Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 29, Issue 3, pp 178–184 | Cite as

5-fluorouracil, leucovorin, hydroxyurea, and escalating doses of continuous-infusion cisplatin with concomitant radiotherapy: a clinical and pharmacologic study

  • Everett E. Vokes
  • Jill A. Moormeier
  • Mark J. Ratain
  • Merrill J. Egorin
  • Daniel J. Haraf
  • Rosemarie Mick
  • Ralph R. Weichselbaum
Original Articles Cisplatin, 5-Fluorouracil, Leucovorin, Hydroxyurea, Radiotherapy

Summary

Cisplatin (CDDP), 5-fluorouracil (5-FU), and hydroxyurea (HU) have individually demonstrated activity against several solid tumors, act synergistically with each other in vitro, and may act as radiation sensitizers. Therefore, we designed a phase I study to determine the maximally tolerated dose of cisplatin as given in addition to our previously described combination of 5-FU, HU, and concomitant radiotherapy (XRT). Patients exhibiting advanced solid tumors requiring palliative XRT were eligible. The regimen consisted of 1 g HU given p.o.b.i.d. on days 1–5,600 mg/m2 5-FU given i.v. daily by continuous infusion (c.i.) on days 1–5, escalating doses of cisplatin starting at 10 mg/m2 daily given by c.i. on days 1–5, and involved-field XRT carried out on days 1–5. The cycle was repeated every 14 days until the target XRT dose had been reached. In all, 19 patients were entered at the first dose level, and cumulative grade 3–4 myelosuppression was seen in 16 subjects. As no dose escalation was feasible, the chemotherapy was subsequently altered by using the above regimen for cycles 1, 3, 5, and 7 and substituting the less myelosuppressive regimen of 1 g HU given p.o.b.i.d. on days 1–5, 400 mg/m2 5-FU given i.v. daily by c.i., and 100 mg leucovorin given p.o. 4 h on days 1–5 for cycles 2, 4, and 6. On this alternating program, 28 patients were treated with escalating doses of CDDP. The dose-limiting toxicity was again myelosuppression, which was prohibitive at a CDDP dose of 20 mg/m2 daily. In the final phase of the protocol, 30 subjects were treated with the above alternating-cycle regimen at a CDDP dose of 20 mg/m2 daily and a decreased HU dose of 500 mg p.o.b.i.d. in an attempt to circumvent the myelosuppression associated with this dose of CDDP. Although severe acute toxicity (cycles 1 and 2) was observed less frequently, cumulative toxicity (all cycles) remained pronounced. The other major toxicity encountered was mucositis, which was particularly pronounced in patients receiving radiation to the head and neck and following leucovorin-containing cycles. Plasma concentrations of free platinum did not correlate with the CDDP dose, possibly due to the narrow range of doses given. Pharmacodynamic modeling demonstrated that the CDDP dose and the HU dose were associated with leukopenia. Antitumor activity was demonstrated in a number of solid tumors, particularly non-small-cell lung cancer and head and neck cancer. Due to the high incidence of severe cumulative toxicity, we recommend further use of this regimen only as part of a curative treatment strategy for patients presenting with locoregionally advanced solid tumors.

