Paclitaxel (175 mg/m2) plus carboplatin (6 AUC) versuspaclitaxel (225 mg/m2) plus carboplatin (6 AUC) in advanced non-small-cell lung cancer (NSCLC): A multicenter randomized trial

Purpose:The combination of paclitaxel and carboplatin has becomea widely used regimen in NSCLC due to phase II reports of moderate toxicity,reasonable activity and easy outpatient administration. Purpose of our presentprospective study was to evaluate the dose–response relationship ofpaclitaxel. Patients and methods:Since July 1996, 198 patients withnon-operable NSCLC and measurable disease without previous chemotherapyentered the trial. Ninety nine patients (group A) were randomized to receivepaclitaxel 175 mg/m² in three-hour infusion plus carboplatin dosedto an area under the concentration–time curve of 6 every 3 weeks and 99(group B) to receive the same regimen with paclitaxel increased to 225mg/m². Eligibility criteria included WHO performance status0–2, documented inoperable stage IIIA and IIIB, IV, no brain metastasis,no prior chemotherapy and adequate renal and hepatic function. Patients inboth groups were well-matched with baseline disease characteristics. Results:In group A with 90 evaluable patients, the response ratewas 25.6%(6 CR, 17 PR) whereas in group B with 88 evaluable patients,the response rate was 31.8% (3 CR, 25 PR),P = 0.733. Mediantime to progression favored the high-dose paclitaxel (4.3 vs. 6.4 months,P = 0.044). The median survival was 9.5 months for group A versus11.4 months for group B (P = 0.16). The one-year survival was37% for group A and 44% for group B (P = 0.35). Thebest prognostic factor for one-year survival was the response rate (P< 0.0001). With a relative dose intensity of paclitaxel 0.94 in bothgroups, neurotoxicity (P = 0.025) and leucopenia (P = 0.038)were more pronounced in group B patients. No toxic death was observed. Conclusions:Higher dose paclitaxel prolongs the median time toprogression but causes more neurotoxicity and leucopenia. The better responserate, the longer overall and better one-year survival seen with the higherdose of paclitaxel are not statistically significant.     

A dose escalation study of paclitaxel and carboplatin in untreated Japanese patients with advanced non-small cell lung cancer.

BACKGROUND: The combination of paclitaxel (225 mg/m(2), 3-h infusion) and carboplatin (area under the curve 6) is widely used for non-small cell lung cancer in the USA. In Japan, however, the recommended dose for single-use paclitaxel in 3-h infusion is 210 mg/m(2) and the optimal dose of this agent in combination with carboplatin has not been established. This dose escalation study was designed to determine the maximum tolerated dose of paclitaxel in 3-h infusion plus carboplatin at a fixed dose of area under the curve 6 for Japanese patients with advanced, untreated non-small cell lung cancer. METHODS: Between October 1999 and May 2000, 19 patients were enrolled and 18 of these patients were evaluable for toxicity. Chemotherapy consisted of carboplatin area under the curve 6 and an escalated dose of paclitaxel on day 1 every 3-4 weeks. The initial dose of paclitaxel was 175 mg/m(2) and was increased by 25 mg/m(2) at each dose level. RESULTS: Neutropenia was the major toxicity observed, but was not dose related. Febrile neutropenia was not observed. No grade 3 or more peripheral neuropathy, myalgia or arthralgia was reported. The maximum tolerated dose was not determined even at the highest paclitaxel dose level (225 mg/m(2)) in this study. Partial responses were observed in six of the 19 patients (31.6%). CONCLUSION: We conclude that paclitaxel at 225 mg/m(2) in 3-h infusion and carboplatin area under the curve 6 can safely be given to Japanese patients with non-small cell lung cancer.     

A phase I/II trial of paclitaxel, carboplatin, and gemcitabine in untreated patients with advanced non-small cell lung cancer.

Paclitaxel and carboplatin is widely used in the treatment of patients with advanced non-small cell lung cancer (NSCLC); however, median survival remains < 1 year. One strategy to improve survival is to add a third active drug with a differing mechanism of action. Gemcitabine is a novel antimetabolite with considerable activity in NSCLC. The primary objective of this Phase I/II study was to determine the maximally tolerated dose of gemcitabine administered with fixed doses of paclitaxel and carboplatin in untreated patients with advanced NSCLC.     

A phase I pharmacokinetic study of bexarotene with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC)

Purpose  

Preclinical data suggest that the synthetic retinoid bexarotene may be an effective chemopreventive agent and that it may act synergistically in combination with platinum-based chemotherapy. The primary objective of this study was to determine whether repeated doses of bexarotene capsules affect pharmacokinetic parameters of paclitaxel or carboplatin in patients with advanced non-small cell lung cancer.     

