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Nodal irradiation improved breast cancer disease-free but not overall survival

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In the modern era, nodal irradiation is necessary only for select patients.

Although the MA.20 and EORTC trials showed that regional nodal irradiation was generally well tolerated, greater risks of lymphedema, pneumonitis, and cutaneous reactions were observed.

In spite of these concerns, the MA.20 and EORTC trials indicate that some patients benefit from comprehensive nodal irradiation after axillary dissection. Treatment selection for the individual patient is the key issue. At the extremes, there is relatively little controversy. There is no rationale for nodal irradiation in patients with negative axillary nodes because nodal recurrence rates after negative results on sentinel-node biopsy are less than 1%, and isolated internal mammary metastases are very uncommon, even in patients with medial tumors. Conversely, a heavy tumor burden, as shown by metastases to four or more lymph nodes or extracapsular extension beyond the lymph nodes, is a strong predictor of increased risk, suggesting the need for nodal irradiation. 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. Postmastectomy radiotherapy has been shown to improve survival for women with one to three affected axillary lymph nodes but only in the context of a 5-year local-regional recurrence rate of 17%, far in excess of current rates. With the use of clinicopathologic characteristics to selectively offer postmastectomy radiotherapy, 5-year local-regional recurrence rates of 3%-4% without radiotherapy are observed, and the majority of women are able to avoid radiotherapy. By extrapolation, 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, an unfavorable molecular profile, and large size.

Dr. Harold J. Burstein is with Dana-Farber Cancer Institute, Brigham & Women’s Hospital, and Harvard Medical School, Boston, and Dr. Monica Morrow is with Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York. These remarks were excerpted from an accompanying editorial (N. Engl. J. Med. 2015 Jul 23 [doi:10.1056/NEJMe1503608]).


 

FROM NEW ENGLAND JOURNAL OF MEDICINE

References

Regional nodal irradiation added to whole-breast or thoracic wall irradiation in an unselected patient population reduces breast cancer recurrence rates and improves disease-free and distant disease-free survival, but has little or no effect on overall survival, results of two large, long-term, randomized clinical trials show.

In the MA.20 trial, there was no significant difference in overall survival at 10-year follow-up between women with early breast cancer treated with breast-conserving surgery, adjuvant systemic therapy, and whole-breast irradiation with or without regional nodal irradiation.

Women who received nodal irradiation had significantly better disease-free survival, but at the cost of higher rates of pneumonitis and lymphedema, report Dr. Timothy J. Whelan from the Juravinski Cancer Centre at Hamilton Health Sciences in Hamilton, Ont., and his colleagues in the July 23 issue of the New England Journal of Medicine (doi:10.1056/NEJMoa1415340).

In the EORTC 22922/10925 study, investigators in the European Organization for Research and Treatment of Cancer randomly assigned women with a centrally or medially located primary tumor irrespective of axillary involvement, or an externally located tumor with axillary involvement, to receive either whole-breast or thoracic wall irradiation alone, or with the addition of regional nodal irradiation.

As in the Canadian study, the investigators found no difference in overall survival at 10 years between women who received nodal irradiation and those who did not. Similarly, the EORTC investigators found that rates of disease-free survival and distant disease-free survival were better among women who received nodal irradiation. The nodal irradiation group also had a significantly lower rate of breast cancer–specific death. The European investigators, however, felt that “the acute side effects of regional nodal irradiation were modest.” The study, by Dr. Philip M. Poortmans of Radboud University in Nijmegen, the Netherlands, also appears in the New England Journal of Medicine (2015 July 23 [doi:10.1056/NEJMoa1415369]).

“The trials by Whelan et al. and Poortmans et al. show the possibilities and the limits of more extensive regional treatment of breast cancer in an unselected population and frame the discussion for the next generation of individualized treatment programs, built largely on genomic characterization of tumor biology,” write Dr. Harold J. Burstein of the Dana-Farber Cancer Institute in Boston and Dr. Monica Morrow of the Memorial Sloan Kettering Cancer in New York, in an accompanying editorial.

MA.20

From March 2000 through February 2007, Dr. Whelan and colleagues in the MA.20 trial enrolled 1,832 women with node-positive or high-risk node-negative cancer treated with breast-conserving surgery and adjuvant systemic therapy. The women were randomly assigned, 916 in each group, to undergo either whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular, and axillary lymph node), or whole-breast irradiation alone (controls).

At 10-year follow-up, overall survival rates were similar, at 82.8% in the nodal irradiation group and 81.8% in the control group (hazard ratio, 0.91, P =.38). However, as noted before, the rate of disease-free survival was 82% in the nodal irradiation group, compared with 77% in the control group (HR, 0.76, P = .01).

When they looked at adverse effects of the additional radiation, however, the investigators found that rates of grade 2 or greater acute pneumonitis were 1.2% among nodal irradiation patients, compared with just 0.2% of controls (P = .001). Lymphedema rates were also nearly twice as high among nodally irradiated patients (8.4% vs. 4.5%, respectively, P = .001).

The authors concluded that the addition of regional nodal irradiation to whole-breast irradiation after breast-conserving surgery in women with node-positive or high-risk node-negative breast cancer did not improve overall survival but did reduce breast-cancer recurrence. “Our findings indicate the importance of basing treatment decisions on a careful discussion of the potential benefits and risks with each patient,” they wrote.

EORTC 22922/10925

In this trial, a total of 4004 women were randomized from 1996 through 2004. The patients had either centrally or medially located primary tumors, irrespective of axillary involvement, or an externally located tumor with axillary involvement.

Most of the women (76.1%) had breast-conserving surgery. Of those who underwent radical mastectomy 73.4% of the patients in both the nodal irradiation and control groups underwent chest wall irradiation.

All but 1% of patients with node-positive disease received adjuvant systemic therapy, as did 66.3% of patients with node-negative disease.

At 10 years, overall survival was not significantly different between the two groups, at 82.3% in the nodal irradiation group and 80.7% in the control group (HR, 0.87; P = 0.06).

As in the Canadian trial, the rate of disease-free survival was significantly better among patients who received nodal-irradiation, at 72.1% vs. 69.1% (HR for disease progression or death, 0.89; P = .04).

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