Patient-Reported and Toxicity Results from the FABREC Study: A Multicenter Randomized Trial of Hypofractionated vs. Conventionally-Fractionated Postmastectomy Radiation Therapy after Implant-Based Reconstruction

Purpose/Objective(s) This randomized trial of fractionation after breast reconstruction (FABREC) sought to compare quality-of-life (QOL) and clinical outcomes of hypofractionated (HF) vs. conventionally-fractionated (CF) postmastectomy radiation therapy (PMRT) in the setting of immediate prosthetic reconstruction. Materials/Methods Between 3/2018 and 11/2021, 400 patients at 18 centers with Stage 0-III breast cancer and immediate placement of tissue expander (TE) or implant (I) after mastectomy were randomized 1:1 to HF or CF photon PMRT. Respective doses in the two arms were 42.56 Gy/16 fractions to the chest wall (CW), with or without axillary/supraclavicular lymph node (LN) radiation (39.9 Gy/15 fractions) and 50 Gy in 25 fractions to CW (46-50 Gy to axillary LNs). A boost was not permitted; bolus was used at physician discretion. CW toxicity was defined as any grade ≥3 adverse event (CTCAE) after PMRT initiation. Patients were censored at study withdrawal or at diagnosis of distant recurrence. Participants completed QOL instruments (FACT-B, BREAST-Q, Lymph-ICF) at baseline, 6, 12 and 18-months from PMRT initiation. Questions regarding financial burden were included with the 6-month survey. Primary endpoint of the study was improvement in the Physical Well-Being (PWB) domain of FACT-B at 6 months with pre-specified stratification by age (younger than 45 vs. 45 years or older). QOL scores were compared using Student's t-test. Results Median follow-up for the 385 patients analyzed was 31.8 months (range, 6.9-54.4); median age was 47.0 years (range, 23-79). Preoperative chemotherapy was used in 67.8% and preoperative endocrine therapy (ET) in 21.5% of the cohort. There were 16 distant (8 in each arm), and 2 local-regional (1 in each arm) recurrences. CW toxicity occurred in 35 patients (19 HF, 16 CF, p=0.58) at medians of 3.4 and 4.8 months after RT initiation in the HF and CF arms, respectively (p=0.82). Post-operative infection before RT (HR=3.31, p=0.03), irradiation of TE vs I (HR=7.74, p=0.046), preoperative endocrine therapy (HR=3.45, p=0.0007) and number of LNs removed (HR=1.06/node, p=0.02) were significant for developing CW toxicity on multivariate analysis, while fractionation was not (HF HR=1.19, p=0.63). There was no significant difference in overall change in PWB scores at 6 months between the two treatment arms (p=0.71) or separately in younger (p=0.15) and older cohorts (p=0.27). However, HF patients younger than 45 were less bothered by side-effects of treatment (p=0.045) and nausea (p=0.02) vs. CF patients younger than 45. Among patients who took unpaid time off from work during treatment (n=51), those receiving HF required fewer hours off than those receiving CF (73.7 vs. 125.8, p=0.046). Conclusion Physical well-being and overall toxicity profile of HF PMRT were comparable between HF and CF PMRT. HF was associated with better 6-month QOL in some domains among younger patients. Our early results support the use of HF PMRT in the setting of TE- or implant-based breast reconstruction. This randomized trial of fractionation after breast reconstruction (FABREC) sought to compare quality-of-life (QOL) and clinical outcomes of hypofractionated (HF) vs. conventionally-fractionated (CF) postmastectomy radiation therapy (PMRT) in the setting of immediate prosthetic reconstruction. Between 3/2018 and 11/2021, 400 patients at 18 centers with Stage 0-III breast cancer and immediate placement of tissue expander (TE) or implant (I) after mastectomy were randomized 1:1 to HF or CF photon PMRT. Respective doses in the two arms were 42.56 Gy/16 fractions to the chest wall (CW), with or without axillary/supraclavicular lymph node (LN) radiation (39.9 Gy/15 fractions) and 50 Gy in 25 fractions to CW (46-50 Gy to axillary LNs). A boost was not permitted; bolus was used at physician discretion. CW toxicity was defined as any grade ≥3 adverse event (CTCAE) after PMRT initiation. Patients were censored at study withdrawal or at diagnosis of distant recurrence. Participants completed QOL instruments (FACT-B, BREAST-Q, Lymph-ICF) at baseline, 6, 12 and 18-months from PMRT initiation. Questions regarding financial burden were included with the 6-month survey. Primary endpoint of the study was improvement in the Physical Well-Being (PWB) domain of FACT-B at 6 months with pre-specified stratification by age (younger than 45 vs. 45 years or older). QOL scores were compared using Student's t-test. Median follow-up for the 385 patients analyzed was 31.8 months (range, 6.9-54.4); median age was 47.0 years (range, 23-79). Preoperative chemotherapy was used in 67.8% and preoperative endocrine therapy (ET) in 21.5% of the cohort. There were 16 distant (8 in each arm), and 2 local-regional (1 in each arm) recurrences. CW toxicity occurred in 35 patients (19 HF, 16 CF, p=0.58) at medians of 3.4 and 4.8 months after RT initiation in the HF and CF arms, respectively (p=0.82). Post-operative infection before RT (HR=3.31, p=0.03), irradiation of TE vs I (HR=7.74, p=0.046), preoperative endocrine therapy (HR=3.45, p=0.0007) and number of LNs removed (HR=1.06/node, p=0.02) were significant for developing CW toxicity on multivariate analysis, while fractionation was not (HF HR=1.19, p=0.63). There was no significant difference in overall change in PWB scores at 6 months between the two treatment arms (p=0.71) or separately in younger (p=0.15) and older cohorts (p=0.27). However, HF patients younger than 45 were less bothered by side-effects of treatment (p=0.045) and nausea (p=0.02) vs. CF patients younger than 45. Among patients who took unpaid time off from work during treatment (n=51), those receiving HF required fewer hours off than those receiving CF (73.7 vs. 125.8, p=0.046). Physical well-being and overall toxicity profile of HF PMRT were comparable between HF and CF PMRT. HF was associated with better 6-month QOL in some domains among younger patients. Our early results support the use of HF PMRT in the setting of TE- or implant-based breast reconstruction.