Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST).

BACKGROUND: The FAST is a 2 × 2 factorial trial addressing two questions: (1) the role of replacing cisplatin (P) with a non-platinum agent, vinorelbine (N), and (2) the role of adding a third agent, ifosfamide (I), in a doublet based on gemcitabine (G). METHODS: A total of 433 stage IIIB-IV non-small cell lung cancer (NSCLC) patients were randomised to one of four arms: gemcitabine-cisplatin (GP), gemcitabine-vinorelbine, gemcitabine-ifosfamide-cisplatin or gemcitabine-ifosfamide-vinorelbine. Two comparisons were performed: N- vs P-containing regimens and I-triplets vs non-I doublets. RESULTS: For N- vs P-containing regimens, adjusted overall survival was 9.7 vs 11.3 months (P=0.044), progression-free survival was 4.9 vs 6.4 months (P=0.020) and response rate was 24% vs 31% (P=0.124), respectively. No statistically significant difference was observed between doublets and triplets. Grade 3-4 haematological toxicity was significantly more frequent in P-containing therapy; grade 3-4 leucopenia was significantly more common in triplets. Concerning non-haematological toxicity, grade 3-4 nausea-vomiting was significantly increased in P-containing regimens. CONCLUSIONS: This trial provides evidence of a slight survival superiority of GP-containing regimens over platinum-free N-containing chemotherapy. This trial also confirms that the addition of a third chemotherapy agent (I) to a standard G-based doublet does not improve treatment outcome.

Epirubicin/paclitaxel/etoposide in extensive-stage small-cell lung cancer: a phase I-II study.

The aim of this study was to evaluate feasibility and toxicity of escalating doses of epirubicin and paclitaxel plus fixed dose of etoposide and to define the activity of the triplet in extensive disease small-cell lung cancer. Thirteen patients entered the phase I study: the maximum tolerated doses were epirubicin (EpiDX) 90 mg m-2 and paclitaxel (P) 175 mg m-2 with febrile neutropenia as dose-limiting toxicity. The recommended schedule for this regimen for the phase II study was EpiDX 75 mg m-2, P 175 mg m-2, etoposide (E) 100 mg m-2 intravenous (fixed dose) days 1-3 with courses repeated every 21 days. The prophylactic use of colony-stimulating factors (CSFs) was not allowed. Twenty patients entered the phase II trial: median age was 61 years (range 50-70), median Eastern Cooperative Oncology Group performance status 0 (0-2); nine patients had visceral disease and 17 had more than two metastatic sites. A total of 100 courses were administered with a median of 5 (range 1-6) per patients. Main toxicity (NCI-CTC) was myelosuppression: neutropenia grades 3 and 4 in 16 and 35% of the courses, respectively. Seven episodes of febrile neutropenia were documented and one patient required hospital admission. Nonhaematological toxicity was moderate. Seven out of 19 evaluable patients achieved a complete response (37%), nine patients (47.3%) a partial response with an overall response rate of 84.2% (95% confidence interval=60.4-96.6). In this poor prognostic population of patients the triplet epirubicin/paclitaxel/etoposide showed high antitumour activity with mild nonhaematological side effects. The use of CSFs should be able to improve the haematological profile.

Gemcitabine, Ifosfamide and Navelbine (GIN): activity and safety of a non-platinum-based triplet in advanced non-small-cell lung cancer (NSCLC).

To evaluate activity and toxicity of a non platinum-based triplet including Gemcitabine, Ifosfamide and Navelbine (GIN) in advanced NSCLC. Stage IIIB/IV NSCLC patients with WHO PS < 2 and bidimensionally measurable disease entered the study. Gemcitabine 1000 mg/sqm day 1 and 1000-800 mg/sqm day 4, Ifosfamide 3 g/sqm day 1 (with Mesna), Navelbine 25 mg/sqm day 1 and 25-20 mg/sqm day 4 were administered intravenously every 3 weeks. Objective responses (ORs) were evaluated every 2 courses: a maximum of 6 courses were administered in responding patients. According to Simon's optimal two-stage design more than 18 ORs out of 54 patients were required to establish the activity of this regimen. Fifty patients entered the study. Main characteristics of the 48 evaluated patients were: median age 63 years, ECOG performance status 0 = 65%, stage IV disease 79% and non-squamous histology 71%. The total number of courses administered was 200, median per patient 4 (range 1-6). Toxicities were evaluated according to WHO criteria: neutropenia grade 3-4 occurred in 47% of the courses; thrombocytopenia grade 3-4 in 6.6%; anaemia grade 3 in 3.5%. Twelve episodes of febrile neutropenia were reported and three patients required hospital admission. No toxic death was reported. Non-haematological toxicity, including skin rash, alopecia and fatigue, were generally. Twenty-five ORs (1 complete response and 24 partial responses) were obtained for a response rate of 52% (95% CI: 37.4-66.5%). One-year survival was 46.5%. This non-platinum-based outpatient triplet showed promising activity against NSCLC with myelosuppression, in particular neutropenia, being dose-limiting. The GIN regimen may represent a valuable alternative to standard platinum-based doublets and triplets in the treatment of advanced NSCLC and further studies with this platinum-free combination are warranted.

