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. 1992 Jul;66(1):159–166. doi: 10.1038/bjc.1992.235

The pharmacokinetic advantages of isolated limb perfusion with melphalan for malignant melanoma.

R N Scott 1, D J Kerr 1, R Blackie 1, J Hughes 1, G Burnside 1, R M MacKie 1, D S Byrne 1, A J McKay 1
PMCID: PMC1977921  PMID: 1637666

Abstract

We describe melphalan pharmacokinetics in 26 patients treated by isolated limb perfusion (ILP). Group A (n = 11) were treated with a bolus of melphalan (1.5 mg kg-1), and in a phase I study the dose was increased to 1.75 mg kg-1. The higher dose was given as a bolus to Group B (n = 9), and by divided dose to Group C (n = 6). Using high performance liquid chromatography (HPLC) the concentrations of melphalan in the arterial and venous perfusate (during ILP) and in the systemic circulation (during and after ILP) were measured. Areas under the concentration time curves for perfusate (AUCa, AUCv) and systemic (AUCs) data were calculated. In all three groups the peak concentrations of melphalan were much higher in the perfusate than in the systemic circulation. The pharmacokinetic advantages of ILP can be quantified by the ratio of AUCa/AUCs, median value 37.8 (2.1-131). AUCa and AUCv were both significantly greater in Group B than in Group A (P values less than 0.01, Mann-Whitney). In Groups B and C acceptable 'toxic' reactions occurred but were not simply related to melphalan levels. Our phase I study has allowed us to increase the dose of melphalan to 1.75 mg kg-1, but we found no pharmacokinetic advantage from divided dose administration.

