In the phase III ABC-06 trial reported in The Lancet Oncology, Angela Lamarca, PhD, and colleagues found that second-line FOLFOX (leucovorin, fluorouracil [5-FU], and oxaliplatin) produced a statistically significant improvement in median overall survival vs active symptom control in patients with advanced biliary tract cancer, with “clinically meaningful” improvements in 6- and 12-month survival.

As stated by the investigators, “Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy.”

Angela Lamarca, PhD

Study Details

The multicenter trial included 162 patients with locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with disease progression after first-line cisplatin and gemcitabine. Patients were randomly assigned between March 2014 and January 2018 to receive active symptom control plus FOLFOX (n = 81) or active symptom control alone (n = 81). FOLFOX treatment consisted of oxaliplatin at 85 mg/m², L-leucovorin at 175 mg or leucovorin at 350 mg, 5-FU bolus at 400 mg/m², and 5-FU at 2,400 mg/m² as a 46-hour continuous infusion every 2 weeks for a maximum of 12 cycles. Active symptom control consisted of early identification and treatment of biliary-related complications and cancer-related symptom management, including biliary drainage, antibiotics, analgesia, steroids, antiemetics, other palliative treatment for symptom control, palliative radiotherapy, and transfusion of blood products.  

The primary endpoint was overall survival in the intention-to-treat population.

Overall Survival

Median follow-up was 21.7 months (interquartile range = 17.2–30.8 months). Median overall survival was 6.2 months (95% confidence interval [CI] = 5.4–7.6 months) in the FOLFOX group vs 5.3 months (95% CI = 4.1–5.8 months) in the active symptom control alone group (adjusted hazard ratio [HR] = 0.69, 95% CI = 0.50–0.97, P = .031). Rates at 6 and 12 months were 50.6% vs 35.5% and 25.9% vs 11.4%, respectively.

In the FOLFOX group, median progression-free survival was 4.0 months (95% CI = 3.2–5.0 months), with 3-, 6-, and 12-month rates of 66.7%, 32.1%, and 8.6%. Objective response was observed in four patients (5%), with complete response in one. An additional 23 patients (28%) had stable disease, yielding a disease control rate of 33%.

Adverse Events

Grade ≥ 3 adverse events irrespective of causality were reported in 69% of patients in the FOLFOX group and 52% of the active symptom control alone group. Chemotherapy-related grade ≥ 3 events in the FOLFOX group included grade 3 events in 28% (most common = fatigue/lethargy in 11%, neutropenia in 10%, infection in 7%), grade 4 events in 6% (neutropenia in 2%, infection in 1%, febrile neutropenia in 1%, and myocardial infarction in 1%), and grade 5 events in 4% (1 death each due to infection, acute kidney injury, and febrile neutropenia).  Treatment was discontinued in 10 patients (12%) in the FOLFOX group due to toxicity.

The investigators concluded, “The addition of FOLFOX to active symptom control improved median overall survival in patients with advanced biliary tract cancer after [disease] progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomized 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 advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials.”

Juan W. Valle, MD, of the University of Manchester, The Christie NHS Foundation Trust, Manchester, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Cancer Research UK, Stand Up To Cancer, AMMF (The UK Cholangiocarcinoma Charity), and others. For full disclosures of the study authors, visit thelancet.com.