Department of Medical Oncology, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Gastroenterology and Technologies for Health, Research Unit INSERM UMR 1052 CNRS UMR 5286, Cancer Research Center of Lyon, Lyon, France.
Digestive Unit, Hôpital Universitaire de Pontchaillou, Rennes, France.
Lancet Oncol. 2023 Mar;24(3):297-306. doi: 10.1016/S1470-2045(23)00001-3. Epub 2023 Feb 2.
There is no standard second-line treatment after platinum-etoposide chemotherapy for gastroenteropancreatic neuroendocrine carcinoma. We aimed to evaluate the efficacy of FOLFIRI plus bevacizumab, and FOLFIRI alone, in this setting.
We did a randomised, non-comparative, open-label, phase 2 trial (PRODIGE 41-BEVANEC) at 26 hospitals in France. We included patients aged 18 years or older with locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinoma or neuroendocrine carcinoma of unknown primary origin, documented progressive disease during or after first-line platinum-etoposide chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1; block size of three), without stratification, to receive FOLFIRI (irinotecan 180 mg/m, calcium folinate 400 mg/m or levofolinate 200 mg/m, and fluorouracil 400 mg/m bolus then 2400 mg/m over 46 h) plus bevacizumab 5 mg/kg or FOLFIRI alone, intravenously, every 2 weeks until disease progression or unacceptable toxicity. Neither patients nor investigators were masked to group assignment. The primary outcome was overall survival at 6 months after randomisation, evaluated in the modified intention-to-treat population (all enrolled and randomly assigned patients who received at least one cycle of FOLFIRI). This study is now complete and is registered with ClinicalTrials.gov, NCT02820857.
Between Sept 5, 2017, and Feb 8, 2022, 150 patients were assessed for eligibility and 133 were enrolled and randomly assigned: 65 to the FOLFIRI plus bevacizumab group and 68 to the FOLFIRI group. 126 patients (59 in the FOLFIRI plus bevacizumab group and 67 in the FOLFIRI group) received at least one cycle of FOLFIRI and were included in the modified intention-to-treat population, 83 (66%) of whom were male and 43 (34%) were female, and the median age of the patients was 67 years (IQR 58-73). The primary tumour location was colorectal in 38 (30%) of 126 patients, pancreatic in 34 (27%), gastro-oesophageal in 22 (17%), and unknown in 23 (18%). After a median follow-up of 25·7 months (95% CI 22·0-38·2), 6-month overall survival was 53% (80% CI 43-61) in the FOLFIRI plus bevacizumab group and 60% (51-68) in the FOLFIRI group. Grade 3-4 adverse events that occurred in at least 5% of patients were neutropenia (eight [14%] patients), diarrhoea (six [10%]), and asthenia (five [8%]) in the FOLFIRI plus bevacizumab group, and neutropenia (seven [10%]) in the FOLFIRI group. One treatment-related death (ischaemic stroke) occurred in the FOLFIRI plus bevacizumab group.
The addition of bevacizumab did not seem to increase the benefit of FOLFIRI with regard to overall survival. FOLFIRI could be considered as a standard second-line treatment in patients with gastroenteropancreatic neuroendocrine carcinoma.
French Ministry of Health and Roche SAS.
在胃肠胰神经内分泌癌患者接受顺铂-依托泊苷化疗后，尚无标准的二线治疗方案。我们旨在评估 FOLFIRI 联合贝伐珠单抗与单纯 FOLFIRI 在此治疗环境下的疗效。
我们在法国 26 家医院进行了一项随机、非对照、开放标签、二期试验（PRODIGE 41-BEVANEC）。我们纳入了年龄在 18 岁及以上的局部晚期或转移性胃肠胰神经内分泌癌或不明原发灶的神经内分泌癌患者，这些患者在一线顺铂-依托泊苷化疗期间或之后疾病进展，以及东部肿瘤协作组体能状态为 0-2 分。患者被随机分配（1:1；分组大小为 3），不进行分层，接受 FOLFIRI（伊立替康 180 mg/m2、亚叶酸钙 400 mg/m2 或左亚叶酸钙 200 mg/m2，氟尿嘧啶 400 mg/m2 推注，然后 2400 mg/m2 持续 46 h）联合贝伐珠单抗 5 mg/kg 或单纯 FOLFIRI 静脉输注，每 2 周一次，直至疾病进展或出现不可接受的毒性。患者和研究者均未对分组情况进行设盲。主要终点为随机分组后 6 个月的总生存期，在改良意向治疗人群中进行评估（所有入组并随机分组的患者至少接受了一个周期的 FOLFIRI 治疗）。本研究现已完成，并在 ClinicalTrials.gov 注册，NCT02820857。
在 2017 年 9 月 5 日至 2022 年 2 月 8 日期间，对 150 名患者进行了入组评估，133 名患者入组并随机分组：65 名患者接受 FOLFIRI 联合贝伐珠单抗治疗，68 名患者接受 FOLFIRI 治疗。126 名患者（FOLFIRI 联合贝伐珠单抗组 69 名，FOLFIRI 组 57 名）至少接受了一个周期的 FOLFIRI 治疗，并纳入改良意向治疗人群，其中 83 名（FOLFIRI 联合贝伐珠单抗组 66%，FOLFIRI 组 67%）为男性，43 名（FOLFIRI 联合贝伐珠单抗组 34%，FOLFIRI 组 34%）为女性，患者的中位年龄为 67 岁（IQR 58-73）。126 名患者的原发肿瘤部位为结直肠 38 例（30%），胰腺 34 例（27%），胃食管 22 例（17%），未知部位 23 例（18%）。在中位随访 25.7 个月（95%CI 22.0-38.2）后，FOLFIRI 联合贝伐珠单抗组和 FOLFIRI 组的 6 个月总生存率分别为 53%（95%CI 43-61）和 60%（95%CI 51-68）。至少 5%的患者发生的 3-4 级不良事件为中性粒细胞减少症（FOLFIRI 联合贝伐珠单抗组 8 例[14%]，FOLFIRI 组 6 例[10%]）、腹泻（FOLFIRI 联合贝伐珠单抗组 6 例[10%]）和乏力（FOLFIRI 联合贝伐珠单抗组 5 例[8%]），FOLFIRI 组为中性粒细胞减少症（FOLFIRI 组 7 例[10%]）。FOLFIRI 联合贝伐珠单抗组发生 1 例与治疗相关的死亡（缺血性卒中）。
贝伐珠单抗的加入似乎并未增加 FOLFIRI 治疗在总生存率方面的获益。FOLFIRI 可被视为胃肠胰神经内分泌癌患者的标准二线治疗方案。
法国卫生部和罗氏公司。