Multicenter randomized phase III trial of epirubicin plus paclitaxel vs epirubicin followed by paclitaxel in metastatic breast cancer patients: focus on cardiac safety.

The aim of the study was to evaluate cardiac safety of two different schedules of Epirubicin and Paclitaxel in advanced breast cancer patients enrolled into a multicenter randomized phase III trial. Patients received Epirubicin 90 mg m(-2) plus Paclitaxel 200 mg m(-2) (3-h infusion) on day 1 every 3 weeks for eight courses (arm A), or Epirubicin 120 mg m(-2) on day 1 every 3 weeks for four courses followed by four courses of Paclitaxel 250 mg m(-2) on day 1 every 3 weeks (arm B). Left ventricular ejection fraction was evaluated by bidimesional echocardiography at baseline, after four and eight courses of chemotherapy and every 4 months during follow-up. Baseline median left ventricular ejection fraction was 60% in arm A and 65% in arm B; after four courses, figures were 57 and 60%, respectively. After eight courses, the median left ventricular ejection fraction in arm A declined to 50% while no further reduction was detected in arm B by adding four courses of high-dose Paclitaxel. Seven episodes of congestive heart failure were observed during treatment in arm A. Present monitoring demonstrated that the risk of congestive heart failure or impairment in the cardiac function correlated only with the cumulative dose of Epirubicin; no impact on cardiotoxicity can be attributed to high-dose Paclitaxel.

Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase III trial in locally advanced breast cancer.

BACKGROUND: The purpose of this study was to evaluate the impact of a dose-dense primary chemotherapy on pathological response rate (pCR) in patients with locally advanced breast cancer (LABC) treated with combined modality therapy. PATIENTS AND METHODS: Stage IIIA/IIIB patients received three courses of induction chemotherapy (ICT) with cyclophosphamide, epirubicin and 5-fluorouracil (CEF) followed by local therapy (total mastectomy or segmental mastectomy with axillary nodes dissection) and adjuvant chemotherapy (ACT) with three courses of CEF alternated with three courses of cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Patients were randomized to receive ICT and ACT every 3 weeks (arm A, 'standard treatment') or every 2 weeks with granulocyte-macrophage colony-stimulating factor (GM-CSF) support (arm B, 'dose-dense treatment'). In both arms radiotherapy was administered after the end of chemotherapy (in selected cases) and patients with hormonal receptor-positive tumors received tamoxifen for 5 years. RESULTS: A total of 150 patients were randomized (77 arm A and 73 arm B) and demographics were well balanced between the two arms. Compliance to treatment was excellent: 95% and 93% of patients in arms A and B, respectively, completed the treatment program with no modification or delay. Median duration of treatment (ICT+local+ACT) was 183 days (range 0-265) in arm A and 139 days (0-226) in arm B. The average relative dose intensity (ARDI) of chemotherapy was 1.3 with a 30% increase in the dose intensity in arm B in comparison with arm A. No difference in clinical [62%; 95% confidence interval (CI) 49% to 73.2%] and pathological response rates to ICT was observed between the two arms. Median follow-up was 5 years (range 1-96 months); median disease-free survivals were 4.8 years in arm A and 4.5 years in arm B. Median overall survival was 7.8 years in standard therapy: this figure has not yet been reached in the dose-dense treatment. CONCLUSIONS: In LABC a dose-dense regimen, while allowing a 30% increase in the dose intensity of chemotherapy, did not provide significant improvement in pathological response rates. However, accelerated chemotherapy reduced the duration of the combined-modality program (6.1 versus 4.6 months) with no additional toxicities.