CISPLATIN AND GEMCITABINE FOR BILLIARY CANCER

April 7, 2010 — The combination of cisplatin and gemcitabine (Gemzar) is an effective treatment option for patients with locally advanced or metastatic biliary tract cancer, according to a study published in the April 8 issue of the New England Journal of Medicine.

British researchers found that cisplatin plus gemcitabine was associated with a significant survival advantage, compared with gemcitabine alone. Toxicity was not substantially increased in patients who received the combination regimen.

The median overall survival was 11.7 months in the combination group and 8.1 months in the gemcitabine-only group of the trial (hazard ratio [HR], 0.64; P < .001). In addition, median progression-free survival was 8.0 months in the combination group and 5.0 months in the gemcitabine-only group (P < .001).

"Many would now consider cisplatin plus gemcitabine to be the standard treatment, as it is certainly the regimen with the most robust supporting data," said study author John Bridgewater, MD, PhD, from the University College London Cancer Institute in the United Kingdom. "The survival benefit was 3.6 months, which compares well with other studies that have defined the standard of care, and critically, this benefit was obtained without added toxicity."

"We believe it is a significant advance," he told Medscape Oncology. "We are planning a series of studies through an international consortium using biologicals to further improve survival."

The results of this study were initially presented during the 2009 annual meeting of the American Society of Clinical Oncologists (ASCO), and were reported by Medscape Oncology at that time. Lead author Juan Valle, MD, a medical oncologist at the University of Manchester in the United Kingdom, presented the data there and reported that "this is the first demonstration of a survival benefit in biliary tract cancer."

Richard Schilsky, MD, professor of medicine at Chicago University in Illinois, and president of ASCO at the time of the 2009 meeting, noted at the time that this was a "definitive and well-conducted study in a difficult-to-treat cancer."

No Standard Regimen

In developed nations, biliary tract cancer is uncommon, although the incidence in increasing, the authors report. The majority of patients present with advanced disease and, despite surgical resection, tend to relapse. However, although advanced biliary tract cancer can respond to chemotherapy, there is no recognized standard palliative regimen.

The reason for this, say the authors, is that no single randomized study has ever been sufficiently robust to define such a schedule.

The authors initially conducted a randomized phase 2 study (the Advanced Biliary Cancer [ABC]-01 trial) of 86 patients to compare cisplatin plus gemcitabine with gemcitabine alone. When an improvement in progression-free survival was observed, the authors extended it to the current phase 3 trial.

Improved Survival and Tumor Response

The trial was designed and developed by the ABC-02 Trial Management Group, and was conducted at 37 centers in the United Kingdom. A total of 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer were randomized to receive 1 of 2 treatments for up to 24 weeks: cisplatin 25 mg/m2 followed by gemcitabine 1000 mg/m2 on days 1 and 8, every 3 weeks for 8 cycles; or gemcitabine alone 1000 mg/m2 on days 1, 8, and 15, every 4 weeks for 6 cycles.

The primary end point was overall survival; secondary outcomes were progression-free survival, tumor response, and adverse events. The median follow-up time was 8.2 months.

The final analysis was conducted 8 months after enrollment of the last patient and, at that time, 327 deaths had occurred (79.8%), and 362 patients experienced tumor progression (88.3%), 278 of whom died.

The authors observed that there was objective tumor response in 303 patients; tumor control (complete or partial response or stable disease) was achieved in 131 of 161 patients who received the combination (81.4%) and in 102 of 142 patients who received gemcitabine alone (71.8%) (P = .049). A complete response was observed in 1 patient from each treatment group.

Tumor Response for All Evaluable Patients
All Evaluable Patients Gemcitabine Alone,
n=142 (%) Cisplatin Plus Gemcitabine,
n=161 (%) P value
Complete response 1 (0.7) 1 (0.6)
Partial response 21 (14.8) 41 (25.5)
Stable disease 80 (56.3) 89 (55.3)
Progressive disease 40 (28.2) 30 (18.6)
Tumor control* 102 (71.8) 131 (81.6) 0.049
*Complete or partial response or stable disease

Overall, patients in the combination group had improved survival; this was consistent across all subtypes of biliary tract cancer. The authors noted that patients who received combination therapy were 36% less likely to die at any time than those who received gemcitabine alone (HR, 0.64; 95% confidence interval, 0.52 - 0.80). The 6-month progression-free survival rate was 59.3% for the combination group and 42.5% for the gemcitabine-only group.

Adverse Events Similar

In general, adverse events were similar in the 2 groups. There was a higher incidence of neutropenia in the combination group, but it was not significant, and infection rates were similar in the 2 groups. Patients in the gemcitabine-only group had significantly worse liver function (27.1%) than those in the combination group (16.7%); the authors speculate that this might reflect better disease control in the combination group.

In an accompanying editorial, Brian M. Wolpin, MD, MPH, and Robert J. Mayer, MD, from the Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts, note that even though the "3-month extension in survival among patients with biliary tract cancer is modest, it is a definite step forward."

Dr. Wolpin and Dr. Mayer explain that the results of this trial indicate that the combination "should be considered a standard treatment option for patients with advanced biliary tract cancer."

"Further meaningful advances will depend on a better understanding of the molecular events that promote the development and sustain the growth of biliary tract cancer," they write.

The study was supported by the University College London Hospitals and the University College London Comprehensive Biomedical Research Centre, University College London, Cancer Research UK; and an unrestricted educational grant from Lilly Oncology. Dr. Valle reports receiving honoraria from Eli Lilly for a speaker presentation; none of his coauthors have disclosed any relevant financial relationships. The editorialists have disclosed no relevant financial relationships.

N Engl J Med. 2010;362:1273-1281, 1335-1337.