Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial
Rosell R.,Catalan Institute of Nanoscience and Nanotechnology |
Rosell R.,University of Barcelona |
Carcereny E.,Catalan Institute of Nanoscience and Nanotechnology |
Gervais R.,Center Francois Baclesse |
And 55 more authors.
The Lancet Oncology | Year: 2012
Background: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. Methods: We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (>18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m 2 on day 1 plus docetaxel (75 mg/m 2 on day 1) or gemcitabine (1250 mg/m 2 on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m 2 or AUC 5 with gemcitabine 1000 mg/m 2) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. Findings: Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p<0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. Interpretation: Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. Funding: Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer. © 2012 Elsevier Ltd.
Grossi F.,Instituto Nazionale per la Ricerca sul Cancro |
De Marinis F.,Ospedale S. Camillo Forlanini |
Gebbia V.,Casa di Cura la Maddalena |
Riccardi F.,Ospedale Cardarelli |
And 8 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2012
Purpose: The aim of this study was to determine the activity and toxicity of two sequential chemotherapy regimens in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). Methods: Eighty-eight chemonaive patients with stage IIIB/IV NSCLC were randomised to receive either three cycles of 75 mg/m2 cisplatin plus 75 mg/m2 docetaxel, both administered on day 1 every 21 days, followed by three cycles of 1,200 mg/m2 gemcitabine on days 1 and 8 every 3 weeks (arm A), or three cycles of 25 mg/m2 cisplatin plus 25 mg/m2 docetaxel on days 1, 8 and 15 every 28 days, followed by three cycles of 1,200 mg/m2 gemcitabine on days 1 and 8 every 3 weeks (arm B). Results: Of the evaluable patients, 61% in arm A (n = 41) and 36% (n = 44) in arm B completed treatment as per the protocol. The best tumour response rates were as follows (arm A and arm B): complete response: 2.4 and 2.3%; partial response: 39 and 20.4%; stable disease: 26.8 and 13.6%; and progressive disease: 31.8 and 45.4%. The median progression-free and overall survival were 3.9 and 12.3 months in arm A, respectively, 3.1 and 7.7 months in arm B. Grade 3-4 adverse events were more common in arm A. Grade 3-4 neutropenia was the main toxicity observed (56.1% in arm A and 11.4% in arm B). Conclusions: Our data demonstrate the feasibility of a sequential approach of cisplatin plus docetaxel followed by single-agent gemcitabine. Weekly administration of platinum-docetaxel is associated with an improved safety profile but lower efficacy than the conventional three-weekly schedule (registration ID 2004-001044-72). © 2011 Springer-Verlag.
Gridelli C.,Azienda Ospedaliera S. Giuseppe Moscati |
Ardizzoni A.,Azienda Ospedaliera Universitaria di Parma |
Barni S.,Azienda Ospedaliera Treviglio Caravaggio |
Crino L.,Azienda Ospedaliera di Perugia |
And 16 more authors.
Lung Cancer | Year: 2011
Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and the majority of people diagnosed with NSCLC have locally advanced or metastatic disease. Treatment algorithms have rapidly changed in the last 10 years because of the introduction of new chemotherapeutic and targeted agents in clinical practice. SUN is a 1-year longitudinal observational multicenter study that has consecutively enrolled patients affected by stage IIIB or IV NSCLC with the aim to describe the pattern of care and evolving approaches in the treatment of advanced NSCLC. 987 consecutive NSCLC patients were enrolled between January 2007 and March 2008 at the 74 participating centers throughout Italy and a 12-month follow-up was performed. Cyto-histological diagnosis was performed mainly by broncoscopy with only 24% by CT-scan guided fine-needle aspiration biopsy. 91.4% of the patients received a first-line medical treatment and 8.6% supportive care only. Median age of patients receiving first-line treatment was 66 years. First-line chemotherapy consisted of a single agent in 20% of patients and combination chemotherapy in 80%. The most frequently used chemotherapy regimens were cisplatin plus gemcitabine and carboplatin plus gemcitabine. Median survival of patients receiving first-line chemotherapy was 9.1 months. 32% percent of patients received a second-line treatment that consisted of chemotherapy in 71% of cases and erlotinib in 29%. Overall third-line treatment was given to 7.3% of patients. These results showed a pattern of care for advanced NSCLC that reflects the current clinical practice in Italy at the study time with a high adherence to the International guidelines by the Italian Oncologists. © 2011 Elsevier Ireland Ltd.
