Skip to main content
SpringerLink
Log in

Chemotherapy Individualization

  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Abstract

The current practice of dosing patients with anticancer drugs based on body size, leads to a large degree of inter-patient variation in clinical outcome following standard doses of chemotherapy. Some patients may fail to respond to treatment, whilst others experience unacceptable side effects. Recent studies have identified more rational approaches to drug dosing, based on patient characteristics such as renal function, pharmacogenetic factors, and drug metabolizing activity. These can be used together with therapeutic drug monitoring and adaptive dosing to achieve a targeted systemic drug exposure in each patient, which may lead to more consistent clinical outcomes in patients receiving comparable chemotherapy dosing regimens. The purpose of this review is to present some approaches to chemotherapy individualization, examples of how this might be applied, and speculation as to how recent advances in pharmacogenetics may lead to further dose-optimization.

Whilst it is hoped that the design of new agents, targeted to specific genes involved in oncogenesis, will lead to increased success in the treatment of cancer patients, it is essential that the drugs currently available are used to their maximum potential.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. 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

    Google Scholar 

  2. Ratain MJ: Body-surface area as a basis for dosing of anticancer agents. J Clin Oncol 16: 2297–2298, 1998

    Google Scholar 

  3. Sharkey I, Boddy AV, Wallace H, Mycroft J, Hollis R, Picton S: Body surface area estimation in children using weight alone: application in paediatric oncology. Br J Cancer 85: 23–28, 2001

    Google Scholar 

  4. Jodrell DI, Egorin MJ, Canetta RM, Langenberg P, Goldbloom EP, Burroughs JN, Goodlow JL, Tan S, Wiltshaw E: Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol 10: 520–528, 1992

    Google Scholar 

  5. Joel SP, Ellis P, O'Byrne K, Papamichael D, Hall M, Penson R, Nicholls S, O'Donnell C, Constantinou A, Woodhull J, Nicholson M, Smith I, Talbot D, Slevin M: Therapeutic monitoring of continuous infusion etoposide in small-cell lung cancer. J Clin Oncol 14: 1903–1912, 1996

    Google Scholar 

  6. Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Ching-Hon P: Conventional compared with individualised chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 338: 499–505, 1998

    Google Scholar 

  7. Calvert AH, Newell DR, Gumbrell LA, O'Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME, Wiltshaw E: Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 7: 1748–1756, 1989

    Google Scholar 

  8. Lennard L: The clinical pharmacology of 6–mercaptopurine. Eur J Clin Pharmacol 43: 329–339, 1992

    Google Scholar 

  9. Diasio RB, Johnson MR: The role of pharmacogenetics and pharmacogenomics in cancer chemotherapy with 5–fluorouracil. Pharmacol 61: 199–203, 2000

    Google Scholar 

  10. Rivory LP, Slaviero K, Seale JP, Hoskins JM, Boyer M, Beale PJ, Millward MJ, Bishop JF, Clarke SJ: Optimizing the erythromycin breath test for use in cancer patients. Clin Cancer Res 6: 3480–3485, 2000

    Google Scholar 

  11. Galpin AJ, Evans WE: Therapeutic drug monitoring in cancer management. Clin Chem 39: 2419–2430, 1993

    Google Scholar 

  12. McCune JS, Gibbs JP, Slattery JT: Plasma concentration monitoring of busulfan: does it improve clinical outcome? Clin Pharmacokin 39: 155–165, 2000

    Google Scholar 

  13. Henwood JM, Brogden RN: Etoposide: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in combination chemotherapy in cancer. Drugs 39: 438–490, 1990

    Google Scholar 

  14. Minami H, Shimokata K, Saka H, Saito H, Ando Y, Senda K, Nomura F, Sakai S: Phase I clinical and pharmacokinetic study of a 14–day infusion of etoposide in patients with lung cancer. J Clin Oncol 11: 1602–1608, 1993

    Google Scholar 

  15. Villablanca JG, Khan AA, Avramis VI, Seeger RC, Matthay KK, Ramsay NKC, Reynolds CP: Phase I trial of 13–cis-retinoic acid in children with neuroblastoma following bone marrow transplantation. J Clin Oncol 13: 894–901, 1995

    Google Scholar 

  16. Lowis S, Price L, Pearson ADJ, Newell DR, Cole M: A study of the feasibility and accuracy of pharmacokinetically guided etoposide dosing in children. Br J Cancer 77: 2318–2323, 1998

    Google Scholar 

  17. Sandstrom M, Karlsson MO, Ljungman P, Hassan Z, Jonssen EN, Nilsson C, Ringden O, Oberg G, Bekassy A, Hassan M: Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow recipients. Bone Marrow Transpl 28: 657–664, 2001

