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Randomised phase III trial of irinotecan combined with cisplatin for advanced non-small-cell lung cancer.

ABSTRACT: To determine a standard combination chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC), we conducted a phase III trial of irinotecan (CPT-11) to test the hypotheses that CPT-11+cisplatin is superior to cisplatin+vindesine and that CPT-11 monotherapy is not inferior to cisplatin+vindesine. A total of 398 patients with previously untreated NSCLC were randomised to receive cisplatin+CPT-11 (CPT-P), cisplatin+vindesine (VDS-P) or CPT-11 alone (CPT). In the CPT-P arm, CPT-11 60 mg m(-2) was administered on days 1, 8 and 15, and cisplatin 80 mg m(-2) was administered on day 1. In the VDS-P arm, cisplatin 80 mg m(-2) was administered on day 1, and vindesine 3 mg m(-2) was administered on days 1, 8 and 15. In the CPT arm, CPT-11 100 mg m(-2) was administered on days 1, 8 and 15. The median survival time was 50.0 weeks for patients on CPT-P, 45.6 weeks for those on VDS-P and 46.0 weeks for those on CPT (P=0.115, CPT-P vs VDS-P; P=0.089, CPT vs VDS-P), and the hazard ratio was 0.85 (95% confidence interval (CI): 0.65-1.11) for CPT-P vs VDS-P and 0.83 (0.64-1.09) for CPT vs VDS-P. The response rate was 43.7% for patients on CPT-P, 31.7% for those on VDS-P and 20.5% for those on CPT. Major adverse reactions were grade 4 neutropenia observed in 37, 54 and 8% of the patients on CPT-P, VDS-P and CPT, respectively; and grades 3 and 4 diarrhoea observed in 12, 3 and 15% of the patients, respectively. CPT-P therapy produces comparable survival to VDS-P in patients with advanced NSCLC. CPT-11 monotherapy is not inferior to VDS-P in terms of survival. The CPT-11-containing regimen is one of the most efficacious and well tolerated in the treatment of advanced NSCLC.

SUBMITTER: Negoro S

PROVIDER: S-EPMC2747545 | biostudies-other | 2003 Feb

REPOSITORIES: biostudies-other

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Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124.

Project description:Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC.Patients were randomly assigned to IP (irinotecan 60 mg/m(2) on days 1, 8, and 15; cisplatin 60 mg/m(2) day 1, every 4 weeks) or EP (etoposide 100 mg/m(2) on days 1 through 3; cisplatin 80 mg/m(2) day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients.Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia.This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.

| S-EPMC2684855 | biostudies-literature

Randomized Phase III Trial of Irinotecan Plus Cisplatin versus Etoposide Plus Cisplatin in Chemotherapy-Naive Korean Patients with Extensive-Disease Small Cell Lung Cancer.

Project description:PurposeThis randomized phase III study was designed to compare the efficacy and safety of irinote-can plus cisplatin (IP) over etoposide plus cisplatin (EP) in Korean patients with extensive-disease small-cell lung cancer (SCLC).Materials and methodsPatients were randomly assigned to receive IP, composed of irinotecan 65 mg/m2 intravenously on days 1 and 8+cisplatin 70 mg/m2 intravenously on day 1 every 3 weeks, or EP, composed of etoposide 100 mg/m2 intravenously on days 1, 2, 3+cisplatin 70 mg/m2 intravenously on day 1, every 3 weeks for a maximum of six cycles, until disease progression, or until unacceptable toxicity occurred. The primary endpoint was overall survival.ResultsA total of 362 patients were randomized to IP (n=173) and EP (n=189) arms. There were no significant differences between IP and EP arms for the median overall survival (10.9 months vs. 10.3 months, p=0.120) and the median progression-free survival (6.5 months vs. 5.8 months, p=0.115). However, there was a significant difference in response rate (62.4% vs. 48.2%, p=0.006). The pre-planned subgroup analyses showed that IP was associated with longer overall survival in male (11.3 months vs. 10.1 months, p=0.036), < 65 years old (12.7 months vs. 11.3 months, p=0.024), and Eastern Cooperative Oncology Group performance status 0/1 (12.4 months vs. 10.9 months, p=0.040) patient groups. The severity of treatment-related adverse events such as grade 3/4 anemia, nausea and diarrhea was more frequent in patients treated with IP.ConclusionThe IP chemotherapy did not significantly improve the survival compared with EP chemotherapy in Korean patients with extensive-disease SCLC.

| S-EPMC6334001 | biostudies-literature

First-line gemcitabine with cisplatin or epirubicin in advanced non-small-cell lung cancer: a phase III trial.

