Search

Aims: To date, precision medicine has revolutionized the clinical management of Non-Small Cell Lung Cancer (NSCLC). International societies approved a rapidly improved mandatory testing biomarkers panel for the clinical stratification of NSCLC patients, but harmonized procedures are required to optimize the diagnostic workflow. In this context a knowledge-based database (Biomarkers ATLAS, https://biomarkersatlas.com/) was developed by a supervising group of expert pathologists and thoracic oncologists collecting updated clinical and molecular records from about 80 referral Italian institutions. Here, we audit molecular and clinical data from n = 1100 NSCLC patients collected from January 2019 to December 2020., Methods: Clinical and molecular records from NSCLC patients were retrospectively collected from the two coordinating institutions (University of Turin and University of Naples). Molecular biomarkers (KRAS, EGFR, BRAF, ROS1, ALK, RET, NTRK, MET) and clinical data (sex, age, histological type, smoker status, PD-L1 expression, therapy) were collected and harmonized., Results: Clinical and molecular data from 1100 (n = 552 mutated and n = 548 wild-type) NSCLC patients were systematized and annotated in the ATLAS knowledge-database. Molecular records from biomarkers testing were matched with main patients' clinical variables., Conclusions: Biomarkers ATLAS (https://biomarkersatlas.com/) represents a unique, easily managing, and reliable diagnostic tool aiming to integrate clinical records with molecular alterations of NSCLC patients in the real-word Italian scenario., Competing Interests: Declaration of competing interest Umberto Malapelle has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientific, Eli Lilly, Diaceutics, GSK, Merck and AstraZeneca, Janssen, Diatech, Novartis and Hedera for work performed. Francesco Passiglia Francesco declared consultant/advisory fee from Astrazaneca, Janssen, Amgen, Sanofi, Brystol Myer Squibb, Merck Sharp and Dohne, Roche, Beigene, Novartis, Thermofisher Scientific. Pasquale Pisapia reports speaking fees from Novartis outside the submitted work. Diego Cortinovis has received personal fees (as consultant and/or speaker bureau) from Advisory Amgen, AstraZeneca, BMS, MSD, Novartis, Roche, Jannsen, Sanofi Genzyme.Domenico Galetta has received personal fees (as consultant and/or speaker bureau) from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, MSD, Novartis, Amgen, Roche for work performed outside of the current study. Paolo Graziano has received personal fees (as consultant and/or speaker bureau) from: Amgen, AstraZeneca, BMS, Eli Lilly, MSD, Novartis, Roche, Pfizer, Boehringer Ingelheim unrelated to the current work. Fabio Pagni has received personal fees (as consultant and/or speaker bureau) from Novartis, Roche, MSD, Amgen, GSK and AstraZeneca, for work performed outside of the current study. Giulia Pasello has received personal fees (as consultant and/or speaker bureau) from: Amgen, AstraZeneca, BMS, Eli Lilly, MSD, Novartis, Roche, Jannsen, AstraZeneca, Roche unrelated to the current work. Sara Pilotto reports personal fees (invited speaker, advisory board) from AstraZeneca, Eli-Lilly, Novartis, AMGEN, Takeda, Sanofi, Bristol Myers Squibb, MSD and Roche; and research grants from AstraZeneca, Bristol Myers Squibb and Roche outside the submitted work. Marcello Tiseo reports personal fees (as consultant and/or speaker bureau) from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, Amgen, Merck, Sanofi. M.T. He received institutional research grants from Astra-Zeneca, Boehringer Ingelheim un related to the current work. Luisella Righi declared consultant/advisory fee from AstraZeneca, Novartis, Roche, Eli Lilly and Boehringer Ingelheim. Giancarlo Troncone reports personal fees (as speaker bureau or advisor) from Roche, MSD, Pfizer and Bayer, unrelated to the current work. Silvia Novello reports personal fees (as speaker bureau or advisor) from Eli Lilly, MSD, Roche, BMS, Takeda, Pfizer, Astra Zeneca and Boehringer Ingelheim, unrelated to the current work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Sotorasib showed a significant improvement of progression free survival (PFS), safety and quality of life over docetaxel in patients with KRASp.G12C-mutated advanced non-small-cell lung cancer (NSCLC) within the CodeBreak-200 study. Here we report real-world efficacy and tolerability data from NSCLC patients who received sotorasib within the Italian expanded access program (EAP)., Methods: Sotorasib (960 mg, orally, once daily) was available on physician request for KRASp.G12C mutant advanced NSCLC patients. Clinical-pathological and molecular data were collected from the Italian ATLAS real-world registry. Patients underwent CT-scan and responses were evaluated by RECIST criteria. Efficacy and tolerability outcomes have been assessed., Results: A total of 196 advanced NSCLC patients were treated across 30 Italian centers. Median age was 69 years old (range 33-86). Most patients were male (61 %), former (49 %) or current smokers (43 %), with ECOG-PS 0/1 (84 %) and adenocarcinoma subtype (90 %). 