Abstract
Purpose
Immune checkpoint inhibitors (ICIs) with anti-PD-1/PD-L1 antibody are promising treatments for hepatocellular carcinoma (HCC), but lack reliable biomarkers of response. In the present study, we aimed to investigate the correlation between pre-treatment body composition measures (muscle, adipose, etc.) and the prognosis of patients with HCC treated with ICIs.
Methods
We measured the total area of all skeletal muscles, total adipose tissue area, subcutaneous adipose tissue area, and visceral adipose tissue area at the level of the third lumbar vertebra using quantitative CT. Then, we calculated the skeletal muscle index, visceral adipose tissue index, subcutaneous adipose tissue index (SATI), and total adipose tissue index. The Cox regression model was used to determine the independent factors of the patient prognosis and construct a nomogram to predict survival. The consistency index (C-index) and calibration curve were used to determine the predictive accuracy and discrimination ability of the nomogram.
Results
Multivariate analysis revealed that the SATI (high- vs. low SATI; HR 0.251; 95% CI 0.109–0.577; P = 0.001), sarcopenia (sarcopenia vs. no sarcopenia; HR 2.171; 95% CI 1.100–4.284; P = 0.026), and portal vein tumor thrombus (PVTT) (PVTT vs. No PVTT; HR 2.429; 95% CI 1. 197–4. 929; P = 0.014) were indicated as independent prognostic factors for OS in multivariate analysis. Multivariate analysis indicated that Child–Pugh class (HR 0.477, 95% CI 0.257–0.885, P = 0.019) and sarcopenia (HR 2.376, 95% CI 1.335–4.230, P = 0.003) were independent prognostic factors of PFS. We established a nomogram using SATI, SA, and PVTT to predict the 12-month and 18-month survival probability of HCC patients treated with ICIs. The C-index of the nomogram was 0.754 (95% CI 0.686–0.823), and the calibration curve confirmed that the predicted results were in good agreement with the actual observations.
Conclusion
Subcutaneous adipose and sarcopenia are significant prognostic factors of patients with HCC receiving ICIs. A nomogram based on body composition parameters and clinical factors could well predict survival in HCC patients treated with ICIs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Adams TD, Heath EM, LaMonte MJ, Gress RE, Pendleton R, Strong M et al (2007) The relationship between body mass index and per cent body fat in the severely obese. Diabetes Obes Metab 9:498–505. https://doi.org/10.1111/j.1463-1326.2006.00631.x
Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10:7252–7259. https://doi.org/10.1158/1078-0432.CCR-04-0713
Chen J, Lu L, Qu C, Deng F, Cai M et al (2022) Body mass index, as a novel predictor of hepatocellular carcinoma patients treated with Anti-PD-1 immunotherapy. Front Med (lausanne) 9:981001. https://doi.org/10.3389/fmed.2022.981001
Ebadi M, Martin L, Ghosh S, Field CJ, Lehner R, Baracos VE et al (2017) Subcutaneous adiposity is an independent predictor of mortality in cancer patients. Br J Cancer 117:148–155. https://doi.org/10.1038/bjc.2017.149
Faron A, Luetkens JA, Schmeel FC, Kuetting DLR, Thomas D, Sprinkart AM (2019) Quantification of fat and skeletal muscle tissue at abdominal computed tomography: associations between single-slice measurements and total compartment volumes. Abdom Radiol (NY) 44:1907–1916. https://doi.org/10.1007/s00261-019-01912-9
Hou GM, Jiang C, Du JP, Yuan KF (2022) Sarcopenia predicts an adverse prognosis in patients with combined hepatocellular carcinoma and cholangiocarcinoma after surgery. Cancer Med 11:317–331. https://doi.org/10.1002/cam4.4448
Kichenadasse G, Miners JO, Mangoni AA, Rowland A, Hopkins AM, Sorich MJ (2020) Association between body mass index and overall survival with immune checkpoint inhibitor therapy for advanced non-small cell lung cancer. JAMA Oncol 6:512–518. https://doi.org/10.1001/jamaoncol.2019.5241
