The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) continues to provide valuable clinically relevant and practice-influencing information garnered from individual patient-level data from numerous randomized trials in breast cancer. The large numbers of patients and long-term follow-up in this database provide a unique opportunity to determine small but clinically meaningful differences in outcomes between the treatment arms, which the smaller individual trials may be underpowered to detect. Over the years, due to the very long-term, detailed follow-up, sophisticated statistical methods, and meticulous processing of individual patient-level data from randomized trials, the EBCTCG has not only demonstrated improvements in outcomes associated with radiation therapy,^1,2 but also has uncovered subtle but clinically important toxicities, including heart disease and second malignancies, associated with radiation.

Continuing Controversy

The benefits of postmastectomy radiotherapy in reducing local-regional relapse rates and improving breast cancer mortality for node-positive breast cancer patients has been clearly demonstrated in individual randomized trials, as well as in previous meta-analysis. While the benefits of postmastectomy radiation in patients with more advanced disease and/or at least four involved nodes has been widely embraced and accepted as the standard of care, the routine use of postmastectomy radiotherapy in patients with one to three involved nodes continues to be controversial. A previous effort by the Radiation Therapy Oncology Group evaluating postmastectomy radiation in patients specifically with one to three positive nodes closed due to poor accrual, though ongoing trials continue to address this issue.

Advocates of postmastectomy radiation point to the local-regional control and breast cancer mortality rates demonstrated in several randomized trials. However, others argue that local-regional relapse rates with earlier detection, current surgical approaches, and more detailed pathologic processing—and with more powerful and effective systemic therapies—are currently much lower. These authors question the risk/benefit ratio, given the potential toxicities of postmastectomy radiation.

The disagreement has resulted in wide variations in the application of postmastectomy radiotherapy for one to three positive nodes, continued debate, and, most important, confusion among patients and referring physicians regarding the benefit of postmastectomy radiotherapy in this group at mastectomy. Appropriately, the majority of clinicians selectively use postmastectomy radiation based on a number of clinical factors, including patient age and comorbidities, primary tumor size, receptor status, lymphovascular space invasion, grade, and other factors.

Valuable Update

The current EBCTCG updated meta-analysis,³ reported in Lancet and reviewed in this issue of The ASCO Post, focuses on patients with one to three positive nodes and provides valuable information regarding the risk/benefit ratio of postmastectomy radiotherapy. The investigators clearly demonstrate a statistically significant and clinically meaningful impact of postmastectomy radiation on local-regional relapse, overall recurrence, and breast cancer mortality in patients with one to three nodes.

While some of the trials included in the meta-analysis were older and in the pre–systemic therapy era, the study did involve more than 1,000 women in trials where systemic therapy was administered to both the radiotherapy and no-radiotherapy groups, in which radiotherapy was associated with a significantly reduced risk in local-regional recurrence, overall recurrence, and breast cancer mortality (41.5% vs 49.4%, rate ratio = 0.78, 2P = .01). Furthermore, there was no difference in the proportional reduction in breast cancer mortality associated with postmastectomy radiation based on whether there were one, two, or three nodes involved. Therefore, it appears that even patients with one involved node derived a significant benefit from postmastectomy radiation.

Current Considerations

Although the reductions in local-regional relapse and breast cancer mortality are impressive, patients in the meta-analysis with one to three nodes randomly assigned to no postmastectomy radiation had relatively high rates of local-regional recurrence (21%) and overall recurrence (45%) compared to current reports. Given earlier detection of disease, improvements in surgical approaches, more detailed pathologic processing with serial sectioning (which often detects nodal micrometastasis), and more effective systemic therapy reported in more contemporary series, the absolute reduction in both local-regional recurrence and breast cancer mortality associated with postmastectomy radiation in patients with one to three involved nodes would be expected to be less in the current era than that reported in this meta-analysis.

On the other hand, improvements in radiation therapy techniques with computed tomography–based planning, lower doses to the nontarget cardiac and pulmonary structures, and more accuracy and precision in delivering radiation to the target chest wall and regional lymphatics are likely to improve the radiation treatment effect, reduce potential toxicities, and improve the therapeutic gain.

Therefore, while the absolute reduction in local-regional relapse rates associated with postmastectomy radiation in patients with one to three positive nodes is likely to be smaller than that reported in the meta-analysis, the relative benefit and risk/benefit ratio of postmastectomy radiation is likely to persist for the majority of patients with one to three involved nodes.

The findings of the EBCTCG meta-analysis are also consistent with recent reports from the Canadian MA.20 trial⁴ and the European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial.⁵ Patients with one to three involved lymph nodes, predominantly treated with breast-conserving surgery, constituted a majority of patients in these trials, in which patients were randomly assigned to radiation directed to the breast/chest wall alone or radiation delivered to the breast/chest wall and regional lymphatics.

Both of these trials also demonstrated reduced distant metastasis and reduced breast cancer mortality in addition to improved local-regional relapse in the cohorts of patients randomized to regional nodal irradiation. The full publications of the MA.20 and EORTC trials in the near future will hopefully provide clinicians with further insight and details regarding the benefits of regional nodal irradiation in these
patients.

Practical Implications

As with the valuable previous efforts of the EBCTCG, this recent analysis demonstrating breast cancer mortality benefit with postmastectomy radiation in patients with one to three positive nodes is likely to have a significant impact on clinical practice. Appropriately, clinicians and patients are still likely to be selective in the use of postmastectomy radiation, utilizing the full spectrum of available clinical data and literature, including age, comorbidities, histology, grade, receptor status, primary tumor size, extent of nodal involvement, and other factors in the ultimate decision of whether to use postmastectomy radiation in patients with low nodal burdens.

The currently available randomized data, however, provide a high level of evidence that postmastectomy radiation is associated with a clinically significant benefit in the majority of patients with positive nodes, including patients with one to three involved nodes. Given these data, it is important to consider and discuss the potential benefits of postmastectomy radiation with all patients who have node-positive disease. ■

Dr. Haffty is Professor and Chair, Department of Radiation Oncology, Rutgers-Cancer Institute of New Jersey, Robert Wood Johnson Medical School and New Jersey Medical School, New Brunswick.

Disclosure: Dr. Haffty reported no potential conflicts of interest.

References

1. 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.

2. Early Breast Cancer Trialists’ Collaborative Group: 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.

3. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group): 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. March 19, 2014 (early release online).

4. Whelan TJ, Olivotto I, Ackerman I, et al: NCIC-CTG MA.20. An Intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol 29(suppl):Abstract LBA1003, 2011.

5. Poortmans PSH, Kirkove C, Budach V, et al: Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast cancer: 10 years results of the EORTC radiation oncology and breast cancer groups phase III trial 22922/10925. Eur J Cancer 47(suppl 2), 2013.