The need for adverse effects reporting standards in oncology clinical trials.

Abstract

In this issue of the Journal of Clinical Oncology, the Groupe d’Oncologie Radiotherapie Tete et Cou (GORTEC) report long-term survival and late effects from a pivotal randomized trial of chemoradiotherapy in advanced head and neck cancer [1]. Although overall survival remains poor in this population, the therapeutic advantage of combined modality is significant and is sustained beyond 5 years. This article adds to other phase III trials supporting the superiority of concurrent chemoradiotherapy over radiotherapy alone in head and neck cancer [2-9] and represents a real success story in clinical research. Combined modality approaches are associated with higher acute toxicity, requiring increased levels of supportive care. However, there are also growing concerns about the high rate of late effects, as well as acute toxicity, which may result in long-term consequential effects such as severe swallowing dysfunction and mucosal injuries. These higher rates of adverse effects have been generally perceived as “worth it” by the oncology community. But how do we really know that the benefits outweigh the harms of these aggressive programs? The truth is that we do not have sufficient information on neither the acute nor, in particular, the late adverse outcomes to make this judgment, making it difficult to properly compare treatments and describe risk in the informed consent process. There are now at least six positive concurrent chemoradiotherapy trials in head and neck cancer, each employing different drug and fractionation combinations. Which is the “best” one for my patient? If I want to consider relative rates of adverse effects among these regimens, are there accepted methods for comparing toxicity profiles? The GORTEC trial reports a 30% risk of high-grade [3,4] late effects at 5 years in the radiation-alone arm compared with 56% in the chemoradiotherapy arm, utilizing the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/ EORTC) [10] grading system for late effects, and the National Cancer Institute Common Toxicity Criteria (NCI/ CTC) [11] for selected late effects not covered by the RTOG/EORTC system. The GORTEC group has also reported a more in-depth evaluation of late toxicity in the same trial [12]. In an effort to compare the utility of different late effects grading systems, forty-four 5-year survivors were systematically screened using the individual criteria scales of three separate grading instruments: the RTOG/ EORTC system, the NCI/CTC, and the Subjective, Objective, Management, Analytic (SOMA) System [13]. They found that each tool covered some nonoverlapping toxicity items. The SOMA system seemed to be the most comprehensive and perhaps the best for grading fibrosis. The rate of late effects, when combining the data from the three tools, was 47% in the control arm and 82% in the experimental arm, which was statistically significant (P .02), in contrast to the difference observed using the RTOG scale alone. The original (1999) paper from the GORTEC study reported rates of 9% and 14% for grade 3 to 4 late effects in the radiotherapy (RT) and the chemoradiotherapy (CRT) arms, respectively [14]. These differences were not statistically significant. The median observation time was 35 months, but these incidence estimates were crude ratios between the number of patients with late effects and the total number of patients treated. Actuarial estimates, typically employing the Kaplan-Meier method, adjust for the number of cases under observation at the time when late effects become clinically manifest, providing a more accurate determination of the prevalence of late effects in longterm survivors. The importance of establishing reporting standards is illustrated by the large range of reported values (even considering some increase in the crude estimate of late effects between years 3 and 5), from 9% to 47% in the RT arm and from 14% to 82% grade 3 to 4 late toxicity in the CRT arm in the three reports from the GORTEC trial. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 1 JANUARY 1 2004