Publications by authors named "Adolfo Favaretto"

81 Publications

Epidemiology and clinical course of severe acute respiratory syndrome coronavirus 2 infection in cancer patients in the Veneto Oncology Network: The Rete Oncologica Veneta covID19 study.

Eur J Cancer 2021 Feb 3;147:120-127. Epub 2021 Feb 3.

Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy. Electronic address:

Introduction: Coronavirus disease 2019 (COVID-19) pandemic started in Italy with clusters identified in Northern Italy. The Veneto Oncology Network (Rete Oncologica Veneta) licenced dedicated guidelines to ensure proper care minimising the risk of infection in patients with cancer. Rete Oncologica Veneta covID19 (ROVID) is a regional registry aimed at describing epidemiology and clinical course of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with cancer.

Materials And Methods: Patients with cancer diagnosis and documented SARS-CoV-2 infection are eligible. Data on cancer diagnosis, comorbidities, anticancer treatments, as well as details on SARS-CoV-2 infection (hospitalisation, treatments, fate of the infection), have been recorded. Logistic regression analysis was applied to calculate the association between clinical/laboratory variables and death from any cause.

Results: One hundred seventy patients have been enrolled. The median age at time of the SARS-CoV infection was 70 years (25-92). The most common cancer type was breast cancer (n = 40). The majority of the patients had stage IV disease. Half of the patients had two or more comorbidities. The majority of the patients (78%) presented with COVID-19 symptoms. More than 77% of the patients were hospitalized and 6% were admitted to intensive care units. Overall, 104 patients have documented resolution of the infection. Fifty-seven patients (33%) have died. In 29 cases (17%), the cause of death was directly correlated to SARS-CoV-2 infection. Factors significantly correlated with the risk of death were the following: Eastern Cooperative Oncology Group performance status (PS), age, presence of two or more comorbidities, presence of dyspnoea, COVID-19 phenotype ≥ 3, hospitalisation, intensive care unit admission, neutrophil/lymphocyte ratio and thrombocytopenia.

Conclusions: The mortality rate reported in this confirms the frailty of this population. These data reinforce the need to protect patients with cancer from SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.ejca.2021.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857033PMC
February 2021

A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-Line Treatment for EGFR Mutation-Positive NSCLC Patients.

J Thorac Oncol 2020 01 14;15(1):80-90. Epub 2019 Oct 14.

Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Republic of School of Medicine, National Yang-Ming University, Taipei, Republic of China.

Introduction: The hepatocyte growth factor receptor mesenchymal-epithelial transition (MET) is reported to be a negative prognostic marker in EGFR-mutant NSCLC and involved in resistance to EGFR inhibitors. Emibetuzumab, a humanized immunoglobulin G4 monoclonal bivalent MET antibody, blocks ligand-dependent and ligand-independent hepatocyte growth factor/MET signaling. This phase 2 study compared erlotinib with and without emibetuzumab in first-line treatment of EGFR-mutant metastatic NSCLC.

Methods: Patients with stage IV EGFR-mutant NSCLC and disease control after an 8-week lead-in with erlotinib (150 mg daily) were randomized to continue taking erlotinib with or without emibetuzumab (750 mg every 2 weeks). The primary end point was progression-free survival (PFS). Additional end points included overall survival, overall response rate, safety, pharmacokinetics, and exploratory analysis of MET expression.

Results: No significant difference in median PFS was observed in the intent-to-treat population (9.3 months with emibetuzumab + erlotinib versus 9.5 months with erlotinib monotherapy [hazard ratio (HR) = 0.89, 90% confidence interval (CI): 0.64-1.23]). The median overall survival was 34.3 months with emibetuzumab plus erlotinib versus 25.4 months with erlotinib (HR = 0.74, 90% CI: 0.49-1.11). Emibetuzumab plus erlotinib was well tolerated, with peripheral edema and mucositis as the only adverse events occurring 10% or more frequently relative to erlotinib. Exploratory post hoc analysis showed an improvement of 15.3 months in median PFS for the 24 patients with the highest MET expression (MET expression level of 3+ in ≥90% of tumor cells) (20.7 with emibetuzumab + erlotinib versus 5.4 months with erlotinib [HR = 0.39, 90% CI: 0.17-0.91]).

Conclusions: No statistically significant difference in PFS was noted in the intent-to-treat population. Exploratory analysis confirmed that high MET expression is a negative prognostic marker for patients treated with erlotinib, indicating that emibetuzumab plus erlotinib may provide clinically meaningful benefit.
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http://dx.doi.org/10.1016/j.jtho.2019.10.003DOI Listing
January 2020

Maintenance with lanreotide in small-cell lung cancer expressing somatostatine receptors: A multicenter, randomized, phase 3 trial.

Lung Cancer 2019 08 11;134:121-126. Epub 2019 Jun 11.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Università Cattolica Del Sacro Cuore, Rome, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.lungcan.2019.06.011DOI Listing
August 2019

From Diagnostic-Therapeutic Pathways to Real-World Data: A Multicenter Prospective Study on Upfront Treatment for -Positive Non-Small Cell Lung Cancer (MOST Study).

Oncologist 2019 06 7;24(6):e318-e326. Epub 2019 Mar 7.

Medical Oncology 2, Istituto Oncologico Veneto (IOV) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy.

Introduction: Gefitinib, erlotinib, and afatinib represent the approved first-line options for epidermal growth factor receptor ()-mutant non-small cell lung cancer (NSCLC). Because pivotal trials frequently lack external validity, real-world data may help to depict the diagnostic-therapeutic pathway and treatment outcome in clinical practice.

Methods: MOST is a multicenter observational study promoted by the Veneto Oncology Network, aiming at monitoring the diagnostic-therapeutic pathway of patients with nonsquamous -mutant NSCLC. We reported treatment outcome in terms of median time to treatment failure (mTTF) and assessed the impact of each agent on the expense of the regional health system, comparing it with a prediction based on the pivotal trials.

Results: An mutation test was performed in 447 enrolled patients, of whom 124 had mutation and who received gefitinib ( = 69, 55%), erlotinib ( = 33, 27%), or afatinib ( = 22, 18%) as first-line treatment. Because erlotinib was administered within a clinical trial to 15 patients, final analysis was limited to 109 patients. mTTF was 15.3 months, regardless of the type of tyrosine kinase inhibitor (TKI) used. In the MOST study, the budget impact analysis showed a total expense of €3,238,602.17, whereas the cost estimation according to median progression-free survival from pivotal phase III trials was €1,813,557.88.

Conclusion: Good regional adherence and compliance to the diagnostic-therapeutic pathway defined for patients with nonsquamous NSCLC was shown. mTTF did not significantly differ among the three targeted TKIs. Our budget impact analysis suggests the potential application of real-world data in the process of drug price negotiation.

