Background Fatigue is a common and disabling symptom experienced by patients (pts) after breast cancer (BC) treatment, significantly impacting their quality of life. However, this complex and multidimensional symptom often remains poorly managed. Previous studies identified some treatment-related factors associated with increased risk of developing severe and persistent fatigue. A better understanding of the relationship between treatment modalities and fatigue may help prevention and management strategies.Multimodal BC treatment often includes radiotherapy (RT) to the breast and/or nodal areas. RT modalities are now increasingly personalized. While an association between receipt of RT and fatigue after BC was previously suggested, large-scale data analyzing the impact of distinct RT modalities on fatigue are lacking.Our aim was to assess the impact of RT modalities on fatigue one year after treatment among patients with early-stage BC. Methods CANcer TOxicity (CANTO; NCT01993498) is a large multicentric nationwide prospective cohort of patients with stage I-III BC diagnosed from June 2012 to February 2017. The present analysis was performed in CANTO-RT, a sub-cohort of CANTO including 3875 patients who received RT in one of the 10 top recruiting CANTO centers. Among those patients, we selected 3797 patients who received unilateral RT.Our primary outcome was severe global fatigue 1 year after RT completion, defined by EORTC QLQ-C30 score ≥ 40/100. Secondary outcomes included severe physical, emotional and cognitive dimensions of fatigue (EORTC QLQ-FA12). The following RT-related variables were used as independent variables: Technique (3D vs IMRT), type of fractionation: Normofractionation (NF) vs Hypofractionation (HF), Boost to tumor bed (Yes vs No), Nodal RT (Yes vs No) and internal mammary chain (IMC) RT (Yes vs No). Multivariable logistic regression models assessed associations between RT-related variables and fatigue, adjusting for clinical, tumor, and BC treatment-related covariates collected at BC diagnosis. Results Our analytic cohort included 3797 patients. Among them, 2348 patients were postmenopausal (63%), 2030 received chemotherapy (52%), and 3068 endocrine therapy (81%). The prevalence of severe global fatigue 1 year after treatment was 33.3%. In addition, 33.1%, 20.4%, and 12.9% of patients reported severe physical, emotional and cognitive fatigue, respectively. Conformal 3D RT was delivered in 3635 patients (96%) mostly NF (2Gy/fraction) (n=2707; 93%). The majority of patients (n=2600; 68%) received a boost. Nodal RT was delivered in 1317 patients (35%) including 819 patients (22%) with IMC RT. After correction for age, BMI, comorbidities, income, smoke behavior, anxiety, depression, receipt of chemo and endocrine therapy, there was a significant relationship between specific RT modalities and severe global fatigue. Specifically, receipt of IMC RT (adjusted OR vs. no 1.57 [95% CI 1.10-2.25; p=0.0134]) and NF RT (adjusted OR vs. HF 1.77 [95% CI 1.01-3.11; p=0.048]) were associated with increased odds of severe global fatigue.In addition, there was a significant association between NF RT (adjusted OR vs. HF 1.75 [95% CI 1.01-3.07; p=0.049]) and an increased likelihood of severe physical fatigue, whereas none of the investigated RT modalities seemed to be associated with emotional and cognitive fatigue dimensions. Conclusions More than one third of patients in this RT-treated cohort reported severe fatigue 1 year after treatment. We found a significant association between RT modalities, such as IMC RT and NF, and increased likelihood of severe global fatigue. NF was also associated with physical fatigue. Our data add to the current understanding of treatment-related factors that can impact fatigue after BC, and inform personalized interventions to improve prevention and management of this disabling symptom.

Citation Format: Youssef Ghannam, Antonio Di Meglio, Thomas Sarrade, Alexandra Jacquet, Sibille Everhard, Youlia Kirova, Karine Peigneaux, Philippe Guilbert, Claire Chara-Brunaud, Julien Blanchecotte, Gilles Crehange, David Pasquier, Séverine Racadot, Céline Bourgier, Julien Geffrelot, Ahmed Benyoucef, Francois Paris, Guillaume Auzac, Inès Vaz-Luis, Sofia Rivera. Improfib: Impact of radiotherapy on fatigue in breast cancer survivors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-07.