Project description:The purpose of our study was to compare progression-free survival and quality of life (QOL) after cisplatin-gemcitabine (CG) or epirubicin-gemcitabine (EG) in chemotherapy-naive patients with unresectable non-small-cell lung cancer. Patients (n=240) were randomised to receive gemcitabine 1125 mg x m(-2) (days 1 and 8) plus either cisplatin 80 mg x m(-2) (day 2) or epirubicin 100 mg x m(-2) (day 1) every 3 weeks for a maximum of five cycles. Eligible patients had normal organ functions and Eastern Cooperative Oncology Group performance status <or=2. QOL was measured with European Organisation for Research and Treatment of Cancer QLQ-C30 and LC13 questionnaires. There were no significant differences in median progression-free survival (CG 26 weeks, EG 23 weeks), median overall survival (CG 43 weeks, EG 36 weeks), or tumour response rates (CG 46%, EG 36%). Toxicity was mainly haematologic. In the EG arm granulocytopenia occurred more frequently, leading to more febrile neutropenia. Also, elevation of serum transaminases, mucositis, fever, and decline in LVEF were more common in the EG arm. In the CG arm, more patients experienced elevated serum creatinine levels, sensory neuropathy, nausea, and vomiting. Global QOL was not different in both arms. Progression-free survival, overall survival, response rate, and QOL were not different between both arms; however, overall toxicity was more severe in the EG arm.

| S-EPMC2394313 | biostudies-other

ERCC1 Expression-Based Randomized Phase II Study of Gemcitabine/Cisplatin Versus Irinotecan/Cisplatin in Patients with Advanced Non-small Cell Lung Cancer.

Project description:PurposeWe evaluated the clinical utility of excision repair cross-complementation group 1 (ERCC1) expression as a predictive biomarker for platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC).Materials and methodsEligible patients were randomly assigned to the GP (gemcitabine 1,250 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1 every 3 weeks) or IP (irinotecan 65 mg/m2 and cisplatin 30 mg/m2 on days 1 and 8 every 3 weeks) arm. The primary goal of this study was to compare the response rate (RR) of the GP and IP arms according to the ERCC1 expression level.ResultsA total of 279 patients were randomly assigned to the GP (n=139) and IP (n=140) arms, among which 63% were ERCC1-positive and 268 patients were assessable for the RR. The GP and IP arms did not differ significantly with respect to the RR (29.8% vs. 27.0%, respectively; p=0.082), median progression-free survival (PFS; 4.5 months vs. 3.9 months, respectively; p=0.117), and overall survival (OS; 16.5 months vs. 16.7 months, respectively; p=0.313). When comparing the efficacy between the ERCC1-positive and ERCC1-negative groups, there was no significant difference in the RR (GP, 28.2% vs. 32.6%, respectively, p=0.509; IP, 30.2% vs. 21.6%, respectively, p=0.536), median PFS (GP, 4.6 months vs. 5.0 months, respectively, p=0.506; IP, 3.9 months vs. 3.7 months, respectively, p=0.748), or median OS (GP, 18.6 months vs. 11.9 months, respectively, p=0.070; IP, 17.5 months vs. 14.0 months, respectively, p=0.821).ConclusionImmunohistochemical analysis of the ERCC1 expression level did not differentiate the efficacy of platinum-based chemotherapy in advanced NSCLC.

| S-EPMC5512356 | biostudies-literature

Irinotecan plus gemcitabine vs irinotecan for the second-line treatment of patients with advanced non-small-cell lung cancer pretreated with docetaxel and cisplatin: a multicentre, randomised, phase II study.