Keywords

CDDP Leukopenia Leucovorin Hydroxyurea Advanced Solid Tumor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Belliveau JF, Posner MR, Ferrari L, Crabtree GW, Cummings FJ, Wiemann MC, O'Leary GP, Griffin H, Phaneuf MA, O'Rourke MA, Calabresi P (1986) Cisplatin administered as a 5-day infusion: plasma platinum levels and urine platinum excretion. Cancer Treat Rep 70: 1215Google Scholar
  2. 2.
    Byfield JE, Calabro-Jones P, Klisak I, Kulhanian F (1982) Pharmacologic requirements for obtaining sensitization of human tumor cells in vitro to combined 5-fluorouracil or ftorafur and X-rays. Int J Radiat Oncol Biol Phys 8: 1923Google Scholar
  3. 3.
    Cantwell BMJ, Veale D, Rivett C, Ghani S, Harris AL (1989) Cisplatin with high-dose infusions of hydroxyurea to inhibit DNA repair. A phase II study in non-small-cell lung cancer. Cancer Chemother Pharmacol 23: 252Google Scholar
  4. 4.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16: 31Google Scholar
  5. 5.
    Coughlin CT, Richmond RC (1989) Biologic and clinical developments of cisplatin combined with radiation: concepts, utility, projections for new trials, and the emergence of carboplatin. Semin Oncol 16 [Suppl 6]: 31Google Scholar
  6. 6.
    Cox DR (1970) Logistic regression (binary outcome), stepwise selection for identifying independent prognostic factors for response. The analysis of binary data. Methuen & Co., LondonGoogle Scholar
  7. 7.
    Donehower RC (1990) Hydroxyurea. In: Chabner BA, Collins YM (eds) Cancer chemotherapy: principles and practice. J. B. Lippincott, Philadelphia, p 225Google Scholar
  8. 8.
    Douple EB (1988) Keynote address: platinum-radiation interactions. NCI Monogr 6: 315Google Scholar
  9. 9.
    Draper N, Smith H (1988) Applied regression analysis, 2nd edn. Wiley and Sons, New YorkGoogle Scholar
  10. 10.
    Forastiere AA, Belliveau JF, Goren MP, Vogel WC, Posner MR, O'Leary GP Jr (1988) Pharmacokinetic and toxicity evaluation of 5-day continuous infusion versus intermittent boluscis-diamminedichloroplatinum(II) in head and neck cancer patients. Cancer Res 48: 3869Google Scholar
  11. 11.
    Frankfurt OS (1973) Enhancement of the antitumor activity of 5-fluorouracil by drug combinations. Cancer Res 73: 1043Google Scholar
  12. 12.
    Hreshehyshyn MM, Aron BS, Boronow RC, Franklin EW III, Shingleton HM, Blessing JA (1979) Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV, cervical cancer confined to the pelvis. Int J Radiat Oncol Biol Phys 5: 317Google Scholar
  13. 15.
    Kanazawa H, Rapacchietta D, Kallman RF (1988) Schedule-dependent therapeutic gain from the combination of fractionated irradiation andcis-diamminedichloroplatinum(II) in C3H/Km mouse model systems. Cancer Res 48: 3158Google Scholar
  14. 14.
    Layergren J, Reichard P (1987) Purine deoxyribonucleosides counteract effects of hydroxyurea on deoxyribonucleoside triphosphate pools and DNA synthesis. Biochem Pharmacol 36: 2485Google Scholar
  15. 15.
    Lelieveld P, Scoles MA, Brown JM, Phil D, Kallman RF (1985) The effect of treatment in fractionated schedules with the combination of X-irradiation and six cytotoxic drugs on the RIF-1 tumor and normal mouse skin. Int J Radiat Oncol Biol Phys 11: 111Google Scholar
  16. 16.
    Levin VA, Wilson CB, Davis R, Wara WM, Pischer TL, Irwin L (1979) A phase III comparison of BCNU, hydroxyurea, and radiation therapy to BCNU and radiation therapy for treatment of primary malignant gliomas. J Neurosurg 51: 526Google Scholar
  17. 17.
    Lo TC, Wiley AL Jr, Ansfield FJ, Brandenburg JH, Davis HL Jr, Gollin FF, Johnson RO, Ramirez G, Vermund H (1976) Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: a randomized study. AJR 126: 229Google Scholar
  18. 18.
    Moertel CG, Frytak S, Hahn RG, O'Connell JM, Reitemeier RJ, Rubin J, Schutt AJ, Weiland LH, Childs DS, Holbrook MA, Lavin PT, Levstone E, Spiro H, Knowlton A, Kalser M, Barkin J, Lessner H, Mann-Kaplan R, Ramming K, Douglas HO, Thomas P, Nave H, Bateman J, Lokich J, Brooks J, Chaffey J, Corson JM, Zamcheck N, Novak JW (1981) Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads+5-fluorouracil), and high dose radiation +5-fluorouracil. Cancer 48: 1705Google Scholar