45 % and 32 % of patients received sotorasib in 2nd and 3rd line, respectively. Overall, response rate was 26 % and the median duration of response was 5.7 months (95 % CI: 4.4-7.0). Median PFS and OS were 5.8 months (95 % CI: 5 - 6.5) and 8.2 months (95 % CI: 6.3 - 9.9). Grade 3-4 TRAEs occurred in 16.5 % of patients, with Grade ≥ 3 liver enzyme increase and TRAEs-related discontinuation reported in 12 % and 4.6 % of cases., Conclusion: Real-world data from the Italian EAP confirm the tolerability and effectiveness of sotorasib in patients with KRASp.G12C-mutated advanced NSCLC and highlight the value of the national ATLAS network as source of real-world evidence driving the clinical management of NSCLC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Pleomorphic lung carcinoma (PLC) is a rare histotype of non-small cell lung cancer (NSCLC) characterized by aggressive clinical course, poor response to therapy and poor prognosis. Therefore, aim of our study is to analyze with 18F-FDG PET/CT a subset of patients affected by PLC to evaluate their metabolic characteristics in terms of SUVmax, MTV and TLG, in order to correlate them with overall survival (OS) and disease-free survival (DFS)., Material and Methods: We retrospectively analyzed 49 consecutive patients with histologically defined PLC occurred to our Institution between 2003 and 2014. All patients underwent F18-FDG PET-CT before surgery and primary tumor was automatically segmented using an isocontour threshold method. SUV threshold for tumor segmentation was defined as the 41 % of lesion SUVmax. Total volume of the segmented VOI (MTV, centimeters cubed) and average SUV (SUVavg, grams per milliliter) in the segmented VOI were measured., Results: In our population men were significantly more affected than women (42:7). According to Youden criteria, SUVmax, MTV41 and TLG41 best cut-off values to predict 2-year mortality were, 18.95, 27.89 and 290.45, respectively, with TLG41 showing best specificity (85 %) and positive predictive value (82.4 %). As concerning 2-year recurrence, SUVmax, MTV41 and TLG41 best cut-off values were 10.08, 27.89 and 134.85, with SUVmax showing best sensitivity (96.7 %) and negative predictive value (85.7 %). ROC curves confirmed that SUVmax, MTV41 and TLG41 were equally accurate to predict 2-year mortality and 2-year recurrence in our population., Conclusion: Metabolic biomarkers such as SUVmax, MTV and TLG can be used as a prognostic index for disease progression, recurrence and death in patients with PLC, independently from other clinical/pathological prognostic elements., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Molecular diagnostics and care of non-small cell lung cancer (NSCLC) are continuously evolving. Few data document the current strategies to manage advanced NSCLC patients beyond progression in clinical practice., Patients and Methods: Be-TeaM is an Italian multi-center observational study conducted on consecutive EGFR-mutated stage IV NSCLC patients, progressed during/after a first-line EGFR-TKI. It consists of a retrospective phase, from first-line EGFR-TKI therapy start until study entry (i.e. beginning of the diagnostic process), and a prospective phase, until treatment choice or for 3 months if no therapy was prescribed. Primary objective was to describe the diagnostic and therapeutic approaches adopted after progression in a real-world setting., Results: Of 308 patients enrolled in 63 centers from July 2017 to June 2018, 289 were included in the analysis. In first line, 53.3 % received gefitinib, 32.5 % afatinib and 14.2 % erlotinib. The testing rate (i.e. rate of all patients undergone any biopsy -liquid and/or tissue- for the T790 M detection) was 90.7 %, with liquid biopsy being the most frequently executed. Of 262 biopsied patients, 64.5 % underwent only 1 liquid biopsy, 10.7 % only 1 tissue biopsy and 18.3 % >1 biopsy, both liquid and solid in 85.4 %. The T790M positivity rate was 45.3 %; of 166 patients undergone only a liquid biopsy and tested for the mutation, 39.8 % were T790M+ and 60.2 % T790M-/undetermined. By the observation end, 87.9 % patients had a post-progression treatment chosen, osimertinib being the most frequent among the T790M+., Conclusion: Be-TeaM provides the first snapshot of current practices for the management of NSCLC patients beyond progression in Italy; in clinical practice, assessing the T790M status is not always feasible., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: Considering the frequent expression of somatostatine receptors, we designed the G04.2011 trial to investigate the efficacy of the somatostatine analogue lanreotide in maintenance for SCLC patients after response to standard treatment., Materials and Methods: A multicenter, randomized, phase 3 trial was conducted in SCLC expressing somatostatine receptors at baseline Octreoscan, responding after platinum-based chemotherapy with/without radiotherapy. Patients were randomized 1:1 to receive maintenance lanreotide 120 mg subcutaneously every 28 days, up to 1 year or progression versus observation. Randomization was stratified according to stage (limited/extended, LD/ED). The primary end-point was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and safety., Results: Seventy-one patients were randomly assigned (39 to lanreotide, 32 to observation) in 9 Italian institutions. Median PFS was 3.6 (95% CI 3.2-3.9) with lanreotide versus 2.3 months (95% CI 1.7-2.9) with observation (HR 1.51, 95% CI 0.90-2.50; P = 0.11). Stage was an independent predictor for PFS (HR 3.14, 95% CI 1.77-5.57; P < 0.0001). Median PFS was 7.0 (95% CI <1-13.5) with lanreotide versus 3.8 months (95% CI <1-8.6) with observation in LD (P = 0.21), and 3.0 (95% CI 2.2-3.8) versus 2.2 (95% 1.7-2.7) in ED (P = 0.19). Median OS was 9.5 (95% CI 4.8-14.3) with lanreotide versus 4.7 months (95% CI <1-16.6) with observation (P = 0.47). Treatment-related adverse events occurred in 28% of patients with lanreotide (grade 3 in two patients)., Conclusion: Although survival outcomes were not significantly prolonged with lanreotide as a maintenance in SCLC expressing somatostatin receptors after response to standard treatment, lanreotide showed a slight PFS benefit in LD SCLC deserving further investigations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Despite the scant docetaxel's tolerability, second-line association with nintedanib still represents a standard-of-care for non-squamous non-small cell lung cancer (nsNSCLC), giving to rapidly-progressing patients the greatest survival advantage. The SENECA trial is a phase IIb, open-label, study evaluating whether nintedanib/docetaxel can be equally effective and safe regardless docetaxel schedule., Materials and Methods: Recurrent nsNSCLC patients were stratified into cohort 1 and 2, according to relapse-time (within or over 3 months) from end of first-line chemotherapy. They were treated with docetaxel (T1: 33 mg/mq on days 1 and 8 in a 21-days cycle; T2: 75 mg/mq q3wks) plus nintedanib, allowing maintenance in case of disease-control. Primary endpoint was progression-free survival (PFS) by investigator's assessment; secondary endpoints: overall survival (OS), safety and quality-of-life., Results: Between January 2016-April 2018, 212 patients were evaluated: 30 resulted screening-failures, 12 were excluded for lack of compliance. According to investigator's choice, 85 patients received T1 docetaxel and 85 T2; 138 (81.2%) were stratified in C1, 32 (18.8%) in C2, with a median relapse-time of 0.54 and 9.29 months, respectively. Baseline characteristics were balanced between groups. After 35.5 months follow-up, no survival differences appear between cohorts and treatments; toxicity seems to be slightly higher in T2, especially for chemotherapy-related events. Perception of quality-of-life remains stable and docetaxel schedule doesn't modify patients' load., Conclusion: The SENECA trial confirms efficacy of second-line nintedanib/docetaxel for nsNSCLC, regardless time of recurrence and docetaxel schedule; higher toxicities for q3wks docetaxel, without alterations in quality-of-life, have been described, underling the possibility, adopting the weekly schedule, to maintain efficacy with better tolerability., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Molecular profiling of advanced non-small-cell lung cancer (NSCLC) is recommended according to European and Italian guidelines. However, molecular routine assessment remains still heterogeneous. This observational study aimed to take a picture of the real clinical practice in molecular testing and therapeutic choices in advanced Italian NSCLCs., Materials and Methods: This study prospectively enrolled newly diagnosed advanced or recurrent NSCLCs referred to 38 Italian centres, from November 2014 to November 2015. Information regarding molecular profiling and treatment choices were collected. Description of patients' outcome included overall survival (OS), progression-free survival in first (PFS1) and second-line (PFS2)., Results and Conclusion: Among 1787 patients enrolled, 1388 (78%) performed at least one molecular analysis during the history of disease: 76% were tested for EGFR, 53% for ALK, 27% for KRAS, 16% for ROS1, 14% for BRAF, 5% for HER2, 4% for MET and 1% for FGFR. The remaining 399 patients (22.3%) did not receive any molecular test. Among patients receiving at least one molecular analysis, 583 (42%) presented a molecular alteration. Considering EGFR mutated and/or ALK rearranged patients (402), for which target agents were routinely reimbursed at time of study in Italy, the 86% received a personalized treatment as first and/or second line: the 90% (286) of EGFR mutants received an EGFR tyrosine kinase inhibitor, mostly gefitinib (41.1%) or afatinib (36.4%) while 74% (62) of ALK translocated patients received an ALK inhibitor, mostly crizotinib (64%). Median OS was 9.34 months (95% CI 8.62-10.0), median PFS1 was 4.61 months (95%CI 4.31-4.84) and median PFS2 was 2.76 months (95%CI 2.57-3.19). In the Italian clinical practice, routine molecular assessment was largely applied in NSCLC patients, according to national guidelines, but a low level of ALK test was reached. Most of EGFR mutants an ALK rearranged patients received a personalized treatment as first and/or second line., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: TAS-102 is an oral combination treatment comprised of an antimetabolite, trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, at a molar ratio of 1:0.5. This antimetabolite has demonstrated efficacy in clinical trials, including a global phase 3 trial in metastatic colorectal cancer. As this agent has shown activity greater than cisplatin in small cell lung cancer xenograft mouse models, the objective of this study was to evaluate TAS-102 in the second-line treatment of small cell lung cancer., Methods: This was a multicenter, open-label, two-arm, randomized phase 2 study designed to compare oral TAS-102 (35mg/m(2)/dose twice daily) versus control (topotecan or amrubicin). Patients requiring second-line chemotherapy for treatment of small cell lung cancer, either refractory or sensitive to frontline platinum-based chemotherapy, were enrolled., Results: Eighteen patients were enrolled. Eight of nine patients receiving TAS-102 discontinued treatment due to progressive disease and one patient died due