neoplasms are among the most common tumors in many parts of the world. Hepatocellular carcinomas and cholangiocarcinomas comprise most of the liver tumors, while endocrine tumors, hepatoblastomas, bile duct cystadenocarcinomas, angiosarcomas, malignant hemangioendotheliomas, rhabdomyosarcomas and primary lymphomas are much rarer and have been reported mostly as case reports. An extensive review of liver tumors has recently been published [1]. Hepatocellular carcinomas have an annual occurrence of at least 1,000,000 new cases [2]. The geographical distribution is highly uneven with three main groups of countries being identified in terms of incidence rates. The highest rates are found in southeast Asia and tropical Africa with an incidence of as high as 150,000 cases/year. The lower rates are found in the western countries, South America and India, while Japan, Middle East and the Mediterranean countries belong to the intermediate group [3, 4]. Overall hepatocellular carcinoma is estimated to be the seventh most common cancer in men and the ninth in women [5]. However, in Japan hepatocellular carcinoma is the third most frequent cause of male cancer deaths [6]. Furthermore, in Japan the number of deaths due to hepatocellular carcinoma is increasing constantly [7]. The reported increase in the hepatocellular carcinoma incidence in western countries is probably due to better diagnostic modalities and detection programs in patients with cirrhosis [8]. It seems that there is no racial predisposition to liver cancer. Differences among races can be explained on the basis of differences in exposure to well-established risk factors, like HBV and HCV infection and aflatoxins or other chemicals [3]. A similar explanation can be given for the observed differences among

immigrants when compared to the population in their native country. It has been established that the incidence of hepatocellular carcinoma in immigrants from countries where the prevalence of the disease is high falls to that of their country of adoption. The mean age of patients is lower in high incidence areas, and Africans seem to develop the tumor earlier in life than Asians. The incidence rates for cholangiocarcinoma are highest in southeast Asia, particularly Hong Kong and Thailand [9,10]. In these areas the high incidence of the disease is linked to infestations with liver flukes, like Clonorchis sinensis and Opisthorchis viverrini. In western countries, cholangiocarcinomas are much less common, but a significant incidence occurs in patients with inflammatory bowel disease and primary sclerosing cholangitis [11, 12]. Among the rarer tumors of the liver, epidemiological data exists for hepatoblastomas. The majority of hepatoblastomas (90%) occur under 5 years of age and account for almost 40% of all liver tumors in childhood but are responsible for only 0.2–5.8% of all infant malignancies [13, 14]. Epidemiology of liver endocrine tumors has not been well established.

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Natural History Little is known about the natural history of untreated primary liver tumors, since some form of treatment is usually attempted. Survival in cases of hepatocellular carcinoma is strongly related to the Okuda classification [15]. In a recent study in Crete, a median survival of 16, 7 and 2 months for Okuda stage I, II and III liver tumors, respectively, was observed for patients who did not receive any therapy [16]. These findings are in agreement with earlier studies [17, 18]. Interestingly in this study, HCV positivity was not a risk factor for decreased survival, while HBeAg or

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anti-c positivity carried a high relative risk of 3.8 and 3.4, respectively. This observation is in accord with the Japanese experience where HBV-related cancer has a reduced 3-year survival rate compared to HCV-related disease [19]. In our study albumin concentration was inversely related to mortality with an 11% decrease in the hazard rate for each unit increase of this protein [16]. The natural history of liver metastatic endocrine tumors is less well known. In a recent study of patients with histologically confirmed liver metastases of endocrine tumors (gastrinomas, carcinoids, nonfunctioning pancreatic tumors and calcitonin-secreting tumors), a 90% progression was observed within a mean of 11.5 months [20]. The natural history of cholangiocarcinomas is dismal. Most patients deteriorate steadily and die within a few months after diagnosis [21]. Current Therapeutic Approach Undoubtedly, the best available treatment for all liver tumors is complete surgical resection. In a recent report, 532 cirrhotics with hepatocellular carcinoma were evaluated. Some form of liver resection was feasible in 44.7% of them (238 patients). Hospital mortality was 4.6% and 5-year actuarial survival rate was 41.3% [22]. Forty-one patients in this series were transplanted with a 5-year actuarial survival rate of 58.1%. Moreover, in most countries a differential diagnosis of hepatocellular carcinoma is made when the tumor is already inoperable. Other therapeutic modalities for liver tumors include selective arterial embolization with either iodine-131 Lipiodol or Lipiodolepirubicin [23]. In a recent report [24], the median survival rates at 6 and 12 months following Lipiodol-epirubicin were less than 65 and 50%, respectively. Only when embolization is performed in stage I Okuda patients, the 12-month survival rates are greater than

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50% [25]. Moreover, following several embolizations, arterial obstruction may give rise to the development of small collateral arteries that make repeated attempts to embolize the tumor difficult. Development of these collaterals may render the tumors resistant to emboli and their growth continues despite repeated treatments [26]. Arterial chemoembolization has been used in the treatment of metastatic endocrine liver tumors as well as primary hepatocellular carcinoma [20]. In a large series of carcinoid tumors, 40 patients with bipolar hepatic disease underwent embolization as primary treatment, followed by octreotide administration [27]. The 5-year survival rate was 56% and was accompanied by markedly decreased 5-hydroxyindole-acetic acid (5-HIAA) levels. Percutaneous ethanol injection has also been used extensively to treat hepatocellular carcinomas, especially tumors not exceeding 2–3 cm in diameter [28]. Histopathologic examination after therapy revealed that in many cases ethanol injection can completely destroy the tumor [29, 30]. In addition ethanol injection has achieved considerably high long-term survival rates. In a study of 162 hepatocellular carcinoma patients with a single nodule the 1-, 2- and 3-year survival rates were 90, 80 and 63%, respectively [30]. In another Italian study of ethanol injection of small tumors, survival rates were clearly associated with the Child-Pugh classification. Five-year survival rates of 47, 29 and 0% were reported for Child A, B and C, respectively [31]. Similar findings were found in 105 western patients with hepatocellular carcinoma smaller than 5 cm in diameter where the 5-year overall survival rate was 32% on Child A and B patients [32]. However, local recurrences are frequent, particularly when the tumor size exceeds 3 cm in diameter [33]. Moreover, in our experience, ethanol injection of larger tumors is of limited value, mainly because the alcohol diffuses

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rapidly into the surrounding liver parenchyma, because these large liver cancers are well vascularized (unpubl. observations). Fewer reports exist on the use of ethanol injection in metastatic liver tumors [34, 35] and cholangiocarcinomas [36]. Long-term survivals have not been reported so far for these tumors, but surgical excision of some tumors after ethanol injection showed an extensive necrosis ranging from 50 to 90% of the tumor. Hepatocellular carcinomas are assumed to be radioresistant. However radiation therapy has been recently reported in 22 patients with hepatocellular cancer receiving a total dose of 58–68 Gy [37]. In these patients the tumor size never exceeded that prior to radiotherapy except in 1 patient. The 1-year survival rate was 68%, but definitive conclusions on this form of treatment cannot be reached, without further studies since the treated tumors in this group were very heterogeneous and additional modalities were also used. Three of the patients had multiple ethanol injections and 17 others had undergone transarterial embolization before the radiation therapy. Only 2 patients had radiation as the only therapeutic modality. Hormonal manipulations have been used for the treatment of hepatocellular carcinomas. In a recent randomized controlled study, 80 patients with Okuda II and Okuda III hepatocellular carcinoma were randomized to either tamoxifen treatment or no treatment. Tamoxifen-treated patients were reported to have a 22% 1-year survival compared to almost 10% of the nontreated patients. Only minor side effects were attributable to tamoxifen [38]. The antiandrogen flutamide has been shown to have no therapeutic benefit in advanced hepatocellular carcinoma. The median survival time of patients treated with the drug was 2–5 months [39]. In a large antiandrogen trial of 244 patients with hepatocel-

lular carcinoma there was no survival advantage and indeed survival rates seemed even better for the placebo group [40]. In cholangiocarcinomas no effective drug treatment has been reported. Chemotherapy has been unsuccessful in the treatment of hepatocellular carcinoma as emphasized by two recent reports using combination chemotherapy. In a pilot study, intrahepatic arterial chemotherapy with methotrexate, 5-fluorouracil, cisplatin and subcutaneous interferon-·2b were used in 16 patients with advanced hepatocellular carcinoma with portal thrombosis [41]. Median survival was 7 months only. In another phase II Italian multicenter study, 5-fluorouracil plus high-dose levofolinic acid and hydroxyurea were used in 50 patients with hepatocellular carcinoma. Median survival was again a disappointing 5.8 months and many patients developed mild leukopenia and thrombocytopenia [42].

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Scientific Background

Presence of Somatostatin Receptors in Neoplastic Tissue The diverse biological effects of somatostatin are mediated through somatostatin receptors that are coupled to a variety of signal transduction pathways. These include adenylate cyclase, ionic conductance channels and protein phosphatase [43]. Recently, five such receptors have been cloned. They belong to the family of G-protein-coupled receptors [44, 45]. The SSTR-2 receptor has so far been best characterized, and its negative effect on cell growth has been established [45]. According to these recent findings, the tyrosine phosphatase SHP1 is an essential component of the inhibitory growth signalling mediated through this receptor [46]. In vitro studies have shown that octreotide demonstrates high affinity binding properties to SSTR-2,

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SSTR-3 and SSTR-5 receptors, while no binding affinity is found towards receptors SSTR-1 and SSTR-4 [47–49]. Therefore when octreotide receptor studies are performed using labelled octreotide only three out of the five known receptors are identified. The presence of somatostatin receptors has been verified in many endocrine tumors by autoradiographic techniques. Moreover, the presence of somatostatin receptors has been extensively investigated in vivo by using 111In-labelled octreotide scintigraphy [50, 51]. In a recent study of metastatic liver colorectal carcinomas, somatostatin receptors were identified in only 1 out of 10 patients included in that study. This study would suggest that either octreotide scintigraphy is not a sensitive method for detection of somatostatin receptors in these patients or that the tumors do not express such receptors [52]. Interestingly, in a small series, octreotide scintigraphy revealed SSTR receptors in 57% of patients with metastatic liver neuroblastomas, and patients with receptors had a better outcome than those who were negative [53]. Similar findings were found in a single case of neuroblastoma [54]. In a large series of patients with the Zollinger-Ellison syndrome, octreotide scintigraphy proved to be very accurate in detecting extrahepatic disease but the specificity of liver hot spots was only 60% [55]. Similar findings were reported for carcinoid tumor, where extrahepatic abdominal metastases were easily detected by scintigraphy but the detection of liver tumors was not superior to CT or ultrasonography [56–58]. In another study of 18 patients with hepatic neuroendocrine tumors, octreotide scintigraphy showed a sensitivity of 94%, indicating that at least in these tumors, there is a large number of receptors easily detected by 111In-octreotide [59]. In contrast, it seems that medullary thyroid carcinomas contain very

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few somatostatin receptors as identified by scintigraphy [60]. Since octreotide mostly binds to SSTR-2 receptors and to a lesser extent to SSTR-3 and SSTR-5 receptors, octreotide scintigraphy will demonstrate only the presence of these subtypes. Receptors in hepatocellular carcinomas were detected by a radioligand method in our own study, but identification of the receptor subtypes was not done [61]. Inhibition of Tumor Growth: In vitro Studies There are very few data from in vitro studies. In pancreatic tumor cells, somatostatin and analogs antagonize the mitogenic effect of growth factors, acting on tyrosine kinase receptors such as epidermal growth factor [62]. In human hepatocellular cell cultures, a 4-fold increase in the expression of IGF-1 binding protein has been reported after incubating the cells with octreotide [63]. Since IGF-1 is considered to be a trophic factor in hepatocellular carcinomas, this upregulation suggests that any antimitotic effect of octreotide on hepatocarcinomas is not likely to be mediated via inhibition of trophic hormones. However, further studies need to be done. Inhibition of Tumor Growth with Octreotide: Animal Models Octreotide has been found effective in inhibiting tumor growth in a variety of experimental models. Early studies demonstrated that experimentally derived (fibrosarcoma and adenocarcinoma) liver metastases are inhibited by octreotide [64, 65]. In an interesting study, nude mice were xenografted with a neuroendocrine cell line and received treatment with either high-dose octreotide or interferon-· or a combination of both. A 3-fold increase of apoptotic cells was observed in the octreotide group while the interferon-· group showed no evidence of increased apoptosis.

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However, tumor growth inhibition was more pronounced in the combination group [66]. Hepatocarcinogenesis induced by nitrosomorpholine in rats was significantly less in animals treated with somatostatin [67]. Morris hepatoma 3924A cells were implanted in the liver and subcutaneous tissues of rats which were partially hepatectomized and treated with either octreotide or placebo. Partial hepatectomy significantly increased tumor growth but treatment with octreotide resulted in a 10-fold decrease in liver tumor growth and a 3-fold reduction in subcutaneous tumor growth compared to controls [68]. Inhibition of liver regeneration after partial hepatectomy by octreotide has been reported in another study. Octreotide did not influence hepatic or portal blood flow. However, octreotide significantly increased reticuloendothelial system activity [69]. In the same study the growth of adenocarcinoma and fibrosarcoma cells implanted into the partially hepatoctomized rat livers was significantly decreased by octreotide. These results confirm earlier observations by the same group who demonstrated that blockade of the reticuloendothelial system resulted in an increased tumor growth while octreotide increased the activity of the reticuloendothelial system [70, 71]. However, octreotide only partially reversed the inhibition of growth and development of hepatic metastases in rats with gadolinium chloride-induced blockade of the Kupffer cells. This observation suggests that apart from stimulation of reticuloendothelial system, octreotide might have other mechanisms of action in inhibiting the growth of hepatic tumors. Two other mechanisms might be implicated. First, a direct antiproliferative effect through receptor-mediated growth inhibition has been postulated but never proved. Second, a reduction in tumor blood flow is a further possibility whereby octreotide may inhibit the growth of hepatic

metastases. Interestingly, the results from the above mentioned group do not confirm earlier studies in experimental hepatic metastases attributing the arrest of tumor growth to a reduction of hepatic arterial flow [72]. It should be noted, however, that reduction of tumor blood flow by octreotide may be dependent on the vascularity of the tumor. Fibrosarcomas are well vascularized while adenocarcinomas are relatively avascular and this difference might account for the divergent results reported in these two studies. Moreover, since tumor blood vessels lack receptors for vasoactive substances, any change of blood flow could be indirect through an effect on blood flow of the normal liver vessels. The distribution of octreotide receptors in normal liver blood vessels has not been studied. Finally, another possibility for the antitumor effect of octreotide could be an indirect action through inhibition of hormonal trophic factors. Although this possibility has not been adequately explored, there is evidence that this might not be an important factor, as previously mentioned. Rats were subcutaneously inoculated with mammary adenocarcinoma cells. A combination treatment with somatostatin plus insulin, which greatly increased the insulin/glucagon ratio, resulted in a reversed cachexia of the host, an effect not found with somatostatin alone. No appreciable effect on tumor growth was reported [73].

