Chemotherapy regimen more effective and more toxic in Japanese patients than in American patients

A chemotherapy regimen commonly used to treat non-small cell lung cancer is both more effective and more toxic in Japanese patients than in American patients, researchers reported Saturday at the annual meeting of the American Society of Clinical Oncologists. The first of its kind, this analysis underscores the importance of genetic variations in medicine and points to a need for increased international collaboration in trials of new cancer treatments.

“Results of a cancer clinical trial performed in one part of the world may not necessarily hold true for populations in other regions,” said lead investigator David Gandara, director of clinical research at UC Davis Cancer Center and professor of medicine at the UC Davis School of Medicine. “We need to be cautious when we extrapolate from one population to another.”

The analysis compared results from two phase III clinical trials designed to evaluate the relative effectiveness of various treatments for patients with advanced non-small cell lung cancer. One trial was conducted in the United States, the other in Japan. The two trials were carefully structured from the outset, through a lengthy series of meetings between U.S. and Japanese investigators and representatives of the Japanese Ministry of Health, to have a “common arm.” The approach allowed researchers to make direct comparisons of one chemotherapy regimen — paclitaxel and carboplatin — in both populations. Patients in both trials were closely matched in terms of age, gender, disease stage and tumor type.

The collaboration is the first to prospectively design a “common arm” in a U.S. cooperative group trial and in one conducted in another country.

Median survival time was 12 months for the Japanese patients in the paclitaxel-carboplatin arm of the study, versus nine months for U.S. patients receiving the same regimen. Half of the Japanese patients (51 percent) survived one year, versus only slightly more than a third (37 percent) of the American patients.

“The reasons for the increased survival among the Japanese patients remain to be determined, but the implications of this observation are of considerable interest,” Gandara said.

The longer survival in the Japanese group was especially striking because those patients had to be given a lower dose of paclitaxel due to toxicity. Even with the lower dose, the Japanese patients were able to complete fewer cycles of the chemotherapy regimen, and some side effects were more severe.

The U.S. patients received 225-milligram doses of paclitaxel; the Japanese patients received 200-milligram doses. Earlier phase I studies of paclitaxel in the U.S. and Japan set these as the maximum tolerated doses for each population.

Despite the reduced dose, only one in four of the Japanese patients (24 percent) completed three cycles of the paclitaxel-carboplatin regimen, versus 100 percent of the U.S. patients. And only about one in 10 Japanese patients (11 percent) completed six cycles, versus more than a third of the U.S. patients (36.5 percent).

Neutropenia, in which levels of infection-fighting white blood cells drop to dangerous levels, was more than twice as common in the Japanese patients. Neutropenia accompanied by fever was more than five times as common in the Japanese patients.

On the other hand, one side effect, neuropathy, was more common in the U.S. patients, for good reason, according to Gandara. Neuropathy results from cumulative exposure to many cycles of paclitaxel, and the U.S. patients completed more cycles. Neuropathy is characterized by tingling, numbness or pain due to nerve damage.

Patients in both trials received equivalent levels of carboplatin.

Gandara and his colleagues believe the differences between the U.S. and Japanese patients are likely due to genetic differences in drug metabolism, an area of science known as pharmacogenomics. Recent research has identified specific genes involved in paclitaxel metabolism, and these genes may prove different from one ethnic group to another.

“These findings underscore both the importance of global clinical trials, and the importance of ensuring that we do them carefully. It will be critical to take into account possible pharmacogenomic differences among populations as we move toward global trials,” Gandara said.

The U.S. trial was conducted through the Southwest Oncology Group, one of the country’s largest National Cancer Institute-sponsored cancer clinical trials cooperative groups, comprising 283 institutions in the United States and Canada.

The Japanese study was conducted through the FACS group, or Four-Arm Comparative Study Group.

The combination of paclitaxel and carboplatin is commonly used to treat non-small cell lung cancer in the U.S., but had never been studied in a large clinical trial in Japan.

While major pharmaceutical companies have conducted global trials of investigational drugs, there is no mechanism at present to conduct joint NCI-sponsored trials internationally. “We hope this analysis will serve as a model for future prospective comparisons of cooperative group trials,” Gandara said.