Division of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, ON, Canada; Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada; Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
Lancet Gastroenterol Hepatol. 2024 Aug;9(8):734-744. doi: 10.1016/S2468-1253(24)00119-5. Epub 2024 Jun 10.
There is an unmet need for effective therapies in pretreated advanced biliary tract cancer. We aimed to evaluate the efficacy of nanoliposomal irinotecan and fluorouracil plus leucovorin compared with fluorouracil plus leucovorin as second-line treatment for biliary tract cancer.
NALIRICC was a multicentre, open-label, randomised, phase 2 trial done in 17 German centres for patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-1, metastatic biliary tract cancer, and progression on gemcitabine-based therapy. Patients were randomly assigned (1:1) to receive intravenous infusions of nanoliposomal irinotecan (70 mg/m), fluorouracil (2400 mg/m), and leucovorin (400 mg/m) every 2 weeks (nanoliposomal irinotecan group) or fluorouracil (2400 mg/m) plus leucovorin (400 mg/m) every 2 weeks (control group). Randomisation was by permutated block randomisation in block sizes of four, stratified by primary tumour site. Investigator-assessed progression-free survival was the primary endpoint, which was evaluated in all randomly assigned patients. Secondary efficacy outcomes were overall survival, objective response rate, and quality of life. Safety was assessed in all randomly assigned patients who received at least one dose of the study treatment. Enrolment for this trial has been completed, and it is registered with ClinicalTrials.gov, NCT03043547.
Between Dec 4, 2017, and Aug 2, 2021, 49 patients were randomly assigned to the nanoliposomal irinotecan group and 51 patients to the control group. Median age was 65 years (IQR 59-71); 45 (45%) of 100 patients were female. Median progression-free survival was 2·6 months (95% CI 1·7-3·6) in the nanoliposomal irinotecan group and 2·3 months (1·6-3·4) in the control group (hazard ratio [HR] 0·87 [0·56-1·35]). Median overall survival was 6·9 months (95% CI 5·3-10·6) in the nanoliposomal irinotecan group and 8·2 months (5·4-11·9) in the control group (HR 1·08 [0·68-1·72]). The objective response rate was 14% (95% CI 6-27; seven patients) in the nanoliposomal irinotecan group and 4% (1-14; two patients) in the control group. The most common grade 3 or worse adverse events in the nanoliposomal irinotecan group were neutropenia (eight [17%] of 48 vs none in the control group), diarrhoea (seven [15%] vs one [2%]), and nausea (four [8%] vs none). In the control group, the most common grade 3 or worse adverse events were cholangitis (four [8%] patients vs none in the nanoliposomal irinotecan group) and bile duct stenosis (four [8%] vs three [6%]). Treatment-related serious adverse events occurred in 16 (33%) patients in the nanoliposomal irinotecan group (grade 2-3 diarrhoea in five patients; one case each of abdominal infection, acute kidney injury, pancytopenia, increased blood bilirubin, colitis, dehydration, dyspnoea, infectious enterocolitis, ileus, oral mucositis, and nausea). One (2%) treatment-related serious adverse event occurred in the control group (worsening of general condition). Median duration until deterioration of global health status, characterised by the time from randomisation to the initial observation of a score decline exceeding 10 points, was 4·0 months (95% CI 2·2-not reached) in the nanoliposomal irinotecan group and 3·7 months (2·7-not reached) in the control group.
The addition of nanoliposomal irinotecan to fluorouracil plus leucovorin did not improve progression-free survival or overall survival and was associated with higher toxicity compared with fluorouracil plus leucovorin. Further research is necessary to define the role of irinotecan-based combinations in second-line treatment of biliary tract cancer.
Servier and AIO-Studien.
在经治的晚期胆道癌中，需要有效的治疗方法。我们旨在评估与氟尿嘧啶加亚叶酸钙相比，奈拉滨脂质体伊立替康和氟尿嘧啶加亚叶酸钙作为胆道癌二线治疗的疗效。
NALIRICC 是一项多中心、开放标签、随机、2 期临床试验，在德国 17 个中心进行，纳入年龄为 18 岁或以上、东部合作肿瘤学组体能状态为 0-1、转移性胆道癌和基于吉西他滨治疗进展的患者。患者以 1:1 的比例随机分配（1:1）接受静脉滴注奈拉滨脂质体伊立替康（70mg/m2）、氟尿嘧啶（2400mg/m2）和亚叶酸钙（400mg/m2），每 2 周一次（奈拉滨脂质体伊立替康组）或氟尿嘧啶（2400mg/m2）加亚叶酸钙（400mg/m2），每 2 周一次（对照组）。随机分组采用大小为 4 的置换块随机化，按主要肿瘤部位分层。研究者评估的无进展生存期是主要终点，在所有随机分配的患者中进行评估。次要疗效终点为总生存期、客观缓解率和生活质量。对至少接受一剂研究治疗的所有随机分配的患者进行安全性评估。这项试验的入组已经完成，并在 ClinicalTrials.gov 上注册，编号为 NCT03043547。
2017 年 12 月 4 日至 2021 年 8 月 2 日，49 例患者被随机分配到奈拉滨脂质体伊立替康组，51 例患者被分配到对照组。中位年龄为 65 岁（IQR 59-71）；100 例患者中 45 例（45%）为女性。奈拉滨脂质体伊立替康组的中位无进展生存期为 2.6 个月（95%CI 1.7-3.6），对照组为 2.3 个月（1.6-3.4）（风险比[HR]0.87[0.56-1.35]）。奈拉滨脂质体伊立替康组的中位总生存期为 6.9 个月（95%CI 5.3-10.6），对照组为 8.2 个月（5.4-11.9）（HR 1.08[0.68-1.72]）。奈拉滨脂质体伊立替康组的客观缓解率为 14%（95%CI 6-27；7 例），对照组为 4%（1-14；2 例）。奈拉滨脂质体伊立替康组最常见的 3 级或更高级别的不良事件为中性粒细胞减少症（48 例中有 8 例[17%]，对照组中无）、腹泻（7 例[15%]vs 对照组中 1 例[2%]）和恶心（4 例[8%]vs 对照组中无）。对照组中最常见的 3 级或更高级别的不良事件为胆管炎（4 例[8%]vs 奈拉滨脂质体伊立替康组无）和胆管狭窄（4 例[8%]vs 对照组 3 例[6%]）。奈拉滨脂质体伊立替康组有 16 例（33%）患者发生与治疗相关的严重不良事件（5 例患者为 2-3 级腹泻；1 例为腹部感染、急性肾损伤、全血细胞减少症、胆红素升高、结肠炎、脱水、呼吸困难、传染性肠炎、肠梗阻、口腔黏膜炎和恶心）。对照组中发生 1 例（2%）与治疗相关的严重不良事件（一般状况恶化）。奈拉滨脂质体伊立替康组全球健康状况恶化的中位时间（定义为从随机分组到首次观察到评分下降超过 10 分的时间）为 4.0 个月（95%CI 2.2-未达到），对照组为 3.7 个月（2.7-未达到）。
与氟尿嘧啶加亚叶酸钙相比，奈拉滨脂质体伊立替康联合氟尿嘧啶加亚叶酸钙并未改善无进展生存期或总生存期，且毒性更高。需要进一步研究来确定伊立替康为基础的联合方案在胆道癌二线治疗中的作用。
Servier 和 AIO-Studien。