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Clinical Studies

Results from Case Reports Most, if not all case reports refer to metastatic liver disease either from primary endocrine malignancies or from adenocarcinoma of the large bowel. An extremely rare case of a 28-year-old woman with a metastatic ACTHsecreting pituitary carcinoma has been re-

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ported. Liver metastases from this ACTHsecreting pituitary carcinoma have been treated with octreotide for almost 2 years. Paradoxically ACTH production was stimulated by octreotide treatment [74]. Despite this unexplained secretion of ACTH, the development of the disease was very slow. Unfortuantely, the influence of octreotide cannot be fully assessed since the patient had a complementary hepatic chemoembolization treatment. Most case reports deal with either metastatic or the rare primary liver carcinoids. Only 18 cases of primary liver carcinoids have been reported so far. One such case of a patient with a malignant carcinoid of the liver with 18 years of follow-up has recently been reported [75]. Artery chemoembolization, hepatic lobectomy and octreotide treatment have all been used for the treatment of carcinoid in this patient who continues to be asymptomatic at the time of publication. A 5-year survival has also been reported in a patient with the carcinoid syndrome after octreotide administration [76]. Two cases of primary liver VIPomas treated with octreotide and followed by liver surgery also resulted in amelioration of symptoms. One of the patients experienced diarrhea, hypokalemia and hypercalcemia. All these manifestations were reversible after treatment. Again arterial liver embolization was also used limiting the assessment of octreotide benefit [77]. This study confirms earlier case reports of longterm successful treatment of hepatic VIPomas with octreotide [78–80]. Patients with metastatic medullary thyroid carcinomas in the liver treated with octreotide have been reported to have a good symptomatic and biochemical response [81] despite the fact that results from octreotide scintigraphy indicated a relative lack of receptors in this type of tumor [60]. However, caution should be exercised in interpreting this finding. As men-

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tioned before scintigraphy will only detect SSTR-2, SSTR-3 and SSTR-5 receptors to which octreotide mostly binds. Moreover, since this is not a sensitive method, relatively large doses of octreotide might act on low receptor levels, not detected by scintigraphy. From case reports the only conclusion that can be drawn is that octreotide provides an effective symptomatic control. There is only one case report of a 68-year-old male with advanced hepatocellular carcinoma, who was successfully treated with the long-acting somatostatin analog lanreotide [82]. No case reports of hepatocellular carcinoma treated with octreotide have been published. Clinical Trials Clinical trials of octreotide in liver tumors are limited and mostly uncontrolled. In an early study of octreotide effectiveness on liver metastases derived from endocrine tumors, a significant reduction in tumor blood flow was caused by octreotide in 8 patients [83]. This finding was associated with a slight temporary reduction of the size of the tumors. Octreotide has been used as a palliative treatment of metastatic carcinoids of the liver. In an uncontrolled trial, 40 patients with bipolar liver disease were treated this way. Urinary 5-HIAA levels were still reduced by 55% after 71 B 11 months of follow-up. The 5-year survival was 56%. Symptomatic relief was found in 85% of patients. Most deaths were related to cardiovascular incidents. For comparison, 14 patients were treated by surgical resection alone, which achieved anatomical and biochemical cure. 5-HIAA levels were normal after 69 B 6.2 months of follow-up and these patients were asymptomatic. Two out of 14 patiens died of causes unrelated to the tumor. Despite the fact that there was no control group for the octreotide group, it is concluded that administration of octreotide

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offers a symptomatic and survival benefit [84]. This report confirms earlier trials. In the largest report from the Mayo Clinic, 66 patients with metastic carcinoid of the liver were treated with octreotide. Complete or nearcomplete control of symptoms of diarrhea was obtained in 77%, of flushing in 87% and a 50% reduction of urinary 5-HIAA was obtained in 70% of patients. The mean survival was more than 3 years, which is longer than in previous reports with combination chemotherapy [85]. In another smaller uncontrolled clinical trial, 10 patients with metastatic liver carcinoids were treated with artery embolization, intra-arterial 5-fluorouracil and octreotide. In 60% of the patients the tumor size was reduced by 50%, while the mean survival was 58 months [86]. In a phase II clinical trial, patients with metastatic carcinoid liver tumors were treated with either 500 or 1,000 Ìg t.i.d. of octreotide. Some patients with metastatic medullary thyroid carcinoma, pancreatic islet cell tumors and Merkel cell carcinomas were also included. The carcinoid syndrome was documented in 16 patients and abnormal urinary 5-HIAA excretion in 15. Median treatment duration was 5 months. Tumor regression, symptom response and biochemical response were evaluated. Symptomatic and biochemical responses were reported as satisfactory with an overall response of 73 and 77%, respectively. However, tumor regression was reported in only 3% of patients [87]. In 27 patients, the disease was stabilized for at least 6 months (range 6–32 months). The median survival for all patients was 22 months (range 1–32 months). In the prospective German octreotide multicenter phase II trial, 200 Ìg octreotide t.i.d. were given daily for 1 year to 103 patients with advanced nonoperable endocrine tumors. Sixty-four patients had a functional

tumor. Most of the patients had either carcinoids or islet cell tumors. Fifty-two patients had a CT-confirmed tumor progression before treatment. Thirty-seven percent of patients from this group experienced stabilization of tumor growth for at least 3 months. Median duration of stable disease was 18 months. Tumor regression has not been seen in any patient [88]. Different results have been reported in an uncontrolled trial of somatostatin in liver metastatic endocrine tumors, where no objective response was found [20]. In conclusion, octreotide seems to have a beneficial effect on symptomatology and biochemical response of endocrine tumors. It also seems to stabilize the tumor growth in some patients while tumor regression is not observed. There is only one randomized controlled trial of octreotide in the management of hepatocellular carcinoma [61]. Somatostatin receptors were identified in liver biopsy tissue from various diseases, including hepatocellular carcinomas, using a radioligand method. Fifty-eight patients, the majority of whom had Okuda stage II and III tumors, were randomized to receive either no treatment or subcutaneous octreotide 250 Ìg twice daily. Treated patients had a significantly increased median survival (13 months) compared to controls (4 months) and a significantly increased cumulative survival rate at 6 and 12 months (75 vs. 37% and 56 vs. 13%, respectively). Furthermore, the quality of life was improved in the treatment group. In 5 patients, small satellite tumors, below 3 cm in diameter, disappeared after 6–12 months of treatment. In 4 additional patients, the size of the tumor remained unchanged. In view of the results from this trial carried out in our unit [61], we currently believe that octreotide is the treatment of choice for inoperable hepatocellular carcinoma. Hitherto no trial has been done on cholangiocarcinomas.

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Conclusions

There is substantial evidence from experimental studies and from a controlled clinical trial in man that octreotide is a useful drug for the treatment of not only metastatic liver endocrine tumors, but also of primary hepatocellular carcinoma, either as an adjuvant therapy after surgical resection, or a sole treatment. The relative lack of side effects of octreotide is particularly promising in this respect. Caution should be excercised in patients with diabetes since hyperglycemia can be a problem. Treatment of hepatic metastases derived from colon carcinoma also seems to be another area in which octreotide treatment is justified, although controlled trials in patients are necessary to assess the efficacy of this somatostatin analog in this indication. Evidence that the antiproliferative effect of octreotide on hepatic tumors is immune-mediated via the stimulation of the reticuloendothelial system of the liver has been carefully documented [70, 71]. However, other modes of action of octreotide on hepatic tumors require further investigation. Projections for the Future In a recent study, gallbladder visualization was obtained with octreotide scintigraphy, indicating that somatostatin receptors are also found in the gallbladder mucosa [89]. If this finding can be verified by more specific studies, octreotide may prove to be useful for the treatment of cholangiocarcinomas. Careful examination of the receptor subtypes in liver and bile duct tissue in health and disease using more sophisticated techniques than octreotide scintigraphy is urgently required. Moreover, the mode of antiproliferative action of octreotide should be delineated. Besides the possible immune modulation through stimulatory effects on Kupffer cells,

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there are certain other possibilities that have not been adequately explored. There is also evidence for a possible effect of octreotide on hepatic tumor angiogenesis, but further studies are required. Similarly a direct antiproliferative effect through somatostatin receptors, or through inhibition of tumor trophic hormones should be examined. Moreover, a recent report indicates that a somatostatin analog activates hepatoma cell apoptosis in vitro in both drug-sensitive and drugresistant cell lines [90]. This is a possible mechanism of octreotide antitumor activity that should be further explored. Another area for future research is the development of longacting octreotide or somatostatin analogs, making protracted treatment with octreotide more acceptable to patients. In this respect Sandostatin-LAR and lanreotide development might prove of particular significance.

Note added in proof Recent studies [91, 92] have explored the clinical potential of lanreotide (30 mg i.m. every 14 days) in the treatment of advanced hepatocellular carcinoma. Besides a successful case report [91], 38% of patients had stable disease while the remaining ones progressed during treatment. Since in vitro studies [92] clearly demonstrated the ability of lanreotide to decrease the S phase fraction along with induction of apoptosis in Hep G2 cells in a dose-dependent fashion, the disappointing clinical results could be ascribed to the use of suboptimal doses of the peptide.

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inhibit the growth of pancreatic cancer by stimulating tyrosine phosphatase. Proc Natl Acad Sci USA 1989; 86:2003–2007. Ren SG, Ezzat S, Melmed S, Brannstein GD: Somatostatin analogue induces insulin-like growth factor binding protein-1 expression in human hepatoma cells. Endocrinology 1992;131:2479–2481. Frizelle FA: Octreotide inhibits the growth and development of three types of experimental liver metastasis. Br J Surg 1995;82:1577. Davies N, Kynaston H, Yates J, Nott DM, Nash J, Taylor BA, Jenkins SA: Octroetide inhibits the growth and development of three types of experimental liver metastasis. Br J Surg 1995;82:840–843. Imam H, Eriksson B, Lumkinius A, Janson ET, Lindgren PG, Wilander E, Oberg K: Induction of apoptosis in neuroendocrine tumours of the digestive system during treatment with somatostatin analogs. Acta Oncol 1997;36:607–614. Nakaizumi A, Uehara H, Bara M, Irishi H, Tatsuta M: Inhibition by somatostatin of hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats. Carcinogenesis 1993;14:2601–2604. Schinded DT, Grosfeld JL: Hepatic resection enhances growth of residual intrahepatic and subcutaneous hepatoma which is inhibited by octreotide. J Pediatr Surg 1997;32: 995–998. Davies N, Yates J, Kynaston H, Taylor BA, Jenkins SA: Effects of octreotide on liver regeneration and tumor growth in the regenerating liver. J Gastroenterol Hepatol 1997; 12:47–53. Davies N, Kynaston H, Yates J, Nott DM, Jenkins SA, Taylor BA: Reticuloendothelial stimulation: Levamisole compared. Dis Colon Rectum 1993;36:1054–1058. Davies N, Kynaston H, Yates J, Taylor BA, Jenkins SA: Octreotide, the reticuloendothelial system and experimental liver tumours. Gut 1995;36:610–614. Hemingway DM, Jenkins SA, Cook TG: The effects of sandostatin (octreotide SMS 201-995) infusion on splanchnic and hepatic blood flow in an experimental model of hepatic metastases. Br J Cancer 1992;65: 396–398.

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73 Bartlett DL, Charland SL, Torosian MH: Reversal of tumor-associated hyperglucagonemia as treatment for cancer cachexia. Surgery 1995;118: 87–97. 74 Lormean B, Miossec P, Sibony M, Valensi P, Attali JR: Adrenocorticotropin producing pituitary carcinoma with liver metastasis. J Endocrinol Invest 1997;20:230–236. 75 Mehta DC, Warner RR, Parnes I, Weiss M: An 18-year follow-up of primary hepatic carcinoid with carcinoid syndrome. J Clin Gastroenterol 1996;23:60–62. 76 Degushi H, Deghuci K, Tsukada T, Murashima S, Iwasaki E, Tsuda M, Kobayashi T, Shirakawa S: Longterm survival in a patient with malignant carcinoid treated with high dose octreotide. Intern Med 1994; 33:100–102. 77 Lundstedt C, Linjawi T, Amin T: Liver vipoma: Report of two cases and literature review. Abdom Imaging 1994;19:433–437. 78 Fluckinger A, Schlup P: Long-term therapy of a metastasizing pancreatic vipoma using the somatostatin derivative octreotide. Schweiz Med Wochenschr 1993;122:1221–1223. 79 Procaccioante F, Piccozzi P, Fantini A, Pacifici M, Di Nardo A, Ribotta G, Delle-Fare G, Catani M, Ruggeri S, Romeo F: Vipoma: Surgical treatment. Minerva Chir 1992;43:135– 142. 80 Bradley C, Haddock G, Pickard RG, Rankin EM: Metastatic vipoma, arising from a colonic primary tumor. Eur J Surg Oncol 1989;15: 386–389. 81 Mahler C, Verhelst J, de Longueville M, Harris A: Long-term treatment of metastatic medullary thyroid carcinoma with the somatostatin analogue octreotide. Clin Endocrinol (Oxf) 1990;33:261–269. 82 Raderer M, Heina MH, Kurtaran A, Kornek GV, Valenck JB, Oberhuber G, Vorbech F, Virgolini I, Scheithauer W: Successful treatment of an advanced hepatocellular carcinoma with the long-acting somatostatin analog lanreotide. Am J Gastroenterol 1999;94:278–279. 83 Cho KJ, Vinik AI: Effect of somatostatin analogue (octreotide) on blood flow to endocrine tumours metastatic to the liver: Angiographic evaluation. Radiology 1990;177: 549–553.

