Temozolomide in grade III gastroenteropancreatic neuroendocrine neoplasms (G3 GEPNENs): A multicentre retrospective review.

Abstract

BACKGROUND\nG3 GEPNENs are often aggressive, and the optimal treatment is unclear for this subgroup of NENs. Temozolomide (TEM)-based regimens have been increasingly used to treat grade 1-2 NENs, but their efficacy in G3 NENs remains undetermined. We aimed to assess the clinical efficacy of TEM-containing regimens in advanced grade 3 GEPNENs.\n\n\nMETHODS\nA multicentre retrospective review (2008-2018) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen was undertaken within a North American partnership to pool data. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports.\n\n\nRESULTS\nOne hundred and thirty patients in six high volume NEN centers were included (median age 55, 64% male, 18% functional, 67% pancreatic NEN). 49% were well-differentiated, 35% poorly-differentiated, and 15% unknown based on local pathology reports. The regimen used was capecitabine and temozolomide (CAP/TEM) in 92% and TEM alone in 8%. Radiological response by local assessment was seen in 36% of patients. Median TTF was 3.6 months and median overall survival (OS) 19.2 months. Six percent of patients required discontinuation of therapy due to adverse events. TTF was longer in first-line treatment (7.8mo vs 2.9mo, HR 1.62, 95% CI 1.11-2.36, p=0.015) and in patients with panNEN compared to GI NEN (5.8 months vs 1.8 months, p=0.04). The overall response rate was higher in the first-line setting (51% vs 29%, p=0.02) and in panNEN (41% vs 23%, p=0.04).\n\n\nCONCLUSION\nThis is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NEN centers as a partnership. Thirty-six percent of patients showed some degree of radiographic response, and treatment was generally well-tolerated, although the median duration of response was short. Response rates and time to treatment failure were superior in the first-line setting. CAPTEM should be considered a viable treatment option in this setting. Further randomized trials are warranted.\n\n\nIMPLICATIONS FOR PRACTICE\nNeuroendocrine neoplasms (NENs) are heterogeneous and optimal treatment for aggressive Grade 3 (G3) NENs remains undetermined. The CAPTEM regimen (capecitabine and temozolomide) has been used in low-grade pancreas NENs but there are few data for its safety and efficacy in the G3 setting. This manuscript reports on the efficacy of temozolomide-containing regimens, particularly CAPTEM, in management of G3 NENs. The good tolerance and response rate show that CAPTEM should be considered a viable regimen in treatment of G3 NENs pending confirmatory prospective studies.