title: Pharmacobiologically based scheduling of capecitabine and docetaxel results in antitumor activity in resistant human malignancies.
abstract: OBJECTIVE
  Capecitabine and docetaxel have demonstrated preclinical antitumor synergy. This synergy is thought to occur from docetaxel-mediated upregulation of thymidine phosphorylase (dThdPase), an enzyme responsible for the relative tumor selectivity of capecitabine. On the basis of the time-dependency and transiency for this upregulation, we performed a phase I study of capecitabine in combination with weekly docetaxel. We hypothesized that weekly docetaxel would result in sustained dThdPase expression and that capecitabine administration at times of maximum dThdPase upregulation would increase the therapeutic index for this combination.
  
  
  METHODS
  Patients with advanced solid malignancies received docetaxel on days 1, 8, and 15, and capecitabine bid on days 5 to 18, every 4 weeks. Docetaxel was fixed at 36 mg/m(2)/wk, whereas capecitabine was escalated in successive patients cohorts.
  
  
  RESULTS
  Sixteen patients received 77 courses at capecitabine doses from 950 to 1,500 mg/m(2)/d. The most common toxicities were hand-foot syndrome, diarrhea, nausea/vomiting, and asthenia. Grades 3 to 4 hematologic toxicities were infrequent and no treatment-related hospitalizations occurred. Three of three patients treated at 1,500/36 mg/m(2) capecitabine/docetaxel developed grade 3 hand-foot syndrome or diarrhea during either their first or second course, whereas only two of 13 patients at 1,250/36 mg/m(2) doses developed significant toxicity. Antitumor responses (n = 7) occurred in patients with hepatocellular, non-small-cell lung, and chemotherapy-refractory breast, bladder, and colorectal carcinomas. Prolonged stabilizations occurred in patients with metastatic mesothelioma (n = 2), chemorefractory non-small-cell lung carcinoma, and bronchioloalveolar carcinoma.
  
  
  CONCLUSIONS
  Capecitabine in combination with weekly docetaxel is well tolerated. Recommended doses are capecitabine 1,250 mg/m(2)/d (625 mg/m(2) bid) with docetaxel 36 mg/m(2)/wk. The acceptable toxicity profile in this dose schedule, and the antitumor activity observed, warrant further evaluation of this regimen.
authors.affiliation: Department of Medicine, Ohio State University College of Medicine and Public Health, Columbus, OH 43210-1240, USA.
authors.forename: Padma
authors.initials: P
authors.lastname: Nadella
authors.forename: Charles
authors.initials: C
authors.lastname: Shapiro
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Otterson
authors.forename: Marsha
authors.initials: M
authors.lastname: Hauger
authors.forename: Selnur
authors.initials: S
authors.lastname: Erdal
authors.forename: Eric
authors.initials: E
authors.lastname: Kraut
authors.forename: Steven
authors.initials: S
authors.lastname: Clinton
authors.forename: Manisha
authors.initials: M
authors.lastname: Shah
authors.forename: Mike
authors.initials: M
authors.lastname: Stanek
authors.forename: Paul
authors.initials: P
authors.lastname: Monk
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalona-Calero
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D043823:Taxoids; D013939:Thymidine Phosphorylase / Q000187:drug effects
chemical_list: D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D000069287:Capecitabine; D013939:Thymidine Phosphorylase; D017239:Paclitaxel; D005472:Fluorouracil