J Gastric Cancer.  2017 Mar;17(1):74-87. 10.5230/jgc.2017.17.e8.

Body Composition as a Prognostic Factor of Neoadjuvant Chemotherapy Toxicity and Outcome in Patients with Locally Advanced Gastric Cancer

• Palmela C
• Velho S
• Agostinho
• Branco F
• Santos M
• Santos MP
• Oliveira M
• Strecht J
• Maio R
• Cravo M
• Baracos VE

• KMID: 2372584
• DOI: http://doi.org/10.5230/jgc.2017.17.e8

Abstract

PURPOSE
Neoadjuvant chemotherapy has been shown to improve survival in locally advanced gastric cancer, but it is associated with significant toxicity. Sarcopenia and sarcopenic obesity have been studied in several types of cancers and have been reported to be associated with higher chemotherapy toxicity and morbi-mortality. The aim of this study was to assess the prevalence of sarcopenia/sarcopenic obesity in patients with gastric cancer, as well as its association with chemotherapy toxicity and long-term outcomes.
MATERIALS AND METHODS
A retrospective analysis was performed using an academic cancer center patient cohort diagnosed with locally advanced gastric cancer between January 2012 and December 2014 and treated with neoadjuvant chemotherapy. We analyzed body composition (skeletal muscle and visceral fat index) in axial computed tomography images.
RESULTS
A total of 48 patients met the inclusion criteria. The mean age was 68±10 years, and 33 patients (69%) were men. Dose-limiting toxicity was observed in 22 patients (46%), and treatment was terminated early owing to toxicity in 17 patients (35%). Median follow-up was 17 months. Sarcopenia and sarcopenic obesity were found at diagnosis in 23% and 10% of patients, respectively. We observed an association between termination of chemotherapy and both sarcopenia (P=0.069) and sarcopenic obesity (P=0.004). On multivariate analysis, the odds of treatment termination were higher in patients with sarcopenia (odds ratio 4.23; P=0.050). Patients with sarcopenic obesity showed lower overall survival (median survival of 6 months [95% confidence interval 3.9-8.5] vs. 25 months [95% confidence interval 20.2-38.2]; log-rank test P=0.000).
CONCLUSIONS
Sarcopenia and sarcopenic obesity were associated with early termination of neoadjuvant chemotherapy in patients with gastric cancer; additionally, sarcopenic obesity was associated with poor survival.

Keyword

Stomach neoplasms; Body composition; Sarcopenia; Neoadjuvant therapy; Prognosis

MeSH Terms

Body Composition*
Cohort Studies
Diagnosis
Drug Therapy*
Follow-Up Studies
Humans
Intra-Abdominal Fat
Male
Multivariate Analysis
Neoadjuvant Therapy
Obesity
Prevalence
Prognosis
Retrospective Studies
Sarcopenia
Stomach Neoplasms*

Figure

• 

  Fig. 1 Axial CT images of the third lumbar vertebra region. CT was analyzed for muscle and fat tissue cross sectional areas and analyzed using appropriate software. SMA (shown in red) was quantified within a HU range of −29 to 150, VFA (shown in yellow) ranged from −150 to −50 HU, and SFA (shown in blue) ranged from −190 to −30 HU. CT = computed tomography; SMA = skeletal muscle area; HU = Hounsfield unit; VFA = visceral fat area; SFA = subcutaneous fat area.

• 

  Fig. 2 ROC curve using treatment termination as dependent variable and age, sarcopenia, and MA as independent variables. Sensitivity: 58.8%; Specificity: 86.7%; Positive predictive value: 21.2%; Negative predictive value: 28.6%. ROC = receiver operating characteristic; MA = muscle radiation attenuation; AUC = area under the curve.

• 

  Fig. 3 Kaplan-Meier survival curves of patients with and without sarcopenia (A) and of obese patients with and without sarcopenia (B) (log-rank P-value).

• 

  Fig. 4 Body composition changes (namely SMI and VFI in cm2/m2) before and after neoadjuvant ChT, according to ChT response (A) and DLT (B). SMI = skeletal muscle index; VFI = visceral fat mass index; ChT = chemotherapy; DLT = dose-limiting toxicity; NS = non-significant.

Reference

1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65:87–108.

2. Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer. J Clin Invest. 2007; 117:60–69.

3. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006; 355:11–20.

4. Tan BH, Brammer K, Randhawa N, Welch NT, Parsons SL, James EJ, et al. Sarcopenia is associated with toxicity in patients undergoing neo-adjuvant chemotherapy for oesophago-gastric cancer. Eur J Surg Oncol. 2015; 41:333–338.

5. Prado CM, Lieffers JR, McCargar LJ, Reiman T, Sawyer MB, Martin L, 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; 9:629–635.

