Patterns, Predictors, and Prognostic Value of Skeletal Muscle Mass Loss in Patients with Locally Advanced Head and Neck Cancer Undergoing Cisplatin-Based Chemoradiotherapy

Low skeletal muscle mass (SMM) is associated with toxicities and decreased survival in head and neck cancer (HNC). Chemoradiotherapy (CRT) may exaggerate loss of SMM. We investigated the changes in SMM, their predictors, and prognostic impact of SMM in patients treated with CRT between 2012 and 2018. Skeletal muscle area (SMA) segmentation was performed on pre- and post-CRT imaging. Observed changes in SMM were categorized into: (I) Stable, (II) moderate gain (III), moderate loss, (IV) large gain, and (V) large loss. In total, 235 HNC patients were included, of which 39% had stable SMM, 55% moderate loss, 13% moderate gain, 0.4% large loss, and 0.4% large gain of SMM. After CRT, SMA decreased compared to pre-CRT (31.6 cm(2) versus 33.3 cm(2), p = 30 kg/m(2) (OR 3.6, 95% CI 1.4-9.3, p < 0.01). Low SMM at diagnosis (HR 2.1; 95% CI 1.1-4.1, p = 0.03) and an HPV-positive oropharyngeal tumor (HR 0.1; 95% CI 0.01-0.9, p = 0.04) were prognostic for overall survival. Changes in SMM were not prognostic for survival. Loss of SMM is highly prevalent after CRT and a high BMI before treatment may aid in identifying patients at risk

Masseter muscle parameters can function as an alternative for skeletal muscle mass assessments on cross-sectional imaging at lumbar or cervical vertebral levels

Background: Patients with head and neck cancer are at increased risk of developing low skeletal muscle mass (SMM), which is associated with adverse treatment outcomes and prognosis. Low SMM is most commonly assessed by the skeletal muscle cross sectional area (CSA) at the third lumbar vertebra (L3) or more recently the third cervical vertebra (C3). L3 is not routinely imaged and C3 may be impacted by disease or treatment. As an alternative we analyzed masseter muscle characteristics and their relationship with L3 and C3 skeletal muscle CSA and overall survival (OS). Methods: In this single-center retrospective study, 99 patients with head and neck cancer who underwent whole body FDG-PET/CT-scans were reviewed. Of these patients, L3 CSA, C3 CSA, masseter CSA, masseter thickness, masseter volume, masseter Hounsfield Unit values, lumbar skeletal muscle index (LSMI), cervical skeletal muscle index (CSMI), and masseter skeletal muscle index (MSMI) were recorded and correlated with each other and with OS. Results: We included 72 male and 27 female patients. The masseter muscle parameters differed significantly between sexes. The Spearman correlation coefficients for C3 CSA-Masseter volume and L3 CSA-Masseter volume were 0.639 and 0.531 (P<0.001) respectively. In multivariate analysis low MSMI was a predictor of OS (HR 2.227, P=0.009). Conclusions: There is a moderate to strong association between the masseter muscle volume (MV) and C3 CSA and L3 CSA. MSMI predicts OS. Further research should investigate the relationship between muscle function and masseter muscle parameters and impacting factors on masseter muscle dimensions

Cut-off values for low skeletal muscle mass at the level of the third cervical vertebra (C3) in patients with head and neck cancer

