Abstract
Intraperitoneal (IP) administration of fluorinated pyrimidines has been evaluated for ovarian and gastrointestinal malignancies in phase I, II, and III trials. The tolerance and pharmacokinetic profile of IP 5-fluoro-2′-deoxyuridine (FUDR) alone and with (R,S)-leucovorin ((R,S)-LV) have each been evaluated in previous phase I studies. FUDR doses of 3 g per day with and without (R,S)-LV doses up to 640 mg per day given IP are well tolerated. The current phase I study was designed to determine the pharmacokinetic profiles and clinical tolerance of escalating doses of the pure biologically activeS-isomer of leucovorin ((S)-LV) given IP with the same dosing schedule of FUDR. A group of 16 patients with disease confined to the abdominal cavity were treated in this study. Pharmacokinetic studies of blood and peritoneal fluid, toxicity profiles, and clinical response for the first three cycles are reported here. The toxicity profile did not significantly differ from the prior two studies. All nonhematologic toxicities, such as fatigue, nausea, vomiting, diarrhea, and abdominal discomfort were less than grade 4, and most were less than grade 3. Neutropenia and thrombocytopenia were uncommon and observed only in patients with compromised bone marrow reserve. The pharmacokinetic profiles were also congruent with the previous studies and indicate a three-log advantage for FUDR. The (S)-LV profiles in the peritoneal cavity paralleled those of FUDR. Antitumor effects or absence of progression until after cessation of therapy were documented in 11 patients. At a median follow-up of 18 months 44% of patients were alive. IP administration of 3-g of FUDR and up to 640 mg (S)-LV daily for three days was well tolerated. The tolerance and antitumor effects observed during IP FUDR and LV in these studies encourage further exploration of this regimen against ovarian and gastrointestinal malignancies. The actual role and optimal dose of LV as an enhancer of the antitumor actions of FUDR administered by this route remain unknown.
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References
Adams SC, Patt YZ, Rosenblum MG (1984) Pharmacokinetics of mitomycin-C following intraperitoneal administration of mitomycin-C and floxuridine for peritoneal carcinomatosis. Proc Am Assoc Cancer Res 25:361
Arbuck SG, Trave F, H Douglass J, Nava H, Zakrewski S, Rustum YM (1986) Phase I and pharmacologic studies of intraperitoneal leucovorin and 5-fluorouracil in patients with advanced cancer. J Clin Oncol 4:1510
Braly P, Hoff S, Leong L, Margolin K, Carr B, Akman S, Doroshow J (1987) Intraperitoneal cisplatin and 5-FU: an active regimen for refractory ovarian cancer. In Proceedings, Second International Conference on Intracavitary Therapy, San Diego
Campora E, Esposito M, Civalleri D, Gogoioso L, Decian F, Falcone A, Nobile MT, Parodi B, Gafaggi S, Bignardi G (1987) Serum urine, and peritoneal fluid levels of 5-FU following intraperitoneal administration. Anticancer Res 7:829
Choi KE, Schilsky RL, Kay GE, Grimmer DA, Guarnier CM (1988) Clinical and pharmacologic study of intraperiitoneal 5-fluorouracil and cisplatin in patients with advanced IP or intrahepatic malignancies. Proc Am Assoc Cancer Res 29:193
Gyves J (1985) Pharmacology of intraperitoneal infusion of 5-fluorouracil and mitomycin C. Sem Oncol 12 [Suppl 4]:29
Louie KA, Ozols RF, Myers CE, Ostchega Y, Jenkins J, Howser D, Young RC (1986) Long term results of a cisplatin-containing regimen for treatment of advanced ovarian carcinoma. J Clin Oncol 4:1579
Ozols RF, Speyer JL, Jenkins J, Myers CE (1984) Phase II trial of 5-FU administered IP to patients with refractory ovarian cancer. Cancer Treat Rep 68:1229
Speyer JL, Collins JM, Dedrick RL, Brennan MF, Buckpitt AR, Londer H, DeVita VT Jr, Myers CE (1981) Portal levels and hepatic clearance of 5-fluorouracil after intraperitoneal administration in humans. Cancer Res 41:1916
