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Journal of Cancer Research and Clinical Oncology logoLink to Journal of Cancer Research and Clinical Oncology
. 1995 Aug;121(8):478–486. doi: 10.1007/BF01218365

The use of the Calvert formula to determine the optimal carboplatin dosage

L J C van Warmerdam 1,2,, S Rodenhuis 1, W W ten Bokkel Huinink 1, R A A Maes 3, J H Beijnen 1,2,3
PMCID: PMC12200317  PMID: 7642691

Abstract

Carboplatin is a chemotherapeutic agent frequently used in the treatment of various malignancies. The myelotoxicity and clinical efficacy of carboplatin correlate with the clearance of the drug, which is correlated to the glomerular filtration rate (GFR). Dosing of this agent based solely upon the patients body surface area is therefore not accurate enough; the GFR, and thus the clearance of carboplatin differ in each patient irrespective of the body area. Consequently, some patients undergo a higher systemic exposure, expressed as the area under the plasma concentration/time curve (AUC), than others when dosages of carboplatin are given on the basis of the body surface area. A high AUC correlates with increased toxicity, thus increasing the risks of the treatment, but in the case of a low AUC the therapeutical efficacy decreases. This indicates that an individual dosing strategy is warranted to obtain the optimal AUC. In this article, the development and application of a simple equation, known as the Calvert formula, are discussed. This formula can be used to calculate the carboplatin dose accurately in order to obtain a target AUC by using only the GFR. The formula is: dose (mg)=AUC (mg ml−1 min)×[GFR (ml/min)+25 (ml/min)]. This formula has proven to be, in both retrospective and prospective studies, a reliable tool to calculate the optimal dose of carboplatin. Future studies should determine the value of the creatinine clearance as a measure for the GFR.

Key words: AUC, Calvert formula, Carboplatin, Glomerular filtration rate, Pharmacodynamics, Pharmacokinetics

