Retrospective and prospective preclinical and clinical data have demonstrated an association between chemotherapy dose intensity and both clinical efficacy and toxicity. The optimum tolerable and effective dose and schedule of chemotherapeutic agents is based on data from dose-finding studies and early clinical trials. There is considerable evidence that reductions in the recommended dose intensity often occurs in actual clinical practice, particularly among overweight and obese patients with cancer. With increasing rates of obesity, and variation and uncertainty about appropriate dosing of chemotherapy in obese patients, ASCO has generated clinical practice guidelines for appropriate chemotherapy dosing for obese adult patients with cancer. Without evidence of any increase in treatment-related toxicity among obese patients receiving chemotherapy, the guidelines recommend that, after considering any accompanying comorbidities, chemotherapy dosing should be calculated based on body surface area using actual weight, rather than an estimate or idealization of weight. While further research is needed, pharmacokinetic studies support the use of actual body weight to calculate chemotherapy doses for most chemotherapy drugs in obese patients. We highlight the issue of chemotherapy dosing in this population, how a more personalized approach can be achieved, as well as discussing areas for further research.
Increasing obesity rates represent a global public health problem that increases the risk of many diseases and conditions, including cancer
Chemotherapy dosing in adult cancer patients is generally based on body surface area; data suggest that obese patients receiving full chemotherapy doses do not experience greater toxicity than healthy weight individuals
Overweight and obese patients with cancer are often undertreated because arbitrary limits are used to calculate the dose of systemic chemotherapeutic agents
Retrospective and prospective clinical trial data suggest that reductions in delivered chemotherapy dose intensity is associated with increased rates of disease recurrence and cancer-associated mortality
Clinical practice guidelines have been developed for appropriate dosing of chemotherapy in adult patients that should enhance the quality of patient care and improve clinical outcomes
Further research on the application of pharmacokinetic and pharmacogenetic principles to chemotherapy dosing may enable more personalized treatment of obese patients with cancer
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Reeves, G. K. et al. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ 335, 1134 (2007).
Lyman, G. H., Dale, D. C. & Crawford, J. Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: a nationwide study of community practices. J. Clin. Oncol. 21, 4524–4531 (2003).
Lyman, G. H., Dale, D. C., Friedberg, J., Crawford, J. & Fisher, R. I. Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin's lymphoma: a nationwide study. J. Clin. Oncol. 22, 4302–4311 (2004).
Griggs, J. J., Sorbero, M. E. & Lyman, G. H. Undertreatment of obese women receiving breast cancer chemotherapy. Arch. Intern. Med. 165, 1267–1273 (2005).
Pinkel, D. The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Res. 18, 853–856 (1958).
Pai, M. P. Drug dosing based on weight and body surface area: mathematical assumptions and limitations in obese adults. Pharmacotherapy 32, 856–868 (2012).
Field, K. M. et al. Chemotherapy dosing strategies in the obese, elderly, and thin patient: results of a nationwide survey. J. Oncol. Pract. 4, 108–113 (2008).
Hunter, R. J. et al. Dosing chemotherapy in obese patients: actual versus assigned body surface area (BSA). Cancer Treat. Rev. 35, 69–78 (2009).
Lyman, G. H. Impact of chemotherapy dose intensity on cancer patient outcomes. J. Natl Compr. Canc. Netw. 7, 99–108 (2009).
Frei, E. 3rd & Canellos, G. P. Dose: a critical factor in cancer chemotherapy. Am. J. Med. 69, 585–594 (1980).
Schabel, F. M. Jr. The use of tumor growth kinetics in planning “curative” chemotherapy of advanced solid tumors. Cancer Res. 29, 2384–2389 (1969).
Skipper, H. E. Kinetics of mammary tumor cell growth and implications for therapy. Cancer 28, 1479–1499 (1971).
Goldie, J. H. & Coldman, A. J. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat. Rep. 63, 1727–1733 (1979).
