In an analysis of long-term outcomes from the phase III NRG/RTOG 9804 trial reported in the Journal of Clinical Oncology, Beryl McCormick, MD, of Memorial Sloan Kettering Cancer Center, and colleagues found that whole-breast irradiation vs observation was associated with a reduced risk of all and invasive ipsilateral breast recurrence at 15 years in women undergoing lumpectomy for good-risk ductal carcinoma in situ (DCIS).¹ 

As stated by the investigators: “To our knowledge, NRG/RTOG 9804 is the only randomized trial to assess the impact of whole-breast irradiation … vs observation … in women with good-risk DCIS, following lumpectomy. [We present] long-term results focusing on [ipsilateral breast recurrence], the primary outcome [of the trial].” 

[Radiotherapy] significantly reduced all and invasive [ipsilateral breast recurrence] for good-risk DCIS with durable results at 15 years.

— Beryl McCormick, MD

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The primary analysis of the trial, reported at 7 years of follow-up, showed that radiotherapy was associated with a reduction in ipsilateral breast recurrence (0.8% vs 7.2%).² 

Study Details

In the trial, 636 women were randomly assigned between 1999 and 2006 to receive whole-breast radiotherapy with or without adjuvant tamoxifen (n = 314) or observation with or without tamoxifen (n = 322). Good-risk DCIS was defined as mammogram-detected (asymptomatic), size ≤ 2.5 cm, final margins ≥ 3 mm, and low or intermediate nuclear grade. 

The trial initially specified radiotherapy at 50 Gy in 25 fractions or 50.4 Gy in 28 fractions; a 2001 amendment permitted the use of 42.5 Gy in 16 fractions. No radiation boost to the lumpectomy cavity was permitted. The trial initially specified that all patients receive tamoxifen at 20 mg/d; a 2001 amendment made tamoxifen use optional. Overall tamoxifen use was intended in 70% of the radiotherapy group vs 69% of the observation group; however, a difference in actual use was observed (58% vs 66%, P = .05). 

Patients had a median age of 58 years, and the mean pathologic DCIS size was 0.60 cm.

Risk of Ipsilateral Breast Recurrence

Median follow-up was 13.9 years (range = 0.01–20 years). A total of 52 ipsilateral breast recurrences were observed, including 14 in the radiotherapy group and 38 in the observation group; of these recurrences, 57% and 76%, respectively, were in the index quadrant. 

The cumulative incidence of ipsilateral breast recurrence was 1.5% (95% confidence interval [CI] = 0.5%–3.7%) in the radiotherapy group vs 9.2% (95% CI = 6.2%–13.0%) in the observation group at 10 years and 7.1% (95% CI = 4.0%–11.5%) in the radiotherapy group vs 15.1% (95% CI = 10.8%–20.2%) in the observation group at 15 years (hazard ratio [HR] = 0.36, 95% CI = 0.20–0.66, P = .0007). The median time to any ipsilateral breast recurrence was 11.5 years in the radiotherapy group vs 7.0 years in the observation group. 

A total of 33 invasive ipsilateral breast recurrences were observed, including 10 in the radiotherapy group and 23 in the observation group. The cumulative incidence of invasive ipsilateral breast recurrence was 0.4% (95% CI = 0.0%–1.9%) in the radiotherapy group vs 4.3% (95% CI = 2.3%–7.2%) in the observation group at 10 years and 5.4% (95% CI = 2.7%–9.5%) in the radiotherapy group vs 9.5% (95% CI = 6.0%–13.9%) in the observation group at 15 years (HR = 0.44, 95% CI = 0.21–0.91, P = .024). 

On multivariate analysis, only radiotherapy (HR = 0.34, 95% CI = 0.19–0.64, P = .0007) and tamoxifen use (HR = 0.45, 95% CI = 0.25–0.78, P = .0047) were significantly associated with a reduced risk of ipsilateral breast recurrence. No significant associations with ipsilateral breast recurrence risk were observed for age (HR = 0.65, 95% CI = 0.34–1.21, P  = .17, for ≥ vs < 50 years), tumor size (HRs = 1.02, 95% CI = 0.51–2.02, P = .96, for 0.6–1.0 cm and 1.50, 95% CI = 0.69–3.25, P = .31, for > 1 cm vs ≤ 0.5 cm), or tumor grade (HR = 0.69, 95% CI = 0.39–1.24, P = .22, for nuclear grade 1 vs 2). 

Additional Outcomes

Contralateral breast events occurred in 25 patients in the radiotherapy group vs 19 in the observation group, with 10- and 15-year cumulative incidence rates of 5.5% vs 4.6% and 10.5% vs 7.4% (HR = 1.39, 95% CI = 0.77–2.52, P = .27, for 15-year estimate). The cumulative incidence of distant metastasis was 1.3% vs 0.4% at 10 years and 2.3% vs 4.0% at 15 years (HR = 0.76, 95% CI = 0.25–2.38, P = .65). 

A total of 27 women underwent subsequent mastectomy, including 21 for ipsilateral breast recurrence. No significant difference between groups in the risk for mastectomy was observed. 

No significant differences between groups were observed for disease-free or overall survival. Disease-free survival rates were 85.0% vs 82.6% at 10 years and 69.4% vs 65.3% at 15 years (HR = 0.87, 95% CI = 0.65–1.17, P = .35). Overall survival rates were 90.2% vs 93.7% at 10 years and 81.2% vs 81.9% at 15 years (HR = 1.15, 95% CI = 0.78–1.70, P = .47). 

Follow-up for late toxicity was performed in the radiotherapy group alone. Late grade 3 toxicities were observed in three patients (1%), consisting of breast pain, congestive heart failure/cardiomyopathy, and abnormal electrocardiogram.  

The investigators concluded: “[Radiotherapy] significantly reduced all and invasive [ipsilateral breast recurrence] for good-risk DCIS with durable results at 15 years. These results are not an absolute indication for [radiotherapy] but rather should inform shared patient-physician treatment decisions about ipsilateral breast risk reduction in the long term following lumpectomy.” 

DISCLOSURE: Dr. McCormick reported having stock or other ownership interests in Varian Medical Systems.

REFERENCES

1. McCormick B, Winter KA, Woodward W, et al: Randomized phase III trial evaluating radiation following surgical excision for good-risk ductal carcinoma in situ. J Clin Oncol. August 18, 2021 (early release online).

2. 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 33:709-715, 2015.