Study Finds Racial Differences in Response to Treatments for Advanced Colon Cancer

Article Outline

• Copyright

In recent years, reports have emerged showing that Americans with colorectal cancer who are black have a lower rate of survival compared with other racial groups.

For both black men and women, colorectal cancer is the third most common cause of cancer deaths, according to the American Cancer Society. Additionally, death rates for cancers of the colon and rectum among blacks are approximately 30% higher than among whites, and more than two times higher than for Asian Americans, Pacific Islanders, American Indians, and Hispanics.

Several reasons have been suggested to explain these differences, including diagnosis at a later disease stage, having more aggressive disease, and having less access to screening tests for earlier diagnosis.

Results of a multicenter study in the United States and Canada point to another possibility: differences in therapeutic responses among blacks to standard chemotherapy treatments for advanced colorectal cancer.

“The aim of this research was to compare African American with Caucasian patients with respect to responses, to the time it took for their cancers to become worse, and their overall survival. We also wanted to see if there was any difference in the side effects profile,” said Dr. Richard M. Goldberg, Professor of Medicine, Chief of the Division and Hematology-Oncology at the University of North Carolina at Chapel Hill, and Associate Director of Clinical Research at UNC Lineberger Comprehensive Cancer Center.

Patients donated blood for DNA studies. “We were looking at their DNA, focusing on minor differences called polymorphisms, or variations in DNA sequences that are present in specific genes in every cell in the patient’s body,” Goldberg said. “The genes that we were particularly interested in are those genes coding for key enzymes involved in drug activation, metabolism and disposition,” Goldberg said.

The findings were presented June 4, 2006, at the American Society of Clinical Oncology meetings in Atlanta (http://www.asco.org/ac/1,1003,_12-002138,00.asp).

Participants in the study were a subset of those who had enrolled in a clinical trial that began in the 1990s and was conducted in 155 locations nationwide and in Canada. The trial helped establish the value of the now-standard chemotherapy regimen FOLFOX4, a combination of 5-fluorouracil (5-FU), leucovorin (LV), and the new drug oxaliplatin. All 1412 participants reported on at the ASCO meeting had advanced colorectal cancer. Blacks were similar to whites in extent of disease, gender, age-range, and prior treatment.

However, blacks had a significantly lower response rate overall, both when all 3 treatment programs were analyzed together and when each chemotherapy combination was analyzed separately. When results of the three treatment arms were analyzed together, blacks showed a response rate of 29% versus 41% in whites.

When FOLFOX was analyzed separately, the 119 black patients showed a response that was 15% lower than that of white patients.

Regarding time to progression or worsening of disease, the study found no significant differences between the racial groups. Disease progression was significantly extended in patients treated with FOLFOX compared with the other chemotherapy combinations, IFL (irinotecan and 5FU/LV), and IROX (irinotecan and oxaliplatin).

In terms of overall survival, the comparison between all patients showed about a 1.5 month difference in overall survival favoring white patients, but that finding was not statistically significant.

Blacks did fare better when it came to adverse side effects. “African Americans had significantly less severe toxicity, mainly due to less severe diarrhea,” Goldberg said.

“This study suggests that since African Americans don’t respond as well to these chemotherapies as Caucasians but don’t have as much toxicity, we may not have arrived at the optimal strategy for their treatment,” Goldberg added. “It would certainly be worth exploring other strategies, including dose-escalation.”

To understand potential mechanisms underpinning these clinical results, Goldberg and colleagues performed genetic tests looking for differences in the frequencies of DNA polymorphisms on blood samples of some of the participants, black and white. About 500 participants provided blood samples for this use.

“We looked at 21 genes that we knew were involved in transporting these drugs into the cell, converting them to active products, de-toxifiying them and preparing them for excretion,” Goldberg said. “And then we correlated the frequencies of polymorphisms in these genes with our clinical endpoints.”

The study found that blacks and whites had “significantly different frequencies of polymorphisms in candidate genes coding for key enzymes involved in drug activation, metabolism, and disposition,” Goldberg said.

He added, however, that while different frequencies of polymorphisms in genes relevant to drug metabolism “may help explain” the clinical differences found in the study, they are based on correlations and, therefore, don’t imply cause-and-effect.

“Perhaps, in time, we’ll be smarter about how we prescribe drugs by doing an analysis of DNA ahead of time, thereby allowing us to individualize the most effective and tolerable drug therapy on a patient-by-patient basis,” Goldberg said.

Collaborators included 150 other institutions with key members of the investigative team hailing from the University of North Carolina at Chapel Hill; Washington University in St. Louis; the Mayo Clinic in Rochester, Minnesota; Iowa Oncology Research Association in Des Moines, Iowa; Cancer and Leukemia Group-B in Boston; Eastern Cooperative Oncology Group in Pittsburgh; University of Kansas in Kansas City; National Cancer Institute of Canada; and St. Catherine’s Hospital in Ontario.