Controversies in Oncology: Size Based vs. Fixed Dosing

  • Peter L. BonateEmail author


To find the right dose and regimen is crucial for the therapeutic effectiveness of oncolytics. Prior to the 1960s, early oncologists dosed their patients at the maximum tolerated dose (MTD) using either fixed doses (sometimes called flat doses) or doses standardized to total body weight (TBW). In the 1960s, this changed as oncology dosing switched to the MTD expressed per patient body surface area (mg/m2), because it was shown that, expressed in this manner, the MTD was approximately the same in humans as in animal species. This remained for decades until in the 1990s when molecularly targeted therapeutics and monoclonal antibodies began to be introduced into clinical practice, and it was no longer necessary to dose patients at the MTD. Further, pharmacokineticists started to realize that using size-based dosing did not reduce interpatient variability for many drugs. Today, the dose regimen developed for new anticancer drugs can be fixed dose, BSA dosed, or TBW dosed. The choice is rigorously evaluated based on sound scientific practice in confirmed in clinical trials. The purpose of this chapter is to discuss the history regarding size-based dosing and current practices for getting “the right dose” in oncology.


Dosing Fixed dose Weight-based dosing Body surface area dosing Monoclonal antibodies Calvert formula Obesity Pediatrics 


  1. Anderson BJ, Holford NHG (2008) Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 48:303–332CrossRefPubMedGoogle Scholar
  2. Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, Gupta M, Tang M, Allison DE, Lu D, Zhang L, Joshi A, Dresser MJ (2012) A guide to rational dosing of monoclonal antibodies. Clin Pharmacokinet 51:119–135CrossRefPubMedGoogle Scholar
  3. Baker SD, Verweij J, Rowinsky E, Donehower RC, Schellens JHM, Grochow LB, Sparreboom A (2002) Role of body surface area in dosing of investigational anticancer agents in adults, 1991–2001. J Natl Cancer Inst 94:1883–1888CrossRefPubMedGoogle Scholar
  4. Bartelink IH, Rademaker CMA, Schobben AFAM, van den Anker J (2006) Guidelines on pediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet 45:1077–1097CrossRefPubMedGoogle Scholar
  5. Bonate PL (2011) Covariate distribution models and simulation. In: Kimko HHC, Peck CC (eds) Clinical trial simulations: applications and trends. Springer, New York, pp 505–526Google Scholar
  6. Bonate PL, Craig A, Gaynon P, Gandhi V, Jeha S, Kadota R, Lam GN, Plunkett W, Razzouk B, Rytting M, Steinherz P, Weitman S (2004) Population pharmacokinetics of clofarabine, a second-generation nucleoside analog, in pediatric patients with acute leukemia. J Clin Pharmacol 44:1309–1322CrossRefPubMedGoogle Scholar
  7. Boxenbaum H (1980) Interspecies variation in liver weight, hepatic blood flow, and antipyrine clearance: extrapolation of data to benzodiazepines and phenytoin. J Pharmacokinet Biopharm 8:165–176CrossRefPubMedGoogle Scholar
  8. Boxenbaum H (1982) Comparative pharmacokinetics of benzodiazepines in dog and man. J Pharmacokinet Biopharm 10:411–426CrossRefPubMedGoogle Scholar
