title: 5-Fluorouracil, leucovorin, hydroxyurea, and escalating doses of continuous-infusion cisplatin with concomitant radiotherapy: a clinical and pharmacologic study.
abstract: 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.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Medicine, University of Chicago, IL 60637-1470.
authors.forename: E E
authors.initials: EE
authors.lastname: Vokes
authors.forename: J A
authors.initials: JA
authors.lastname: Moormeier
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: M J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: D J
authors.initials: DJ
authors.lastname: Haraf
authors.forename: R
authors.initials: R
authors.lastname: Mick
authors.forename: R R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000532:radiotherapy; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000532:radiotherapy; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D002955:Leucovorin / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D010984:Platinum / Q000097:blood
chemical_list: D010984:Platinum; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil; D006918:Hydroxyurea