1. There was no significant 10 year survival benefit after axillary and medial supraclavicular nodal irradiation in patients with stages 1, 2 and 3 breast adenocarcinoma.
2. The study was initiated in the early 1990s, when adjuvant systemic therapy was not as variable then as it is today. Unfortunately, little information was collected on this potentially confounding variable.
Evidence Rating Level: 1 (Excellent)
Study Rundown: For most patients with breast cancer, adjuvant chemotherapy and radiation have become cornerstone therapies for maintaining remission post-mastectomy. Regional nodes such as internal mammary are not often involved with local cancer spread given the direction of lymphatic drainage. Surgical dissection of internal mammary nodes has been attempted in the past for axillary node-positive breast cancers with no difference in survival. However, regional node irradiation (ie. internal mammary and medial supraclavicular nodes) for these patients has never been well-studied in a large trial.
This multi-center trial randomized 4004 patients with stage 1, 2 or 3 breast adenocarcinoma to either regional irradiation or no irradiation. The primary endpoint of overall survival at 10 years follow-up was not statistically significant (nodal-irradiation versus none, 82.3% versus 80.7%, p=0.06). However, nodal-irradiation improved disease-free survival at 10 years and the rate of first recurrence of breast cancer at 10 years; both of which were secondary end points. Pulmonary fibrosis was a long-term side effect noted to be higher in the irradiated group (nodal-irradiation versus none, 4.4% versus 1.7%, p<0.001).
Over the past ten years, chemotherapies and biomarker profiling for breast cancer have quickly evolved. Breast cancer patients in this study were enrolled between 1996 and 2004 when fewer therapies were available and therefore the results of this study may not be generalizable to current patients with newer chemotherapies. Nevertheless, this study raises an interesting question as to where radiation fits in the complex subgroups of breast cancer patients that now have several lines of different therapies.
In-Depth [randomized controlled trial]: Between 1996 and 2004, a total of 4004 patients were enrolled from 46 institutions in 13 countries. Eligible patients had stages 1, 2 or 3 breast adenocarcinoma with some form of surgical reduction (ie. mastectomy or breast-conserving surgery with axillary dissection). Randomization occurred in a 1:1 fashion to either regional nodal irradiation or none. Baseline characteristics were well-matched. Primary tumour size was < 5cm in 95.8% of patients. Primary end point of overall survival was not statistically significant between the two groups. However, at 10 years, regional nodal irradiation improved disease-free survival (72.1% versus 69.1%, p=0.04) and lowered the rate of first recurrence of breast cancer (19.4% versus 22.9%, p=0.02). Further subgroup analysis adjusting for type of surgery, type of axillary node dissection, pathologic tumor-nodal staging did not reveal any statistical differences between groups. Acute side effects were small and the rate of death from all other causes were not increased.
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