New Drugs Paclitaxel
Paclitaxel, a member of the taxoid family, is an antimicrotubule agent that promotes the assembly and stabilisation of microtubules from tubulin dimers. The drug has been investigated in three phase II trials.5–7 All patients were heavily pre-treated with standard chemotherapy regimens. Many had cisplatin-refractory disease and received a third or subsequent line of treatment. At a dose of 2256 to 250mg/m2,5 paclitaxel induced an objective response in 12 of 51 patients (23%). A response occurred in only two of 18 patients (11%) with doses of between 170 and 200mg/m2.7 These studies provided interesting results and sufficient background to include paclitaxel in both first-line8 and salvage treatments.9
Paclitaxel, Ifosfamide and Cisplatin First-line Salvage Therapy
Paclitaxel-based combinations have been tested for standard salvage chemotherapy using a paclitaxel plus ifosfamide and cisplatin (TIP) regimen9 and in combination with sequential HDCT.10 At the Memorial Sloan Kettering Cancer Center (MSKCC), paclitaxel was given at a dose of 200mg/m2 administered as a 24-hour continuous infusion on day one of the cycle. In the German group, paclitaxel was given on day one at a dose of 175mg/m2 and was administered as a three-hour infusion.11 The same dose and schedule were used in trials published by the Medical Research Council (MRC)12 and Mardiak et al.13 In the trial conducted by the French group, the dose of paclitaxel was 250mg/m2 administered as a three-hour infusion.14 At the MSKCC, the TIP regimen9 was administered as first-line salvage therapy in favourable-risk patients. Thirty patients were treated: the rates of CR, continuous CR and non-evolutive disease (NED) were 80, 73 and 80%, respectively. Similar TIP protocols induced a CR rate of 60% in 43 patients included in the MRC trial,12 and 65% in the study by Mardiak et al.13
Combination of Paclitaxel and High-dose Chemotherapy plus Peripheral Blood Stem Cell Transplantation in First-line Salvage Therapy
The German group developed a protocol with three cycles of TIP followed by one cycle of high-dose etoposide, carboplatin and thiotepa.11 Eighty patients were treated: 67% were treated in the first-line salvage setting, 76% were cisplatin-sensitive and only 35% had achieved previous CR. One patient experienced a toxic death and 18 patients did not receive HDCT. The CR, continuous CR and NED rates were 35, 26 and 33%, respectively.
The French group has developed a protocol with two cycles of epirubicin plus paclitaxel followed by one cycle of high-dose cyclophosphamide and thiotepa and two cycles of high-dose carboplatin plus etoposide (CE).14 Forty-five patients were studied. Of these, 15% were in the first-line salvage setting (refractory disease). Only 33 patients received HDCT, of whom 22 completed the programme. There were five treatment-related deaths. The CR, continuous CR and NED rates were 22, 19 and 23%, respectively.