Project description:To compare irinotecan (CPT-11)+gemcitabine vs CPT-11 alone as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC) progressing after docetaxel-cisplatinum-based therapy. A total of 147 evaluable, pretreated patients, with NSCLC, received either gemcitabine (1000 mg m(-2), days 1 and 8)+CPT-11 (300 mg m(-2), day 8) (Group A, n=76) or CPT-11 (300 mg m(-2), day 1) (Group B, n=71), every 3 weeks. All patients were evaluable for response and toxicity. The objective response rate was 18.4% (95% CI: 9.71-27.14%) and 4.2% (95% CI: 0-8.90%) (P=0.009) for groups A and B, respectively. No significant differences between the two groups in terms of the median duration of response, time to tumour progression, overall survival and 1-year survival were observed. The CPT-11/gemcitabine regimen significantly improved the patients' quality of life ('general mood today' (P=0.014), 'coughing' (P=0.003) and 'intensity of symptoms' (P=0.034)) compared with CPT-11. More cycles had to be delayed (P=0.001) and required prophylactic growth factor support (P=0.001) in Group A than B. Three (3.9%) patients in Group A and eight (11.3%) in Group B developed febrile neutropenia (P=0.09); one patient died of sepsis in each group. Three additional (Group A, n=1; Group B, n=2) treatment-related deaths were observed. Grade 3-4 haematologic toxicity was comparable in the two groups except anaemia (P=0.03 in favour of CPT-11). Other nonhaematologic toxicities were mild and similar in the two groups. CPT-11+gemcitabine resulted in a higher response rate and better control of disease-related symptoms than CPT-11 alone, but without any improvement in the overall survival.

| S-EPMC2409833 | biostudies-other

A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial.

Project description:BackgroundPlatinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL).Patients and methodsPatients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0-1 and adequate organ function were randomized to receive either oral S-1 80 mg/m(2)/day on days 1-21 plus cisplatin 60 mg/m(2) on day 8 every 4-5 weeks, or docetaxel 60 mg/m(2) on day 1 plus cisplatin 80 mg/m(2) on day 1 every 3-4 weeks, both up to six cycles.ResultsA total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin [median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837-1.227]. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin.ConclusionOral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC.Clinical trial numberUMIN000000608.

| S-EPMC4478975 | biostudies-literature

A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations.

Project description:BackgroundA phase III trial was conducted to compare the safety and efficacy of erlotinib with that of gefitinib in advanced non-small cell lung cancer harbouring epidermal growth factor receptor mutations in exon 19 or 21.MethodsEligible patients were randomised to receive erlotinib (150 mg per day) or gefitinib (250 mg per day) orally until disease progression or unacceptable toxicity. We aimed to determine whether erlotinib is superior to gefitinib in efficacy. The primary end point was progression-free survival.ResultsA total of 256 patients were randomised to receive erlotinib (N=128) or gefitinib (N=128). Median progression-free survival was not better with erlotinib than with gefitinib (13.0 vs 10.4 months, 95% confidence interval (CI) 0.62-1.05, P=0.108). The corresponding response rates and median overall survival were 56.3% vs 52.3% (P=0.530) and 22.9 vs 20.1 months (95% CI 0.63-1.13, P=0.250), respectively. There were no significant differences in grade 3/4 toxicities between the two arms (P=0.172).ConclusionsThe primary end point was not met. Erlotinib was not significantly superior to gefitinib in terms of efficacy in advanced non-small cell lung cancer with epidermal growth factor receptor mutations in exon 19 or 21, and the two treatments had similar toxicities.

| S-EPMC5344291 | biostudies-literature

Randomized phase III trial of amrubicin/cisplatin versus etoposide/cisplatin as first-line treatment for extensive small-cell lung cancer.

