Skeletal Muscle Loss during Multikinase Inhibitors Therapy: Molecular Pathways, Clinical Implications, and Nutritional Challenges

In cancer patients, loss of muscle mass is significantly associated with low tolerability of chemotherapy and poor survival. Despite the great strides in the treatment of cancer, targeted therapies such as tyrosine kinase inhibitors (TKIs) could exacerbate muscle wasting. Over recent years, the impact of skeletal muscle loss during TKI therapy on clinical outcomes has been in the spotlight. In this review, we focus on the different molecular pathways of TKIs potentially involved in muscle wasting. Then, we report the results of the studies assessing the effects of different TKI therapies—such as sorafenib, regorafenib, sunitinib, and lenvatinib—on muscle mass, and highlight their potential clinical implications. Finally, we discuss an integrative nutritional approach to be adopted during TKI treatment. The assessment of muscle mass from computerized tomography imaging could be helpful in predicting toxicity and prognosis in patients treated with TKI such as sorafenib. Early recognition of low muscle mass and effective personalized nutritional support could prevent or attenuate muscle mass wasting. However, the role of nutrition is still overlooked, and future clinical trials are needed to find the optimal nutritional support to countermeasure muscle mass depletion during TKI therapy.

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Delving into disability in Crohn's disease: Dysregulation of molecular pathways may explain skeletal muscle loss in Crohn's disease

Journal of Crohn s and Colitis ◽

10.1016/j.crohns.2013.11.024 ◽

2014 ◽

Vol 8 (7) ◽

pp. 626-634 ◽

Cited By ~ 32

Author(s):

D.R. van Langenberg ◽

P. Della Gatta ◽

B. Hill ◽

E. Zacharewicz ◽

P.R. Gibson ◽

...

Keyword(s):

Skeletal Muscle ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Molecular Pathways ◽

Muscle Loss ◽

Skeletal Muscle Loss

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The Impact of Critical Illness on Skeletal Muscle Structure

10.1093/med/9780199653461.003.0034 ◽

2014 ◽

Author(s):

Catherine L Hough

Keyword(s):

Skeletal Muscle ◽

Critical Illness ◽

Thick Filament ◽

Muscle Membrane ◽

Type I ◽

Muscle Loss ◽

Muscle Structure ◽

Muscle Necrosis ◽

Skeletal Muscle Loss ◽

The Impact

Patients with critical illness are at risk of profound weakness and skeletal muscle loss, and recovery is marked by prolonged physical functional impairment in many survivors. Muscle and nerve abnormalities found in critically ill patients include loss of muscle mass, muscle membrane inexcitability, polyneuropathy, mitochondrial dysfunction with bioenergetic failure, as well as changes in skeletal muscle structure. The most common histological abnormalities are atrophy of both type I and II fibres and thick filament loss; muscle necrosis is less common. While recent studies have illuminated the pathogenesis of critical illness myopathy, additional high-quality translational research is needed to identify targets for therapeutic intervention.

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The impact of skeletal muscle loss for hepatocellular carcinoma treated with lenvatinib.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.493 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 493-493

Author(s):

Mao Okada ◽

Hiroyuki Nakanishi ◽

Masayuki Kurosaki ◽

Kento Inada ◽

Sakura Kirino ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Skeletal Muscle ◽