  9. Brill MJE, Diepstraten J, van Rongen A, van Kralingen S, van der Anker JN, Knibbe CAJ (2012) Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet 51:277–304CrossRefPubMedGoogle Scholar
  10. Bruno R, Vivier N, Vergniol JC, De Phillips SL, Montay G, Shiener LB (1996) A population pharmacokinetic model for docetaxel (Taxotere): model building and validation. J Pharmacokinet Biopharm 24:153–172CrossRefPubMedGoogle Scholar
  11. Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME, Wiltshaw E (1989) Carboplatin dosing: prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748–1756PubMedGoogle Scholar
  12. Crawford J, Terry M, Rourke G (1958) Simplification of drug dosage calculation by application of the body surface area principle. Pediatrics 5:783–790Google Scholar
  13. de Jonge FE, Verweij J, Loos WJ, de Wit R, de Jonge MJA, Planting AS, Nooter K, Stoter G, Sparreboom A (2001) Body surface area based dosing does not increase accuracy of predicting cisplatin exposure. J Clin Oncol 19:3733–3739PubMedGoogle Scholar
  14. de Jonge FE, Gallo JM, Shen M, Verweij J, Sparreboom A (2004) Population pharmacokinetics of cisplatin in cancer patients. Cancer Chemother Pharmacol 54:105–112CrossRefGoogle Scholar
  15. Dirks NL, Meibohm B (2010) Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 49:633–659CrossRefPubMedGoogle Scholar
  16. Dirks NL, Nolting A, Kovar A, Meibohm B (2008) Population pharmacokinetics of cetuximab in patients with squamous cell carcinoma of the head and neck. J Clin Pharmacol 48:267–278CrossRefPubMedGoogle Scholar
  17. Dreyer G, Ray W (1910) The blood volume of mammals as determined by experiments in rabbits, guinea pigs, and mice in its relationship to body weight into the surface area expressed as a formula. Philos Trans R Soc Lond B 201:133–160CrossRefGoogle Scholar
  18. Dreyer G, Ray W (1912) Further experiments on the blood volume of mammals and its relation to surface area of the body. Philos Trans R Soc Lond B 202:191–212CrossRefGoogle Scholar
  19. Felici A, Verweij J, Sparreboom A (2002) Dosing strategies for anticancer drugs: the good, the bad, and the body surface area. Eur J Cancer 38:1677–1684CrossRefPubMedGoogle Scholar
  20. Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE (1966) Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep 50:219–244PubMedGoogle Scholar
  21. Griggs JJ, Mangu PB, Anderson H, Balaban EP, Dignam JJ, Hryniuk WM, Morrison VA, Pini TM, Runowicz CD, Rosner GL, Shayne M, Sparreboom A, Sucheston LE, Lyman GH (2012) Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 30:1553–1561CrossRefPubMedGoogle Scholar
  22. Grochow LB, Baraldi C, Noe D (1990) Is dose normalization to weight or body surface area useful in adults? J Natl Cancer Inst 82:323–325CrossRefPubMedGoogle Scholar
  23. Grollman A (1929) Physiological variations in cardiac output in man. VI. The value of cardiac output of the normal individual in the basal, resting condition. Am J Phys 90:210–217Google Scholar
  24. Ivy SP, Zwiebel J, Mooney M (2010) Follow-up for information letter regarding AUC-based dosing of carboplatin. Department of Health and Human Services; National Health Service; National Cancer Institute, Bethesda, MDGoogle Scholar