References

  1. Alberts DS, Green S, Hannigan E, O'Toole R, Stock-Novack D, Anderson P, Surwit EA, Malvlya VK, Nahas WA, Jolles CJ (1992) Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the South-west Oncology group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol 10: 706–717 [DOI] [PubMed] [Google Scholar]
  2. Belani CP, Egorin MJ, Abrams JS, Hiponia D, Eisenberger M, Aisner J, van Echo (1989) A novel pharmacodynamically based approach to dose optimization of carboplatin when used in combination with etoposide. J Clin Oncol 7: 1896–1902 [DOI] [PubMed] [Google Scholar]
  3. Belani CP, Egorin MJ (1990) Reply to letter. J Clin Oncol 8: 1284–1285 [Google Scholar]
  4. Bokkel Huinink WW ten, Warmerdam LJC van, Dubbelman AC, McVie JG, Beijnen JH (1994) Intraperitoneal-administered carboplatin in patients with ovarian cancer; influence of a delltime on toxicity and response. Ann Oncol 5: 133–139 [DOI] [PubMed] [Google Scholar]
  5. Calvert AH, Newell DR, Gumbrell LA, O'Reilly S, Burnell M, Boxcall FE, Siddik ZH, Judson IR, Gore ME, Wiltshaw E (1989) Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 7: 1748–1756 [DOI] [PubMed] [Google Scholar]
  6. Calvert H, Judson I, Vijgh WJF van der (1993) Platinum complexes in cancer medicine: pharmacokinetics and pharmacodynamics in relation to toxicity and therapeutic activity. Cancer Surv 17: 189–217 [PubMed] [Google Scholar]
  7. Chantler C, Garnett ES (1969) Glomerular filtration rate measurement in man by the single injection method using51CrEDTA method. J Clin Sci 37: 169–190 [PubMed] [Google Scholar]
  8. Chatelut E, Pujol A, Chevreau C, Roché H, Mutin P, Houin G, Bugat R, Canal P (1994) Simple formula to predict the carboplatin clearance. Proc Am Soc Clin Oncol 13: 148 [Google Scholar]
  9. Childs WJ, Nicholls EJ, Horwich A (1992) The optimisation of carboplatin, etoposide and bleomycin combination chemotherapy for good prognosis metastatic nonseminomatous germ cell tumours of the testis. Ann Oncol 3: 291–296 [DOI] [PubMed] [Google Scholar]
  10. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16: 31–41 [DOI] [PubMed] [Google Scholar]
  11. Daugaard G, Rossing N, Rorth M (1988) Effects of cisplatin on different measures of glomerular function in the human kidney with special emphasis on high-dose. Cancer Chemother Pharmacol 21: 163–7 [DOI] [PubMed] [Google Scholar]
  12. Egorin MJ, Van Echo DA, Tipping SJ, Olman EA, Whitacre MY, Thompson BW, Aisner J (1984) Pharmacokinetics and dosage reduction of cis-diammine (1,1-cyclobutanedicarboxylato) platinum in patients with impaired renal function. Cancer Res 44: 5432–5438 [PubMed] [Google Scholar]
  13. Gaver RC, Colombo N, Green MD, George AM, Deeb G, Morris AD, Canetta RM, Speyer JL, Farmen RH, Muggia FM (1988) The disposition of carboplatin in ovarian cancer patients. Cancer Chemother Pharmacol 22: 263–270 [DOI] [PubMed] [Google Scholar]
  14. Green JA, Smith K (1990) Dose intensity of carboplatin in combination with cyclophosphamide or ifosfamide. Cancer Chemother Pharmacol 26 [Suppl]: s22-s25 [DOI] [PubMed] [Google Scholar]
  15. Groth S (1984) Calculation of51CrEDTA clearance in children from the activity in one plasma sample by transformation of the biexponential plasma time-activity curve into a monoexponential with identical integral area below the time-activity curve. Clin Physiol 4: 61–74 [DOI] [PubMed] [Google Scholar]
  16. Harland SJ, Gumbrell LA, Horwich A (1991) Carboplatin dose in combination chemotherapy for testicular cancer. Eur J Cancer 27: 691–5 [DOI] [PubMed] [Google Scholar]
  17. Horwich A, Dearnaley DP, Nicholls J, Jay G, Mason M, Harland S, Peckham MJ, Hendrey WF (1991) Effectiveness of carboplatin, etoposide, and bleomycin combination chemotherapy in goodprognosis metastatic testicular nonseminomatous germ cell tumours. J Clin Oncol 9: 62–69 [DOI] [PubMed] [Google Scholar]
  18. Jodrell DI, Egorin MJ, Canetta RM, Langenberg P, Goldbloom EP, Burroughs JN, Goodlow JL, Tan S, Wiltshaw E (1992) Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol 10: 520–528 [DOI] [PubMed] [Google Scholar]
  19. Jones A, Wiltshaw E, Harper P, Slevin M, Shepherd J, Mansi J, Blake P, Tan S, Gore M (1992) A randomised study of high versus conventional dose carboplatin for previously untreated ovarian cancer. Br J Cancer 65 [Suppl 16]: 15 [Google Scholar]
  20. Krigel RL, Palackdharry CS, Padavic K, Haas N, Kilpatrick D, Langer C, Comis R (1994) Ifosfamide, carboplatin, and etoposide plus granulocyte-macrophage colony-stimulating factor: a phase I study with apparent activity in non-small-cell lung cancer. J Clin Oncol 12: 1251–1258 [DOI] [PubMed] [Google Scholar]
