Targeted cancer drugs less toxic than traditional chemotherapeutics at phase I

Molecularly targeted agents (MTAs) being tested in phase I trials appear to carry a much lower risk of the most serious side effects than do traditional chemotherapeutic drugs, according to a new study from The Institute of Cancer Research in London, England.

As noted in a statement from the Institute, most of the cancer drugs developed over recent years are targeted agents that attack the specific genetic or molecular faults driving cancer growth. This differs from the approach of the “one size fits all” chemotherapeutic agents, which destroy all rapidly dividing cells.

Phase I trials are designed to evaluate the safety as well as the optimal dose of a drug. A team led by medical oncologist L. Rhoda Molife, of the Institute and of The Royal Marsden National Health Service Foundation Trust, also in London, conducted a retrospective analysis of participants in 36 phase I MTA trials run by the Drug Development Unit, a joint venture of the two organizations. Data from 687 patients (median age 59.1 years; range 12.5–85.5 years) were evaluated to determine the rate of treatment-related grade 3 and grade 4 toxic effects, mortality, and risk factors associated with toxicity of grade 3 or higher.

The investigators reported in Annals of Oncology (2012;23[8]:1968-1973) that phase I trial patients were approximately seven times less likely to suffer a life-threatening side effect with an MTA than with a traditional cytotoxic agent. Specifically, the overall risk of suffering a grade 4, life-threatening side effect in this study was 1.9%, compared with 14% found in an analysis of trials from 1991 to 2002. Similarly, the risk of grade 3, severe side effects was 14% in Molife's study, compared with 10% to 36% found across two previous analyses of phase I cytotoxic agents. Mortality was low among the MTA patients, at 0.43%.

The most common grade 3 and grade 4 MTA events were gastrointestinal, such as loss of appetite, diarrhea, and vomiting, as well as fatigue. Side effects of cytotoxic drugs are generally hematologic or cardiovascular. MTA patients were most likely to suffer side effects if they were given a higher dose than the trial later found to be optimal or if they were more ill at trial enrollment.

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