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Evidence summaries

Radiotherapy and Surgery in Early Breast Cancer

Radiotherapy plus surgery reduces local recurrence and 15-year breast cancer mortality as compared with surgery alone in early breast cancer. Level of evidence: "A"

A meta-analysis 2 of individual patient data included 10 801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery. 8 337 patients had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease. Overall, radiotherapy reduced the 10-year risk of any (locoregional or distant) first recurrence from 35.0% to 19.3% (absolute reduction 15.7%, 95% CI 13.7 to 7.7; 2p<0.00001) and reduced the 15-year risk of breast cancer death from 25.2% to 21.4% (absolute reduction 3.8%, 1.6 to 6.0; 2p=0.00005). In women with pN0 disease (n=7 287), radiotherapy reduced these risks from 31.0% to 15.6% (absolute recurrence reduction 15.4%, 13.2 to 17.6; 2p<0·00001) and from 20.5% to 17.2% (absolute mortality reduction 3.3%, 0.8 to 5.8; 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery. In the few women with pN+ disease (n=1 050), radiotherapy reduced the 10-year recurrence risk from 63.7% to 42.5% (absolute reduction 21.2%, 95% CI 14.5 to 27.9; 2p<0·00001) and the 15-year risk of breast cancer death from 51.3% to 42.8% (absolute reduction 8.5%, 1.8 to 15.2; 2p=0·01). Overall, about 1 breast cancer death was avoided by year 15 for every 4 recurrences avoided by year 10.

Another meta-analysis 3 of individual data included 8 135 women randomly assigned to treatment groups in 22 trials of radiotherapy to the chest wall and regional lymph nodes after mastectomy and axillary surgery versus the same surgery but no radiotherapy. 3786 women had axillary dissection to at least level II and had 0, 1 to 3, or 4 or more positive nodes. For 700 women with axillary dissection and no positive nodes, radiotherapy had no significant effect on locoregional recurrence (2p>0.1), overall recurrence (irradiated vs not, RR 1.06, 95% CI 0.76 to 1.48; 2p>0.1), or breast cancer mortality (RR 1.18, 95% CI 0.89 to 1.55; 2p>0.1). For 1 314 women with axillary dissection and 1 to 3 positive nodes, radiotherapy reduced locoregional recurrence (2p<0.00001), overall recurrence (RR 0.68, 95% CI 0.57 to 0.82; 2p=0.00006), and breast cancer mortality (RR 0.80, 95% CI 0.67 to 0..9; 2p=0.01). 1 133 women were in trials in which systemic therapy (cyclophosphamide, methotrexate, and fluorouracil, or tamoxifen) was given in both trial groups and, for them, radiotherapy again reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0.67, 95% CI 0.5 to 0.82; 2p=0.00009), and breast cancer mortality (RR 0.78, 95% CI 0.64 to 0.94; 2p=0.01). For 1 772 women with axillary dissection and 4 or more positive nodes, radiotherapy reduced locoregional recurrence (2p<0.00001), overall recurrence (RR 0.79, 95% CI 0.69 to 0.90; 2p=0.0003), and breast cancer mortality (RR 0.87, 95% CI 0.77 to 0.99, 2p=0.04).

A systematic review 1 included 78 randomised treatment comparisons with 42 000 women (radiotherapy vs. no radiotherapy n=23 500; more vs. less surgery n=9 300; more surgery vs. radiotherapy n=9 300). 24 types of local treatment comparison were identified.

In the comparisons that involved little (<10%) difference in 5-year local recurrence risk there was little difference in 15-year breast cancer mortality. The comparisons that involved substantial (>10%) differences in the 5-year local recurrence risk included 25 000 women and were analysed separately. These included 7 300 women who underwent breast-conserving surgery (BCS) and received radiotherapy (generally just to the conserved breast). Among these, the 5-year local recurrence risks (mainly in the conserved breast, as most had axillary clearance and node-negative disease) were 7% vs. 26% as compared to controls. Respectively, the 15-year breast cancer mortality risks were 30.5% vs. 35.9% (reduction 5.4%, SE 1.7, 2p=0.0002; overall mortality reduction 5.3%, SE 1.8, 2p=0.005).

The 8 500 women with mastectomy, axillary clearance, and node-positive disease showed similar absolute gains from radiotherapy (generally to the chest wall and regional lymph nodes): 5-year local recurrence risks (mainly at these sites) 6% vs. 23%, and 15-year breast cancer mortality risks 54.7% vs. 60.1% (reduction 5.4%, SE 1.3, 2p=0.0002; overall mortality reduction 4.4%, SE 1.2, 2p=0.0009).

Considering the side-effects of radiotherapy, there was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer (rate ratio 1.18, SE 0.06, 2p=0.002) and a significant excess of non-breast-cancer mortality in irradiated women (rate ratio 1.12, SE 0.04, 2p=0.001). Both were slight during the first 5 years, but continued after year 15. The excess mortality was mainly from heart disease (rate ratio 1.27, SE 0.07, 2p=0.0001) and lung cancer (rate ratio 1.78, SE 0.22, 2p=0.0004).

A meta-analysis 4 included 4 RCTs (n=3680) addressing the role of adjuvant radiotherapy following lumpectomy for ductal carcinoma in-situ (DCIS) with more than 10-years follow-up. Patients who received radiotherapy had almost half of risk of ipsilateral breast recurrence (RR 0.53, 95% CI 0.45 to 0.62) and regional recurrence (RR 0.54, 95% CI 0.32 to 0.91) compared to those who did not receive radiotherapy - there was absolute risk reduction in 15% for ipsilateral breast recurrences. There was no significant difference in distant recurrence (RR 1.06, 95% CI 0.74 to 1.53), contralateral breast events (RR 1.22, 95% CI 0.98 to 1.52) and overall mortality (RR 0.93, 95% CI 0.79 to 1.09).

    References

    • Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, Godwin J, Gray R, Hicks C, James S, MacKinnon E, McGale P, McHugh T, Peto R, Taylor C, Wang Y, Early Breast Cancer Trialists' Collaborative Group (EBCTCG). 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 2005 Dec 17;366(9503):2087-106. [PubMed]
    • Early Breast Cancer Trialists' Collaborative Group (EBCTCG)., Darby S, McGale P et al. 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 2011;378(9804):1707-16. [PubMed]
    • EBCTCG (Early Breast Cancer Trialists' Collaborative Group)., McGale P, Taylor C et al. 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 2014;383(9935):2127-35. [PubMed]
    • Garg PK, Jakhetiya A, Pandey R et al. Adjuvant radiotherapy versus observation following lumpectomy in ductal carcinoma in-situ: A meta-analysis of randomized controlled trials. Breast J 2018;24(3):233-239. [PubMed]

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