Sarcopenia and cancer-related inflammation measurements in advanced gastric and junctional cancers—ready for prime time?

Despite major advances in treating metastatic cancer over the past decade, most patients with advanced disease ultimately die from their malignancy. Much focus has been placed on new therapeutics, using a precision oncology approach, with the use of prognostic and predictive biomarkers yielding valuable insights into tailoring treatments. However, there has been considerably less success in targeting the harder-to-understand, non-specific yet profound systemic impacts of cancer, particularly cachexia and its relationship with cancer-associated inflammation, both of which contribute significantly to functional decline and death. Parameters reflecting ‘illness’ or conversely ‘well-being’ are much less well understood. In everyday clinical practice, we have not progressed far beyond vaguely assessing the volume and anatomy of metastatic disease as a marker of ‘disease burden’, documenting Eastern Cooperative Oncology Group (ECOG) performance status and measuring a few inflammatory markers.1Hwang J.E. Kim H.N. Kim D.E. et al.Prognostic significance of a systemic inflammatory response in patients receiving first-line palliative chemotherapy for recurred or metastatic gastric cancer.BMC Cancer. 2011; 11: 489Crossref PubMed Scopus (63) Google Scholar,2Crumley A.B. McMillan D.C. McKernan M. McDonald A.C. Stuart R.C. Evaluation of an inflammation-based prognostic score in patients with inoperable gastro-oesophageal cancer.Br J Cancer. 2006; 94: 637-641Crossref PubMed Scopus (253) Google Scholar The challenge is to define and refine tools that capture the impact of the systemic processes associated with advanced cancer that are reliable in predicting disease and treatment outcomes. One such emerging tool is the modified Glasgow prognostic score (mGPS), which is a simple score incorporating C-reactive protein and albumin that has been validated as a prognostic marker in gastric and esophagogastric junction cancers, as well as other histologies.1Hwang J.E. Kim H.N. Kim D.E. et al.Prognostic significance of a systemic inflammatory response in patients receiving first-line palliative chemotherapy for recurred or metastatic gastric cancer.BMC Cancer. 2011; 11: 489Crossref PubMed Scopus (63) Google Scholar,3Nozoe T. Iguchi T. Egashira A. Adachi E. Matsukuma A. Ezaki T. Significance of modified Glasgow prognostic score as a useful indicator for prognosis of patients with gastric carcinoma.Am J Surg. 2011; 201: 186-191Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar There has been increasing interest in the impact of sarcopenia, defined by a loss of skeletal muscle mass irrespective of fat mass, as a measure of systemic cancer effect.4Fearon K. Strasser F. Anker S.D. et al.Definition and classification of cancer cachexia: an international consensus.Lancet Oncol. 2011; 12: 489-495Abstract Full Text Full Text PDF PubMed Scopus (3377) Google Scholar The utility of sarcopenia emanated from research into the aging process, but it is particularly suitable for study in oncology by virtue of capitalizing on serial computed tomography (CT) imaging integral to clinical practice. Different methodologies and cut-off thresholds have been used; however, calculation of muscle mass at the third lumbar vertebra using CT imaging is considered to be the gold standard.5Prado C.M. Lieffers J.R. McCargar L.J. et al.Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.Lancet Oncol. 2008; 9: 629-635Abstract Full Text Full Text PDF PubMed Scopus (2070) Google Scholar Sarcopenia is thought to be important as a reflection of a patient’s nutritional status and the degree to which the cancer has impacted physical well-being. Studies have demonstrated an inverse relationship between muscle mass and chemotherapy toxicity, particularly for drugs dosed based on body surface area.6Cespedes Feliciano E.M. Lee V.S. Prado C.M. et al.Muscle mass at the time of diagnosis of nonmetastatic colon cancer and early discontinuation of chemotherapy, delays, and dose reductions on adjuvant FOLFOX: the C-SCANS study.Cancer. 2017; 123: 4868-4877Crossref PubMed Scopus (56) Google Scholar,7Prado C.M. Baracos V.E. McCargar L.J. et al.Body composition as an independent determinant of 5-fluorouracil-based chemotherapy toxicity.Clin Cancer Res. 2007; 13: 3264-3268Crossref PubMed Scopus (442) Google Scholar Furthermore, sarcopenia may be useful in patients who are of high body mass index. However, whether it is approaching readiness for ‘prime time’ as an independent and clinically useful marker of nutritional status, cachexia and/or cancer-related inflammation is uncertain, pending further data such as validation in large randomized clinical trials. Hence, the study by Hacker et al. in this issue is timely; progress in this field cannot come quickly enough.8Hacker U.T. Hasenclever D. Baber R. et al.Modified Glasgow prognostic score (mGPS) is correlated with sarcopenia and dominates the prognostic role of baseline body composition parameters in advanced gastric and esophagogastric junction cancer patients undergoing first-line treatment from the phase III EXPAND trial.Ann Oncol. 