to clinical progression during the safety follow-up. Unplanned interim futility considerations were made, and the study was terminated early because it was unlikely that superiority of TAS-102 versus comparator could be demonstrated. Six control patients discontinued therapy due to progressive disease and one due to an adverse event. Median progression-free survival was 1.4 months (range 0.9-1.8) versus 2.7 months (range 1.0-6.8) for TAS-102 and control, respectively, with a hazard ratio of 3.76 (80% CI, 1.68-8.40) favoring control. The most common adverse events with TAS-102 were neutropenia, diarrhea, anemia, anorexia, and fatigue, each in three patients., Conclusion: TAS-102 showed no evidence of activity in second-line small cell lung cancer., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Non-small-cell-lung-cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations develop drug resistance after 9-12 months of EGFR tyrosine kinase inhibitors (TKIs) therapy pointing out the issue of the second-line treatment choice., Materials and Methods: From June 2009 until May 2013 patients affected by advanced NSCLC harbouring EGFR mutations receiving first-line TKI were collected mainly retrospectively in 24 Italian Centers. Primary objective was to describe the percentage of EGFR mutated patients receiving second-line therapy after progression to first-line EGFR-TKIs assessing the type, the activity in terms of objective response rate (ORR), efficacy in terms of progression free survival (PFS) and overall survival (OS), and safety of second-line treatment. Secondary objective was to describe the efficacy of first-line EGFR-TKIs., Results: 312 patients were included. Most of them were females (203, 65.1%), never smokers (200, 64.1%), with adenocarcinoma histology (290, 92.9%). The most common mutations were EGFR exon 19 deletion and L858R, detected in 186 and 97 cases (59.6% and 31.1%), respectively. At data cut-off, 274 patients (95.1%) received any second-line treatment (including best supportive care or local treatments only). A total of 163 patients received second-line systemic therapy with an ORR of 20.9% (95% CI:14.62-27.10), a median PFS and OS of 4.7 (95% CI:3.81-5.26) and 24.5 (95% CI:21.65-27.37) months, respectively. Grade 3-4 hematological and non-hematological toxicities were reported in 9% and 6.3% of 144 patients treated with chemotherapy while non-hematological toxicity was reported in 4 cases of the 17 patients receiving second-line target agents., Conclusions: BE-Positive is the first multicenter observational study reporting outcomes of therapies in a "real-life Caucasian EGFR-mutated population", highlighting the need of further researches about new treatment strategies in this setting., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Patients with small-cell lung cancer (SCLC) that progress after first-line chemotherapy have a poor prognosis and the evidence of a benefit from second-line (SL) chemotherapy is limited. Patients relapsing or progressing more than 90 days after completion of first-line treatment are considered platinum sensitive and may be rechallenged with platinum-based chemotherapy. Topotecan is approved as SL treatment independent of time to progression. This retrospective analysis evaluates the clinical outcomes of SCLC patients who received SL chemotherapy after platinum-etoposide chemotherapy., Patients and Methods: We retrospectively reviewed 161 patients who received SL chemotherapy for SCLC. Patients were divided into four subgroups by type of SL treatment: (1) platinum-based rechallenge; (2) anthracycline-based regimens; (3) topotecan; (4) other single agents. The endpoints were overall survival (OS), progression-free survival (PFS) and response rate (RR). Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival., Results: The median age was 63. There were 125 males and 36 females. Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0, 1 and 2 in 12.5%, 62.5% and 25% of patients, respectively. Platinum sensitive/platinum resistant/platinum refractory/unknown=121/29/3/8 patients. Median time to SL chemotherapy was 6.9 months. The median PFS from starting second-line treatment was 4.3 months and median OS was 5.8 months. The overall RR was 22.9%. There was a trend toward higher RR (34.5% vs 17.5%, p for trend: 0.06) and OS (9.2 months vs 5.8 months, p=0.08) for patients with sensitive disease who were rechallenged with platinum-based chemotherapy. A multivariate analysis that adjusted for the time to SL treatment showed that a platinum-containing regimen achieves better RR, PFS and OS independently of the time to SL chemotherapy and that response to first-line treatment and PS at SL are the only independent prognostic factors., Conclusions: The outcome for second-line therapy for SCLC was poor and benefit appeared to be limited to those patients with good PS and rechallenged with platinum-based chemotherapy. Platinum-based rechallenge should be considered as a standard comparator in future randomized controlled trials of SL chemotherapy., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: More than 50% of brain metastases (BMs) occur in advanced non-small cell lung cancer (NSCLC) patients. Untreated patients with BMs have a poor prognosis with a median survival of 2 months. In most cases BMs are multiple and their optimal therapy is whole-brain radiation therapy (WBRT). The role of systemic therapies for these patients is still a matter for investigation due to concerns about