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Selected References

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  1. Ardiet C., Tranchand B., Biron P., Rebattu P., Philip T. Pharmacokinetics of high-dose intravenous melphalan in children and adults with forced diuresis. Report in 26 cases. Cancer Chemother Pharmacol. 1986;16(3):300–305. doi: 10.1007/BF00293997. [DOI] [PubMed] [Google Scholar]
  2. Benckhuijsen C., Kroon B. B., van Geel A. N., Wieberdink J. Regional perfusion treatment with melphalan for melanoma in a limb: an evaluation of drug kinetics. Eur J Surg Oncol. 1988 Apr;14(2):157–163. [PubMed] [Google Scholar]
  3. Benckhuijsen C., Varossieau F. J., Hart A. A., Wieberdink J., Noordhoek J. Pharmacokinetics of melphalan in isolated perfusion of the limbs. J Pharmacol Exp Ther. 1986 May;237(2):583–588. [PubMed] [Google Scholar]
  4. Briele H. A., Djuric M., Jung D. T., Mortell T., Patel M. K., Das Gupta T. K. Pharmacokinetics of melphalan in clinical isolation perfusion of the extremities. Cancer Res. 1985 Apr;45(4):1885–1889. [PubMed] [Google Scholar]
  5. Bulman A. S., Jamieson C. W. Isolated limb perfusion with melphalan in the treatment of malignant melanoma. Br J Surg. 1980 Sep;67(9):660–662. doi: 10.1002/bjs.1800670919. [DOI] [PubMed] [Google Scholar]
  6. Chang S. Y., Alberts D. S., Farquhar D., Melnick L. R., Walson P. D., Salmon S. E. Hydrolysis and protein binding of melphalan. J Pharm Sci. 1978 May;67(5):682–684. doi: 10.1002/jps.2600670530. [DOI] [PubMed] [Google Scholar]
  7. Chang S. Y., Alberts D. S., Melnick L. R., Walson P. D., Salmon S. E. High-pressure liquid chromatographic analysis of melphalan in plasma. J Pharm Sci. 1978 May;67(5):679–682. doi: 10.1002/jps.2600670529. [DOI] [PubMed] [Google Scholar]
  8. Ehrsson H., Lönroth U. Degradation of melphalan in aqueous solutions--influence of human albumin binding. J Pharm Sci. 1982 Jul;71(7):826–827. doi: 10.1002/jps.2600710729. [DOI] [PubMed] [Google Scholar]
  9. Fontaine C. J., Jamieson C. W. Perfusion in limb melanoma: indications and results. Proc R Soc Med. 1974 Feb;67(2):99–100. [PMC free article] [PubMed] [Google Scholar]
  10. Ghussen F., Nagel K., Groth W., Müller J. M., Stützer H. A prospective randomized study of regional extremity perfusion in patients with malignant melanoma. Ann Surg. 1984 Dec;200(6):764–768. doi: 10.1097/00000658-198412000-00016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gouyette A., Hartmann O., Pico J. L. Pharmacokinetics of high-dose melphalan in children and adults. Cancer Chemother Pharmacol. 1986;16(2):184–189. doi: 10.1007/BF00256174. [DOI] [PubMed] [Google Scholar]
  12. Greig N. H., Sweeney D. J., Rapoport S. I. Melphalan concentration dependent plasma protein binding in healthy humans and rats. Eur J Clin Pharmacol. 1987;32(2):179–185. doi: 10.1007/BF00542192. [DOI] [PubMed] [Google Scholar]
  13. Hafström L., Hugander A., Jönsson P. E., Westling H., Ehrsson H. Blood leakage and melphalan leakage from the perfusion circuit during regional hyperthermic perfusion for malignant melanoma. Cancer Treat Rep. 1984 Jun;68(6):867–872. [PubMed] [Google Scholar]
  14. Hansson J. A., Simert G., Vang J. The effect of regional perfusion treatment on recurrent melanoma of the extremities. Acta Chir Scand. 1977;143(1):33–39. [PubMed] [Google Scholar]
  15. Hansson J., Lewensohn R., Ringborg U., Nilsson B. Formation and removal of DNA cross-links induced by melphalan and nitrogen mustard in relation to drug-induced cytotoxicity in human melanoma cells. Cancer Res. 1987 May 15;47(10):2631–2637. [PubMed] [Google Scholar]
  16. Krementz E. T., Carter R. D., Sutherland C. M., Muchmore J. H. Chemotherapy by regional perfusion for limb melanoma. Am Surg. 1987 Mar;53(3):133–140. [PubMed] [Google Scholar]
  17. Krementz E. T. Lucy Wortham James lecture. Regional perfusion. Current sophistication, what next? Cancer. 1986 Feb 1;57(3):416–432. doi: 10.1002/1097-0142(19860201)57:3<416::aid-cncr2820570304>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  18. Lejeune F. J., Ghanem G. E. A simple and accurate new method for cytostatics dosimetry in isolation perfusion of the limbs based on exchangeable blood volume determination. Cancer Res. 1987 Jan 15;47(2):639–643. [PubMed] [Google Scholar]
  19. Martijn H., Schraffordt Koops H., Milton G. W., Nap M., Oosterhuis J. W., Shaw H. M., Oldhoff J. Comparison of two methods of treating primary malignant melanomas Clark IV and V, thickness 1.5 mm and greater, localized on the extremities. Wide surgical excision with and without adjuvant regional perfusion. Cancer. 1986 May 15;57(10):1923–1930. doi: 10.1002/1097-0142(19860515)57:10<1923::aid-cncr2820571006>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