Implications For Practice: The MOST study is a real-world data collection reporting a multicenter adherence and compliance to diagnostic-therapeutic pathways defined for patients with epidermal growth factor receptor-mutant non-small cell lung cancer. This represents an essential element of evidence-based medicine, providing information on patients and situations that may be challenging to assess using only data from randomized controlled trials, e.g., turn-around time of diagnostic tests, treatment compliance and persistence, guideline adherence, challenging-to-treat populations, drug safety, comparative effectiveness, and cost effectiveness. This study may be of interest to various stakeholders (patients, clinicians, and payers), providing a meaningful picture of the value of a given therapy in routine clinical practice.
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http://dx.doi.org/10.1634/theoncologist.2018-0712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656504PMC
June 2019

The Genotype for DPYD Risk Variants in Patients With Colorectal Cancer and the Related Toxicity Management Costs in Clinical Practice.

Clin Pharmacol Ther 2019 04 22;105(4):994-1002. Epub 2018 Nov 22.

Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081, Aviano, Italy.

Lack of information on the clinical utility of preemptive DPYD screening before fluoropyrimidine treatment is a major barrier preventing its use in clinical practice. This study aimed to define the association between DPYD variants and fluoropyrimidine-related toxicity management costs. A cost analysis was conducted on the toxicities experienced by 550 patients with colorectal cancer treated with fluoropyrimidine-based chemotherapy. Genotyping for DPYD*2A, DPYD*13, DPYDc. 2846A>T, DPYD-HapB3, and UGT1A1*28 was done retrospectively and did not affect patients' treatments. Carriers of at least one DPYD variant experienced higher toxicity management costs (€2,972; 95% confidence interval (CI), €2,456-€3,505) than noncarriers (€825; 95% CI, €785-€864) (P < 0.0001) and had a higher risk for toxicity requiring hospitalization (odds ratio, 4.14; 95% CI, 1.87-9.14). In patients receiving fluoropyrimidine/irinotecan, the incremental cost between DPYD variant and UGT1A1*28/*28 carriers and noncarriers was €2,975. This study suggests that the toxicity management costs during fluoropyrimidine-based therapy are associated with DPYD and UGT1A1*28 variants and supports the utility of genotyping.
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http://dx.doi.org/10.1002/cpt.1257DOI Listing
April 2019

A Clinical-Genetic Score to Identify Surgically Resected Colorectal Cancer Patients Benefiting From an Adjuvant Fluoropyrimidine-Based Therapy.

Front Pharmacol 2018 4;9:1101. Epub 2018 Oct 4.

Experimental and Clinical Pharmacology Unit, CRO Aviano National Cancer Institute, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.

There are clinical challenges related to adjuvant treatment in colorectal cancer (CRC) and novel molecular markers are needed for better risk stratification of patients. Our aim was to integrate our previously reported clinical-genetic prognostic score with new immunogenetic markers of 5-year disease-free survival (DFS) to evaluate the recurrence risk stratification before fluoropyrimidine (FL)-based adjuvant therapy. The study population included a total of 270 stage II-III CRC patients treated with adjuvant FL with (FL + OXA, = 119) or without oxaliplatin (FL, = 151). Patients were genotyped for a panel of 192 tagging polymorphisms in 34 immune-related genes. The -rs1861494 polymorphism was associated with worse DFS in the FL + OXA (HR = 2.14, 95%CI 1.13-4.08; = 0.020, -value = 0.249) and FL (HR = 1.97, 95%CI 1.00-3.86; = 0.049) cohorts, according to a dominant model. The integration of -rs1861494 in our previous clinical genetic multiparametric score of DFS improved the patients' risk stratification (Log-rank = 0.0026 in the pooled population). These findings could improve the discrimination of patients who would benefit from adjuvant treatment. In addition, the results may help better elucidate the interplay between the immune system and chemotherapeutics and help determine the efficacy of anti-tumor strategies.
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http://dx.doi.org/10.3389/fphar.2018.01101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180157PMC
October 2018

Retrospective Assessment of a Serum Proteomic Test in a Phase III Study Comparing Erlotinib plus Placebo with Erlotinib plus Tivantinib (MARQUEE) in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer.

Oncologist 2019 06 23;24(6):e251-e259. Epub 2018 Aug 23.

Division of Medical Oncology, Department of Oncology, University of Torino at San Luigi Gonzaga Hospital, Turin, Italy

Background: The VeriStrat test provides accurate predictions of outcomes in all lines of therapy for patients with non-small cell lung cancer (NSCLC). We investigated the predictive and prognostic role of VeriStrat in patients enrolled on the MARQUEE phase III trial of tivantinib plus erlotinib (T+E) versus placebo plus erlotinib (P+E) in previously treated patients with advanced NSCLC.

Methods: Pretreatment plasma samples were available for 996 patients and were analyzed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry to generate VeriStrat labels (good, VS-G, or poor, VS-P).

Results: Overall, no significant benefit in overall survival (OS) and progression-free survival (PFS) were observed for the addition of tivantinib to erlotinib. Regardless of treatment arm, patients who were classified as VS-G had significantly longer PFS (3.8 mo for T+E arm, 2.0 mo for P+E arm) and OS (11.6 mo for T+E, 10.2 mo for P+E arm) than patients classified as VS-P (PFS: 1.9 mo for both arms, hazard ratio [HR], 0.584; 95% confidence interval [CI], 0.468-0.733; < .0001 for T+E, HR, 0.686; 95% CI, 0.546-0.870; = .0015 for P+E; OS: 4.0 mo for both arms, HR, 0.333; 95% CI, 0.264-0.422; < .0001 for T+E; HR, 0.449; 95% CI, 0.353-0.576; < .0001 for P+E). The VS-G population had higher OS than the VS-P population within Eastern Cooperative Oncology Group (ECOG) performance score (PS) categories. VS-G patients on the T+E arm had longer PFS, but not OS, than VS-G patients on the P+E arm ( = .0108). Among EGFR mutation-positive patients, those with VS-G status had a median OS more than twice that of any other group (OS: 31.6 mo for T+E and 22.8 mo for P+E), whereas VS-P patients had similar survival rates as VS-G, EGFR-wild type patients (OS: 13.7 mo for T+E and 6.5 mo for P+E).

Conclusion: In these analyses, VeriStrat showed a prognostic role within EGOC PS categories and regardless of treatment arm and EGFR status, suggesting that VeriStrat could be used to identify EGFR mutation-positive patients who will have a poor response to EGFR tyrosine kinase inhibitors.

Implications For Practice: This study suggests that VeriStrat testing could enhance the prognostic role of performance status and smoking status and replicates findings from other trials that showed that the VeriStrat test identifies EGFR mutation-positive patients likely to have a poor response to EGFR tyrosine kinase inhibitors (TKIs). Although these findings should be confirmed in other populations, VeriStrat use could be considered in EGFR mutation-positive patients as an additional prognostic tool, and these results suggest that EGFR mutation-positive patients with VeriStrat "poor" classification could benefit from other therapeutic agents given in conjunction with TKI monotherapy.
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http://dx.doi.org/10.1634/theoncologist.2018-0089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656491PMC
June 2019

Second-line Treatment of Advanced Non-small Cell Lung Cancer Non-oncogene Addicted: New Treatment Algorithm in the Era of Novel Immunotherapy.