84 Ahlman H, Westberg G, Wangberg B, Nilsson O, Tylen U, Schersten T, Tisill LE: Treatment of liver metastases of carcinoid tumors. World J Surg 1996;20:196–202. 85 Krols LK: Therapy of the malignant carcinoid syndrome. Endocrinol Metab Clin North Am 1989;18: 557–568. 86 Diaco DS, Hajarizadeh H, Mueller CR, Fletcher WS, Pommier RF, Woltering EA: Treatment of metastatic carcinoid tumours using multimodality therapy of octreotide acetate, intra-arterial chemotherapy and hepatic arterial chemoembolization. Am J Surg 1995;169:523–528. 87 di Bartolomeo M, Bajetta E, Buzzoni R, Mariani L, Carnaghi C, Somma L, Zilembo N, di Leo A: Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumours. A study by the Italian Trials in Medical Oncology Group. Cancer 1996;77:402–408. 88 Arnold R, Trautmann MF, Creutzfeldt W, Benning R, Benning M, Neuhaus C, Jurgensen R, Stein K, Schafer H, Bruns C, Dennler HJ, Sandostatin Multicentre Study Group: Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenterol pancreatic tumours. Gut 1996;38:430–438. 89 Kipper MS, Krohn LD: Gallbladder visualization at twenty-four hours with octreotide scintigraphy. Potential false-positive finding. Clin Nucl Med 1997;22:253–254. 90 Diaconu CC, Szathmari M, Keri G, Venetianer A: Apoptosis is induced in both drug-sensitive and multidrug-resistant hepatoma cells by somatostatin analogue TT-232. Br J Cancer 1999;80:1197–1203. 91 Raderer M, Hejna MH, Kurtaran A, Kornek GV, Valencak JB, Oberhuber G, Vorbeck F, Virgolini I, Scheithauer W: Successful treatment of an advanced hepatocellular carcinoma with the long-acting somatostatin analog lanreotide. Am J Gastroenterol 1999;94:278–279. 92 Raderer M, Hejna MH, Muller C, Kornek GV, Kurtaran A, Virgolini I, Fiebieger W, Hamilton G, Scheithauer W: Treatment of hepatocellular cancer with the long acting somatostatin analog lanreotide in vitro and in vivo. Int J Oncol 2000;16: 1197−1201.

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Somatostatin Analogs in Oncology: A Look to the Future Spencer A. Jenkins a Howard G. Kynaston b Nick Davies c John N. Baxter a David M. Nott d a Academic

Department of Surgery, Postgraduate Medical School, Morriston Hospital, Swansea, b Department of Urology, University Hospital of Wales, Cardiff, c Departments of Surgery, Royal Bournemouth Hospital, and d Chelsea and Westminster Hospital, London, UK

Key Words Somatostatin analogs W Neoplasms W Therapy W Review

Abstract In the past 15 years considerable advances have been made in our understanding of the molecular pharmacology of the mechanisms whereby somatostatin and its analogs mediate their direct and indirect antineoplastic effects. However, some important issues remain to be resolved, in particular the functional roles of the individual somatostatin receptors (SSTR-1–5) in tumor tissue and up- or downregulation of the hSSTRs with prolonged administration of somatostatin analogs. Answers to these questions are essential before we can maximize the therapeutic efficacy of somatostatin analogs in cancer. For example, is continuous administration more or less effective than intermittent therapy? The role of somatostatin analogs in the management of acromegaly

ABC

© 2001 S. Karger AG, Basel 0009–3157/01/0478–0162$17.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/che

and to a lesser extent neuroendocrine tumors is firmly established. The development of depot preparations of all 3 somatostatin analogs currently available for clinical use will undoubtedly improve both patient compliance and quality of life in patients with these conditions. There are only likely to be minor differences in the therapeutic efficacy of octreotide, lanreotide and vapreotide since all three analogs exert the majority of their antineoplastic effects via hSSTR-2 and hSSTR-5 and at the end of the day, price may well dictate which of these drugs oncologists use to provide symptomatic palliation of acromegaly and neuroendocrine tumors. Apart from some notable exceptions, somatostatin analog therapy has proven to be very disappointing in the management of advanced malignancy. Improvements in the management of solid tumors are likely to come only from combination therapy of somatostatin analogs with cytotoxic agents or other hormones in both advanced malignancy and in the adjuvant setting. Clinical

S.A. Jenkins, MD Departments of General Surgery & Urology Ward 5-A, University Hospital of Wales Health Park, Cardiff CF 14 4XW (UK) Tel. +44 2920 744971, Fax +44 2920 744179

Hypothalamic factors which regulate the secretion of growth hormone were first identified in 1968 by Krulich et al. [1]. Subsequently, in 1973, Brazeau et al. [2] identified a 14amino acid peptide inhibitor of growth hormone release-inhibiting factor (SRIF), the name subsequently being changed to somatostatin. Following production of a synthetic replicate of the native hormone [3] it soon became apparent that somatostatin had a wide variety of effects on the endocrine, gastrointestinal, immune, circulatory and central nervous systems. Although somatostatin is widely distributed throughout the body, immunochemical studies indicated that the peptide is confined

to three cell types. Somatostatin is found in classic ‘open type’ endocrine cells from which it is directly excreted into the blood [4], paracrine cells with long cytoplasmic extensions which terminate on putative effector cells [5] and in neurones where it may function as a neurotransmitter [6–8] or is released from the nerve endings into the blood [4]. Thus, depending on its site of elaboration, somatostatin may function as a hormone, a neurohormone, a neurotransmitter or a parahormone. Consequently, the sites of elaboration and release of somatostatin in the body, together with a short half-life of approximately 2 min [9], make it the almost ideal regulatory peptide. The plethora of effects mediated by somatostatin led to the suggestion that the hormone could have a therapeutically beneficial effect in a wide variety of indications. However, the short half-life of somatostatin restricts its application as a drug since it has to be administered by a continuous infusion to maintain a sustained biological effect and hence a therapeutic response. Although intravenous administration of somatostatin does not present a problem in the management of patients hospitalized for acute indications such as variceal and nonvariceal upper gastrointestinal bleeding or acute pancreatitis, its short plasma half-life is a serious disadvantage to the exploitation of its full therapeutic potential in those conditions requiring longterm treatment. Not surprisingly therefore, following determination of the structure of somatostatin, peptide chemists began to try and synthesize more stable agonists with a longer duration of action. Furthermore, since somatostatin inhibits the release of such a vast array of hormones, the other and perhaps the most formidable challenge for the peptide chemists was to design analogs which were not only stable, but more selective in their mode of action.

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trials with clear-cut objective outcome measures and health-related quality of life assessment are needed to evaluate the therapeutic efficacy of combination treatment in advanced malignancy and as an adjuvant to surgery. Particular attention needs to be paid to possible adverse effects of somatostatin analog therapy on the immune response to cancer. Further studies are required to establish whether the adverse effects of somatostatin analog therapy alone or in combination with cytotoxics or other hormones can be reversed with appropriate immunomodulatory treatment. Targeted somatostatin analog radiotherapy and chemotherapy are currently being investigated and the results of these studies are awaited with interest. Novel approaches using combinations of somatostatin analogs with antiangiogenic drugs or gene therapy are of particular interest and may provide important advances in the management of cancer in the not too distant future. Copyright © 2001 S. Karger AG, Basel

Introduction

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Mechanism of Action of Somatostatin and Its Analogs

In the past 15 years substantial advances have been made in elucidating the mechanisms whereby somatostatin and its analogs exert their antineoplastic effects [for comprehensive reviews see 10–15]. In brief, somatostatin and its analogs elicit direct antineoplastic effects via a complex variety of intracellular transduction pathways leading to inhibition of cell proliferation or by stimulation of apoptosis. Clearly, the direct antineoplastic effects of somatostatin and its analogs are confined to cells expressing hSSTRs. However, somatostatin and its analogs can exert antineoplastic effects via a number of indirect mechanisms including inhibition of the release and end-organ effects of trophic growth factors and hormones, angiogenesis and a reduction in tumor blood flow. Stimulation of the reticuloendothelial system (RES) appears to be a very important mechanism whereby somatostatin and its analogs inhibit the growth and development of liver tumors [11]. The indirect antineoplastic effects of somatostatin and its analogs are independent of the presence of hSSTRs on the tumor cells. Therefore, a possible beneficial effect of somatostatin analog therapy is not restricted to tumors expressing hSSTRs.

Future Prospects

Before discussing how it may be possible to improve somatostatin analog therapy of neoplasia it is important at the outset to emphasize the limitations of such treatment. Thus, apart from the stimulation of apoptosis by somatostatin and its analogs which could be considered cytotoxic, the remainder of their antineoplastic effects are cytotoxic. Therefore, somatostatin analog therapy of neoplasia

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in symptomatic patients cannot be expected to be curative but only to provide remission and palliation of unpleasant and sometimes life-threatening side effects, thereby increasing survival and improving the quality of life. This is well illustrated by the experience of octreotide in the management of hypersecretory GEP tumors. Control of hormone hypersecretion by octreotide is observed in approximately 55% of patients with vasoactive intestinal polypeptide (VIP)-omas and a reduction in the size of liver metastases has been reported in approximately 10%. Control of tumor growth occurs in approximately 50% of VIP-oma patients treated with octreotide. However, the reduction in the size of liver metastases secondary to VIP-omas is temporary and transient and control of tumor growth in response to octreotide therapy is lost after 8–16 months of treatment. Eventually, all the patients escape from the inhibitory effects of octreotide therapy on tumor progression and hormonal hypersecretion and become symptomatic. The major challenge for somatostatin analog therapy in oncological indications is, therefore, to determine how we can take full advantage of their antineoplastic effects which, of course, will vary with the type of cancer being treated. For most solid tumors, surgery offers the only chance of cure and should be offered to all patients who are fit enough to undergo surgical intervention. However, for the majority of patients, a truly curative resection of their tumor(s) may not be feasible. In such patients debulking or neoadjuvant therapy to reduce the tumor burden may improve the response to adjuvant therapies and, in some cancers, increase the resectability rate. Finally, in patients with advanced metastatic malignancy, surgery may be contraindicated and in this situation effective palliation to maintain quality of life for as long as possible is the primary challenge for the oncologist. It seems likely, therefore, that the

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major role of somatostatin analog therapy is an adjuvant to surgery and in providing effective palliation for patients with advanced malignancies for most of the major cancers. There are, however, some exceptions to this rule. For example, elderly acromegalics with small tumors are particularly sensitive to the antineoplastic effects of octreotide. Furthermore, no escape from the inhibitory effects of octreotide on the hypersecretion of hormones by pituitary tumors occurs in the vast majority of acromegalics even after 10 years of therapy. Therefore, in elderly acromegalics, somatostatin analog therapy is the treatment of choice since the life expectancy of such patients is unlikely to be influenced by their pituitary tumor. In order to maximize the therapeutic potential of somatostatin analog therapy in neoplasia there are a number of areas which require further investigation, in particular, the significance of heterogeneous expression of individual hSSTRs within and between different tumors, and their functional role and their desensitization and downregulation.

Early competitive binding assays using radiolabelled somatostatin and its analogs and autoradiography indicated that somatostatin receptors were expressed in a wide variety of normal tissue and tumors such as those of the nervous system, pituitary, gastrointestinal tract, pancreas, endocrine glands and lymphoid tissue [15–17]. The early binding studies indicated that the majority of human tumors expressed somatostatin receptors with a high binding affinity for somatostatin-14, somatostatin-28 and octreotide. However, a number of tumors appeared to express somatostatin receptors with a high binding affinity

for somatostatin but a low binding affinity for octreotide, e.g. pituitary adenomas, glial tumors, meningiomas, some GEP tumors, medullary thyroid carcinomas, ovarian cancers and breast tumors. Furthermore, normal and cancerous gastric and colonic tissue were demonstrated to express somatostatin receptors with a high binding affinity for the native hormone, low binding affinities for lanreotide and somatuline but with little or no binding affinity for octreotide [18]. Interestingly, these early binding receptor studies suggested that somatostatin receptors were preferentially expressed in well-differentiated compared to less differentiated tumors [19, 20]. These observations suggest somatostatin receptors may represent markers of differentiation in some cancers and that loss of functional hSSTRs may be of clinical importance in the progression of neoplasia. Thus, since somatostatin receptors play an important role in the physiological control of cell proliferation, loss of hSSTR expression in neoplastic cells would confer a proliferative advantage to those cells and their progeny. The net result would be the emergence of a dominant rapidly proliferating clone of hSSTR-negative cells and the progression of the neoplasm to a more aggressive, less differentiated tumor. Although it has not yet been established which of the 5 hSSTR are responsible for the progression of a tumor to a less differentiated more aggressive phenotype, the genes which encode for these receptors and their proteins which mediate their intracellular transduction pathways should be regarded as tumor suppressor genes. This suggestion is supported by the observation that a point mutation in the gene encoding for hSSTR-2 results in a proliferative advantage in small cell lung cancer cells in vitro [21]. These observations have two important clinical correlates. Firstly, it is well established that long-term somatostatin analog therapy results in downregula-

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tion of hSSTRs. Clearly, it will be important to establish whether or not long-term therapy with somatostatin analogs results in well-differentiated tumors becoming phenotypically more aggressive, thereby adversely affecting survival. Secondly, restoration or modulation of hSSTR expression in anaplastic tumors by gene transfer may revolutionize somatostatin analog therapy of neoplasia. More recently, cloning of 5 hSSTR has enabled the expression of individual somatostatin receptor expressions to be determined using techniques such as in situ hybridization, RNA-ase protection and reverse transcriptase polymerase chain reactions (RT-PCR) [22– 37]. Studies using these techniques indicate that there is considerable heterogeneity between and within individual tumors with respect to the density of the individual hSSTRs expressed. Thus, in most tumors, hSSTR-2 which is thought to be the receptor whereby somatostatin analogs exert the majority of their antiproliferative effects was expressed in the highest density. The other hSSTRs were also expressed in tumors expressing hSSTR-2, but in lower densities and in differing patterns in individual neoplasms. Perhaps more importantly with respect to the present generation of somatostatin analogs available for clinical use, some of the most common malignancies such as cancers of the pancreas, stomach and prostate do not express hSSTR-2 [18, 34]. In addition there is some controversy on whether or not colorectal adenocarcinomas express hSSTR-2. In an early report using competitive binding assays, primary cultures of both normal and cancerous colonic tissue were reported not to bind to octreotide suggesting that these cells do not express hSSTR2 [18]. However, in a subsequent study using RT-PCR the same group reported that the mucosa of colonic cancer and adjacent normal tissue expressed all 5 hSSTRs [37]. One possible explanation for these divergent re-

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sults is that high affinity somatostatin receptors have been reported on vascular and stromal cells [34, 38, 39]. Thus, in the second study by the Southampton group [37], the highly sensitive PT-PCR technique used to determine the hSSTR expression in colonic biopsies may have detected hSSTR-2 in contaminating peritumoral blood vessels and stroma rather than on the tumor cells per se. Finally, a proportion of tumors which normally express a high density of hSSTR-2 do not express this subtype [15, 16]. The variable expression of the hSSTRs between various tumors emphasizes the need to define the precise characteristics of the receptor subtypes in tumor tissue prior to somatostatin analog therapy if the direct antineoplastic effects of these drugs are to be maximized. Clearly such studies should be carried out on tumor cells per se and not on whole tissue homogenates, because of possible confounding contamination with peritumoral blood vessels and/or stroma. In addition, there is a need to define the proportion of binding attributable to each of the hSSTRs on the neoplastic cell to further optimize somatostatin analoge therapy and maximize the direct antineoplastic effects of these drugs. However, determination of hSSTR expression may not in itself be sufficient to fully exploit the direct antineoplastic effects of somatostatin analog therapy since it has yet to be determined whether or not detection of hSSTR mRNA implies the presence of functional proteins on the cell surface and intact intracellular pathways. Clearly, the relationship between hSSTR expression and functional receptor-proteins requires the development of specific antibodies to the latter. Not surprisingly therefore, the biological roles of each of the hSSTRs remains to be elucidated and defining the functional role of each of the subtypes requires the development of specific analogs, antagonists and antibodies. The complexity of the problems provides a major chal-

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lenge to peptide chemists and molecular biologists but such studies are essential to fully exploit the therapeutic potential of somatostatin analog therapy in neoplasia.

