NRG RTOG 1005: A Phase III Trial of Hypo Fractionated Whole Breast Irradiation with Concurrent Boost vs. Conventional Whole Breast Irradiation Plus Sequential Boost Following Lumpectomy for High Risk Early-Stage Breast Cancer

Abstract

<h3>Purpose/Objective(s)</h3> Randomized trials support a supplemental radiation dose (Boost) to the lumpectomy (L) cavity region after whole breast irradiation (WBI), providing a 20-30% relative reduction of in-breast recurrence (IBR); with the disadvantage that it extends treatment duration ⁓ 1 week. Hypofractionated WBI (H-WBI) in ≤ 3 weeks is used after L to deliver adjuvant WBI with acceptable toxicity and comparable IBR as conventional WBI (C-WBI) 50 Gy in 2 Gy fractions (F). NRG RTOG 1005 sought to determine whether a boost delivered concomitantly with H-WBI over 15 F is non-inferior for IBR compared to boost delivered sequentially after C-WBI in patients (pts) considered at High Risk of IBR. <h3>Materials/Methods</h3> Protocol-specified High Risk pts post L with stages 0, I & II breast cancer were randomized to C-WBI 50 Gy in 25 F or 42.7 Gy in 16 F plus sequential boost of 12 Gy in 6 F or 14 Gy in 7 F (Arm I) or H-WBI 40 Gy in 15 F plus concomitant boost of 8 Gy in 15 F of 0.53 Gy per day (Arm II). Radiation was target based 3-dimensional conformal radiation therapy (3DCRT) or intensity modulated radiation therapy (IMRT) and quality review (QA) was required. Stratification was by age (<50 vs ≥ 50), adjuvant chemotherapy (Y vs N), ER status (+ vs -) and histologic grade (1, 2 v 3). The primary endpoint is IBR. Assuming Arm I 5‐year IBR of 1.59%, 90% CI upper bound hazard ratio (HR) of 2.12 and 1‐sided significance level = 0.05, 2150 pts with at least 46 IBR events provide >80% power to conclude non‐inferiority. IBR was analyzed comparing the cause-specific hazards. Adverse Events (AE) were graded with NCI CTCAE v4. Physician-reported NRG-RTOG Global Cosmetic Score (GCS) was grouped as excellent/good vs fair/poor, and arms compared with chi-square. <h3>Results</h3> 2262 of 2354 randomized pts were eligible (Arm I n=1124; Arm II n=1138). Median age 55 years, 34% Stage II, 52% grade 3, 30% ER-, 17% close/+ margins consistent with a "High Risk" population. Radiation was 3DCRT 81%, IMRT 19%, and the QA was per protocol 81% and 88% on Arm I vs II, respectively. With a median follow-up of 7.3 years and 56 IBR events, the 5 and 7-year IBR were 2.0% and 2.2% on Arm I and 1.9% and 2.6% on Arm II. The non-inferiority comparison (Arm I reference level) resulted in a HR (90% CI): 1.32 (0.84, 2.05) and p = 0.039, thus meeting non-inferiority. No differences in AEs noted between arms, with low rates of ≥ grade 3 treatment-related AEs, 3.3% vs 3.5% for Arm I vs II, respectively (p=0.79). No difference in 3-year excellent/good cosmesis by arm: 86% for Arm I vs 84% Arm II (p=0.61). <h3>Conclusion</h3> Concomitant boost with H-WBI results in non-inferior IBR compared to sequential boost after C-WBI in high-risk cases and reduces overall treatment time. Using target based 3DCRT or IMRT, there are no differences in toxicity or cosmetic outcome for concomitant v sequential boost or the WBI fractionation regimen.