Goldie, J. H. & Coldman, A. J. The genetic origin of drug resistance in neoplasms: implications for systemic therapy. Cancer Res. 44, 3643–3653 (1984).
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365, 1687–1717 (2005).
Early Breast Cancer Trialists' Collaborative Group (EBCTCG) et al. Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patient-level meta-analysis of randomised trials. Lancet 371, 29–40 (2008).
Early Breast Cancer Trialists' Collaborative Group (EBCTCG) et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379, 432–444 (2012).
Bonadonna, G., Valagussa, P., Moliterni, A., Zambetti, M. & Brambilla, C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N. Engl. J. Med. 332, 901–906 (1995).
Hryniuk, W. & Levine, M. N. Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J. Clin. Oncol. 4, 1162–1170 (1986).
Hanna, R. K. et al. Predictors of reduced relative dose intensity and its relationship to mortality in women receiving multi-agent chemotherapy for epithelial ovarian cancer. Gynecol. Oncol. 129, 74–80 (2013).
Bosly, A. et al. Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP. Ann. Hematol. 87, 277–283 (2008).
Kwak, L. W., Halpern, J., Olshen, R. A. & Horning, S. J. Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. J. Clin. Oncol. 8, 963–977 (1990).
Pettengell, R., Schwenkglenks, M. & Bosly, A. Association of reduced relative dose intensity and survival in lymphoma patients receiving CHOP-21 chemotherapy. Ann. Hematol. 87, 429–430 (2008).
Di Maio, M. et al. Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials. Lancet Oncol. 6, 669–677 (2005).
Mayers, C., Panzarella, T. & Tannock, I. F. Analysis of the prognostic effects of inclusion in a clinical trial and of myelosuppression on survival after adjuvant chemotherapy for breast carcinoma. Cancer 91, 2246–2257 (2001).
Griggs, J. J. et al. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J. Clin. Oncol. 25, 2522–2527 (2007).
Griggs, J. J. et al. Effect of patient socioeconomic status and body mass index on the quality of breast cancer adjuvant chemotherapy. J. Clin. Oncol. 25, 277–284 (2007).
Shayne, M. et al. Dose intensity and hematologic toxicity in older breast cancer patients receiving systemic chemotherapy. Cancer 115, 5319–5328 (2009).
Weycker, D., Barron, R., Edelsberg, J., Kartashov, A. & Lyman, G. H. Incidence of reduced chemotherapy relative dose intensity among women with early stage breast cancer in US clinical practice. Breast Cancer Res. Treat. 133, 301–310 (2012).
Bonneterre, J. et al. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J. Clin. Oncol. 23, 2686–2693 (2005).
Budman, D. R. et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group, B. J. Natl Cancer Inst. 90, 1205–1211 (1998).
Lyman, G. H. et al. Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-stimulating factor: a systematic review. J. Clin. Oncol. 28, 2914–2924 (2010).
Norton, L. & Simon, R. Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat. Rep. 61, 1307–1317 (1977).
Norton, L. & Simon, R. Growth curve of an experimental solid tumor following radiotherapy. J. Natl Cancer Inst. 58, 1735–1741 (1977).
Citron, M. L. et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J. Clin. Oncol. 21, 1431–1439 (2003).
Pfreundschuh, M. et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 104, 634–641 (2004).
Pfreundschuh, M. et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood 104, 626–633 (2004).
DiPaolo, J. A., Moore, G. E. & Niedbala, T. F. Experimental studies with actinomycin D. Cancer Res. 17, 1127–1134 (1957).
Farber, S., Toch, R., Sears, E. & Pinkel, D. Advances in chemotherapy of cancer in man. Adv. Cancer Res. 4, 1–71 (1956).
Reagan-Shaw, S., Nihal, M. & Ahmad, N. Dose translation from animal to human studies revisited. FASEB J. 22, 659–661 (2008).
Mosteller, R. D. Simplified calculation of body-surface area. N. Engl. J. Med. 317, 1098 (1987).
