In a prespecified secondary analysis of the HOPE study which enroled more than 300 patients of age 65 years and older with early breast cancer (EBC) treated with standard-of-care neoadjuvant/adjuvant chemotherapy, one in five patients received low relative dose intensity. Factors associated with low relative dose intensity were age, performance status, and treatment regimens, specifically use of anthracyclines or CMF. Older patients with low relative dose intensity had higher mortality than patients who received at least 85% relative dose intensity. However, there were no enough cause-specific events to determine whether this increased mortality was due to breast cancer or other causes. The findings are reported by Dr. Mina S. Sedrak of the City of Hope Comprehensive Cancer Center in Duarte, CA, US and colleagues on 1 December 2022 in the Journal of Clinical Oncology.
Patients with high-risk EBC benefit from adjuvant chemotherapy, irrespective of age. Compared with younger and healthier patients, older and more frail patients with EBC experience increased side effects from chemotherapy, resulting in dose reductions and treatment delays. Patients with EBC who require dose reductions and treatment delays are more likely to experience disease recurrence and death than patients who complete their full chemotherapy dose on time. Chronological age is a well-established risk factor for low (< 85%) relative dose intensity. However, the incidence, risk factors, and outcomes of low relative dose intensity in older patients with EBC have been inconsistent and are limited to retrospective analyses.
The HOPE investigators leveraged a multicentre prospective study of older patients (age ≥ 65 years) with EBC treated with current standard neoadjuvant/adjuvant chemotherapy to evaluate the incidence of low relative dose intensity, risk factors associated with low relative dose intensity, and relationship between low relative dose intensity and overall survival (OS) as well as breast cancer–specific (BCS) and non–breast cancer-related mortality.
Relative dose intensity was calculated as the ratio of delivered to planned chemotherapy dose intensity. The primary outcome was low relative dose intensity, defined as relative dose intensity < 85%. Multivariable logistic regression with stepwise selection was used to evaluate the association between baseline variables (demographic, clinical, and geriatric assessment) and low relative dose intensity. Survival probability was estimated using the Kaplan-Meier method, and the log-rank test was used to compare OS.
In total, 322 patients with median age of 70 years at diagnosis (range, 65-86 years) were included. The median follow-up was 4 years. Low relative dose intensity was recorded in 62 patients (21%). Age ≥ 76 years (odds ratio [OR] 2.57; 95% confidence interval [CI] 1.12 to 5.91; p = 0.03), lower performance status (OR 4.32; 95% CI 1.98 to 9.42; p < 0.001), and use of anthracycline-based or CMF regimens (OR 3.47; 95% CI 1.71 to 7.05; p < 0.001) were associated with low relative dose intensity. The 5-year OS probability was 0.80 versus 0.91 in patients with relative dose intensity < 85 versus ≥ 85% (log-rank p = 0.02).
The authors commented that observed non-significant increase in the hazard ratio for both BCS and non–breast cancer-related mortality among patients with low relative dose intensity cannot be used to draw practice-changing conclusions. They realized the importance of this distinction as it answers the question of whether patients had inferior survival because they did not derive the full benefit of treatment or if the side effects associated with low relative dose intensity led to persistent decline and early mortality. To address this question, they plan to extend follow-up and collect long-term OS and cause-specific survival data.
Clinicians often have a lower threshold to reduce chemotherapy dose intensity in older patients to reduce the risk of serious side effects. This study informs clinical practice by highlighting the importance of preserving dose intensity in older patients with breast cancer. Furthermore, older patients at risk of receiving low relative dose intensity may be identified and targeted upfront before initiating chemotherapy. The authors underlined that understanding which patients are at risk of receiving suboptimal relative dose intensity may inform treatment discussions and guide early, targeted supportive care or geriatric co-management interventions.
The findings were previously presented at the 42nd San Antonio Breast Cancer Symposium in San Antonio, TX, US (10-14 December 2019).
The study was supported by the US National Institute on Aging, the Breast Cancer Research Foundation, the Center for Cancer and Aging at City of Hope (COH), the COH Cancer Control and Population Sciences Pilot Award, and the Waisman Innovation Award. Support also came from the US National Cancer Institute, American Cancer Society, and Susan G. Komen for the Cure.
Sedrak MS, Sun C-L, Ji J, et al. Low-Intensity Adjuvant Chemotherapy for Breast Cancer in Older Women: Results From the Prospective Multicenter HOPE Trial. JCO; Published online 1 December 2022. DOI: 10.1200/JCO.22.01440