title: Intravenous 3-weekly paclitaxel and metronomic oral cyclophosphamide in patients with advanced urothelial cancer previously treated with gemcitabine and platinum.
abstract: BACKGROUND
  Taxane-based chemotherapy is one of the most commonly used agents in patients with advanced urothelial carcinoma who developed disease progression after gemcitabine and cisplatin combination chemotherapy. The response rates, however, are dismal reported around 10-20%. Recently, promising efficacy results of paclitaxel when combined with oral cyclophosphamide as metronomic therapy have been reported.
  
  
  METHODS
  Patients received paclitaxel 175 mg/m(2) intravenously over 3 h on day 1 and cyclophosphamide 50 mg/day orally on days 1-7 every 3 weeks. For patients with ECOG, performance status was two or previous radiotherapy on 25% or more of their bone marrow, paclitaxel was given at a dose of 135 mg/m(2) for the first cycle, followed by intra-patient dose escalation to 175 mg/m(2) if clinically significant toxicities were not observed during the first cycle. Oral cyclophosphamide was administered for extended 3 weeks after the safety of 1-week metronomic therapy was confirmed. The primary end points were response rate (RECIST v.1.1) and progression-free survival.
  
  
  RESULTS
  From March 2012 to March 2014, 46 patients with bladder or upper urinary tract cancer were treated with this regimen in our institution after failure to gemcitabine and cisplatin combination chemotherapy. After excluding four patients with pathologies other than urothelial carcinoma (one collecting duct carcinoma, two small cell carcinoma, and one squamous cell carcinoma), a total of 42 patients were included in this study. The platinum-free interval was <6 months in 33 (78.6%) patients, and 39 (92.8%) were categorized into the intermediate or poor prognosis group according to Bajorin's risk model. The objective response rate was 33.3% (n = 14) with a median response duration of 4.3 months. The median time to progression was 3.0 months (95% CI 1.7-4.3 months), and the median OS was 6.3 months (95% CI 4.6-8.0 months). The most frequent and clinically significant non-hematologic toxicities were peripheral sensory neuropathy (56%), fatigue (35%), and myalgia (28%) in order, but none of them showed severity of grade 3 or more. Grade ≥ 3 neutropenia occurred only in two patients (6%), and one of them developed febrile neutropenia. The duration of metronomic cyclophosphamide did not significantly affect the toxicity profile, and it could be safely administered for whole cycles.
  
  
  CONCLUSIONS
  Metronomic oral cyclophosphamide combined with paclitaxel appears to be both efficacious and safe as a salvage chemotherapy, particularly in heavily pretreated patients with advanced urothelial carcinoma after gemcitabine-cisplatin failure.
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 138-736, Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Jae-Lyun
authors.initials: JL
authors.lastname: Lee
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use*; D011379:Prognosis; D016879:Salvage Therapy / Q000379:methods; D016019:Survival Analysis; D017211:Treatment Failure; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000188:drug therapy*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D009944:Organoplatinum Compounds; D003841:Deoxycytidine; D003520:Cyclophosphamide; D017239:Paclitaxel; D000093542:Gemcitabine