Li Y, Wang WB, Yang L, Wang QY, Dai J, Xia L et al (2022) The combination of body composition conditions and systemic inflammatory markers has prognostic value for patients with gastric cancer treated with adjuvant chemoradiotherapy. Nutrition 93:111464. https://doi.org/10.1016/j.nut.2021.111464
Loosen SH, Jördens MS, Schoon B, Antoch G, Luedde T, Minko P et al (2023) Sarcopenia indicate poor survival in patients undergoing transarterial chemoembolization (TACE) for hepatic malignancies. J Cancer Res Clin Oncol. https://doi.org/10.1007/s00432-022-04519-8
Martin L, Birdsell L, Macdonald N, Reiman T, Clandinin MT, McCargar LJ 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. https://doi.org/10.1200/JCO.2012.45.2722
McQuade JL, Daniel CR, Hess KR, Mak C, Wang DY, Rai RR et al (2018) Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. Lancet Oncol 19:310–322. https://doi.org/10.1016/S1470-2045(18)30078-0
Nishikawa H, Nishijima N, Enomoto H, Sakamoto A, Nasu A, Komekado H et al (2017) Prognostic significance of sarcopenia in patients with hepatocellular carcinoma undergoing sorafenib therapy. Oncol Lett 14:1637–1647. https://doi.org/10.3892/ol.2017.6287
Patel HP, Al-Shanti N, Davies LC, Barton SJ, Grounds MD, Tellam RL et al (2014) Lean mass, muscle strength and gene expression in community dwelling older men: findings from the Hertfordshire Sarcopenia Study (HSS). Calcif Tissue Int 95:308–316. https://doi.org/10.1007/s00223-014-9894-z
Pei Q, Yi X, Chen C, Pang P, Fu Y, Lei G et al (2022) Pre-treatment CT-based radiomics nomogram for predicting microsatellite instability status in colorectal cancer. Eur Radiol 32:714–724. https://doi.org/10.1007/s00330-021-08167-3
Porter SA, Massaro JM, Hoffmann U, Vasan RS, O’Donnel CJ, Fox CS (2009) Abdominal subcutaneous adipose tissue: a protective fat depot? Diabetes Care 32:1068–1075. https://doi.org/10.2337/dc08-2280
Qin S, Ren Z, Meng Z, Chen Z, Chai X, Xiong J et al (2020) Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol 21:571–580. https://doi.org/10.1016/S1470-2045(20)30011-5
Roayaie S, Jibara G, Tabrizian P, Park JW, Yang J, Yan L et al (2015) The role of hepatic resection in the treatment of hepatocellular cancer. Hepatology 62:440–451. https://doi.org/10.1002/hep.27745
Romero-Corral A, Somers VK, Sierra-Johnson J, Thomas RJ, Collazo-Clavell ML, Korinek J et al (2008) Accuracy of body mass index in diagnosing obesity in the adult general population. Int J Obes (lond) 32:959–966. https://doi.org/10.1038/ijo.2008.11
Rutkowski P, Indini A, De Luca M, Merelli B, Mariuk-Jarema A, Teterycz P et al (2020) Body mass index (BMI) and outcome of metastatic melanoma patients receiving targeted therapy and immunotherapy: a multicenter international retrospective study. J Immunother Cancer 8:e001117. https://doi.org/10.1136/jitc-2020-001117
Saini J, McPhee JS, Al-Dabbagh S, Stewart CE, Al-Shanti N (2016) Regenerative function of immune system: modulation of muscle stem cells. Ageing Res Rev 27:67–76. https://doi.org/10.1016/j.arr.2016.03.006
Sharpe AH, Pauken KE (2018) The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 18:153–167. https://doi.org/10.1038/nri.2017.108
Shen W, Punyanitya M, Wang Z, Gallagher D, St-Onge MP, Albu J et al (2004) Total body skeletal muscle and adipose tissue volumes: estimation from a single abdominal cross-sectional image. J Appl Physiol (1985) 97:2333–2338. https://doi.org/10.1152/japplphysiol.00744.2004
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249. https://doi.org/10.3322/caac.21660
Tenuta M, Gelibter A, Pandozzi C, Sirgiovanni G, Campolo F, Venneri MA et al (2021) Impact of sarcopenia and inflammation on patients with advanced non-small cell lung cancer (NCSCL) treated with immune checkpoint inhibitors (ICIs): a prospective study. Cancers (basel) 13:6355. https://doi.org/10.3390/cancers13246355