Cells can regulate their sensitivity to ligands such as drugs or hormones by modifying their response (desensitization) or altering receptor density (downregulation or upregulation). Desensitization or tachyphylaxis may be achieved rapidly through functional uncoupling of the receptor proteins on the cell membrane that activate intracellular transduction pathways and is thought to be the initial response whereby cells regulate their response to continuous application of agonists. Cells can also modulate their response to continuous exposure of an agonist via a decrease in receptor density achieved by internalization of receptors (downregulation). In the case of persistent presence of an agonist, the agonist-receptor complex is internalized the structurally intact receptors stored within the cell and at this stage could be recycled if the stimulus was withdrawn. If stimulation persists the receptors are eventually broken down but can be resynthesized when the stimulus is eventually removed. Through the uncoupling and downregulation of receptors, cells are capable of decreasing the magnitude of their response to a constant level of agonist stimulation. This phenomenon is well illustrated by the effects of somatostatin on the modulation of potassium channels in neocortical cells [40]. Thus, some cells rapidly desensitize to continuous somatostatin application (less than 30 s) whereas other neurones are only partially desensitized or are refractory to more prolonged exposure of the hormone (5 min). However, with prolonged exposure (30 min) to somatostatin all neocortical cells

are completely desensitized [40]. It seems likely that rapid desensitization of some neocortical cells following that exposure to somatostatin (less than 30 s) results from uncoupling of the G proteins from the somatostatin receptors whereas desensitization of neurones initially refractory to continuous exposure of hormone may require downregulation of the receptor. Desensitization and downregulation have important consequences for the clinical use of somatostatin analogs. As long ago as 1989 Londong et al. [41] demonstrated that the initial potent inhibition of gastric secretion by relatively low doses of subcutaneous administration of octreotide was lost after 7 days of continuous administration. Subsequently, the initial potent inhibitory effects of octreotide on pancreatic enzyme excretion were also demonstrated to be lost after 7 days’ continuous subcutaneous administration [42]. The important question with respect to oncology is whether or not long-term somatostatin analog therapy results in downregulation of the receptors responsible for mediating their antineoplastic effects and which of the hSSTR are affected. There is good evidence that somatostatin and its analogs can upregulate or downregulate SSTR expression in a variety of cell lines and in tumor-bearing experimental animals [43–52]. It is now clear that regulation of individual SSTR expression by somatostatin and its analogs is cell subtype- and agonistspecific [43–52]. Furthermore, there is considerable evidence to suggest that SSTR expression is sensitive to the regulatory effects of glucocorticoids, thyroid hormones, estrogens, insulin and growth factors [53–57], which, at least in part, may explain why somatostatin analogs exhibit both a proliferative and antiproliferative effect on the same cell line depending on the culture conditions [58–62]. Although much progress has been made in our understanding of SSTR expres-

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sion at the cellular level the molecular events responsible for these effects are poorly under stood. In addition, the functional significance of either upregulation or downregulation of the individual SSTRs has yet to be elucidated, and in particular, with respect to the therapeutic and diagnostic use of somatostatin analogues, whether or not the expression of mRNAs for the individual hSSTRs by neoplastic cells implies a functional receptor protein and intact signal transduction mechanism(s). It is also important to distinguish between internalization and downregulation. Thus, internalization of the hSSTRs after brief exposure to somatostatin or its analogs is cell-, agonist- and receptor-specific [43–52] and involves endocytosis of the receptorligand complex which may be accompanied by recruitment of cellular SSTRs to the cell membrane [46] and may represent an important upregulatory mechanism whereby cells can rapidly modulate their response to agonist stimulation. Upregulation, whereby neoplastic cells increase the density of cell membrane SSTRs, has obvious implications in both the visualization (somatostatin scintigraphy) and therapy (targeted chemotherapy or radiotherapy) of tumors using somatostatin analogs. However, as described earlier in this section, internalization is also the first step involved in downregulation in response to a persistent stimulus. It should be possible to distinguish between internalization resulting in upregulation from internalization heralding the onset of downregulation by repeat somatostatin receptor scintigraphy, if these were the only mechanisms involved in determining the response to escape from the antineoplastic effects of somatostatin analog therapy. Moreover, clinically, the situation is more complex since there are other mechanisms which may be responsible for escape from the inhibitory effects of somatostatin analog therapy on tumor growth and hypersecretory states.

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For example, the antineoplastic effects of somatostatin analogs on tumor growth would be limited to those cells bearing hSSTRs or whose growth is inhibited by their indirect antiproliferative effects. Thus, a proportion of cells in each tumor will not respond to either the direct or indirect antineoplastic effects of somatostatin analog therapy, the net result being the growth and development of clones of differentiated cells refractory to analog treatment. It seems likely that escape is a combination of these phenomena since in a small proportion of VIP-oma patients the initial inhibitory effects octreotide on hormone hypersecretion is lost after as little as 4 days’ therapy [63]. Downregulation or desensitization of hSSTRs responsible for the inhibitory effects of octreotide would appear to be the only plausible explanation for escape in these patients. However, for the majority of VIP-oma patients escape appears after a much longer period of octreotide therapy (6– 16 months) suggesting that downregulation and possibly the growth of rapidly proliferating clones of cells may both be responsible for loss of efficacy of analog therapy. Possibly, somatostatin scintigraphy before and after somatostatin analog therapy may, at least in part, be able to differentiate between the relative roles of downregulation and the growth of hSSTR-negative clones in the phenomenon of escape, but is unlikely to provide a definitive answer to this problem. Irrespective of the mechanisms responsible for escape from somatostatin analog therapy, this phenomenon represents a considerable problem to the longterm use of these drugs in oncology. However, the problem of developing resistance to drug therapy is not new and applies to a wide variety of therapeutic agents. For example, it is well established that chronic antibiotic therapy is the best way to induce antibiotic resistance. Similarly with respect to oncology, it has long been recognized that prolonged che-

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motherapy leads to the development of cytotoxic resistant clones of tumor cells. More recently, it has been generally accepted that androgen blockade with luteinizing hormonereleasing hormone (LHRH) or antiandrogens needed to be permanent to normalize surrogate end points such as prostatic-specific antigen (PSA) and improve survival in patients with prostatic cancer. This hypothesis was based on the assumption that total androgen deprivation resulted in a rapid sustained response which outweighed the development of hormone resistance. More recently, intermittent androgen blockade in a relatively small number of patients was demonstrated to be without risk and to significantly improve quality of life after initial normalization of PSA in patients with prostate cancer [64, 65]. It remains to be established in randomized controlled trials whether intermittent androgen blockade, by delaying development of hormone resistance, improves survival compared to continuous therapy in patients with carcinoma of the prostate. However, there are no good data on whether or not intermittent somatostatin analog therapy prevents or reduces the rate of downregulation or the development of hormone resistant clones of differentiated cells. Unfortunately, the three analogs currently available for clinical use, octreotide, vapreotide and lanreotide, have very similar antineoplastic effects, the majority of which are mediated predominantly via the same hSSTR. Therefore, a treatment option alternating octreotide, vapreotide and lanreotide is unlikely to delay escape. A more realistic approach may be intermittent administration of long-acting depot preparations of octreotide, lanreotide and vapreotide, but such clinical studies will require careful monitoring until the reliability and safety of such an approach can be justified.

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Future Clinical Studies

In the past 15 years by far and away the most successful use of octreotide has been in the treatment of acromegaly. As discussed earlier, although octreotide and other somatostatin analogs effectively control hypersecretion of growth hormone or insulin-like growth factor-1 (IGF-1) in acromegalics, these drugs are cytotaxic and not cytotoxic. Consequently, in younger patients surgery is the treatment of choice since it offers the change of a complete cure. If surgery is not curative, radiotherapy is a second option but normalization of growth hormone and IGF-1 can take up to 2 years following such treatment. Octreotide is very effective in providing good long-term (112 years) control of hormone hypersecretion in acromegalics who fail surgery and/or radiotherapy. Since no escape occurs from octreotide inhibition of hypersecretion even during very prolonged periods of treatment in acromegalics, somatostatin analog therapy is the treatment of choice in elderly patients with this pituitary tumor. A number of reports suggest that lanreotide and vapreotide are as effective as octreotide in the management of acromegaly, but since these analogs have only fairly recently become available for clinical use, there is obviously no information on very long-term therapy in acromegalics. An important advance in the management of acromegaly with somatostatin analog therapy has been the development of long-acting depot preparations of octreotide, lanteotide and vapreotide which will improve patient compliance and more importantly quality of life. The role of somatostatin analog therapy in GEP tumors is limited because relapse occurs in all patients usually within 2 years following commencement of treatment. Consequently, somatostatin analog therapy is now considered to be palliative and should be

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reserved for when other treatment options have failed. Surgery is the only treatment which offers the chance of a complete cure in patients with GEP tumors even when liver metastases are present. There is little doubt that surgery for GEP tumors has been greatly enhanced by somatostatin scintigraphy [66] or positron emission tomography for in vivo studies of 5-hydroxytryptophan metabolism [67]. Both techniques are superior to conventional radiological techniques in localizing small lesions preoperatively and enable the surgeon to increase the chance of achieving a curative resection. There is some evidence that surgery can alter the natural history of gastrinomas [68] but there is an urgent need for good randomized controlled trials to establish the benefits of radical surgical intervention in patients with GEP tumors. Furthermore, even if radical curative surgery cannot be performed, debulking procedures should be considered to reduce the tumor load which may enhance the efficacy of medical treatments such as chemotherapy with or without liver embolization, tumor-targeted radiotherapy, immunotherapy and somatostatin analog treatment. The precise role and timing of the adjuvant therapies has yet to be fully determined and a multimodality approach, using different therapies synchronously or metachronously, is required to maximize the benefits of medical treatment of GEP tumors which are not resectable. Such studies should take the form of controlled trials, survival and quality of life being the primary outcome measures. Interestingly, neuroendocrine tumors of the gastrointestinal tract and pancreas are the only cancers where hepatic metastases are not a contraindication to liver transplantation. However, extrahepatic disease is a contraindication to liver transplantation. Thus, several reports indicate that liver transplantation provides good symptomatic relief and is occasionally curative in

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patients with neuroendocrine tumors in whom resection is not feasible [69–72]. Disease recurrence is common but good palliation can be achieved with medical therapy and survival is longer in patients with carcinoid tumors than other neuroendocrine tumors following liver transplantation [72]. However, the indications and timing of transplantation still needs to be evaluated for neuroendocrine tumors. Furthermore, liver transplantation is not a realistic treatment option for the majority of patients with metastatic GEP tumors because of the shortage of donor livers. With respect to somatostatin analog therapy of GEP tumors, it is generally accepted that it should be reserved for patients in whom all treatment options have failed. However, somatostatin analog therapy can potentiate cytotoxic therapy in vitro and in experimental animals [73–75]. Furthermore, there is compelling experimental evidence that octreotide is a very potent inhibitor of the growth and development of hepatic metastases in experimental animals [11]. Consequently, it is feasible that short-term somatostatin analog therapy of GEP tumors in combination with cytotoxic therapy, liver embolization and hepatic resection may potentiate the palliative effects of these treatment modalities. Such an approach may prolong the time during which these adjuvant therapies provide symptomatic control without precluding the use of somatostatin analogs as a palliative therapy when all other treatment options have been exhausted. However, further controlled trials are required to substantiate this hypothesis. Clinical experience with somatostatin analogs over the past 15 years has clearly demonstrated that these compounds are very successful in the management of acromegaly and are a valuable palliative therapy for neuroendocrine tumors. In contrast, although there

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is considerable evidence that somatostatin analogs have a potent antineoplastic effect on neoplasms of the breast, colon, pancreas, prostate, lung and other common malignancies in experimental animals and in vitro, the results of clinical trials of these drugs have been very disappointing (see other papers in this volume for detailed reviews on the results of somatostatin analog therapies in individual malignancies). However, the vast majority of early clinical trials were uncontrolled and carried out in patients with advanced metastatic disease and the methodology used to assess health-related quality of life (HRQL) inadequate. It is important to recognize that we should not be deterred by the lack of a therapeutic benefit of somatostatin analogs in advanced malignancy since the majority of antineoplastic treatments are also ineffective in this clinical setting but are substantially more effective in patients with a relatively low tumor burden. There is no reason to suspect that somatostatin analog therapy will not be more effective in patients with a low tumor burden compared to those with advanced disease and, indeed, there is a wealth of preclinical evidence to suggest that this is the case. However, there is a paucity of good studies in man to support this hypothesis, and as yet, we must accept that the clinical efficacy of somatostatin analog therapy in patients with a low tumor burden is unproven. This immediately raises ethical problems of conducting controlled trials of somatostatin analog therapy in patients with a relatively low tumor burden if other treatments have been previously demonstrated to exert a clinically beneficial effect. This problem can be overcome by carrying out randomized controlled trials comparing a therapy with established clinical efficacy alone or combined with somatostatin analogs. Such an approach has an advantage in patient recruitment since more will be amenable to participate in a trial in which

they are randomized to receive a treatment with an established therapeutic benefit alone or in combination with a novel drug with as yet unproven clinical efficacy. On the other hand, such an approach requires very large numbers of patients to be recruited into the trial to identify significant differences in outcome attributable to somatostatin analog therapy over and above that observed with the established therapy with adequate power. There can be little argument that future trials of somatostatin analog therapy of neoplasia should be randomized controlled studies wherever possible. In general, the methodology for the design of clinical trials is well documented and investigators should take care to include all the data required by medical journals for the reporting and publication of such studies in preparing the protocol [76]. With respect to somatostatin analog therapy of neoplasia, additional problems need to be addressed, in particular HRQL and dosing regimes. HRQL includes both specific and generic instruments and care must be taken in analyzing the data since there are methodological difficulties which have not been completely resolved for randomized controlled trials. Thus, generic and specific questionnaires used to assess the HRQL have multiple questions covering several domains which give rise to analytical problems. Analysis of individual questions or subscales would increase the likelihood of obtaining a considerable number of significant difference by chance whereas combining a large number of question into a single HRQL index may not be advisable as information may be lost. A reasonable compromise is to limit the number of individual questions analyzed to those relevant to the disease and expected treatment effects and to combine only those that are related. However, advice should be sought from an expert in statistics and health services research, particularly experienced with

