S. Kudoh

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

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.

Risk factors of pneumonitis following chemoradiotherapy for lung cancer

The purpose of this retrospective study was to identify risk factors associated with development of pneumonitis following chemoradiotherapy (CRT). We examined 60 patients (pts) who received CRT from May 1993 to August 1995. Factors evaluated included total radiation dose, field-size, irradiated site, type of chemotherapy, pulmonary fibrosis and treatment schedule (concurrent versus sequential). There were 17 pts (28.3%) who had > or = Grade 2 pulmonary toxicity. There was no significant relationship between total radiation dose, field-size > or = 200 cm2, pulmonary fibrosis or treatment schedule and risk of pneumonitis. In the sequential treatment group (22 pts), no relationship was noted between any factor and the risk of pneumonitis, while in the concurrent treatment group (38 pts), the incidence of pneumonitis was more frequent (53.8%) in patients with field-size > or = 200 cm2 than in patients with field-size < 200 cm2 (P < 0.05). In those who received concurrent treatment, including weekly CPT-11, pneumonitis was more frequent (56.3%) than in those without CPT-11 (13.6%, P < 0.01). When the lower lung field was included in the radiation site, the incidence of pneumonitis was 70% compared with 20% for other sites (P < 0.01). Multivariate analysis revealed a significant relationship between radiation site and the risk of pneumonitis (P = 0.0096). CPT-11 was significant (P = 0.038) only in the concurrent group. Pneumonitis was reversible in all but one pt by steroid therapy. Thus, irradiated site (included lower lung field) and concurrent CRT used with weekly CPT-11 were treatment factors significantly associated with a higher risk of pneumonitis following CRT.

Phase I and pharmacologic study of irinotecan in combination with cisplatin for advanced lung cancer

We have conducted a Phase I trial to determine the maximum tolerated dose of CPT-11 together with a fixed dose of cisplatin in patients with advanced lung cancer, and the dose-limiting toxicities of this combination. Fourteen previously untreated patients with stage IIIB or IV disease were treated with CPT-11 (90-min intravenous infusion on days 1, 8, and 15) plus cisplatin (60 mg m-2, intravenously on day 1). The starting dose of CPT-11 was 60 mg m-2, and diarrhea was the dose-limiting toxicity at the 90 mg m-2 dose level. All three patients (all four cycles) given 90 mg m-2 of CPT-11 experienced grade 3 diarrhea. Hematologic toxicity was relatively mild. Elimination of CPT-11 was biphasic with a mean (+/- s.d.) beta half-life of 11.36 +/- 7.26 h. The mean terminal half-life of the major metabolite (7-ethyl-10-hydroxycamptothecin; SN-38) was 22.13 +/- 13.28 (s.d.) h, and modest escalation of the CPT-11 dose from 80 mg m-2 to 90 mg m-2 resulted in a statistically significant apparent increase in the plasma concentrations of SN-38. There were one complete response (7%) and five partial responses (36%) among the 14 patients for an overall response rate of 43%. The recommended dose for Phase II studies is 80 mg m-2 of CPT-11 and 60 mg m-2 of cisplatin.

Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG0104)

BACKGROUND This trial evaluated whether a combination of docetaxel and gemcitabine provides better survival than docetaxel alone in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Eligibility included pathologically or cytologically proven NSCLC, failure of one platinum-based regimen, performance status of zero or one, 20-75 years old, and adequate organ function. Patients received docetaxel 60 mg/m(2) (day 1) or docetaxel 60 mg/m(2) (day 8) and gemcitabine 800 mg/m(2) (days 1 and 8), both administered every 21 days until disease progression. RESULTS Sixty-five patients participated in each arm. This trial was terminated early due to an unexpected high incidence of interstitial lung disease (ILD) and three treatment-related deaths due to ILD in the combination arm. Docetaxel plus gemcitabine compared with docetaxel-alone patients experienced similar grade and incidence of toxicity, except for ILD. No baseline factor was identified for predicting ILD. Median survival times were 10.3 and 10.1 months (one-sided P = 0.36) for docetaxel plus gemcitabine and docetaxel arms, respectively. CONCLUSION Docetaxel alone is still the standard second-line treatment for NSCLC. The incidence of ILD is higher for docetaxel combined with gemcitabine than for docetaxel alone in patients with previously treated NSCLC.

