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Invited Commentary
Oncology
August 10, 2018

Systemic Effects of Radiotherapy in Ductal Carcinoma In Situ

Author Affiliations
  • 1Department of Oncology, McMaster University, Hamilton, Ontario, Canada
JAMA Network Open. 2018;1(4):e181102. doi:10.1001/jamanetworkopen.2018.1102

Giannakeas and colleagues1 report results of a cohort study of more than 140 000 women with primary ductal carcinoma in situ (DCIS) treated by lumpectomy alone, lumpectomy plus radiation, or mastectomy enrolled in the Surveillance, Epidemiology, and End Results (SEER) database from 1998 to 2014. Using a matched-pair design with propensity weighting, the 15-year breast cancer mortality rates were reduced in patients treated with lumpectomy plus radiation compared with lumpectomy alone (1.78% vs 2.05%; hazard ratio [HR], 0.77; 95% CI, 0.67-0.88). Breast cancer mortality was also reduced in patients treated with lumpectomy plus radiation compared with mastectomy (HR, 0.75; 95% CI, 0.65-0.87), but no difference was detected when mastectomy was compared with lumpectomy alone (HR, 0.91; 95% CI, 0.78-1.05).

The methods used in this epidemiologic database analysis were rigorous. Investigators were careful to match for year and age at diagnosis, tumor grade, estrogen receptor status, and propensity score, taking into account ethnicity, household income, tumor size, and progesterone receptor status. Cumulative breast cancer mortality rates were determined using the Kaplan-Meier method, and groups were compared using the Cox proportional hazards model. Results were similar when adjusted for competing risks of death or when inverse-probability treatment weighting was used.

In any observational study, the effect of interventions can be influenced by factors, either measured or unmeasured, called confounders. In a radiation study, imbalance between treatment groups for baseline prognostic factors, or factors that are associated with response to radiation, can bias comparison of the treatments. Despite rigorous methods and careful matching of treatment groups in the study by Giannakeas et al, there is concern that groups may not be well matched for factors not controlled for, eg, microinvasion and the use of endocrine therapy, that could potentially influence the observed treatment effects. For example, it is of interest that estrogen receptor–positive status was more common in patients treated by lumpectomy with radiotherapy than in the groups treated with lumpectomy alone or mastectomy, potentially resulting in a higher use of endocrine therapy in the former group compared with the latter two.

How do the results of this observational study compare with those from prospective controlled studies? Previous randomized trials have demonstrated that whole-breast irradiation following lumpectomy for DCIS substantially reduces local invasive and noninvasive recurrences but have been unable to demonstrate an effect on breast cancer mortality.2,3 A meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group involving 3729 patients randomized to lumpectomy or lumpectomy plus radiation demonstrated a reduction in any local recurrence at 10 years from 28.1% to 12.9% (P < .001) but was unable to demonstrate an effect on breast cancer mortality, likely as a result of reduced power.4 The failure to detect a mortality difference in the meta-analysis is not surprising given the relatively small absolute benefit of radiation observed in the very large study by Giannakeas and colleagues.

The results observed in this study are consistent with another recent observational study of 32 144 patients with DCIS enrolled in the SEER database before 2008.5 Investigators demonstrated breast radiotherapy was associated with a reduction in breast cancer mortality from 2.1% to 1.8% (HR, 0.73; 95% CI, 0.62-0.88). The benefit observed was directly correlated with a prognostic score for recurrence based on younger age, high tumor grade, and large tumor size. These results are consistent with those of Giannakeas et al, who found that on subgroup analysis of the lumpectomy plus radiation vs lumpectomy alone groups, the treatment effect appeared to be greater for patients with high-grade disease and larger tumor size. In patients with invasive breast cancer, radiotherapy is associated with a reduction in mortality that has been attributed to a reduction in local recurrence and prevention of secondary distant metastases, with the benefits on breast cancer mortality related to the absolute reduction in local recurrence observed.6,7 The explanation for the mortality reduction with radiotherapy in DCIS is possibly the same, as the effect of radiation appeared greater in patients at higher risk of local recurrence: those with larger tumor size and higher tumor grade. In their final comments, the authors speculate that this may not be the only mechanism. In cross-group comparisons, they did not observe a relationship between the magnitude of reduction in local recurrence (which appeared to be underreported) and the effect on breast cancer mortality and suggest that there may be additional systemic effects of radiotherapy, perhaps as a result of an elicited immune response or radiation scatter to tissues beyond the breast. While theoretically possible, these results could also be explained by confounding, eg, unrecognized increased use of endocrine therapy preferentially in patients treated with lumpectomy plus radiation.8