the ability of these drugs to cross the blood-brain barrier (BBB). Cisplatin (CDDP) remains the backbone for medical treatment of NSCLC and fotemustine (FTM) is a nitrosurea able to cross the BBB., Methods: Patients with advanced NSCLC, ECOG performance status (PS) 0-1 and multiple BMs not amenable to surgery or stereotactic radiotherapy were treated with 2 cycles of FTM 80 mg/m(2) days 1, 8 and CDDP 80 mg/m(2) day 1, every 3 weeks followed by WBRT 30 Gy (3 Gy daily in 10 fractions). Radiological restaging was performed before WBRT to assess the role of chemotherapy both for cranial and extracranial disease. Patients with disease control (DC: complete response plus partial response) received 4 more cycles. To assess the basic activities of daily living (ADL), the Barthel ADL Index was used to score patients' performance every 2 cycles. The trial design provides a two-step evaluation according to the optimal two-stage design of Simon. In the first phase 29 patients were enrolled in order to verify if this schedule showed more than 25% response rate both for cranial and extracranial disease. If so, enrollment added up to a total of 81 patients., Results: After the first evaluation 4 out of 29 patients were excluded from the study (3 untreated/1 not included for administrative reasons). At the time of the planned interim analysis patient's characteristics were the following: median age 61 years (range 44-70), M/F = 16/9, adenocarcinoma 11, squamous 5, large cell 2, undefined NSCLC 7; PS 0/1 in 11/14 cases, median Barthel Index score was 20 [13-20]. Three (12%) partial responses were observed, 9 subjects (36%) with stable disease and 13 (52%) showing disease progression. These data did not satisfy the pre-planned hypothesis and the study was stopped. At the time of the first evaluation before WBRT 12/25 (48%) patients had a systemic DC in contrast with 15/25 (60%) patients with BMs DC. Chemotherapy was relatively well tolerated with a prevalence of asthenia as the most relevant specific toxicity while the haematological toxicity was mild., Conclusion: CDDP and FTM combined with WBRT do not represent a therapeutic option for patients with NSCLC. Therefore further studies to evaluate the combination of systemic treatments with WBRT are warranted., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Quality of life (QoL) has gained greater importance in the management of metastatic non-small-cell lung cancer due to the palliative nature of treatment. Docetaxel (DCT) and cisplatin (CDDP) doublet has been reported to be associated to a better QoL than the weekly vinorelbine (VNR) and CDDP regimen. Recently a newer more tolerated schedule of the VNR/CDDP regimen has been published and is widely employed in medical practice. The impact of these regimens on patients' QoL as well as symptoms control and type and grading chemo-related side-effects has been compared prospectically., Methods: Patients received CDDP 75 mg/m(2) plus DCT 75 mg/m(2) on day 1 every weeks (arm A) or CDDP 80 mg/m(2) on day 1 plus VNR 30 mg/m(2) day 1 and 8 every 3 weeks (arm B). G-CSF and/or EPO were employed as needed. Health-related QoL was assessed at entry and after every cycle by the EORTC-QLQ-C30 and LC13 questionnaires, toxicity by the NCI-NCCN CTC vs 2, and intent-to-treat objective response by the Recist criteria., Results: The QoL questionnaires were completed by 37 pts (88%) in the DCT/CDDP arm and 39 pts (87%) in the VNR/CDDP one. Baseline mean scores and rates at which pts failed to complete QoL assessment were similar in the two arms. Global health status of the EORTC QLQ-C30 scale and specific symptoms control (LC13 module) improved during treatment without any statistically significant difference between the two arms. Emotional functioning remained stable in both groups during treatment, whereas physical and role improved slightly. In the DCT/CDDP arm 14 pts (33%; 95%CL 24-40%) had PR, and 10 (24%) SD for a 57% TGCR. In the VNR/CDDP arm 12 pts (27%) achieved PR, 18 (41%) SD a 68% TGCR. Differences were not statistically significant. Median time-to-progression was 4.2 months in the DCT/CDDP arm and 4.5 months in the VNR/CDDP one, and median overall survival was 12.1 (range 1-26+ months) and 12.5 months (range 1-28+ months) for DCT/CDDP and VNR/CDDP arms, respectively. Febrile neutropenia rate was higher in the VNR/CDDP arm (p=0.02) as well as G3-4 anemia (p=0.005) and G-CSF/EPO use (p=0.019)., Conclusions: Global and specific health-related QoL data similar in both treatment groups with no statistically significant difference. Efficacy measures, overall response rate, time-to-progression and overall survival were equivalent in both arms. However, severe anemia and febrile neutropenia are statistically more frequent in the VNR/CDDP arm than in the DCT/CDDP one. These data should be considered in treatment decision-making for pts with advanced non-small-cell lung cancer and for the design of future trials with chemotherapy plus biologics., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose: A phase III randomized trial was carried out to compare two schedules of the vinorelbine (VNR)-cisplatin (CDDP) regimen in patients with locally advanced unresectable poor prognosis stage IIIB or metastatic stage IV non-small cell lung cancer. The primary endpoints were overall survival (OS) and analysis of toxicity, while secondary endpoints included response rates, time-to-progression (TTP) and quality of life (QoL)., Patients and Methods: Eligible patients