Body Composition, Adherence to Anthracycline and Taxane-Based Chemotherapy, and Survival After Nonmetastatic Breast Cancer | Breast Cancer | JAMA Oncology | JAMA Network
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National Cancer Institute Surveillance Epidemiology and End Results. Cancer stat facts: female breast cancer. Cancer Statistics 2015; Accessed September 19, 2018.
Muss  HB, Berry  DA, Cirrincione  C,  et al; Cancer and Leukemia Group B Experience.  Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: the Cancer and Leukemia Group B Experience.  J Clin Oncol. 2007;25(24):3699-3704. doi:10.1200/JCO.2007.10.9710PubMedGoogle ScholarCrossref
Prado  CM.  Body composition in chemotherapy: the promising role of CT scans.  Curr Opin Clin Nutr Metab Care. 2013;16(5):525-533. doi:10.1097/MCO.0b013e328363bcfbPubMedGoogle ScholarCrossref
Prado  CM, Birdsell  LA, Baracos  VE.  The emerging role of computerized tomography in assessing cancer cachexia.  Curr Opin Support Palliat Care. 2009;3(4):269-275. doi:10.1097/SPC.0b013e328331124aPubMedGoogle ScholarCrossref
Wong  AL, Seng  KY, Ong  EM,  et al.  Body fat composition impacts the hematologic toxicities and pharmacokinetics of doxorubicin in Asian breast cancer patients.  Breast Cancer Res Treat. 2014;144(1):143-152. doi:10.1007/s10549-014-2843-8PubMedGoogle ScholarCrossref
Prado  CM, Lima  IS, Baracos  VE,  et al.  An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity.  Cancer Chemother Pharmacol. 2011;67(1):93-101. doi:10.1007/s00280-010-1288-yPubMedGoogle ScholarCrossref
Griggs  JJ, Mangu  PB, Anderson  H,  et al; American Society of Clinical Oncology.  Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline.  J Clin Oncol. 2012;30(13):1553-1561. doi:10.1200/JCO.2011.39.9436PubMedGoogle ScholarCrossref
Prado  CM, Cushen  SJ, Orsso  CE, Ryan  AM.  Sarcopenia and cachexia in the era of obesity: clinical and nutritional impact.  Proc Nutr Soc. 2016;75(2):188-198. doi:10.1017/S0029665115004279PubMedGoogle ScholarCrossref
Shachar  SS, Deal  AM, Weinberg  M,  et al.  Body composition as a predictor of toxicity in patients receiving anthracycline and taxane-based chemotherapy for early-stage breast cancer.  Clin Cancer Res. 2017;23(14):3537-3543. doi:10.1158/1078-0432.CCR-16-2266PubMedGoogle ScholarCrossref
van den Berg  MMGA, Kok  DE, Posthuma  L,  et al.  Body composition is associated with risk of toxicity-induced modifications of treatment in women with stage I-IIIB breast cancer receiving chemotherapy.  Breast Cancer Res Treat. 2019;173(2):475-481. doi:10.1007/s10549-018-5014-5PubMedGoogle ScholarCrossref
Mazzuca  F, Onesti  CE, Roberto  M,  et al.  Lean body mass wasting and toxicity in early breast cancer patients receiving anthracyclines.  Oncotarget. 2018;9(39):25714-25722. doi:10.18632/oncotarget.25394PubMedGoogle ScholarCrossref
Gouérant  S, Leheurteur  M, Chaker  M,  et al.  A higher body mass index and fat mass are factors predictive of docetaxel dose intensity.  Anticancer Res. 2013;33(12):5655-5662.PubMedGoogle Scholar
Caan  BJ, Cespedes Feliciano  EM, Prado  CM,  et al.  Association of muscle and adiposity measured by computed tomography with survival in patients with nonmetastatic breast cancer.  JAMA Oncol. 2018;4(6):798-804. doi:10.1001/jamaoncol.2018.0137PubMedGoogle ScholarCrossref
Aubrey  J, Esfandiari  N, Baracos  VE,  et al.  Measurement of skeletal muscle radiation attenuation and basis of its biological variation.  Acta Physiol (Oxf). 2014;210(3):489-497. doi:10.1111/apha.12224PubMedGoogle ScholarCrossref
Goetz  MP, Gradishar  WJ, Anderson  BO,  et al.  Breast cancer, version 3.2018: featured updates to the NCCN Guidelines.  J Natl Compr Canc Netw. 2019;17(2):118-126. doi:10.6004/jnccn.2019.0009PubMedGoogle ScholarCrossref
Hryniuk  WM, Goodyear  M.  The calculation of received dose intensity.  J Clin Oncol. 1990;8(12):1935-1937. doi:10.1200/JCO.1990.8.12.1935PubMedGoogle ScholarCrossref
Griggs  JJ, Sorbero  ME, Stark  AT, Heininger  SE, Dick  AW.  Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy.  Breast Cancer Res Treat. 2003;81(1):21-31. doi:10.1023/A:1025481505537PubMedGoogle ScholarCrossref