Dose Intensity ◽

Muscle Loss ◽

Muscle Area ◽

Chronological Change ◽

Significant Difference ◽

Skeletal Muscle Loss ◽

Tki Treatment ◽

The Impact

493 Background: Many previous reports have shown that skeletal muscle loss (SML) is one of the prognostic factors for hepatocellular carcinoma (HCC) patients treated with sorafenib. However, there are few reports about the impact of SML for the HCC patients treated with lenvatinib. Therefore, we evaluated the relation between SML and overall survival (OS) of HCC patients treated with lenvatinib (LEN). Methods: We retrospectively analyzed 50 HCC patients treated with LEN from April 2018 to February 2019. We included 36 patients who continued LEN more than 8 weeks and evaluated CT scans before treatment and after 8 weeks. Skeletal muscle area was measured on axial image at the level of the third lumber vertebra (L3) using sliceOmatic. Skeletal Mass Index (SMI) was calculated by dividing the muscle area (㎠) with square of height (㎡). The definition of myopenia is based on the guideline described by the Japan Society of Hepatology (42㎠/㎡ in men and 38 ㎠/㎡ in women). ΔSMI is a chronological change of SMI for 8 weeks. We calculated decreasing rate of ΔSMI. We evaluated the relation between chronological change of SMI and OS. Results: The patients with myopenia at baseline were 12 (33.3 %). The decreasing rate of ΔSMI at 8 weeks was -2.57 % [-5.9, 0.2]. SMI had decreased in 27 patients (75 %) for 8 weeks. There was no significant difference between OS and baseline myopenia (p = 0.2), ALBI grade (p = 0.2), BCLC stage (p = 0.5), up to 7 in or out (p = 0.35), previous TKI treatment (p = 0.15), metastasis (p = 0.91), or vascular invasion (p = 0.12). However, the patients who had decreased SMI had significantly poor prognosis (p = 0.028). In backgrounds, there was no significant difference between patients with or without decreasing of ΔSMI, such as baseline myopenia (p = 0.7), ALBI grade (p = 0.4), BCLC stage (p = 1.0), Child Pugh score (p = 0.8), age (p = 0.6), sex (p = 0.3), up to7 in or out (p = 1.0), previous TKI treatment (p = 0.3), and relative dose intensity at 4 weeks (p = 0.9). Conclusions: There was no significant correlation between baseline myopenia and OS. However, chronological decreasing of SMI for 8 weeks was a prognostic factor of HCC patients treated with LEN. Therefore, monitoring and preventing of decreasing of skeletal muscle mass may be important.

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Impact of preoperative nutritional support on patients with skeletal muscle loss undergoing pancreatoduodenectomy

HPB ◽

10.1016/j.hpb.2020.11.716 ◽

2021 ◽

Vol 23 ◽

pp. S284

Author(s):

M. Tsukagoshi ◽

N. Harimoto ◽

K. Araki ◽

N. Kubo ◽

A. Watanabe ◽

...

Keyword(s):

Skeletal Muscle ◽

Nutritional Support ◽

Muscle Loss ◽

Skeletal Muscle Loss

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Skeletal muscle loss after total gastrectomy, exacerbated by adjuvant chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.168 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 168-168

Author(s):

Kazumasa Fujitani ◽

Yusuke Yamaoka ◽

Toshimasa Tsujinaka ◽

Kazuyoshi Yamamoto ◽

Motohiro Hirao ◽

...

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Adjuvant Chemotherapy ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Significant Loss ◽

Muscle Loss ◽

Clinical Factors ◽

Improved Outcomes ◽

Skeletal Muscle Loss

168 Background: Skeletal muscle loss is associated with physical disability, nosocomial infections, postoperative complications, and decreased survival. Preventing the loss of skeletal muscle mass after gastrectomy may lead to improved outcomes. The aims of this study were to assess changes in skeletal muscle mass after total gastrectomy (TG) and to clarify the clinical factors affecting significant loss of skeletal muscle after TG. Methods: One hundred and two patients undergoing TG for primary gastric cancer underwent abdominal computed tomography (CT) before and 1 year after TG to precisely quantify postoperative changes in skeletal muscle and adipose tissue. Univariate and multivariate logistic regression analyses identified clinical factors contributing to significant loss of skeletal muscle after TG. Results: At 1 year after TG, the mass of both skeletal muscle and adipose tissue was reduced by 6.20±6.80% and 65.8±36.1% of the preoperative values, respectively, and 26 patients (25.5%) showed a significant loss of skeletal muscle of more than 10%. Adjuvant chemotherapy with S-1 for ≥6 months (hazard ratio 26.75, 95% confidence interval 3.511 to 203.9) was identified as the single independent risk factor for a significant loss of skeletal muscle. Conclusions: Skeletal muscle loss was exacerbated by extended adjuvant chemotherapy after TG. Further research should identify appropriate nutritional interventions for maintaining skeletal muscle mass and leading to improved outcomes.

