RT Journal Article
SR Electronic
T1 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
JF International Journal of Gynecologic Cancer
JO Int J Gynecol Cancer
FD BMJ Publishing Group Ltd
SP 478
OP 485
DO 10.1097/IGC.0b013e31820d738c
VO 21
IS 3
A1 Guillermo Crespo
A1 Marta Sierra
A1 Raquel Losa
A1 José Pablo Berros
A1 Noemí Villanueva
A1 Joaquín Fra
A1 Paula J. Fonseca
A1 María Luque
A1 Yolanda Fernández
A1 Pilar Blay
A1 Miguel Sanmamed
A1 Carolina Muriel
A1 Emilio Esteban
A1 Ángel J. Lacave
YR 2011
UL http://ijgc.bmj.com/content/21/3/478.abstract
AB Introduction 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/m2 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.Conclusion 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/m2 per minute in 28-day cycles.