A multicenter phase I trial of metronomic oral vinorelbine plus cisplatin in patients with NSCLC.

The purpose of the present study was to determine the maximum-tolerated doses (MTDs) and the dose-limiting toxicities of a metronomic administration of oral vinorelbine and cisplatin in patients with advanced/metastatic NSCLC. Twenty-six patients with advanced/metastatic NSCLC were enrolled. Escalating doses of vinorelbine (40-70 mg p.o./trice per week) and cisplatin (70-85 mg/m(2) intravenous infusion) were administered on day 1 every 3 weeks. ΜΤDs were reached at 60 mg thrice/week p.o. for vinorelbine and 85 mg/m(2) for cisplatin. Grade 4 neutropenia, febrile neutropenia and grade 4 diarrhea were the dose-limiting events during the first cycle of chemotherapy. The most common grade III-IV hematologic toxicity was neutropenia occurring in seven (27%) patients, while non-hematological toxicities were relatively infrequent and mostly of grade I or II. Objective responses were observed in 20.8% of patients with measurable disease. The regimen of metronomic administration and cisplatin is feasible and active in patients with NSCLC.

A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic non-small cell lung cancer.

BACKGROUND: To compare the activity and toxicity of docetaxel/carboplatin (DC) doublet vs single agent docetaxel (D) as second-line treatment in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients pre-treated with front-line platinum-free regimens, were randomized to receive either docetaxel/carboplatin (DC), (docetaxel 50 mg/m2; carboplatin AUC4; both drugs administered on days 1 and 15) or docetaxel single-agent (D), (docetaxel 50 mg/m2 on days 1 and 15). RESULTS: Response rate was similar between the two arms (DC vs D: 10.4% vs 7.7%; p = 0.764). After a median follow-up time of 28.0 months for DC arm and 34.5 months for D arm, progression free survival (PFS) was significantly higher in the DC arm (DC vs D:3.33 months vs 2.60 months; p-value = 0.012), while no significant difference was observed in terms of overall survival (OS) (DC vs D: 10.3 months vs 7.70 months; p-value = 0.550). Chemotherapy was well-tolerated and grade III/IV toxicities were relatively infrequent. No toxic deaths were observed. CONCLUSIONS: This study has not achieved its primary objective of significant OS prolongation with docetaxel/carboplatin combination over single-agent docetaxel in patients who had not received front-line docetaxel; however, the docetaxel/carboplatin combination was associated with a significant clinical benefit in terms of PFS.

Phase III study comparing sequential versus alternate administration of cisplatin-etoposide and topotecan as first-line treatment in small cell lung cancer.

AIM: To compare the efficacy and tolerance of sequential versus alternate front-line administration of cisplatin-etoposide (PE) and topotecan (T) in patients with extensive stage small cell lung cancer (SCLC). PATIENTS AND METHODS: Patients were randomized to receive either 4 cycles PE (cisplatin 80 mg/m(2) i.v. day 1 and etoposide100 mg/m(2)/d i.v. days 1-3 every 21 days) followed by 4 cycles T (1.5 mg/m(2)/d i.v. days 1-5 every 21 days) (arm A, 183 patients) or the same regimens using an alternate sequence (arm B, 181 patients). RESULTS: There was no significant difference in terms of compliance with treatment, overall response rates (51.4% vs. 55.2%; p=0.458), median response duration (4.3 vs. 5.2 months; p=0.780), median time to tumour progression (5.7 vs. 6.4 months; p=0.494), median overall survival (10.9 vs. 9.8 months; p=0.186) and 1-year survival (43.8% vs. 36.5%) between the two arms. The incidence of severe grade 3-4 haematological and grade 2-4 non-haematological (asthenia, mucositis, diarrhoea and neurotoxicity) toxicity was comparable between the two arms. CONCLUSION: The comparison of sequential versus alternate administration of cisplatin-etoposide and topotecan as front-line treatment of patients with extensive stage SCLC revealed no clinically meaningful differences in terms of efficacy and tolerance.

A multicenter randomized phase II study of the irinotecan/gemcitabine doublet versus irinotecan monotherapy in previously treated patients with extensive stage small-cell lung cancer.