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Association between Skeletal Muscle Loss and the Response to Neoadjuvant Chemotherapy for Breast Cancer

Cancers ◽

10.3390/cancers13081806 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1806

Author(s):

Byung Min Lee ◽

Yeona Cho ◽

Jun Won Kim ◽

Sung Gwe Ahn ◽

Jee Hung Kim ◽

...

Keyword(s):

Breast Cancer ◽

Skeletal Muscle ◽

Neoadjuvant Chemotherapy ◽

Cancer Patients ◽

Muscle Loss ◽

Breast Cancer Patients ◽

Skeletal Muscle Index ◽

Skeletal Muscle Loss ◽

The Impact ◽

Response To Neoadjuvant Chemotherapy

There are no means to predict patient response to neoadjuvant chemotherapy (NAC); the impact of skeletal muscle loss on the response to NAC remains undefined. We investigated the association between response to chemotherapy and skeletal muscle loss in breast cancer patients. Patients diagnosed with invasive breast cancer who were treated with NAC, surgery, and radiotherapy were analyzed. We quantified skeletal muscle loss using pre-NAC and post-NAC computed tomography scans. The response to treatment was determined using the Response Evaluation Criteria in Solid Tumors. We included 246 patients in this study (median follow-up, 28.85 months). The median age was 48 years old (interquartile range 42–54) and 115 patients were less than 48 years old (46.7%). Patients showing a complete or partial response were categorized into the responder group (208 patients); the rest were categorized into the non-responder group (38 patients). The skeletal muscle mass cut-off value was determined using a receiver operating characteristic curve; it showed areas under the curve of 0.732 and 0.885 for the pre-NAC and post-NAC skeletal muscle index (p < 0.001 for both), respectively. Skeletal muscle loss and cancer stage were significantly associated with poor response to NAC in locally advanced breast cancer patients. Accurately measuring muscle loss to guide treatment and delaying muscle loss through various interventions would help enhance the response to NAC and improve clinical outcomes.

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Interventional strategies to combat muscle disuse atrophy in humans: focus on neuromuscular electrical stimulation and dietary protein

Journal of Applied Physiology ◽

10.1152/japplphysiol.00985.2016 ◽

2018 ◽

Vol 125 (3) ◽

pp. 850-861 ◽

Cited By ~ 12

Author(s):

Marlou L. Dirks ◽

Benjamin T. Wall ◽

Luc J. C. van Loon

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Dietary Protein ◽

Nutritional Support ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Neuromuscular Electrical Stimulation ◽

Muscle Loss ◽

Disuse Atrophy ◽

Muscle Disuse

Numerous situations, such as the recovery from illness or rehabilitation after injury, necessitate a period of muscle disuse in otherwise healthy individuals. Even a few days of immobilization or bed rest can lead to substantial loss of skeletal muscle tissue and compromise metabolic health. The decline in muscle mass is attributed largely to a decline in postabsorptive and postprandial muscle protein synthesis rates. Reintroduction of some level of muscle contraction by the application of neuromuscular electrical stimulation (NMES) can augment both postabsorptive and postprandial muscle protein synthesis rates and, as such, prevent or attenuate muscle loss during short-term disuse in various clinical populations. Whereas maintenance of habitual dietary protein consumption is a prerequisite for muscle mass maintenance, supplementing dietary protein above habitual intake levels does not prevent muscle loss during disuse in otherwise healthy humans. Combining the anabolic properties of physical activity (or surrogates) with appropriate nutritional support likely further increases the capacity to preserve skeletal muscle mass during a period of disuse. Therefore, effective interventional strategies to prevent or alleviate muscle disuse atrophy should include both exercise (mimetics) and appropriate nutritional support.

