Abstract
Background: Advanced biliary tract cancer (ABC) has a poor prognosis for which cisplatin and gemcitabine is the reference first-line chemotherapy. No robust evidence is available for second-line chemotherapy; the aim of this randomised study was to determine the benefit derived from second-line FOLFOX chemotherapy in ABC.
Methods: The ABC-06 clinical trial was a phase III randomised, open-label study. Patients who were Eastern Cooperative Oncology Group performance status 0-1, 18 years of age or older and who had histologically- or cytologically-verified locally advanced or metastatic ABC (including cholangiocarcinoma (CCA), gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy were randomised (1:1) to active symptom control (ASC) and oxaliplatin and 5-fluorouracil (FOLFOX) or ASC alone. FOLFOX chemotherapy was administered intravenously every two weeks for a maximum of 12 cycles [oxaliplatin 85 mg/m2, L-folinic acid 175 mg (or folinic acid 350 mg), 5-fluorouracil 400 mg/m2 (bolus) and 5-fluorouracil 2400 mg/m2 46-hour continuous IV infusion]. Randomisation was performed following a minimisation algorithm using platinum sensitivity, albumin, and stage as stratification factors. The primary end-point was overall survival (OS; defined as the time from randomisation to death), which was assessed in the intention-to-treat population; recruitment of 162 patients was required, to deliver 148 events (hypothesised hazard ratio (HR) 0.63; 80% power; 5% two-sided alpha). Secondary end-points included progression-free survival (PFS) and response rate (ASC+FOLFOX arm only). The study has completed recruitment, final results (150 events reached) are provided. Trial registration number: NCT01926236, EudraCT: 2013-001812-30.
Results: A total of 162 patients were randomised (81 in each arm) between 27 March 2014 and 04 January 2018. The median age was 65 years in each arm; overall, the primary tumour sites were intrahepatic CCA 72 (44%), extrahepatic CCA 45 (28%), gallbladder 34 (21%) and ampullary cancer 11 (7%). After 150 OS events, the adjusted HR was 0.69 (95% CI 0.50-0.97; p=0.031; ASC+FOLFOX vs. ASC). Median OS (months (m)), 6m- and 12m-OS rates (%) were 6.2 m, 50.6% and 25.9% for the ASC+FOLFOX and 5.3 m, 35.5%, 11.4% for the ASC arm, respectively. Grade 3-5 adverse events (AEs) were reported in 56 (69%) and 42 (52%) patients in the ASC+FOLFOX and ASC arm, respectively, including three chemotherapy-related deaths. The most frequently reported grade 3-5 FOLFOX-related AEs were neutropenia (10 patients, 12%), fatigue / lethargy (9 patients, 11%), and infection (8 patients, 10%).
Conclusion: FOLFOX improved OS after progression to cisplatin and gemcitabine with a clinically-meaningful increase in 6m- and 12m-OS rate. To our knowledge, this is the first prospective, adequately-powered randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in ABC. Based on the results of ABC-06, FOLFOX should become standard of care chemotherapy in second-line for ABC and the reference regimen for further clinical trials.
Methods: The ABC-06 clinical trial was a phase III randomised, open-label study. Patients who were Eastern Cooperative Oncology Group performance status 0-1, 18 years of age or older and who had histologically- or cytologically-verified locally advanced or metastatic ABC (including cholangiocarcinoma (CCA), gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy were randomised (1:1) to active symptom control (ASC) and oxaliplatin and 5-fluorouracil (FOLFOX) or ASC alone. FOLFOX chemotherapy was administered intravenously every two weeks for a maximum of 12 cycles [oxaliplatin 85 mg/m2, L-folinic acid 175 mg (or folinic acid 350 mg), 5-fluorouracil 400 mg/m2 (bolus) and 5-fluorouracil 2400 mg/m2 46-hour continuous IV infusion]. Randomisation was performed following a minimisation algorithm using platinum sensitivity, albumin, and stage as stratification factors. The primary end-point was overall survival (OS; defined as the time from randomisation to death), which was assessed in the intention-to-treat population; recruitment of 162 patients was required, to deliver 148 events (hypothesised hazard ratio (HR) 0.63; 80% power; 5% two-sided alpha). Secondary end-points included progression-free survival (PFS) and response rate (ASC+FOLFOX arm only). The study has completed recruitment, final results (150 events reached) are provided. Trial registration number: NCT01926236, EudraCT: 2013-001812-30.
Results: A total of 162 patients were randomised (81 in each arm) between 27 March 2014 and 04 January 2018. The median age was 65 years in each arm; overall, the primary tumour sites were intrahepatic CCA 72 (44%), extrahepatic CCA 45 (28%), gallbladder 34 (21%) and ampullary cancer 11 (7%). After 150 OS events, the adjusted HR was 0.69 (95% CI 0.50-0.97; p=0.031; ASC+FOLFOX vs. ASC). Median OS (months (m)), 6m- and 12m-OS rates (%) were 6.2 m, 50.6% and 25.9% for the ASC+FOLFOX and 5.3 m, 35.5%, 11.4% for the ASC arm, respectively. Grade 3-5 adverse events (AEs) were reported in 56 (69%) and 42 (52%) patients in the ASC+FOLFOX and ASC arm, respectively, including three chemotherapy-related deaths. The most frequently reported grade 3-5 FOLFOX-related AEs were neutropenia (10 patients, 12%), fatigue / lethargy (9 patients, 11%), and infection (8 patients, 10%).
Conclusion: FOLFOX improved OS after progression to cisplatin and gemcitabine with a clinically-meaningful increase in 6m- and 12m-OS rate. To our knowledge, this is the first prospective, adequately-powered randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in ABC. Based on the results of ABC-06, FOLFOX should become standard of care chemotherapy in second-line for ABC and the reference regimen for further clinical trials.
| Original language | English |
|---|---|
| Journal | Lancet Oncology |
| Publication status | Accepted/In press - 12 Jan 2021 |