Charlson  ME, Pompei  P, Ales  KL, MacKenzie  CR.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.  J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8PubMedGoogle ScholarCrossref
Lin  G, So  Y, Johnston  G. Analyzing survival data with competing risks using SAS software. SAS Global Forum 2012. Accessed October 22, 2019.
Fine  JP, Gray  RJ.  A proportional hazards model for the subdistribution of a competing risk.  J Am Stat Assoc. 1999;94(446):496-509. doi:10.1080/01621459.1999.10474144Google ScholarCrossref
Nevo  D, Liao  X, Spiegelman  D.  Estimation and inference for the mediation proportion  [published online September 20, 2017].  Int J Biostat. 2017;13(2):20170006. doi:10.1515/ijb-2017-0006PubMedGoogle Scholar
Baker  SD, Verweij  J, Rowinsky  EK,  et al.  Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001.  J Natl Cancer Inst. 2002;94(24):1883-1888. doi:10.1093/jnci/94.24.1883PubMedGoogle ScholarCrossref
Gurney  H.  Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative.  J Clin Oncol. 1996;14(9):2590-2611. doi:10.1200/JCO.1996.14.9.2590PubMedGoogle ScholarCrossref
Miller  AA.  Body surface area in dosing anticancer agents: scratch the surface!  J Natl Cancer Inst. 2002;94(24):1822-1823. doi:10.1093/jnci/94.24.1822PubMedGoogle ScholarCrossref
Ratain  MJ.  Body-surface area as a basis for dosing of anticancer agents: science, myth, or habit?  J Clin Oncol. 1998;16(7):2297-2298. doi:10.1200/JCO.1998.16.7.2297PubMedGoogle ScholarCrossref
Rodvold  KA, Rushing  DA, Tewksbury  DA.  Doxorubicin clearance in the obese.  J Clin Oncol. 1988;6(8):1321-1327. doi:10.1200/JCO.1988.6.8.1321PubMedGoogle ScholarCrossref
Sparreboom  A, Wolff  AC, Mathijssen  RHJ,  et al.  Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese.  J Clin Oncol. 2007;25(30):4707-4713. doi:10.1200/JCO.2007.11.2938PubMedGoogle ScholarCrossref
Abdel-Rahman  O.  Outcomes of early-stage breast cancer patients treated with sequential anthracyclines-taxanes in relationship to relative dosing intensity: a secondary analysis of a randomized controlled trial.  Clin Transl Oncol. 2019;21(2):239-245. doi:10.1007/s12094-018-1915-3PubMedGoogle ScholarCrossref
Liutkauskiene  S, Grizas  S, Jureniene  K, Suipyte  J, Statnickaite  A, Juozaityte  E.  Retrospective analysis of the impact of anthracycline dose reduction and chemotherapy delays on the outcomes of early breast cancer molecular subtypes.  BMC Cancer. 2018;18(1):453. doi:10.1186/s12885-018-4365-yPubMedGoogle ScholarCrossref
Sandy  J, Della-Fiorentina  S.  Relative dose intensity in early stage breast cancer chemotherapy: a retrospective analysis of incidence, risk factors and outcomes at a south-west Sydney cancer clinic.  Asia Pac J Clin Oncol. 2013;9(4):365-372. doi:10.1111/ajco.12093PubMedGoogle ScholarCrossref
Schraa  SJ, Frerichs  KA, Agterof  MJ, Hunting  JCB, Los  M, de Jong  PC.  Relative dose intensity as a proxy measure of quality and prognosis in adjuvant chemotherapy for breast cancer in daily clinical practice.  Eur J Cancer. 2017;79:152-157. doi:10.1016/j.ejca.2017.04.001PubMedGoogle ScholarCrossref
Zhang  L, Yu  Q, Wu  XC,  et al.  Impact of chemotherapy relative dose intensity on cause-specific and overall survival for stage I-III breast cancer: ER+/PR+, HER2- vs. triple-negative.  Breast Cancer Res Treat. 2018;169(1):175-187. doi:10.1007/s10549-017-4646-1PubMedGoogle ScholarCrossref
Courneya  KS, Segal  RJ, Mackey  JR,  et al.  Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial.  J Clin Oncol. 2007;25(28):4396-4404. doi:10.1200/JCO.2006.08.2024PubMedGoogle ScholarCrossref
Cheema  BS, Kilbreath  SL, Fahey  PP, Delaney  GP, Atlantis  E.  Safety and efficacy of progressive resistance training in breast cancer: a systematic review and meta-analysis.  Breast Cancer Res Treat. 2014;148(2):249-268. doi:10.1007/s10549-014-3162-9PubMedGoogle ScholarCrossref
35. Focus on Reducing Dose-limiting Toxicities in Colon Cancer With Resistance Exercise Study (FORCE). NCT03291951. Accessed July 26, 2019.
36. A Study Comparing Chemotherapy Dosing Based on Either Standard Body Surface Area or Lean Body Mass in Patients With Advanced Lung Cancer. NCT01624051. Accessed July 26, 2019.
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    Original Investigation
    December 5, 2019