Pignata S.,Instituto Nazionale Tumori |
Scambia G.,Catholic University of the Sacred Heart |
Ferrandina G.,Catholic University of the Sacred Heart |
Savarese A.,Instituto Nazionale Tumori Regina Elena |
And 26 more authors.
Journal of Clinical Oncology | Year: 2011
Purpose Carboplatin/paclitaxel is the standard first-line chemotherapy for patients with advanced ovarian cancer. Multicentre Italian Trials in Ovarian Cancer-2 (MITO-2), an academic multicenter phase III trial, tested whether carboplatin/pegylated liposomal doxorubicin (PLD) was more effective than standard chemotherapy. Patients and Methods Chemotherapy-naive patients with stage IC to IV ovarian cancer (age ≤ 75 years; Eastern Cooperative Oncology Group performance status ≤ 2) were randomly assigned to carboplatin area under the curve (AUC) 5 plus paclitaxel 175 mg/m2 or to carboplatin AUC 5 plus PLD 30 mg/m2, every 3 weeks for six cycles. Primary end point was progression-free survival (PFS). With 632 events in 820 enrolled patients, the study would have 80% power to detect a 0.80 hazard ratio (HR) of PFS. Results Eight hundred twenty patients were randomly assigned. Disease stages III and IV were prevalent. Occurrence of PFS events substantially slowed before obtaining the planned number. Therefore, in concert with the Independent Data Monitoring Committee, final analysis was performed with 556 events, after a median follow-up of 40 months. Median PFS times were 19.0 and 16.8 months with carboplatin/PLD and carboplatin/paclitaxel, respectively (HR, 0.95; 95% CI, 0.81 to 1.13; P = .58). Median overall survival times were 61.6 and 53.2 months with carboplatin/PLD and carboplatin/paclitaxel, respectively (HR, 0.89; 95% CI, 0.72 to 1.12; P = .32). Carboplatin/PLD produced a similar response rate but different toxicity (less neurotoxicity and alopecia but more hematologic adverse effects). There was no relevant difference in global quality of life after three and six cycles. Conclusion Carboplatin/PLD was not superior to carboplatin/paclitaxel, which remains the standard first-line chemotherapy for advanced ovarian cancer. However, given the observed CIs and the different toxicity, carboplatin/PLD could be considered an alternative to standard therapy. © 2011 by American Society of Clinical Oncology.
Gridelli C.,Sg Moscati Hospital |
Ciardiello F.,The Second University of Naples |
Gallo C.,The Second University of Naples |
Butts C.,Cross Cancer Institute |
And 21 more authors.
Journal of Clinical Oncology | Year: 2012
Purpose: Erlotinib prolonged survival of unselected patients with advanced non-small-cell lung cancer (NSCLC) who were not eligible for further chemotherapy, and two phase II studies suggested it might be an alternative to first-line chemotherapy. A randomized phase III trial was designed to test whether first-line erlotinib followed at progression by cisplatin-gemcitabine was not inferior in terms of survival to the standard inverse sequence. Patients and Methods: Patients with stage IIIB (with pleural effusion or supraclavicular nodes) to IV NSCLC and performance status of 0 to 1 were eligible. With a 95% CI upper limit of 1.25 for the hazard ratio (HR) for death, 80% power, a one-sided α = .025, and two interim analyses, a sample size of 900 patients was planned. Results: At the first planned interim analysis with half the events, the inferiority boundary was crossed, and the Independent Data Monitoring Committee recommended early termination of the study. Seven hundred sixty patients (median age, 62 years; range, 27 to 81 years) had been randomly assigned. Baseline characteristics were balanced between study arms. As of June 1, 2011, median follow-up was 24.3 months, and 536 deaths were recorded (263 in the standard treatment arm and 273 in the experimental arm). Median survival was 11.6 months (95% CI, 10.2 to 13.3 months) in the standard arm and 8.7 months (95% CI, 7.4 to 10.5 months) in the experimental arm. Adjusted HR of death in the experimental arm was 1.24 (95% CI, 1.04 to 1.47). There was no heterogeneity across sex, smoking habit, histotype, and epidermal growth factor receptor (EGFR) mutation. Conclusion: In unselected patients with advanced NSCLC, first-line erlotinib followed at progression by cisplatin-gemcitabine was significantly inferior in terms of overall survival compared with the standard sequence of first-line chemotherapy followed by erlotinib. © 2012 by American Society of Clinical Oncology.
