Numerous BC treatment guidelines are available from the U.S. and Europe. However, these guidelines often lack direct quantitative estimates of the risk of adjuvant or neoadjuvant chemotherapy and radiation on mortality. Investigators conducted a systematic review of BC guidelines focusing on the relative risk of different treatments that can contribute to BC–related or non-BC–related mortality.
The highest-ranking evidence on the effects of adjuvant and neoadjuvant chemotherapy regimens and radiation on mortality was identified. Guidelines were included if their purpose, scope, methodology, and conflict of interest policy were clearly stated; if they were available open access; and if they were published in English between 2016 and 2021. Databases were searched for meta-analyses on adjuvant or neoadjuvant treatment and radiotherapy for stages I, IIA, IIB, and IIA BC.
Studies were eligible for inclusion if they compared the treatment effects on BC or non-BC mortality, had a median of a 3-year follow-up, and were published from 2008 onwards. Studies were excluded if they were not randomized, involved patients with metastatic disease or other cancer types, or were conference abstracts. If more than one eligible meta-analysis was identified for a particular stage/treatment, the strongest evidence for each treatment option was chosen.
Meta-analyses that contained individual patient data and all relevant randomized trials, both published and unpublished, were given the highest consideration, while meta-analyses that did not include individual patient data and were missing some relevant randomized trials were rated the lowest. The rate ratio (RR), which refers to the rate at which a particular endpoint occurs in patients allocated to one specific treatment option divided by the corresponding rate in patients allocated to a different treatment option, but for whom all other aspects of care are identical, was utilized in this study.
For each selected meta-analysis (or clinical trial if a high-quality meta-analysis was not available), RRs were examined for BC and non–BC mortality and individual causes of death. For chemotherapy, anti-HER2 therapy, endocrine therapy, and bisphosphonates, RRs were extracted for standard dose regimens recommended in the guidelines. Dose-response relationships were examined for radiation therapy and its role on mortality based on effects of relevant organs that would be affected by this treatment modality.
The BC guidelines that were included in the study were the National Comprehensive Cancer Network, American Society of Clinical Oncology/American Society of Radiation Oncology, European Society of Medical Oncology, St. Gallen International Consensus Guidelines, and the National Institute for Health and Care Excellence.
The following chemotherapeutic regimens were associated with a statistically significant beneficial effect on BC mortality: anthracyclines versus no chemotherapy for all women followed for 10 years (RR = 0.79); taxane-anthracycline versus anthracycline alone in all women followed to 8 years (RR = 0.86); trastuzumab versus no trastuzumab in HER2+ BC followed to 10 years (RR = 0.67); 5 years of tamoxifen versus no tamoxifen in women of any age followed for 15 years (RR = 0.70); extended tamoxifen >10 years versus 5 years followed for 5 or more years in women of any age (RR = 0.88); aromatase inhibitor versus tamoxifen for 5 years followed for 10 years in postmenopausal women (RR = 0.85); and tamoxifen switching to an aromatase inhibitor versus staying on tamoxifen for 5 years in postmenopausal women followed for 8 years (RR = 0.84). RR were not reported for other chemotherapeutic regimens nor was their effect on mortality.
A statistically significant benefit on BC mortality was also seen for bisphosphonates versus no bisphosphonates followed for 10 years in postmenopausal women (RR = 0.82). Whole breast radiation versus no radiation after breast conserving surgery followed for 15 years (RR = 0.82), chest wall and regional node radiation versus no radiation after mastectomy or lymph node dissection in node positive disease followed for 20 years (RR = 0.84), and regional node radiation versus no radiation for any surgery, target, or node in BC followed for 15 years (RR = 0.81).
Switching to an aromatase inhibitor from tamoxifen for 5 years in postmenopausal women followed for 8 years was associated with a significantly reduced risk of non–BC mortality (RR = 0.79). On the other hand, radiation following any surgery, target or node versus no radiation was associated with a significantly increased RR for non–BC mortality (RR = 1.15). Anthracycline use was associated with a significantly increased risk of developing acute myeloid leukemia (P = .004) and a trend toward an increased risk of heart disease (RR = 1.61, CI 1.00-2.22) The risk of leukemia associated with taxane therapy was significantly increased (RR = 11.0), but the risk of leukemia was rare overall.
The causes of non–BC mortality that were significantly associated with radiation therapy included heart disease (RR = 1.30), lung cancer (RR = 1.64), esophageal cancer (RR = 2.51), and thromboembolism (RR = 2.10).
This article provides pharmacists with useful information in assessing the risk versus benefit on BC and non–BC mortality for different treatment modalities found in clinical practice guidelines.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
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