November 2016, Vol. 5, No. 9
Published Studies Underreport Toxicities Associated with Targeted Therapy and Immunotherapy
Most oncologists’ knowledge about toxicities associated with newer therapies comes mainly from clinical trials, but publications of clinical trial safety results may be misleading, according to a study presented at the European Society for Medical Oncology 2016 Congress. The study investigators found suboptimal reporting of adverse events in studies of immunotherapy and targeted therapy published over the past 15 years. In particular, the investigators identified suboptimal reporting of recurrent or late toxicities and the duration of adverse events associated with immunotherapy and targeted therapy.
“Reporting adverse events from clinical trials with new agents is a crucial point, as this will inform physicians and patients regarding the safety profile of that drug and what to expect when starting this therapy in a new patient in everyday clinical practice,” said lead investigator Paolo Bossi, MD, Head & Neck Unit at the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
The study was based on a review of 81 trials of targeted therapies and immunotherapies that were approved by the FDA from 2000 to October 2015 for the treatment of solid tumors in adult patients. Each study was assessed using a 24-point score based on the Consolidated Standards of Reporting Trials guidance.
The trials were conducted mainly in colorectal, lung, and breast cancer and in melanoma and involved more than 45,000 patients; 95% of the trials were conducted in advanced cancers. The experimental drug was studied as a single agent in 51% of cases and in combination with chemotherapy in 32%.
The investigators found that more than 90% of the trials had poor scores related to reporting recurrent and late toxicities, as well as in reporting the duration of adverse events; 86% did not adequately report the time the adverse events occurred, and 75% restricted reporting to adverse events that occurred at a frequency above a fixed threshold.
More than 50% of the reported studies had limitations in the way adverse events were presented, in describing toxicities leading to treatment cessation, and in the follow-up interval assessments. One-third of the studies failed to report dose reductions due to adverse events.
“Toxicities of targeted agents and immunotherapy are obviously different from the toxicities we are used to observing and treating due to chemotherapy, and there are some aspects of the toxicities of these newer agents that we are not so well informed about,” Dr Bossi said.
The 3 axes of reporting toxicities include frequency, severity, and duration of an adverse event. The duration of an adverse event is not typically considered when a new drug comes to market, he noted.
Dr Bossi said he was encouraged to see a trend toward improved reporting of adverse events in recent years. New instruments are available to help physicians both improve the quality of reporting adverse events and discuss potential toxicities with their patients.
He cited the National Cancer Institute’s PRO-CTCAE form, a patient-reported outcome instrument for reporting adverse events. “[This] will allow physicians to collect symptoms as reported by the patients, considering also the severity, intensity, and influence of the symptoms on their quality of life,” Dr Bossi said.
Commenting on this study, Nathan Cherny, MD, Shaare Zedek Medical Center in Jerusalem, noted that evidence shows clinicians underreport adverse events as well as their severity, compared with patient reports.
“These findings lend further support to the proposal to radically reevaluate the collection and reporting of adverse event data to give weighting to patient-reported data,” Dr Cherny said.
In recent years, the cancer patient’s experience has been recognized as an important factor in determining the value of a treatment. According to patient reports, their quality of life (QOL) remained stable on the immunotherapy nivolumab, whereas it significantly deteriorated on chemotherapy, as shown in an analysis of a phase [ Read More ]
The Knudson Two-Hit Hypothesis is the accepted common mechanism for transformation in patients with most familial cancer syndromes. A germline deleterious mutation in a tumor suppressor gene (TSG) increases the risk of developing specific malignancies. The gatekeeper event is loss of heterozygosity (LOH) or loss of expression of normal protein [ Read More ]