A triplet chemotherapy with cisplatin, docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer: a phase I/II study.

PURPOSE: We conducted a phase I/II study of triplet chemotherapy consisting of cisplatin (CDDP), docetaxel (DCT) and gemcitabine (GEM) in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Fifty-three untreated patients with stage IIIB or IV NSCLC were enrolled. All drugs were given on days 1 and 8. The doses of CDDP and DCT were fixed at 40 mg/m(2) and 30 mg/m(2), respectively. In the phase I portion, a dose escalation study of GEM with starting dose of 400 mg/m(2) was conducted and primary objective in the phase II portion was response rate. RESULTS: The maximally tolerated dose (MTD) and recommended dose (RD) of GEM were determined as 800 mg/m(2) because grade 3 non-hematological toxicity (liver damage, diarrhea, and fatigue) developed in three of nine patients evaluated at that dose level. In pharmacokinetic analysis, C (max) and AUC of dFdC and dFdU were increased along with the dose escalation of GEM. However, no relationship between pharmacokinetic parameters and toxicity or response was observed. Objective response rate was 34% and median survival time was 11.7 months. Though major toxicity was myelosuppression, there were no life-threatening toxicities. CONCLUSION: These results indicate that this triplet chemotherapy is feasible and effective in patients with advanced NSCLC.

Influence of altering administration sequence of docetaxel, gemcitabine and cisplatin in patients with advanced non-small cell lung cancer.

BACKGROUND: A phase II study of a triplet chemotherapy with the administration sequence of gemcitabine (GEM), docetaxel (DCT) and cisplatin (CDDP) (OLCSG9908) was previously conducted in patients with advanced non-small cell lung cancer (NSCLC). The objective response rate was 34% and the median survival time (MST) and 1-year survival rate were 11.7 months and 49%, respectively. In an in vitro study of different sequence exposures to GEM and DCT, it was reported that the synergistic effect was more prominent using the administration sequence of DCT followed by GEM compared with the reverse sequence. In order to estimate the effects of the administration sequence, a phase II study of the same triplet chemotherapy was conducted with the administration sequence of DCT, CDDP and GEM. PATIENTS AND METHODS: Patients with unresectable stage IIIB/IV NSCLC were eligible. All drugs were given intravenously on days 1 and 8, and repeated every 4 weeks for up to 4 cycles. DCT (30 mg/m2) was given first, followed by CDDP (40 mg/m2) and GEM (800 mg/m2). RESULTS: Thirty-four patients were enrolled on this study (OLCSG0101). The objective response rate was 38% (95% CI: 22-56%). As grade 3/4 hematological toxicities, neutropenia, thrombocytopenia and anemia were observed in 70%, 41% and 21%, respectively, and febrile neutropenia was observed in 12%. As grade 3/4 non-hematological toxicities, vomiting and liver dysfunction were observed in 15% and 18%, respectively. These toxicities were manageable by conventional therapy. The MST and 1-year survival rate were 13.3 months (95% CI: 7.8-18.7 months) and 55% (95% CI: 38-73%), respectively. These results were similar to those of OLCSG9908. CONCLUSION: This triplet chemotherapy is well tolerated and effective in patients with advanced NSCLC, however, the treatment outcome was not significantly influenced by the administration sequence of DCT and GEM.

A phase III randomized trial comparing vindesine and cisplatin with or without ifosfamide in patients with advanced non-small-cell lung cancer: long-term follow-up results and analysis of prognostic factors.

UNLABELLED: In order to evaluate the activity and toxicity of a three-drug combination of vindesine, ifosfamide and cisplatin (VIP) for inoperable non-small-cell lung cancer (NSCLC), we conducted a randomized trial comparing VIP with a two-drug combination of cisplatin and vindesine (VP). Between September 1987 and March 1992, a total of 132 patients with stage III or IV NSCLC were randomly allocated to either VIP or VP. The VIP regimen consisted of vindesine (VDS 3 mg/m(2) on days 1 and 8), ifosfamide (IFX 1300 mg/m(2) on days 1-5), and cisplatin (CDDP 20 mg/m(2) on days 1-5). The VP regimen consisted of VDS and CDDP with the same dose and schedule as the VIP regimen. Both regimens were repeated every 4 weeks. Objective response rates were 49.3% (95% confidence interval: 95%CI, 43.1-55.4%) in the VIP arm and 44.6% (95%CI, 38.4-50.2%) in the VP arm; the difference was not significant (P=0.5390). Median response duration, median survival time, and two-year survival rates were 26.5 weeks, 49.6 weeks, and 14.9% in the VIP arm and 28.7 weeks, 37.1 weeks, and 12.3% in the VP arm, respectively. There were also no significant differences between these two treatment arms. In comparison with the VP regimen, however, a survival advantage of the VIP regimen could be confirmed when the data were evaluated with Cox's multivariate analysis (P=0.0131). In both arms, the principal toxicity was myelosuppression, which was significantly more frequent in the VIP arm, although generally well tolerated. CONCLUSION: This study suggested the survival advantage of the VIP regimen over the VP regimen for treatment of patients with advanced NSCLC.