  21. Lind MJ, Millward MJ, Chapman F, Simmons D, Proctor M, Gumbrell L, Aswad S, Sinha D, Cantwell B, Calvert AH (1992) The use of rHGCSF to increase the delivered dose intensity of carboplatin in women with advanced epithelial ovarian cancer. Proc Am Assoc Clin Oncol 11: 230 [Google Scholar]
  22. Luke DR, Halstenson CE, Opsahl JA, Matzke GR (1990) Validity of creatinine clearance estimates in the assessment of renal function. Clin Pharmacol Ther 48: 503–508 [DOI] [PubMed] [Google Scholar]
  23. Marina NM, Rodman J, Shema S, Bowman LC, Duoglass E, Furman W, Santana VM, Hudson M, Wilimas J, Meyer W, Madden T, Pratt C (1993) Phase I study of escalating targeted doses of carboplatin combined with ifosfamide and etoposide in children with relapsed solid tumors. J Clin Oncol 11: 554–560 [DOI] [PubMed] [Google Scholar]
  24. Neijt JP (1992) Treatment of advanced ovarian cancer: 10 years of experience. Ann Oncol 3: 17–27 [DOI] [PubMed] [Google Scholar]
  25. Newell DR, Eeles RA, Gumbrell LA, Boxall FE, Horwich A, Calvert AH (1989) Carboplatin and etoposide pharmacokinetics in patients with testicular teratoma. Cancer Chemother Pharmacol 23: 367–372 [DOI] [PubMed] [Google Scholar]
  26. Newell DR, Pearson ADJ, Balmanno K, Price L, Wyllie RA, Keir M, Calvert AH, Lewis IJ, Pinkerton CR, Stevens MCG (1993) Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. J Clin Oncol 11: 2314–2323 [DOI] [PubMed] [Google Scholar]
  27. O'Brien MER, Talbot DC, Smith IE (1993) Carboplatin in the treatment of advanced brest cancer: a phase II study using a pharmacokinetically guided dosing schedule. J Clin Oncol 11: 2112–2117 [DOI] [PubMed] [Google Scholar]
  28. O'Reilly SM, Rustin GJ, Smith DB, Newlands ES (1992) Single agent activity of carboplatin in patients with previously untreated nonseminomatous germ cell tumours. Ann Oncol 3: 163–164 [DOI] [PubMed] [Google Scholar]
  29. Pinkerton CR, McElwain TJ (1989) High dose carboplatin in combination regimes using autologous bone marrow rescue in neuroblastoma and soft tissue sarcoma. Med Pediatr Oncol 17: 310 [Google Scholar]
  30. Reyno LM, Egorin MJ, Canetta RM, Jodrell DI, Swenerton KD, Pater JL, Burroughs JN, Novak MJ, Sridhara R (1993) Impact of cyclophosphamide on relationships between carboplatin exposure and response or toxicity when used in the treatment of advanced ovarian cancer. J Clin Oncol 11: 1156–1164 [DOI] [PubMed] [Google Scholar]
  31. Rodman J, Murry DJ, Marina N, Madden T, Sandlund T, Furman W, Meyer W (1993) Controlling carboplatin pharmacokinetic variability in pediatric patients. Proc Am Soc Clin Oncol 12:134 [Google Scholar]
  32. Sadan S, Bajorin DF, Mazumdar M, Vlamis V, Motzer RJ, Bosl GJ (1993) Correlation of carboplatin area under the curve (AUC) with myelosuppression and infection in germ cell tumor patients. Proc Am Soc Clin Oncol 12:159 [Google Scholar]
  33. Sessa C, Goldhirsch A, Martinelli G, Alcerci, Imburgia L, Cavalli F (1991) Phase I study of the combination of monthly carboplatin and weekly cisplatin. Ann Oncol 2:123–129 [DOI] [PubMed] [Google Scholar]
  34. Sørensen BT, Strömgren A, Jakobsen P, Jakobsen A (1992a) Dose-toxicity relationship of carboplatin in combination with cyclophosphamide in ovarian cancer patients. Cancer Chemother Pharmacol 28:397–401 [DOI] [PubMed] [Google Scholar]
  35. Sørensen BT, Strömgren A, Jakobsen P, Nielsen JT, Andersen LS, Jakobsen A (1992b) Renal handling of carboplatin. Cancer Chemother Pharmacol 30:317–320 [DOI] [PubMed] [Google Scholar]
  36. Sørensen BT, Strömgren A, Jakobsen P, Jakobsen A (1993) Is creatinine clearance a sufficient measure for GFR in carboplatin dose calculation? Eur J Cancer 29:S110 [Google Scholar]
  37. Stewart W, for the Advanced Ovarian Cancer Trialist Group (1991) Chemotherapy in advanced ovarian cancer, an overview of randomized trials. Br Med J 303:884–93 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Vermorken JB, ten Bokkel Huinink WW, Eisenhower EA, Favalli G, Belpomme D, Conte PF, Kaye SB (1993) Carboplatin versus cisplatin. Ann Oncol 4[Suppl 4]:S41-S48 [PubMed] [Google Scholar]
  39. Vijgh WJF van der (1991) Clinical pharmacokinetics of carboplatin. Clin Pharmacokinet 21:242–61 [DOI] [PubMed] [Google Scholar]
  40. Wagstaff AJ, Ward A, Benfield P, Heel RC (1989) Carboplatin, a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of cancer. Drugs 37:162–90 [DOI] [PubMed] [Google Scholar]

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