    Body Composition, Adherence to Anthracycline and Taxane-Based Chemotherapy, and Survival After Nonmetastatic Breast Cancer

    Author Affiliations
    • 1Division of Research, Kaiser Permanente Northern California, Oakland
    • 2Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
    • 3Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
    • 4Department of Agricultural, Food and Nutritional Science, University of Alberta, 2-06 Agriculture/Forestry Centre, Edmonton, Alberta, Canada
    • 5Covenant Health Palliative Institute, Grey Nuns Community Hospital, St. Marguerite Health Services Centre, Edmonton, Alberta, Canada
    • 6Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill
    • 7Division of Oncology, Rambam Health Care Campus, Haifa, Israel
    JAMA Oncol. 2020;6(2):264-270. doi:10.1001/jamaoncol.2019.4668
    Key Points

    Question  Is body composition associated with tolerance and adherence to anthracycline and taxane-based chemotherapy and, thus, breast cancer mortality?

    Findings  In this cohort study of 1395 patients with nonmetastatic breast cancer, greater adiposity was associated with lower relative dose intensity (ratio of delivered to planned chemotherapy dose). Lower relative dose intensity was associated with increased risk of death after breast cancer and partially mediated the association of greater adiposity with mortality.

    Meaning  Although most chemotherapies are dosed according to body surface area, body composition may identify patients at risk for lower relative dose intensity, which could compromise therapeutic efficacy and may be one of multiple pathways through which adiposity is associated with increases in breast cancer mortality.


    Importance  Although most chemotherapies are dosed on body surface area or weight, body composition (ie, the amount and distribution of muscle and adipose tissues) is thought to be associated with chemotherapy tolerance and adherence.

    Objectives  To evaluate whether body composition is associated with relative dose intensity (RDI) on anthracycline and taxane-based chemotherapy or hematologic toxic effects and whether lower RDI mediates the association of adiposity with mortality.

    Design, Setting, and Participants  An observational cohort study with prospectively collected electronic medical record data was conducted at Kaiser Permanente Northern California, a multicenter, community oncology setting within an integrated health care delivery system. Participants included 1395 patients with nonmetastatic breast cancer diagnosed between January 1, 2005, and December 31, 2013, and treated with anthracycline and taxane-based chemotherapy. Data analysis was performed between February 25 and September 4, 2019.

    Exposures  Intramuscular, visceral, and subcutaneous adiposity as well as skeletal muscle were evaluated from clinically acquired computed tomographic scans at diagnosis.

    Main Outcomes and Measures  The primary outcome was low RDI (<0.85), which is the ratio of delivered to planned chemotherapy dose, derived from infusion records; in addition, hematologic toxic effects were defined based on laboratory test values. To evaluate associations with overall and breast cancer–specific mortality, logistic regression models adjusted for age and body surface area were fit as well as Cox proportional hazards models adjusted for age, race/ethnicity, adiposity, Charlson comorbidity index score, and tumor stage and subtype. The mediation proportion was computed using the difference method.

    Results  The mean (SD) age at diagnosis of the 1395 women included in the study was 52.8 (10.2) years. Greater visceral (odds ratio [OR], 1.19; 95% CI, 1.02-1.39 per SD) and intramuscular (OR, 1.16; 95% CI, 1.01-1.34 per SD) adiposity were associated with increased odds of RDI less than 0.85. Greater muscle mass was associated with a decreased odds of hematologic toxic effects (OR, 0.84; 95% CI, 0.71-0.98 per SD). Relative dose intensity less than 0.85 was associated with a 30% increased risk of death (hazard ratio, 1.30; 95% CI, 1.02-1.65). Lower RDI partially explained the association of adiposity with breast cancer–specific mortality (mediation proportion, 0.20; 95% CI, 0.05-0.55).

    Conclusions and Relevance  Excess adiposity, presenting as larger visceral or intramuscular adiposity, was associated with lower RDI. Lower RDI partially mediated the association of adiposity with worse breast cancer–specific survival. Body composition may help to identify patients likely to experience toxic effects and subsequent dose delays or reductions, which could compromise chemotherapeutic efficacy.