Phase I/II study of altered schedule of cisplatin and etoposide administration and concurrent accelerated hyperfractionated thoracic radiotherapy for limited-stage small-cell lung cancer.

To improve the efficacy of a combination of cisplatin and etoposide and concurrent accelerated twice-daily thoracic radiotherapy against limited-stage small-cell lung cancer, we conducted a phase I/II study using an altered schedule of chemotherapy administration. Chemotherapy consisted of four cycles of cisplatin (days 1 and 8) and etoposide (days 1, 2, 8, and 9) every 4 weeks. Accelerated hyperfractionated thoracic radiation (1.5 Gy twice daily x 30 fractions, total dose of 45 Gy) was concurrently given with the first cycle of chemotherapy. The recommended doses of cisplatin and etoposide determined in the phase I study were 40 and 80 mg/m(2), respectively. In the phase II study, the overall response rate was 100% (complete response: 32%, partial response: 68%). By a median follow-up time of 29 months, median radiation-outfield progression-free survival was 13.4 months, while radiation-infield progression-free survival did not reach median value. The median overall survival time was 22.9 months, with survival rate of 48.4% at 2 years. Major toxicities were leukopenia and neutropenia (>/=grade 3, 92% each). The local control and overall survival demonstrated in this study were excellent. However, the insufficient distant control suggests a need for development of more active chemotherapy regimens.

Clinical and pharmacokinetic study of docetaxel in elderly non-small-cell lung cancer patients.

PURPOSE: To evaluate the usefulness and pharmacokinetics of docetaxel in the treatment of elderly patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS: Chemotherapy-naive elderly patients (aged at least 76 years) with locally advanced or metastatic non-small-cell lung cancer were accrued. Eligible patients received at least two cycles of docetaxel at a dose of 60 mg/m2 on day 1 over 1 h every 3 weeks. Patients who were considered ineligible for this study were also registered. Symptom control was assessed using a questionnaire during the treatment period. The pharmacokinetics of docetaxel were evaluated in the first cycle of chemotherapy. RESULTS: Of 35 elderly patients, 15 (43%) met the study eligibility criteria. The reasons for ineligibility consisted mainly of poor performance status, poor bone marrow function, and hypoxemia (six patients each). A total of 49 cycles of chemotherapy (median 2 cycles, range 1-12 cycles) were administered to the eligible patients, six of whom achieved a partial response (overall response rate 40%, 95% confidence interval 15-65%). The major toxicity was hematologic, with grade 3 or greater neutropenia and grade 3 neutropenic fever developing in 13 patients (87%) and five patients (33%), respectively. Symptoms, as assessed in terms of the symptom control score, did not clearly decline during the treatment period. The values (mean+/-SD) of Cmax, AUC(0-->inf), and t(1/2) were 1.35+/-0.32 microg/ml, 1.79+/-0.52 microg h/ml, and 4.1+/-2.3 h, respectively. CONCLUSIONS: Although the validity of the results of this study is limited due to the small sample size, docetaxel appears effective in selected elderly patients with advanced non-small-cell lung cancer.

Fractionated administration of irinotecan and cisplatin for treatment of extensive-disease small-cell lung cancer: a phase II study.

BACKGROUND: A combination of irinotecan (CPT-11) and cisplatin (CDDP) was shown to be effective for extensive-disease small-cell lung cancer (ED-SCLC). To take maximum advantage of the synergistic effect between CPT-11 and CDDP, we designed a fractionated administration schedule. PATIENTS AND METHODS: Between August 1995 and September 1998, 15 previously untreated patients with ED-SCLC were enrolled. Both CPT-11 at a dose of 50 mg/m2 and CDDP at a dose of 60 mg/m2 were given on days 1 and 8, and repeated every 4 weeks up to four cycles. RESULTS: Fifteen patients were assessed for response and survival, and fourteen for toxicity. Although twelve patients (80.0%; 95% confidence interval, 51.9-95.7) achieved an objective response, complete response (CR) was not obtained. The median survival time and the actual 1-year survival rate were 9.4 months and 40.0%, respectively. Grade 3 or 4 leukopenia, neutropenia and diarrhea occurred in 71.4%, 100% and 14.3% of the patients, respectively. Enrollment into this study was stopped because CR, which was the primary endpoint, was not obtained in the consecutive 15 patients and the survival appeared to be inferior to the previous multi-institutional study (Kudoh et al, Clin Oncol 16: 1068-1074, 1998). The projected dose intensity in the present study was lower in CPT-11 and higher in CDDP compared to that in the previous report. CONCLUSION: These results suggest that the dose intensity of CPT-11 may have a major role on the activity of SCLC in this combination.

