The new concept of therapeutic strategy for neuroendocrine tumors: important information from a case report of gastrinoma.

Neuroendocrine tumors (NETs) have been regarded as rare diseases; however the US Surveillance, Epidemiology, and End Results (SEER) Program recently suggested that the incidence and prevalence of NETs has increased substantially over the past three decades (1). Gastrinoma is characterized by the secretion of gastrin, which causes hyperchlorhydria, thereby producing the Zollinger-Ellison syndrome (2). The presence of liver metastases decreases life expectancy in gastrinoma. The 5-year survival rate of patients with metastatic gastrinoma is reported to be only 2040% and effective management remains to be established (2). At diagnosis, 5-10% of duodenal gastrinoma and 20-25% of pancreatic gastrinoma are associated with liver metastases, which are the most important prognostic factor. The recent epidemiological study of NETs in Japan showed that the distribution of gastrinoma was 7.9% of pancreatic NETs and distant metastasis was observed in 25% of patients (3). Jensen et al reported that 40% of patients with liver metastases have an aggressive clinical course (2). Poor prognostic factors in addition to liver metastases include: inadequate control gastric acid hypersecretion; presence of lymph node metastases; female gender; absence of MEN1; markedly increased fasting gastrin levels; presence of a large primary tumor (>3 cm); a pancreatic primary gastrinoma; histological features including Ki-67 index >2 (2). To date no therapeutic strategy with consensus for unresectable or metastatic gastrinoma has been presented. For some patients with advanced disease, cytoreductive surgery, radiofrequency ablation, hepatic artery embolization, or chemoembolization has been performed to manage the liver metastases. While for others, systemic chemotherapy including streptozotocin/doxorubicin or dacarbazine has been selected (2). Octreotide is an analog of the cyclic polypeptide somatostatin, which has a strong affinity for one of the five subtypes of somatostatin receptors, SSTR2. The antisecretory effects of somatostatin on various hormones seem to be mainly regulated by SSTR2 and SSTR5, while antitumor effects of somatostatin analogs are mainly mediated by SSTR1, SSTR2, SSTR3 and SSTR5 (4). Octreotide has been available in clinical practice for more than 20 years and is the gold standard for inhibition of clinical symptoms related to hypersecretion of amines and peptides from NETs. Furthermore, previous studies have showed that somatostatin analogs inhibit cell proliferation, and reduce growth factor receptor expression and angiogenesis in NETs (4, 5). Recently, Yamaguchi et al reported the case of a young woman with pancreatic and duodenal gastrinoma and liver metastases (5). This patient had MEN-type 1 and the biopsy samples of the duodenal tumor revealed the welldifferentiated neuroendocrine carcinoma and the Ki-67 proliferation index of the tumor was 0.5%. The octreotide therapy was started and surprisingly, her good response to octreotide has been maintained for more than seven years. The tumors have grown very slowly and after seven years of treatment the tumor tissue samples showed the strong expression of SSTR2 and the Ki-67 proliferation index of the tumor was still 0.5%. Initially the serum gastrin level increased to more than 20,000 pg/mL, however her gastrin level has been suppressed at around 650 pg/mL for seven years resulting in no clinical symptoms. Recently, Rinke et al reported the antitumor effects of the somatostatin analog octreotide LAR (long-acting release) in the PROMID (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) study (6). The 85 patients with well-differentiated neuroendocrine tumors of the small intestine were randomized to receive either placebo or 30 mg oc-