  20. McBride C. M., Clark R. L. Experience with 1-phenylalanine mustard dihydrochloride in isolation-perfusion of extremities for malignant melanoma. Cancer. 1971 Nov;28(5):1293–1296. doi: 10.1002/1097-0142(1971)28:5<1293::aid-cncr2820280531>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  21. Mikhail R. A., Boddie A. W., Jr, Ames F. C., Zimmerman S. O., McBride C. M. Effect of variation of drug dosage on disease control and regional toxicity in prophylactic perfusion for Stage I extremity melanoma. J Surg Oncol. 1984 Dec;27(4):215–218. doi: 10.1002/jso.2930270402. [DOI] [PubMed] [Google Scholar]
  22. Minor D. R., Allen R. E., Alberts D., Peng Y. M., Tardelli G., Hutchinson J. A clinical and pharmacokinetic study of isolated limb perfusion with heat and melphalan for melanoma. Cancer. 1985 Jun 1;55(11):2638–2644. doi: 10.1002/1097-0142(19850601)55:11<2638::aid-cncr2820551118>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
  23. Osterheld H. K., Musch E., von Unruh G. E., Loos U., Rauschecker H., Mühlenbruch B. J. A sensitive high-performance liquid chromatographic assay for melphalan and its hydrolysis products in blood and plasma. Cancer Chemother Pharmacol. 1988;21(2):156–162. doi: 10.1007/BF00257364. [DOI] [PubMed] [Google Scholar]
  24. Rege V. B., Leone L. A., Soderberg C. H., Jr, Coleman G. V., Robidoux H. J., Fijman R., Brown J. Hyperthermic adjuvant perfusion chemotherapy for Stage I malignant melanoma of the extremity with literature review. Cancer. 1983 Dec 1;52(11):2033–2039. doi: 10.1002/1097-0142(19831201)52:11<2033::aid-cncr2820521111>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
  25. Rosin R. D., Westbury G. Isolated limb perfusion for malignant melanoma. Practitioner. 1980 Oct;224(1348):1031–1036. [PubMed] [Google Scholar]
  26. Schraffordt Koops H., Beekhuis H., Oldhoff J., Oosterhuis J. W., van der Ploeg E., Vermey A. Local recurrence and survival in patients with (Clark Level IV/V and over 1.5-mm thickness) stage I malignant melanoma of the extremities after regional perfusion. Cancer. 1981 Nov 1;48(9):1952–1957. doi: 10.1002/1097-0142(19811101)48:9<1952::aid-cncr2820480907>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  27. Schraffordt Koops H., Oldhoff J., Oosterhuis J. W., Beekhuis H. Isolated regional perfusion in malignant melanoma of the extremities. World J Surg. 1987 Aug;11(4):527–533. doi: 10.1007/BF01655819. [DOI] [PubMed] [Google Scholar]
  28. Schraffordt Koops H., Oldhoff J., van der Ploeg E., Vermey A., Eibergen R. Regional perfusion for recurrent malignant melanoma of the extremities. Am J Surg. 1977 Feb;133(2):221–224. doi: 10.1016/0002-9610(77)90085-x. [DOI] [PubMed] [Google Scholar]
  29. Shingleton W. W., Seigler H. F., Stocks L. H., Downs R. W., Jr Management of recurrent melanoma of the extremity. Cancer. 1975 Mar;35(3):574–579. doi: 10.1002/1097-0142(197503)35:3<574::aid-cncr2820350303>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  30. Siddik Z. H., Edwards M. J., Boddie A. W. Isolated limb perfusion with chemotherapeutic agents for melanoma: a reevaluation of drug dosimetry. Eur J Cancer Clin Oncol. 1989 Oct;25(10):1393–1397. doi: 10.1016/0277-5379(89)90095-3. [DOI] [PubMed] [Google Scholar]
  31. Stehlin J. S., Jr Hyperthermic perfusion with chemotherapy for cancers of the extremities. Surg Gynecol Obstet. 1969 Aug;129(2):305–308. [PubMed] [Google Scholar]
  32. Storm F. K., Morton D. L. Value of therapeutic hyperthermic limb perfusion in advanced recurrent melanoma of the lower extremity. Am J Surg. 1985 Jul;150(1):32–35. doi: 10.1016/0002-9610(85)90006-6. [DOI] [PubMed] [Google Scholar]
  33. Sugarbaker E. V., McBride C. M. Survival and regional disease control after isolation-perfusion for invasive stage I melanoma of the extremities. Cancer. 1976 Jan;37(1):188–198. doi: 10.1002/1097-0142(197601)37:1<188::aid-cncr2820370127>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  34. Wieberdink J., Benckhuysen C., Braat R. P., van Slooten E. A., Olthuis G. A. Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions. Eur J Cancer Clin Oncol. 1982 Oct;18(10):905–910. doi: 10.1016/0277-5379(82)90235-8. [DOI] [PubMed] [Google Scholar]
  35. van Os J., Schraffordt Koops H., Oldhoff J. Dosimetry of cytostatics in hyperthermic regional isolated perfusion. Cancer. 1985 Feb 15;55(4):698–701. doi: 10.1002/1097-0142(19850215)55:4<698::aid-cncr2820550404>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]

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