OBJECTIVES: To compare the efficacy and safety profile of irinotecan (I) versus the combination of irinotecan/gemcitabine (IG) as second-line treatment of patients with extensive stage small-cell lung cancer (SCLC). TREATMENT: Patients with SCLC who have received at least one chemotherapy regimen were randomized to receive either the IG regimen (gemcitabine 1000mg/m(2) intravenous (i.v.) on days 1 and 8 and irinotecan 300mg/m(2) i.v. on day 8) or I monotherapy (300mg/m(2) i.v. on day 1) both every 3 weeks. RESULTS: Thirty-eight patients were enrolled in the IG and 31 in the I arm. Due to slow accrual an early closure of the study was decided. Response rate was significantly higher in the IG than in I arm (23.7% vs. 0%; p=0.004). The median time to progression (TTP) was 3.9 months (range: 0.5-14.5 months; 95% CI: 1.4-6.6) and 1.7 months (range: 0.5-9.9 months; 95% CI: 1.2-2.3) (p=0.010) for the IG and I arms, respectively. There was no difference in terms of median overall survival between the two arms (6.8 months and 4.6 months for the IG and I arm, respectively). The most frequent toxicities were grade III/IV neutropenia and grade III/IV diarrhea. CONCLUSIONS: Although the IG regimen seems to be more active than the I monotherapy, the premature closure of the study prevents the drawing of definitive conclusions.

Pooled analysis of elderly patients with non-small cell lung cancer treated with front line docetaxel/gemcitabine regimen: the Hellenic Oncology Research Group experience.

INTRODUCTION: Thirty to 40% of patients with non-small cell lung cancer (NSCLC) are older than 70 years and rarely are enrolled in clinical trials. Moreover, in clinical practice, > 75% of patients older than 65 years with metastatic NSCLC never receive any kind of chemotherapy. PURPOSE: To retrospectively evaluate the impact of age on efficacy and toxicity of chemotherapy regimens in patients with advanced NSCLC treated with the docetaxel-gemcitabine combination. PATIENTS AND METHODS: Pooled data from six clinical trials of the Hellenic Oncology Research Group were analyzed. According to their age, patients were divided into two groups: those with age < 70 years and those with > or = 70 years. RESULTS: A total of 858 patients were included in this analysis. Six hundred sixty-six (77.6%) patients were younger than 70 years, whereas 192 (22.4%) patients where > or = 70-year-old. Overall response rate was 30.3% and 30.2% for patients < 70 years and > or = 70 years, respectively (p = 0.974). The median time to tumor progression was 4.1 and 4.5 months for patients < 70 years and > or = 70 years, respectively (p = 0.948). Median overall survival was 9.9 and 9.2 months for patients < 70 and > or = 70, respectively (p = 0.117). The multivariate analysis revealed performance status (PS) (p = 0.0001) and stage (p = 0.0001) as independent factors with significant impact on the hazard of death. Chemotherapy was well tolerated, but the incidence of grade III/IV mucositis was significantly higher in elderly patients (0.2% versus 1.5% for patients < 70 versus > or = 70 years, respectively; p = 0.011). CONCLUSION: The docetaxel/gemcitabine regimen has a comparable efficacy and tolerance in young (< 70 years) and elderly (> or = 70 years) patients.

Predictive value of D-dimer plasma levels in response and progressive disease in patients with lung cancer.

Patients with cancer may present with one or more circulatory markers of haemostatic activation which may be associated with tumor growth and cancer cell dissemination. In our clinical practice we observed haemostatic abnormalities with or without thrombotic episodes in cancer patients. The aim of the present study was to detect the D-dimer plasma levels in advanced-stage lung cancer patients before, during and after chemotherapy, and to determine whether there is a correlation with response rate, disease recurrence and survival, in order to estimate the possible predictive value of D-dimer plasma levels. Forty-seven/52 patients were evaluable and analysed; 38 patients had non-small-cell lung cancer (NSCLC) and 9 small-cell lung cancer (SCLC) and all were at an advanced stage or inoperable. Two (4.3%) achieved complete response (CR), 17 (36.2%) partial response (PR), and 16 (34%) had progressive disease (PD). We found that 14/19 (73.7%) patients with CR or PR showed a reduction in D-dimer plasma values and 11/16 (68.8%) with PD showed increased values; also, in patients with recurrent disease (12/13, 92.3%), D-dimer plasma levels were increased. All of the above values were statistically significant. D-Dimer plasma levels decrease or increase after response and progressive disease, respectively, and can act as a predictive factor of the evolution of the disease.