CODE chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer.

Sixty-three patients with extensive-stage small-cell lung cancer were randomized to receive either cyclophosphamide, vincristine, doxorubicin and etoposide (CODE) alone or CODE plus recombinant human granulocyte colony-stimulating factor (rhG-CSF). rhG-CSF administration in support of CODE chemotherapy resulted in increased mean total received dose intensity for all drugs (P = 0.03) with a significant improvement in survival (P = 0.004).

Phase II trial of carboplatin plus oral etoposide for elderly patients with small-cell lung cancer.

A phase II trial was conducted to evaluate the efficacy and toxicity of the Egorins carboplatin dosing formula with 14-day oral etoposide in 38 elderly patients with small-cell lung cancer (SCLC). The overall response rate was 81%. Median survival times were 15.1 months for 16 limited-disease (LD) and 8.6 months for 22 extensive-disease (ED) patients. Myelosuppression was the principal side-effect. This regimen is an active regimen in the treatment of elderly SCLC patients.

A phase I study of pemetrexed (LY231514) supplemented with folate and vitamin B12 in Japanese patients with solid tumours

The purpose of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of pemetrexed with folate and vitamin B12 supplementation (FA/VB12) in Japanese patients with solid tumours and to investigate the safety, efficacy, and pharmacokinetics of pemetrexed. Eligible patients had incurable solid tumours by standard treatments, a performance status 0–2, and adequate organ function. Pemetrexed from 300 to 1200 mg m−2 was administered as a 10-min infusion on day 1 of a 21-day cycle with FA/VB12. Totally, 31 patients were treated. Dose-limiting toxicities were alanine aminotransferase (ALT) elevation at 700 mg m−2, and infection and skin rash at 1200 mg m−2. The MTD/RD were determined to be 1200/1000 mg m−2, respectively. The most common grade 3/4 toxicities were neutropenia (grade (G) 3:29, G4:3%), leucopenia (G3:13, G4:3%), lympopenia (G3:13%) and ALT elevation (G3:13%). Pemetrexed pharmacokinetics in Japanese were not overtly different from those in western patients. Partial response was achieved for 5/23 evaluable patients (four with non-small cell lung cancer (NSCLC) and one with thymoma). The MTD/RD of pemetrexed were determined to be 1200/1000 mg m−2, respectively, that is, a higher RD than without FA/VB12 (500 mg m−2). Pemetrexed with FA/VB12 showed a tolerable toxicity profile and potent antitumour activity against NSCLC in this study.

Efficacy and safety analysis according to histology for S-1 in combination with carboplatin as first-line chemotherapy in patients with advanced non-small-cell lung cancer: updated results of the West Japan Oncology Group LETS study

BACKGROUND A phase III study (Lung Cancer Evaluation of TS-1) previously demonstrated noninferiority in terms of overall survival (OS) at interim analysis for carboplatin-S-1 compared with carboplatin-paclitaxel for first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS A total of 564 patients were randomly assigned to receive either carboplatin on day 1 plus oral S-1 on days 1-14 or carboplatin-paclitaxel on day 1 every 21 days. Updated results and post hoc subgroup analysis according to tumor histology are presented. RESULTS The updated analysis revealed a median OS of 15.2 months in the carboplatin-S-1 arm and 13.1 months in the carboplatin-paclitaxel arm, with a hazard ratio (HR) of 0.956 [95% confidence interval (CI) 0.793-1.151], consistent with the previous primary analysis. Median OS was 14.0 months in the carboplatin-S-1 arm and 10.6 months in the carboplatin-paclitaxel arm (HR 0.713; 95% CI 0.476-1.068) for patients with squamous cell carcinoma (SCC), with corresponding values of 15.5 and 13.9 months (HR 1.060; 95% CI 0.859-1.308) for those with non-SCC. CONCLUSIONS These results establish the efficacy and safety of carboplatin-S-1 in patients with advanced NSCLC regardless of tumor histology.

