Radiation therapy clearly decreases local tumor recurrence, but its effect on overall survival and which patients may benefit remain unclear. Comprehensive nodal irradiation is not for all node-positive patients.
—Alice Chung, MD, and Armando E. Giuliano, MD
Management of the regional nodes in breast cancer has evolved from the era of the extended radical mastectomy to exclusion of axillary dissection in appropriately selected patients. Throughout this evolution, studies of nodal irradiation have been shown to improve locoregional control, usually without a clear impact on overall survival. Concerns regarding toxicity and a possible lack of survival benefit resulted in the selective use of nodal irradiation only for the highest risk patients.
With improvements in radiation techniques that minimize radiation exposure to vital structures and publication of studies and a meta-analysis suggesting a survival benefit from postmastectomy nodal irradiation,1 the potential utility of nodal irradiation in a more moderate-risk population has been proposed, even for women treated with breast-conserving therapy.
As summarized in this issue of The ASCO Post, the National Cancer Institute of Canada Clinical Trials Group MA.20 clinical trial, reported by Whelan and colleagues, was a randomized study that evaluated irradiation of the ipsilateral internal mammary, supraclavicular, and axillary nodes in N1 or high-risk node-negative patients treated with breast-conserving surgery.2 The European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial, reported by Poortmans and colleagues, evaluated the role of internal mammary and medial supraclavicular nodal irradiation in women with centrally or medially located tumors regardless of nodal involvement and externally located tumors with nodal disease. Most patients had fewer than three involved nodes.3
Both trials had follow-up of approximately 10 years and demonstrated significant reductions in local and distant recurrences. Disease-free survival was reduced by nodal irradiation from 82% to 77% in the MA.20 trial and from 72% to 69% in the EORTC trial. The isolated regional recurrence rate in the MA.20 study was reduced from 2.5% in the whole-breast irradiation arm to 0.5% in the nodal-irradiation arm. The MA.20 trial did not show an improvement in overall survival with the addition of nodal irradiation, whereas the EORTC trial showed a minimal survival benefit (1.6%) from internal mammary/supraclavicular nodal irradiation.
Toxicity in the MA.20 trial included higher rates of grade ≥ 2 acute pneumonitis and lymphedema in the nodal-irradiation group. In the EORTC trial, there was a 3% rate of pulmonary fibrosis and a 1% occurrence of cardiac fibrosis—only in patients treated with internal mammary/supraclavicular nodal irradiation.
Are Results Practice Changing?
The results of these trials confirm that nodal irradiation in the moderate-risk population indeed reduces recurrence, but the very modest survival benefit demonstrated in the EORTC trial may not be enough to change clinical practice. The purpose of nodal irradiation is to reduce nodal recurrence. However, the difference in regional recurrence between the two arms in the MA.20 trial was only 2%, which is unlikely to lead to a significant improvement in survival. Regional recurrence rates were not reported in the EORTC trial.
One may argue that reduction in recurrence should eventually translate into reduction in mortality. The Early Breast Cancer Trialists’ Collaborative Group’s meta-analysis of radiotherapy after breast-conserving surgery showed that one breast cancer death in 15 years could be avoided for every four recurrences that were avoided in 10 years.4 However, the reduction in breast cancer mortality observed in the meta-analysis was significant only when the absolute reduction in recurrence was greater than 10%.5 This recurrence rate is markedly greater than the recurrence reduction seen in the MA.20 or EORTC trial; therefore, the results of the meta-analysis may not be applicable to these trials. In addition, medical management of breast cancer has changed since the inception of these trials, and it is possible that the rates of recurrence with modern-day systemic therapy would be even lower than those reported in the trials.
Further Risk Stratification Needed
Treatment recommendations in this group of patients remain a challenge, as there is a need for further risk stratification. Clearly, not all patients with one to three positive nodes or node-negative medial tumors will benefit from comprehensive nodal irradiation.
