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Clinical Trial Results

Summaries of Newsworthy Clinical Trial Results
  • Posted: 05/11/2010

Cisplatin Plus Gemcitabine Improves Survival of Patients with Advanced Biliary Tract Cancer

Key Words

Biliary tract (in the bile ducts and gallbladder) cancer, cholangiocarcinoma, ampullary cancer, combination chemotherapy, gemcitabine (Gemzar®), cisplatin (Platinol®). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

Summary

Compared to gemcitabine alone, the chemotherapy combination of cisplatin and gemcitabine improved overall survival of patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer. These phase III clinical trial results from the United Kingdom provide the strongest evidence yet that chemotherapy is effective against advanced biliary tract cancers and may help to establish the standard of care.

Source

New England Journal of Medicine, April 8, 2010 (see the journal abstract).

Background

Biliary tract cancers are fairly rare in developed countries. Each year in the United States there are about 6,500 new cases of gallbladder cancer and about 6,000 bile duct cancers, known as cholangiocarcinomas. Surgery is the only curative approach, but most patients are diagnosed with locally advanced or metastatic disease, and relapse is common. Five-year survival is only 15 percent.

Because these cancers are rare and many patients have advanced disease and receive only palliative care, few phase III clinical trials have been conducted in this setting. However, small, early-phase clinical trials have indicated that chemotherapy can have some effect. Drugs in common use include gemcitabine, cisplatin, and fluoropyrimidines. The gemcitabine/cisplatin combination is used in a number of other cancers and has shown some promise for patients with advanced biliary tract cancer in smaller trials.

The Advanced Biliary Cancer (ABC-02) trial described here is the largest phase III randomized controlled trial in this group of diseases to date.

The Study

Between 2002 and 2008, researchers enrolled 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer (cancer of the ampulla of Vater, which is formed by the union of the pancreatic duct and the common bile duct) at 37 centers throughout the United Kingdom. Patients were randomly assigned to receive the chemotherapy combination of gemcitabine and cisplatin (204 patients) or gemcitabine alone (206 patients).

The study was initially designed as a randomized phase II trial, and 86 patients were enrolled through 2004. When results showed an improvement in progression-free survival among those receiving combination chemotherapy, on the phase II trial (ABC-01) was extended to a phase III trial, ABC-02, which included the original patients.

The drugs were given by intravenous infusion for 12 weeks and patients’ tumors were then evaluated by imaging. If patients’ measurable disease had not progressed, they were permitted to continue treatment for up to another 12 weeks. More patients in the combination arm (63 percent) than in the gemcitabine-alone arm (52 percent) continued beyond the first 12 weeks.

The lead author is Juan Valle, M.D., of Christie Hospital and the University of Manchester in the United Kingdom. The trial was conducted by the Upper Gastrointestinal Cancer Clinical Studies Group of the United Kingdom National Cancer Research Institute.

Results

In the original ABC-01 study, patients taking gemcitabine and cisplatin were more likely to have no disease progression (57 percent) after 6 months than were patients taking gemcitabine alone (48 percent). In the ABC-02 study, after a median follow-up time of just over 8 months, patients in the combination arm were 36 percent less likely to die at any time, surviving a median of 11.7 months compared with 8.1 months for patients in the gemcitabine-alone arm.

The combination chemotherapy also improved progression-free survival, which was a median of 8 months for those in the combination arm and 5 months for those in the gemcitabine-alone arm.  Improved overall survival with the combination treatment was seen for all subtypes of biliary tract cancer.

Abnormal liver function was experienced by 27 percent of patients in the gemcitabine-alone arm and 17 percent of patients in the combination arm, and hematologic toxic effects were seen in 24 percent of patients in the gemcitabine arm and 32 percent of those in the combination arm. All other toxicities were similar for both groups.

Comments

While there has been no single standard of care for advanced biliary tract cancers, “this is a really strong result,” said Jack Welch, M.D., Ph.D., from NCI’s Division of Cancer Treatment and Diagnosis. “This is the closest we have to a gold standard. Physicians can now feel confident they are practicing evidence-based medicine in recommending this combination to their patients.”

The researchers did “an extraordinary job of recruiting” patients into this trial, added Dr. Welch. For years, no studies worldwide were able to enroll enough patients to demonstrate a result this persuasive for advanced biliary tract cancer. Although there are only about 1,000 new patients each year in the UK who might qualify, the trial organizers were able to enroll the necessary 400-plus patients in a span of less than 6 years.

Finally, Dr. Welch notes, the large size of the study gave the most accurate assessment of overall survival yet available for gemcitabine, the single agent most commonly used for advanced biliary tract cancer, in the context of a multi-institutional study.

In an accompanying editorial, Brian M. Wolpin, M.D., M.P.H., and Robert J. Mayer, M.D., from Harvard Medical School, write “Valle and colleagues have provided an important foundation on which future clinical trials in biliary tract cancer can be built.” In designing future clinical trials, explained Dr. Welch, researchers are likely to consider using the combination as a standard arm against which to measure candidate treatments being tested.

Limitations

One somewhat unusual aspect of this study is the fact that the trial began as a smaller phase II study and was extended to a phase III design. Nevertheless, the results are still valid, said Dr. Welch, who pointed out that this strategy has often been followed in the United States in other settings and diseases.

The drug manufacturer Lilly Oncology provided the gemcitabine for the study.

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