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.

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.

Α multicenter phase II study of pegylated liposomal doxorubicin in combination with irinotecan as second-line treatment of patients with refractory small-cell lung cancer.

PURPOSE: To evaluate efficacy and toxicity of a combination of pegylated liposomal doxorubicin and irinotecan in patients with refractory small-cell lung cancer. PATIENTS AND METHODS: Thirty-one patients with early relapse after first-line therapy with cisplatin/etoposide were treated with pegylated liposomal doxorubicin 15 mg/m(2) and irinotecan 125 mg/m(2) on days 1 and 15. Treatment was repeated every 28 days. RESULTS: A total of 144 chemotherapy courses were administered. All patients were evaluable for toxicity and twenty-six (84%) for response. Grade 3 neutropenia occurred in two (6.5%) patients and grade 1 thrombocytopenia in one (3.2%). Fatigue was the most frequent grade 3 non-hematologic toxicity and was observed in seven patients (23%). Four (12.9; 95% CI: 1.1-24.7%) patients achieved a partial response, and disease stabilization was observed in additional two (6.5%) patients (Tumor Growth Control: 19.4; 95% CI: 5.5-33.3%). The median TTP was 2.03 months, and the median survival time was 3.16 months. CONCLUSIONS: The combination of pegylated doxorubicin and irinotecan is very well tolerated but with modest activity in patients with refractory SCLC.

Salvage treatment in metastatic breast cancer with weekly paclitaxel and bevacizumab.

BACKGROUND: Weekly paclitaxel (P) in combination with bevacizumab (B) is an effective regimen as initial treatment of metastatic breast cancer (MBC). We investigated in a phase II study the activity of the same regimen as salvage therapy in MBC. METHODS: Pretreated women with MBC received weekly P (90 mg/m(2) days 1, 8, 15) and B (10 mg/kg days 1, 15) every 28 days. B could continue after discontinuing P until disease progression. This was second-line chemotherapy for 30% and third-line or more for 70% of patients. RESULTS: A total of 40 patients were enrolled. Median age: 61 (range 32-80) years; postmenopausal: 80%; baseline ECOG performance status <2 in 80% of patients. Two patients (5%) achieved complete response, 10 (25%) partial response (overall response rate 30%; 95% CI 15.8-44.2), and 10 (25%) stable disease. The response rate was 28% for the patients who had previously received taxanes. After a median follow-up of 20.6 months, the median time to progression was 4.8 months (95% CI 1.7-7.8), median survival 13.0 months (95% CI 10.3-15.7), and the probability of 1-year survival 55.5%. Main grade 3-4 toxicities were neutropenia 42.5%, febrile neutropenia 5%, and asthenia 10%. There was one toxic death due to sepsis. CONCLUSION: The PB regimen is well tolerated and active as salvage therapy in pretreated women with MBC. It could be an effective option even for patients exposed to taxanes during prior treatments.

A dose-escalation study of pemetrexed and docetaxel in non-small-cell lung cancer.

A phase I study was conducted to determine the maximum tolerated doses (MTD) and the dose-limiting toxicities (DLT) of pemetrexed and docetaxel in patients with advanced unresectable or metastatic non-small-cell lung cancer (NSCLC). Patients were treated with escalating doses of pemetrexed (400-600 mg/m(2) as a 10-min intravenous infusion) and docetaxel (65-85 mg/m(2) as a 1-h intravenous infusion) on day 1, every 3 weeks. An expanded accrual at the level of the recommended dose (RD) had been scheduled. Forty-two patients with metastatic NSCLC were enrolled in the phase I study and 20 additional patients at the RD level. The MTD could not be reached even at the doses of 550 and 85 mg/m(2) for pemetrexed and docetaxel, respectively, which are higher than the recommended dose for each drug given as a single agent. Therefore, the RD was defined at 500 mg/m(2) pemetrexed and 75 mg/m(2) docetaxel. Among the 164 administered chemotherapy cycles (phase I part), there were three episodes of febrile neutropenia whereas 13 (7.9%) and 11 (6.7%) cycles were complicated with grade III and IV neutropenia, respectively. Three patients developed grade III/IV thrombocytopenia. Non-hematologic toxicity was mild with grade III fatigue occurring in three (6.7%) patients. There was no toxic death. The favorable toxicity profile of the regimen was confirmed in patients treated at the RD level. Overall, one complete (CR) and 13 partial responses (PR) (overall response rate = 23; 95% C.I:12.4-33.5%] were documented. The combination of pemetrexed and docetaxel seems to be an effective regimen in NSCLC with acceptable and manageable toxicity, which merits further investigation.

Clinical outcome of patients with non-small cell lung cancer receiving front-line chemotherapy according to EGFR and K-RAS mutation status.

BACKGROUND: Somatic mutations in EGFR and K-RAS may predict for sensitivity and resistance to EGFR tyrosine kinase inhibitors (TKIs). Whether EGFR and K-RAS mutations could also predict clinical outcome of non-small cell lung cancer (NSCLC) patients following front-line chemotherapy has not yet been established. PATIENTS AND METHODS: One hundred and sixty-two chemotherapy-naïve patients with locally advanced/metastatic NSCLC who received front-line chemotherapy were included in this retrospective study and their clinical outcome data was analyzed according to EGFR and K-RAS mutation status of their tumors. RESULTS: Classical activating EGFR and K-RAS mutations were found in 8.2 and 22.6% of patients respectively and were not associated with patients' clinicopathological characteristics. Patients with classical EGFR mutations had a higher probability of response to front-line chemotherapy as compared to those with wild type EGFR (p=0.023). Multivariate analysis showed that the presence of activating EGFR mutations was an independent factor associated with response to front-line chemotherapy (HR=4.85; 95% CI: 1.13-20.83, p=0.034). K-RAS mutation status was not associated with response to front-line chemotherapy. The presence of activating EGFR but not of K-RAS mutations was associated with a significantly higher overall survival compared to patients without mutations treated with platinum-based front-line chemotherapy (p=0.043). CONCLUSIONS: The data indicate that EGFR mutation status could be predictive for response to cytotoxic front-line chemotherapy in patients with NSCLC. Additional prospective studies are needed in order to validate this observation and to define whether these patients should be preferentially treated with front-line TKIs or chemotherapy.