Intrapleural Administration of Cisplatin and Etoposide to Treat Malignant Pleural Effusions in Patients with Non-Small Cell Lung Cancer

Background: To determine the efficacy, toxicity and pharmacokinetics of intrapleural cisplatin (CDDP) and etoposide as a treatment for malignant pleural effusions (MPE) in patients with non-small cell lung cancer (NSCLC). Methods: Seventy patients with MPE associated with NSCLC were enrolled in this study. In 68 patients, a catheter was inserted into the pleural cavity, within 24 h after complete drainage of the pleural effusion, CDDP (80 mg/m2) and etoposide (80 mg/m2) were simultaneously administered successfully via the catheter and the catheter was clamped. Seventy-two hours later, the catheter was unclamped to allow drainage. The catheter was removed when the accumulated intrapleural fluid decreased to 20 ml or less per day. Results: The pharmacokinetic profiles showed high maximum concentrations of CDDP (free form, 88 µg/ml) and etoposide (182.4 µg/ml) in intrapleural fluids. CDDP did not remain for a long period (free form, β-phase half-life = 10.51 h) in the fluids, while etoposide persisted for a long period (β-phase half-life = 62.53 h). The overall response rate was 46.2%, the median survival time 32.3 weeks, the 1-year survival rate 28.7% and the 2-year survival rate 12.8%. The most serious adverse reactions were WHO grade 3 anemia (3 patients), grade 3 nausea and vomiting (17 patients), grade 3 constipation (1 patient), grade 3 pulmonary toxicity (1 patient), grade 4 fever (1 patient), grade 3 infection (1 patient) and grade 3 mental disorder (1 patient). Conclusion: Intrapleural administration of CDDP and etoposide was an effective and acceptable regimen for patients with MPE due to NSCLC.

Randomised, phase III trial of epoetin-β to treat chemotherapy-induced anaemia according to the EU regulation

Background:Erythropoietin-stimulating agents (ESAs) effectively decrease the transfusion requirements of patients with chemotherapy-induced anaemia (CIA). Recent studies indicate that ESAs increase mortality and accelerate tumour progression. The studies also identify a 1.6-fold increased risk of venous thromboembolism. The ESA labelling was thus revised in Europe and the United States in 2008. This is the first randomised, phase III trial evaluating the efficacy and safety of epoetin-β (EPO), an ESA, dosed in accordance with the revised labelling, which specifies that ESAs should be administered to CIA patients with a haemoglobin level of ⩽10 g dl–1 and that a sustained haemoglobin level of >12 g dl–1 should be avoided.Methods:A total of 186 CIA patients (8.0 g dl–1⩽ haemoglobin ⩽10.0 g dl–1) with lung or gynaecological cancer were randomised to receive EPO 36 000 IU or placebo weekly for 12 weeks.Results:The proportion of patients receiving transfusions or with haemoglobin <8.0 g dl–1 between week 5 and the end of the treatment period as the primary end point was significantly lower in the EPO group (n=89) than in the placebo group (n=92; 10.0% vs 56.4%, P<0.001). The proportion receiving transfusions was significantly lower in the EPO group (4.5% vs 19.6%, P=0.002). Changes in quality of life were not different. No significant differences in adverse events – for example, the incidence of thromboembolic events was 1.1% for each group – or the 1-year overall survival were observed between groups.Conclusion:Weekly EPO administered according to the revised labelling approved by the European Medicines Agency is effective and well tolerated for CIA treatment. Further investigations are needed on the effect of ESAs on mortality.