March 14, 1997

Colorectal cancer regimen shows early promise

Colorectal cancer regimen shows early promise

reporter_3.14.97_4.jpg (26k)

Dr. Charles Blanke is studying a new three-drug combination to combat colorectal cancer.

A new combination of chemotherapeutic drugs is showing promising early results in treating colorectal cancer.

In a study conducted at Vanderbilt University Medical Center, the new three-drug regimen produced an overall response rate of 50 percent among colorectal cancer patients, a marked improvement over the existing standard treatment's 23 percent overall response rate.

VUMC researchers found that by combining the standard treatment for colorectal cancer ‹ the drugs 5-fluorouracil (5FU) and leucovorin ‹ with the drug trimetrexate, response rates in patients with unresectable or metastatic colorectal cancer improved, said Dr. Charles D. Blanke, assistant professor of Medicine and the study's principal investigator.

"We observed a 50 percent overall response rate. Also, 7 percent of patients had a complete response, which is a larger number than we expected. These are exciting results," Blanke said.

The results of the phase II trial were recently published in the Journal of Clinical Oncology.

The complete responses were seen in patients with disease which had spread only to the liver, but partial responses were seen in all disease sites, Blanke said. The median duration of response was 15.5 weeks. Median survival for the entire group of study participants was 53.4 weeks, a slight improvement over previously reported analyses, which averaged approximately 10 months.

Colorectal cancer persists as a major health problem, representing the third most frequently diagnosed cancer among both men and women as well as the third leading cause of cancer death. According to Blanke, 131,200 people will be diagnosed with colorectal cancer this year, and 54,900 will die. The five-year survival rate for all patients with the colorectal cancer is 62 percent, which plummets to less than 7 percent for those with metastatic disease.

"Current survival rates for people with advanced colorectal cancer are dismally low," Blanke said. "Our intention is to discover new methods of improving response rates and overall survival for these patients."

The drug trimetrexate has previously been used in the treatment of pneumonia and AIDS, but is now being applied to cancer research. A synthetic inhibitor of dihydrofolate reductase, trimetrexate differs from classical antifolates such as methotrexate in several ways. It does not require activation by the enzyme folylpolyglutarnyl synthetase, and does not use the reduced folate transport system to enter cancer cells, thus avoiding competition for uptake when administered with leucovorin.

Trimetrexate has a broader spectrum of in vitro and in vivo activity than methotrexate and may be effective in cells resistant to methotrexate.

The phase II trial involved 36 patients, age 18 or older, who had incurable recurrent or metastatic cancer of the colon or rectum. Prior radiation or adjuvant chemotherapy were allowed, provided at least six months had passed since chemotherapy.

The triple combination of drugs was generally considered to be manageable. Hematologic toxicity tended to be low-grade, and side effects primarily involved the gastrointestinal tract, with 58 percent of patients experiencing severe diarrhea.

The promising results of the completed phase II trial are now being tested further in a phase III trial currently under way. In this study, the three-drug regimen's efficacy will be tested head-to-head against the standard treatment.

"The next trial will look more closely at survival issues," Blanke said. "We hope these exciting preliminary results will be duplicated in ongoing phase III studies."