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.

中文翻译：

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转移性胰腺神经内分泌肿瘤中的烷基化剂再挑战。

在基于烷基化的化学疗法 (ALK) 对胰腺神经内分泌肿瘤 (PanNET) 的初步疗效后，再次挑战是常见的。高 MGMT 表达似乎与对 ALK 的较低反应有关。我们旨在评估 ALK 再激发在 PanNET 中的功效和毒性，并评估 ALK 下 MGMT 表达的演变。回顾性研究了所有连续接受初始 ALK（实现肿瘤控制）的晚期 PanNET 患者，随后暂停 > 3 个月，然后在进展时再次接受 ALK 攻击（ALK2）（队列 A）。主要终点是 ALK2 (PFS2) 下的无进展生存期。在 ALK 后手术切除的连续 PanNET（队列 B）中，通过免疫组织化学（H 评分）回顾性评估 MGMT 表达。我们发现队列 A 包括 62 名患者（中位数 Ki67 8%），ALK1 停顿后的客观缓解率为 55%，PFS1 为 23.7 个月（95% IC，19.8-27.6）。ALK2 在 62% 的患者中没有达到客观反应和稳定性。中位 PFS2 为 9.2 个月（IC 95% 7.1-11.3）。在多变量分析中，激素综合征 (P = 0.032) 和超过 12 个月的停顿 (P = 0.041) 与较长的 PFS2 相关。在队列 B（17 名患者）中，中位 MGMT H 评分从 ALK 前的 45（IQR 18-105）增加到 ALK 后的 100（IQR 56-180）（P = 0.003）。我们得出的结论是，在 ALK 治疗取得初步疗效后，暂停再使用 ALK 可能适合延长肿瘤控制、改善生活质量和限制长期不良事件。ALK 下 MGMT 表达增加可能解释了 ALK 再攻击的低功效。