were randomized to receive: (a) VNR 25mg/m(2) on day 1, 8 and 15 plus CDDP 100mg/m(2) on day 1 every 4 weeks or (b) VNR 30 mg/m(2) on day 1 and 8 plus CDDP 80 mg/m(2) on day 1 every 3 weeks. All patients were chemotherapy-naïve and had an ECOG performance status (PS) of 0-1., Results: Overall 278 patients were enrolled into the trial. Overall response rate was 34% (95% CL 26-42%) in the weekly VNR/CDDP arm, and 32% (95% CL 24-40%) in patients treated with day 1-8 VNR/CDDP without any statistically significant difference. Median TTP was 4.5 and 4.6 months respectively for weekly VNR/CDDP arm and the day 1-8 VNR/CDDP one. This difference was not statistically significant (log-rank test, p=0.818). Median OS was 9.45 and 10 months respectively for weekly VNR/CDDP arm and the day 1-8 VNR/CDDP one without statistically a significant difference (log-rank test, p=0.259). The 1- and 2-year survival rates were 31 and 36%, and 10 and 11% respectively. The incidence of severe neutropenia (34% versus 68%; p=0.0001) and of febrile neutropenia (5% versus 12%; p=0.026), as well as the rate of therapy omissions (10% versus 24%; p=0.0037) were higher in the weekly VNR/CDDP arm than in the day 1-8 VNR/CDDP one. The weekly VNR/CDDP regimen was associated with a lower received dose intensity in a statistically significant fashion (9% versus 22%; p=0.0001) and with a lower non-statistically significant quality of life score as compared to the day 1-8 VNR/CDDP schedule., Conclusions: The combination of day 1-8 VNR plus CDDP every 3 weeks is less toxic and better tolerated than the regimen of weekly VNR plus CDDP every 4 weeks. The two schedules are equivalent in terms of overall response rate, median time-to-progression and overall survival. The combination of VNR on day 1-8 plus CDDP every 3 weeks may be considered as a reference regimen for the treatment of patients with advanced disease and those who deserve a postoperative therapy, and for future studies.

Rationale: Thymic masses may represent an unsolved diagnostic problem which often require surgical procedures for an accurate staging. A non-invasive way to determine the nature of thymic lesions would help identify the patients which are true candidates for surgery. Our retrospective study aims to assess multidetector computed tomography and 2-[(18)F]fluoro-2-deoxyglucose positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) capacity to distinguish benign from malignant thymic lesions., Methods: Helical multidetector CT (MDCT) and [(18)F]FDG-PET/CT of twenty consecutive patients presenting with a thymic mass at our Institute were retrospectively analyzed. MDCT scans were focused on morphologic features and invasiveness characteristics. Qualitative and semi-quantitative analyses by maximum standardized uptake value corrected for body weight (SUVbw max) were performed on [(18)F]FDG-PET/CT. In all cases, readers were blinded to pathology findings. Both imaging techniques were correlated to final pathology. Student's t-test was performed on SUVbw max stratified for thymic epithelial tumors., Results: In the group of benign lesions MDCT correctly identified well-defined margins of masses in 8 out of 8 patients whereas [(18)F]FDG-PET/CT was negative in 7 out of 8 patients. Among malignant lesions MDCT revealed mediastinum fat or infiltration of adjacent organs in 10/12 patients. On the other hand [(18)F]FDG-PET/CT showed increased radiotracer uptake in 12/12 patients., Conclusions: MDCT and [(18)F]FDG-PET/CT alone are not able to differentiate the nature of thymic lesions. However, they are two non-invasive complementary techniques which can be used to differentiate benign from high-risk malignant thymic lesions. These findings should be taken into account before surgery is performed as a diagnostic procedure.

Background: To investigate the efficacy of an inpatient Pulmonary Rehabilitation program (i-PR) after lung resection (LR) for Non-Small Cell Lung Cancer (NSCLC)., Patients and Methods: From January 2001 to December 2004, 211 out of 618 patients who underwent LR were considered eligible for i-PR. Twenty-five patients accepted the i-PR and were included in the case group. The remaining 186 who refused i-PR were taken as controls., Results: The two study groups were comparable for demographic and surgical characteristics, as well as for the peri-operative morbidity (4% in the controls and 3% among patients undergoing i-PR). Most functional parameters among treated patients were improved when baseline versus 1-month figures were compared, despite the strong correction for multiple comparison limited statistical significance to Borg scale dyspnoea on exertion - median - (2 versus 0; p<0.01); pH (7.45 versus 7.42; p<0.05); timed walk-6MWD (297.8m versus 393.4m; p<0.01) and Hb saturation during 6MWD (95.4% versus 93.9%; p<0.05). On the contrary, global function in the group of controls was homogeneously decreased (FEV(1) and PEF p<0.01) after operation. The comparison of treated and untreated patients 1 month after the operation did not show any significant difference in terms of FEV(1), FVC, PEF, distance, Hb saturation, and KCO that instead were homogeneously and significantly worse at baseline (before the surgical operation) in the case group., Conclusions: Respiratory Function and exercise capacity significantly improve following a post-operative 4-week i-PR in lung resected patients. i-PR could be regarded as a component of the management of patients who have undergone LR for cancer.