    Google Scholar 

  18. Nebert DW, McKinnon RA, Puga A: Human drug-metabolizing enzyme polymorphisms — effects on risk of toxicity and cancer. DNA Cell Biol 15: 273–280, 1996

    Google Scholar 

  19. Brockmoller J, Kerb R, Drakoulis N, Staffeldt B, Roots I: Glutathione-S-transferase-m1 and its variant-A and variant-B as host factors of bladder-cancer susceptibility — a case-control study. Cancer Res 54: 4103–4111, 1994

    Google Scholar 

  20. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U: Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci 97: 3473–3478, 2000

    Google Scholar 

  21. Parker WB, Cheng YC: Metabolism and mechanism of action of 5–fluorouracil. Pharmacol Therapeutics 48: 381–395, 1990

    Google Scholar 

  22. Diasio RB, Beavers TL, Carpenter JT: Familial deficiency of dihydropyrimidine dehydrogenase — biochemical basis for familial pyrimidinemia and severe 5–fluorouracil-induced toxicity. J Clin Invest 81: 47–51, 1988

    Google Scholar 

  23. Ridge SA, Sludden J, Brown O, Roberston L, Wei XX, Sapone A, Fernandez-Salguero PM, Gonzalez FJ, Vreken P, van Kuilenburg ABP, van Gennip AH, McLeod HL: Dihydropyrimidine dehydrogenase pharmacogenetics in Caucasian subjects. Br J Clin Pharmacol 46: 151–156, 1998

    Google Scholar 

  24. Wei XX, Elizondo G, Sapone A, McLeod HL, Raunio H, Fenandez-Salguero P, Gonzalez FJ: Characterization of the human dihydropyrimidine dehydrogenase gene. Genomics 51: 391–400, 1998

    Google Scholar 

  25. Harris BE, Carpenter JT, Diasio RB: Severe 5–fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase-deficiency — a potentially more common pharmacogenetic syndrome. Cancer 68: 499–501, 1991

    Google Scholar 

  26. Adjei AA, Doucett M, Spector T, Khor SP, Sartorius SE, Bowling MK, Baker S, Donehower RC, Grochow LB, Hohneker J, Rowinsky EK: 5–ethinyluracil (776C85), an inhibitor of dihydropyrimidine dehydrogenase, permits reliable oral dosing of 5–fluorouracil and prolongs its half-life. Am Soc Clin Oncol 14: 459, 1995

    Google Scholar 

  27. Gupta E, Lestingi TM, Mick R, Ramirez J, Yokes EE, Ratain MJ: Metabolic fate of irinotecan in humans; correlation of glucuronidation with diarrhea. Cancer Res 54: 3723–3725, 1994

    Google Scholar 

  28. Ratain MJ, Mick R, Janisch L, Berezin F, Schilsky RI, Vogelzang NJ, Kut M: Individulized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender. Pharmacogen 6: 93–101, 1996

    Google Scholar 

  29. Newell DR, Siddik ZH, Gumbrell LA, Boxall FE, Gore ME, Smith IE, Calvert AH: Plasma free platinum pharmacokinetics in patients treated with high dose carboplatin. Eur J Cancer Clin Oncol 23: 1399–1405, 1987

    Google Scholar 

  30. Madden T, Sunderland M, Santana VM, Rodman JH: The pharmacokinetics of high-dose carboplatin in pediatric patients with cancer. Clin Pharmacol Ther 51: 701–707, 1992

    Google Scholar 

  31. Murry DJ, Sandlund JT, Stricklin LM, Rodman JH: Pharmacokinetics and acute renal effects of continuously infused carboplatin. Clin Pharmacol Ther 54: 374–380, 1993

    Google Scholar 

  32. Harland SJ, Newell DR, Siddik ZH, Chadwick R, Calvert AH, Harrap KR: Pharmacokinetics of cis-diammine-1, 1–cyclobutane dicarboxylate platinum(II) in patients with normal and impaired renal function. Cancer Res 44: 1693–1697, 1984

    Google Scholar 

  33. Egorin M, Van Echo D, Tipping S, Olman E, Whitacre M, Thompson B, Asiner J: Pharmacokinetics and dosage reduction of carboplatin in patients with impaired renal function. Cancer Res 44: 5432–5438, 1984

    Google Scholar 

  34. Calvert AH, Harland SJ, Newell DR, Siddik ZH, Harrap KR: Phase I studies with carboplatin at the Royal Marsden Hospital. Cancer Treat Rev 12: 51–57, 1985

    Google Scholar 

  35. Sorensen BT, Stromgren A, Jakobsen P, Nielsen JT, Andersen LS, Jakobsen A: Renal handling of carboplatin. Cancer Chemother Pharmacol 30: 317–320, 1992

