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Abstract
Objective: The aim of this study was to identify the comprehensive risk factors for lymphedema, thereby enabling a more informed multidisciplinary treatment decision-making.

Summary background data: Lymphedema is a serious long-term complication in breast cancer patients post-surgery; however, the influence of multimodal therapy on its occurrence remains unclear.

Methods: We retrospectively collected treatment-related data from 5549 breast cancer patients who underwent surgery between 2007 and 2015 at our institution. Individual radiotherapy plans were reviewed for regional nodal irradiation (RNI) field design and fractionation type. We identified lymphedema risk factors and used them to construct nomograms to predict individual risk of lymphedema. Nomograms were validated internally using 100 bootstrap samples and externally using 2 separate datasets of 1877 Asian and 191 Western patients.

Results: Six hundred thirty-nine patients developed lymphedema during a median follow-up of 60 months. The 3-year lymphedema incidence was 10.5%; this rate increased with larger irradiation volumes (no RNI vs RNI excluding axilla I-II vs RNI including axilla I-II: 5.7% vs 16.8% vs 24.1%) and when using conventional fractionation instead of hypofractionation (13.5% vs 6.8%). On multivariate analysis, higher body mass index, larger number of dissected nodes, taxane-based regimen, total mastectomy, larger irradiation field, and conventional fractionation were strongly associated with lymphedema (all P < 0.001). Nomograms constructed based on these variables showed good calibration and discrimination internally (concordance index: 0.774) and externally (0.832 for Asian and 0.820 for Western patients).

Conclusions: Trimodality breast cancer treatment factors interact to promote lymphedema. Lymphedema risk can be decreased by deintensifying node dissection, chemotherapy regimen, and field and dose of radiotherapy. Deescalation strategies on a multidisciplinary basis might minimize lymphedema risk.

Affiliations

Hwa Kyung Byun  1 , Jee Suk Chang  1 , Sang Hee Im  2 , Youlia M Kirova  3   4 , Alexandre Arsene-Henry  3 , Seo Hee Choi  1 , Young Up Cho  5 , Hyung Seok Park  5 , Jee Ye Kim  5 , Chang-Ok Suh  1   6 , Ki Chang Keum  1 , Joo Hyuk Sohn  7 , Gun Min Kim  7 , Ik Jae Lee  8 , Jun Won Kim  8 , Yong Bae Kim  1
1 Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
2 Department of Rehabilitation Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
3 Department of Radiation Oncology, Institut Curie, Paris, France.
4 University Versailles St Quentin, France.
5 Department of Surgery, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
6 Department of Radiation Oncology, Bundang CHA Medical Center, CHA University, Gyeonggi-do, Korea.
7 Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
8 Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.