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Regional nodal irradiation yields marginal benefit for early-stage breast cancer
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Irradiation of the regional nodes marginally improved OS in patients with early-stage breast cancer who underwent mastectomy or breast-conserving surgery, according to study results.
Further, regional node irradiation significantly improved DFS and distant DFS and reduced breast cancer mortality, results also showed.
“Elective irradiation of the regional nodes remained widely used until the late 1980s, when it became less popular on the basis of an overview of older trials that showed no survival benefit, despite improvement in control of locoregional disease,” Philip M. Poortmans, MD, PhD, professor of radiation oncology at Radboud University Medical Center in Nijmegen, Netherlands, and colleagues wrote. “A renewed interest in the role of elective irradiation of the regional lymph nodes emerged after publication of results of studies that showed a favorable effect of postmastectomy radiation therapy and after improvement in techniques that led to less cardiac exposure.”
The analysis included 4,004 women (median age, 54 years; range, 19-75) with a centrally or medically located primary tumor — regardless of axillary involvement — or an externally located tumor with axillary involvement.
Poortmans and colleagues randomly assigned patients to undergo whole-breast or thoracic-wall irradiation alone (control group) or with regional nodal irradiation (nodal-irradiation group). The researchers defined regional nodal irradiation as internal mammary and medial supraclavicular lymph node irradiation.
OS served as the primary endpoint. Secondary endpoints included DFS, distant DFS and breast cancer mortality.
A majority of patients (76.1%) underwent breast-conserving surgery. Seventy-three percent of patients who underwent mastectomy received chest-wall irradiation, regardless of treatment group.
Ninety-nine percent of patients had node-positive disease and 66.3% of patients with node-negative disease received adjuvant systemic treatment.
Median follow-up was 10.9 years, during which 811 patients died.
A marginally greater proportion of patients who underwent regional nodal irradiation achieved 10-year OS compared with the control group (82.3% vs. 80.7%; HR = 0.87; 95% CI, 0.76-1).
However, significantly more patients who underwent regional nodal irradiation achieved 10-year DFS (72.1% vs. 69.1%; HR = 0.89; 95% CI, 0.8-1) and distant DFS (78% vs. 75%; HR = 0.86; 95% CI, 0.76-0.98). The rate for breast cancer-specific mortality also appeared significantly improved in the nodal irradiation arm (12.5% vs. 14.4%; HR = 0.82; 95% CI, 0.7-0.97).
The researchers observed increases in the rates for acute adverse events among patients undergoing regional nodal irradiation, including pulmonary fibrosis (4.4% vs. 1.7%; P < .001), cardiac fibrosis (1.2% vs. 0.6%) and cardiac disease (6.5% vs. 5.6%).
The incidence of other late adverse events or performance status did not differ between study arms. A similar number of second cancers occurred in both groups (191 vs. 222).
The researchers acknowledged that the inclusion of the medial supraclavicular nodes to regional nodal irradiation rendered it impossible to determine whether internal mammary irradiation or medial supraclavicular irradiation contributed more to treatment outcomes.
“We found that regional nodal irradiation was beneficial to women with early-stage breast cancer,” Poortmans and colleagues concluded. “Our data do not apply to patients with lateral node-negative cancers, which is the largest patient subgroup in industrialized countries. Post-treatment follow-up for a median of 20 years is ongoing.”
Identifying the patients who will benefit the most from regional nodal irradiation will be important to its efficacious future use, Harold J. Burstein, MD, PhD, senior physician at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, and Monica Morrow, MD, chief of breast service at Memorial Sloan Kettering Cancer Center, wrote in an accompanying editorial.
“At the extremes, there is relatively little controversy,” Burstein and Morrow wrote. “The dilemma resides among patients with one to three nodal metastases, particularly when such findings are associated with a small primary tumor (< 5 cm) and parallels the controversy over postmastectomy radiotherapy in this group. … We would consider regional nodal irradiation for patients with one to three lymph node metastases only when other adverse prognostic factors are present. These factors include an age under 50 years and tumor characteristics such as extensive lymphovascular invasion, a high histologic grade, and unfavorable molecular profile and large size.” - by Cameron Kelsall
Disclosure: Poortmans and Burstein reports no relevant financial disclosures. Morrow reports personal fees from Genomic Health outside the submitted work. Please see the full study for a list of all researchers’ relevant financial disclosures.
Perspective
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Shelly Bowers Hayes, MD
Poortmans and colleagues report the results of an EORTC randomized trial of 4,004 patients with stage I, II or III breast cancer with a centrally or medially located tumor irrespective of axillary nodal involvement, or an outer quadrant tumor with positive axillary nodes who underwent either mastectomy or lumpectomy and an axillary nodal dissection. Researchers randomly assigned patients to whole-breast or chest wall radiation with or without radiation to the internal mammary nodes and medial supraclavicular nodes. Radiation to the axilla was not routine given as this was felt to be adequately treated surgically. Patients received systemic therapy — either chemotherapy or endocrine therapy —depending upon their nodal status, grade and age.
This study shows that DFS at 10 years was improved when the internal mammary and medial supraclavicular nodes were radiated in addition to the breast (for breast conservation patients) or the chest wall (for mastectomy patients). In addition, the 10-year distant DFS was improved in the nodal irradiation group (78% vs. 75%) and the rate of any first recurrence of breast cancer at 10 years was lower in the regional node irradiation group (19.4% vs. 22.9%). OS was not statistically significant between the groups, however, it approached significance (82.3% vs. 80.7%, P = .06). The number-needed-to-treat to avoid one relapse of breast cancer was 30. There was a low rate of radiation-related complications, including a low rate of heart disease and death from heart disease.
There have been other studies, including two meta-analyses from the Early Breast Cancer Trialists' Collaborative Group, studying the effects of regional nodal irradiation. The first one showed that in patients with involved axillary nodes after mastectomy, locoregional irradiation was associated with significantly lower rates of regional and overall recurrences and death from breast cancer. The second study by the same group showed a similar benefit to regional nodal irradiation after breast-conserving surgery.
This study corroborates the findings of the two above-mentioned meta-analyses and — like the MA.20 study by Whelan and colleagues published in this issue of The New England Journal of Medicine — provides further evidence that comprehensive regional nodal irradiation improves breast-cancer specific survival.
References:
Early Breast Cancer Trialists’ Collaborative Group. Lancet. 2011;doi:10.1016/S0140-6736(11)61629-2.
Early Breast Cancer Trialists’ Collaborative Group. Lancet. 2014;doi:10.1016/S0140-6736(14)60488-8.
Whelan TJ, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1415340.
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