Eric P. Krenning

BACKGROUND: Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. METHODS: Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. RESULTS: Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. CONCLUSIONS: Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

PURPOSE: Despite the fact that most gastroenteropancreatic neuroendocrine tumors (GEPNETs) are slow-growing, median overall survival (OS) in patients with liver metastases is 2 to 4 years. In metastatic disease, cytoreductive therapeutic options are limited. A relatively new therapy is peptide receptor radionuclide therapy with the radiolabeled somatostatin analog [(177)Lu-DOTA(0),Tyr(3)]octreotate. Here we report on the toxicity and efficacy of this treatment, performed in over 500 patients. PATIENTS AND METHODS: Patients were treated up to a cumulative dose of 750 to 800 mCi (27.8-29.6 GBq), usually in four treatment cycles, with treatment intervals of 6 to 10 weeks. Toxicity analysis was done in 504 patients, and efficacy analysis in 310 patients. RESULTS: Any hematologic toxicity grade 3 or 4 occurred after 3.6% of administrations. Serious adverse events that were likely attributable to the treatment were myelodysplastic syndrome in three patients, and temporary, nonfatal, liver toxicity in two patients. Complete and partial tumor remissions occurred in 2% and 28% of 310 GEPNET patients, respectively. Minor tumor response (decrease in size > 25% and < 50%) occurred in 16%. Median time to progression was 40 months. Median OS from start of treatment was 46 months, median OS from diagnosis was 128 months. Compared with historical controls, there was a survival benefit of 40 to 72 months from diagnosis. CONCLUSION: Treatment with [(177)Lu-DOTA(0),Tyr(3)]octreotate has few adverse effects. Tumor response rates and progression-free survival compare favorably to the limited number of alternative treatment modalities. Compared with historical controls, there is a benefit in OS from time of diagnosis of several years.

ENETS Consensus Guidelines for the Management of Patients with Liver and Other Distant Metastases from Neuroendocrine Neoplasms of Foregut, Midgut, Hindgut, and Unknown Primary

LONG-term therapy with somatostatin analogs has been reported to result in the control of hormonal hypersecretion, in improvement of symptomatology, and in tumor shrinkage in patients with acromegaly, endocrine pancreatic tumors, and metastatic carcinoids. One of these somatostatin analogs, octreotide, has been approved for clinical use in most countries, including the United States. It is a well-tolerated, but expensive drug. Experimental studies show that chronic administration of somatostatin analogs causes growth inhibition of a number of (transplantable) tumors in animals, including chondrosarcomas, pancreatic, prostatic, breast, and pituitary cancers. Somatostatin receptors have been demonstrated on a variety of human tumors by classical biochemical binding techniques, as well as by in vitro autoradiography. These tumors include those with amine precursor uptake and decarboxylation (APUD) characteristics (pituitary tumors, endocrine pancreatic tumors, carcinoids, paragangliomas, small cell lung cancers, medullary thyroid carcinomas, pheochromocytomas), as well as meningiomas, well-differentiated brain tumors (astrocytomas), neuroblastomas, and some human breast cancers. Recently we developed a technique that allows the in vivo visualization in man of the somatostatin receptorpositive tumors mentioned above after the iv administration of the 123I-coupled somatostatin analog Tyr3-octreotide. We have simplified, as well as improved, this technique, which should be available for general use in 1992.