    Google Scholar 

  36. Egorin M, Van Echo D, Olman E, Whitacre M, Forrest A, Aisner J: Prospective validation of a pharmacokinetically based dosing scheme for the cis-diamminedichloro-platinum(II) analogue diamminecyclobutanedicarboxylato-platinum. Cancer Res 45: 6502–6506, 1985

    Google Scholar 

  37. Thomas HD, Boddy AV, English MW, Hobson R, Imeson J, Lewis I, Morland B, Pearson ADJ, Pinkerton R, Price L, Stevens M, Newell DR: Prospective validation of renal function-based carboplatin dosing in children with cancer: a United Kingdom Children's Cancer Study Group trial. J Clin Oncol 18: 3614–3621, 2000

    Google Scholar 

  38. Veal GJ, Boddy AV, Thomas HD, Price E, Parry A, Hale J, Pearson ADJ, Dick G, Atra A, Newell DR: Real-time monitoring of carboplatin pharmacokinetics in paediatric patients receiving high dose chemotherapy. Br J Cancer 80(suppl 2): 93, 1999

    Google Scholar 

  39. Grigg A, Szer J, Skov K, Barnett M: Multi-organ dysfunction associated with high-dose carboplatin therapy prior to autologous transplantation. Bone Marrow Transpl 17: 67–74, 1996

    Google Scholar 

  40. Evans W, Crom W, Abromowitch M, Dodge R, Look, AT, Bowman WP, George SL, Pui C-H: Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. N Engl J Med 314: 471–477, 1986

    Google Scholar 

  41. Chabner B, Allegra C, Curt G: Polyglutamation of methotrexate: is methotrexate a prodrug. J Natl Cancer Inst 76: 907–912, 1985

    Google Scholar 

  42. Kerr IG, Jolivet J, Collins JM, Drake JC, Chabner BA: Test dose for predicting high dose methotrexate infusions. Clin Pharmacol Ther 33: 44–51, 1983

    Google Scholar 

  43. Stoller RG, Hande KR, Jacobs SA, Rosenberg SA, Chabner BA: Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med 297: 630–634, 1977

    Google Scholar 

  44. Nirenberg A, Mosende C, Mehta BM, Gisolfi AL, Rosen G: High-dose methotrexate with citrovorum factor rescue: predictive value of serum methotrexate concentrations and corrective measures to avert toxicity. Cancer Treat Rep 61: 779–783, 1977

    Google Scholar 

  45. Widemann BC, Balis FM, Murphy RF, Sorensen JM, Montello MJ, O'Brien M, Adamson PC: Carboxypeptidase-G(2), thymidine and leucovorin rescue in patients with methotrexate-induced renal dysfunction. J Clin Oncol 15: 2125–2134, 1997

    Google Scholar 

  46. Bertino JR: Improving the curability of acute leukemia: Pharmacologic approaches. Semin Hematol 28: 9–11, 1991

    Google Scholar 

  47. Weinshilboum RM, Sladek SL: Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 32: 651–662, 1980

    Google Scholar 

  48. Lennard L, van Loon JA, Lilleyman JS, Weinshilboum RM: Correlation of erythrocyte thiopurine methyltransferase activity and 6–thioguanine nucleotide concentrations. Clin Pharmacol Ther 41: 18–25, 1987

    Google Scholar 

  49. Lennard L, Lilleyman JS, van Loon J, Weinshilboum RM: Genetic variation in response to 6–mercaptopurine for childhood acute leukaemia. Lancet 336: 225–229, 1990

    Google Scholar 

  50. McLeod HL, Relling MV, Lieu Q, Pui C-H, Evans WE: Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blases from children with acute lymphoblastic leukemia. Blood 85: 1897–1902, 1995

    Google Scholar 

  51. Schmiegelow K, Schroder H, Gustafsson G, Kristinsson J, Glomstein A, Salmi T, Wranne L: Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. J Clin Oncol 13: 345–351, 1995

    Google Scholar 

  52. Schutz E, Gummert J, Mohr FW, Armstrong VW, Oellerich M: Azathioprine myelotoxicity related to elevated 6–thioguanine nucleotides in heart transplantation. Transpl Proc 27: 1298–1300, 1995

    Google Scholar 

  53. Bostrom B, Erdmann G: Cellular pharmacology of 6–mercaptopurine in acute lymphoblastic leukemia. Am J Pediat Hematol 15: 80–86, 1993