6. Awad S, Tan BH, Cui H, Bhalla A, Fearon KC, Parsons SL, et al. Marked changes in body composition following neoadjuvant chemotherapy for oesophagogastric cancer. Clin Nutr. 2012; 31:74–77.

7. Prado CM, Baracos VE, McCargar LJ, Mourtzakis M, Mulder KE, Reiman T, et al. Body composition as an independent determinant of 5-fluorouracil-based chemotherapy toxicity. Clin Cancer Res. 2007; 13:3264–3268.

8. Peng P, Hyder O, Firoozmand A, Kneuertz P, Schulick RD, Huang D, et al. Impact of sarcopenia on outcomes following resection of pancreatic adenocarcinoma. J Gastrointest Surg. 2012; 16:1478–1486.

9. Huang DD, Zhou CJ, Wang SL, et al. Impact of different sarcopenia stages on the postoperative outcomes after radical gastrectomy for gastric cancer. Surgery. 2017; 161:680–693.

10. Chen FF, Zhang FY, Zhou XY, Shen X, Yu Z, Zhuang CL. Role of frailty and nutritional status in predicting complications following total gastrectomy with D2 lymphadenectomy in patients with gastric cancer: a prospective study. Langenbecks Arch Surg. 2016; 401:813–822.

11. Zhuang CL, Huang DD, Pang WY, Zhou CJ, Wang SL, Lou N, et al. Sarcopenia is an independent predictor of severe postoperative complications and long-term survival after radical gastrectomy for gastric cancer: analysis from a large-scale cohort. Medicine (Baltimore). 2016; 95:e3164.

12. Wang SL, Zhuang CL, Huang DD, Pang WY, Lou N, Chen FF, et al. Sarcopenia adversely impacts postoperative clinical outcomes following gastrectomy in patients with gastric cancer: a prospective study. Ann Surg Oncol. 2016; 23:556–564.

13. Fukuda Y, Yamamoto K, Hirao M, Nishikawa K, Nagatsuma Y, Nakayama T, et al. Sarcopenia is associated with severe postoperative complications in elderly gastric cancer patients undergoing gastrectomy. Gastric Cancer. 2016; 19:986–993.

14. Hayashi N, Ando Y, Gyawali B, Shimokata T, Maeda O, Fukaya M, et al. Low skeletal muscle density is associated with poor survival in patients who receive chemotherapy for metastatic gastric cancer. Oncol Rep. 2016; 35:1727–1731.

15. Huang DD, Chen XX, Chen XY, Wang SL, Shen X, Chen XL, et al. Sarcopenia predicts 1-year mortality in elderly patients undergoing curative gastrectomy for gastric cancer: a prospective study. J Cancer Res Clin Oncol. 2016; 142:2347–2356.

16. Li XT, Tang L, Chen Y, Li YL, Zhang XP, Sun YS. Visceral and subcutaneous fat as new independent predictive factors of survival in locally advanced gastric carcinoma patients treated with neo-adjuvant chemotherapy. J Cancer Res Clin Oncol. 2015; 141:1237–1247.

17. Malietzis G, Currie AC, Athanasiou T, Johns N, Anyamene N, Glynne-Jones R, et al. Influence of body composition profile on outcomes following colorectal cancer surgery. Br J Surg. 2016; 103:572–580.

18. Lou N, Chi CH, Chen XD, et al. Sarcopenia in overweight and obese patients is a predictive factor for postoperative complication in gastric cancer: a prospective study. Eur J Surg Oncol. 2017; 43:188–195.

19. Nishigori T, Tsunoda S, Okabe H, Tanaka E, Hisamori S, Hosogi H, et al. Impact of sarcopenic obesity on surgical site infection after laparoscopic total gastrectomy. Ann Surg Oncol. 2016; 23:524–531.

20. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45:228–247.

21. Martin L, Birdsell L, Macdonald N, Reiman T, Clandinin MT, McCargar LJ, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013; 31:1539–1547.

22. Lieffers JR, Bathe OF, Fassbender K, Winget M, Baracos VE. Sarcopenia is associated with postoperative infection and delayed recovery from colorectal cancer resection surgery. Br J Cancer. 2012; 107:931–936.

23. Tan BH, Birdsell LA, Martin L, Baracos VE, Fearon KC. Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer. Clin Cancer Res. 2009; 15:6973–6979.

24. Reisinger KW, van Vugt JL, Tegels JJ, Snijders C, Hulsewé KW, Hoofwijk AG, et al. Functional compromise reflected by sarcopenia, frailty, and nutritional depletion predicts adverse postoperative outcome after colorectal cancer surgery. Ann Surg. 2015; 261:345–352.

