Newer, More Effective Anti­cancer Drugs Increase Toxicity, Requiring Individualized Approach to Therapy

The FDA approval of new drugs for advanced solid tumors is relying heavily on demonstration of increased survival duration in phase 3 clinical trials. Most trials, however, are not designed to detect differences in quality of life (QOL) or in toxicity levels. A new meta-analysis reviewed pivotal clinical trials that have led to FDA approval of new anticancer drugs focusing on QOL outcomes in 3 areas—treatment-related differences in grade 3 or 4 adverse events (AEs), treatment discontinuation, and toxic deaths (Niraula S, et al. J Clin Oncol. 2012;30:3012-3019).

This meta-analysis included 38 randomized controlled trials of targeted drugs or chemotherapeutic drugs ap­proved by the FDA for the treatment of cancer in the United States between 2000 and 2010, excluding supportive care drugs. Overall, the newer drugs had greater odds of resulting in toxic deaths than the comparator therapy of nontargeted drugs (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.15-1.70; P <.001) and greater odds of treatment discontinuation (OR, 1.33; 95% CI, 1.22-1.45; P <.001). Grade 3 or 4 AEs, especially nonhematologic AEs (eg, diarrhea, skin reactions, and neuropathy), were more common with the newer agents (OR, 1.52; 95% CI, 1.35-1.71; P <.001).

The increased toxicity was not limited to targeted drugs and applied to new chemotherapeutic agents as well. Indeed, targeted therapies are overall less toxic than chemotherapy; when targeted drugs used as monotherapies were compared with new chemotherapeutic agents, treatment discontinuation and hematologic toxicity rates were lower with the targeted agents. However, because patients in clinical practice are “less selected” than in clinical trials, the likelihood of newer therapy-related toxicity is greater in the real world than in a clinical trial, the investigators suggest. Therefore, they conclude, the use of newer agents and newer chemotherapy must be selective and individualized; oncologists must consider the health status of the individual patient when prescribing therapy with newer agents.