  1. Jen JF, Cutler DL, Pai SM, Batra VK, Affrime MB, Zambas DN, Heft S, Hajian G (2000) Population pharmacokinetics of temozolomide in cancer patients. Pharm Res 17:1284–1289CrossRefPubMedGoogle Scholar
  2. Keizer RJ, Huitema AD, Schellens JH, Beijnen JH (2010) Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 49:493–507CrossRefPubMedGoogle Scholar
  3. Kleiber M (1932) Body size and metabolism. Hilgardia 6:315–333CrossRefGoogle Scholar
  4. Leveque D (2008) Evaluation of fixed dosing of new anticancer agents in Phase I studies. Anticancer Res 28:3075–3078PubMedGoogle Scholar
  5. Loos WJ, Gelderblom H, Sparreboom A, Verweij J, de Jonge MJA (2000) Inter- and intrapatient variability in oral topotecan pharmacokinetics: implications for body surface area dosage regimens. Clin Cancer Res 6:2685–2689PubMedGoogle Scholar
  6. Lu JF, Bruno R, Eppler S, Novotny W, Lum BL, Gaudreault J (2008) Clinical pharmacokinetics of bevacizumab in patients with solid tumors. Cancer Chemother Pharmacol 62:779–786CrossRefPubMedGoogle Scholar
  7. Lyman GH, Sparreboom A (2013) Chemotherapy dosing in overweight and obese patients with cancer. Nat Rev Cancer 10:451–459Google Scholar
  8. Mahmood I (2010) Theoretical versus empirical allometry: facts behind theories and applications to pharmacokinetics. J Pharm Sci 99:2927–2933CrossRefPubMedGoogle Scholar
  9. Mathijssen RHJ, Verweij J, de Jonge MJA, Nooter K, Stoter G, Sparreboom A (2002) Impact of body size measures on irinotecan clearance: alternative dosing recommendations. J Clin Oncol 1:81–87CrossRefGoogle Scholar
  10. Mazundar M, Smith A, Tong WP, Motzer RJ (2000) Calvert’s formula for dosing carboplatin: overview and concerns of applicable in high dose settings. J Natl Cancer Inst 92:1434–1436CrossRefGoogle Scholar
  11. Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D (2006) Rationale for fixed dosing of pertuzumab in cancer patients based on population pharmacokinetic analysis. Pharm Res 23:1275–1284CrossRefPubMedGoogle Scholar
  12. Nguyen L, Chatelut E, Chevreau C, Tranchand B, Lochon I, Bachaud JM, Pujol A, Houin G, Bugat R, Canal P (1998) Population pharmacokinetics of total and unbound etoposide. Cancer Chemother Pharmacol 41:125–132CrossRefPubMedGoogle Scholar
  13. Peters RH (1983) The ecological implications of body size. Cambridge University Press, CambridgeCrossRefGoogle Scholar
  14. Pinkel D (1958) The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Res 18:853–856PubMedGoogle Scholar
  15. Rubern M (1883) Euber den einsluss der koperfrosse stoff- und kraftwechsel. Z Biol 19:535–562Google Scholar
  16. Sheiner LB, Beal SL (1980) Evaluation of methods for estimating population pharmacokinetics parameters. I. Michaelis-Menten model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm 8:553–571CrossRefPubMedGoogle Scholar
  17. Sheiner LB, Beal SL (1981) Evaluation of methods for estimating population pharmacokinetic parameters. II. Biexponential model and experimental pharmacokinetic data. J Pharmacokinet Biopharm 9:635–651CrossRefPubMedGoogle Scholar
  18. Sheiner LB, Beal SL (1983) Evaluation of methods for estimating population pharmacokinetic parameters. III Monoexponential model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm 11:303–319CrossRefPubMedGoogle Scholar
  19. Smith HW (1951) The kidney: structure and function in health and disease. Oxford University Press, New YorkGoogle Scholar
  20. Smorenberg CH, Sparreboom A, Bontenbal M, Stoter G, Nooter K, Verweij J (2003) Randomized crossover evaluation of body surface area based dosing versus flat-fixed dosing of paclitaxel. J Clin Oncol 21:197–202CrossRefGoogle Scholar
  21. U. S. Department of Health and Human Services, Center for Disease Control and Prevention and National Center for Health Statistics (2007) National Health and Nutrition Examination Survey, 2007–2008.
  22. Verbraecken J, Van de Heyning P, De Backer W, van Gaal L (2006) Body surface area in normal weight, overweight, and obese adults. A comparative study. Metabolism 55:515–524CrossRefPubMedGoogle Scholar
  23. Wang D, Zhang S, Zhao H, Men AY, Parivar K (2009) Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol 49:1012–1024CrossRefPubMedGoogle Scholar
  24. West GB, Brown JH, Enquist BJ (1997) A general model for the origin of allometric scaling laws in biology. Science 276:122–126CrossRefPubMedGoogle Scholar
  25. White CR, Seymour RS (2005) Allometric scaling of mammalian metabolism. J Exp Biol 208:1611–1619CrossRefPubMedGoogle Scholar
  26. Yaffe SJ, Aranda JV (2010) Neonatal and pediatric pharmacology: therapeutic principles in practice. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Pharmacokinetics/Modeling/Simulation 2N.184 Astellas, Global Clinical Pharmacology and Exploratory DevelopmentNorthbrookUSA

Personalised recommendations