title: Bromodeoxyuridine alternating with radiation for advanced uterine cervix cancer: a phase I and drug incorporation study.
abstract: OBJECTIVE
  Preclinical studies show a significant increase in the ratio of the radiosensitizer bromodeoxyuridine (BUdR) in tumors versus the intestinal mucosa during the drug elimination period, compared with the ratio during drug infusion. We constructed a phase I study in patients with locally advanced cervix cancer, using alternating cycles of BUdR and radiation therapy (RT).
  
  
  METHODS
  Eighteen patients with stage IIB to IVA cervix cancer participated. A treatment cycle consisted of a 4-day BUdR infusion followed by a week of pelvic RT, 15 Gy twice daily in 1.5-Gy fractions. After three cycles, additional BUdR was infused, followed by brachytherapy. The fraction of thymidine replaced by BUdR and the fraction of cells incorporating BUdR were determined in rectal mucosa and tumor biopsies at the end of the first BUdR infusion (day 5), at the middle of the first RT week (day 10), and at the time of brachytherapy.
  
  
  RESULTS
  Dose-limiting toxicity was observed in one of 16 patients receiving 1,000 mg/m2/d x 4 days and in both patients receiving 1,333 mg/m2/d x 4 days each cycle. After a median follow-up of 39 months, 12 patients (66%) were free of pelvic disease and nine (50%) were alive and disease free. The ratio of tumor to rectum BUdR incorporation averaged 1.5 to 1.8 and did not differ significantly between day 5 and day 10. A trend toward reduced ratio was observed at brachytherapy. Drug-containing cells in rectal biopsies migrated from the crypts to the mucosal surface.
  
  
  CONCLUSIONS
  In this schedule, 1,000 mg/m2/d is the maximum-tolerated dose of BUdR. BUdR incorporation levels in tumors were consistent with clinically significant radiosensitization. The migration of BUdR-containing rectal mucosa cells from the crypts to the surface at the time of RT suggests that this regimen may offer a relative sparing of the mucosa from radiosensitization.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, USA. eisbruch@umich.edu
authors.forename: A
authors.initials: A
authors.lastname: Eisbruch
authors.forename: J M
authors.initials: JM
authors.lastname: Robertson
authors.forename: C M
authors.initials: CM
authors.lastname: Johnston
authors.forename: J
authors.initials: J
authors.lastname: Tworek
authors.forename: K R
authors.initials: KR
authors.lastname: Reynolds
authors.forename: J A
authors.initials: JA
authors.lastname: Roberts
authors.forename: T S
authors.initials: TS
authors.lastname: Lawrence
mesh_terms: D000230:Adenocarcinoma / Q000532:radiotherapy / Q000556:secondary; D000328:Adult; D000368:Aged; D001706:Biopsy; D001918:Brachytherapy; D001973:Bromodeoxyuridine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002294:Carcinoma, Squamous Cell / Q000532:radiotherapy / Q000556:secondary; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011879:Radiotherapy Dosage; D015996:Survival Rate; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*
chemical_list: D011838:Radiation-Sensitizing Agents; D001973:Bromodeoxyuridine