Background: Low skeletal muscle mass is associated with adverse outcomes in patients with cancer. For patients with head and neck cancer (HNC), skeletal muscle mass is often assessed at the third cervical vertebra on head and neck imaging. Due to the unavailability of standardized cut-off values for low skeletal muscle mass in patients with head and cancer, there is heterogeneousness of cut-off values for low skeletal muscle mass described in literature. Therefore, we aim to provide standardized cut-off values for low skeletal muscle mass in HNC patients. Methods: A retrospective cohort study was performed. Between 2008 and 2018, HNC patients with head and neck imaging were included. Skeletal muscle area (SMA) was manually delineated at the level of the third cervical vertebra and corrected for patients squared height to obtain the cervical skeletal muscle mass index. Gender and body-mass index specific cut-off values for low skeletal muscle mass were calculated based on mean cervical skeletal muscle mass index minus 2 standard deviations as suggested in literature. Results: Of the 1,415 included patients, the majority was male (69.8%) and had a body mass index below 25 kg/m2 (59.2%). A primary tumor localization in the oropharynx (35.3%) and a tumor, node, metastasis stage IV tumor (60.5%) were most frequently observed. Cervical skeletal muscle mass index was significantly correlated with gender (r2=0.4, P<0.01) and body mass index (r2=0.4, P<0.01). For male patients with a body mass index <25 and ≥25 kg/m2, a cervical skeletal muscle mass index of respectively ≤6.8 and ≤8.5 cm2/m2 was defined for low skeletal muscle mass. For female patients with a body mass index <25 and ≥25 kg/m2, a cervical skeletal muscle mass index of respectively ≤5.3 and ≤6.4 cm2/m2 was defined for low skeletal muscle mass. Conclusions: This study is the first to provide standardized cut-off values for low skeletal muscle mass at the level of the third cervical vertebra in patients with HNC. This information may aid in the uniformity of low skeletal muscle mass definition in research

The predictive value of low skeletal muscle mass assessed on cross-sectional imaging for anti-cancer drug toxicity: A systematic review and meta-analysis

Low skeletal muscle mass (LSMM) is increasingly recognized for its predictive value for adverse events in cancer patients. In specific, the predictive value of LSMM has been demonstrated for anti-cancer drug toxicity in a variety of cancer types and anti-cancer drugs. However, due to the limited sample size and study populations focused on a single cancer type, an overall predictive value of LSMM for anti-cancer drug toxicity remains unknown. Therefore, this review aims to provide a comprehensive overview of the predictive value of LSMM and perform a meta-analysis to analyse the overall effect. A systematic search was conducted of MEDLINE, Scopus, EMBASE, and Cochrane. Inclusion criteria were skeletal muscle mass (SMM) evaluated with computed tomography (CT) or magnetic resonance imaging (MRI), articles published in English, SMM studied in humans, SMM measurement normalized for height, and patients did not receive an intervention to treat or prevent LSMM. A meta-analysis was performed using a random-effects model and expressed in odds ratio (OR) with 95% confidence interval (CI). Heterogeneity was assessed using χ2 and I2 statistics. The search yielded 907 studies. 31 studies were included in the systematic review. Sample sizes ranged from 21 to 414 patients. The occurrence of LSMM ranged from 12.2% to 89.0%. The most frequently studied cancer types were oesophageal, renal, colorectal, breast, and head and neck cancer. Patients with LSMM had a higher risk of severe toxicity (OR 4.08; 95% CI 2.48–6.70; p < 0.001) and dose-limiting toxicity (OR 2.24; 95% CI 1.28–3.92; p < 0.001) compared to patients without LSMM. To conclude, the predictive value of LSMM for anti-cancer drug toxicity can be observed across cancer types. This information increases the need for further research into interventions that could treat LSMM as well as the possibility to adapt treatment regimens based on the presence of LSMM

Sarcopenia measured with handgrip strength and skeletal muscle mass to assess frailty in older patients with head and neck cancer

OBJECTIVES: Patients with head and neck cancer (HNC) have a risk of sarcopenia which is associated with adverse health outcomes. Frailty is also associated with adverse outcomes and is diagnosed by a comprehensive geriatric assessment (CGA). Because a CGA is time-consuming and not all patients benefit from it, frailty screening questionnaires are used to select patients for CGA. Sarcopenia measurement may be a biomarker for frailty. Our objective was to examine the association between sarcopenia and a frailty screening questionnaire. MATERIALS AND METHODS: In this single-center retrospective study, 150 patients (≥ 60-years old) with HNC were reviewed. Sarcopenia was defined as the combination of reduced handgrip strength and loss of skeletal muscle mass, calculated as skeletal muscle index (SMI), according to the EWGSOP-criteria. Frailty screening was performed using the Geriatrics 8 (G8) questionnaire. RESULTS: The 150 patients included 101 men and 49 women. Frail patients were more likely to be sarcopenic at diagnosis. G8 frailty score showed a significant though weak correlation with SMI. Univariate regression analysis with frailty as a dependent variable distinguished comorbidity score, handgrip strength, SMI, and sarcopenia as significant. These variables were subjected to a multivariate analysis in which comorbidity score and SMI remained significant. CONCLUSION: There is an association between sarcopenia and the G8 frailty screening questionnaire. Therefore, sarcopenia measurement could be interchangeable with the G8 frailty screening questionnaire. Further research should compare the gold standard for frailty, i.e. CGA, with sarcopenia