Gehan, E. A. & George, S. L. Estimation of human body surface area from height and weight. Cancer Chemother. Rep. 54, 225–235 (1970).
Haycock, G. B., Schwartz, G. J. & Wisotsky, D. H. Geometric method for measuring body surface area: a height-weight formula validated in infants, children, and adults. J. Pediatr. 93, 62–66 (1978).
Griggs, J. J. et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J. Clin. Oncol. 30, 1553–1561 (2012).
Grochow, L. B., Baraldi, C. & Noe, D. Is dose normalization to weight or body surface area useful in adults? J. Natl Cancer Inst. 82, 323–325 (1990).
Gurney, H. Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative. J. Clin. Oncol. 14, 2590–2611 (1996).
Reilly, J. J. & Workman, P. Normalisation of anti-cancer drug dosage using body weight and surface area: is it worthwhile? A review of theoretical and practical considerations. Cancer Chemother. Pharmacol. 32, 411–418 (1993).
Smorenburg, C. H. et al. Randomized cross-over evaluation of body-surface area-based dosing versus flat-fixed dosing of paclitaxel. J. Clin. Oncol. 21, 197–202 (2003).
Mathijssen, R. H. et al. Flat-fixed dosing versus body surface area based dosing of anticancer drugs in adults: does it make a difference? Oncologist 12, 913–923 (2007).
Chatelut, E. et al. Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents. Br. J. Cancer 107, 1100–1106 (2012).
DeVita, V. T. Jr et al. Curability of advanced Hodgkin's disease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute. Ann. Intern. Med. 92, 587–595 (1980).
Jones, S. E. et al. Superiority of adriamycin-containing combination chemotherapy in the treatment of diffuse lymphoma: a Southwest Oncology Group study. Cancer 43, 417–425 (1979).
Hryniuk, W. & Bush, H. The importance of dose intensity in chemotherapy of metastatic breast cancer. J. Clin. Oncol. 2, 1281–1288 (1984).
Shayne, M. et al. Predictors of reduced dose intensity in patients with early-stage breast cancer receiving adjuvant chemotherapy. Breast Cancer Res. Treat. 100, 255–262 (2006).
Shayne, M. et al. Dose intensity and hematologic toxicity in older cancer patients receiving systemic chemotherapy. Cancer 110, 1611–1620 (2007).
Crawford, J. et al. Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: the results of a prospective nationwide study of oncology practice. J. Natl Compr. Canc. Netw. 6, 109–118 (2008).
Dale, D. C., McCarter, G. C., Crawford, J. & Lyman, G. H. Myelotoxicity and dose intensity of chemotherapy: reporting practices from randomized clinical trials. J. Natl Compr. Canc. Netw. 1, 440–454 (2003).
World Health Organization. Obesity and overweight [online], (2013).
Eheman, C. et al. Annual Report to the Nation on the status of cancer, 1975–2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer 118, 2338–2366 (2012).
Wang, Y. C., McPherson, K., Marsh, T., Gortmaker, S. L. & Brown, M. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 378, 815–825 (2011).
Schapira, D. V., Kumar, N. B., Lyman, G. H. & Cox, C. E. Abdominal obesity and breast cancer risk. Ann. Intern. Med. 112, 182–186 (1990).
Protani, M., Coory, M. & Martin, J. H. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res. Treat. 123, 627–635 (2010).
Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. S. adults. N. Engl. J. Med. 348, 1625–1638 (2003).
Ewertz, M. et al. Effect of obesity on prognosis after early-stage breast cancer. J. Clin. Oncol. 29, 25–31 (2011).
Bastarrachea, J., Hortobagyi, G. N., Smith, T. L., Kau, S. W. & Buzdar, A. U. Obesity as an adverse prognostic factor for patients receiving adjuvant chemotherapy for breast cancer. Ann. Intern. Med. 120, 18–25 (1994).