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HRQL, prior to commencing any study, not only to select the best generic and specific instruments and how to analyze the data, but also to check that the study has sufficient power to detect important changes in HRQL where they exist with 95% confidence intervals. The dosing regime for somatostatin analog therapy in controlled studies of their efficacy in solid tumors is difficult to define. It may well be that higher doses of somatostatin analog are required to control tumor growth than to control hormone hypersecretion characteristic of acromegaly and neuroendocrine tumors, indications in which the greater part of the evidence of clinical efficacy of these drugs in neoplasia has been accumulated. Unlike chemotherapy, somatostatin analogs are well tolerated even at very high doses and hence the dosage cannot be based on maximal tolerable side effects. It is tempting to select a highdose regime for somatostatin analog therapy but this may not be advisable since as will be discussed in a subsequent section, these drugs may have adverse effects on the immune system. Therefore, care must be taken to ensure that any increased antineoplastic effects of high-dose somatostatin analog therapy are not negated by increasing suppression of the immune system, the body’s major defense against neoplasia. In addition, high-dose somatostatin analog therapy may result in more rapid downregulation of the hSSTRs responsible for mediating the antineoplastic effects of somatostatin analogs and/or the development of somatostatin-resistant clones of tumor cells. At present, therefore, the dosing regime for somatostatin analog therapy of solid tumors has to be somewhat empirical and based on information from the few studies which have demonstrated a clinical benefit in patients with advanced malignancy or extrapolation of doses that result in plasma levels of these drugs in experimental animals in which antineoplastic effects have been ob-

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served. The latter approach is fraught with difficulties, however, since extrapolation of results obtained in experimental animals can be very misleading when applied to man. At present, there is perhaps arguably, only one really well-designed prospective randomized control of somatostatin analog therapy in advanced malignancy which has clearly demonstrated the therapeutic potential of these drugs as antineoplastic agents [77]. In this study, patients with advanced inoperable somatostatin receptor-positive hepatocellular carcinoma were randomized to 500 Ìg octreotide s.c. b.d. or no treatment. The results of this study clearly indicated that the survival of octreotide treated patients was significantly better than that of controls. Multivariate analysis confirmed that octreotide was a major factor influencing survival. Tumor size was also investigated at regular intervals in both groups of patients. In patients randomized to receive no treatment all tumors continued to grow until the death of the patient. Similarly in the octreotide-treated patients, all large tumors continued to grow. However, small satellite tumors (!3 cm in diameter) either disappeared or remained the same size after prolonged octreotide therapy [77]. Therefore, for the present, it would be reasonable to use a dose of 500 Ìg somatostatin analog twice a day in initial formal clinical trials to evaluate the therapeutic potential of these drugs in patients with advanced malignancy and possibly a reduced dose in patients with a relatively low tumor load. The response to somatostatin analog therapy may vary with both the hSSTR expression of individual tumors and any therapy used in combination with these drugs. There is no information available on how these confounding factors may influence the response to somatostatin analog therapy, and until such data becomes available, it would be unwise to speculate on varying dosing regimes.

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With respect to clinical trial methodology of the efficacy of somatostatin analog therapy it is important to specify in the eligibility criteria that only patients with somatostatin receptor-positive tumors are included. Fortunately, most human solid tumors express hSSTR-2 and hSSTR-5 and can be detected by somatostatin scintigraphy using stable radioisotopes of octreotide and vapreotide or by positron emission tomography (PET). However, there are exceptions such as cancer of the prostate which do not express hSSTR-2 or hSSTR-5 and in these tumors the presence of somatostatin receptors needs to be based on tissue obtained by biopsy or at operation. Indeed, ideally tissue should be obtained from all tumors prior to therapy with somatostatin analog therapy to establish the hSSTR profile in order to determine whether or not this may influence the response to therapy with these drugs.

Chemotherapy In many ways, the role of cytotoxic therapy in malignancy resembles that of somatostatin analogs. Thus, early dramatic responses achieved by chemotherapy in fairly uncommon malignancies such as Hodgkin’s disease, histiocytic lymphoma, germ cell tumors, choriocarcinoma and various solid tumors of childhood led to a bewildering number of clinical studies of cytotoxic therapy in all cancers. However, it is now greatly accepted that chemotherapy alone is rarely curative and in the majority of patients is used to provide palliation. In this situation, a decision to use cytotoxic drugs inevitably entails balancing the potential benefits against the toxic side effects of chemotherapy. Consequently, the use of toxic and hence potentially fatal cytotoxics should be questioned unless they are

likely to lead to a high incidence of durable complete remissions with the occasional cure or regression of the tumor to such an extent that symptomatic relief offers a prolonged improvement in HRQL. However, for most advanced metastatic cancers the effects of chemotherapy have been largely disappointing, cytotoxics providing only modest improvements in response rates and survival. A good example is provided by a critical meta-analysis of the large number of randomized controlled trials comparing single agent versus polychemotherapy in the management of recurrent early breast cancer [78]. In general, this meta-analysis indicated that polychemotherapy resulted in a modest increase in response and survival compared to single agent chemotherapy but at the expense of increased toxicity. However, the clinical relevance of this large meta-analysis of chemotherapy of early breast cancer recurrence is limited because of the paucity of data on HRQL [78]. Fortunately, in the case of breast cancer, these tumors respond to less toxic hormonal treatment. Thus, in recurrent early breast cancer, hormonal treatment, single agent or combination of tamoxifen, megestrol and aromatase inhibitors compared favorably in terms of response rate and survival with the majority of chemotherapeutic regimes [78]. However, there was no improvement in response rates or survival in trials comparing chemotherapy alone or combined with hormone treatment [79]. For the medical oncologist, the results of these randomized controlled trials of chemotherapy and hormonal treatment allow for some limited clinical decision making in the management of advanced metastatic breast cancer. Hence, most oncologists would prefer single agent or combination hormonal therapy to chemotherapy because of the relatively reduced toxicity. For many solid tumors, however, cytotoxic therapy may be the only therapeutic modality available for the man-

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agement of advanced metastatic malignancy. In these situations it is much more difficult to decide whether or not cytotoxic therapy has any overall beneficial effects particularly because of the lack of good HRQL data. Somatostatin analogs potentiate the cytotoxic effects and decrease the toxicity of cytotoxic agents [73–75], suggesting they may improve the response rate, survival and HRQL of chemotherapy of advanced metastatic disease. This hypothesis merits further investigation in the form of large randomized controlled trials and particular emphasis should be placed on the HRQL component of the studies which hitherto has largely been neglected. Targeted Chemotherapy An interesting and challenging concept is the targeting of chemotherapy to somatostatin receptor-positive tumors by synthesizing conjugates of somatostatin analogs and cytotoxics [79, 80]. These preliminary studies indicated that the antineoplastic effects of the cytotoxic radicals in these conjugates on growth of a variety of human cancer effects was preserved in vitro. Although conjugation of the cytotoxic somatostatin analogs reduced their binding affinities to somatostatin receptors, the conjugates were still capable of inhibiting the release of growth hormone in the nanomolar range. Finally, conjugates of somatostatin analogs and cytotoxics were less toxic and more potent in inhibiting the growth of breast and pancreatic tumors in experimental animals than the cytotoxic agents alone following intravenous administration [79, 80]. Although these preliminary results are a potentially exciting development in the use of somatostatin analogs in oncology there are a number of problems which require further evaluation. Firstly, somatostatin statin receptor-positive cells are widely distributed throughout the body and hSSTR-2 is

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the most commonly expressed subtype in both normal and neoplastic tissue. Unfortunately, the present generation of somatostatin analogs all bind to hSSTR-2 with high affinity. Therefore, synthesis of conjugates of octreotide, lanreotide and vapreotide cytotoxics would not really target chemotherapy to neoplastic tissue per se, but to all cells expressing hSSTR-2 or hSSTR-5. In the preliminary studies of conjugates or somatostatin analogs and cytotoxics tissues distribution was not determined and toxicity was defined only in terms of death during a very short treatment period [79, 80]. Clearly much work is required to address these issues to establish the relative toxicities of the conjugates of cytotoxics and somatostatin analogs compared to the chemotherapeutic agent alone. In addition, targeting of chemotherapy to tumors after systemic administration of somatostatin analog and cytotoxics will require the development of newer hSSTR-selective analogs to tumors not expressing hSSTRs to which octreotide, lanreotide and vapreotide do not bind. If, however, these problems can be resolved somatostatin analog targeting of cytotoxics to neoplastic cells may prove to be a valuable treatment option for advanced metastatic cancer.

Hepatic Metastases Derived from Colorectal Primaries

At present, the most promising role of chemotherapy in cancer is as an adjuvant to surgery and/or radiotherapy. Of particularly interest with respect to somatostatin analog therapy is their potential benefit when used in combination with cytotoxics as an adjuvant to surgery in common abdominal malignancies. Space does not allow for a comprehensive discussion of the natural history of all types of gastrointestinal malignancies and the rationale for adjuvant cytotoxic therapy in these

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Table 1. Colorectal cancer stage,

definitions, frequency at diagnosis and survival

Dukes stage

Definition

Approximate 5-year frequency survival at diagnosis % %

A B1

Cancer confined to bowel wall Cancer which penetrates the bowel wall without spread through serosa Cancer which penetrates wall of bowel beyond serosa Lymph node involvement Liver metastases

10

80–85

10–15

70–75

20–30 25 30

60–70 35–40 3–6

B2 C D

indications following surgery, but perhaps is best illustrated by colorectal cancer. The prognosis for patients with colorectal cancer is summarized in table 1 and is associated with the staging of the disease, which in turn, is predominantly influenced by the development of liver metastases which have traditionally been equated with the imminent demise of the patient. For patients who undergo a theoretically curative resection of their colorectal primary and in whom no overt hepatic metastases are present at the time of operation, only 35–40% will be truly cured. A small proportion (12–15%) will develop extrahepatic hepatic disease (including local recurrence) and the remainder will develop liver metastases within 2–5 years of their theoretically curative resection. These observations would suggest that in those patients who develop hepatic metastases, occult micrometastases are present in the liver at the time of their theoretically curative resection of their colorectal primary or that tumorigenic cells are shed into the portal circulation during surgery and seed in the hepatic parenchyma. Not surprisingly, therefore, there has been considerable interest in the use of adjuvant chemotherapy, systemic or regional, to prevent or delay the development of hepatic

metastases and hence improve survival after a theoretically curative resection of a colorectal primary. In brief, as long ago as 1988 a metaanalysis of randomized adjuvant trials of 5fluorouracil (5-FU) for up to 1 year demonstrated a marginal overall reduction in the relative risk of death by approximately 17% and an absolute 5-year survival benefit of 3–4% [81, 82]. More recently, however, much more impressive results have been reported using 6–12 months’ adjuvant combination therapy with 5-FU and the immunomodulatory drug levamisole or by biomodulating 5-FU with leucovorin [81]. However, the statistical significant improvement in survival of these systemic therapies was confined to patients with Dukes C tumors and correlated with a similar reduction in the incidence of hepatic metastases [81]. Similar improvements in survival and the incidence of liver metastases is associated with a 7-day perioperative portal vein infusion of 5-FU following resection of a colorectal primary [81]. As would be expected, the toxicity of 7 days of 5-FU was markedly less than 6–12 months’ treatment with this cytotoxic. The major risk reduction of developing overt hepatic metastases and overall survival improvement, with portal vein infusion of 5FU, was confined to patients with Dukes C

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Fig. 1. Percentage of hepatic replacement by K12Tr tumor in octreotide-treated rats with or without blockade of RES with gadolinium chloride (GAD). Octreotide almost completely inhibited the growth of hepatic tumor in rats with a functional hepatic RES. Blockade of the hepatic RES with GAD significantly increased tumor growth compared to controls. Octreotide inhibited tumor growth in rats with hepatic RES blockade but not to the same extent as it did in animals with a functional hepatic RES [after 90].

disease [81]. Furthermore, the benefits of 6– 12 months of treatment with 5-FU and levamisole or folinic acid are equivalent to those of 7 days’ perioperative portal vein with 5-FU, although the combination of the two could be additive. Consequently, there is now a substantial body of evidence to suggest that all patients with Dukes C colorectal primaries should be treated with adjuvant systemic cytotoxic therapy using 5-FU combined with levamisole or folinic acid or a perioperative intraportal infusion of 5-FU. The situation in patients with Dukes B lesions is less certain since they are less likely to develop hepatic metastases than those with Dukes C disease, and hence, could be entered into a trial comparing surgery alone or combined with cytotoxic therapy. We have clearly demonstrated that octreotide inhibits the growth and development of hepatic tumors derived by intraportal injection of a variety of tumorigenic cells [11]. The mechanisms whereby octreotide inhibits the growth and development of hepatic tumors is mediated primarily via stimulation of the hepatic RES system (fig. 1) although direct and indirect antiproliferative

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effects of the somatostatin analogs are also contributory [11]. Levamisole stimulates hepatic RES activity, and this may partly explain its beneficial effect when used with 5FU as an adjuvant to surgical resection of colorectal tumors [81]. However, octreotide is significantly more potent than levamisole in stimulating hepatic RES activity [11]. Furthermore, since octreotide has additional direct and indirect antineoplastic effects apart from stimulation of hepatic RES activity, it may be superior to levamisole when combined with 5-FU in inhibiting the development of liver metastases after surgical resection of a primary colorectal tumor. Finally, since somatostatin and its analogs are cytoprotective with respect to the liver [11], concomitant administration of cytotoxics with somatostatin analogs may improve the response rates [73–75] and at the same time, protect the liver from hepatotoxic effects of the chemotherapeutic agents. We believe that the available evidence, although experimental, suggests that somatostatin analogs may have a beneficial effect on the development of liver metastases when used as an

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adjuvant to surgery in colorectal cancer and that this area warrants urgent clinical investigation.