2022; 33: 685-692Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar The investigators sought to address the correlations of various measures of systemic cancer impact with overall survival in the seminal phase III first-line EXPAND randomized controlled study in advanced gastric and esophagogastric cancers, comparing capecitabine–cisplatin with/without cetuximab, published in 2013. The study did not meet its primary endpoint of progression-free survival, but the large number of patients enrolled (n = 904) makes it an attractive study for exploratory analyses and we commend Hacker et al. for this endeavor. Using established CT techniques to measure sarcopenia, both skeletal muscle index (SMI) and muscle attenuation (MA) were correlated with baseline mGPS and the clinical outcome of overall survival. The authors first found that baseline mGPS correlated with inferior median overall survival, consistent with previous studies.3Nozoe T. Iguchi T. Egashira A. Adachi E. Matsukuma A. Ezaki T. Significance of modified Glasgow prognostic score as a useful indicator for prognosis of patients with gastric carcinoma.Am J Surg. 2011; 201: 186-191Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,9Dolan R.D. Lim J. McSorley S.T. Horgan P.G. McMillan D.C. The role of the systemic inflammatory response in predicting outcomes in patients with operable cancer: systematic review and meta-analysis.Sci Rep. 2017; 7: 16717Crossref PubMed Scopus (182) Google Scholar This simple measurement is thought to reflect the highly complex role that chronic inflammation plays in cancer progression. The next step should be to move this marker into a stratification factor for prospective trials, to determine its value as predicting for benefit of anticancer as well as nutritional treatments and interventions. However, data describing serial nutrition status and exercise practices, both of which may be confounders, will need to be detailed—a notoriously difficult task within both trials and daily clinical practice. The functional relationship between inflammation and tumorigenesis has been refined over the past few decades, with tumor-promoting inflammation recognized as one of the hallmarks of cancer.10Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (45043) Google Scholar Tumor cell proliferation by cytokines, inflammatory cells and activated stroma is perpetuated within the tumor microenvironment, and is influenced by the function of various components of the immune system, such as tumor-associated macrophages.11Coussens L.M. Werb Z. Inflammation and cancer.Nature. 2002; 420: 860-867Crossref PubMed Scopus (11581) Google Scholar However, the effects of cancer-associated inflammation extend beyond the tumor and surrounding tissues, with the mechanism(s) for the systemic effect remaining poorly understood. Not surprisingly, multiple clinical trials of anti-inflammatory agents have shown limited activity in solid tumors.10Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (45043) Google Scholar,12Hou J. Karin M. Sun B. Targeting cancer-promoting inflammation - have anti-inflammatory therapies come of age?.Nat Rev Clin Oncol. 2021; 18: 261-279Crossref PubMed Scopus (114) Google Scholar Next, the authors showed that at study baseline, mGPS correlated with one of the two sarcopenia measures, MA but not SMI. However, ECOG performance status correlated with SMI but not MA, a surprising finding which raises the question of whether SMI should be incorporated into the measurement of sarcopenia. This itself warrants further research. Nevertheless, mGPS was unable to predict a decline for MA or SMI from baseline to week 12 on study, and more importantly, a decline in either sarcopenia measure was unable to predict overall survival. This result is disappointing and questions if sarcopenia is indeed the best measure of body composition and nutritional needs to consider in treatment planning. A quick ‘shout-out’ to ECOG, as the one factor that time after time remains prognostic—a reminder to all oncologists not to undervalue this robust and simple tool. To explain the finding, the authors suggest that if sarcopenia was a late symptom, the follow-up imaging at only 12 weeks was insufficient to predict a survival difference. The median progression-free survival was 4.4 months [95% confidence interval (CI) 4.2-5.5 months] in the treatment arm and 5.6 months (95% CI 5.1-5.7 months) in the control arm, which could account for this hypothesis.13Lordick F. Kang Y.K. Chung H.C. et al.Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial.Lancet Oncol. 2013; 14: 490-499Abstract Full Text Full Text PDF PubMed Scopus (685) Google Scholar Further study of sarcopenia measures at serial time points would be helpful but would require ongoing imaging beyond progression to be collected in trials. Other factors that may have impacted the interplay between measures of inflammation and sarcopenia include the degree and timing of weight loss before and throughout the study, the pattern and dose of steroid use and toxicity from the anticancer systemic therapy, which varied between the arms. Indeed, there have been several studies that have shown an association between sarcopenia and cancer-related inflammation, including in colorectal cancer, head and neck cancer and biliary cancer.14Feliciano E.M.C. Kroenke C.H. Meyerhardt J.A. et al.Association of systemic inflammation and sarcopenia with survival in nonmetastatic colorectal cancer: results from the C SCANS study.JAMA Oncol. 