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive ⩽6 cycles of carboplatin area under the plasma concentration–time curve 6 mg ml⁻¹ min and paclitaxel 175 mg m⁻² (CP, n=36) or standard therapy plus ASA404 1200 mg m⁻² (ASA404-CP, n=37). There was little change in the systemic exposure of either total or free carboplatin or paclitaxel on addition of ASA404. Safety profiles were similar and manageable in both groups, with most adverse effects attributed to standard therapy. Tumour response rate (31 vs 22%), median time to tumour progression (5.4 vs 4.4 months) and median survival (14.0 vs 8.8 months, hazard ratio 0.73, 95% CI 0.39, 1.38) were improved in the ASA404 combination group compared with the standard therapy group. In conclusion, this study establishes the feasibility of combining ASA404 with carboplatin and paclitaxel in patients with previously untreated, advanced NSCLC, demonstrating a manageable safety profile and lack of adverse pharmacokinetic interactions. The results indicate that there may be a benefit associated with ASA404, but this needs to be evaluated in a larger trial.     

Phase I study of biweekly paclitaxel and carboplatin administration in patients with advanced non-small cell lung cancer

A phase I study of a biweekly outpatient regimen composed of carboplatin (CBDCA) and paclitaxel (TXL) was conducted for advanced non-small cell lung cancer. TXL was given in combination with a fixed dose of CBDCA (AUC 3) every 2 weeks. The starting dose of TXL was 100 mg/m2, and the dose was escalated in increments of 20 mg/m2. Three to six patients were allocated to each level. Toxicities were evaluated in the first 4 courses to determine the maximum tolerated dose (MTD). TXL 160 mg/m2 dosages proved to be MTD, and the dose limiting toxicity (DLT) was hematotoxicity (neutropenia). The patients, however, recovered from neutropenia using G-CSF immediately, when G-CSF was used. Gastrointestinal toxicity was well-tolerated. A response was found in 9 out of 20 patients who received 4 courses or more (45%). These results suggest that the recommended dose would be CBDCA (AUC 3) + TXL 140 mg/m2. The biweekly regimen has a high level clinical activity and excellent tolerability, and is suitable for outpatients. We started a phase II study because of these results.     

Phase I study of paclitaxel,carboplatin and UFT in chemo-naive patients with advanced non-small cell lung cancer (NSCLC)

Objective We conducted a phase I study of paclitaxel (PTX), carboplatin (CBDCA), and UFT in chemo-naive patients with advanced non-small cell lung cancer (NSCLC). Method Twenty-one chemo-naive patients with advanced NSCLC were enrolled. The study was conducted as a phase I dose-escalation study of various doses of systemic PTX followed by CBDCA on day 1 and oral UFT (400 mg/m²) on days 1–5 and 8–12, with the cycle repeated at 21-day intervals. At least three patients were enrolled in each step. Results The main toxicities were neutropenia and paresthesia, but were tolerable and reversible in all cases. Overall response rate was 57% (12 out of 21). The MTD was not reached at the highest dose level after the first cycle. Given previous recommends of PTX at 225 mg/m² and CBDCA AUC 6 for two-drug therapy, the recommended dose for the phase II study under our regimen was set at PTX 225 mg/m² on day 1, CBDCA AUC 6 on day 1, and UFT 400 mg/m² on days 1–5 and 8–12. Conclusion The combination of PTX, CBDCA, and UFT showed promising activity and acceptable toxicity in these chemo-naive patients, supporting the development of this combination as a feasible chemotherapeutic option for advanced NSCLC.     

Gemcitabine/carboplatin in advanced non-small cell lung cancer

Gemcitabine/cisplatin is among the most widely used regimens in Europe for first-line treatment of non-small cell lung cancer (NSCLC). Problems with cisplatin use in this setting include significant nonhematologic toxicity and difficulty of use in outpatients. Carboplatin constitutes a reasonable alternative to cisplatin in this combination, since it shows synergy with gemcitabine in vitro, is easier to use in ambulatory patients, and has a better nonhematologic toxicity profile. Studies of gemcitabine/cisplatin on a 28-day schedule (gemcitabine on days 1, 8, 15 and carboplatin on day 1) generally indicate excessive thrombocytopenia. Use of a 21-day schedule (e.g. gemcitabine on days 1 and 8, carboplatin on day 1) is associated with reduced toxicity and comparable efficacy. Results of one randomized phase II study suggest reduced toxicity and reduced objective response rate with gemcitabine/carboplatin versus gemcitabine/cisplatin. We are currently conducting a phase III comparison of gemcitabine 1200 mg/m(2) on days 1 and 8 plus carboplatin at an area under the curve of 5 mg/ml/min on day 1 versus gemcitabine at the same dose plus cisplatin 80 mg/m(2) on day 1 every 21 days in chemotherapy-nai;ve patients with stage IIIB/IV NSCLC; interim analysis indicates comparable response rates (47 and 48%). A better understanding of the relative toxicities of these regimens should be provided by the final results of this trial.     