Feasibility of assessment of skeletal muscle mass on a single cross-sectional image at the level of the fourth thoracic vertebra

Background Skeletal muscle mass (SMM) determined on computed tomography (CT) is emerging as a novel imaging biomarker. Cross-sectional area (CSA) of SMM at the level of the third lumbar vertebra (L3) on abdominal imaging is considered the clinical reference standard for measuring SMM. In certain patient groups, such as those with oncological or non-oncological lung disease like COVID-19, a chest CT may be available while an abdominal CT is not. The purpose of this study was to investigate whether determining SMM on a chest CT is a feasible alternative to abdominal CT.  Research question What is the correlation between SMM measurements at the level of L3 and the level of the fourth thoracic vertebra (Th4)?  Study design and methods  In this study we retrospectively analyzed abdominal and thoracic series of whole-body CT-scans of trauma patients (N = 47) and head and neck cancer patients (N = 194). All abdominal muscles were delineated on a single axial slice at the level of L3. The erector spinae, levator scapulae, rhomboideus minor and major and pectoralis minor and major muscles were delineated on a single axial slice at the level of Th4. CSA of the muscles at Th4 and the L3 level were compared using linear regression, and a multivariate linear regression model was established.  Results Muscle CSA at level Th4 strongly correlates with L3 muscle CSA (r = 0.791, p < 0.05). A multivariate model incorporating the patient characteristics arm positioning, age, sex, and weight achieved a stronger correlation (r = 0.856, p < 0.05). Interpretation: Skeletal muscle CSA measured at the level of Th4 is a feasible alternative to measurements at L3. This allows diagnosing low SMM using clinically available thoracic CT-scans. SMM measurements at the level of Th4 may become a prognostic or triage tool when faced with mechanical ventilator shortage

The association of pretreatment low skeletal muscle mass with chemotherapy dose-limiting toxicity in patients with head and neck cancer undergoing primary chemoradiotherapy with high-dose cisplatin

BACKGROUND: Low skeletal muscle mass (SMM) is an adverse prognostic factor for chemotherapy dose-limiting toxicity (CDLT). In patients with locally advanced head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy (CRT), low SMM is a predictor for CDLT. We aimed to validate these findings. METHODS: Consecutive LA-HNSCC patients treated with primary CRT with high-dose cisplatin were retrospectively included. SMM was measured on pre-treatment CT-imaging. A cumulative cisplatin dose below 200 mg/m 2 was defined as CDLT. RESULTS: One hundred and fifty three patients were included; 37 (24.2%) experienced CDLT, and 84 had low SMM (54.9%). Patients with low SMM experienced more CDLT than patients with normal SMM (35.7% vs. 10.1%, p < 0.01). Low SMM (OR 3.99 [95% CI 1.56-10.23], p = 0.01) and an eGFR of 60-70 ml/min (OR 5.40 [95% CI 1.57-18.65], p < 0.01) were predictors for CDLT. CONCLUSION: Pre-treatment low SMM is associated with CDLT in LA-HNSCC patients treated with primary CRT. Routine SMM assessment may allow for CDLT risk assessment and treatment optimization

The association of cisplatin pharmacokinetics and skeletal muscle mass in patients with head and neck cancer: The prospective PLATISMA study

