Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast

October 2022 Clinical Practice Andrea Enguita

Although whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence, 10-year local recurrence rates are still high for some patients. A novel study now showed that a tumour bed boost after WBI reduces local recurrence after postoperative WBI in non-low-risk DCIS, supporting its use in this setting.  Additionally, no differences in the outcomes were found between conventional and hypofractionated WBI.

EXPERT OPINION OF DR. DIRK SCHRIJVERS, MEDICAL ONCOLOGIST, ZNA

“Adjuvant whole breast irradiation (WBI) decreases the local recurrence rate in patients with ductal carcinoma in situ. In this study, patients with non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins were assigned to no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. A tumour bed boost after WBI reduced significantly (hazard ratio 0.47) local recurrence with an increase in grade 2 or greater toxicity”

After breast-conserving surgery for ductal carcinoma in situ (DCIS), patients are at risk of a local recurrence, of which 50% of cases are invasive, with the potential for metastatic spread and an increased risk of mortality. Whole-breast irradiation (WBI) after conservative surgery halves the local recurrence rates.  A conventional WBI dose fractionation of 50 Gy in 2-Gy daily fractions has been used in randomised trials examining DCIS. However, 10-year local recurrence rates were found to be high in some patient subgroups. A boost to the tumour bed after WBI significantly decreased local recurrence in most women with invasive breast cancer, but there were no similar randomised trial data for DCIS. The Breast International Group (BIG) 3-07 and Trans-Tasman Radiation Oncology Group (TROG) 07.01 study investigated whether a tumour bed boost after WBI decreased local recurrence, and to examine WBI fractionation sensitivity in patients with non-low-risk DCIS who were administered breast-conserving therapy.

Study design

This international, phase III, randomised trial enrolled adult women with unilateral non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial section margins.  Patients had to have at least one clinical or pathological marker for an increased local recurrence risk, including – but not limited to – a younger age (<50 years), symptomatic presentation, palpable tumour, multifocal disease or central necrosis. Additionally, patients must be suitable for postoperative WBI and available for long-term follow-up of 10 years. Before local study activation, each centre chose to participate in one of three WBI categories. Category A was a random assignment of patients to one of four groups: boost to the tumour bed vs. no boost and conventional vs. hypofractionated WBI (allocation ratio, 1:1:1:1). Category B was a two-group random assignment of boost vs. no boost after conventional WBI, and category C was a two-group random assignment between boost vs. no boost after hypofractionated WBI (allocation ratio for both, 1:1). The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42.5 Gy in sixteen fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. The primary endpoint was time to local recurrence.

Results

Between June 2007 and June 2014, 1,608 patients were randomly assigned (category A, 503 patients; category B, 581 patients; category C, 524 patients) to the no-boost group (805 patients) or the boost group (803 patients). WBI was conventional in 831 patients, and hypofractionated in 777 patients. Median follow-up was 6.6 years. The 5-year free-from-local recurrence rates were 92.7% in the no-boost group and 97.1% in the boost group (HR[95%CI]: 0.47[0.31-0.72]; p<0.001). In the no-boost and boost-groups, 44% vs. 45% of the local recurrences were invasive. In an exploratory analysis, there were no significant differences found in the effect of the tumour bed boost on local recurrence according to age, tumour size, nuclear grade, comedo necrosis, surgical margin width, or endocrine therapy use. There were no statistically significant differences in 5-year free-from-local-recurrence rates between conventional (94.4%) and hypofractionated (93.7%) WBI groups in category A (HR[95%CI]: 0.94[0.51-1.73]; p= 0.84) or in all randomly assigned patients (94.9% vs. 94.9% in conventional and hypofractionated; HR[95%CI]: 0.94[0.51-1.74]; p= 0.85]. The 5-year free-from-disease-recurrence rates were lower in the no-boost than in the boost group (89.6% vs. 93.7%; HR[95%CI]:0.63[0.46-0.87]; p= 0.0042). There were no statistically significant differences in 5-year free-from-disease-recurrence rates between conventional vs. hypofractionated WBI groups in category A (90.0% vs. 92.4%, HR[95%CI]: 0.79[0.47-1.31]; p= 0.36) or in all randomly assigned patients (91.0% vs. 92.4% HR[95%CI]: 0.83[0.50-1.38; p= 0.46). There was no statistically significant difference in 5-year overall survival rates between the no-boost and boost groups (98.2% vs. 99.0%; HR[95%CI]: 0.81[0.45-1.45]; p= 0.47). Grade 4 events were rare, and no grade 5 events were reported. The boost group had higher rates of grade ≥2 breast pain (14% vs. 10%, p=0.003) and induration (14% vs 6%, p<0.001) than the no-boost group. There was no significant increase in radiation pneumonitis, cardiac disease, or radiation-related second malignancy in the boost group.

Conclusion

This study showed that a tumour bed boost after WBI reduced local recurrence in patients with resected non-low-risk DCIS. The boost group experienced an increase in grade ≥2 adverse events but no grade 5 events were reported and grade 4 were rare.  No differences were found in 5-year free-from-local-recurrence and free-from-disease-recurrence rates between conventional and hypofractionated WBI. Taken all together, this study supports the use of boost radiation after postoperative WBI in these patients to improve local control, and the adoption of moderately hypofractionated WBI in practice to improve the balance of local control, toxicity, and socioeconomic burdens of treatment.

Reference

Chua BH, Link EK, Kunkler IH, et al. Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3–07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study.

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