CTRI

Background	Moderate three week hypofractionated adjuvant radiotherapy schedule is a standard care in breast cancers. A five day schedule has been demonstrated to be iso-toxic as a standard three week schedule. Recently studies have also demonstrated the safety and feasibility of simultaneous integrated boost in this setting. This randomized trial will investigate if a one-week course of hypofractionated breast radiotherapy is non-inferior to a three week course.
Aim	To determine if one-week schedule of adjuvant radiotherapy in breast cancer is non-inferior to a three week schedule.
Primary objective (endpoint)	Locoregional Recurrence Rate (LRR) (Cumulative incidence of locoregional recurrence) at 5 years
Secondary objectives (endpoints)	Overall survival (OS) (Time from randomization to death) Invasive Disease-free survival (iDFS) (Time from randomization to any invasive disease recurrence, death due to any cause or second invasive malignancy) Late adverse events (AE) Quality of Life (QoL)
Hypotheses	1 week schedule will be non-inferior to a three week schedule for Locoregional Recurrence Rate 1 week schedule will be non-inferior to a three week schedule for OS 1 week schedule will be not result in worse late adverse events as compared to 3 week schedule Proportion of patients decrease in quality of life will not differ between the two arms at 12 months
Design	Open-label, parallel group, two arm, randomised, phase III, non-inferiority trial.
Population	Patients with breast cancer who need adjuvant radiotherapy after breast conservation or mastectomy.
Interventions	Patients will be randomized to 15 days or 5 days of radiotherapy to the whole breast or chest wall or reconstructed breast. Nodal radiation will be delivered as indicated. A simultaneous integrated boost (SIB) will be delivered to patients who need a tumor bed boost after breast cancer. The following dose schedules will be tested: Control Group: 40 Gy in 15 fractions (alongside SIB of 8 Gy) Test Group: 26 Gy in 5 fractions (alongside SIB of 6 Gy).
Outcomes and Measures	LRR : Cumulative incidence of ipsilateral Locoregional Recurrence after treatment at 5 years. OS: Time from randomization to the time of death due to any cause. Cumulative proportion reported at 5 years. iDFS: Time from randomization to any disease recurrence, death due to any cause or second primary invasive cancer. Cumulative proportion reported at 5 years. AE: Proportion of patients with late Grade 2 or more AE as defined by the CTCAE 5 criteria QoL: Proportion of patients with a worse summary score in the EORTC QLQ C30 at 12 months post-treatment as compared to the baseline score.
Assessments	History and Physical Examination before registration, completion of RT, every 6 months for 1st to 5th year.
Statistical considerations	The sample size is 2100 patients with equal allocation in each group. This provides 80% power with a 1 sided alpha error of 0.025 to exclude a worsening of 3% in the 5-year locoregional recurrence rate while assuming that the rate in the control arm is 95%. Stratification will be done based on the type of surgery (Breast conservation vs Mastectomy), node positivity (Node-positive or Node Negative) and Triple Negative Breast Cancer (TNBC) (yes or no). The total number of events required is 140 and an interim analysis is planned once 16 events would have occurred or at 3 years whichever is earlier.
Feasibility	Tata Medical Center treats approximately 300 new breast cancer patients annually with adjuvant radiotherapy and about 30% of the patients are referred outside. With the expansion of radiotherapy services approximately 500 new breast cancer patients would be treated at the center annually. It is thus feasible to recruit the required number of patients over a period of 5 years from Tata Medical Center itself. However for a trial of this magnitude we will be expanding the access to the trial to multiple centers and initial talks have been conducted with several national centers.
Significance	This study will provide level I evidence regarding the safety and efficacy of a 5-day schedule of radiotherapy. This will allow the establishment of a resource sparing schedule of radiotherapy that can result in significant direct and indirect cost savings.