Regional nodal irradiation can reduce breast cancer recurrence in patients with node-positive or high-risk node-negative disease, but offers no survival benefit, according to two large clinical trials.
Results from the MA.20 study and a European study conducted by the EORTC Radiation Oncology and Breast Cancer Groups were published in the July 23 issue of the New England Journal of Medicine.
Both studies compared standard breast radiotherapy with regional radiotherapy that included the breast and nodal fields.
"Although the two trials differed in certain technical aspects of treatment, they both showed a lower risk of local–regional recurrence and of metastatic breast cancer with the use of extended radiation therapy," Harold J Burstein, MD, PhD, from the Dana-Farber Cancer Institute in Boston, and Monica Morrow, MD, from the Memorial Sloan Kettering Cancer Center in New York City, write in an accompanying editorial.
"However, there was no improvement in the rate of overall survival in either trial," they point out.
Almost all patients with breast cancer now receive some form of adjuvant drug treatment. In fact, recognizing the benefit of systemic therapy on local disease control has transformed breast surgery, they write. These treatments have decreased the need for axillary dissection in patients with node-positive breast cancers and have helped prevent reoperation.
"Within this changing treatment approach — more systemic therapy, less local extirpation — clinicians must interpret the long-term results from these two important trials," the editorialists emphasize.
The MA.20 study was conducted from 2000 to 2007 and the European study was conducted from 1996 to 2004. The two studies did not universally include systemic treatments that are now known to reduce local recurrence and improve survival or more effective endocrine strategies. "Limited axillary surgery in the two studies might have contributed to the observed benefit of regional nodal radiation," the editorialists report.
So which patients ar the best candidates and the most likely to benefit from nodal irradiation?
Treatment selection for the individual patient is the key issue, Drs Burstein and Morrow explain.
"We tried to suggest that a risk-tailored approach made most sense," Dr Burstein told Medscape Medical News.
"If a patient is node-negative, then no regional radiotherapy is needed, but a patient with four or more positive nodes is definitely a good candidate," he said.
For patients with one to three nodes, radiotherapy might be indicated if other high-risk factors are present, such as young age, adverse histology, larger tumor size, and unfavorable molecular profile, he added.
Details of the MA.20 Study
Interim 5-year results from the MA.20 study, which was conducted by the National Cancer Institute of Canada Clinical Trials Group and American and Australian clinical trials groups, were initially presented at the 2011 Annual Meeting of the American Society of Clinical Oncology, as reported by Medscape Medical News.
Now, 10-year results have been published.
The 1832 study participants with node-positive or high-risk node-negative breast cancer were treated with breast-conserving surgery and adjuvant systemic therapy. They were randomized to either whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular, and axillary lymph nodes) or whole-breast irradiation alone (control group).
At 10-year follow-up, there was no significant difference in overall survival between the nodal-irradiation group and the control group (82.8% vs 81.8%; hazard ratio [HR], 0.91; P = .38), report Timothy J. Whelan, BM, BCh, from McMaster University and the Juravinski Cancer Centre in Hamilton, Ontario, Canada, and colleagues.
The 10-year rate of disease-free survival, however, was significantly higher in the nodal-irradiation group than in the control group (82.0% vs 77.0%; HR, 0.76; P = .01).
The 10-year rate of isolated locoregional disease-free survival was 95.2% in the nodal-irradiation group and 92.2% in the control group (HR, 0.59; P = .009), and the treatment effect was primarily associated with a reduction in the rate of regional recurrence, Dr Whelan and colleagues report. The majority of regional treatment failures included the axillary nodes (in 63% of patients) or the supraclavicular nodes (in 27%).
Rates of acute pneumonitis of at least grade 2 were higher in the nodal-irradiation group than in the control group (1.2% vs 0.2%; P = .01), as were rates of lymphedema (8.4% vs 4.5%; P = .001).
"Additional radiation to the surrounding lymph nodes reduced the risk of subsequent recurrence of breast cancer both locally, such as under the arm, and at sites distant from the breast, such as the bone, liver, and lung," Dr Whelan said in a statement.
He noted that it did not increase survival, "but follow-up is still relatively early."
Details of European Study
Initial findings from the European study were presented at the European Cancer Conference 2013, as reported by Medscape Medical News, and more details were reported last year at the European Society for Radiotherapy and Oncology meeting.
Now, 10-year results from this study have also been published.
The 4004 patients had a centrally or medially located primary tumor or an externally located tumor with axillary involvement. They were randomized to either whole-breast or thoracic-wall irradiation plus regional nodal irradiation or whole-breast or thoracic-wall irradiation alone (control group).
Most (99%) of the patients with node-positive disease and 66.3% of the patients with node-negative disease received adjuvant systemic treatment, and 76.1% underwent breast-conserving surgery.
At 10 years, overall survival was similar in the nodal-irradiation group and the control group (82.3% vs 80.7%). With nodal irradiation, the HR for death was 0.87 (P = .06).
But regional nodal irradiation was associated with "a small but significant benefit" for disease-free survival, distant disease-free survival, and death from breast cancer, report Philip M. Poortmans, PhD, from Radboud University Medical Center in Nijmegen, the Netherlands, and colleagues.
Table. Outcomes
| Outcome | Nodal-Irradiation Group, % | Control Group, % | HR for Disease Progression or Death | PValue |
| Disease-free survival | 72.1 | 69.1 | 0.89 | .04 |
| Distant disease-free survival | 78.0 | 75.0 | 0.86 | .02 |
| Breast-cancer mortality | 12.5 | 14.4 | 0.82 | .02 |
At 10 years, there was more pulmonary fibrosis in the nodal-irradiation group than in the control group (4.4% vs 1.7%; P < .001), more cardiac fibrosis (1.2% vs 0.6%; P = .06), and more cardiac disease (6.5% vs 5.6%; P = .25).
"We found that regional nodal irradiation was beneficial to women with early-stage breast cancer," Dr Poortmans and colleagues conclude. "It improved the rates of disease-free and distant disease-free survival and reduced the rate of death from breast cancer among patients with involved axillary nodes, a medially or centrally located primary tumor, or both."
However, they point out, "our data do not apply to patients with lateral node-negative cancers, which is the largest patient subgroup in industrialized countries." They note the lack of any effect on overall survival, and say they will continue to follow-up for the next 10 years.
The MA.20 study was supported by grants from the Canadian Cancer Society Research Institute to the NCIC Clinical Trials Group; the Canadian Breast Cancer Research Initiative; the US National Cancer Institute; and the Cancer Council of Victoria, New South Wales, Queensland, and South Australia. Dr Whelan reports receiving fees for serving on an advisory board from Genomic Health and testing reagents for another study from NanoString Technologies. Coauthor Kathleen Pritchard, MD, from Centre Universitaire de Sherbrooke at Fleurimont Hospital in Quebec, reports receiving fees for serving on advisory boards from AstraZeneca, Pfizer, Roche, Amgen, Novartis, GlaxoSmithKline, and Eisai; receiving consulting fees from Pfizer and Novartis; receiving lecture fees from Novartis; and receiving grant support from AstraZeneca, Pfizer, Roche, Novartis, and Eisai. The European study was supported by Fonds Cancer. The authors and Dr Burstein have disclosed no relevant financial relationships. Dr Morrow reports receiving personal fees from Genomic Health.
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