Alkylating agent rechallenge in metastatic pancreatic neuroendocrine tumors

in Endocrine-Related Cancer
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  • 1 Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital, Clichy, France
  • 2 Université de Paris, Centre de Recherche sur l’Inflammation, INSERM, Paris, France
  • 3 Department of Gastro-enterology and oncology, Hospices Civils de Lyon, Edouard Herriot University Hospital, Lyon, France
  • 4 Department of Hepato-Gastroenterology and Digestive Oncology, Robert Debré University Hospital, Reims, France
  • 5 Department of Gastroenterology, Cochin University Hospital, Paris, France
  • 6 Department of Pathology, ENETS Centre of Excellence, Bichat/Beaujon University Hospital, Paris/Clichy, France

Correspondence should be addressed to L de Mestier: louis.demestier@aphp.fr
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A rechallenge is common after the initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with a lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET, and to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause of > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (cohort A). The primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (cohort B). We found that Cohort A included 62 patients (median Ki67 8%), for whom ALK1 followed by a pause achieved an objective response rate of 55% and a PFS1 of 23.7 months (95% IC, 19.8–27.6). ALK2 achieved no objective response and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1–11.3). At multivariable analysis, a hormonal syndrome (P = 0.032) and a pause longer than 12 months (P = 0.041) were associated with a longer PFS2. In cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18–105) before ALK to 100 (IQR 56–180) after ALK (P = 0.003). We conclude that after the initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain the low efficacy of ALK rechallenge.

 

Society for Endocrinology

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