25. Joglekar S, Asghar A, Mott SL, Johnson BE, Button AM, Clark E, et al. Sarcopenia is an independent predictor of complications following pancreatectomy for adenocarcinoma. J Surg Oncol. 2015; 111:771–775.

26. Harimoto N, Shirabe K, Yamashita YI, Ikegami T, Yoshizumi T, Soejima Y, et al. Sarcopenia as a predictor of prognosis in patients following hepatectomy for hepatocellular carcinoma. Br J Surg. 2013; 100:1523–1530.

27. Reisinger KW, Bosmans JW, Uittenbogaart M, Alsoumali A, Poeze M, Sosef MN, et al. Loss of skeletal muscle mass during neoadjuvant chemoradiotherapy predicts postoperative mortality in esophageal cancer surgery. Ann Surg Oncol. 2015; 22:4445–4452.

28. Yip C, Goh V, Davies A, Gossage J, Mitchell-Hay R, Hynes O, et al. Assessment of sarcopenia and changes in body composition after neoadjuvant chemotherapy and associations with clinical outcomes in oesophageal cancer. Eur Radiol. 2014; 24:998–1005.

29. Wagner D, DeMarco MM, Amini N, Buttner S, Segev D, Gani F, et al. Role of frailty and sarcopenia in predicting outcomes among patients undergoing gastrointestinal surgery. World J Gastrointest Surg. 2016; 8:27–40.

30. Huang DD, Wang SL, Zhuang CL, Zheng BS, Lu JX, Chen FF, et al. Sarcopenia, as defined by low muscle mass, strength and physical performance, predicts complications after surgery for colorectal cancer. Colorectal Dis. 2015; 17:O256–O264.

31. Amini N, Spolverato G, Gupta R, Margonis GA, Kim Y, Wagner D, et al. Impact total psoas volume on short- and long-term outcomes in patients undergoing curative resection for pancreatic adenocarcinoma: a new tool to assess sarcopenia. J Gastrointest Surg. 2015; 19:1593–1602.

32. Hansen RD, Williamson DA, Finnegan TP, Lloyd BD, Grady JN, Diamond TH, et al. Estimation of thigh muscle cross-sectional area by dual-energy X-ray absorptiometry in frail elderly patients. Am J Clin Nutr. 2007; 86:952–958.

33. Kazemi-Bajestani SM, Mazurak VC, Baracos V. Computed tomography-defined muscle and fat wasting are associated with cancer clinical outcomes. Semin Cell Dev Biol. 2016; 54:2–10.

34. Ali R, Baracos VE, Sawyer MB, Bianchi L, Roberts S, Assenat E, et al. Lean body mass as an independent determinant of dose-limiting toxicity and neuropathy in patients with colon cancer treated with FOLFOX regimens. Cancer Med. 2016; 5:607–616.

35. Sjøblom B, Grønberg BH, Benth JS, Baracos VE, Fløtten Ø, Hjermstad MJ, et al. Low muscle mass is associated with chemotherapy-induced haematological toxicity in advanced non-small cell lung cancer. Lung Cancer. 2015; 90:85–91.

36. Tegels JJ, van Vugt JL, Reisinger KW, Hulsewé KW, Hoofwijk AG, Derikx JP, et al. Sarcopenia is highly prevalent in patients undergoing surgery for gastric cancer but not associated with worse outcomes. J Surg Oncol. 2015; 112:403–407.

37. Irigaray P, Newby JA, Lacomme S, Belpomme D. Overweight/obesity and cancer genesis: more than a biological link. Biomed Pharmacother. 2007; 61:665–678.

38. Guiu B, Petit JM, Bonnetain F, Ladoire S, Guiu S, Cercueil JP, et al. Visceral fat area is an independent predictive biomarker of outcome after first-line bevacizumab-based treatment in metastatic colorectal cancer. Gut. 2010; 59:341–347.

39. Gaujoux S, Torres J, Olson S, Winston C, Gonen M, Brennan MF, et al. Impact of obesity and body fat distribution on survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg Oncol. 2012; 19:2908–2916.

40. Ladoire S, Bonnetain F, Gauthier M, Zanetta S, Petit JM, Guiu S, et al. Visceral fat area as a new independent predictive factor of survival in patients with metastatic renal cell carcinoma treated with antiangiogenic agents. Oncologist. 2011; 16:71–81.

41. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007; 132:2169–2180.

42. Sjøblom B, Benth JS, Grønberg BH, Baracos VE, Sawyer MB, Fløtten Ø, et al. Drug dose per kilogram lean body mass predicts hematologic toxicity from carboplatin-doublet chemotherapy in advanced non-small-cell lung cancer. [Epub ahead of print]. Clin Lung Cancer. 2016.