Sequential versus alternating administration of cisplatin/etoposide and topotecan as first-line treatment in extensive-stage small-cell lung cancer: preliminary results of a Phase III Trial of the Hellenic Oncology Research Group.

BACKGROUND: This trial was designed to compare the efficacy and toxicity of sequential versus alternating administration of cisplatin/etoposide and topotecan in patients with previously untreated extensive-stage small-cell lung cancer (SCLC). PATIENTS AND METHODS: Two hundred eighty-four chemotherapy-naive patients were randomized between the sequential therapy arm (n=142; 4 cycles of cisplatin 75 mg/m2 intravenously [I.V.] on day 1 with etoposide 100 mg/m2 per day I.V. on days 1-3 followed by 4 cycles of topotecan 1.5 mg/m2 per day I.V. on days 1-5) and the alternating arm (n=142; same doses of cisplatin/etoposide on cycles 1, 3, 5, and 7 and topotecan on cycles 2, 4, 6, and 8). Treatment cycles for both regimens were administered every 3 weeks. RESULTS: At this preliminary analysis, no statistically significant difference in the overall response rate, duration of response, time to disease progression, or median survival was observed between the 2 arms. A total of 756 cycles of the sequential therapy and 830 cycles of the alternating therapy were administered, with a median numbers of 6 and 7 cycles per patient, respectively. Topotecan was administered in 85 patients on the sequential arm and 132 patients on the alternating arm. Dose reductions for toxicity were similar in both arms. Grade 3/4 toxicities in the sequential and alternating arms, respectively, included neutropenia (51% and 52%; P=NS), anemia (12% and 11%; P=NS), febrile neutropenia (7% and 9%; P=NS), thrombocytopenia (19% and 20%; P=NS), and asthenia (8% and 2%; P=0.02). There were 4 toxicity-related deaths in the sequential arm versus 3 in the alternating arm. CONCLUSION: Our preliminary conclusion is that the sequential and alternating regimens resulted in comparable activity and tolerability in previously untreated patients with extensive-stage SCLC.

A multicenter phase II study of the combination of irinotecan and gemcitabine in previously treated patients with small-cell lung cancer.

OBJECTIVE: To evaluate efficacy and toxicity of the combination of irinotecan and gemcitabine in pretreated patients having small-cell lung cancer. PATIENTS AND METHODS: Thirty-one patients (median age 60 years, performance status 0-1 in 87% and 2 in 13% of the patients) with limited or extensive-stage disease, refractory or relapsing after at least one prior chemotherapy regimen, received gemcitabine 1,000 mg/m(2) on days 1 and 8 and irinotecan 300 mg/m(2) on day 8, every 21 days. Sixteen (52%) patients had sensitive and 15 (48%) refractory disease. Fifteen patients (48%) had received > or =2 prior regimens. RESULTS: All patients were evaluable for toxicity and 26 for response analysis. A median of three (range 1-6) cycles per patient was administered. Three partial responses were documented for an overall response rate of 10% (95% CI 0.73-20.09), and disease stabilization was obtained in 7 patients (22%; intention-to-treat analysis). Two of the responders had refractory, and 1 had sensitive disease. The median time to progression was 4.5 months, the median duration of responses was 2.5 months, and the median survival time was 6 months. Grade 3-4 (WHO) neutropenia was observed in 9 patients (29%), grade 3-4 thrombocytopenia in 4 (13%), and grade 3-4 diahrrea in 3 patients (10%). Three patients experienced febrile neutropenia. No toxic deaths occurred. CONCLUSIONS: The combination showed modest activity in this patient group with a poor prognosis. Thus we believe it merits further investigation in the treatment of patients with small-cell lung cancer who have failed one prior chemotherapy regimen.