Tolerability of bevacizumab and chemotherapy in a phase 3 clinical trial with human epidermal growth factor receptor 2–negative breast cancer: A trajectory analysis of adverse events

Abstract

BACKGROUND: E5103 was a study designed to evaluate the efficacy and safety of bevacizumab. It was a negative trial for the end points of invasive disease-free survival and overall survival. The current work examines the tolerability of bevacizumab and other medication exposures with respect to clinical outcomes and patient-reported outcomes (PROs). METHODS: Adverse events (AEs) collected from the Common Terminology Criteria for Adverse Events were summarized to form an AE profile at each treatment cycle. All-grade and high-grade events were separately analyzed. The change in the AE profile over the treatment cycle was delineated as distinct AE trajectory clusters. AE-related and any-reason early treatment discontinuations were treated as clinical outcome measures. PROs were measured with the Functional Assessment of Cancer Therapy-Breast + Lymphedema. The relationships between the AE trajectory and early treatment discontinuation as well as PROs were analyzed. RESULTS: More than half of all AEs (57.5%) were low-grade. A cluster of patients with broad and mixed AE (all-grade) trajectory grades was significantly associated with any-reason early treatment discontinuation (odds ratio [OR], 2.87; P = .01) as well as AE-related discontinuation (OR, 4.14; P = .001). This cluster had the highest count of all-grade AEs per cycle in comparison with other clusters. Another cluster of patients with primary neuropathic AEs in their trajectories had poorer physical well-being in comparison with a trajectory of no or few AEs (P < .01). A high-grade AE trajectory did not predict discontinuations. CONCLUSIONS: A sustained and cumulative burden of across-the-board toxicities, which were not necessarily all recognized as high-grade AEs, contributed to early treatment discontinuation. Patients with neuropathic all-grade AEs may require additional attention for preventing deterioration in their physical well-being.

Importance of Low- and Moderate-Grade Adverse Events in Patients' Treatment Experience and Treatment Discontinuation: An Analysis of the E1912 Trial

“…Finally, we do not assess the differential impact of specific AE types on bother or discontinuation. Assessing such associations is complex and extends beyond the scope of our work, but future work could address this issue using methods such as that of Ip et al 21 In conclusion, these results, on the basis of a single trial, demonstrate the importance of collecting AE data across all grades, particularly symptomatic AEs. Ignoring low-and moderate-grade AEs may inhibit us from truly understanding patient burden in cancer trials and what drives them to discontinue treatment, particularly as regimens continue to shift toward targeted therapies with different toxicity profiles compared with conventional chemotherapy.…”

“…Finally, we do not assess the differential impact of specific AE types on bother or discontinuation. Assessing such associations is complex and extends beyond the scope of our work, but future work could address this issue using methods such as that of Ip et al 21…”

Reply to S. Zhang et al and S. Selukar

“…One option to could be adapting a cumulative toxicity score such as the Toxicity Index 4 to incorporate time. Another possible solution could be to use latent class models to define patient AE trajectory profiles (similar to those defined by Ip et al 5 ) that summarize patient AE burden in earlier cycles of treatment. While the scope of answering this question was beyond the scope of our original paper, it is a question we have given much thought to and is of high priority in our continued research on low- and moderate-grade AEs.…”