Curr Clin Pharmacol 2018 ;13(2):76-84

Thoracic Division, Medical Oncology Department, European Institute of Oncology, Milan, Italy.

Background: Most patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and receive limited benefit from conventional treatments, especially in later lines of therapy. In recent years, several novel therapies have been approved for second- and third-line treatment of advanced NSCLC beyond old chemotherapy agents (docetaxel and pemetrexed) and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI, erlotinib). In particular, the new antiangiogenetics (nindetanib and ramucirumab) in combination with docetaxel and immunotherapy (nivolumab, pembrolizumab and atezolizumab) have been recently approved and represent new treatment options.

Methods: The Italian Association of Thoracic Oncology (AIOT) organized five meetings in different Italian regions representing North, Middle and South of the country in order to discuss the issue.

Results: In light of these new approvals, it is valuable to understand the uptake of these new therapies in routine clinical practice and their impact on patient care. With these treatment options to define an appropriate algorythm is object of debate.

Conclusion: The present paper discusses the old and new treatment opportunities, proposing a shared algorithm for second-line setting in advanced NSCLC.
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http://dx.doi.org/10.2174/1574884713666180711160008DOI Listing
June 2019

Negative prognostic factors and resulting clinical outcome in patients with metastatic renal cell carcinoma included in the Italian nivolumab-expanded access program.

Future Oncol 2018 Jun 18;14(14):1347-1354. Epub 2018 May 18.

IRCCS Policlinico 'S Matteo', Pavia, Italy.

Aim: We report the outcomes observed with nivolumab in metastatic renal cell carcinoma patients with poor prognostic features enrolled in the Italian expanded access program.

Patients & Methods: Nivolumab was available for patients who relapsed after at least one prior systemic treatment in the advanced or metastatic setting.

Results: Of 389 patients, 32 (8%) had brain metastasis, 129 (33%) had liver and 193 (50%) had bone metastasis. These subpopulations achieved a disease control rate of 53, 45 and 47%, respectively. Fifty-one patients had G4 tumor, and they showed 23% objective response rate. The safety profile of the subgroups was in line with the expanded access program population. No new safety signals were reported.

Conclusion: Patients with poor prognostic features may derive relevant benefits from nivolumab.
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http://dx.doi.org/10.2217/fon-2017-0570DOI Listing
June 2018

NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial.

Lancet Oncol 2018 06 9;19(6):799-811. Epub 2018 May 9.

The Royal Marsden Hospital, Sutton, UK.

Background: Malignant pleural mesothelioma is an aggressive cancer with highly vascularised tumours. It has poor prognosis and few treatment options after failure of first-line chemotherapy. NGR-hTNF is a vascular-targeting drug that increases penetration of intratumoral chemotherapy and T-cell infiltration by modifying the tumour microenvironment. In this trial, we aimed to investigate the efficacy and safety of NGR-hTNF in patients with malignant pleural mesothelioma who had progressed during or after a first-line treatment.

Methods: NGR015 was a randomised, double-blind, placebo-controlled phase 3 trial done in 41 centres in 12 countries. Eligible participants had malignant pleural mesothelioma of any histological subtype (epithelial, sarcomatoid, or mixed), were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0-2 and radiologically documented progressive disease after one pemetrexed-based chemotherapy regimen. Participants were randomly assigned to receive weekly NGR-hTNF 0·8 μg/m intravenously plus best investigator choice (n=200), or placebo plus best investigator choice (n=200). Best investigator choice was decided before random assignment and could be single-agent gemcitabine (1000-1250 mg/m intravenously), vinorelbine (25 mg/m intravenously or 60 mg/m orally), doxorubicin (60-75 mg/m intravenously), or best supportive care only. Patients were randomised (1:1) with a block size of four after stratification for performance status and best investigator choice. The primary study endpoint was overall survival in the intention-to-treat population. The trial is closed to new participants and is registered with ClinicalTrials.gov (NCT01098266).

Findings: Between April 12, 2010 and Jan 21, 2013, we enrolled 400 eligible participants. 381 (95%) of 400 patients were selected to receive chemotherapy before all participants were randomly assigned to receive NGF-hTNF plus best investigator choice (n=200) or placebo plus best investigator choice (n=200). At the cutoff date (April 29, 2014), the median follow-up was 18·7 months (IQR 15·1-24·4), and overall survival did not differ between the two treatment groups (median 8·5 months [95% CI 7·2-9·9] in the NGR-hTNF group vs 8·0 months [6·6-8·9] in the placebo group; hazard ratio 0·94, 95% CI 0·75-1·18; p=0·58). Grade 3 or worse study-emergent adverse events occurred in 136 (70%) of patients receiving NGR-hTNF versus 118 (61%) of patients receiving placebo, with the most common being neutropenia (35 [18%] of 193 patients vs 36 [19%] of 193 patients), pain (11 [6%] vs 16 [8%]), dyspnoea (nine [5%] vs seven [4%]), and chills (nine [5%] vs none). 50 (26%) patients in the NGR-hTNF group had a serious adverse event, compared with 47 (24%) in the placebo group. Treatment-related serious adverse events occurred in 17 (9%) patients in the NGR-hTNF group and 20 patients (10%) in the placebo group. There were 12 deaths in the NGR-hTNF group and 13 deaths in the placebo group, but none were treatment related.

Interpretation: The study did not meet its primary endpoint. The hypothesis-generating findings from the subgroup analyses deserve a confirmatory randomised trial because patients who rapidly progress after first-line treatment have a poor prognosis.

Funding: MolMed.
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http://dx.doi.org/10.1016/S1470-2045(18)30193-1DOI Listing
June 2018

Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy.

J Clin Oncol 2018 02 14;36(4):342-349. Epub 2017 Dec 14.

Paolo Andrea Zucali, Matteo Simonelli, Matteo Perrino, Fabio De Vincenzo, Laura Giordano, Monica Bertossi, Annarita Destro, Luca Di Tommaso, and Armando Santoro¸ Humanitas Clinical and Research Hospital; Tommaso De Pas, Francesca Toffalorio, Fabio Conforti, and Angela Cioffi, European Institute of Oncology; Paolo Andrea Zucali, Matteo Simonelli, Luca Di Tommaso, and Armando Santoro, Humanitas University, Milan; Giovannella Palmieri, Vincenzo Damiano, Margaret Ottaviano, and Sabino De Placido, Università Federico II, Naples; Adolfo Favaretto and Giulia Pasello, Istituto Oncologico Veneto, Padua; Antonio Chella and Erika Garbella, University Hospital, Pisa; Marcello Tiseo, Azienda Ospedaliero-Universitaria of Parma, Parma; and Michele Caruso and Marco Ali, Humanitas Centro Catanese di Oncologia, Catania, Italy.