2017; 3e172319PubMed Google Scholar, 15Cho Y. Kim J.W. Keum K.C. Lee C.G. Jeung H.C. Lee I.J. Prognostic significance of sarcopenia with inflammation in patients with head and neck cancer who underwent definitive chemoradiotherapy.Front Oncol. 2018; 8: 457Crossref PubMed Scopus (63) Google Scholar, 16Lee B.M. Cho Y. Kim J.W. Jeung H.C. Lee I.J. Prognostic significance of sarcopenia in advanced biliary tract cancer patients.Front Oncol. 2020; 10: 1581Crossref PubMed Scopus (12) Google Scholar Across these studies, survival correlated with a systemic inflammatory state as measured from peripheral blood using the neutrophil-to-lymphocyte ratio (NLR). However, a recent meta-analysis across multiple cancer types failed to demonstrate a consistent relationship between NLR and survival, likely due to heterogeneity and small-study effects.17Cupp M.A. Cariolou M. Tzoulaki I. Aune D. Evangelou E. Berlanga-Taylor A.J. Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies.BMC Med. 2020; 18: 360Crossref PubMed Scopus (140) Google Scholar We can conclude that we have not yet landed on a standard, easy-to-measure marker that reflects cancer-associated inflammation. Despite the lack of correlation of sarcopenia with clinical outcome in the study reported in this journal, there is a universal desire by multidisciplinary clinical teams to address nutrition in cancer patients. To date, there is some evidence that protein intake and exercise routines may improve sarcopenia in cancer patients.18Prado C.M. Purcell S.A. Laviano A. Nutrition interventions to treat low muscle mass in cancer.J Cachexia Sarcopenia Muscle. 2020; 11: 366-380Crossref PubMed Scopus (160) Google Scholar This needs to be studied further to see if it impacts clinical outcomes such as quality of life and survival. Studies of multiple pharmacological agents to reduce sarcopenia and cachexia have failed to show benefit, including testosterone, interleukin-1α and β-receptor blockade.19Wright T.J. Dillon E.L. Durham W.J. et al.A randomized trial of adjunct testosterone for cancer-related muscle loss in men and women.J Cachexia Sarcopenia Muscle. 2018; 9: 482-496Crossref PubMed Scopus (53) Google Scholar, 20Hong D.S. Hui D. Bruera E. et al.MABp1, a first-in-class true human antibody targeting interleukin-1α in refractory cancers: an open-label, phase 1 dose-escalation and expansion study.Lancet Oncol. 2014; 15: 656-666Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 21Stewart Coats A.J. Ho G.F. Prabhash K. et al.Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: a randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial).J Cachexia Sarcopenia Muscle. 2016; 7: 355-365Crossref PubMed Scopus (111) Google Scholar One agent that showed increase in muscle mass in non-small-cell lung cancer patients was anamorelin, a ghrelin receptor agonist; however, this did not gain regulatory approval because there was no improvement seen in functional muscle strength or overall survival.22Nishie K. Yamamoto S. Nagata C. Koizumi T. Hanaoka M. Anamorelin for advanced non-small-cell lung cancer with cachexia: systematic review and meta-analysis.Lung Cancer. 2017; 112: 25-34Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar By intervening early with regard to nutrition, it is believed that we can improve outcomes by optimizing the patient’s clinical benefit from systemic therapy, including by increasing tolerability/reducing toxicity. There are many resource and health system limitations to addressing nutrition and exercise, especially in low-income countries where underlying nutrition issues may be present before cancer diagnoses. Conversely, in middle- and high-income countries, obesity and poor exercise practices are likely to impact. Additionally, access to dieticians and exercise physiologists is an almost universal cancer workforce problem.23Roeland E.J. Dunne R.F. The impact of early referrals to dietitians for patients with esophagogastric cancer.J Natl Compr Canc Netw. 2021; 19: 235-238Crossref PubMed Scopus (2) Google Scholar,24Zhou S. Davison K. Qin F. Lin K.F. Chow B.C. Zhao J.X. The roles of exercise professionals in the health care system: a comparison between Australia and China.J Exerc Sci Fit. 2019; 17: 81-90Crossref PubMed Scopus (12) Google Scholar This brings us back to the issue of measuring sarcopenia and cancer-related inflammation, and the interplay between the two. Is sarcopenia the best measure of nutrition in patients with advanced cancer, or even valuable at all, given the results reported from the EXPAND study? How do we integrate these measures into treatment algorithms and how can we use simple scores such as mGPS, NLR and potentially sarcopenia to triage patients into nutritional interventions and predict appropriateness for various toxic systemic therapies? Many challenges remain, and studies such as Hacker et al. make valuable contributions to our approaches for better defining predictive and prognostic markers of the less ‘precise’ effects of cancer, in this era of precision oncology. None declared.