Breast Cancer: RNI Prolongs Disease-free Survival for Women with One to Three Involved Nodes
The therapeutic benefits of adding regional node irradiation (RNI) to breast-conserving surgery plus whole breast irradiation (WBI) and chemotherapy outweigh the additional toxicities for women with early breast cancer (Abstract LBA1003). Timothy Whelan, BM, BCh, MSc, of the Juravinski Cancer Centre at Hamilton Health Sciences, Canada, presented data from the National Cancer Institute of Canada Clinical Trials Group protocol MA.20 on behalf of his colleagues during the Breast Cancer — Triplenegative/Cytotoxics/Local Therapy Oral Abstract Session yesterday.
The goal of this Intergroup study was to establish the role of chest wall and regional node irradiation for women with one to three positive axillary lymph nodes. Women with highrisk, node-negative breast cancer were also eligible. All patients with node-positive disease were treated with level one and two axillary dissection, adjuvant chemotherapy, and/or endocrine therapy. The patients were stratified by number of axillary nodes removed, number of positive nodes, and type of adjuvant therapy, and were then randomly assigned to WBI (916 women) or WBI plus RNI to the internal mammary, supraclavicular, and apical axillary lymph nodes (916 women).
A protocol-specified interim analysis of the primary endpoint, which was overall survival, was undertaken at 5 years. Because the death rate was low, the analysis was expanded to include relapse patterns, distant disease-free survival, and toxicity. The efficacy analysis was performed on an intention- to-treat basis and the safety analysis was based on actual treatment. Median follow-up was 62 months. The addition of RNI to WBI alone had a positive outcome on a number of secondary endpoints.
Disease-free survival was improved (hazard ratio [HR]: 0.67; 95% CI [0.52, 0.87]; p = 0.003, stratified; 5-year risk: 89.7% and 84.0%, respectively).
Isolated locoregional disease-free survival was prolonged (HR: 0.58, 95% CI [0.37, 0.92]; p = 0.02, stratified; 5-year risk: 96.8% and 94.5%, respectively).
Distant disease-free survival was extended (HR: 0.64; 95% CI [0.47, 0.85]; p = 0.002, stratified; 5-year risk: 92.4% and 87.0% respectively).
A trend toward improved overall survival was observed (HR: 0.76; 95% CI [0.56, 1.03]; p = 0.07, stratified; 5-year risk: 92.3% and 90.7% respectively). The survival curves began to diverge at about 18 months of follow up.
The addition of RNI to WBI alone was associated with a significant increase in adverse events, mostly of grade 2 severity. Acute adverse effects included pneumonitis (1.3% and 0.2%, respectively, p = 0.01) and radiation dermatitis (50% and 40%, respectively, p < 0.001); delayed lymphedema was observed in 7% and 4% of the patients, respectively (p = 0.004). Patient-rated adverse cosmetic outcome increased over time in both treatment groups; at 5 years the difference between the RNI group (36%) and the WBI-alone group (29%) reached significance (p = 0.047).
In closing, Dr. Whelan stated that the results warrant offering RNI to all women with nodepositive disease. Thomas A. Buchholz, MD, of the University of Texas M. D. Anderson Cancer Center, agreed in his opening comments that the results of MA.20 have major clinical implications and are most certainly practice changing, emphasizing that the benefits of RNI are additional to those already established for WBI plus adjuvant chemotherapy.
Dr. Buchholz characterized the effect of RNI on distant metastases as surprising, but suggestive that RNI will improve overall survival with further follow up and, therefore, the benefits of adding RNI to standard therapy clearly outweigh the risks. Other clinical implications to be considered are that RNI may exclude patients from receiving hypofractional radiotherapy and complicate postmastectomy reconstructive options. Another obvious implication is that more patients will be receiving treatment.
Dr. Buchholz acknowledged the value of RNI, but deemed that the population of "all women with one to three positive nodes" is a heterogeneous group with different risks for relapse, so accrual of additional data to facilitate subanalyses, especially of the group of patients who have low risk for residual regional disease, is necessary before RNI should be made a general recommendation.