Purpose No effective salvage treatments are available for patients with advanced/recurrent thymoma (T) or thymic carcinoma (TC) who have progressed after platinum-based chemotherapy. This study evaluated the activity of everolimus in patients with advanced/recurrent T or TC previously treated with cisplatin-containing chemotherapy. Patients and Methods This was a single-arm, single-stage, open-label, multicenter, phase II trial. Patients received oral everolimus 10 mg/d until disease progression, unacceptable toxicity, or patient refusal. A Fleming phase II trial was designed. The null hypothesis of a true disease control rate (DCR) of 40% was tested against a one-sided alternative of a true DCR of 60% (α = β = 0.10): If disease control were achieved in ≥ 21 of the first 41 evaluable patients, everolimus could be recommended for further evaluation. Progression-free survival, overall survival, and safety were also evaluated. Results From 2011 to 2013, 51 patients were enrolled (T, n = 32; TC, n = 19). Complete remission was observed in one patient with TC, partial response in five patients (T, n = 3; TC, n = 2), and stable disease in 38 patients (T, n = 27; TC, n= 11), with a DCR of 88% (T,: 93.8%; TC, 77.8%). With a median follow up of 25.7 months, median progression-free survival was 10.1 months (T,: 16.6 months; TC, 5.6 months), and median overall survival was 25.7 months (T, not reached; TC, 14.7 months). Fourteen patients had a serious drug-related adverse event; of these patients, nine permanently discontinued treatment. Three patients died of pneumonitis while in the study. Immunohistochemical positivity for p4E-BP1 or insulin-like growth factor-1 receptor was statistically significantly related to a shorter survival. Conclusion Everolimus may induce durable disease control in a high percentage of patients with T or TC, albeit with a potential high risk of fatal pneumonitis.
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http://dx.doi.org/10.1200/JCO.2017.74.4078DOI Listing
February 2018

HLA-G 3'UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer.

Int J Mol Sci 2017 Jun 27;18(7). Epub 2017 Jun 27.

Experimental and Clinical Pharmacology Unit, CRO Aviano National Cancer Institute, IRCCS, via F. Gallini 2, Aviano (PN) 33081, Italy.

Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC) that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4). Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4) toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify 3' untranslated region (3'UTR) polymorphisms and related haplotypes and evaluate their impact on the risk of developing G3-4 toxicities (i.e., neutropenia, hematological/non-hematological toxicity, neurotoxicity) with logistic regression. The rs1610696- polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, = 0.015) and neurotoxicity (OR = 8.78, = 0.016); rs371194629- was associated with increased risk of neurotoxicity (OR = 5.49, = 0.027). 3'UTR-2, which contains rs1610696- and rs371194629- polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, = 0.017) and neurotoxicity (OR = 11.29, = 0.009). A bootstrap analysis confirmed the predictive value of rs1610696 and rs371194629, but the UTR-2 haplotype was validated only for neurotoxicity. This exploratory study identified new 3'UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC.
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http://dx.doi.org/10.3390/ijms18071366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535859PMC
June 2017

A multicenter, randomized, phase 3 trial comparing fixed dose versus toxicity-adjusted dose of cisplatin + etoposide in extensive small-cell lung cancer (SCLC) patients: The Small-cell-lung cancer Toxicity Adjusted Dosing (STAD-1) trial.

Lung Cancer 2017 06 27;108:15-21. Epub 2017 Feb 27.

Medical Oncology, S.G. Moscati Hospital, Avellino, Italy. Electronic address:

Objectives: Data supporting the prognostic role of chemotherapy induced haematological toxicity suggest that toxicity-adjusted-dosing (TAD) of chemotherapy might improve treatment efficacy. We tested whether TAD of the cisplatin-etoposide combination might improve the response rate, in previously untreated extensive stage disease (ED)-SCLC patients, as compared with standard fixed-dosing (FD).

Methods: Patients with ED-SCLC were randomized to receive either TAD or FD of cisplatin-etoposide as first-line treatment. Primary endpoint was the objective response rate (ORR) according to the RECIST 1.0 criteria, secondary endpoints included progression free survival (PFS), overall survival (OS) and toxicity.

Results: Hundred-fifty-eight patients were randomized. Most patients were male, with ECOG-PS 1, without brain metastases and had not received radiotherapy before study entry. Response rate was 54.4 (95%CI: 43.5-64.9%) and 58.2 (95%CI: 47.2-68.5%) in the control and experimental arms, respectively (P=0.75). No significant differences were found in terms of PFS (HR 1.04; 95%CI: 0.74-1.44, P=0.84) and OS (HR1.01; 95%CI 0.71-1.42, p=0.97). Seven patients died on treatment, one in the standard arm and 6 in the experimental arm. The most frequent cause of death was neutropenia with infection and, apart in one, death was not related to dose modification. Severe toxicity was more frequent in the experimental arm (91% vs 60%).

Conclusions: In our population of chemonaïve ED SCLC patients, TAD failed to improve the ORR, PFS and OS over the FD of cisplatin-etoposide as first line chemotherapy and was associated with increased toxicity.
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http://dx.doi.org/10.1016/j.lungcan.2017.02.016DOI Listing
June 2017

EAGLES study: First-line Bevacizumab in Combination with Chemotherapy in Elderly Patients with Advanced, Metastatic, Non-squamous Non-small Cell Lung Cancer.

Anticancer Res 2017 05;37(5):2457-2464

Division of Medical Oncology, San Giuseppe Moscati Hospital, Avellino, Italy.

Background/aim: The management of elderly patients with advanced non-squamous NSCLC includes several strategies.

Patients And Methods: Patients (≥70 years) were randomly assigned to bevacizumab (7.5 mg/kg i.v. on day 1) plus gemcitabine (1,200 mg/m i.v. on days 1-8) (arm A) or bevacizumab (7.5 mg/kg i.v.) and cisplatin (60 mg/m i.v.) plus gemcitabine (1,000 mg/m i.v. on days 1-8) (arm B), to independently evaluate treatments. The primary endpoint was progression-free rate at 6 months; secondary endpoints included progression-free survival (PFS) and safety profiles.

Results: At 6 months, 5 (11.6%) patients in arm A and 5 patients (12.5%) in arm B were found to be progression-free. Median PFS was 4.8 months in arm A and 6.5 months in arm B, respectively.

Conclusion: In our experience, combination of bevacizumab and chemotherapy had encouraging anti-tumor efficacy as first-line therapy in elderly patients with non-squamous NSCLC.
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http://dx.doi.org/10.21873/anticanres.11586DOI Listing
May 2017

Clinical features and treatment outcome of non-small cell lung cancer (NSCLC) patients with uncommon or complex epidermal growth factor receptor (EGFR) mutations.

Oncotarget 2017 May;8(20):32626-32638

Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy.

Introduction: Tyrosine-kinase inhibitors (TKIs) represent the best treatment for advanced non-small cell lung cancer (NSCLC) with common exon 19 deletion or exon 21 epidermal growth factor receptor mutation (EGFRm). This is an observational study investigating epidemiology, clinical features and treatment outcome of NSCLC cases harbouring rare/complex EGFRm.

