Is it time to widen the use of somatostatin analogs in neuroendocrine tumors?

Neuroendocrine tumors are considered rare, although their incidence and prevalence have significantly increased over the last two decades. 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). 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. 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. 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. 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. In this issue of Journal of Clinical Oncology, Rinke et al 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-naive 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%. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 28 OCTOBER 1 2009