The primary aim of using radiotherapy in patients with DCIS is to reduce local recurrence of DCIS or invasive cancer, thereby avoiding mastectomy. With the widespread use of screening mammography and improvements in technology to detect even smaller breast lesions, there is increased concern about the overdiagnosis of DCIS. Recent studies suggest that there are patients with good prognostic factors who have a low risk of local recurrence at 10 years (≤10%) and are unlikely to gain major benefits from radiotherapy.9 In addition, there is increasing interest in using molecular markers to better identify patients at lower risk for whom radiotherapy may be omitted.10 The results of the study by Giannakeas and colleagues are reassuring. The risk of breast cancer mortality in patients with DCIS was very low, and the potential absolute benefit of radiotherapy was quite small (number needed to treat to prevent a breast cancer death = 370). Such data continue to support a strategy in patients with DCIS of omitting radiotherapy after lumpectomy in low-risk patients, especially when one considers the negative effects of treatment: the cost and inconvenience of 5 to 6 weeks of daily treatments, acute adverse effects such as breast pain and fatigue, and potential long-term toxic effects of cardiac disease and second cancers.

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Article Information

Published: August 10, 2018. doi:10.1001/jamanetworkopen.2018.1102

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Goldberg M et al. JAMA Network Open.

Corresponding Author: Timothy J. Whelan, BM, BCh, Division of Radiation Oncology, Juravinski Cancer Centre, 699 Concession St, Room 4-204, Hamilton, ON L8V 5C2, Canada (twhelan@hhsc.ca).

Conflict of Interest Disclosures: Dr Whelan has received research support from Genomic Health Inc. No other disclosures were reported.

References
1.
Giannakeas  V, Sopik  V, Narod  SA.  Association of radiotherapy with survival in women treated for ductal carcinoma in situ with lumpectomy or mastectomy.  JAMA Netw Open. 2018;1(4):e181100. doi:10.1001/jamanetworkopen.2018.1100Google Scholar
2.
Fisher  B, Dignam  J, Wolmark  N,  et al.  Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17.  J Clin Oncol. 1998;16(2):441-452. doi:10.1200/JCO.1998.16.2.441PubMedGoogle ScholarCrossref
3.
Bijker  N, Meijnen  P, Peterse  JL,  et al; EORTC Breast Cancer Cooperative Group; EORTC Radiotherapy Group.  Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853—a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group.  J Clin Oncol. 2006;24(21):3381-3387. doi:10.1200/JCO.2006.06.1366PubMedGoogle ScholarCrossref
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Correa  C, McGale  P, Taylor  C,  et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).  Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast.  J Natl Cancer Inst Monogr. 2010;2010(41):162-177. doi:10.1093/jncimonographs/lgq039PubMedGoogle ScholarCrossref
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Sagara  Y, Freedman  RA, Vaz-Luis  I,  et al.  Patient prognostic score and associations with survival improvement offered by radiotherapy after breast-conserving surgery for ductal carcinoma in situ: a population-based longitudinal cohort study.  J Clin Oncol. 2016;34(11):1190-1196. doi:10.1200/JCO.2015.65.1869PubMedGoogle ScholarCrossref
6.
Clarke  M, Collins  R, Darby  S,  et al; 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;366(9503):2087-2106. doi:10.1016/S0140-6736(05)67887-7PubMedGoogle ScholarCrossref
7.
Darby  S, McGale  P, Correa  C,  et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).  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):1707-1716. doi:10.1016/S0140-6736(11)61629-2PubMedGoogle ScholarCrossref
8.
Cuzick  J, Sestak  I, Pinder  SE,  et al.  Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial.  Lancet Oncol. 2011;12(1):21-29. doi:10.1016/S1470-2045(10)70266-7PubMedGoogle ScholarCrossref
9.
McCormick  B, Winter  K, Hudis  C,  et al.  RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation.  J Clin Oncol. 2015;33(7):709-715. doi:10.1200/JCO.2014.57.9029PubMedGoogle ScholarCrossref
10.
Solin  LJ, Gray  R, Baehner  FL,  et al.  A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast.  J Natl Cancer Inst. 2013;105(10):701-710. doi:10.1093/jnci/djt067PubMedGoogle ScholarCrossref
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