  19. 19.
    Moran RG, Danenberg PV, Heidelberger C (1982) Therapeutic response of leukemic mice treated with fluorinated pyrimidines and inhibitors of deoxyuridylate synthesis. Biochem Pharmacol 31: 2929Google Scholar
  20. 20.
    Piver MS, Barlow JJ, Vongtama V, Blumenson L (1983) Hydroxyurea: a radiation potentiator in carcinoma of the uterine cervix. Am J Obstet Gynecol 147: 803Google Scholar
  21. 21.
    Scanlon KY, Newman EM, Priest DG (1986) Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. Proc Natl Acad Sci USA 83: 8923Google Scholar
  22. 22.
    Sinclair WK (1967) Hydroxyurea: effects on Chinese hamster cells grown in culture. Cancer Res 27: 297Google Scholar
  23. 23.
    Sinclair WK (1968) The combined effect of hydroxyurea and X-rays on Chinese hamster cells in vitro. Cancer Res 28: 198Google Scholar
  24. 24.
    Snedecor GW, Cochran WG (1980) Chi-square test of association (r x c tables) for comparison of categorical variables for 2 or more groups. In: Snedecor GW, Cochran WG (eds) Statistical methods, 7th edn. Iowa State University Press, Ames, IowaGoogle Scholar
  25. 25.
    Swinnen LJ, Barnes DM, Fisher SG, Albain KS, Fisher RI, Erickson LC (1989) 1-β-d-Arabinofuranosylcytosine and hydroxyurea production of cytotoxic synergy withcis-diamminedichloroplatinum(II) and modification of platinum-induced DNA interstrand cross-linking. Cancer Res 49: 1383Google Scholar
  26. 26.
    Snyder RD (1984) Inhibitors of ribonucleotide reductase alter DNA repair in human fibroblasts through specific depletion of purine deoxynucleotide triphosphates. Cell Biol Toxicol 1: 81Google Scholar
  27. 27.
    Tanabe M, Godat D, Kallman RF (1987) Effects of fractionated schedules of irradiation combined withcis-diamminedichloroplatinum(II) on the SCCVII/ST tumor and normal tissues of the C3H/KM mouse. Int J Radiat Oncol Biol Phys 13: 1523Google Scholar
  28. 28.
    Vermorken MB, Vijgh WJF van der, Klein I, Gall HE, Groeningen CJ van, Hart GAM, Pinedo HM (1986) Pharmacokinetics of free and total platinum species after rapid and prolonged infusions of cisplatin. Clin Pharmacol Ther 39: 136Google Scholar
  29. 29.
    Vermund H, Hodgett J, Ansfield FJ (1961) Effects of combined irradiation and chemotherapy on transplanted tumors in mice. AJR 85: 559Google Scholar
  30. 30.
    Vokes EE, Weichselbaum RR (1990) Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors. J Clin Oncol 8: 911Google Scholar
  31. 31.
    Vokes EE, Choi KE, Schilsky RL, Moran WJ, Guarnieri CM, Weichselbaum RR, Panje WR (1988) Cisplatin, 5-fluorouracil and high-dose leucovorin for recurrent or metastatic head and neck cancer. J Clin Oncol 6: 618Google Scholar
  32. 32.
    Vokes EE, Panje WR, Schilsky RL, Mick R, Awan AM, Moran WJ, Goldman MD, Tybor AG, Weichselbaum RR (1989) Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head and neck cancer: a phase I–II study. J Clin Oncol 7: 761Google Scholar
  33. 33.
    Vokes EE, Schilsky RL, Weichselbaum RR, Kozloff M, Panje WR (1990) Neoadjuvant cisplatin, fluorouracil and high-doseleucovorin for locally advanced head and neck cancer: a clinical and pharmacologic analysis. J Clin Oncol 8: 241Google Scholar
  34. 34.
    Wawra E, Wintersberger E (1983) Does hydroxyurea inhibit DNA replication in mouse cells by more than one mechanism? Mol Cell Biol 3: 297Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Everett E. Vokes
    • 4
    • 2
  • Jill A. Moormeier
    • 4
  • Mark J. Ratain
    • 4
    • 1
  • Merrill J. Egorin
    • 3
  • Daniel J. Haraf
    • 2
  • Rosemarie Mick
    • 4
  • Ralph R. Weichselbaum
    • 2
  1. 1.Committee on Clinical PharmacologyUniversity of ChicagoUSA
  2. 2.Department of Radiation and Cellular OncologyUniversity of ChicagoUSA
  3. 3.Division of Developmental TherapeuticsUniversity of Maryland Cancer CenterUSA
  4. 4.Department of Medicine, Section of Hematology/OncologyUniversity of ChicagoChicagoUSA

Personalised recommendations