Results: Among 764 non-squamous NSCLC cases with known EGFRm status, 26(3.4%) harboured rare/complex EGFRm. Patients receiving first-line TKIs (N = 17) achieved median Progression Free Survival (PFS) and Overall Survival (OS) of 53 (IC 95%, 2-105) and 84 (CI 95%, 27-141) weeks respectively, without significant covariate impact. Response Rate and Disease Control Rate (DCR) were 47% and 65%, respectively. Uncommon exon 19 mutations achieved longer OS and PFS and higher DCR compared with exon 18 and 20 mutations. No additional gene mutation was discovered by MassARRAY analysis. TKIs were globally well tolerated.

Materials And Methods: A retrospective review of advanced non-squamous NSCLC harbouring rare/complex EGFRm referred to our Center between 2010 and 2015 was performed. Additional molecular pathways disregulation was explored in selected cases, through MassARRAY analysis.

Conclusions: Peculiar clinical features and lower TKIs sensitivity of uncommon/complex compared with common EGFRm were shown. Exon 19 EGFRm achieved the best TKIs treatment outcome, while the optimal treatment of exon 18 and 20 mutations should be further clarified.
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http://dx.doi.org/10.18632/oncotarget.15945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464815PMC
May 2017

Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial.

Lancet Respir Med 2017 05 10;5(5):435-444. Epub 2017 Apr 10.

University Hospital Zurich, Clinic of Oncology, Zurich, Switzerland; Swiss Group of Clinical Cancer Research, Bern, Switzerland. Electronic address:

Background: The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR-mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation.

Methods: BELIEF was an international, multicentre, single-arm, phase 2 trial done at 29 centres in eight European countries. Eligible patients were aged 18 years or older and had treatment-naive, pathologically confirmed stage IIIB or stage IV lung adenocarcinoma with a confirmed, activating EGFR mutation (exon 19 deletion or L858R mutation). Patients received oral erlotinib 150 mg per day and intravenous bevacizumab 15 mg/kg every 21 days and were tested centrally for the pretreatment T790M resistance mutation with a peptide nucleic acid probe-based real-time PCR. The primary endpoint was progression-free survival. The primary efficacy analysis was done in the intention-to-treat population and was stratified into two parallel substudies according to the centrally confirmed pretreatment T790M mutation status of enrolled patients (T790M positive or negative). The safety analysis was done in all patients that have received at least one dose of trial treatment. This trial was registered with ClinicalTrials.gov, number NCT01562028.

Findings: Between June 11, 2012, and Oct 28, 2014, 109 patients were enrolled and included in the efficacy analysis. 37 patients were T790M mutation positive and 72 negative. The overall median progression-free survival was 13·2 months (95% CI 10·3-15·5), with a 12 month progression-free survival of 55% (95% CI 45-64). The primary endpoint was met only in substudy one (T790M-positive patients). In the T790M-positive group, median progression-free survival was 16·0 months (12·7 to not estimable), with a 12 month progression-free survival of 68% (50-81), whereas in the T790M-negative group, median progression-free survival was 10·5 months (9·4-14·2), with a 12 month progression-free survival of 48% (36-59). Of 106 patients included in the safety analysis, five had grade 4 adverse events (one acute coronary syndrome, one biliary tract infection, one other neoplasms, and two colonic perforations) and one died due to sepsis.

Interpretation: The BELIEF trial provides further evidence of benefit for the combined use of erlotinib and bevacizumab in patients with NSCLC harbouring activating EGFR mutations.

Funding: European Thoracic Oncology Platform, Roche.
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http://dx.doi.org/10.1016/S2213-2600(17)30129-7DOI Listing
May 2017

LKB1 Expression Correlates with Increased Survival in Patients with Advanced Non-Small Cell Lung Cancer Treated with Chemotherapy and Bevacizumab.

Clin Cancer Res 2017 07 24;23(13):3316-3324. Epub 2017 Jan 24.

Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.

LKB1 is a key sensor of metabolic stress, including hypoxia and glucose deprivation, two features of the tumor microenvironment exacerbated by antiangiogenic therapy. We investigated the role of LKB1 as a potential predictive marker of sensitivity to bevacizumab in advanced non-small cell lung cancer (aNSCLC). We retrospectively analyzed LKB1 expression by IHC in 98 samples from 125 patients with aNSCLC, including 59 patients treated with chemotherapy and 39 treated with chemotherapy plus bevacizumab. IHC intensity was recoded in two classes (negative/weak vs. moderate/intense) and correlated with outcome according to treatment arm. Patient-derived tumor xenografts (PDXs) were used to investigate mechanisms involved in preclinical models. In the whole study population (125), median OS and PFS were 11.7 [95% confidence interval (CI), 9.1-15.3] and 6.7 (95% CI, 5.7-7.2) months, respectively. Differential impact of the marker on outcome of the 98 patients was highlighted according to the treatment. Patients with negative/weak LKB1 status did not have a statistically significant benefit from bevacizumab added to chemotherapy (HR for patients treated with bevacizumab: 0.89; 95% CI, 0.51-1.56; = 0.6803), whereas patients expressing moderate/intense LKB1 and receiving bevacizumab had significant lower risk of death compared with those not receiving bevacizumab (HR, 0.26; 95% CI, 0.10-0.64; = 0.0035). Loss of LKB1 was associated with reduced AMPK activation in PDXs and increased tumor necrosis following bevacizumab administration, highlighting impaired control of the metabolic stress caused by this antiangiogenic drug. Our data hint at a possible predictive impact of LKB1 expression in patients with aNSCLC treated with chemotherapy plus bevacizumab. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2410DOI Listing
July 2017

Randomized phase III PITCAP trial and meta-analysis of induction chemotherapy followed by thoracic irradiation with or without concurrent taxane-based chemotherapy in locally advanced NSCLC.

Lung Cancer 2016 10 27;100:30-37. Epub 2016 Jul 27.

Radiotherapy Unit, La Spezia Hospital, Italy.

Background: Chemo-radiotherapy is standard of care in the treatment of unresectable stage III NSCLC. We aimed at assessing whether the addition of concurrent taxane-chemotherapy to thoracic irradiation following chemotherapy was able to improve treatment outcome.

Material And Methods: In PITCAP trial, patients with unresectable stage III NSCLC were randomized to receive 2 cycles of platinum-paclitaxel followed by 60-61.2Gy thoracic irradiation (control arm) or by same radiotherapy with concomitant weekly paclitaxel (experimental arm). A literature-based meta-analysis including all studies with same design was also performed.

Results: At the time of the second interim analysis, when 151 patients were randomized, accrual was terminated. With a median follow-up of 6.1 years, median survival was 13.2 vs 15.1 months, with a 3-year survival rate of 19.5 vs 21.2% in the control and experimental arm, respectively (HR: 0.97; 95% CI 0.69-1.36; p=0.845). Treatment toxicity was manageable in both arms. The meta-analysis of 5 trials (n=866) confirmed the lack of a meaningful effect on 1-year overall survival of a taxane added concurrently to radiotherapy.

