A drug developed 50 years ago and abandoned because it was considered to be too toxic has gained a second life in an international clinical trial. Research showed the drug and a potentiating agent lengthened the lives of patients with metastatic colorectal cancer, all of whom had exhausted available standard treatments.
In a paper published by the New England Journal of Medicine, researchers found that the drug combination - given as a single pill known as TAS-102 - not only extended patients' overall survival, but also delayed the advance of the disease and did so with very few side effects.
According to the study authors, the results are especially impressive because half of the patients had just finished treatment with the standard class of chemotherapy agents - fluoropyrimidines (e.g. 5-fluorouracil [5-FU] or capecitabine [Xeloda]) but had failed to benefit from them. The fact that TAS-102 temporarily halted the disease in many of these patients suggests that it operates through a different biochemical pathway than 5-FU, and therefore may serve as an alternative to standard therapy.
The trial, a phase 3 study, enrolled 800 patients with metastatic colorectal cancer that was progressing despite previous treatment. Participants were randomly assigned to receive TAS-102 or a placebo pill. The median survival period for patients receiving TAS-102 was 7.1 months, compared to 5.3 months for patients taking a placebo, investigators reported. The median time before the disease worsened was 5.7 months for the TAS-102 group and 4.0 months for the placebo group.
Although these gains may seem small, the fact that they occurred in patients whose cancer no longer responded to other therapies suggests TAS-102 holds real promise as a treatment for the disease, the study authors said.
The cancer cell-killing component of TAS-102, a drug known as trifluridine, was developed in the late 1950s, at about the same period as 5-FU. At the time, 5-FU was thought to work by being incorporated into cancer cells' DNA and preventing the cells from metabolizing nutrients. Later, it was learned that the drug actually works by blocking an enzyme (thymidylate synthase) that the cells need for survival.
Trifluridine, by contrast, does integrate into cancer cell DNA, but proved to be too toxic to patients when given in doses necessary to kill the cancer cells. About 15 years ago, the Japanese company Taiho Pharmaceutical began testing trifluridine in combination with tipiracil hydrochloride, an agent that blocks the metabolism of trifluridine. The combination allowed trifluridine to exert its beneficial effect without reaching toxic levels, thereby making it a potentially useful form of anticancer therapy.
The next step will be to test TAS-102 in combination with other drugs that are customarily used in conjunction with 5-FU, and compare results.
Based on material originally posted by Dana-Farber Cancer Institute.