Morabito F.,UOC di Ematologia |
Hohaus S.,University Cattolica ore |
Mammi C.,U.O. Genetica |
Marcheselli L.,University of Modena and Reggio Emilia |
And 11 more authors.
Leukemia and Lymphoma | Year: 2012
Polymorphisms of the Glutathione-S Transferase (GST) family may influence the prognosis in lymphoma patients. We aimed to validate the impact of GSTT1 and GSTM1 deletions and of the GSTP1Ile105Val polymorphism on outcome and toxicity in 140 patients with advanced Hodgkin's lymphoma enrolled in the prospective multicenter HD2000-GISL trial, comparing ABVD, BEACOPP and CEC regimens. Carriers of the GSTP1Ile105Val polymorphism had a higher rate of grade 3-4 anemia following treatment. Overall, our study failed to validate GST genotyping as prognostic factor for progression-free survival (PFS). Only the small cohort of patients with an international prognostic score (IPS) >3 and undeleted GSTT1 and/or GSTM1, treated with ABVD had worse progression-free survival (PFS) (GSTT1 + vs GSTT1-: HR 5.02, 95% C.I., 1.1621.8, p = 0.031, GSTM1 + /GSTT1 + vs GSTM1-and/or GSTT1-: HR 4.61, 95% C.I. 1.28 16.6, p = 0.019, respectively). No differences were observed for patients treated with intensified regimens, as BEACOPP and CEC. In conclusion, the prognostic role of GST polymorphism, if at all, is limited to a small subgroup of patients treated with standard ABVD regimen. © 2012 Informa UK, Ltd.
Camarda L.,University of Palermo |
D'Arienzo M.,University of Palermo |
Patera G.P.,Casa di Cura La Maddalena |
Filosto L.,Casa di Cura La Maddalena |
LaPrade R.F.,Steadman Philippon Research Institute
Knee Surgery, Sports Traumatology, Arthroscopy | Year: 2011
Purpose: The purpose of this study was to evaluate the risk of tunnel collisions of the fibular collateral ligament (FCL) and posterolateral bundle anterior cruciate ligament (PLB-ACL) tunnels during a combined FCL and double-dundle (DB) ACL reconstruction. Methods: Thirty-six 4th-generation synthetic femurs (Sawbones, Pacific Research Laboratories, Vashon, WA) were utilized, and two different femur sizes were used. A FCL tunnel and a PLB-ACL tunnel were reamed on each femur. The tunnels of synthetic specimens that did not have a collision were filled with an epoxy resin augmented with BaSO4 and radiographic evaluation, and Multidetector CT exams of the specimens were performed. Results: The rate of tunnel collision when the FCL tunnel was reamed to a depth of 30 mm was 75 and 69.4% for the 25 mm depth. There was a significantly increased risk of tunnel collision when the FCL tunnel was reamed proximally with coronal angulations of 20° and 40°. No collisions were noted when the FCL tunnel was reamed parallel to the distal condylar line and with axial angulations of 20° and 40°. Conclusion: This study provides new insight into tunnel positioning during a combined FCL and DB-ACL reconstruction. The results show that a concomitant FCL injury do not represent a contraindication to perform a DB-ACL reconstruction as long as the FCL tunnel is reamed with no proximal angulation and is directed anteriorly with an axial angulation between 20° and 40°. © 2010 Springer-Verlag.