Conclusions: These results do not support a meaningful survival benefit with the addition of single agent taxane given concurrently to radiotherapy after platinum-based induction in locally advanced NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2016.07.026DOI Listing
October 2016

Radiological response and survival in locally advanced non-small-cell lung cancer patients treated with three-drug induction chemotherapy followed by radical local treatment.

Onco Targets Ther 2016 21;9:3671-81. Epub 2016 Jun 21.

Medical Oncology Unit 2, Veneto Institute of Oncology IOV-IRCCS.

Objectives: If concurrent chemoradiotherapy cannot be performed, induction chemotherapy followed by radical-intent surgical treatment is an acceptable option for non primarily resectable non-small-cell lung cancers (NSCLCs). No markers are available to predict which patients may benefit from local treatment after induction. This exploratory study aims to assess the feasibility and the activity of multimodality treatment, including triple-agent chemotherapy followed by radical surgery and/or radiotherapy in locally advanced NSCLCs.

Methods: We retrospectively collected data from locally advanced NSCLCs treated with induction chemotherapy with carboplatin (area under the curve 6, d [day]1), paclitaxel (200 mg/m(2), d1), and gemcitabine (1,000 mg/m(2) d1, 8) for three to four courses, followed by radical surgery and/or radiotherapy. We analyzed radiological response and toxicity. Estimated progression-free survival (PFS) and overall survival (OS) were correlated to response, surgery, and clinical features.

Results: In all, 58 NSCLCs were included in the study: 40 staged as IIIA, 18 as IIIB (according to TNM Classification of Malignant Tumors-7th edition staging system). A total of 36 (62%) patients achieved partial response (PR), and six (10%) progressions were recorded. Grade 3-4 hematological toxicity was observed in 36 (62%) cases. After chemotherapy, 37 (64%) patients underwent surgery followed by adjuvant radiotherapy, and two patients received radical-intent radiotherapy. The median PFS and OS were 11 months and 23 months, respectively. Both PFS and OS were significantly correlated to objective response (P<0.0001) and surgery (P<0.0001 and P=0.002). Patients obtaining PR and receiving local treatment achieved a median PFS and OS of 35 and 48 months, respectively. Median PFS and OS of patients not achieving PR or not receiving local treatment were 5-7 and 11-15 months, respectively. The extension of surgery did not affect the outcome.

Conclusion: The multimodality treatment was feasible, and triple-agent induction was associated with a considerable rate of PR. Patients achieving PR and receiving radical surgery or radiotherapy (53%) achieved a median OS of 4 years.
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http://dx.doi.org/10.2147/OTT.S98435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922786PMC
July 2016

Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer.

BMC Cancer 2016 05 14;16:312. Epub 2016 May 14.

Catalan Institute of Oncology, Barcelona, Spain.

Background: BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality to improve the BRCA1 predictive model.

Methods: We retrospectively analyzed 71 paraffin-embedded tumor samples from advanced non-small-cell lung cancer patients treated with first-line platinum based chemotherapy and measured the mRNA expression levels of BRCA1, RNF8, UBC13 and HERC2 using real-time PCR. The mRNA expression was categorized using median value as cut-off point.

Results: The median progression-free survival of all 71 patients was 7.2 months whereas the median overall survival of the study population was 10.7 months. Among patients with low BRCA1 expression, the median PFS was 7.4 months in the presence of low HERC2 levels and 5.9 months for patients expressing high HERC2 levels (p = 0.01). The median OS was 15.3 months for patients expressing low levels of both genes and 7.4 months for those with low BRCA1 but high HERC2 (p = 0.008). The multivariate analysis showed that among patients with Eastern Cooperative Oncology Group performance status 0-1, the combined low expression of both BRCA1 and HERC2 clearly reduced the risk of progression (p = 0.03) and of death (p = 0.004).

Conclusions: These findings confirm the potentiality of integrated DNA repair components analysis in predicting the sensitivity to platinum in lung cancer. The study indicates a predictive role for HERC2 mRNA expression and paves the way for further refinement of the BRCA1 predictive model.
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http://dx.doi.org/10.1186/s12885-016-2339-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868003PMC
May 2016

Morphological and genetic heterogeneity in multifocal lung adenocarcinoma: The case of a never-smoker woman.

Lung Cancer 2016 06 25;96:52-5. Epub 2016 Mar 25.

Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, via Gattamelata 64, 35128 Padova, Italy. Electronic address:

Discrimination of multifocal primary lung cancers from lung metastases is crucial to allow for an appropriate clinical management. We report here a case of multifocal lung adenocarcinomas with different morphological and molecular patterns. Radical surgery of one lung nodule was performed at the time of diagnosis, and subsequently on two other lung nodules. At the time of distant relapse, biopsy was repeated for molecular characterization. The patient was treated with EGFR tyrosine kinase inhibitor according to the detection of EGFR exon 21 mutation in metastatic sample and in one of the three lung tumors, characterized by lower mutated allele frequency. The progression free survival was three months according to radiological criteria and the treatment was provided for six months, until clinical progression. Following the assessment of EGFR mutations by pyrosequencing, tumor samples were analyzed by a 30-gene next generation sequencing (NGS) panel, allowing to study intra- and inter-tumor heterogeneity and to confirm the three lung tumors as independent. Different molecular profiles of synchronous tumors and identical EGFR, PIK3CA and TP53 mutations in one of three primary lung tumors and the metachronous metastasis were identified. In conclusion, morphological and molecular characterization of multiple lung nodules by NGS may help to define synchronous and metachronous adenocarcinomas, thus affecting surgical indication and systemic treatment. Intratumor heterogeneity may be associated with differential sensitivity to targeted treatment.
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http://dx.doi.org/10.1016/j.lungcan.2016.03.009DOI Listing
June 2016

Squamous cell carcinomas of the lung and of the head and neck: new insights on molecular characterization.

Oncotarget 2016 May;7(18):25050-63

Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy.

Squamous cell carcinomas of the lung and of the head and neck district share strong association with smoking habits and are characterized by smoke-related genetic alterations. Driver mutations have been identified in small percentage of lung squamous cell carcinoma. In parallel, squamous head and neck tumors are classified according to the HPV positivity, thus identifying two different clinical and molecular subgroups of disease.This review depicts different molecular portraits and potential clinical application in the field of targeted therapy, immunotherapy and chemotherapy personalization.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041888PMC
http://dx.doi.org/10.18632/oncotarget.7732DOI Listing
May 2016

MDM2 and HIF1alpha expression levels in different histologic subtypes of malignant pleural mesothelioma: correlation with pathological and clinical data.

