Greater Adverse Effect Bother Associated With Early Treatment Discontinuation

A recent Cancer study found that patients with cancer who reported greater bother from adverse events (AE) were more likely to discontinue treatment early due to AEs, supporting the use of the patient report as a valuable measure of treatment tolerability.¹

The objective of the study was to determine how well adverse effect bother, captured by the Functional Assessment of Cancer Treatment item GP5, indicates treatment tolerability. Item GP5 prompts patients to respond to the statement, “I am bothered by side effects of treatment,” with response options on a numeric scale ranging from 0 (“not at all” to 4 (“very much”).

Investigators used logistic regression models to estimate odds of early treatment discontinuation (ETD) due to AEs based on GP5 responses of patients with various cancers from across 4 clinical studies. Separate models were created for each trial and GP5 responses at baseline, 3 months, and 6 months.

These models yielded consistently significant associations between GP5 response and ETD, especially early in the treatment course (3 months), with positive odds ratios (ORs) (range, 2.59–6.77) and 95% confidence intervals (CIs) not crossing 1 for all associations. Notably, the largest associations were observed among patients with melanoma, with an unadjusted OR of 6.74 (95% CI, 2.91–15.64) and adjusted OR of 6.77 (95% CI, 2.88–15.92).

These observed associations are in line with findings from a previous analysis of patients with multiple myeloma, where post-baseline GP5 was associated with 2.0 to 4.5 times greater odds of ETD due to AEs.² These latest findings now expand the generalizability of this pattern to a wider range of tumor types.

“The consistent association between GP5 responses and ETD suggests the GP5’s ability to capture how well patients tolerate treatment, especially when [adverse] effect bother is observed early in the course of treatment, and signals an opportunity to develop interventions to promote treatment adherence,” wrote Peipert et al, study authors.¹

Of note, these associations weakened over time as evidenced by the generally lower 6-month ORs (range, 1.62–3.73) and most 95% CIs exceeding 1. The authors commented on this finding, hypothesizing that patients who stayed on treatment to the 6-month mark may have developed better tolerability for adverse effects compared with those who discontinued by 3 months. “The current analyses were not able to answer these questions, and they should be the subject of future analyses,” they urged.¹

Importantly, given the heterogeneity of ORs observed across trials, these findings underscore the potential utility of the GP5 item in future cancer clinical trials as an indicator of tolerability.

“The growing movement to assess tolerability from the patient’s perspective within cancer trials has pointed to the need for end points around overall [adverse] effect impact,” the authors noted.¹ “These results also help inform implementation of the GP5 item in future trials by demonstrating differences in results, depending on how the GP5 is operationalized.”

Patient Datasets and Treatment Regimens

Datasets were derived from 4 clinical studies coordinated by the ECOG-ACRIN Cancer Research Group, evaluating treatments for breast cancer, melanoma, and chronic lymphocytic leukemia (CLL).

Patients from 2 observational breast cancer studies were included: E1Z11 (NCT01824836) and E1Z03 (NCT00090974). E1Z11 was a cohort study that examined genetic predictors of aromatase inhibitor musculoskeletal symptoms among postmenopausal patients with stage I–III, hormone receptor-positive, early breast cancer who were treated with aromatase inhibitor therapy. Here, 1046 patients received anastrozole (Arimidex) for 12 months. In E1Z03, 1253 patients with receptor-positive primary breast cancer were examined for AEs related to anastrozole or exemestane (Aromasin) treatment for up to 5 years.

Data for patients with melanoma were drawn from the phase 3 E1609 trial (NCT01274338), which evaluated the efficacy and safety of adjuvant ipilimumab (Yervoy) at 3- and 10-mg/kg doses against high-dose interferon alfa-2b. Here, 1673 adult patients with resected, high-risk, stage III–IV melanoma were randomized to a regimen of either 4 doses of ipilimumab every 3 weeks as induction therapy followed by up to 4 more doses every 12 weeks, or 5 days of interferon alfa-2b for 4 weeks followed by administration every other day, 3 weeks apart, for up to 48 weeks.

Lastly, the phase 3 E1912 trial (NCT02048813) enrolled 529 patients with previously untreated CLL or small lymphocytic lymphoma. Upon randomization, patients received either ibrutinib (Imbruvica) plus rituximab (Rituxan) or a standard chemoimmunotherapy regimen.

All patients for whom GP5 response data were available were included for analyses.

REFERENCES

1. Peipert JD, Ganatra S, Zhao F, et al. Overall side‐effect bother consistently associated with early treatment discontinuation due to adverse events in four clinical trials with various cancer types and treatments. Cancer. 2025;131(S2). doi:10.1002/cncr.70084

2. Peipert JD, Zhao F, Lee JW, et al. Patient-reported adverse events and early treatment discontinuation among patients with multiple myeloma. JAMA Netw Open. 2024; 7(3):e243854. doi:10.1001/jamanetworkopen.2024.3854