Side-effects related to adjuvant CAPOX treatment for colorectal cancer are associated with intermuscular fat area, not with total skeletal muscle or fat, a retrospective observational study.

Rogier Leendert Charles Plas, Klaske van Norren, Harm van Baar, Carla van Aller, Maarten de Bakker, Nadia Botros, Renger F. Witkamp, Annebeth Haringhuizen, Ellen Kampman, Renate Winkels



Background: Chemotherapeutic treatment is regularly accompanied by side-effects. Hydrophilic chemotherapeutics such as capecitabine and oxaliplatin (CAPOX), often used in colorectal cancer treatment, predominantly accumulate in non-adipose tissues. From this we hypothesized that body composition and fat infiltration in the muscle (muscle attenuation and intermuscular-adipose-tissue [IMAT] content) are associated with chemotherapy-induced toxicities.

Methods: In this retrospective observational study, we collected data from 115 colorectal cancer patients receiving adjuvant CAPOX chemotherapy between 2006 and 2015. Information on cancer characteristics were obtained from the Netherlands Cancer Registry. Diagnostic CT scans were retrieved to assess cross-sectional areas of skeletal muscle and adipose tissue at the third lumbar vertebrae. Information on dose-limiting toxicity [DLT] and relative administered dose (as % of BSA-based-planned-dose) were retrieved from medical charts. Associations between body composition, muscle quality and chemotherapy-induced toxicities were determined using Cox-regression and linear-regression analyses.

Results: We found that DLT incidence was 90% in our cohort: 50% had their dose reduced, 30% their next cycle postponed, 4% a full treatment stop and 6% was hospitalized at their first DLT. Most common were reductions in oxaliplatin dose whilst keeping the capecitabine dose constant. Cox regression analysis indicated no association between body composition or muscle quality and DLT during the first treatment cycle or time to the first DLT. Multiple linear regression showed that higher IMAT-index and IMAT muscle percentage were associated with a lower relative administered dose of oxaliplatin.

Conclusions: In conclusion; only IMAT, not skeletal or fat area was associated with dose-limiting toxicities among these CRC patients who received CAPOX treatment.

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Felici A, Verweij J, Sparreboom A. Dosing strategies for anticancer drugs: The good, the bad and body-surface area. Eur. J. Cancer. Elsevier; 2002;38:1677–84.

Walko CM, Lindley C. Capecitabine: A review. Clin. Ther. Elsevier; 2005. p. 23–44.

Graham MA, Lockwood GF, Greenslade D, Brienza S, Bayssas M, Gamelin E. Clinical pharmacokinetics of oxaliplatin: A critical review. Clin. Cancer Res. Clinical Cancer Research; 2000;6:1205–18.

Graham J, Muhsin M, Kirkpatrick P. Fresh from the pipeline: Oxaliplatin. Nat. Rev. Drug Discov. Nature Publishing Group; 2004;3:11–2.

Mosteller. R.D. Simplified Calculation of Body Suface Area. N. Engl. J. Med. 1987;317:1098.

Mourtzakis M, Prado CMM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE. 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. 2008;33:997–1006.

Shen W, Punyanitya M, Wang Z, Gallagher D, St-Onge M-P, Albu J, et al. Total body skeletal muscle and adipose tissue volumes: estimation from a single abdominal cross-sectional image. J. Appl. Physiol. American Physiological Society; 2004;97:2333–8.

Shachar SS, Williams GR, Muss HB, Nishijima TF. Prognostic value of sarcopenia in adults with solid tumours: A meta-analysis and systematic review. Eur. J. Cancer. 2016;57:58–67.

Barret M, Antoun S, Dalban C, Malka D, Mansourbakht T, Zaanan A, et al. Sarcopenia is linked to treatment toxicity in patients with metastatic colorectal cancer. Nutr. Cancer. Routledge; 2014;66:583–9.

Jung H-W, Kim JW, Kim J-Y, Kim S-W, Yang HK, Lee JW, et al. Effect of muscle mass on toxicity and survival in patients with colon cancer undergoing adjuvant chemotherapy. Support. Care Cancer. Springer Berlin Heidelberg; 2015;23:687–94.

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;5:607–16.

Prado CMM, 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. Clinical Cancer Research; 2007;13:3264–8.

Hopkins JJ, Sawyer MB. Expert Review of Clinical Pharmacology A Review of Body Composition and Pharmacokinetics in Oncology A Review of Body Composition and Pharmacokinetics in Oncology. Expert Rev. Clin. Pharmacol. ISSN. Taylor & Francis; 2017;2433:1–10.

Aubrey J, Esfandiari N, Baracos VE, Buteau FA, Frenette J, Putman CT, et al. Measurement of skeletal muscle radiation attenuation and basis of its biological variation. Acta Physiol. 2014;210:489–97.

Antoun S, Lanoy E, Iacovelli R, Albiges-Sauvin L, Loriot Y, Merad-Taoufik M, et al. Skeletal muscle density predicts prognosis in patients with metastatic renal cell carcinoma treated with targeted therapies. Cancer. 2013;119:3377–84.

Daly LE, Power DG, O’Reilly Á, Donnellan P, Cushen SJ, O’Sullivan K, et al. The impact of body composition parameters on ipilimumab toxicity and survival in patients with metastatic melanoma. Br. J. Cancer. 2017;116:310–7.

Malietzis G, Johns N, Al-Hassi HO, Knight SC, Kennedy RH, Fearon KCH, et al. Low Muscularity and Myosteatosis Is Related to the Host Systemic Inflammatory Response in Patients Undergoing Surgery for Colorectal Cancer. Ann. Surg. 2015;263:320–5.

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. American Society of Clinical Oncology; 2013;31:1539–47.

Stein BN, Petrelli NJ, Douglass HO, Driscoll DL, Arcangeli G, Meropol NJ. Age and sex are independent predictors of 5???fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer. 1995;75:11–7.

Goodpaster BH, Kelley DE, Thaete FL, He J, Ross R. Skeletal muscle attenuation determined by computed tomography is associated with skeletal muscle lipid content. J. Appl. Physiol. 2000;89:104–10.

Addison O, Marcus RL, Lastayo PC, Ryan AS. Intermuscular fat: A review of the consequences and causes. Int. J. Endocrinol. Hindawi Publishing Corporation; 2014. p. 1–11.

Neugut AI, Matasar M, Wang X, McBride R, Jacobson JS, Tsai WY, et al. Duration of adjuvant chemotherapy for colon cancer and survival among the elderly. J. Clin. Oncol. 2006;24:2368–75.

van Erning FN, Janssen-Heijnen MLG, Creemers GJ, Pruijt JFM, Maas HAAM, Lemmens VEPP. Recurrence-free and overall survival among elderly stage III colon cancer patients treated with CAPOX or capecitabine monotherapy. Int. J. Cancer. 2017;140:224–33.

Mitsiopoulos N, Baumgartner RN, Heymsfield SB, Lyons W, Gallagher D, Ross R. Cadaver validation of skeletal muscle measurement by magnetic resonance imaging and computerized tomography Cadaver validation of skeletal muscle measurement by magnetic resonance imaging and computerized tomography. J. Appl. Physiol. 1998;85:115–22.



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