Oncotarget 2015 Dec;6(39):42053-66

Department of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, Italy.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited treatment options. Sarcomatoid/biphasic mesotheliomas are characterized by more aggressive behaviour and a poorer prognosis compared with the epithelioid subtype. To date prognostic and tailored therapeutic biomarkers are lacking. The present study analyzed the expression levels of MDM2 and HIF1alpha in different histologic subtypes from chemonaive MPM patients. Diagnostic biopsies of MPM patients from four Italian cancer centers were centrally collected and analyzed. MDM2 and HIF1alpha expression levels were investigated through immunohistochemistry and RT-qPCR. Pathological assessment of necrosis, inflammation and proliferation index was also performed. Molecular markers, pathological features and clinical characteristics were correlated to overall survival (OS) and progression free survival (PFS). Sixty MPM patients were included in the study (32 epithelioid and 28 non-epithelioid). Higher levels of MDM2 (p < 0.001), HIF1alpha (p = 0.013), necrosis (p = 0.013) and proliferation index (p < 0.001) were seen mainly in sarcomatoid/biphasic subtypes. Higher levels of inflammation were significantly associated with epithelioid subtype (p = 0.044). MDM2 expression levels were correlated with HIF1alpha levels (p = 0.0001), necrosis (p = 0.008) and proliferation index (p = 0.009). Univariate analysis showed a significant correlation of non-epithelioid histology (p = 0.04), high levels of necrosis (p = 0.037) and proliferation index (p = 0.0002) with shorter PFS. Sarcomatoid/biphasic and epithelioid mesotheliomas showed different MDM2 and HIF1alpha expression levels and were characterized by different levels of necrosis, proliferation and inflammation. Further studies are warranted to confirm a prognostic and predictive role of such markers and features.
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http://dx.doi.org/10.18632/oncotarget.5974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747209PMC
December 2015

Non-Small Cell Lung Cancer in a Very Young Woman: A Case Report and Critical Review of the Literature.

Am J Case Rep 2015 Nov 3;16:782-9. Epub 2015 Nov 3.

Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy.

Background: Lung cancer in young patients is quite uncommon; clinical presentation and outcome in this population compared to the older group are not yet well defined and data about this setting are mostly single-institutional retrospective analyses.

Case Report: We report here a case of a very young woman with diagnosis of early-stage lung adenocarcinoma harboring EML4-ALK rearrangement; she underwent radical surgery and adjuvant chemotherapy according to the pathologic stage. Potential risk factors for lung cancer in our patient are discussed and clinico-pathologic features and outcomes of lung cancer in the young population compared to the elderly are reviewed through discussing studies with sample sizes larger than 100 patients.

Conclusions: A wide clinical overview should be performed when lung cancer is diagnosed in a young patient. Large-population studies are required to define the molecular signature and clinical behavior of lung cancer in young patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642365PMC
http://dx.doi.org/10.12659/ajcr.894426DOI Listing
November 2015

Critical review about MDM2 in cancer: Possible role in malignant mesothelioma and implications for treatment.

Crit Rev Oncol Hematol 2016 Jan 22;97:220-30. Epub 2015 Aug 22.

Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy. Electronic address:

The tumor suppressor p53 regulates genes involved in DNA repair, metabolism, cell cycle arrest, apoptosis and senescence. p53 is mutated in about 50% of the human cancers, while in tumors with wild-type p53 gene, the protein function may be lost because of overexpression of Murine Double Minute 2 (MDM2). MDM2 targets p53 for ubiquitylation and proteasomal degradation. p53 reactivation through MDM2 inhibitors seems to be a promising strategy to sensitize p53 wild-type cancer cells to apoptosis. Moreover, additional p53-independent molecular functions of MDM2, such as neoangiogenesis promotion, have been suggested. Thus, MDM2 might be a target for anticancer treatment because of its antiapoptotic and proangiogenetic role. Malignant pleural mesothelioma (MPM) is an aggressive asbestos-related tumor where wild-type p53 might be present. The present review gives a complete landscape about the role of MDM2 in cancer pathogenesis, prognosis and treatment, with particular focus on Malignant Pleural Mesothelioma.
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http://dx.doi.org/10.1016/j.critrevonc.2015.08.019DOI Listing
January 2016

Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or Metastatic Nonsquamous Non-Small-Cell Lung Cancer.

J Clin Oncol 2015 Aug 13;33(24):2667-74. Epub 2015 Jul 13.

Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ.

Purpose: Tivantinib, a MET receptor tyrosine kinase inhibitor, demonstrated increased anticancer activity in preclinical and early clinical studies when combined with erlotinib. Our study aimed to confirm efficacy and safety of the combination in previously treated patients with non-small-cell lung cancer (NSCLC).

Patients And Methods: Patients with advanced nonsquamous NSCLC previously treated with one to two systemic regimens, including a platinum doublet, were randomly assigned at a 1:1 ratio to receive erlotinib 150 mg daily plus oral tivantinib 360 mg twice daily (E + T) or erlotinib plus placebo (E + P) until disease progression. Tumor specimens were evaluated for EGFR and KRAS mutations, MET expression, and MET gene amplification. The primary end point was overall survival (OS). Secondary and exploratory objectives included progression-free survival (PFS), OS in molecular subgroups, and safety.

Results: The study enrolled 1,048 patients and was discontinued for futility at the interim analysis. OS did not improve with E + T versus E + P (median OS, 8.5 v 7.8 months, respectively; hazard ratio [HR], 0.98; 95% CI, 0.84 to 1.15; P = .81), even though PFS increased (median PFS, 3.6 v 1.9 months; HR, 0.74; 95% CI, 0.62 to 0.89; P < .001). Exploratory subgroup analyses suggested OS improvement in patients with high MET expression (HR, 0.70; 95% CI, 0.49 to 1.01). Most common adverse events occurring with E + T versus E + P were rash (33.1% v 37.3%, respectively), diarrhea (34.6% v 41.0%), asthenia or fatigue (43.5% v 38.1%), and neutropenia (grade 3 to 4; 8.5% v 0.8%).

Conclusion: E + T was well tolerated and increased PFS but did not improve OS in the overall nonsquamous NSCLC population.
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http://dx.doi.org/10.1200/JCO.2014.60.7317DOI Listing
August 2015

Treatment of Unfit Patients With Advanced Non-Small-Cell Lung Cancer: Definition Criteria According an Expert Panel.

Clin Lung Cancer 2015 Nov 30;16(6):399-405. Epub 2015 Apr 30.

"SG Moscati" Hospital, Avellino, Italy.