Pancreatic Cancer

The possible therapeutic potential of somatostatin analogs as an adjuvant to surgery is not confined to the development of hepatic metastases derived from colorectal primaries. Thus, other gastrointestinal malignancies such as those of the stomach, pancreas, small intestine, gallbladder and extrahepatic bile ducts frequently metastasize to the liver. Some of these cancers such as pancreatic adenocarcinoma have low resectability rates and curative surgery is only possible in 6–8% of patients [see 82]. Furthermore, even following a theoretically extensive resection of adenocarcinoma of the pancreas the 5-year survival is only approximately 25%. Following surgical resection for adenocarcinoma of the pancreas there are three major patterns of recurrence which occur with approximately equal frequency, namely local recurrence, hepatic metastases undetected at the time of operation and local recurrence with metastatic disease. There is now compelling evidence that the best means of preventing local recurrence after resection for pancreatic adenocarcinoma is radiotherapy whereas for metastatic spread chemotherapy is the treatment of choice. However, since the pattern of recurrence after pancreatic resection is both local and systemic, an improvement in survival is only likely to be observed with combinations of radiotherapy and chemotherapy. In view of the poor prognosis, even after a theoretically curative resection and because there is some limited evidence from phase 2 trials that adjuvant chemotherapy and radiotherapy may improve survival of patients with pancreatic adenocarcinoma, it is both surprising and dis-

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appointing that there are a paucity of randomized controlled trials to evaluate the efficacy of adjuvant therapies in this indication. Clearly, there is an urgent need for confirmation of these putative benefits of adjuvant radiotherapy and chemotherapy in patients with resectable pancreatic tumors in the form of large controlled randomized trials. Somatostatin analog therapy could be a valuable option for such phase III studies since there is good evidence that these compounds potentiate the cytotoxic effects and reduce the side effects of chemotherapy [73–75]. In addition, as discussed above, stimulation of hepatic RES activity by somatostatin analogs may be particularly important in inhibiting the growth and development of liver metastases [11]. All patients with pancreatic cancer in which surgery is possible should be entered into such randomized controlled trials irrespective of the size of the tumor and such studies should be sufficiently large to detect differences between the therapies under investigation and between predefined subgroups with sufficient power.

Gastric Cancer

Like pancreatic adenocarcinoma, gastric cancer has a very dismal prognosis and a high proportion of patients develop liver metastases. As discussed by Cascinu et al. [83] in another paper in this volume, there is an urgent need for large controlled trials to evaluate the efficacy of adjuvant therapies after surgery. Somatostatin analog therapy may, as discussed earlier for colorectal and pancreatic cancer, be a valuable treatment for gastric cancer to potentiate the effects of chemotherapy and via their stimulatory effect on hepatic RES activity inhibit the growth and development of liver metastases. Since colorectal, pancreatic and gastric cancers do not express

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hSSTR-2, the receptor subtype whereby octreotide, vapreotide and lanreotide exert their direct and antineoplastic effects, the development of specific analogs with high binding affinities for individual hSSTRs would be required to maximize somatostatin analog therapy of any of these tumor cells remaining after resection. It is unlikely, however, that such analogs will be available for clinical use in the near future. An alternative strategy could be to use native somatostatin rather than one of its analogs perioperatively in conjunction with intraportal 5-FU in those cancers which do not express hSSTR-2 to maximize the potential antineoplastic effects of the hormone. Subsequently, 6–12 months of systemically administered 5-FU which may provide additional benefits to 7 days of intraportal administration of this cytotoxic [81] could be again given concomitantly with somatostatin analogs. Such an approach would, however, be very expensive and the therapeutic advantage of such therapy would have to be demonstrated to be very beneficial to justify the costs. Furthermore, in order to demonstrate a marked therapeutic advantage of somatostatin and its analogs currently available for clinical use, over and above adjuvant cytotoxic and radiotherapy in patients with gastric, pancreatic and colorectal cancer would require very large randomized controlled trials which would be both difficult to organize and fund.

Liver Tumors

The presence of overt liver metastases is not uncommon in gastrointestinal malignancies and is associated with a very poor prognosis. Colonic cancer is unique among solid tumors in that surgical resection of hepatic and pulmonary metastases can prolong longterm survival and offers the only real possibil-

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ity of cure [84–86]. Nevertheless, even after a technically curative resection of colorectal hepatic metastases, recurrence occurs in approximately 60% of patients [86] suggesting that there is an urgent need for postoperative adjuvant therapy. The role of chemotherapy, immunotherapy, hepatic artery or portal vein embolization, brachytherapy, cryotherapy, interstitial laser hypothermia and alcohol injection as adjuvant and neoadjuvant therapies in the management of colorectal hepatic metastases has been critically examined in a recent review [87]. A strong case can be made for a multimodality approach using combinations of techniques to optimize the management of colonic liver metastases and hence prolong survival and increase the chance of cure. However, the efficacy of new adjuvant and neoadjuvant therapies have yet to be rigorously evaluated in randomized controlled trials before they are incorporated into formal structured management strategies for the management of colonic metastases. Theoretically, somatostatin analog therapy may have a potentially beneficial effect when used in conjunction with these adjuvant or neoadjuvant treatment modalities for the management of colonic hepatic metastases. Thus, somatostatin analogs may potentiate the effects of adjuvant or neoadjuvant chemotherapy and reduce the hepatoxicity of cytotoxic agents [11, 73–75]. Perhaps more importantly, however, the growth and development of hepatic tumors is significantly increased following partial hepatectomy [88, 89]. Octreotide inhibits the growth of hepatic tumors after partial hepatectomy, possibly via stimulation of hepatic (RES) activity which is significantly reduced after liver resection [89]. However, the direct and indirect antineoplastic effects of octreotide may also be contributory to the inhibition of tumor growth by this somatostatin analog after partial hepatectomy [11]. On the negative side, in addition to inhibiting the

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growth of hepatic tumors, octreotide also suppresses liver regeneration following partial hepatectomy. The potential for inhibition of regeneration in the human liver by somatostatin analogs may cause some concern. However, anecdotal evidence suggests that octreotide has no clinically detectable effect on liver regeneration in patients undergoing hepatic resection [Wu, pers. commun.]. Nevertheless, the potential detrimental effect of octreotide on liver resection after partial hepatectomy needs to be addressed more formally prior to advocating the use of somatostatin analogs as an adjuvant to surgery in patients with liver metastases. There is an urgent need for further investigation of the effects of somatostatin analogs in this area since the benefits of such treatment combined with other adjuvant and neoadjuvant therapies to surgery could be considerable in the management of hepatic metastases.

There is compelling experimental evidence to suggest that somatostatin analog therapy may be of value when used in combination with other hormonal treatments in the management of estrogen-positive breast cancer and prostate cancer which is discussed in detail in another paper in this volume [90– 92]. However, the results of clinical studies of somatostatin analogs in combination with other hormonal therapies in the management of breast and prostate cancer have been very disappointing [91]. It is generally accepted that tamoxifen is the hormonal treatment of choice for estrogen-positive metastatic breast cancer. In spite of compelling evidence that octreotide in combination with tamoxifen may be more effective than tamoxifen alone in the management of metastatic breast cancer there is now good evidence from two ran-

domized controlled trials that this is not the case [92, 93]. Thus, in both trials the time to disease progression, objective response rates and survival were not significantly different between patients treated with tamoxifen alone or combined with octreotide [92–94]. Moreover, in both trials the incidence of side effects was higher in patients treated with combination therapy than with tamoxifen alone [92, 93]. One of these studies initially randomized patients to tamoxifen or octreotide alone or combination therapy [92]. The octreotide only arm of the trial was dropped when the somatostatin analog was found to be associated with a rapid time to disease progression and to produce no objective response [92]. Finally, in one of these trials, combined tamoxifen and octreotide treatment resulted in a significantly greater reduction in serum IGF-1 than tamoxifen alone in a limited cohort of patients [92]. Both these clinical trials can be criticized on the grounds that they were underpowered, particularly since multiple outcome measures were assessed, to completely evaluate any possible benefit of octreotide in the management of metastatic breast cancer. However, both studies are strongly suggestive that combined tamoxifen and octreotide therapy is unlikely to confer any worthwhile clinical benefit over tamoxifen alone, particularly since combination therapy was associated with an increased number of side effects which could adversely affect HRQL. It is unlikely that vapreotide or lanreotide are more effective than octreotide when used in combination with tamoxifen in the management of metastatic breast cancer since all three analogs exhibit similar biological effects. Therefore, any benefit of these two newer analogs over octreotide is likely to be only marginal. The mechanisms whereby octreotide and tamoxifen in combination do not confer any therapeutic benefit over and above that of

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antiestrogen therapy alone is not clear. In the trial carried out by Ingle et al. [92], combined octreotide and tamoxifen therapy resulted in significantly greater reductions in serum IGF1 than tamoxifen alone in patients with metastatic breast cancer without conferring any clinical benefits over and above that obtained with antiestrogen alone. However, in this study, serum IGF-1 levels were only measured in a cohort of patients before and 6 weeks after commencing combined tamoxifen and octreotide therapy or tamoxifen alone [92]. It has previously been reported that the initial suppression of serum IGF-1 levels by octreotide in patients with breast cancer is gradually lost approximately 8–14 weeks after commencing therapy [95]. Possibly, therefore, the failure of combined octreotide and tamoxifen to confer any additional clinical benefits compared to antiestrogen alone in patients with breast cancer may be due, at least in part, to the gradual loss of efficacy in the control of IGF-1 and possibly other mitogenic factors, with prolonged administration of the somatostatin analog. This hypothesis requires further investigation in patients with breast cancer since it could suggest alternative dosing regimes which may provide improvements in clinical outcome. For example, withdrawal of octreotide therapy as soon as IGF-1 levels begin to increase and recommencement when the serum levels of this mitogen are within the range of those observed in patients with breast carcinoma treated with tamoxifen alone may prolong the period whereby combination therapy potentiates suppression of this growth factor. Intermittent octreotide administration combined with continuous tamoxifen therapy may delay complete loss of efficacy of the somatostatin analog in the control of IGF-1 secretions thereby possibly conferring a clinical benefit in patients with breast cancer. The molecular pharmacology of the relationship between the effects of estrogen, an-

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tiestrogens and somatostatin analogs on the expression of hSSTRs is complex and not fully understood. Firstly, estrogen has been reported to upregulate hSSTR-2 and hSSTR-3 expression in prolactin-secreting rat pituitary tumor 7315b cells both in vivo and in vitro [56]. Secondly, tamoxifen either decreases or increases estrogen-induced expression of hSSTRs in different human breast cancer cell lines in vitro [96]. Thirdly, in vitro studies have demonstrated that the antineoplastic effects of somatostatin on MCF-7 estrogenreceptor-positive human breast cancer cells are attenuated by estradiol [97]. Fourthly, tamoxifen potentiates the suppression of both IGF-1 expression and serum levels of IGF-1 [98, 99]. Finally, octreotide potentiates the antineoplastic effects of tamoxifen in oophorectomized rats with 7,12-dimethylbenz(a)anthracene-induced mammary tumors [100]. The above observations clearly indicate that the relationships between somatostatin analogs, estrogens and antiestrogens are complex and require further investigation. Of particular importance is the as yet unknown effects of tamoxifen on individual hSSTR expression in patients with breast cancer. Studies in vitro indicate that this antiestrogen can upregulate or downregulate somatostatin receptor expression in different human breast cancer cell lines [96]. Clearly, depending on its overall effect on in vivo hSSTR expression in patients with breast cancer, tamoxifen could potentiate or attenuate the direct antineoplastic effects of somatostatin analog therapy. However, it should be pointed out that we do not as yet know the functional roles of hSSTRs in breast cancer and, hence, the possible therapeutic benefits of somatostatin analogs in terms of their direct antineoplastic effects. There is some preliminary evidence to suggest that hSSTR expression may play a functional role in the growth and development of breast cancer in man. Thus, preliminary observa-

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tions indicate that the presence of hSSTRs in the tumor of patients with breast cancer increases the probability of a longer disease-free survival compared to those in whom the tumors are hSSTR-negative [20]. It should be borne in mind, however, that hSSTRs are not homogeneously distributed in breast cancer [101]. Furthermore, the expression of individual hSSTRs in human breast cancer is variable [27]. The majority of human breast cancers do express hSSTR-2, the subtype whereby the current generation of somatostatin analogs mediate most of their antineoplastic effects. Some breast tumors do not, however, express hSSTR-2 [27]. These observations suggest that hSSTR-positive areas of the tumor may respond to the direct antineoplastic effects of somatostatin analog therapy thereby conferring a growth advantage compared to those neoplastic cells which do not express somatostatin receptors. However, any beneficial effects that somatostatin analog therapy may have in terms of their direct antineoplastic cells may be lost during long-term administration due to the development of somatostatin-resistant clones of breast tumor cells. At present, there is no clear indication of the temporal relationships between the commencement of somatostatin analog therapy and downregulation of the hSSTRs which mediate their direct antiproliferative effect in breast cancer. Furthermore, it is unknown whether tamoxifen, by upregulating hSSTR expression, potentiates the direct antineoplastic effects of somatostatin analogs. Alternatively, if tamoxifen downregulates hSSTR expression in breast cancer it could attenuate the direct antineoplastic effects of somatostatin analog therapy. Finally, tamoxifen may not have any effect on hSSTR expression in patients with breast cancer. Clearly, the issues discussed above are complex and will not be easy to resolve in patients with breast cancer. Nevertheless, there is an urgent need to an-

swer at least some of these questions in order to fully rationalize the therapeutic potential of combination tamoxifen and somatostatin analog therapy in breast cancer. For example, intermittent somatostatin analog administration may be more beneficial than continuous treatment to delay the downregulation of hSSTR expression and the loss of efficacy in suppressing IGF-1 secretion during combination therapy with tamoxifen in breast cancer. There are a considerable number of permutations of how to maximize somatostatin analog therapy for breast carcinoma in combination with tamoxifen alone, as an adjuvant to chemotherapy prior to commencing tamoxifen treatment or intermittent administration, and all eventualities need to be explored in good phase 2 trials before proceeding to phase 3 randomized controlled trials. All we can conclude at present is that somatostatin analogs in combination with tamoxifen confer no advantage over antiestrogen treatment alone in the management of metastatic breast cancer. Indeed in both randomized controlled trials the complication rate was higher with combination therapy than with tamoxifen alone which may adversely affect the HRQL [91, 92]. In a third very small randomized controlled trial tamoxifen was compared with triple therapy comprising the antiestrogen in combination with octreotide and a prolactin inhibitor in patients with breast cancer [102]. Interestingly, unlike previous controlled trials [91, 92], serum IGF-1 levels were not significantly different between the two groups of patients [102]. The objective response rates were better in patients receiving triple therapy compared to tamoxifen alone but survival was not improved [102]. However, it is very difficult to make any definitive conclusions on the efficacy of triple therapy compared with tamoxifen alone since the study was considerably underpowered. Furthermore, in our

