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Abstract
Purpose: To develop and test a multivariable normal tissue complication probability (NTCP) model predicting lymphedema in patients with breast cancer receiving radiation therapy.

Methods and materials: We retrospectively reviewed 1345 patients with breast cancer who received radiation therapy from 2 independent institutions. The patients were divided into a training cohort (institution A, n = 368, all treated with 3-dimensional conformal external beam radiation therapy [RT] with 2 Gy/fraction) and an external validation cohort (institution B, n = 977, treated either with 3-dimensional conformal external beam RT or with volumetric modulated RT and either with 1.8-2.0 Gy/fraction or with 2.67 Gy/fraction). Axillary-lateral thoracic vessel juncture (ALTJ) was delineated. The multivariable model was generated using dosimetric and clinical parameters. The performance of the model was comprehensively validated internally and externally.

Results: During a median follow-up of 78.7 months for the entire cohort, 97 patients (7.2%) developed lymphedema. The multivariable model that took into account the number of lymph nodes dissected, as well as the volume of the ALTJ receiving a dose ≥35 Gy equivalent doses in 2-Gy fractions (ALTJ V35), showed good agreement between predicted and observed results for both internal and external validation (Hosmer-Lemeshow P value > .05). The area under the receiver operating characteristic curve (AUC) and negative log-likelihood values for the multivariable NTCP model were 0.89 and 0.19 in internal validation and 0.83 and 0.19 in external validation. In addition, the multivariable model performance was acceptable for hypofractionated regimens (AUC 0.70) and volumetric modulated arc therapy (AUC 0.69). The number of lymph nodes dissected and ALTJ V35 were found to be the most important factors influencing lymphedema after radiation therapy.

Conclusions: We first developed and validated the multivariable NTCP model for the lymphedema incidence in patients with breast cancer after radiation therapy. The multivariable NTCP model showed excellent performance and robustness in predicting lymphedema in both internal and completely independent external validations. The multivariable model for lymphedema prediction was robust and reliable for different treatment modalities and fractionation regimens.

Affiliations

Ye-In Park 1, Jee Suk Chang 1, Heejoo Ko 2, Sang Hee Im 3, Jin Sung Kim 1, Hwa Kyung Byun 1, Yong Bae Kim 1, Wonguen Jung 4, Kyubo Kim 5, Chae-Seon Hong 6
1Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea.
2College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
3Department of Rehabilitation Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
4Department of Radiation Oncology, Ewha Womans University College of Medicine, Seoul, Republic of Korea.
5Department of Radiation Oncology, Ewha Womans University College of Medicine, Seoul, Republic of Korea. Electronic address: kyubokim.ro@gmail.com.
6Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: cs.hong@yuhs.ac.