Niraula, S., Ocana, A., Ennis, M. & Goodwin, P. J. Body size and breast cancer prognosis in relation to hormone receptor and menopausal status: a meta-analysis. Breast Cancer Res. Treat. 134, 769–781 (2012).
Meyerhardt, J. A. et al. Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: findings from Cancer and Leukemia Group B 89803. J. Clin. Oncol. 26, 4109–4115 (2008).
Protani, M. M., Nagle, C. M. & Webb, P. M. Obesity and ovarian cancer survival: a systematic review and meta-analysis. Cancer Prev. Res. (Phila.) 5, 901–910 (2012).
Sinicrope, F. A. et al. Body mass index at diagnosis and survival among colon cancer patients enrolled in clinical trials of adjuvant chemotherapy. Cancer 119, 1528–1536 (2013).
Ethier, M. C. et al. Association between obesity at diagnosis and weight change during induction and survival in pediatric acute lymphoblastic leukemia. Leuk. Lymphoma 53, 1677–1681 (2012).
Simkens, L. H. et al. Influence of body mass index on outcome in advanced colorectal cancer patients receiving chemotherapy with or without targeted therapy. Eur. J. Cancer 47, 2560–2567 (2011).
Griggs, J. J., Sorbero, M. E., Stark, A. T., Heininger, S. E. & Dick, A. W. Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res. Treat. 81, 21–31 (2003).
Lyman, G. H. Weight-based chemotherapy dosing in obese patients with cancer: back to the future. J. Oncol. Pract. 8, e62–e64 (2012).
Thompson, L. A., Lawson, A. P., Sutphin, S. D., Steinke, D. & Adams, V. R. Description of current practices of empiric chemotherapy dose adjustment in obese adult patients. J. Oncol. Pract. 6, 141–145 (2010).
Georgiadis, M. S., Steinberg, S. M., Hankins, L. A., Ihde, D. C. & Johnson, B. E. Obesity and therapy-related toxicity in patients treated for small-cell lung cancer. J. Natl Cancer Inst. 87, 361–366 (1995).
Poikonen, P., Blomqvist, C. & Joensuu, H. Effect of obesity on the leukocyte nadir in women treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil dosed according to body surface area. Acta Oncol. 40, 67–71 (2001).
Rosner, G. L. et al. Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from cancer and leukemia group B study 8541. J. Clin. Oncol. 14, 3000–3008 (1996).
Carroll, J., Protani, M., Walpole, E. & Martin, J. H. Effect of obesity on toxicity in women treated with adjuvant chemotherapy for early-stage breast cancer: a systematic review. Breast Cancer Res. Treat. 136, 323–330 (2012).
Schwartz, J., Toste, B. & Dizon, D. S. Chemotherapy toxicity in gynecologic cancer patients with a body surface area (BSA)>2 m2. Gynecol. Oncol. 114, 53–56 (2009).
Greenman, C. G., Jagielski, C. H. & Griggs, J. J. Breast cancer adjuvant chemotherapy dosing in obese patients: dissemination of information from clinical trials to clinical practice. Cancer 112, 2159–2165 (2008).
Baker, S. D. et al. Factors affecting cytochrome P-450 3A activity in cancer patients. Clin. Cancer Res. 10, 8341–8350 (2004).
Hanley, M. J., Abernethy, D. R. & Greenblatt, D. J. Effect of obesity on the pharmacokinetics of drugs in humans. Clin. Pharmacokinet. 49, 71–87 (2010).
Ciarimboli, G. et al. Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients. Clin. Cancer Res. 18, 1101–1108 (2012).
Green, B. & Duffull, S. B. What is the best size descriptor to use for pharmacokinetic studies in the obese? Br. J. Clin. Pharmacol. 58, 119–133 (2004).
Han, P. Y., Duffull, S. B., Kirkpatrick, C. M. & Green, B. Dosing in obesity: a simple solution to a big problem. Clin. Pharmacol. Ther. 82, 505–508 (2007).