[Combination chemotherapy with carboplatin and etoposide for elderly patients aged 76 years or older with small cell lung cancer].

Eighteen elderly patients aged 76 years or older with small cell lung cancer were treated with carboplatin (AUC = 4 mg/ml.min, i.v. day 1) and etoposide (70 mg/m2 i.v. day 1-3) and 17 patients were evaluable. The median age of the study population was 77 years (range: 76-81). Eight patients had limited disease (LD) and nine did extensive disease (ED). The overall response rate was 88% for LD patients and 67% for ED patients. Median survival time was 219 days for LD patients and 158 days for ED patients. Grade 3 and 4 leukopenia, neutropenia, thrombocytopenia and anemia occurred in 41%, 76%, 24% and 6% of patients, respectively. There was one treatment-related death due to pneumonitis.

Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007.

PURPOSE: To demonstrate the efficacy of docetaxel and cisplatin (DP) chemotherapy with concurrent thoracic radiotherapy (TRT) for patients with locally advanced non-small-cell lung cancer (LA-NSCLC). PATIENTS AND METHODS: Patients age 75 years or younger with LA-NSCLC, stratified by performance status, stage, and institution, were randomly assigned to two arms consisting of DP (docetaxel 40 mg/m(2) and cisplatin 40 mg/m(2) on days 1, 8, 29, and 36) or mitomycin, vindesine, and cisplatin (MVP) chemotherapy with concurrent TRT. RESULTS: Between July 2000 and July 2005, 200 patients were allocated into either the DP or MVP arm. The survival time at 2 years, a primary end point, was favorable to the DP arm (P = .059 by a stratified log-rank test as a planned analysis and P = .044 by an early-period, weighted log-rank as an unplanned analysis). There was a trend toward improved response rate, 2-year survival rate, median progression-free time, and median survival in the DP arm (78.8%, 60.3%,13.4 months, and 26.8 months, respectively) compared with the MVP arm (70.3%, 48.1%, 10.5 months, and 23.7 months, respectively), which was not statistically significant (P > .05). Grade 3 febrile neutropenia occurred more often in the MVP arm than in the DP arm (39% v 22%, respectively; P = .012), and grade 3 to 4 radiation esophagitis was likely to be more common in the DP arm than in the MVP arm (14% v 6%, P = .056). CONCLUSION: DP chemotherapy combined with concurrent TRT is an alternative to MVP chemotherapy for patients with LA-NSCLC.

Phase II study of concurrent administration of doxorubicin and docetaxel as first-line chemotherapy for metastatic breast cancer.

OBJECTIVE: To evaluate the efficacy and toxicity of concurrent administration of doxorubicin and docetaxel, without prophylactic use of granulocyte colony-stimulating factor, as first-line chemotherapy in patients with metastatic breast cancer (MBC). METHODS: This multi-institutional study enrolled 40 women; 37 were assessable for efficacy and all 40 patients were evaluated for toxicity. Treatment consisted of 50 mg/m(2) doxorubicin and 60 mg/m(2) docetaxel on day 1 every 3-4 weeks. RESULTS: Patients received a total of 251 cycles of chemotherapy (median, 5 cycles; range, 1-13 cycles). Of the 37 patients assessable for efficacy, 2 had a complete response and 24 had partial responses, which accounted for a 70% objective response rate (95% confidence interval, 53-84%). The median time to treatment failure was 30.1 weeks (range, 3.3-80.7 weeks). Grade 4 neutropenia was observed in 88% of patients and was the most frequent haematological toxicity. Febrile neutropenia was seen in 40% of patients, but no severe infections were observed. Non-haematological toxicity was generally tolerable. There were 2 grade 4 adverse events, which included 1 bleeding duodenal ulcer and 1 hypersensitivity reaction, but grade 3 episodes were infrequent. None of the patients developed congestive heart failure or asymptomatic decrease of left ventricular ejection fraction to less than 50%. Fluid retention syndrome