    Google Scholar 

  54. Lilleyman JS, Lennard L: Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia. Lancet 343: 1188–1190, 1994

    Google Scholar 

  55. Leipold AP, Schutz E, Haas JP, Oellerich M: Azathioprine-induced severe pancytopenia due to a homozygous two-point mutation of the thiopurine methyltransferase gene in a patient with juvenile HLA-B27–associated spondylarthritis. Arthritis Rheum 40: 1896–1898, 1997

    Google Scholar 

  56. Ben Ari Z, Mehta A, Lennard L, Burroughs AK: Azathioprine-induced myelosuppression due to thiopurine methyltransferase deficiency in a patient with autoimmune hepatitis. J Hepatol 23: 351–354, 1995

    Google Scholar 

  57. Lennard L, van Loon JA, Weinshilboum RM: Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 46: 149–154, 1989

    Google Scholar 

  58. Jackson AP, Hall AG, McLelland J: Thiopurine methyltransferase levels should be measured before commencing patients on azathioprine. Br J Dermatol 136: 133–134, 1997

    Google Scholar 

  59. Evans WE, Horner M, Chu YQ, Kalwinsky D, Roberts WM: Altered mercaptopurine metabolism, toxic effects and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 119: 985–989, 1991

    Google Scholar 

  60. Andersen JB, Szumlanski C, Weinshilboum RM, Schmiegelow K: Pharmacokinetics, dose adjustments and 6–mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr 87: 108–111, 1998

    Google Scholar 

  61. Lennard L, Gibson BES, Nicole T, Lilleyman JS: Congenital thiopurine methyltransferase deficiency and 6–mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia. Arch Dis Childhood 69: 577–579, 1993

    Google Scholar 

  62. Krynetski EY, Evans WE: Pharmacogenetics as a molecular basis for individualized drug therapy: the thipurine S-methyltransferase paradigm. Pharm Res 16: 342–349, 1999

    Google Scholar 

  63. Evans W, Rodman J, Relling M, Crom W, Rivera G, Crist W, Pui C-H: Individualized dosages of chemotherapy as a strategy for acute lymphoblastic leukemia. Semin Oncol 28: 15–21, 1991

    Google Scholar 

  64. McLeod HL, Miller DR, Evans WE: Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet 341: 1151, 1993

    Google Scholar 

  65. Thomsen JB, Schroder H, Kristinsson J, Madsen B, Szumlanski C, Weinshilboum R, Andersen JB, Schmiegelow K: Possible carcinogenic effect of 6–mercaptopurine on bone marrow stem cells — relation to thiopurine metabolism. Cancer 86: 1080–1086, 1999

    Google Scholar 

  66. Relling MV, Yanishevski Y, Nemec I, Evans WE, Boyett JM, Behm FG, Poi C-H: Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia. Leukemia 12: 346–352, 1998

    Google Scholar 

  67. Relling MV, Rubnitz JE, Rivera GK, Boyett JM, Hancock ML, Felix CA, Kun LE, Walter AW, Evans WE, Pui C-H: High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet 354: 34–39, 1999

    Google Scholar 

  68. Pui C-H, Relling MW: Topoisomerase II inhibitor-related acute myeloid leukaemia. Br J Haematol 109: 13–23, 2000

    Google Scholar 

  69. McLeod HL, Evans WE: Pharmacogenomics: unlocking the human genome for better drug therapy. Ann Rev Pharmacol Toxicol 41: 101–121, 2001

    Google Scholar 

  70. Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie H-G, McKinsey J, Zhou S, Lan L-B, Schuetz JD, Schuetz EG, Wilkinson GR: Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70: 189–199, 2001

    Google Scholar 

  71. Cobleigh MA, Bogel CL, Tripathy D, Tobert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2–overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17: 2639–2648, 1999

    Google Scholar 

  72. Clark GM: Should selection of adjuvant chemotherapy for patients with breast cancer be based on erbB-2 status. J Natl Cancer Inst 90: 1320–1321, 1998

    Google Scholar 

  73. Petit T, Borel C, Ghnassia J-P, Rodier J-F, Escande A, Mors R, Haegele P: Chemotherapy response of breast cancer depends on HER-2 status and anthracycline dose intensity in the neoadjuvant setting. Clin Cancer Res 7: 1577–1581, 2001

    Google Scholar 

  74. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers C: Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. N Eng J Med 344: 1031–1037, 2001

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Northern Institute for Cancer Research, Medical School, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, NE2 4HH, United Kingdom

    Gareth J. Veal, Sally A. Coulthard & Alan V. Boddy

Authors
  1. Gareth J. Veal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sally A. Coulthard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alan V. Boddy
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Veal, G.J., Coulthard, S.A. & Boddy, A.V. Chemotherapy Individualization. Invest New Drugs 21, 149–156 (2003). https://doi.org/10.1023/A:1023517311879

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1023517311879

Search

Navigation