External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.

BACKGROUND: Whole breast irradiation delivered once per day over 3-5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. METHODS: We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5-8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035. FINDINGS: Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3-9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9-4·0) in the APBI group and 2·8% (1·8-3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84-1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5-15·0), 5 years (16·5%, 12·5-20·4), and 7 years (17·7%, 12·9-22·3). INTERPRETATION: External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. FUNDING: Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

Which prediction models best identify additional axillary disease after a positive sentinel node biopsy for breast cancer?

To determine which web-based model best identifies women at low risk of further axillary disease after a positive sentinel lymph node (SLN+) biopsy. 673 women with T1-2cN0M0 SNB+ breast cancer who underwent completion axillary dissection (AxD) were identified. A subgroup not eligible to avoid AxD as part of the Z0011 study was defined (Z0011 exclusion group). Predicted risk of further axillary disease was generated using seven web-based models. "Low risk" was defined as a ≤10% risk of further axillary disease. False negative ("low risk" prediction but AxD+) rates (FNRs), area under the receiver operating characteristic curve (AUC), and Brier score were determined for each model. 6 of 7 models identified "low risk" patients but FNRs ranged from 14 to 30%. The Stanford and Memorial Sloan-Kettering (MSKCC) models had the best FNRs. FNRs were lower with SLN micrometastasis (7-15%) and higher in the Z0011 exclusion group (21-41%). All models under-predicted further nodal disease in low risk patients and over-predicted in higher-risk patients. The Stanford and MSKCC models were able to identify women with SLN micrometastasis with a ≤10% FNR. Models were not able to accurately identify low risk women from a cohort that would have been excluded from Z0011.

Three-year outcomes of a Canadian multicenter study of accelerated partial breast irradiation using conformal radiation therapy.

PURPOSE: To report 3-year toxicity, cosmesis, and efficacy of a multicenter study of external beam, accelerated partial breast irradiation (APBI) for early-stage breast cancer. METHODS AND MATERIALS: Between March 2005 and August 2006, 127 women aged ≥40 years with ductal carcinoma in situ or node-negative invasive breast cancer ≤3 cm in diameter, treated with breast-conserving surgery achieving negative margins, were accrued to a prospective study involving five Canadian cancer centers. Women meeting predefined dose constraints were treated with APBI using 3 to 5 photon beams, delivering 35 to 38.5 Gy in 10 fractions, twice a day, over 1 week. Patients were assessed for treatment-related toxicities, cosmesis, and efficacy before APBI and at specified time points for as long as 3 years after APBI. RESULTS: 104 women had planning computed tomography scans showing visible seromas, met dosimetric constraints, and were treated with APBI to doses of 35 Gy (n=9), 36 Gy (n=33), or 38.5 Gy (n=62). Eighty-seven patients were evaluated with minimum 3-year follow-up after APBI. Radiation dermatitis, breast edema, breast induration, and fatigue decreased from baseline levels or stabilized by the 3-year follow-up. Hypopigmentation, hyperpigmentation, breast pain, and telangiectasia slightly increased from baseline levels. Most toxicities at 3 years were Grade 1. Only 1 patient had a Grade 3 toxicity with telangiectasia in a skin fold inside the 95% isodose. Cosmesis was good to excellent in 86% (89/104) of women at baseline and 82% (70/85) at 3 years. The 3-year disease-free survival was 97%, with only one local recurrence that occurred in a different quadrant away from the treated site and two distant recurrences. CONCLUSIONS: At 3 years, toxicity and cosmesis were acceptable, and local control and disease-free survival were excellent, supporting continued accrual to randomized APBI trials.

3D ultrasound can contribute to planning CT to define the target for partial breast radiotherapy.

PURPOSE: The role of three-dimensional breast ultrasound (3D US) in planning partial breast radiotherapy (PBRT) is unknown. This study evaluated the accuracy of coregistration of 3D US to planning computerized tomography (CT) images, the seroma contouring consistency of radiation oncologists using the two imaging modalities and the clinical situations in which US was associated with improved contouring consistency compared to CT. MATERIALS AND METHODS: Twenty consecutive women with early-stage breast cancer were enrolled prospectively after breast-conserving surgery. Subjects underwent 3D US at CT simulation for adjuvant RT. Three radiation oncologists independently contoured the seroma on separate CT and 3D US image sets. Seroma clarity, seroma volumes, and interobserver contouring consistency were compared between the imaging modalities. Associations between clinical characteristics and seroma clarity were examined using Pearson correlation statistics. RESULTS: 3D US and CT coregistration was accurate to within 2 mm or less in 19/20 (95%) cases. CT seroma clarity was reduced with dense breast parenchyma (p = 0.035), small seroma volume (p < 0.001), and small volume of excised breast tissue (p = 0.01). US seroma clarity was not affected by these factors (p = NS). US was associated with improved interobserver consistency compared with CT in 8/20 (40%) cases. Of these 8 cases, 7 had low CT seroma clarity scores and 4 had heterogeneously to extremely dense breast parenchyma. CONCLUSION: 3D US can be a useful adjunct to CT in planning PBRT. Radiation oncologists were able to use US images to contour the seroma target, with improved interobserver consistency compared with CT in cases with dense breast parenchyma and poor CT seroma clarity.