The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial showed no survival advantage with surgical treatment of the regional nodes in sentinel node–positive patients treated with breast-conserving surgery.6 This trial led to a marked reduction in the treatment of axillary nodes in low-risk node-positive patients. Although patients in the ACOSOG Z0011 trial had less nodal burden of disease than those in the MA.20 or EORTC trial, the ACOSOG Z0011 study clearly showed that some women with nodal metastases do not require nodal-specific therapy.
Certain Subgroups May Benefit
The MA.20 and EORTC trials evaluated a higher-risk population and demonstrated a significant reduction in recurrences with comprehensive nodal radiation, but the survival benefit was marginal. However, within this population, there may be certain subgroups that benefit from nodal irradiation. Subgroup analyses in the MA.20 trial showed that the treatment effect of nodal irradiation was greater in patients with estrogen receptor–negative or progesterone receptor–negative tumors, but the subgroup analyses were not adequately powered.
A series of retrospective studies have identified certain high-risk features among patients with T1-2,N1 tumors who have undergone mastectomy, including young age, tumor size > 2 cm, high grade, > 25% of excised nodes involved with metastases, medial tumor location, estrogen receptor–negative status, lymphovascular invasion, and no use of systemic therapy.7-11 In the future, we must rely on patient and tumor characteristics to identify which patients within this population may be both at increased risk for recurrence and may benefit from more-extensive nodal therapy. More radiation is not likely to improve survival in patients with subclinical metastases at the time of initial treatment.
The trials by Whelan et al. and Poortmans et al. address important questions in a challenging and common clinical scenario. As the landscape of oncologic care continues to evolve, selection of patients and individualized treatment will continue to shift toward more of a basis in tumor biology and genomics, leading to enhancement in strategies for risk stratification. Radiation therapy clearly decreases local tumor recurrence, but its effect on overall survival and which patients may benefit remain unclear. Comprehensive nodal irradiation is not for all node-positive patients. ■
Disclosure: Drs. Chung and Giuliano reported no potential conflicts of interest.
1. McGale P, Taylor C, Correa C, et al: Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 383:2127-2135, 2014.
2. Whelan TJ, Olivotto IA, Parulekar WR, et al: Regional nodal irradiation in early-stage breast cancer. N Engl J Med 373:307-316, 2015.
3. Poortmans PM, Collette S, Kirkove C, et al: Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med 373:317-327, 2015.
4. Darby S, McGale P, Correa C, et al: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011.
5. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005.
6. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA 305:569-575, 2011.
7. Abi-Raad R, Boutrus R, Wang R, et al: Patterns and risk factors of locoregional recurrence in T1-T2 node negative breast cancer patients treated with mastectomy: Implications for postmastectomy radiotherapy. Int J Radiat Oncol Biol Phys 81:e151-e157, 2011.
8. Macdonald SM, Abi-Raad RF, Alm El-Din MA, et al: Chest wall radiotherapy: Middle ground for treatment of patients with one to three positive lymph nodes after mastectomy. Int J Radiat Oncol Biol Phys 75:1297-1303, 2009.
9. Truong PT, Olivotto IA, Kader HA, et al: Selecting breast cancer patients with T1-T2 tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 61:1337-1347, 2005.
10. Truong PT, Lesperance M, Culhaci A, et al: Patient subsets with T1-T2, node-negative breast cancer at high locoregional recurrence risk after mastectomy. Int J Radiat Oncol Biol Phys 62:175-182, 2005.
11. Sharma R, Bedrosian I, Lucci A, et al: Present-day locoregional control in patients with t1 or t2 breast cancer with 0 and 1 to 3 positive lymph nodes after mastectomy without radiotherapy. Ann Surg Oncol 17:2899-2908, 2010.
Dr. Chung is Assistant Professor of Surgery, Division of Surgical Oncology, Cedars-Sinai Medical Center, Los Angeles, California, and Dr. Giuliano is Professor of Surgery, Executive Vice Chair, Surgery, Associate Director, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center.
Two phase III trials recently reported in The New England Journal of Medicine indicated that the addition of regional nodal irradiation was associated with no or marginal overall survival benefit but significantly improved disease-free survival in patients with early-stage breast cancer.1,2