Treatment will be delivered 5 days a week treating one fraction a day. All fields will be treated together. Dosimetric quality assurance of all plans will be performed with point dose measurements along with fluence profile checks if IMRT is used. The center will prespecify the imaging verification protocol to be used for their patients.

Criteria for discontinuation and modifying allocated interventions {11b}

Breast cancer radiotherapy is not expected to result in substantial acute toxicity. Treatment should not be interrupted unless a patient has a Grade III-IV CTCAE adverse event. After this treatment can be restarted once the toxicity has reduced to Grade I or less and if in the treating physician’s opinion it is safe to continue with treatment.

Strategies to improve adhere to intervention {11c}

Patients will be counselled about the need to adhere to the treatment schedule. They will be reviewed weekly during treatment to discuss and manage any treatment related adverse events they may be encountering. Any missed fraction would be informed to the treating team and attempts will be made to communicate with the patient to avoid this in future.

Relevant concomitant care permitted or prohibited during the trial {11d}

No specific contraindications to any medication except for the receipt of concurrent chemotherapy. Patients may continue with planned endocrine therapy and anti-HER2 therapy during the course of radiotherapy.

Provisions for post-trial care {30}

Routine follow up care will be provided for all patients including appropriate clinical evaluation, adjuvant endocrine therapy, maintenance anti-HER2 therapy as well as chemotherapy as required. Compensation for trial related injuries will be provided as per extant Indian laws after the review by the Institutional review board.

Outcomes {12}

Primary Outcome

The primary outcome of interest is the locoregional recurrence, which is defined as any invasive recurrence in the ipsilateral breast or chest wall or ipsilateral axillary, supraclavicular or internal mammary lymph nodes (ipsilateral lymph nodes level 1 - 4 and internal mammary nodes as defined by Offersen et al(34)). Cumulative proportion of patients with locoregional recurrence at 5 years will be estimated and hazard ratio of the locoregional recurrence rate between the two groups will be reported.

Secondary Outcomes

  1. Overall survival: This is defined as the interval of time between the date of randomization to the date of death due to any cause. We will attempt to obtain the reason for death wherever feasible. The duration will be calculated using the actuarial method and patients who are alive at last follow up will be censored on the same date. Cumulative proportion of patients surviving at 5 years will be reported along with hazard ratio for the two arms.
  2. Invasive disease free survival: This is defined as the time from randomization to the time any recurrence (pre-invasive / invasive), distant metastases, death from any cause and second invasive primaries, including invasive neoplasms of the breast. Cumulative proportion of patients without invasive disease recurrence at 5 years will be reported along with hazard ratio for the two arms.
  3. Adverse Events (AE): The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be used to classify and grade the severity of adverse events. Clinician reported AE grades would be collected in addition to patient reported outcomes measures to be collected as a part of assessment of Quality of Life. Adverse events due to radiotherapy (CTCAE 5.0) will be classified into the following categories:
  4. Start of RT to 90 days after RT: Acute toxicity
  5. > 90 days after RT: Late toxicity.
  6. Quality of Life: Quality of life will be assessed using self administered EORTC QLQ C30 and the FACT-B questionnaires before the start of radiotherapy, at the end of radiotherapy and then at 6, 12 and 18 months. While various QoL endpoints are of interest, the primary QoL endpoint of interest will be the summary score of EORTC QLQ C30 derived from 15 questions as defined by Giesinger et al(37). We will be comparing the proportion of patients in whom the summary score of the EORTC QLQ C30 is equal to or better than the baseline at 12 months in the two arms.

Participant Timeline {13}

The participant timeline for treatment and assessments is shown in the table below.