Abstract
Background
Skeletal muscle loss is a hallmark of malignancies, including advanced gastric cancer (GC). Although programmed death (PD)-1 inhibitors, including nivolumab, have promising anti-cancer effects, there is limited information regarding markers that can predict these therapeutic effects, which include PD-ligand 1 (PD-L1) expression and the tumor mutation burden. Therefore, we evaluated whether the baseline psoas muscle mass index (PMI, a surrogate for skeletal muscle mass) could predict the response of GC to nivolumab treatment, based on progression-free survival (PFS), the objective response rate, and the disease control rate.
Methods
This retrospective study evaluated 31 Japanese patients who received nivolumab for advanced GC and underwent imaging analysis between November 2017 and November 2019. The computed tomography results were used to estimate the psoas major muscle mass. Sex-specific cut-off values were used for the PMI, with low PMI values defined as < 3.6 cm2/m2 for male patients and < 2.9 cm2/m2 for female patients.
Results
The median PFS interval was 2.3 months for the patients with stage IV GC. Nine patients (29%) had a low baseline PMI, and these patients had significantly shorter median PFS than the group with a non-low baseline PMI (0.5 months vs. 2.4 months, P = 0.004).
Conclusions
As a surrogate marker for skeletal muscle loss, the PMI may be useful for predicting the response to nivolumab among patients with advanced GC.
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References
Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 6:394–424
Katai H, Ishikawa T, Akazawa K et al (2018) Five-year survival analysis of surgically resected gastric cancer cases in Japan: a retrospective analysis of more than 100,000 patients from the nationwide registry of the Japanese Gastric Cancer Association (2001–2007). Gastric Cancer 1:144–154
Prado CM, Lieffers JR, McCargar LJ et al (2008) Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol 9:629–635
Martin L, Birdsell L, Macdonald N et al (2013) Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol 31:1539–1547
Ongaro E, Buoro V, Cinausero M et al (2017) Sarcopenia in gastric cancer: when the loss costs too much. Gastric Cancer 20:563–572
Shiroyama T, Nagatomo I, Koyama S et al (2019) Impact of sarcopenia in patients with advanced non-small cell lung cancer treated with PD-1 inhibitors: a preliminary retrospective study. Sci Rep 9:2447
Yamaoka Y, Fujitani K, Tsujinaka T et al (2015) Skeletal muscle loss after total gastrectomy, exacerbated by adjuvant chemotherapy. Gastric Cancer 18:382–389
Shiroyama T, Suzuki H, Tamiya M et al (2018) Pretreatment advanced lung cancer inflammation index (ALI) for predicting early progression in nivolumab-treated patients with advanced non-small cell lung cancer. Cancer Med 7:13–20
Nakamura R, Inage Y, Tobita R et al (2018) Sarcopenia in resected NSCLC: effect on postoperative outcomes. J Thorac Oncol 13:895–903
Kato K, Satoh T, Muro K et al (2019) A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2). Gastric Cancer 22:344–354
Gibney GT, Weiner LM, Atkins MB (2016) Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 17:e542-551
Mishima S, Kawazoe A, Nakamura Y et al (2019) Clinicopathological and molecular features of responders to nivolumab for patients with advanced gastric cancer. J Immunother Cancer 1:24
Ogata T, Satake H, Ogata M et al (2018) Neutrophil-to-lymphocyte ratio as a predictive or prognostic factor for gastric cancer treated with nivolumab: a multicenter retrospective study. Oncotarget 9:34520–34527
Cortellini A, Palumbo P, Porzio G et al (2018) Single-institution study of correlations between skeletal muscle mass, its density, and clinical outcomes in non-small cell lung cancer patients treated with first-line chemotherapy. Thorac Cancer 9:1623–1630
Hamaguchi Y, Kaido T, Okumura S et al (2016) Proposal for new diagnostic criteria for low skeletal muscle mass based on computed tomography imaging in Asian adults. Nutrition 32:1200–1205
National Cancer Institute (2009) Cancer Therapy Evaluation Program (CTEP), Common Toxicity Criteria (CTC) Version 4.0, Available from: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2:228–247
Heymsfield SB (2008) Development of imaging methods to assess adiposity and metabolism. Int J Obes (Lond) 32(Suppl 7):S76–S82
Mourtzakis M, Prado CM, Lieffers JR et al (2008) A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab 5:997–1006
Lutz CT, Quinn LS (2012) Sarcopenia, obesity, and natural killer cell immune senescence in aging: altered cytokine levels as a common mechanism. Aging (Albany NY) 4:535–546
Afzali AM, Muntefering T, Wiendl H et al (2018) Skeletal muscle cells actively shape (auto)immune responses. Autoimmun Rev 17:518–529
Heidelberger V, Goldwasser F, Kramkimel N et al (2017) Sarcopenic overweight is associated with early acute limiting toxicity of anti-PD1 checkpoint inhibitors in melanoma patients. Invest New Drugs 35:436–441
Mariathasan S, Turley SJ, Nickles D et al (2018) TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 7693:544–548
Tsukamoto H, Fujieda K, Miyashita A et al (2018) Combined blockade of IL6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Res 17:5011–5022
Pedersen BK, Febbraio MA (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8:457–465
Chamoto K, Chowdhury PS, Kumar A et al (2017) Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc Natl Acad Sci U S A 5:e761–e770
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Kano, M., Hihara, J., Tokumoto, N. et al. Association between skeletal muscle loss and the response to nivolumab immunotherapy in advanced gastric cancer patients. Int J Clin Oncol 26, 523–531 (2021). https://doi.org/10.1007/s10147-020-01833-4
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DOI: https://doi.org/10.1007/s10147-020-01833-4