Project description:BackgroundExtensive-disease small-cell lung cancer (ED-SCLC) is characterized by rapid progression and relapse, despite high initial response rates to chemotherapy. The primary objective of this trial was to demonstrate the non-inferiority of amrubicin and cisplatin (AP) combination therapy compared with the standard first-line regimen of etoposide and cisplatin (EP) for previously untreated ED-SCLC in a Chinese population. When non-inferiority was verified, the objective was switched from non-inferiority to superiority.MethodsFrom June 2008 to July 2010, 300 patients were enrolled and randomly assigned at a 1:1 ratio to AP and EP groups. AP-treated patients received cisplatin (60 mg/m(2), day 1) and amrubicin (40 mg/m(2), days 1-3) once every 21 days. EP-treated patients received cisplatin (80 mg/m(2), day 1) and etoposide (100 mg/m(2), days 1-3) once every 21 days. Treatment was continued for four to six cycles, except in cases of progressive disease or toxicity, and patient refusal.ResultsMedian overall survival (OS) for AP vs. EP treatment was 11.8 vs. 10.3 months (p = 0.08), respectively, demonstrating non-inferiority of AP to EP (AP group: 95% confidence interval for hazard ratio 0.63-1.03 months). Median progression-free survival and overall response rates for AP vs. EP groups were 6.8 vs. 5.7 months (p = 0.35) and 69.8% vs. 57.3%, respectively. Drug-related adverse events in both groups were similar, with neutropenia being the most frequent (AP 54.4%; EP 44.0%). Leukopenia, pyrexia, and fatigue were more prevalent in the AP group, but all were clinically reversible and manageable.ConclusionsAP therapy demonstrated non-inferiority to EP therapy, prolonging OS for 1.5 months, but this difference was not statistically significant; thus we propose AP as a promising treatment option for ED-SCLC in China.Trial registrationThis trial was registered on 10 April 2008 (ClinicalTrials.gov NCT00660504).

| S-EPMC4826513 | biostudies-literature

Phase I/II study of cisplatin combined with weekly paclitaxel in patients with advanced non-small-cell lung cancer.

Project description:To determine the maximum-tolerated dose (MTD) and the recommended dose (RD) of paclitaxel administered weekly with a fixed dose of cisplatin, and to assess the toxicity and activity of this combination, we conducted a phase I/II trial in patients with advanced non-small-cell lung cancer (NSCLC). In this study, patients with stage IIIB/IV NSCLC were eligible. Paclitaxel, at a starting dose of 40 mg x m(-2) week(-1) on days 1, 8, and 15, was combined with a fixed dose of cisplatin 80 mg x m(-2) on day 1. Chemotherapy was given in a 4-week cycle. In this phase I/II study, 38 patients were enrolled. Dose-limiting toxicities (DLT) were neutropenia, fatigue, and omission of treatment due to leucopenia, thrombocytopenia, or febrile neutropenia. The MTD and RD were estimated to be 70 mg x m(-2). Of the 37 assessable patients, 23 had a partial response and one had a complete response. Overall response rate was 62.1% (95% confidence interval (CI): 46.5-77.7%). The progression-free survival, the median survival time, and the 1-year survival rate were 5.5 months, 13.7 months, and 56.9%, respectively. This regimen is tolerable and very active against advanced NSCLC, and its efficacy should be confirmed in a phase III study.

| S-EPMC2409643 | biostudies-other

A randomised phase II trial of S-1 plus cisplatin versus vinorelbine plus cisplatin with concurrent thoracic radiotherapy for unresectable, locally advanced non-small cell lung cancer: WJOG5008L.

Project description:BACKGROUND:Cisplatin-based chemoradiotherapy is the standard treatment for unresectable, locally advanced non-small-cell lung cancer (NSCLC). This trial evaluated two experimental regimens that combine chemotherapy with concurrent radiotherapy. METHODS:Eligible patients with unresectable stage III NSCLC were randomised to either the SP arm (S-1 and cisplatin) or VP arm (vinorelbine and cisplatin), with early concurrent thoracic radiotherapy of 60?Gy, comprising 2?Gy per daily fraction. The primary endpoint was the overall survival rate at 2 years (2-year overall survival (OS)) (Study ID: UMIN000002420). RESULTS:From September 2009 to September 2012, 112 patients were enroled. Of the 108 eligible patients, the 2-year OS was 75.6% (80% confidence interval (CI), 67-82%) in the SP arm and 68.5% (80% CI: 60-76%) in the VP arm. The hazard ratio (HR) for death between the two arms was 0.85 (0.48-1.49). The median progression-free survival was 14.8 months for the SP arm and 12.3 months for the VP arm with an HR of 0.92 (0.58-1.44). There were four treatment-related deaths in the SP arm and five in the VP arm. CONCLUSIONS:The null hypotheses for 2-year OS were rejected in both arms. The West Japan Oncology Group will employ the SP arm as the investigational arm in a future phase III study.

| S-EPMC6173687 | biostudies-literature

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