The DCIS Cochrane review by Goodwin et al. 2009 included 4 randomised control trials; NSABP B-17, EORTC10853, UKCCCR and SweDCIS.r The review compared the addition of radiotherapy to breast conserving surgery (BCS) (n=3925 women). They reported a statistically significant (SS) benefit from the addition of radiotherapy on all ipsilateral breast events (HR 0.49; 95% CI: 0.41-0.59, P< 0.00001) and ipsilateral recurrence (HR 0.64; 95% CI: 0.41 to 1.01, p=0.05).r The addition of radiotherapy reduced the risk of recurrence of either DCIS or invasive cancer in the treated breast by 51%.
The 15-year combined analysis of the NSABP B-17 and B-24 trials showed that the reduction in risk of local recurrence appeared to persist in the long term.r The ipsilateral breast recurrence rate was reduced from 19.4% to 8.9% with radiotherapy at 15 years. The overall survival (OS) rate was similar, 83% versus 84%.
Further evidence supporting this protocol was provided by a second meta-analysis by Correa et al..r This meta-analysis reviewed individual patient data for the same four trials (n=3925 women) and also compared BCS alone to BCS with adjuvant radiotherapy. The ten-year ipsilateral breast recurrence rate with surgery alone was 28% compared to 13% for BCS with radiotherapy (SS). This benefit was greater in women >50 years old (28% vs 11%) compared with women <50 years old (29% vs 18%). Women with small, low-grade tumours and negative surgical margins still benefited (30% vs 12%, SS). There was no effect on breast cancer specific mortality (~4%), other-cause mortality (~5%), and all-cause mortality (~8%).
A meta-analysis conducted by Stuart et al. 2015 included 9391 patients with 10-year follow-up also reported that adjuvant radiotherapy after BCS was associated with greater local control when compared to patients who were managed with BCS and biopsy alone.r
Bijker et al. 2006 reported the inclusion of radiotherapy resulted in a 48% reduction in the 10-year local recurrence (LR) rate in DCIS (14% with BSC vs. 7% with BSC and radiotherapy [SS]). Factors that increased the risk for LR were age <40 years old, grade 2 or 3, cribriform or solid growth pattern, doubtful margin, and local excision alone. Size was not a prognostic factor. There was no difference reported in OS or distant mets.r
Twenty-year follow-up of the sweDCIS trial showed that the absolute risk reduction of ipsilateral breast recurrence in the RT arm was 12.0% at 20 years (95% CI: 6.5 to 17.7), with a relative risk reduction of 37.5%.r Absolute reduction was 10.0% (95% CI: 6.0 to 14.0) for DCIS. The cumulative incidence of invasive ipsilateral recurrences was found to continuously rise over the 20-year period before plateauing.
Role of hypofractionation and boost
The role of hypofractionated radiotherapy and breast boost are examined in a meta-analysis of observational trials published in 2015.r No difference in the risk of local recurrence was observed between the patients that received boost vs. no boost in the general cohort (12 studies, 6943 patients; Odds Ratio [OR]: 0.91, 95% CI: 0.77-1.08, very low level of evidence). There was a reduced risk for local recurrence when a boost was administered in patients with positive margins compared to no boost (6 studies, 811 patients; OR: 0.56, 95% CI: 0.36-0.87, very low level of evidence). No difference in local recurrence rate between patients who received hypofractionated vs. standard radiotherapy was observed (4 studies, 2534 patients; OR: 0.78, 95% CI: 0.58-1.03, low level of evidence). These studies provide a low level of evidence.
Moran et al. 2017 examined the role of breast boost in a retrospective analysis of 4131 patients from ten institutions.r The delivery of a breast boost was associated with lower ipsilateral breast tumour recurrence (IBTR) (HR 0.73) and IBTR-free survival at five, ten and fifteen years. On multivariate analysis, Moran et al. found grade, presence of necrosis, margin status, age (<50 or ≥50 years), tumour size and a lack of tamoxifen use to be significantly contributory to IBTR.
We await the results of the randomised TROG DCIS trial regarding hypofractionation and boost for DCIS patients where accrual is complete.r
Although it is widely accepted that positive margins definitively increase the risk of locoregional recurrence (LRR) in patients who undergo BCS even with adjuvant radiotherapy the exact optimal margin threshold is not yet defined at an international level.rrr
ASTRO guidelines and other eminent groups recommend a >2mm margin.rrrrr Other groups infer that smaller margins may be acceptable in selected cases.rrr
Tadros et al. 2019 recently published a retrospective analysis of a cohort of 1491 ‘contemporary’ patients with DCIS.r They reported no SS difference in locoregional control between patients with <2mm and ≥2mm negative margins who underwent adjuvant radiotherapy. For patients who did not undergo adjuvant radiotherapy however, those with margins <2mm were significantly more likely to develop LRR than those with margins ≥2mm.
Van Zee et al. 2015 echoed the above in their retrospective analysis of 2996 patients.r They reported no significant association between negative margin width and risk of LRR for patients who received adjuvant RT, however; in patients with smaller negative margins who did not receive radiotherapy there was a significant risk of LRR.
The 2016 ASTRO guidelines noted that clinical judgement must be used when deciding on the need for re-excision in patients with >0-1mm margins. Factors to consider include residual calcifications on post excision mammography, extent of DCIS in proximity to margin, which margin is close (superficial/deep vs radial), cosmetic impact of re-excision, and overall life expectancy.r
The reference committee consensus is that clear margins ≥2mm is optimal, however; narrower margins may be acceptable in selected cases.
Omission of radiotherapy may be considered in some low-risk patients such as those who were eligible for RTOG 9804 Good-Risk DCIS trial.r
The RTOG 9804 eligibility criteria includes:
- Mammogram detected DCIS or incidental finding of DCIS in tissue of an otherwise benign biopsy
- Unicentric disease
- Low or intermediate nuclear grade
- Size <2.5cm
- Margin ≥3mm to ink
- Negative post-excision mammogram
Although the benefit of the addition of radiotherapy has been demonstrated in all sub-groups of patients, absolute benefit in these patients is small (1% risk of recurrence per year is halved by the addition of radiotherapy).rThe known and increasing long-term risk of a local recurrence must be considered in the context of a patient's longevity and wellbeing.
Consider the use of a DCIS recurrence nomogram to assist in decision making.r
Trials under investigation
LORIS, a phase III trial investigating surgery vs active monitoring (core biopsy alone) for low-risk DCIS patients is currently underway.r