Schedule- and dose-intensified paclitaxel as weekly 1-hour infusion in pretreated solid tumors: results of a phase I/II trial.
ABSTRACT Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been studied primarily on a 3-week schedule as a 3-, 24-, or 96-hour infusion at doses ranging from 135 to 250 mg/m2. The observed toxicity profile seems to be both dose and schedule dependent. Dose densification of paclitaxel given weekly over 6 weeks on a split-dose schedule for an overall increase in dose intensity was thought to improve the therapeutic index of paclitaxel in a variety of advanced malignancies and to be suitable for outpatient administration. For this study, chemotherapy consisted of a weekly 1-hour infusion of paclitaxel at a starting dose of 40 mg/m2/wk for 6 weeks, followed by a 2- to 3-week interval. Paclitaxel dosage was escalated in 10 mg/m2/wk increments in subsequent patients, to a maximum dosage of 90 mg/m2/wk. Intravenous dexamethasone, cimetidine, clemastine, and ondansetron were administered immediately before the paclitaxel infusion. Fifty patients participated in the study. The male to female ratio was 21 to 29, the median age was 53.2 years (age range, 33 to 74), and the median performance status was 1. All patients were chemotherapeutically pretreated. Overall response included five complete responses (10%), 15 partial responses (30%), 19 no change (38%), and 11 disease progressions (22%). Median dose intensity was 410 mg/m2/6 wk (range, 200 to 540 mg/m2/6 wk). Hematologic toxicity was mild, with no grade 3 or 4 toxicity up to 90 mg/m2/wk. No hypersensitivity reactions or neurologic or cardiac toxicities were documented. Dose-densified, weekly paclitaxel is concluded to be active in a variety of pretreated tumor entities. The overall low hematologic and peripheral toxicity profile suggests that further dose intensification of weekly paclitaxel and/or combination with other cytotoxic agents (eg, cisplatin/carboplatin, ifosfamide, etoposide) may be warranted. Paclitaxel can be given safely in the outpatient setting. Paclitaxel 90 mg/m2/wk is recommended for single-agent treatment. Dose-densified paclitaxel may be considered a valuable and promising alternative to standard 3-week treatment, with further options possible in combination chemotherapy.
- [Show abstract] [Hide abstract]
ABSTRACT: OBJECTIVE: A phase II trial on neoadjuvant trans-uterine arterial chemotherapy (TUAC) followed by type III radical hysterectomy (RH) was conducted for patients with bulky cervical adenocarcinoma (AC). METHODS: Tumors of >4cm were eligible. The neoadjuvant regimen comprised paclitaxel (60mg/m(2) intravenously on days 1, 8, and 15) and cisplatin (70mg/m(2) TUAC followed by transcatheter embolization with gelatin sponge particles on day 2) repeated every 3weeks for 3cycles. The primary endpoints were clinical and pathological responses. RESULTS: Twenty-two patients (median age, 51years; range, 33-75years) were enrolled. The International Federation of Gynecology and Obstetrics stages were IB2 (9 patients), IIA-IIB (8), IIIB (3), and IVA (2). The adeno/adenosquamous ratio was 16/6. The overall clinical response rate was 95.4% (95% confidence interval [CI], 86.7-100%). RH was completed in 19 patients (86%), including 2 stage IVA patients who underwent anterior or posterior pelvic exenteration. Of the 19 patients, no residual malignant cells were found pathologically in 4; thus, the pathological complete response rate was 18% (4/22). No patients experienced grade 4 thrombocytopenia or febrile neutropenia or required platelet transfusions. The 5-year progression-free survival and overall survival rates in stages IB2-IIB were 70.0% (95%CI, 48.1-92.1%) and 69.5% (95%CI, 47.0-92.0%), respectively. The 2 patients with stage IVA tumors were alive without recurrence for 72 and 84months after enrollment. CONCLUSIONS: TUAC showed high clinical and pathological response rates. TUAC is promising for stage IB2-IIB and IVA bulky AC.Gynecologic Oncology 01/2013; · 3.93 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Weekly paclitaxel is a highly active and well tolerated regimen that is increasingly being adopted for the treatment of relapsed ovarian cancer. This regimen is usually administered at 80-90 mg/m(2)/week, and the use of a 1 h infusion helps minimize myelosuppression. When compared with the 3-weekly schedule, weekly paclitaxel is better tolerated, with a reduced frequency of grade 3-4 toxic effects. Single-agent weekly paclitaxel for relapsed ovarian cancer yields response rates in the range of 20-62%; however, response duration can be short. Responses to weekly paclitaxel have been observed in patients whose tumors are resistant to 3-weekly paclitaxel. The level of activity of weekly paclitaxel for relapsed disease has led to its detailed evaluation in the first-line setting, and interest has been enhanced by the results of a Japanese Gynecological Oncology Group study that demonstrated a survival advantage for weekly paclitaxel compared with 3-weekly paclitaxel in combination with carboplatin as initial treatment. The enhanced efficacy of weekly paclitaxel may be due to greater drug exposure, a direct antiangiogenic effect, or both. Current research topics include the combination of weekly paclitaxel with molecular-targeted agents and the use of molecular profiling to better select patients for treatment.Nature Reviews Clinical Oncology 10/2010; 7(10):575-82. · 15.03 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: To evaluate the disease control rate (DCR) in heavily pretreated and relapsed ovarian cancer patients re-challenged with a weekly paclitaxel schedule and to establish whether a correlation between dose intensity, progression-free interval (PFI) and overall survival (OS) exists. Retrospective data were collected from 30 heavily pretreated metastatic ovarian cancer patients who received 80 mg/m(2)/week paclitaxel regimen. The treatment was well tolerated and showed a DCR in 70% of the patients, with only one case of grade 3 hematological toxicity. One patient (3%) showed a complete response, 15 patients (50%) a partial response and five patients (17%) a stabilization of their disease. The regimen was mostly used as a fourth-line chemotherapy (range 2-7). The median dose intensity in responding patients was 57.5 mg/m(2)/week and in those with progressive disease 49.7 mg/m(2)/week. (p = 0.20). PFI and OS were increased in the responder patient groups with a log-rank test of 25.64 (p < 0.001) and 15.10 (p = 0.0001), respectively. Weekly administration of paclitaxel was active and well tolerated as a salvage therapy for heavily pretreated ovarian cancer patients.Archives of Gynecology 07/2011; 285(2):499-503. · 0.91 Impact Factor