Phase I/II dose finding study of paclitaxel and carboplatin in advanced non-small cell lung cancer.

INTRODUCTION: This phase I study was designed to establish the maximum tolerated dose (MTD) of the carboplatin paclitaxel combination, given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. PATIENTS AND METHODS: Fifty patients (one stage IIIa, 31 stage IIIb and 18 stage IV) were sequentially assigned to one of 14 treatment groups in which paclitaxel and carboplatin were administered in doses ranging from 130 to 235 mg/m2 and from 230 to 375 mg/m2 , respectively. Paclitaxel was administered as a 3-h intravenous infusion using non-polyvinylchloride tubing and connectors. The carboplatin infusion, over 30 min, was administered at the completion of the paclitaxel infusion. RESULTS: The MTD for the combination has been reached at 235 mg/m2 of paclitaxel and at 375 mg/m2 of carboplatin. The combination shows a good safety profile with very few and brief episodes of neutropenia without any infectious episodes. At the doses tested thrombocytopenia did not occur at all. Among 47 assessable patients there was one complete response and 17 partial responses for an overall response rate of 38%. There has been a tendency to a dose-response relationship for the combination with only six partial responses (27%) reported in 22 patients who received paclitaxel at doses < or = 195 mg/m2 and carboplatin at doses < 350 mg/m2 and 12 partial responses in 25 patients (48%) receiving paclitaxel > 195 mg/m2 and carboplatin > or = 350 mg/m2, respectively. The median event-free survival time is 33 weeks (range, 4-156 +). With a minimum follow up duration of 57 weeks the median overall survival time is 51.81 weeks (range, 7-162 +) and the 1-year survival rate is 49%. CONCLUSION: In advanced NSCLC the carboplatin-paclitaxel combination can be safely administered at the doses of 375 and 225 mg/m2 every 4 weeks, it appears to be active and well tolerated.     

A phase II study of weekly paclitaxel and carboplatin in previously untreated patients with advanced non-small-cell lung cancer

Purpose: Both paclitaxel (P) and carboplatin (C) have a significant activity in non-small cell lung cancer (NSCLC). Weekly administration of P is active, is dose intense, and has a favorable toxicity profile. To evaluate the efficacy and toxicity of weekly P and C in advanced-stage NSCLC, we initiated this phase II study in patients with advanced NSCLC (III B with pleural effusion and stage IV). Patients and Methods: Eligible patients were treated with paclitaxel 100 mg/m² intravenously (iv) over 1 h followed by carboplatin AUC 2 iv over 30 min. This treatment was administered weekly for 3 of every 4 wk until disease progression or intolerable toxicities. Results: Of the 30 patients enrolled in the study, one patient did not meet the eligibility criteria. Of the remaining 29 patients, 6 did not complete at least two cycles of treatment and hence were not assessable for response. The overall response rate was 43.5% (10/23) (all partial responses). An additional 43.5% had stable disease. The median time to progression was 162 d and the median duration of response was 169 d. Overall survival at 1 yr on intent-to-treat analyses was 44% and median survival was 10.8 mo. We observed the following grade 3/4 toxicities: hypersensitivity to paclitaxel (13%), hypersensitivity to carboplatin (3%), neutropenia (31%), thrombocytopenia (7%); 31% experienced grade 1 neuropathy and 17% experienced grade 2 neuropathy. Conclusions: We conclude that weekly paclitaxel and carboplatin is active and very well tolerated in patients with advanced NSCLC.     

紫杉醇联合卡铂治疗晚期非小细胞肺癌的临床观察

目的:评价紫杉醇联合卡铂化疗方案治疗晚期非小细胞肺癌的近期疗效和不良反应.方法: 25例晚期非小细胞肺癌,应用紫杉醇150mg-175mg/m2、卡铂按浓度/时间曲线下面积(AUC)＝5给药联合化疗,每3周重复,进行3-4周期.结果: 全组CR 0例,PR 12例,SD 10例,PD 3例,总有效率48 %,不良反应主要为关节肌肉酸痛、骨髓抑制、轻度胃肠道反应、脱发.结论: 紫杉醇联合卡铂治疗晚期非小细胞肺癌疗效较好,不良反应可耐受,有较好的临床应用价值.     

