Originally published as JCO Early Release 10.1200/JCO.2009.23.6711 on August 24 2009

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Is It Time to Widen the Use of Somatostatin Analogs in Neuroendocrine Tumors?

Department of Endocrine Oncology, University Hospital, Uppsala, Sweden

Neuroendocrine tumors are considered rare, although their incidence and prevalence have significantly increased over the last two decades.¹ They are heterogeneous tumors in terms of clinical and biologic features, and they originate from neuroendocrine cells in the thymus, lung, pancreas, and GI tract. They may be associated with specific symptoms because of hormone hypersecretion, which differentiates "functioning" from "nonfunctioning"; in the latter, symptoms are related to mass effect from tumor growth only. Most neuroendocrine tumors (> 80%) express a high density of somatostatin receptors. To date, five subtypes of somatostatin receptors have been identified (SSTR1-5).² Each receptor subtype activates multiple intracellular transduction pathways, and the antisecretory effects of somatostatin on various hormones involve particularly SSTR2 and SSTR5. Native somatostatin 14, which was isolated by Brazeau and Guillemin in 1973 from sheep hypothalamic tissue, binds to all five somatostatin receptors with almost equal potencies. Because of its short half-life (< 2 minutes), native somatostatin has not been useful in clinical practice. In 1980, Bauer et al at Sandoz synthesized an analog with the name octreotide, constituting an octapeptide with three unnatural amino acids, whereby the compound became resistant to metabolic degradation and presented a half-life of 3 to 4 hours in circulation. This peptide binds with high affinity to SSTR2 and SSTR5 and is therefore effective in inhibiting the secretion of peptides and amines from neuroendocrine cells. Other octapeptides with similar affinity to SSTR2 and SSTR5 were developed later, such as lanreotide and vapreotide. Both octreotide and lanreotide have long-acting formulations that can be given once per month. These two analogs have been the gold standard in the treatment of acromegaly and different functioning neuroendocrine tumors. Octreotide has been registered worldwide for functioning neuroendocrine tumors such as carcinoid tumors with the carcinoid syndrome, endocrine pancreatic tumors with glucagonoma, or Verner-Morrison syndrome.³

Possible antitumor effects of somatostatin analogs have always been in question, but octreotide has not been registered in any country as an antitumor agent. However, in some countries, octreotide can be used at the doctor's discretion in nonfunctioning tumors, and various studies have indicated a low but significant antitumor effect.⁴ No randomized trials have been published to date. The antitumor effects of somatostatin can be divided into direct and indirect effects. Direct effects are mediated through binding directly to receptors on the tumor cells whereas indirect effects are via inhibition of growth factors, stimulation of the immune system, or inhibition of angiogenesis.⁵

Octreotide has been available in clinical practice for more than two decades and has been the most effective drug to inhibit clinical symptoms related to hypersecretion of amines and peptides in neuroendocrine tumors. Diarrhea and flushing can be controlled in 40% to 50% of patients with the carcinoid syndrome. Other patients benefiting from treatment with octreotide include those with functional neuroendocrine tumors of the pancreas, such as glucagonomas, VIPomas (VIP, vasoactive intestinal polypeptide) and, to a lesser extent, gastrinomas and metastatic insulinomas. Other clinical syndromes for which octreotide may provide benefit include ectopic adrenocorticotropic hormone (ACTH) secretion with Cushing's syndrome, ectopic gonadotropin-releasing hormone receptor (GHRH) secretion, and oncogenic osteomalacia and hypercalcemia caused by secretion of ectopic parathyroid hormone–related peptide. Octreotide therapy results in remission or stabilization of tumor markers, such as serotonin and chromogranin A, in approximately 60% to 70% of patients.

A more controversial area has been the treatment of nonfunctioning neuroendocrine tumors with somatostatin analogs. Nonrandomized studies have so far given disappointing results with regard to significant tumor regression according to criteria from WHO or RECIST (Response Evaluation Criteria in Solid Tumors). Tumor shrinkage is demonstrated in less than 5% of patients. However, stabilization of tumor growth after computed tomography–documented progression before somatostatin analog treatment occurs in up to 50% of patients with neuroendocrine tumors.⁴

In this issue of Journal of Clinical Oncology, Rinke et al⁶ have reported on the double-blind PROMID study (Placebo-Controlled Prospective Randomized Study on the Antiproliferative Efficacy of Octreotide LAR in Patients with Metastatic Neuroendocrine Midgut Tumors). Treatment-naïve patients were randomly assigned to either placebo or octreotide LAR 30 mg intramuscularly every month until tumor progression. The primary efficacy end point of the study was time to progression, and secondary end points were survival time and tumor response. The study was conducted at 18 German academic centers and was planned for enrollment of 162 patients. However, enrollment stopped after 85 patients (43 patients received octreotide and 42 patients received placebo) at the time of planned interim analysis. Inclusion criteria were locally inoperable metastatic neuroendocrine tumors with well-differentiated tumor histology, low Ki-67 index (< 2%), and a Karnofsky performance status of more than 60%. The median time to tumor progression in the octreotide LAR group was 15.6 months versus 5.9 months in the placebo group (hazard ratio [HR], 0.34; 95% CI, 0.20 to 0.59; P = .000072) after 6 months of treatment. Stable disease was observed in 66.7% of the patients in the octreotide LAR group and in 37.2% of the patients in the placebo group. Functionally active and inactive tumors responded similarly. The most favorable effect was observed in patients with low hepatic tumor load (< 10%) and resected primary tumors (median, 27.1 months v 7.2 months; P < .0001). The study was not designed to demonstrate superior survival since patients progressing in the placebo group received treatment with octreotide LAR. The authors concluded that octreotide LAR significantly lengthens median time to tumor progression compared with placebo in patients with functionally active and inactive metastatic neuroendocrine tumors of the midgut.