The assessment of special categories of non-small-cell lung cancer (NSCLC) patients requires a comprehensive analysis of all factors potentially influencing the daily quality of life and the relative contribution of tumor-related symptoms on the overall patient health status. While for elderly patients prospective evidence and recommendations allow clinicians to better address their patients to a shared treatment, a paucity of reliable data refers to treatment opportunities for these patients, termed frail or unfit, who are not considered eligible for chemotherapy usually administered to adult patients. This consensus was inspired by the absence of clear criteria to define the category of unfit patients in the context of advanced NSCLC in order to share all the available tools for their classification and evaluation and to support decisions for clinical practice on a daily basis. After review of the literature and panelist consensus, a series of items was identified as relevant: age, performance status, renal function, heart failure, previous cerebrovascular events, uncontrolled hypertension, neuropathy, hearing loss, symptomatic brain metastases, severe psychiatric disorders, and absence of caregiver support. On the basis of these factors, a treatment algorithm for clinical practice to categorize unfit NSCLC patient into 3 major clinical scenarios was defined: (1) unfit for cisplatin-based chemotherapy, (2) unfit for carboplatin-based chemotherapy, and (3) unfit for single-agent chemotherapy.
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http://dx.doi.org/10.1016/j.cllc.2015.04.008DOI Listing
November 2015

Epirubicin plus paclitaxel regimen as second-line treatment of patients with small-cell lung cancer.

Anticancer Res 2015 Apr;35(4):2183-9

Medical Oncology 2, Venetian Oncological Institute, Padova, Italy.

Background/aim: Most patients with small cell lung cancer (SCLC) experience relapse within one year after first-line treatment. The aim of this study was to describe activity and safety of second-line with epirubicin at 70 mg/m(2) followed by paclitaxel at 135 mg/m(2) on day 1 every three weeks for a maximum of six cycles.

Patients And Methods: This is a retrospective review of all patients with SCLC evaluated for second-line treatment between 2003 and 2013 at our Institution.

Results: Sixty-eight patients received the study regimen of epirubicin with paclitaxel. We observed partial response in 19 (30%), stable disease in 22 (34%) and total early failure rate in 23 (36%) patients. Median progression free and overall survival were 21.8 and 26.5 weeks, respectively. Haematological toxicities were as follows: grade 3-4 leukopenia and neutropenia in 18 (31%) and 30 (22%) of patients, respectively; grade 3 anaemia and grade 4 thrombocytopenia were reported in 2 (3%) and 5 (9%) of patients, respectively.

Conclusion: Epirubicin with paclitaxel is an active and tolerable second-line regimen in patients with SCLC.
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April 2015

Results of surgical resection after induction chemoradiation for Pancoast tumours †.

Interact Cardiovasc Thorac Surg 2015 Jun 10;20(6):805-11; discussion 811-2. Epub 2015 Mar 10.

Department of Cardiologic, Thoracic and Vascular Sciences, Thoracic Surgery Unit, University of Padova, Padova, Italy.

Objectives: Pancoast tumour is a rare neoplasia in which the optimal therapeutic management is still controversial. The traditional treatment of Pancoast tumour (surgery, radiotherapy or a combination of both) have led to an unsatisfactory outcome due to the high rate of incomplete resection and the lack of local and systemic control. The aim of the study was to determine the efficacy of the trimodality approach.

Methods: Fifty-six patients (male/female ratio: 47/9, median age: 64 years) in stage IIB to IIIB were treated during a period between 1994 and 2013. Induction therapy consisted of 2-3 cycles of a platinum-based chemotherapy associated with radiotherapy (30-44 Gy). After restaging, eligible patients underwent surgery 2 to 4-week post-radiation.

Results: Thirty-two (57.1%) patients were cT3 and 24 (42.9%) cT4, 47 (83.9%) were N0 and 9 (16.1%) N+. Forty-eight (85.7%) patients underwent R0 resection and 10 (17.9%) had a complete pathological response (CPR). Thirty-day mortality rate was 5.4%, major surgical complications occurred in 6 (10.7%) patients. At the end of the follow-up, 17 (30.4%) patients were alive and 39 (69.6%) died (29 for cancer-related causes), with an overall 5-year survival of 38%. At statistical analysis, stage IIB (P = 0.003), R0 resection (P = 0.03), T3 tumour (P = 0.002) and CPR (P = 0.01) were significant independent predictors of better prognosis.

Conclusions: This combined approach is feasible, and allows for a good rate of complete resection. Long-term survival rates are acceptable, especially for early stage tumours radically resected. Systemic control of disease still remains poor, with distant recurrence being the most common cause of death.
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http://dx.doi.org/10.1093/icvts/ivv032DOI Listing
June 2015

Symptomatic toxicities experienced during anticancer treatment: agreement between patient and physician reporting in three randomized trials.

J Clin Oncol 2015 Mar 26;33(8):910-5. Epub 2015 Jan 26.

Massimo Di Maio, Maria Carmela Piccirillo, Gennaro Daniele, Francesco Nuzzo, Andrea de Matteis, Jane Bryce, Alessandro Morabito, Gaetano Rocco, and Francesco Perrone, Istituto Nazionale Tumori-Fondazione "G. Pascale" Istituto di Ricovero e Cura a Carattere Scientifico; Ciro Gallo, Fortunato Ciardiello, and Simona Signoriello, Second University; Sabino De Placido, Federico II University, Napoli; Cesare Gridelli, S.G. Moscati Hospital, Avellino; Vittorio Gebbia, Istituto La Maddalena, Palermo; Anna Ceribelli, Regina Elena National Cancer Institute, Roma; Adolfo G. Favaretto, Istituto Oncologico Veneto, Padova, Italy; Natasha B. Leighl and Ronald Feld, Princess Margaret Hospital/University Health Network, Toronto; and Charles Butts, Cross Cancer Institute, Edmonton, Alberta, Canada.

Purpose: Information about symptomatic toxicities of anticancer treatments is not based on direct report by patients, but rather on reports by clinicians in trials. Given the potential for under-reporting, our aim was to compare reporting by patients and physicians of six toxicities (anorexia, nausea, vomiting, constipation, diarrhea, and hair loss) within three randomized trials.

Patients And Methods: In one trial, elderly patients with breast cancer received adjuvant chemotherapy; in two trials, patients with advanced non-small-cell lung cancer received first-line treatment. Toxicity was prospectively collected by investigators (graded by National Cancer Institute Common Toxicity Criteria [version 2.0] or Common Terminology Criteria for Adverse Events [version 3]). At the end of each cycle, patients completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaires, including toxicity-related symptom items. Possible answers were "not at all," "a little," "quite a bit," and "very much." Analysis was limited to the first three cycles. For each toxicity, agreement between patients and physicians and under-reporting by physicians (ie, toxicity reported by patients but not reported by physicians) were calculated.

Results: Overall, 1,090 patients (2,482 cycles) were included. Agreement between patients and physicians was low for all toxicities. Toxicity rates reported by physicians were always lower than those reported by patients. For patients who reported toxicity (any severity), under-reporting by physicians ranged from 40.7% to 74.4%. Examining only patients who reported "very much" toxicity, under-reporting by physicians ranged from 13.0% to 50.0%.

Conclusion: Subjective toxicities are at high risk of under-reporting by physicians, even when prospectively collected within randomized trials. This strongly supports the incorporation of patient-reported outcomes into toxicity reporting in clinical trials.
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http://dx.doi.org/10.1200/JCO.2014.57.9334DOI Listing
March 2015