Voron T, Tselikas L, Pietrasz D, Pigneur F, Laurent A, Compagnon P et al (2015) Sarcopenia impacts on short- and long-term results of hepatectomy for hepatocellular carcinoma. Ann Surg 261:1173–1183. https://doi.org/10.1097/SLA.0000000000000743
Wang Z, Aguilar EG, Luna JI, Dunai C, Khuat LT, Le CT, Mirsoian A et al (2019) Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med 25:141–151. https://doi.org/10.1038/s41591-018-0221-5
Wang X, Zhang C, Cao F, Wang CB, Dong JN, Wang ZH (2022) Nomogram of combining CT-based body composition analyses and prognostic inflammation score: prediction of survival in advanced epithelial ovarian cancer patients. Acad Radiol 29:1394–1403. https://doi.org/10.1016/j.acra.2021.11.011
Wang J, Dong P, Qu Y, Xu W, Zhou Z, Ning K et al (2023) Association of computed tomography-based body composition with survival in metastatic renal cancer patient received immunotherapy: a multicenter, retrospective study. Eur Radiol 33:3232–3242. https://doi.org/10.1007/s00330-022-09345-7
Xiao Y, Li W, Wan H, Tan Y, Wu H (2018) Central hepatectomy versus major hepatectomy for patients with centrally located hepatocellular carcinoma: a meta-analysis. Int J Surg 52:297–302. https://doi.org/10.1016/j.ijsu.2018.02.059
Xiao LS, Li RN, Cui H, Hong C, Huang CY, Li QM et al (2022) Use of computed tomography-derived body composition to determine the prognosis of patients with primary liver cancer treated with immune checkpoint inhibitors: a retrospective cohort study. BMC Cancer 22:737. https://doi.org/10.1186/s12885-022-09823-7
Zeng X, Shi ZW, Yu JJ, Wang LF, Luo YY, Jin SM et al (2021) Sarcopenia as a prognostic predictor of liver cirrhosis: a multicentre study in China. J Cachexia Sarcopenia Muscle 12:1948–1958. https://doi.org/10.1002/jcsm.12797
Zhang C, Zhao R, Chen F, Zhu Y, Chen L (2021) Preoperative prediction of microvascular invasion in non-metastatic hepatocellular carcinoma based on nomogram analysis. Transl Oncol 14:100875. https://doi.org/10.1016/j.tranon.2020.100875
Acknowledgements
This study was completed with the support of the Department of Medical Imaging and Interventional Oncology of the First Affiliated Hospital of the University of Science and Technology of China. We thank Professor Jiangning Dong from the Department of Medical Imaging, Changlong Hou from the Department of Interventional Oncology, and the doctors involved in the diagnosis and treatment.
Funding
This work was supported by National Cancer Center Climbing Foundation (No. NCC 201912B01); Wu Jieping Medical Foundation (No. 320.6750.2020-11-27); and China International Medical Foundation (No. Z-2014-06-2103).
Author information
Authors and Affiliations
Contributions
CH, FG, BX, and BF designed the study; YW, FG, BX, and BF recruited the patients; FG, BX, and BF performed assessment of body composition; BX performed statistical analysis and generated figures and tables; CH and FG provided intellectual input; CH, FG, BX, and BF drafted the manuscript; all authors approved the paper.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Ethics statement
The Declaration of Helsinki and the International Conference on Good Clinical Practice Standards were both followed during the conduct of this investigation. Due to the non-interventional nature of this investigation, ethical review and approval were waived. This waiver was granted by the First Affiliated Hospital of University of Science and Technology of China Ethics Committee. The data in this article are anonymous, and the requirement for informed consent was therefore waived.
Consent for publication
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Xiong, B., Fu, B., Wu, Y. et al. Body composition predicts prognosis of hepatocellular carcinoma patients undergoing immune checkpoint inhibitors. J Cancer Res Clin Oncol 149, 11607–11617 (2023). https://doi.org/10.1007/s00432-023-05051-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-023-05051-z