Phase I and pharmacological study of paclitaxel given over 3 h with cisplatin for advanced non-small cell lung cancer.
ABSTRACT To establish the toxicities and maximum tolerated dose of paclitaxel given over 3 h in combination with cisplatin, to determine the pharmacokinetic profiles of these two drugs and to observe their antitumor activity, we conducted a combination phase I study in non-small cell lung cancer.
Patients received paclitaxel doses of 150-210 mg/m2 given over 3 h and cisplatin doses of 60-80 mg/m2 as a 1 h infusion 2 h after the end of the paclitaxel infusion.
A total of 25 patients with previously untreated non-small cell lung cancer were enrolled. Granulocytopenia was the most frequent hematological toxicity and the most prominent non-hematological toxicity was sensory dominant neuropathy. Two of six patients experienced dose limiting toxicities (leukopenia, infection and neuropathy) at a dose of paclitaxel 210 mg/m2 and cisplatin 60 mg/m2, which was considered the maximum tolerated dose. There were seven partial responses among 24 evaluable patients, for an overall response rate of 29%. The median survival time was 341 days and the 1 year survival rate was 45.8%. As the paclitaxel pharmacokinetic parameters in this study were consistent with those of our previous single agent study, we found no significant drug-drug interaction between the 3 h infusion paclitaxel and cisplatin.
The recommended doses for further study are determined to be paclitaxel 180 mg/m2 and cisplatin 80 mg/m2. This is a well-tolerated and active regimen for non-small cell lung cancer. In view of the promising survival outcome, further evaluation in prospective randomized trials versus other regimens is warranted.
Article: Mifepristone prevents repopulation of ovarian cancer cells escaping cisplatin-paclitaxel therapy.[show abstract] [hide abstract]
ABSTRACT: Advanced ovarian cancer is treated with cytoreductive surgery and combination platinum- and taxane-based chemotherapy. Although most patients have acute clinical response to this strategy, the disease ultimately recurs. In this work we questioned whether the synthetic steroid mifepristone, which as monotherapy inhibits the growth of ovarian cancer cells, is capable of preventing repopulation of ovarian cancer cells if given after a round of lethal cisplatin-paclitaxel combination treatment. We established an in vitro approach wherein ovarian cancer cells with various sensitivities to cisplatin or paclitaxel were exposed to a round of lethal doses of cisplatin for 1 h plus paclitaxel for 3 h. Thereafter, cells were maintained in media with or without mifepristone, and short- and long-term cytotoxicity was assessed. Four days after treatment the lethality of cisplatin-paclitaxel was evidenced by reduced number of cells, increased hypodiploid DNA content, morphological features of apoptosis, DNA fragmentation, and cleavage of caspase-3, and of its downstream substrate PARP. Short-term presence of mifepristone either enhanced or did not modify such acute lethality. Seven days after receiving cisplatin-paclitaxel, cultures showed signs of relapse with escaping colonies that repopulated the plate in a time-dependent manner. Conversely, cultures exposed to cisplatin-paclitaxel followed by mifepristone not only did not display signs of repopulation following initial chemotherapy, but they also had their clonogenic capacity drastically reduced when compared to cells repopulating after cisplatin-paclitaxel. Cytostatic concentrations of mifepristone after exposure to lethal doses of cisplatin and paclitaxel in combination blocks repopulation of remnant cells surviving and escaping the cytotoxic drugs.BMC Cancer 05/2012; 12:200. · 3.01 Impact Factor