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opinion it would be unwise to proceed to controlled trials comparing tamoxifen with polyhormonal therapies until the issues relating to combining the antiestrogen with somatostatin analogs have been fully resolved. It has been suggested that tamoxifen plus somatostatin analog therapy may be more effective than tamoxifen alone in the adjuvant setting than in metastatic breast cancer. This hypothesis is based on phase 2 studies suggesting that somatostatin analogs potentiate the effects of tamoxifen in suppressing serum IGF-1 levels [99] and from experimental studies which indicate that combination therapy is more effective than monotherapy in rats with a low tumor burden from those with more advanced neoplasia [100]. Indeed, clinical trials are currently in progress to examine this hypothesis. However, in view of the very disappointing results obtained with combined tamoxifen and somatostatin analog therapy in patients with metastatic breast disease [91, 92] adjuvant trials of such combination therapy should be monitored carefully by independent Safety Monitoring and Advisory Committees (SMAC). Furthermore, adjuvant tamoxifen therapy for patients with early breast cancer is established as being both safe and effective [103]. The only controversy over tamoxifen as an adjuvant therapy for early breast cancer is for how long treatment should be continued after surgery for early breast cancer, i.e. 1, 2 or 5 years [103]. Given that we know that prolonged somatostatin analog therapy can lead to downregulation of hSSTR expression and loss of efficacy in controlling IGF-1 secretion, it is very difficult to see a role for these drugs in very long-term adjuvant management programs for preventing recurrent early breast cancer. Furthermore, in view of the increased risk of side effects of combined tamoxifen and somatostatin analog therapy compared with tamoxifen alone in patients with metastatic breast cancer [91,

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92], particularly attention should be paid to HRQL by SMAC’s monitoring adjuvant trials of this combination therapy. When assessing HRQL account must also be taken of the pattern of the method of delivery of the somatostatin analogs, since although facilitated by the availability of long-acting depot preparations of octreotide, vapreotide and lanreotide, this still involves injections. Finally, although not always the ideal setting for carrying out complex economic analyses, this does need to be taken into account when considering prolonged expensive adjuvant therapies. Perhaps somatostatin analog therapy in combination with tamoxifen may prove to be superior to antiestrogen alone in the prevention of recurrent early breast cancer but we will not be able to answer this until the results of such trials become available. The rationale for the use of somatostatin analogs in the management of advanced prostatic cancer and the results of preliminary phase 1 and phase 2 clinical trials are discussed in detail by Vainas [91] in a separate paper in this volume. In brief, hSSTR expression is different in normal and neoplastic cells and between stromal and epithelial cells [34]. Of particular importance is that apart from hSSTR-5, the other hSSTRs expressed in primary cultures of epithelial and stromal cells (table 2) do not bind with high affinity to the somatostatin analogs currently available for clinical use [34]. These observations would suggest that any beneficial effects of octreotide, vapreotide or lanreotide in advanced prostatic cancer are likely to be mediated by their indirect rather than direct antineoplastic mechanisms of action. Exploitation of the full direct antineoplastic effects of somatostatin analog therapy in prostate cancer patients awaits (1) the development of novel analogs specific for hSSTR-1 or hSSTR-5 subtypes or (2) effective methods of delivering the hSSTR-2 gene to neoplastic cells. Thus, at

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Table 2. Expression of somatostatin receptor subtypes (hSSTR) in primary cultures of epithelial and stromal cells on normal human prostates and prostate cancers [after 34]

hSSTR-1 hSSTR-2 hSSTR-3 hSSTR-4 hSSTR-5 Normal epithelial cells Normal stromal cells Neoplastic epithelial cells Neoplastic stromal cells

– – + –

+ – – –

– – – –

+ – + –

+ – + –

– = Not detectable; + = detectable.

present, any benefit of somatostatin analog therapy in prostatic cancer is likely to be mediated largely by their indirect antineoplastic effects. With respect to the clinical trials of somatostatin analog therapy in advanced prostate cancer it is difficult to make any conclusions on their therapeutic efficacy [91] since such studies in general included (1) patients with hormone-refractory or non-hormone-refractory disease, (2) relatively small numbers of patients, (3) used somatostatin analog therapy alone or combined with bromocriptine or complete androgen blockade, (4) used wide variations in the dosing regimes and (5) lacked objective outcome measures including HRQL. Consequently, at present it would be unwise to embark on large randomized controlled trials of somatostatin analog therapy in cancer of the prostate but rather to carry out good quality phase 2 trials to determine the therapeutic efficacy and tolerability of octreotide, lanreotide and vapreotide in this indication. An obvious clinical setting to initially examine the therapeutic efficacy and tolerability of somatostatin analogs is in patients with hormone-refractory prostate cancer since at present there are no clear-cut treatment algorithms for second-line management. Hormone-refractory prostate cancer usually manifests itself after complete androgen blockade and is thought to be the result of selection

and/or cloning of preexisting or de novo hormone-independent cell lines. Hormonal escape of prostate cancer cells during complete androgen blockade is a gradual event and monitoring of PSA has become accepted as the diagnostic test of choice to measure the progression of disease. Early diagnosis of hormonal escape based on a rise in PSA levels in patients with advanced prostate cancer who are still asymptomatic provides an opportunity for early institution of adjuvant therapies, and hence gives a reasonable chance for investigating both the efficacy and tolerability of the additional treatment being investigated. The principal outcome measure should be survival and the main secondary end point HRQL, the latter being assessed by both specific and generic instruments. With respect to somatostatin analog therapy as adjuvant to complete androgen blockade some consideration should be given to whether treatment should be intermittent or continuous. It has been demonstrated that octreotide in combination with complete androgen blockade in patients with advanced prostate cancer resulted in significant reductions in the serum levels of IGF-1 and epidermal growth factor (EGF) which paralleled the reduction in PSA [104]. Possibly therefore, serum IGF-1 and EGF levels could be used as serum markers of early escape from somatostatin analog therapy. Somatostatin analog therapy could then be stopped and re-instituted when the serum

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levels of IGF-1 and EGF return to those observed prior to commencing treatment. A reduction of serum IGF-1 and EGF levels after recommencing somatostatin analog therapy to those observed when these drugs were initially administered would be strongly suggestive that intermittent treatment dosing regimes may be preferable to continuous administration. This hypothesis clearly needs to be initially substantiated in phase 2 trials. It is mandatory that serum PSA levels are monitored at regular intervals in patients with advanced prostate cancer being treated with a somatostatin analog as an adjuvant in the event that combination therapy results in rapid progression of disease. In patients with advanced prostate cancer in whom the disease is completely refractory to complete androgen blockade, somatostatin analog therapy appears to be of very limited value [91]. Only in this setting should phase 2 trials of somatostatin analog therapy combined with other treatment modalities such as bombesin antagonists, LHRH antagonists or chemotherapy be considered. The principal primary and secondary outcome measures should again be survival and HRQL. As discussed above, consideration should be given as to whether somatostatin analog therapy should be intermittent or continuous. In recent years, there has been increasing interest on whether or not intermittent complete androgen blockade may delay the onset of hormone-refractory prostate cancer compared to continuous treatment and hence improve survival and increase the tolerability of chemical castration [64, 65]. Although the results of preliminary trials suggest that intermittent complete androgen blockade may be superior to continuous treatment [64, 65], a comparison of these two forms of treatment urgently requires confirmation in a randomized controlled trial. It is tempting to specu-

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late that somatostatin analog therapy may confer an additional benefit, if used for limited periods between cycles of androgen suppression in patients with advanced prostate cancer. Increases in the serum levels of IGF-1 or EGF could be used as indicators of escape from hormone suppression by the somatostatin analogs and to discontinue treatment. Serum PSA could be used to both detect any deleterious effect of somatostatin analog therapy on tumor progression and for recommencing androgen suppression. Intermittent androgen suppression and somatostatin analog therapy may be a tempting therapeutic modality for the management of advanced prostate cancer, particularly in the younger male but it has to be borne in mind that intermittent androgen blockade has yet to be demonstrated to be superior to continuous therapy in prolonging survival. Furthermore, the potential for harm exists for both intermittent androgen suppression and for somatostatin analog therapy. Any trials evaluating alternating androgen suppression with somatostatin analog therapy should be very carefully monitored. Pancreatic cancer is associated with an extremely poor prognosis even following a theoretically curative resection. The etiology, prognosis and therapeutic modalities for adenocarcinoma of the pancreas are discussed in detail by Rosenberg [82] in another paper in this volume. In brief, pancreatic adenocarcinoma cells express receptors for estrogens, progesterone and androgens suggesting that this neoplasm may be responsive to hormonal treatment. Indeed, there is some evidence to suggest that somatostatin analog therapy combined with either tamoxifen [105] or LHRH analogs [106] may have some clinically beneficial effects in adenocarcinoma of the pancreas and the results of these studies are discussed in detail by Rosenberg [82]. Suffice it to say that both studies suggest that pancreatic

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cancer may be responsive to hormonal manipulation with somatostatin analog therapy combined with either tamoxifen [105] or LHRH analogs [106] and warrants further investigation particularly in patients with small tumors who undergo a theoretically curative resection.

Cancer cells expressing tumor-specific antigens initiate a complex immune response involving a complex cascade of cellular and molecular interactions to destroy the tumor cell [107]. There is accumulating evidence to suggest that the failure of the immune system to eliminate a tumor results from the ability of tumor antigens to stimulate an effective immune response [107]. Possibilities for such failure include loss of major histocompatibility class 1 or its costimulator B7 expression, aberrant antigen presentation and the inhibition of the cellular and molecular components of the immune system by factors secreted from or expressed on tumor cells [107]. Further, surgical or anesthetic trauma compromise immune function [108–114] and can stimulate the release of growth factors [115]. Thus, in the immediate postoperative period in the cancer patient, these changes in immune function may accelerate the growth of microscopic local tumor cells and distant micrometastatic deposits and increase the risk of tumor cells that shed into the circulation during resection of the primary cancer establishing themselves as distant micrometastases. Not surprisingly, in the past 20 years there has been increasing interest in developing therapies to stimulate the immune response against tumors in patients with advanced metastatic disease to stabilize disease progression and as an adjuvant to surgery to increase the chances of achieving a curative

resection. A variety of immunotherapies have been suggested to stimulate the immune system in cancer patients including (1) intralesional administration of nonspecific immunostimulants such as BCG or Cryptosporidium parvum, (2) administration of cytokines, (3) adoptive immunotherapy with lymphokine-activated killer cells administered either systematically or regionally, alone or in combination with cytokines or chemotherapy and (4) combination therapy with cytokines and immunomodulating hormones [116– 120]. It is beyond the scope of this paper to discuss the clinical efficacy of all these therapeutic modalities except to state that none of these immunotherapies for neoplasia have fulfilled their potential and that future strategies are likely to focus on genetic immunotherapy. Of particular relevance to this paper are the consequences of somatostatin analog therapy on the immune response to cancer and whether or not the clinical efficacy of these drugs could be improved by concomitant immunotherapy. Initial interest in the use of combination somatostatin analog and immunotherapy focused on the possible synergistic effects of octreotide and interferon-· in inhibiting the proliferation of endocrine tumor cells [120]. This approach appeared to be justified by early anecdotal reports suggesting that octreotide and interferon-· in combination appeared to be a valuable immunoendocrine therapy for metastatic carcinoid tumors [121, 122]. However, interferon-· elicits a number of other immune responses apart from its antiproliferative effect on endocrine cells including stimulation of natural killer cell activity [118] suggesting that it may be a valuable adjuvant to somatostatin analog treatment of nonendocrine tumors. Unfortunately, the therapeutic potential of somatostatin analog therapy combined with immunotherapies has been relatively ignored as an option for the manage-

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ment of cancer. This may represent a considerable oversight since hSSTRs are expressed on a variety of normal and neoplastic lymphoid cells [38]. Furthermore, somatostatin analogs inhibit the proliferation of a variety of lymphoid cells, immunoglobulin production and natural killer cell activity [38, 123–126]. These inhibitory effects of somatostatin analog therapy on the immune system may have profound implications on their therapeutic efficacy in neoplasia. Apart from suggesting that somatostatin analog therapy may play a role in the management of lymphomas, these drugs may attenuate or completely negate any potential therapeutic benefit in terms of the direct and indirect antineoplastic effects on tumor growth. It is even possible that the immunosuppressive effects of somatostatin analogs outweigh their therapeutic beneficial effects resulting in a more rapid tumor progression. Although purely speculative at present the immunosuppressant effects of somatostatin analog may account, at least in part, for the very disappointing results of these drugs in advanced malignancy. Furthermore, careful consideration should be given to the use of adjuvant somatostatin analog therapy as an adjuvant to surgery in the immediate postoperative period. As discussed above, surgery and anesthesia compromise the immune system [108–114] and administration of somatostatin analogs intra- or postoperatively may, by further immunocompromising the patient, accelerate the growth of tumor deposits remaining after radical resection. There is an abundance of evidence to indicate that somatostatin analog therapy used as and adjuvant to surgery may prevent the growth and development of hepatic metastases via stimulation of hepatic RES activity [11] but this may be at the expense of early local recurrence. Similarly, somatostatin analogs, because of their inhibitory effects on other functions of the immune system, may ac-

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celerate the growth of established micrometastases in locations other than the liver. Again these hypotheses require further investigation. Finally, and perhaps more importantly, investigations are required to determine whether or not it is possible to potentiate the individual benefits of somatostatin analog and concomitant therapies such as the administration of cytotoxics, by stimulating immune function by adoptive immunotherapy or genetic immunotherapy by combination treatments. Resolving all the problems discussed above represent a considerable challenge to oncologists and immunologists and require carefully designed studies in experimental animals and in man. Nevertheless, such studies are required to substantiate the above hypotheses since they are critical to optimizing somatostatin analog therapy of neoplasia.