Howell SB, Kirmani S, McClay EF, Kim S, Braly P, Plaxe S (1991) Intraperitoneal cisplatin-based chemotherapy. Semin Oncol 18 [Suppl 3]:5
Schilsky RL, Choi KE, Grayhack J, Grimmer D, Guarnieri C, Fullem L (1990) Phase I and pharmacologic study of intraperitoneal cisplatin and fluorouracil in patients with advanced intraabdominal cancer. J Clin Oncol 8:2054
Muggia FM, Chan KK, Russell C, Colombo N, Speyer JL, Sehgal K, Jeffers S, Sorich J, Leichman L, Beller U, et al (1991) Phase I and pharmacologic evaluation of intraperitoneal 5-fluoro-2′-deoxyuridine. Cancer Chemother Pharmacol 28:241
Muggia F, Alberts D, Liu P, Terada K, Wallace D (1994) Intraperitoneal mitoxantrone vs. intraperitoneal fluxuridine in ovarian cancer patients with minimal residual disease after second look surgery. Proc Am Soc Clin Oncol 13:249
Nobile MT, Videli MG, Sobrero A, Sertoli MR, Cannobio L, Fassio T, Rubagetti A, Gallo L, Lo Re G, Galligioni E, et al (1988) 5-Fluorouracil alone or in combination with high-dose folinic acid in advanced colorectal cancer — a randomized trial. Proc Am Soc Clin Oncol 7:97
Petrelli N, Stablein D, Bruckner H, Megibow A, Mayer R, and Douglas H (1988) A prospective randomized phase II trial of 5-fluorouracil vs 5-FU + high dose leucovorin vs 5-FU + low dose leucovorin in patients with metastatic colorectal carcinoma. A report of the Gastrointestinal Tumor Study Group. Proc Am Soc Clin Oncol 7:94
Petrelli N, Douglas HO Jr, Herrera L, Russell D, Stablein DM, Bruckner HW, Mayer RJ, Schinella R, Green MD, Muggia FM, et al (1989) The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase IIII trial. J Clin Oncol 7:1419
Keyomarsi K, Moran RG (1986) Folinic acid augmentation of the effects of fluoropyrimidines on murine and human leukemic cells. Cancer Res 46:5229
Muggia FM, Tulpule A, Retzios A, Chen F, Jeffers S, Leichman CG, Leichman L, Spears CP, Chan KK (1994) Intraperitoneal 5-fluoro-2′-deoxyuridine with escalating doses of leucovorin: pharmacology and clinical tolerance. Invest New Drugs 12:197
Muggia FM, LePoidevin E, Jeffers S, Russell C, Boswell W, Morrow CP, Curtin J, Schlaerth J (1992) Intraperitoneal therapy for ovarian cancer: an analysis of fluid distribution by computerized tomography. Ann Oncol 3:149
Au JL, Rustum YM, Ledesma EJ, Mittleman A, Creaven PJ (1982) 5-Fluorouracil and thymidine in the treatment of colorectal carcinoma. Cancer Res 43:2930
Matsubayashi Y, Izumi Y, Mori Y, Itoh K, Morioka A, Tatuta H, Hashimoto A, Kotera T, Itoh A, Jo I (1991) Salicylazosul-fapyridine-induced agranulocytosis in a patients with ulcerative colitis, successfully treated with granulocyte stimulating factor. Jpn J Gastroenterol 88:87
Rijk MC, Lier HJ van, Tongeren JH van (1992) Relapse-preventing effect and safety of sulfasalazine and olsalazine in patients with ulcerative colitis in remission: a prospective, double-blind, randomized multicenter study. The Ulcerative Colitis Multicenter Study. Am J Gastroenterol 87:438
Sugarbaker PH, Gianola FJ, Speyer JC, Wesley R, Barofsky I, Myers CE (1985) Prospective randomized trial of intravenous vs intraperitoneal 5-FU in patients with advanced primary colon or rectal cancer. Surgery 68:1229
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Supported in part by RO1 CA-50412, Cancer Center Core Grant, and NIH National Center for Research Resources of the General Clinical Research Center Grant MO1RR-43
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Israel, V.K., Jiang, C., Muggia, F.M. et al. Intraperitoneal 5-fluoro-2′-deoxyuridine (FUDR) and (S)-leucovorin for disease predominantly confined to the peritoneal cavity: a pharmacokinetic and toxicity study. Cancer Chemother. Pharmacol. 37, 32–38 (1995). https://doi.org/10.1007/BF00685626
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DOI: https://doi.org/10.1007/BF00685626