Background: Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with cisplatin-based chemoradiotherapy (CRT). Cisplatin is associated with severe toxicity, which negatively affects survival. In recent years, a relationship between low skeletal muscle mass (SMM) and increased toxicity has been described. This increased toxicity may be related to altered cisplatin distribution and binding in the fat-free body mass of which SMM is the largest contributor. This study aims to investigate the association between cisplatin pharmacokinetics and SMM in patients with HNSCC. Methods: We performed a prospective observational study in patients with HNSCC treated with CRT. Patients received standard-of-care chemotherapy with three cycles of cisplatin at a dose of 100 mg/m 2 per cycle. Quantitative data on SMM, measured on computed tomography scans and cisplatin pharmacokinetics (total and ultrafilterable plasma concentrations) were collected, as well as data on toxicity. Results: A total of 45 evaluable patients were included in the study. A large proportion of the study population had a low SMM (46.7%). The majority of patients (57.8%) experienced cisplatin dose-limiting toxicities. Pharmacokinetic analysis showed a significant relationship between cisplatin pharmacokinetics and SMM, weight, fat-free mass and body surface area (p < 0.005). In a simulation, patients with a low SMM (<25.8 kg) were predicted to reach higher-bound cisplatin concentrations. Conclusion: We found an association between cisplatin pharmacokinetics and SMM; however, this relationship was also seen between cisplatin pharmacokinetics and other body composition descriptors

Arterial calcification on preoperative computed tomography imaging as a risk factor for pharyngocutaneous fistula formation after total laryngectomy

BACKGROUND: Research in esophageal surgery showed that computed tomography (CT) assessed arterial calcification (AC) is associated with postoperative complications. We investigated the association between AC and pharyngocutaneous fistula (PCF) formation after laryngectomy. METHODS: This was a retrospective cohort study of patients undergoing laryngectomy. AC was scored at 10 different anatomical locations on CT imaging, blinded for PCF occurrence. Association with PCF was investigated using logistic regression. RESULTS: The 224 patients were included; 62 (27.7%) developed a PCF. Moderate to severe AC was widespread in patients undergoing TL; 7.1% of patients had at most mild AC, of whom 1 experienced a PCF (p = 0.05). A higher cumulative calcification score was associated with PCF in univariable (OR 1.11, p = 0.04) and multivariable analysis (OR 1.14, p = 0.05). CONCLUSION: AC is widespread in patients undergoing laryngectomy and its burden is associated with PCF. Extensive AC on preoperative imaging may be considered a risk factor for PCF

Systematic review with meta-analysis: branched-chain amino acid supplementation in liver disease

BACKGROUND: Dietary supplementation with branched-chain amino acids (BCAA) is often used in cirrhotic patients to improve nutritional status. We wanted to explore the evidence for BCAA supplementation in chronic liver disease. METHODS: We searched MEDLINE and EMBASE for studies with BCAA supplementation with the presence of a disease-control group (placebo or no intervention) using search terms 'liver cirrhosis', 'hepatocellular carcinoma', 'branched chain amino acids' and relevant synonyms. Risk of bias was assessed using ROBINS-I and RoB 2.0 tools. Meta-analyses were performed with a random-effects model. Results were reported following EQUATOR guidelines. RESULTS: Of 3378 studies screened by title and abstract, 54 were included (34 randomized controlled trials, 5 prospective case-control studies, 13 retrospective case-control studies: in total 2308 patients BCAA supplementation, 2876 disease-controls). Risk of bias was high/serious for almost all studies. According to meta-analyses, long-term (at least 6 months) BCAA supplementation in cirrhotic patients significantly improved event-free survival (p = .008; RR .61 95% CI .42-.88) and tended to improve overall survival (p = .05; RR .58 95% CI .34-1.00). Two retrospective studies suggested the beneficial effects during sorafenib for hepatocellular carcinoma. Available studies reported no beneficial effects or contradictory results of BCAA after other specific therapeutic interventions (resection or radiological interventions for hepatocellular carcinoma, liver transplantation, paracentesis or variceal ligation). No convincing beneficial effects of BCAA supplementation on liver function, nutritional status or quality of life were found. No study reported serious side effects of BCAA. CONCLUSIONS: Prophylactic BCAA supplementation appears safe and might improve survival in cirrhotic patients