De Rycke Ophélie, Walter Thomas, Perrier Marine, Hentic Olivia, Lombard-Bohas Catherine, Coriat Romain, Cadiot Guillaume, Couvelard Anne, Ruszniewski Philippe, Cros Jérôme, de Mestier Louis
Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital, Clichy, France.
Université de Paris, Centre de Recherche sur l'Inflammation, INSERM, Paris, France.
Endocr Relat Cancer. 2021 Jun 11;28(7):457-466. doi: 10.1530/ERC-21-0034.
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.
在基于烷化剂的化疗（ALK）对胰腺神经内分泌肿瘤（PanNET）产生初始疗效后，再次挑战治疗很常见。MGMT高表达似乎与对ALK的反应较低有关。我们旨在评估ALK再次挑战治疗在PanNET中的疗效和毒性，并评估MGMT表达在ALK治疗下的变化情况。对所有连续的晚期PanNET患者进行回顾性研究，这些患者接受了初始ALK治疗（实现肿瘤控制），随后暂停治疗>3个月，然后在疾病进展时进行ALK再次挑战治疗（ALK2）（队列A）。主要终点是ALK2治疗下的无进展生存期（PFS2）。通过免疫组织化学（H评分）对ALK治疗后连续接受手术切除的PanNET患者的MGMT表达进行回顾性评估（队列B）。我们发现队列A包括62例患者（中位Ki67为8%），其中ALK1治疗后暂停治疗的客观缓解率为55%，PFS1为23.7个月（95%置信区间，19.8 - 27.6）。ALK2治疗在62%的患者中未获得客观缓解且病情稳定。中位PFS2为9.2个月（95%置信区间7.1 - 11.3）。在多变量分析中，激素综合征（P = 0.032）和暂停治疗超过12个月（P = 0.041）与更长的PFS2相关。在队列B（17例患者）中，MGMT中位H评分从ALK治疗前的45（四分位间距18 - 105）增加到ALK治疗后的100（四分位间距56 - 180）（P = 0.003）。我们得出结论，在ALK治疗产生初始疗效后，暂停治疗后进行ALK再次挑战治疗可能适合延长肿瘤控制时间、改善生活质量并限制长期不良事件。ALK治疗下MGMT表达增加可能解释了ALK再次挑战治疗疗效低的原因。