A phase II study of weekly paclitaxel combined with carboplatin for elderly patients with advanced non-small cell lung cancer

We conducted this phase II study to explore the efficacy and safety of weekly paclitaxel combined with carboplatin in elderly patients with advanced non-small cell lung cancer (NSCLC). Elderly patients (> or = 70 years old) of stage IIIB, IV, or recurrent NSCLC with PS 0 or 1 were enrolled. Patients received paclitaxel at a dose of 70 mg/m2 on Days 1, 8, 15, and carboplatin at the target dose of the area under the curve (AUC) of six on Day 1 every 28 days for at least two cycles. Forty-two patients were enrolled and 40 patients were treated with a median of three cycles (range, 1-5). The overall response rate (ORR) was 45% (95% confidence interval, 30-60%). The median survival time (MST) was 14 months and the 1-year survival rate was 62%. Twenty-eight patients (70%) had grade 3/4 neutropenia and two patients (5%) experienced grade 3 febrile neutropenia. Non-hematological toxicities were generally mild to moderate and grade 3 peripheral neuropathy was seen in one patient (3%). There was one treatment-related death by infection due to neutropenia. Weekly paclitaxel and carboplatin combination chemotherapy was an effective and safe regimen in elderly patients with advanced NSCLC. A randomized trial comparing this treatment with the conventional tri-weekly regimen of paclitaxel and carboplatin is warranted.     

A phase II study of carboplatin and paclitaxel as first line chemotherapy in elderly patients with advanced non-small cell lung cancer (NSCLC)

INTRODUCTION: Lung cancer is the leading cause of tumour-related deaths in the elderly population but the optimal management of advanced NSCLC in older patients has not been defined to date. The present phase II study was planned to evaluate the efficacy and toxicity of the combination of carboplatin and paclitaxel in elderly patients with advanced NSCLC. PATIENTS AND METHODS: Patients (>70 years old) who had pathologically been proven to have a NSCLC and measurable lesions were treated with paclitaxel (175 mg/m2 for 3h) and carboplatin [area under the concentration-time curve (AUC=5)] on day 1 every 3 weeks. RESULTS: Forty patients were enrolled into the study. The median age was 74 years (range, 70-78 years). Approximately 85% of the patients had stage IV and 80% had a performance status (PS) of 0-1. Nine of the 40 (22.5%; 90% CI 17.6-28.1) included patients had a partial response; one patient (2.5%; 90% CI 1.7-3.2) achieved a complete response. The overall response rate was 25% (90% CI 15.3-38.6). In addition stable disease was observed in 13 patients (32.5%; 90% CI 24.3-40.7). The median survival was 7.8 months (95% confidence interval, 5.1-11.8 months). The actual 1-year survival was 18% (95% confidence interval, 12-29%). The median time to disease progression was 4.1 months (95% CI 2.8-8.5). Overall, 37.5% of patients experienced grade 3-4 neutropenia of any duration with only two patients (5%) developing neutropenic fever. Grade 3 or 4 non-haematological toxicity was uncommon apart alopecia. CONCLUSIONS: In the present phase II study the combination of paclitaxel and carboplatin has demonstrated to be active and safe in an age-selected population.     

Phase II study of high-dose paclitaxel and carboplatin in previously untreated, unresectable non-small cell lung cancer.

INTRODUCTION: This phase II study was designed to assess the activity and tolerability of the carboplatin-paclitaxel combination, given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. PATIENTS AND METHODS: Sixty patients (15 stage IIIb and 45 stage IV) received paclitaxel 225 mg/ml on day 1, followed by carboplatin AUC 6 mg/ml per minute (Calvert formula) every 3 weeks. Paclitaxel was administered as a 3-h intravenous infusion followed by carboplatin over 30 min, on completion of paclitaxel administration. RESULTS: The combination showed a good safety profile with Grade 4 neutropenia occurring in 31% of patients without any serious infectious episodes requiring hospitalization. Moderate to severe anemia and thrombocytopenia seldom occurred. Sensorimotor peripheral neuropathy (Grade 2-3) and myalgia (Grade 3-4) were documented in 34 and 20% of the patients, respectively. Among 59 evaluable patients, there was one complete response and 26 partial responses for an overall response rate of 46% (95% C.I.: 34-59%). With a minimum follow-up duration of 16.5 months, the median overall survival time is 52 weeks and the 1-year survival rate is 50%. Median duration of response is 20 weeks (range: 4-52) and progression-free survival is 22 weeks (range: 5-77). CONCLUSION: In advanced NSCLC, the combination carboplatin-paclitaxel at doses of AUC 6 mg/ml per minute and 225 mg/ml every 3 weeks, is both active and relatively well-tolerated.