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Thoracic Skeletal Muscle Quantification Using Computed Tomography And Prognosis Of Elderly ICU Patients

10.21203/rs.3.rs-144315/v1 ◽

2021 ◽

Author(s):

Sung Woo Moon ◽

Song Yee Kim ◽

Ji Soo Choi ◽

Ah Young Leem ◽

Su Hwan Lee ◽

...

Keyword(s):

Computed Tomography ◽

Skeletal Muscle ◽

Muscle Mass ◽

Sofa Score ◽

Pectoralis Muscle ◽

Muscle Loss ◽

Icu Patients ◽

Icu Admission ◽

Prolonged Ventilation ◽

Skeletal Muscle Loss

Abstract Background: In elderly ICU patients, the prevalence of skeletal muscle loss is high. And the consequences of skeletal muscle loss can be severe in elderly. Correlations have been found between the muscle cross-sectional area (CSA) at a single thoracic level on chest computed tomography (CT). Correlation between thoracic muscle mass and mortality has been found in ICU patients. But longitudinal effect of thoracic muscles especially in elderly ICU patients are unclear although skeletal muscle loss is related with the short- and long-term outcomes. Objective: This study aimed to evaluate whether pectoralis muscle mass could be a predictor of prognosis in elderly ICU patients.Methods: We retrospectively evaluated 190 elderly patients admitted in the ICU between January 2010 and December 2015 in one tertiary care hospital in South Korea. We measured the CSA of the pectoralis muscle area (PMCSA) at the fourth vertebral region. CT scans within two days before ICU admission were used for analysis. Mortality, prolonged mechanical ventilation, and longitudinal change in Sequential Organ Failure Assessment (SOFA) scores were examined. Multivariate logistic regression, linear mixed, and multivariate Cox proportional hazards models were used.Results: PMCSA below median was significantly related with prolonged ventilation. (odds ratio 2.92, 95% CI: 1.02-1.42, P=0.06) and a higher SOFA score during the ICU stay (estimated mean = 0.94, P = 0.03). PMCSA below median was a significant risk for all-cause mortality (HR: 2.06, 95% CI: 1.23-3.47, P=0.01)Conclusions: In elderly ICU patients, low ICU admission PMCSA was associated with prolonged ventilation, a higher SOFA score during the ICU stay and higher mortality. Adding thoracic skeletal muscle CSA at the time of ICU admission into consideration in deciding therapeutic intensity in elderly ICU patients may help in making medical decisions.

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Nutritional Approach to Cancer Cachexia: A Proposal for Dietitians

Nutrients ◽

10.3390/nu14020345 ◽

2022 ◽

Vol 14 (2) ◽

pp. 345

Author(s):

Kotone Tanaka ◽

Sho Nakamura ◽

Hiroto Narimatsu

Keyword(s):

Skeletal Muscle ◽

Nutritional Support ◽

Skeletal Muscle Mass ◽

Cancer Cachexia ◽

The Body ◽

Current Evidence ◽

Muscle Loss ◽

Related Factors ◽

Skeletal Muscle Loss

Cachexia is one of the most common, related factors of malnutrition in cancer patients. Cancer cachexia is a multifactorial syndrome characterized by persistent loss of skeletal muscle mass and fat mass, resulting in irreversible and progressive functional impairment. The skeletal muscle loss cannot be reversed by conventional nutritional support, and a combination of anti-inflammatory agents and other nutrients is recommended. In this review, we reviewed the effects of nutrients that are expected to combat muscle loss caused by cancer cachexia (eicosapentaenoic acid, β-hydroxy-β-methylbutyrate, creatine, and carnitine) to propose nutritional approaches that can be taken at present. Current evidence is based on the intake of nutrients as supplements; however, the long-term and continuous intake of nutrients as food has the potential to be useful for the body. Therefore, in addition to conventional nutritional support, we believe that it is important for the dietitian to work with the clinical team to first fully assess the patient’s condition and then to safely incorporate nutrients that are expected to have specific functions for cancer cachexia from foods and supplements.

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