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.

Trial registration: ClinicalTrials.gov NCT00433511.

Keywords: adverse events; breast cancer; drug treatment; early treatment discontinuation; patient-reported outcome; peripheral neuropathy.

© 2021 American Cancer Society.

Figures

Figure 1.

(A) Randomization for the original sample and (B) selection for the subsample for ECOG-ACRIN E5103. AC indicates intravenous doxorubicin and cyclophosphamide; B, bevacizumab; BAC, bevacizumab concurrent with intravenous doxorubicin and cyclophosphamide; BT, bevacizumab concurrent with paclitaxel; T, paclitaxel.

Figure 2.

(A) Profiles of the AE states. Each bar indicates the probability of having the specific AE and grade (1–2 = low; 3–4 = high). (B) Prevalence of AE states over 8 cycles. The order for the states from top to bottom is as follows: Low 2, Low 1, Neuropathic, Cardiac, and Mixed Reactions. AE indicates adverse event; breath, breathing-related; GI, gastrointestinal; hemor, hemorrhage; metabol, metabolic; neuro, neuropathic; reaction, reaction-related.

Figure 3.

Percentages of treatment intolerability outcomes by AE trajectory groups. The 4 clusters of bar graphs from left to right indicate the incidence rate of AEs per cycle, drug modification in any cycle, early treatment discontinuation due to any reason, and discontinuation due to an AE. **P < .01, and ***P < .001 for all pairwise comparisons with the Low AE Traj group. AE indicates adverse event; Discont, discontinuation.

Figure 4.

Schematic diagram summarizing significant relationships between bevacizumab exposure, the AE trajectory group, clinical outcomes, and patient-reported outcomes. The thickest arrow indicates P < .001, medium arrows indicate P < .01, and thin arrows indicate P < .05. For Cardiac Traj group → physical well-being domain, P = .054. AE indicates adverse event; Cardiac, Cardiac Traj group; Neuro, Neuro Traj group; Mixed Reactions, Mixed Reactions Traj group, Low AE, Low AE Traj group.