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
| Autor: | Joaquin Fra, Miguel F. Sanmamed, J.P. Berros, Noemi Villanueva, Marta I. Sierra, M. Luque, Raquel Losa, Angel J. Lacave, Paula Jiménez Fonseca, Guillermo Crespo, Yolanda Fernández, Emilio Esteban, C. Muriel, Pilar Blay |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Adult
Oncology medicine.medical_specialty Maximum Tolerated Dose Phases of clinical research Neutropenia Deoxycytidine Gastroenterology Polyethylene Glycols Pharmacokinetics Internal medicine Antineoplastic Combined Chemotherapy Protocols Humans Medicine Tissue Distribution Survival rate Aged Neoplasm Staging Ovarian Neoplasms business.industry Obstetrics and Gynecology Deoxycytidine kinase Middle Aged medicine.disease Adenocarcinoma Mucinous Gemcitabine Cystadenocarcinoma Serous Endometrial Neoplasms Survival Rate Treatment Outcome Doxorubicin Toxicity Female Neoplasm Recurrence Local business Ovarian cancer Adenocarcinoma Clear Cell medicine.drug |
| Zdroj: | International Journal of Gynecologic Cancer. 21:478-485 |
| ISSN: | 1525-1438 1048-891X |
| DOI: | 10.1097/igc.0b013e31820d738c |
| Popis: | IntroductionPegylated 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.MethodsThe starting dose of gemcitabine was 1500 mg/m2, 10 mg/m2per minute, every 2 weeks (±250 mg gemcitabine titration depending on toxicity), followed by PLD 35 mg/m2every 4 weeks. Gemcitabine pharmacokinetics and equilibrative nucleoside transporter 1, deoxycytidine kinase, and ribonucleotide reductase M1 gene expression levels were studied.ResultsThirty-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/m2on day 1 and PLD 35 mg/m2on days 1 and 15). Of 10 evaluable nonfrail patients, 4 displayed dose-limiting toxicity. Frail patients were treated at DL-2 (G 1250 mg/m2on day 1 and PLD 35 mg/m2on 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.ConclusionThe recommended dose for a phase II study of patients with recurrent ovarian cancer having poor prognosis is PLD, 35 mg/m2on day 1, and gemcitabine, 1000 mg/m2on days 1 and 15 delivered at an FDRI of 10 mg/m2per minute in 28-day cycles. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|