Mathijssen, R. H. & Sparreboom, A. Influence of lean body weight on anticancer drug clearance. Clin. Pharmacol. Ther. 8, 23 (2009).
de Jongh, F. E. et al. Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure. J. Clin. Oncol. 19, 3733–3739 (2001).
Rudek, M. A. et al. Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur. J. Cancer 40, 1170–1178 (2004).
Sparreboom, A. et al. Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese. J. Clin. Oncol. 25, 4707–4713 (2007).
Blouin, R. A., Kolpek, J. H. & Mann, H. J. Influence of obesity on drug disposition. Clin. Pharm. 6, 706–714 (1987).
Gibbs, J. P. et al. The impact of obesity and disease on busulfan oral clearance in adults. Blood 93, 4436–4440 (1999).
Lyman, G. H. Commentary: chemotherapy dosing in obese patients with cancer-the need for evidence-based clinical practice guidelines. J. Oncol. Pract. 7, 17–18 (2011).
American Society of Clinical Oncology. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology Clinical Practice guideline data supplement. ASCO [online], (2012).
Meyerhardt, J. A. et al. Influence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma. Cancer 98, 484–495 (2003).
Meyerhardt, J. A. et al. Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: findings from Intergroup Trial 0114. J. Clin. Oncol. 22, 648–657 (2004).
Barrett, S. V. et al. Does body mass index affect progression-free or overall survival in patients with ovarian cancer? Results from SCOTROC I trial. Ann. Oncol. 19, 898–902 (2008).
Smith, T. J. & Desch, C. E. Neutropenia-wise and pound-foolish: safe and effective chemotherapy in massively obese patients. South Med. J. 84, 883–885 (1991).
Okamoto, H., Nagatomo, A., Kunitoh, H., Kunikane, H. & Watanabe, K. Prediction of carboplatin clearance calculated by patient characteristics or 24-hour creatinine clearance: a comparison of the performance of three formulae. Cancer Chemother. Pharmacol. 42, 307–312 (1998).
Wang, Y. & Beydoun, M. A. The obesity epidemic in the United States--gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol. Rev. 29, 6–28 (2007).
Cossrow, N. & Falkner, B. Race/ethnic issues in obesity and obesity-related comorbidities. J. Clin. Endocrinol. Metab. 89, 2590–2594 (2004).
Liao, Y. et al. REACH 2010 Surveillance for Health Status in Minority Communities—United States, 2001--2002. MMWR Surveill. Summ. 53, 1–36 (2004).
Jenkins, P., Elyan, S. & Freeman, S. Obesity is not associated with increased myelosuppression in patients receiving chemotherapy for breast cancer. Eur. J. Cancer 43, 544–548 (2007).
Smith, T. J. et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J. Clin. Oncol. 24, 3187–3205 (2006).
Lyman, G. H. Comparative effectiveness research in oncology: the need for clarity, transparency and vision. Cancer Invest. 27, 593–597 (2009).
Lyman, G. H. & Levine, M. Comparative effectiveness research in oncology: an overview. J. Clin. Oncol. 30, 4181–4184 (2012).
De Jonge, M. E., Mathot, R. A., Van Dam, S. M., Beijnen, J. H. & Rodenhuis, S. Extremely high exposures in an obese patient receiving high-dose cyclophosphamide, thiotepa and carboplatin. Cancer Chemother. Pharmacol. 50, 251–255 (2002).
Sassi, F. Obesity and the economics of prevention: fit not fat (OECD Publishing, 2010).
G. H. Lyman is co-chair and A. Sparreboom is a member of the ASCO Expert Panel involved in formulating the guidelines on appropriate chemotherapy dosing for obese adult patients with cancer.
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Lyman, G., Sparreboom, A. Chemotherapy dosing in overweight and obese patients with cancer. Nat Rev Clin Oncol 10, 451–459 (2013). https://doi.org/10.1038/nrclinonc.2013.108
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