Lung cancer may involve the pulmonary artery (PA) either by direct extension of the primary tumor or by invasion of the hilar lymph nodes. In these instances, a radical resection is usually a pneumonectomy despite distal functioning lung tissue. To spare the lung parenchyma, angioplastic procedures requiring removal of a portion of the arterial wall or a circumferential resection with arterial reconstruction have been used. Several techniques of pulmonary arterioplasty have been explored suggesting that the incidence of postoperative complications is acceptably low and long-term local control can be achieved. Over a period of 7 years, 84 angioplastic procedures (alone or associated with bronchoplasty) were performed at our institution. Partial PA resection was performed in 80 (95.2%) patients. Reconstruction was performed by running suture in 63 (75%) patients and using a pericardial patch in 17 (20.2%) cases (16 autologous and 1 heterologous). A complete PA resection and reconstruction was performed in four (4.8%) patients by a polytetrafluoroethylene (PTFE) prosthesis (n=2) and by a custom-made bovine pericardial conduit (n=2). The latter are the topic of this report.

Purpose: We performed a multicenter phase II trial to evaluate the impact on the activity, efficacy, symptom control and safety of using two active regimens in a sequential schedule (cisplatin/gemcitabine followed by mitoxantrone/methotrexate/mitomycin) as first-line chemotherapy for unresectable malignant pleural mesothelioma (MPM)., Patients and Methods: A total of 54 patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1,200 mg/m(2) on days 1 and 8, every 3 weeks for four courses (CG regimen) followed by mitoxantrone 10 mg/m(2) on day 1, methotrexate 35 mg/m(2) on day 1 and mitomycin 7 mg/m(2) on day 1, every 3 weeks with mitomycin in alternate cycles for four courses (MMM regimen)., Results: We observed 3 complete responses (CRs) (5.6%) and 13 partial responses (PRs) (24.0%), with an overall response rate (ORR) of 29.6% (95% confidence interval, 17-42%), 33 stable disease (SD) (61.1%) and 5 progressive disease (PD) (9.2%). Median time to progression (TTP) was 9.5 months (range, 2-23). Median overall survival (OS) was 13 months (range, 3-33); 1-year survival rate was 63%. The treatment produced a good symptom control, with an improvement during chemotherapy in dyspnea and pain in 52.9 and 48.3% of patients, respectively. The major toxicity observed was hematological. Grades 3-4 NCI-CTC v 2.0 toxicity with the CG regimen included: neutropenia (11.1%), anemia (1.9%), thrombocytopenia (7.4%), vomiting (11.1%) and with the MMM regimen: neutropenia (35.2%), anemia (5.5%), thrombocytopenia (7.4%) and stomatitis (1.9%)., Conclusion: This phase II study with the sequential approach of two active regimens showed a good disease control in MPM, with symptom improvement and only mild toxicity.

Purpose: we carried out a phase III randomized trial to compare vinorelbine-cisplatin regimen to gemcitabine-cisplatin regimen, and to a sequential administration of gemcitabine-ifosfamide followed by vinorelbine-cisplatin or the opposite sequence of vinorelbine-cisplatin followed by ifosfamide-gemcitabine according to the 'worst drug rule' hypothesis in patients with locally advanced unresectable stage IIIB or metastatic stage IV non-small cell lung cancer. The primary endpoint was survival parameters, while secondary endpoints included analysis of response rates and toxicity., Patients and Methods: patients were randomized to receive: (a) gemcitabine 1000 mg/m(2) on days 1, 8 and 15 plus ifosfamide 1500 mg/m(2) on days 8-12 with mesna uroprotection (GI regimen) followed by vinorelbine 25 mg/m(2) on days 1 and 8 plus cisplatin 100 mg/m(2) on day 1 (GI --> VC regimen); (b) the opposite sequence (VC --> GI); (c) vinorelbine plus cisplatin as above described (VC regimen); or (d) gemcitabine 1400 mg/m(2) on days 1 and 8 plus cisplatin 100 mg/m(2) on day 8 (GC regimen). All regimens were given every 4 weeks. All patients were chemotherapy naive and had a ECOG PS 0-2., Results: 400 patients were enrolled into the trial. Interim analysis after inclusion of 243 patients showed that ORR were 19% in the GI --> VC arm, 32% in the inverse sequence arm (CV --> GI), 42% in the VC arm, and 30% in the GC arm. The VC arm was statistically superior over the GI --> VC arm (p = 0.0074), but not over the other regimens. Median TTP was 3.1 months in the GI --> VC arm versus 5.0 months in the VC --> GI arm (p = 0.014). For these reasons the GI --> VC and VC --> GI arm were closed since the 'worst drug rule' hypothesis was rejected. Accrual in the VC and GC arms continued up to 140 and 138 patients respectively. Final ORR were 44% for the VC regimen (4 CR), and 34% for the GC regimen (1 CR). This difference was statistically significant (p = 0.032). OS was 9.0 and 8.2 months, respectively, with no statistically significant difference. The 1-year survival rate was 24 and 20%, respectively for VC and GC regimens. As expected the incidence of phlebitis was higher in the VC arm, while thrombocytopenia, flu-like syndrome and asthenia were more frequent in the GC arm., Conclusions: the results of this trial indicate that the combination of vinorelbine and cisplatin and that of gemcitabine and cisplatin are equivalent in terms of median TTP and OS, although the vinorelbine-cisplatin regimen is associated with a higher ORR. Both regimens may be considered as reference treatments for future studies. Moreover, our data reject the 'worst drug rule' hypothesis of sequential treatments in NSCCL at least with the combination used in this study., (Copyright 2002 Elsevier Science Ireland Ltd.)

