The system for monitoring adverse events in oncology clinical trials is in urgent need of reform, contend the authors of a commentary recently published by Journal of Clinical Oncology. Ronald M. Witteles, MD, and Melinda Telli, MD, both of Stanford University School of Medicine in Stanford, California, used the example of sunitinib (Sutent) to showcase the need for standardized measurements of the potential toxicity of cancer drugs during clinical trials in order to prevent the publication of misleading results.
Used in the treatment of renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors, sunitinib is associated with cardiac toxicity. However, the FDA labeling for the drug warned of a much higher incidence of such problems than were reported in the clinical trials, according to Witteles and Telli.
“[Sunitinib and other cancer-fighting agents that are prone to the same underreporting of side effects] are exceptionally useful drugs, but clinicians need to know the full array of possible cardiac side effects so that they can monitor cardiac function appropriately and consider starting cardiac medications or [with]holding the anticancer therapy altogether when necessary,” explained Witteles in a separate statement.
Witteles and Telli noted in their commentary that “few practitioners comprehensively read package inserts for the drugs they prescribe,” often relying instead on the information presented in journal articles.
In the case of sunitinib, the authors identified problems with the Common Terminology Criteria for Adverse Events (CTCAE) as one reason for the differences between reported rates of cardiac toxicity. The CTCAE aims to achieve consistency in the reporting of adverse events in all oncology clinical trials, but Witteles and Telli described how a hypothetical patient who develops an asymptomatic treatment-emergent left ventricular ejection fraction (LVEF) drop from 60% to 35% could be reported in three different ways under the system, depending on the interpretation of the study investigators. One of those ways classifies the reaction as a grade 0 event, another as a grade 1 event, and the third as a grade 3 event.
Witteles and Telli also pointed out that the clinical trial reporting system relies heavily on investigator judgment for reporting adverse events. Many side effects, such as edema and dyspnea, can’t be validated by objective data the way events such as LVEF declines and hypokalemia can.
Finally, in the case of heart failure in particular, symptoms can easily be misattributed to noncardiac adverse effects from cancer therapies or to effects of the malignancy itself.
Witteles and Telli proposed solutions to help reduce disparities in the reporting of adverse events for cancer drugs. One such recommendation is to have routine cardiac monitoring built into any drug trial in which there has been an indication of heart toxicity.