Clinical trialPhase 3Bile duct and gallbladder cancer (biliary tract cancer)

Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial

Lancet Oncol · 2021162 patients (81 per group)

Lamarca A, Palmer DH, Wasan HS, et al. Lancet Oncol. 2021. 22:690-701

Study type: Clinical trial
Study name: ABC-06
Phase: Phase 3
Design: Randomised, open-label, controlled trial in 20 UK centres experienced in biliary tract cancer; central 1:1 randomisation by minimisation (platinum sensitivity, serum albumin and stage)
Sample size: 162 patients (81 per group)
Source: Lancet Oncol · 2021
Trial registration: NCT01926236

In plain words

People whose advanced bile duct cancer had grown after the first chemotherapy (gemcitabine and cisplatin) received either FOLFOX chemotherapy plus care to control symptoms, or symptom-control care alone. With FOLFOX, patients lived a little longer, and a year later more than twice as many were alive. Severe side effects were also more frequent with FOLFOX.

Key results

6.2 vs 5.3 months

Median overall survival

Adjusted HR 0.69 (95% CI 0.50–0.97); P=0.031

50.6% vs 35.5%

6-month overall survival

25.9% vs 11.4%

12-month overall survival

4.0 months

Median progression-free survival in the FOLFOX group

95% CI 3.2–5.0

Objective response in the FOLFOX group

1 complete and 3 partial responses among 81 patients

Drugs in this study:Fluorouracil (5-FU)Oxaliplatin (Eloxatin)

Dose and schedule cards

FOLFOX after cisplatin–gemcitabine (ABC-06)

Radiological progression after cisplatin–gemcitabine; ECOG 0–1; adequate biliary drainage; start within 6 weeks of progressionCycle length: Every 14 daysOn the page “Bile duct and gallbladder cancer (biliary tract cancer)” · After progression on first line: chemotherapy and targeted therapy

Radiological progression after cisplatin–gemcitabine; ECOG 0–1; adequate biliary drainage; start within 6 weeks of progression

Drug	Dose	Route	Schedule
Oxaliplatin	85 mg/m² (2-hour infusion)	IV	Day 1
Leucovorin	L-folinic acid 175 mg (or folinic acid 350 mg), 2-hour infusion concurrently with oxaliplatin	IV	Day 1
Fluorouracil	400 mg/m² (bolus over 5–10 minutes)	IV	Day 1
Fluorouracil	2400 mg/m² (46-hour continuous infusion)	IV	Days 1–2

Cycle length: Every 14 days
Duration: Up to 12 cycles (6 months)

Dose source: ABC-06. From cycle 2, neutrophils at least 1.5×10⁹/L and platelets at least 75×10⁹/L. With creatinine clearance 30–60, oxaliplatin 65 mg/m²; over 70 years, fluorouracil may start at 80% of the dose at the physician's discretion; body surface area capped at 2.2 m²; two dose-reduction levels (20% and 50%). Regimen page: FOLFOX

On the page “Bile duct and gallbladder cancer (biliary tract cancer)” · After progression on first line: chemotherapy and targeted therapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Active symptom control + FOLFOX (81 patients)

Intravenous FOLFOX every 2 weeks for up to 12 cycles (6 months), given over 2 days: oxaliplatin 85 mg/m² in 250–500 mL of 5% glucose over 2 hours; L-folinic acid 175 mg (or folinic acid 350 mg) over 2 hours, concurrently with oxaliplatin; fluorouracil 400 mg/m² bolus over 5–10 minutes on day 1; then fluorouracil 2400 mg/m² as a continuous intravenous infusion from day 1 to day 2 (46 hours). Over 70 years, fluorouracil could start at 80% of the dose at the investigator's discretion; with creatinine clearance 30–60 mL/min, oxaliplatin 65 mg/m²; body surface area capped at 2.2 m²; from cycle 2, neutrophils at least 1.5×10⁹/L and platelets at least 75×10⁹/L; at most two dose-reduction levels per drug (20% and 50%). Active symptom control as in the other group.

2Active symptom control alone (81 patients)

Early identification and treatment of biliary complications and control of cancer symptoms as needed: biliary drainage, antibiotics, analgesia, corticosteroids, antiemetics, palliative radiotherapy (for example for painful bone metastases) and transfusion of blood products; visits every 4 weeks.

Source of the regimen details: Full text of the paper (Lancet Oncol 2021; PMC8082275), Methods section

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults aged 18 or older with histologically or cytologically confirmed locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological progression after first-line cisplatin–gemcitabine, ECOG performance status 0–1, life expectancy over 3 months and adequate haematological, renal and hepatic function, without active infection or inadequate biliary drainage; at most 6 weeks between progression and the start of second-line treatment. Clinical brain metastases and significant cardiovascular disease were exclusion criteria.

Endpoints

Primary endpoint: overall survival (time from randomisation to death from any cause) in the intention-to-treat population, by multivariable Cox regression adjusted for the stratification factors. Secondary endpoints: progression-free survival and radiological response (RECIST 1.1) in the FOLFOX group only; adverse events, quality of life and health economics in both groups.

Safety and side effects

Grade 3–5 adverse events occurred in 56 (69%) of 81 patients in the FOLFOX group and 42 (52%) of 81 in the symptom-control group, including 3 chemotherapy-related deaths (one each from infection, acute kidney injury and febrile neutropenia). The most frequent grade 3–5 FOLFOX-related events were neutropenia (10 patients, 12%), fatigue or lethargy (9 patients, 11%) and infection (8 patients, 10%).

Clinical significance and place in guidelines

ABC-06 was the first randomised phase 3 trial of second-line treatment in biliary tract cancer and made FOLFOX the standard second line after cisplatin–gemcitabine. ESMO 2023 recommends it [I, A], and ASCO 2026 recommends FOLFOX with symptom control, or symptom control alone, for patients without a targetable marker. In patients with a targetable genetic change, targeted drugs are the other second-line options.

Limitations

The difference in median overall survival was small (0.9 months) and the objective response rate only 5%. The trial was open label and run only in the UK; the FOLFOX group was seen every 2 weeks and the control group every 4 weeks, so symptom care may have been more thorough in the chemotherapy group. Patients were enrolled before first-line immunotherapy was used.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.