title: Pegylated liposomal doxorubicin and gemcitabine in a fixed dose rate infusion for the treatment of patients with poor prognosis of recurrent ovarian cancer: a phase Ib study.
abstract: BACKGROUND
  Pegylated liposomal doxorubicin (PLD) is currently the reference treatment for platinum-resistant ovarian cancer. The combination of PLD and gemcitabine and the administration of gemcitabine at a fixed dose rate infusion (FDRI) seem to have additive activity in this disease setting. We have launched a phase Ib study with the combination of FDRI gemcitabine followed by PLD in recurrent ovarian cancer with a platinum-free interval of less than 1 year, with parallel pharmacokinetic and pharmacogenetic studies.
  
  
  METHODS
  The starting dose of gemcitabine was 1500 mg/m², 10 mg/m² per minute, every 2 weeks (± 250 mg gemcitabine titration depending on toxicity), followed by PLD 35 mg/m² every 4 weeks. Gemcitabine pharmacokinetics and equilibrative nucleoside transporter 1, deoxycytidine kinase, and ribonucleotide reductase M1 gene expression levels were studied.
  
  
  RESULTS
  Thirty-five patients were treated at 3 different dose levels (DL). Dose level 1 was not tolerated. Nonfrail patients continued to be treated at DL-1 (G 1250 mg/m² on day 1 and PLD 35 mg/m² on days 1 and 15). Of 10 evaluable nonfrail patients, 4 displayed dose-limiting toxicity. Frail patients were treated at DL-2 (G 1250 mg/m on day 1 and PLD 35 mg/m² on days 1 and 15). Of the 12 evaluable frail patients, 3 developed dose-limiting toxicity. Neutropenia, palmar-plantar erythrodysesthesia and stomatitis were the most common toxicities. The response rate was 42.8% (95% confidence interval [CI], 34.5%-51.1%), with 17.1% (6/35) complete responses and 25.7% (9/35) partial responses. The median progression-free survival was 7.7 months (95% CI, 2.2-13.1). The median overall survival was 13.9 months (95% CI, 9.4-18.4). The administration of PLD after gemcitabine did not influence gemcitabine pharmacokinetics or its metabolites. The addition of PLD to gemcitabine caused a larger and longer induction of the ribonucleotide reductase M1 gene. Patients with higher baseline levels of deoxycytidine kinase had longer progression-free survival.
  
  
  CONCLUSIONS
  The recommended dose for a phase II study of patients with recurrent ovarian cancer having poor prognosis is PLD, 35 mg/m² on day 1, and gemcitabine, 1000 mg/m² on days 1 and 15 delivered at an FDRI of 10 mg/m per minute in 28-day cycles.
authors: Department of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain. gcrespoherrero@hotmail.com
authors: Guillermo
authors: G
authors: Crespo
authors: Marta
authors: M
authors: Sierra
authors: Raquel
authors: R
authors: Losa
authors: José Pablo
authors: JP
authors: Berros
authors: Noemí
authors: N
authors: Villanueva
authors: Joaquín
authors: J
authors: Fra
authors: Paula J
authors: PJ
authors: Fonseca
authors: María
authors: M
authors: Luque
authors: Yolanda
authors: Y
authors: Fernández
authors: Pilar
authors: P
authors: Blay
authors: Miguel
authors: M
authors: Sanmamed
authors: Carolina
authors: C
authors: Muriel
authors: Emilio
authors: E
authors: Esteban
authors: Angel J
authors: AJ
authors: Lacave
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy*; D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D016889:Endometrial Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: C506643:liposomal doxorubicin; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000093542:Gemcitabine