To the best of my knowledge, PROMID is the first randomized prospective trial demonstrating a possible antitumor effect for octreotide LAR compared with a placebo in patients with well-differentiated neuroendocrine tumors of midgut origin, limited tumor mass, and resected primary tumor. The long accrual time (8 years) indicates the problems involved in conducting a placebo-controlled study of neuroendocrine tumors. Over the years, it has been debated whether octreotide LAR has any significant antiproliferative effect. This study supports an antiproliferative effect in well-differentiated midgut carcinoid tumors, with stabilization being the most frequent tumor response. However, only a limited group of patients—those with less than 10% tumor mass in the liver along with resected primary tumors—responded to treatment. There was no significant difference in time to tumor progression between octreotide LAR and placebo in patients with larger tumor burden. Patients could be included in the placebo-controlled study because of limited clinical symptomatology (flushing or diarrhea). The authors concluded that newly diagnosed patients with a low hepatic tumor burden and resected primary tumor were candidates for treatment with octreotide LAR. New studies are needed to determine whether patients with a higher hepatic tumor load might be candidates for this treatment. Survival data are not available in the study and therefore it is not possible to tell whether this initial increased time to tumor progression translates into a survival benefit in the long run. It has also been suggested that this study might support the use of octreotide LAR in an adjuvant setting after surgery with a curative intent in patients with well-differentiated, low-proliferating neuroendocrine tumors. However, PROMID was not designed to answer this question. A randomized study is needed that compares no treatment with treatment using octreotide LAR to be able to show significance in an adjuvant setting.

This randomized, placebo-controlled study shows that 30 mg octreotide LAR in low-volume, well-differentiated neuroendocrine tumors of the midgut has an antiproliferative effect in patients with both functioning and nonfunctioning tumors. That will of course widen the indication for the use of octreotide in both functioning and nonfunctioning small intestinal neuroendocrine tumors of well-differentiated origin. The role of somatostatin analogs in high-proliferating tumors needs to be defined in forthcoming studies. During the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 3, 2009, the National Comprehensive Cancer Network (NCCN) presented an updated version of their guidelines for treatment of carcinoids; octreotide was included for treatment of asymptomatic unresectable carcinoids as well as for symptomatic tumors with significant tumor burden or significant progression. The cost for treatment of carcinoid tumors will increase, particularly since the current cost for treatment with octreotide LAR in the United States is significantly higher than in Sweden. The cost for the drug is not significantly different, averaging US$3,218 for 30 mg octreotide LAR in the United States versus US$2,000 in Sweden. The real difference is what the patients will be charged for the administration of the drug, which might reach US$7,000-9,000/mo in the United States compared to US$35/mo in Sweden. The European Neuroendocrine Tumor Society has not yet upgraded their guidelines, but I assume that octreotide will be suggested as a therapeutic option for nonfunctioning carcinoid tumors. There is another placebo-controlled, randomized trial ongoing with lanreotide (Somatuline Autogel, lpsen Pharma Biotech, Signes, France) in nonfunctioning neuroendocrine tumors of different types, and we are awaiting the results from this study. If this study confirms the PROMID data, it will further strengthen the role of somatostatin analogs as antitumor agents in nonfunctioning neuroendocrine tumors. The answer to the question in the title of this editorial will be "yes" for well-differentiated, low-proliferating small intestinal neuroendocrine tumors, but "maybe" for other subtypes of neuroendocrine tumors.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a"U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Kjell E. Öberg, Novartis, Ipsen Research Funding: None Expert Testimony: None Other Remuneration: None

REFERENCES

1. Yao JC, Hassan M, Phan A, et al: One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063–3072, 2008.[Abstract/Free Full Text]

2. Reubi JC, Waser B, Schaer JC, et al: Somatostatin receptor SST1-SST5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med 28:836–846, 2001.[CrossRef][Medline]

3. Eriksson B, Oberg K: Summing up 15 years of somatostatin analog therapy in neuroendocrine tumors: Future outlook. Ann Oncol 10:S31–S38, 1999.[Abstract/Free Full Text]

4. Plöckinger U, Wiedenmann B: Neuroendocrine tumors. Biotherapy. Best Pract Res Clin Endocrinol Metab 21:145–162, 2007.[CrossRef][Medline]

5. Susini C, Buscail L: Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol 17:1733–1742, 2006.[Abstract/Free Full Text]

6. Rinke A, Müller H-H, Schade-Brittinger C, et al: Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID Study Group. J Clin Oncol 27:4656–4663, 2009.[Abstract/Free Full Text]

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