Introduction: Platinum-based chemotherapy is the gold standard in advanced non-small cell lung cancer (NSCLC), although with relevant toxic effects. Both docetaxel (DCT) and gemcitabine (GEM) have shown activity as single agent in advanced NSCLC with a different toxicity profile and a lack of cross-resistance., Materials and Methods: From April 2000 to May 2001, 47 consecutive patients were enrolled in a multicenter phase II trial. Main inclusion criteria included untreated patients with histologically confirmed NSCLC, age

Purpose: To compare a regimen of vinorelbine and cisplatin (VC) to the combination of mitomycin, vindesine, and cisplatin (MVP) in patients with stage IIIB or stage IV non-small cell lung cancer (NSCLC). The main endpoits were analysis of objective response rates, toxicity, time to progression, and overall survival., Patients and Methods: 247 eligible patients were randomized to receive (a) vinorelbine 25 mg/m(2) intravenous bolus on days 1 and 8 plus cisplatin 100 mg/m(2) on day 1 every 4 weeks, or (b) mitomycin c 8 mg/m(2) i.v. on day 1, vindesine 3 mg/m(2) i.v. on days 1, 8, 15 and 22, plus cisplatin 100 mg/m(2) on day 1 every 4 weeks. In subsequent cycles vindesine was given every other week. For both treatments a maximum of six cycles was planned. Patients with performance status 0-2 according to the ECOG scale were enrolled. Response and toxicity were evaluated according to the WHO criteria. Analysis of clinical efficacy was performed according to an intent-to-treat analysis., Results: No statistically significant differences in clinical efficacy were observed between the two chemotherapy regimens. The overall objective response rates were 39% (95% CL, 31-49%) in the VC arm and 42% (95% CL, 33-51%) in the MVP arm (P=0.13). Median time to progression was 4.2 and 4.5 months for the MVP arm and the VC arm, respectively. Median overall survival was 7 months in the VC arm and 8 months in the MVP one (log-rank test, P=0.898). These differences were not statistically significant. However, leukopenia and thrombocytopenia were significantly higher in the MVP arm than in the VC (P=0.0001; P=0.0002). Grade 3 alopecia was more frequent in the MVP arm than in the VC one (P<0.001), which was associated with higher rate of phlebitis (P=0.037)., Conclusion: Data achieved in this study suggest that the vinorelbine-cisplatin doublet is similar to the three-drug MVP regimen in term of overall response rate, time to progressive disease, and overall survival. However, hematological toxicity and alopecia are more frequent and severe in the MVP regimen which therefore appears to be less tolerable than the VC regimen. The combination of vinorelbine and cisplatin may be considered as a reference treatment for future studies on the treatment of advanced NSCLC.

Objective: to report the surgical facts of unresectable patients with locally advanced non-small cell lung cancer (NSCLC) treated in a phase I trial with concurrent weekly gemcitabine and radiotherapy who achieved a clinical downstaging so as to re-enter resectability., Materials and Methods: from 3/99 to 11/00, 30 patients (ten stage IIIa, 16 IIIb and four IV) with histologically proven, unresectable NSCLC, were enrolled in this phase I trial. Gemcitabine was given weekly for 5 consecutive weeks as a 30-min intravenous infusion, at least 4 h before radiotherapy. Starting dose: 100 mg/m(2). Maximum tolerated dose (MTD): 350 mg/m(2). Radiotherapy total dose: 50.4 Gy (1.8 Gy/day) on primitive tumour and involved lymph nodes., Results: 27 out of 30 patients (90%) were evaluable for clinical restaging (three patients who decided to continue their treatment elsewhere have been excluded). A major clinical response (partial+complete response) was observed in 17 out of 27 cases (62.9%). Clinical complete response rate was 3.7% (1/27) while partial response rate was 59.2% (16/27). Nine patients (33.4%) showed a clinical stable disease and one a disease progression (3.7%). Fourteen patients re-entered resectability and were operated upon: seven lobectomies; four bilobectomies; two pneumonectomies and one explorative thoracotomy. Mean operation duration time was 112 min; mean blood loss was 390 cc. Thirty-day morbidity and mortality were nil. Mean post-operative hospital stay was 6.8 days. A slight increase in operational technical difficulty was encountered. Definitive histology showed a pathologic downstaging of 71.4% (10/14). In four patients, only microscopic neoplastic remnants were found., Conclusions: combined treatment with weekly gemcitabine and concurrent radiotherapy is feasible. In patients with advanced NSCLC who achieved a good clinical response and therefore were judged to be resectable, surgery was possible without any increase in thirty-day morbidity and mortality. Satisfactory pathologic results were obtained.