Outcome of 15 Versus 5 Fractions in Adjuvant Breast Radiotherapy in Women Over 65 Years (HAI-5-III)

A Partially Randomized Patient Preference Trial, Comparing Adjuvant Hypofractionated Radiotherapy in 15 Versus 5 Fractions After Breast Conserving Surgery or Mastectomy for Early or Locally Advanced Breast Cancer in Women Above 65 Years

This study will evaluate the effect of highly accelerated external beam radiotherapy (EBRT) in 5 fractions over 10 days compared to 15 fractions over 3 weeks for early as well as locally-advanced stage breast cancer. Primary endpoint will be chronic toxicity (breast deformation and retraction). Secondary endpoints are acute toxicity, loco-regional and distant tumor control, patient reported QoL and cosmetic satisfaction. Patients with lymph node irradiation will be closely monitored for radiation induced plexopathy.

Over the age of 65, uptake of adjuvant radiotherapy after surgery for breast cancer declines, even in women with poor prognostic stage or adverse tumor characteristics. Lowering the number of fractions may reduce reluctancy for radiotherapy in this age group. In a preceding prospective phase I-II trial, evaluating EBRT over 10 days, results on technical feasibility and acute toxicity were positively evaluated. However, data on the chronic effects of breast irradiation using high doses per fraction are still sparse. This trial is developed to compare standard hypo-fractionation in 15 fractions (if needed with simultaneously integrated boost - SIB) with highly accelerated radiotherapy in 5 fractions. Patients referred for adjuvant radiotherapy after breast conserving surgery will preferably be randomized, depending on the indication, to a study-arm with whole breast irradiation (WBI) +/- SIB or to a study-arm with WBI+/- SIB and lymph node irradiation (LNI). If patients after breast conserving surgery (BCS) have a strong preference for 5 or 15 fractions, they will be invited to enter the parallel observational arm (patient preference). Patients referred for adjuvant radiotherapy after mastectomy +/- LNI accepting to participate, can choose a 5 or 15-fraction schedule. No randomization is foreseen in this last observational group.

Grade 1: mild; Grade 2: moderate, limiting activity of daily living (ADL); grade 3: severe, limiting ADL

Chronic toxicity - prevalence of radiation induced brachial plexopathy (RIBP) (standardized screening questionnaire), confirmed by electromyogram (EMG)

If a screening reveals unilateral pain, loss of function or muscular atrophy in the ipsilateral arm, an EMG will be performed to confirm/exclude RIBP

Number of patients alive and without breast cancer recurrence at 2 and 5 years after adjuvant radiotherapy

Patients can accept clinical trial but refuse randomization. In this case they will be allocated to a patient preference study arm, existing also of a 5 or 15 fraction-schedule. The choice of the patient: acceptance or non-acceptance of study, acceptance or non-acceptance of randomization, in case of patient preference arm: acceptance or 5 or 15 fractions.

Inclusion Criteria: breast conserving surgery or mastectomy for breast carcinoma multidisciplinary decision of adjuvant irradiation absence of distant metastases informed consent obtained, signed and dated before specific protocol procedures Exclusion Criteria: History of previous radiation treatment to the same region Bilateral breast irradiation Life expectancy of less than 2 years Planned reconstructive breast surgery Condition making toxicity evaluation difficult, e.g. skin disorders, pre-existing brachial plexus injury, … Inability to respect constraints on skin, heart, lungs, esophagus, ribs, brachial plexus or any other organ at risk Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study Patient unlikely to comply with the protocol; i.e. uncooperative attitude, inability to return for follow-up visits or unlikely to complete the study