title: A phase I and pharmacokinetic study of irinotecan given as a 7-day continuous infusion in metastatic colorectal cancer patients pretreated with 5-fluorouracil or raltitrexed.
abstract: OBJECTIVE
  The purpose is to determine the plasma pharmacokinetics, the maximum-tolerable dose and to preliminary evaluate the antitumor activity of irinotecan administered as a 7-day continuous infusion every 21 days in metastatic colorectal cancer patients pretreated with 5-fluorouracil or raltitrexed.
  
  
  METHODS
  A total of 13 patients entered the study. Three received irinotecan at 20 mg/m(2)/day (dose level I), 6 at 25 mg/m(2)/day (dose level II), and 4 at 22.5 mg/m(2)/day (dose level III). In 8 patients, plasma levels of irinotecan and its metabolites SN-38 and SN-38 glucuronide (SN-38glu) were measured by high-performance liquid chromatography and main pharmacokinetic parameters, including steady-state concentration, area under the time-concentration curve, and clearance, were calculated and normalized to the dose level of 22.5 mg/m(2)/day.
  
  
  RESULTS
  Dose-limiting toxicity was grade 3-4 diarrhea, which occurred in 4 of 6 patients at dose level II and in 2 of 4 patients at dose level III. Therefore, we defined 22.5 mg/m(2)/day the maximum-tolerable dose and 20.0 mg/m(2)/day the recommended dose for Phase II studies. Hematological toxicity was rare. The pharmacokinetic data provided evidence that continuous infusion increased the metabolism of irinotecan to SN-38 with respect to standard 30/90-min administration. Indeed, the steady-state concentration of irinotecan, SN-38, and SN-38glu were 42.7 +/- 25.2, 14.9 +/- 1.9, and 31.7 +/- 3.5 nmol/liter, respectively, and the area under the time-concentration curves of irinotecan, SN-38, and SN-38glu were 6.94 +/- 0.41, 1.92 +/- 0.30, and 4.23 +/- 0.52 hx micro mol/liter, respectively. Twelve patients were evaluable for activity, and we observed 3 (25%) partial responses, 2 (17%) minor responses, and 4 (33%) disease stabilizations.
  
  
  CONCLUSIONS
  The administration of irinotecan as a 7-day continuous infusion every 21 days is feasible with diarrhea being the dose-limiting toxicity; recommended dose for Phase II studies is 20.0 mg/m(2)/day. The comparison of the present data with those obtained after a standard 30-90 min. i.v. infusion of irinotecan demonstrates that continuous infusion improves the transformation of irinotecan to SN-38 and also results in increased glucuronidation of the active metabolite. Antitumor activity in pretreated metastatic colorectal cancer patients is encouraging.
authors.affiliation: Department of Oncology, Civil Hospital, Livorno, Italy. gl.masi@tin.it
authors.forename: Gianluca
authors.initials: G
authors.lastname: Masi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Antonello
authors.initials: A
authors.lastname: Di Paolo
authors.forename: Giacomo
authors.initials: G
authors.lastname: Allegrini
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Cecilia
authors.initials: C
authors.lastname: Barbara
authors.forename: Samanta
authors.initials: S
authors.lastname: Cupini
authors.forename: Mario
authors.initials: M
authors.lastname: Del Tacca
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use / Q000633:toxicity; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D020719:Glucuronides / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009362:Neoplasm Metastasis; D018579:Patient Selection; D011799:Quinazolines / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*; D014839:Vomiting / Q000139:chemically induced
chemical_list: C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D011799:Quinazolines; D013876:Thiophenes; D000077146:Irinotecan; C068874:raltitrexed; D005472:Fluorouracil; D002166:Camptothecin