Novel Therapeutic Approaches to the Management of Neoplasia

Targeted Radiotherapy Somatostatin scintigraphy using stable radiolabelled compounds of octreotide and more recently vapreotide is a well-established technique for the localization of primary and metastatic tumors expressing hSSTR-2 and hSSTR-5. Somatostatin receptor scintigraphy can, and indeed should, be used for the selection of patients with neuroendocrine and other solid tumors who are likely to benefit from somatostatin therapy and for monitoring treatment. The major limitation of somatostatin receptor scintigraphy using radiolabelled ligands of octreotide is that the technique will only allow detection of those tumors expressing hSSTR-2 and hSSTR-5 and possibly those neoplasms expressing hSSTR-3 in sufficient density to allow visualization. Radioligands of vapreotide may be more use-

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ful than radiolabelled ligands of octreotide in visualizing those tumors that express hSSTR4 in a sufficient density, but not hSSTR-2 and hSSTR-5. Visualization of tumors by vapreotide scintigraphy but not by octreotide scintigraphy may provide a rationale for the selection of patients that are likely to benefit from therapy with vapreotide or lanreotide rather than octreotide, but this hypothesis requires confirmation in prospective controlled trials. Targeted radiotherapy based on the binding of somatostatin analog radioligands to tumors expressing hSSTRs is an obvious extension of somatostatin scintigraphy. This is not a new concept and as long ago as 1995 Wiseman and Kvols [127] reviewed the results of targeted radiotherapy using 131I-metaiodobenzylguanidine (131I-MIBG) and 111InDTPA- D- Phe1octreotide (111In- pentetreotide) in patients with pheochromocytoma, neuroblastoma, carcinoid tumors, medullary thyroid carcinoma and paragangliomas. Targeted radiotherapy with 131I-MIBG resulted in variable tumor responses with the most encouraging results being observed in patients with pheochromocytomas [127]. 111In-pentetreotide has also been used for targeting radiotherapy in a very small number of patients with neuroendocrine tumors and resulted in objective tumor responses [127]. These authors concluded that targeted radiotherapy with somatostatin analogs coupled to ß- or ·emitting radioisotopes would be necessary to obtain a significant and desirable tumor response [127]. This point has been emphasized repeatedly by medical oncologists and indeed there are a number of experimental studies evaluating ß- or ·-emitting somatostatin radioligands. For example, rhenium-188 (t1/2 16.9 h; beta-max 2.5 units) coupled to vapreotide administered intralesionally (prostate) or intracavitarily (mammary and small cell lung cancer) significantly reduced or eliminated the tumor burden in nude mice [128]. Local

or regional administration of radiolabelled high energy ß- or Á-radioligands of somatostatin analogs may have some advantages over intravenous administration. Firstly, local or regional administration of such radioligands may reduce systemic toxicity. Secondly, somatostatin receptors are widely distributed in normal tissues throughout the body and intravenous administration of high energy ß- or Áradioligands of somatostatin analogs may produce side effects over and above those observed with regional conventional or somatostatin analog-targeted radiotherapy. Finally, recent studies have suggested that there may be a blood-tumor barrier, thereby possibly preventing diffusion of radiolabelled somatostatin analogs from the capillary tumor to neoplastic cells [129]. The concept of targeted radiotherapy of tumors using radioligands of somatostatin analogs remains a very attractive approach for the treatment of neoplasia. The fact that it is over 12 years since the concept of octreotide-targeted radiotherapy of neoplasia was first proposed and we are still awaiting any good phase 2 clinical trials of the efficacy and tolerability of this technique highlights the practical difficulties involved in developing this therapy. Nevertheless, a number of groups are actively investigating targeted radiotherapy of tumors using high energy ß- and Á-emitters of somatostatin analog radioligands and the results of early studies in patients are awaited with interest.

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Angiogenesis Angiogenesis is defined as the development of de novo capillaries from preexisting blood vessels and is an important process in the growth of solid cancers. The pathophysiology of angiogenesis in solid tumors and the potential role of somatostatin analogs as antiangiogenic drugs in neoplasia has been comprehensively reviewed by Danesi and Del

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Tacca [130] and Woltering et al. [131]. In brief, using in vitro models of angiogenesis, octreotide inhibits the development but not the growth of new capillaries [130, 131]. Furthermore, octreotide has been demonstrated to inhibit angiogenesis after chemical-induced corneal injury in rats and possibly in patients with diabetic retinopathy [130]. Although it is almost impossible to quantify the antiangiogenic effects of somatostatin analog therapy on tumor progression directly, inhibition of angiogenesis is theoretically an important mechanism whereby these drugs exert their antineoplastic effects. Thus, tumor cells are genetically diverse and unstable and hence the direct and indirect antineoplastic effects of somatostatin analog therapy may not result in complete elimination of all cancer cells. In contrast, endothelial cells in tumor vessels are genetically more stable and less likely to develop resistance to therapeutic procedures. For example, endogenous antagonists to angiogenesis such as angiostatin and endostatin which selectively inhibit endothelial cells to respond to antigenic signals elicit marked regression of tumors in experimental animals [132, 133]. Furthermore, gene transfer of angiostatin significantly inhibits tumor growth in experimental animals [134]. Alternatively, although a large number of angiogenic factors are implicated in tumor vascularization, strategies targeted at blocking these factors can reduce tumor growth [131]. A promising approach to inhibition of tumor growth by inhibiting angiogenesis is the development of gene therapies. For example, transfection of tumor cells with antisense oligonucleotides against vascular endothelial growth factor mRNA has been reported to reduce the growth rate of gliomas [135]. Similarly, genetic transfer of a soluble Tie 2 receptor (endothelium-specific receptor tyrosine kinase) blocks activation of Tie 2 receptors on tumor cells [135]. Furthermore, these investigators

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demonstrated that treatment of tumor-bearing animals with the soluble Tie 2 receptor using recombinant adenovirus as a vector almost completely inhibited angiogenesis but significantly inhibited the growth of both the primary tumor and metastases [135]. Although the efficacy and tolerability of the specific antagonists and genetic therapy of angiogenesis has not yet been reported in man, clinical studies are ongoing. It appeared logical to us that the direct and indirect antineoplastic effects of somatostatin analog therapy combined with its antigenic action could potentiate the effects of specific antagonists and gene therapy of angiogenesis. We are currently evaluating this hypothesis intensively and if the results of our studies suggest that somatostatin analogs potentiate that of specific antiangiogenic therapies, this may prove to be a very valuable approach to the management of neoplasia. Gene Therapy Gene therapy has immense potential for the treatment of many forms of diseases including cancer [136]. Although there are a number of problems which remain to be resolved before gene therapy can be routinely applied to patients with malignancy, initial studies in man are very promising [136]. With respect to somatostatin analog therapy there are a number of areas in which effective gene therapy may be used to potentiate the antineoplastic effects of these drugs. Perhaps the most obvious application of gene therapy to somatostatin analog treatment of neoplasia is the delivery of hSSTR-2 and hSSTR-5 genes together with the genes that encode their membrane proteins to cancers such as pancreatic, gastric and colorectal cancers that do not express these receptor subtypes. The somatostatin analogs currently available for clinical uses, octreotide, vapreotide and lanreotide, exert the majority of their antineo-

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plastic effects via hSSTR-2 and hSSTR-5 and it follows therefore that effective transfer of genes encoding for hSSTR-2 and hSSTR-5 as well as their membrane proteins to cancers which do not express these receptors subtypes may render them responsive to the direct antineoplastic effects of the current generation of somatostatin analogs. In some tumors such as breast cancer, hSSTRs are not uniformly distributed throughout the neoplastic tissue [100]. Using genetic transfer of genes encoding for hSSTR-2 and hSSTR-5 and their membrane proteins, it may be possible to increase the number of cells expressing hSSTRs, thereby enhancing the efficacy of somatostatin analog therapy. Tissue targeting is crucial to effective gene therapy and this problem has still to be overcome before such treatment can become part of routine clinical practice for common malignancies. The use of retroviral vectors which preferentially target cancer cells by their specific integration into proliferating cells may be one option. However, perhaps a more practical approach to ensure tumor-restricted expression of the transgenes is the use of tumor-specific promoters or high affinity monoclonal antibodies. Currently, there is an explosion of activity in researching effective, specific and less toxic delivery of genes to target tissue and it is not overoptimistic to speculate that in the not too distant future, genetic transfer of hSSTRs and their membrane proteins will potentiate the direct antineoplastic effects of somatostatin analogs in tumors which do not express hSSTR-2 or hSSTR-5. It is also not inconceivable that genetic transfer of hSSTRs to hormone-resistant tumor cells in tumors resulting from prolonged somatostatin analog administration may prevent or delay escape from the antineoplastic effects of these drugs. Somatostatin analog therapy of cancer may also be enhanced by genetic therapy of oncogenes and replacement of tumor suppres-

sor genes. For example, antisense inhibition of IGF-1 has been demonstrated to induce apoptosis in rat hepatocellular carcinoma cells [137]. A number of tumors express IGF1 receptors and suppression of IGF-1 levels by somatostatin analogs, as discussed previously, provides a rationale for the indirect antineoplastic effects of these drugs in a variety of human neoplasms. A combination of somatostatin analog therapy alone or combined with other hormonal treatments or chemotherapy on tumor cells transfected with antisense inhibitors of IGF-1 may well result in increased tumor responses. A high proportion of human cancers contain mutations of the p53 suppressor gene [138]. There is considerable evidence to suggest that p53-dependent apoptosis plays an important role in enhancing the therapeutic efficacy of chemotherapy and radiotherapy. Conversely, tumors that contain p53 mutations generally, but not always, are more resistant to chemotherapy and radiotherapy. Not surprisingly, therefore, there has been considerable interest in restoration or modulation of p53 function by gene therapy to increase apoptosis and enhance tumor sensitivity to chemotherapy and radiotherapy. Studies on human cancer cell lines and experimental animals suggest that restoration of p53 function using retroviral or adenoviral vectors inhibits cell proliferation in vitro, the growth of tumors in vivo and sensitizes tumor cells to chemotherapy [139–141]. Further, as long ago as 1996, Roth et al. [139] reported that retroviral wild-type p53 gene transfer in 9 patients with non-small-cell lung cancer, in whom conventional therapy had failed, resulted in increased apoptosis and tumor regression in 3 patients. These data suggest that gene replacement with p53 is a promising therapeutic approach to the management of malignancy. However, it should be pointed out that as yet, available gene vectors for p53 are not highly

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efficient but work is ongoing to increase p53 transduction efficiency. Furthermore, malfunctions of other components of the p53 pathway may be important in the development of malignancy. For example, overexpression of the mdm-2 oncogene (which encodes for a phosphoprotein which blocks the activity of p53) in human sarcomas may be responsible for the development towards malignancy although p53 per se is normal [142]. Since mdm-2 interacts with p53 via a small molecular interface to inhibit its function, it is possible that a small molecule could be designed to disrupt this interaction. Nevertheless, in spite of the complexity of p53 function in carcinogenesis, the observation that p53 can be restored by gene therapy in some tumors raises the possibility of combining such treatment with somatostatin analog administration. This suggestion is based on observations which suggest somatostatin analogs upregulate p53 function and hence apoptosis by activation of hSSTR-3 [143]. Possibly, therefore, the beneficial effects of genetic transfer of p53 to tumors that contain mutations of this suppressed gene may be enhanced by combination therapy with somatostatin analogs. Upregulation of p53 function by combination with somatostatin analogs may also increase the sensitivity of the tumors to chemotherapy and radiation therapy. Clearly, further studies are required to substantiate these hypotheses. The examples of a possibility of potentiating gene therapy by concomitant somatostatin analog administration discussed above and in the sections on Angiogenesis and Immunotherapy only represent a small number of the large number of possibilities for maximizing the therapeutic efficacy of these drugs by taking advantage of the impact that the ‘genetic revolution’ is likely to make on the management of neoplasia in the not too distant future.

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Summary and Conclusion

The role of somatostatin therapy in the management of acromegaly is well established. Similarly, somatostatin analog therapy of neuroendocrine tumors is accepted as a valuable treatment option for providing excellent palliation when all else fails, although there may be room for improvement. In contrast the therapeutic efficacy of somatostatin analog monotherapy in the management of nonendocrine solid tumors has proven to be largely very disappointing. Combination therapy of somatostatin analogs with cytotoxics or other hormonal treatments targeted somatostatin analog chemotherapy or radiotherapy in both advanced malignancy and in the adjuvant setting may prove to be very much more effective than somatostatin analog monotherapy. Carefully controlled clinical studies with objective outcome measures and HRQL assessments are required to evaluate combination therapies. Particular attention should be given to the possible adverse effects of somatostatin analog therapy on the immune response to neoplasia and consideration given to the possibility of concomitant immunostimulatory therapy. The question of whether or not intermittent somatostatin analog therapy is preferable to continuous treatment needs to be addressed formally. This is now possible with slow-release preparations of octreotide, vapreotide and lanreotide. Other possible novel therapeutic approaches such as combination treatment with antiangiogenic drugs require investigation. Of particular importance in the future is the need to exploit the major advances in gene therapy to optimize the full potential of somatostatin analogs in the management of neoplasia. Although somatostatin analogs have not turned out to be the ‘magic bullet’ for the management of cancer as many oncologists thought they would when octreotide was first intro-

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duced into clinical medicine all is not doom and gloom. Indeed, if we heed the lessons learned from previous experience with somatostatin analog therapy in the management of neoplasia and logically and formally explore possible combinational treatments to maximize the therapeutic potential of these drugs in cancer the rewards could be significant. To quote Winston Churchill at the end of the

North African Campaign in the Second World War: ‘This is not the end, nor is it the beginning of the end, it is only the end of the beginning’. He proved to be correct and this may very well turn out to be the case for the role of somatostatin analogs in the management of cancer.

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Author Index Vol. 47, Suppl. 2, 2001

Agostinelli, R. 127 Amoroso, D. 62 Baldelli, A.M. 127 Baxter, J.N. 162 Boccardo, F. 62 Bousquet, C. 30 Buscail, L. 30 Carney, D.N. 78 Cascinu, S. 127 Catalano, G. 127 Catalano, V. 127 Davies, N. 162 Dean, A. 54 Giordani, P. 127 Jenkins, S.A. 162

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Kouroumalis, E.A. 150 Kynaston, H.G. 162 Nott, D.M. 162 Öberg, K. 40 O’Byrne, K.J. 78 Pelosini, I. 1 Puente, E. 30 Rosenberg, L. 134 Scarpignato, C. 1 Schally, A.V. 78 Steward, W.P. 78 Susini, C. 30 Thomas, A. 78 Vainas, I.G. 109 Vaysse, N. 30

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Subject Index Vol. 47, Suppl. 2, 2001

Antiandrogen blockade, complete 109 Breast cancer 62 Cancer treatment 1 Chemotherapy 78, 127 Gastrointestinal cancers 127 [111In]pentetreotide 78 Hepatocellular carcinoma 150 Hormonal maneuvers, alternative 109 Lanreotide 1, 40 Liver tumors 150 Lung cancer 78 Neoplasms 162 Neuroendocrine tumors 40 Octastatin 40 Octreoscan 40 Octreotide 1, 40, 109, 127, 134, 150

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Opioids 54 Palliative care 54 Pancreatic cancer 134 Proliferation 30 Prostate cancer, hormonerefractory 109 RC-160 134 Receptor 78 – signaling 30 Review 162 Somatostatin 1, 54, 62, 78, 134 – analogs 62, 134, 162 – receptors 30, 134, 150 – – scintigraphy 1 – receptor-targeted radiotherapy 1 Therapy 162 Vapreotide 1