HYPORT Adjuvant: One-week versus Three-week hypofractionated adjuvant breast radiotherapy in a high-risk Indian population — Protocol, Acute toxicity, Quality Assurance and Cardiac safety
Authors: Prof. Dr. Rajesh Balakrishnan
Institution: Christian Medical College, Vellore, India
Introduction
FAST-Forward established 26 Gy in 5 fractions as non-inferior to 40 Gy in 15 fractions, but in a predominantly older, screen-detected, breast-conserved population, without simultaneous integrated boost (SIB) and with little regional nodal irradiation (RNI). Its applicability to younger women with larger tumours, mastectomy, neoadjuvant chemotherapy (NACT) and RNI, the typical profile in India, is untested. HYPORT Adjuvant (NCT03788213) addresses this gap.
Methods
HYPORT Adjuvant is a multicentre, open-label, phase III non-inferiority randomised trial. Women with stage I–III invasive breast cancer needing adjuvant radiotherapy after breast-conserving surgery or mastectomy, including after NACT, were randomised to 40 Gy/15 fractions/3 weeks or 26 Gy/5 fractions/1 week to the breast or chest wall, with regional nodes as indicated. Randomisation was stratified by surgery type, RNI, triple-negative status and institute. Tumour-bed boost was delivered as SIB (8 Gy/15 fractions vs 6 Gy/5 fractions) or sequentially (12 Gy/4 fractions). The primary endpoint is 5-year locoregional recurrence (control 5%, non-inferiority margin 3%, n = 2100, 140 events, one-sided α 2.5%, power 80%). Secondary endpoints are overall survival, invasive disease-free survival, late toxicity and quality of life (QoL). Mandatory organ-at-risk constraints and patient-specific dosimetric QA were applied. Acute toxicity (CTCAE v5.0, to 23 weeks) was analysed in the first 271 patients. Cardiac risk was modelled from patient-level dose–volume histograms using EQD2 mean heart dose, the Darby dose–response model and Global Burden of Disease India ischaemic heart disease (IHD) mortality data.
Results
In the interim cohort (135 one-week, 136 three-week), 57% had mastectomy, 35% NACT, 73% grade III tumours and 71% supraclavicular RNI, and 105 received SIB. All mandatory dosimetric criteria were met except in one patient (contralateral breast dose with internal mammary nodal coverage). Median point-dose deviation was under 1% in both arms. With tangential fields, the median mean heart dose was 0.55 Gy (one week) versus 0.68 Gy (three weeks), and the median mean LAD dose was 1.59 versus 2.34 Gy. Maximum grade 2–3 dermatitis occurred in 2.9% versus 11.1%. Grade 3 dermatitis occurred in 0.7% versus 1.5%, all after mastectomy with scar bolus and none with SIB. No other grade ≥3 toxicity occurred. In the RNI cohort, EORTC QLQ-C30 and FACT-B global, functional and symptom scores were comparable between arms at 18 months. In a single-centre financial sub-study (n = 71), the one-week schedule lowered direct costs about 1.5-fold and carer productivity loss by 58% (p = 0.001); at six months, 71% versus 64% reported no financial toxicity. In the cardiac sub-study of 1075 patients (546 left-sided), estimated lifetime IHD-related mortality was 0.50% with five fractions versus 0.72% with fifteen (p < 0.001), an absolute excess below 1% despite a higher baseline IHD risk among Indian women.
Conclusion
One-week adjuvant breast radiotherapy, including SIB and RNI, is feasible and reproducibly quality-assured in a younger, higher-risk, unscreened Indian population. It produced less acute skin toxicity, equivalent QoL, lower financial burden and no excess, and possibly reduced, modelled cardiac mortality. Accrual is complete and follow-up for the primary 5-year locoregional endpoint is ongoing.