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In medRxiv : the preprint server for health sciences

PURPOSE : Sarcopenia is an established prognostic factor in patients diagnosed with head and neck squamous cell carcinoma (HNSCC). The quantification of sarcopenia assessed by imaging is typically achieved through the skeletal muscle index (SMI), which can be derived from cervical neck skeletal muscle (SM) segmentation and cross-sectional area. However, manual SM segmentation is labor-intensive, prone to inter-observer variability, and impractical for large-scale clinical use. To overcome this challenge, we have developed and externally validated a fully-automated image-based deep learning (DL) platform for cervical vertebral SM segmentation and SMI calculation, and evaluated the relevance of this with survival and toxicity outcomes.

MATERIALS AND METHODS : 899 patients diagnosed as having HNSCC with CT scans from multiple institutes were included, with 335 cases utilized for training, 96 for validation, 48 for internal testing and 393 for external testing. Ground truth single-slice segmentations of SM at the C3 vertebra level were manually generated by experienced radiation oncologists. To develop an efficient method of segmenting the SM, a multi-stage DL pipeline was implemented, consisting of a 2D convolutional neural network (CNN) to select the middle slice of C3 section and a 2D U-Net to segment SM areas. The model performance was evaluated using the Dice Similarity Coefficient (DSC) as the primary metric for the internal test set, and for the external test set the quality of automated segmentation was assessed manually by two experienced radiation oncologists. The L3 skeletal muscle area (SMA) and SMI were then calculated from the C3 cross sectional area (CSA) of the auto-segmented SM. Finally, established SMI cut-offs were used to perform further analyses to assess the correlation with survival and toxicity endpoints in the external institution with univariable and multivariable Cox regression.

RESULTS : DSCs for validation set (n = 96) and internal test set (n = 48) were 0.90 (95% CI: 0.90 - 0.91) and 0.90 (95% CI: 0.89 - 0.91), respectively. The predicted CSA is highly correlated with the ground-truth CSA in both validation (r = 0.99, p < 0.0001) and test sets (r = 0.96, p < 0.0001). In the external test set (n = 377), 96.2% of the SM segmentations were deemed acceptable by consensus expert review. Predicted SMA and SMI values were highly correlated with the ground-truth values, with Pearson r β 0.99 (p < 0.0001) for both the female and male patients in all datasets. Sarcopenia was associated with worse OS (HR 2.05 [95% CI 1.04 - 4.04], p = 0.04) and longer PEG tube duration (median 162 days vs. 134 days, HR 1.51 [95% CI 1.12 - 2.08], p = 0.006 in multivariate analysis.

CONCLUSION : We developed and externally validated a fully-automated platform that strongly correlates with imaging-assessed sarcopenia in patients with H&N cancer that correlates with survival and toxicity outcomes. This study constitutes a significant stride towards the integration of sarcopenia assessment into decision-making for individuals diagnosed with HNSCC.

SUMMARY STATEMENT : In this study, we developed and externally validated a deep learning model to investigate the impact of sarcopenia, defined as the loss of skeletal muscle mass, on patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy. We demonstrated an efficient, fullyautomated deep learning pipeline that can accurately segment C3 skeletal muscle area, calculate cross-sectional area, and derive a skeletal muscle index to diagnose sarcopenia from a standard of care CT scan. In multi-institutional data, we found that pre-treatment sarcopenia was associated with significantly reduced overall survival and an increased risk of adverse events. Given the increased vulnerability of patients with HNSCC, the assessment of sarcopenia prior to radiotherapy may aid in informed treatment decision-making and serve as a predictive marker for the necessity of early supportive measures.

Ye Zezhong, Saraf Anurag, Ravipati Yashwanth, Hoebers Frank, Zha Yining, Zapaishchykova Anna, Likitlersuang Jirapat, Tishler Roy B, Schoenfeld Jonathan D, Margalit Danielle N, Haddad Robert I, Mak Raymond H, Naser Mohamed, Wahid Kareem A, Sahlsten Jaakko, Jaskari Joel, Kaski Kimmo, Mäkitie Antti A, Fuller Clifton D, Aerts Hugo J W L, Kann Benjamin H