Matteo Perrino

Thymidylate Synthase and Excision Repair Cross-Complementing Group-1 as Predictors of Responsiveness in Mesothelioma Patients Treated with Pemetrexed/Carboplatin

Purpose: The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting. Experimental design: Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients. Results: A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P = 0.027), longer progression-free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease (P = 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome. Conclusions: In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted. Clin Cancer Res; 17(8); 2581–90. ©2011 AACR.

Increased SOX2 Gene Copy Number Is Associated with FGFR1 and PIK3CA Gene Gain in Non-Small Cell Lung Cancer and Predicts Improved Survival in Early Stage Disease

Background We aimed to investigate prevalence and prognostic role of SOX2, PIK3CA, FGFR1 and BRF2 gene gain in patients with surgically resected non-small cell lung cancer (NSCLC). Methods SOX2, PIK3CA, FGFR1 and BRF2 gene copy number was assessed by fluorescence in situ hybridization (FISH) in arrayed tissue cores from 447 resected NSCLCs. Results Increased gene copy number (FISH+) for SOX2, PIK3CA, FGFR1 and BRF2 was observed in 23.6%, 29.2%, 16.6% and 14.9% of cases, respectively. FISH+ status for each gene was significantly associated with smoking history, squamous cell carcinoma (SCC) histology, and increased copy number of the other studied genes. Multivariate analysis of overall survival indicated increased SOX2 gene copy number (P = 0.008), stage I-II (P<0.001), and adenocarcinoma or SCC histology (P = 0.016) as independent, favorable prognostic factors. A statistically significant interaction was observed between stage and SOX2 gene status (P = 0.021), indicating that the prognostic impact of SOX2 gene gain differs across stages and is limited to patients with stage I-II disease (HR 0.44, 95% CI: 0.25–0.77; P = 0.004, adjusted for histology). Conclusions Increased SOX2 gene copy number is an independent and favorable prognostic factor in surgically resected, early stage NSCLC, regardless of histology. SOX2, PIK3CA, FGFR1 and BRF2 gene gains are likely to occur concurrently, with potentially relevant implications for the development of new therapeutic strategies.

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

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.

Phase I and pharmacodynamic study of high-dose NGR–hTNF in patients with refractory solid tumours

Background:NGR–hTNF exploits the peptide asparagine–glycine–arginine (NGR) for selectively targeting tumour necrosis factor (TNF) to CD13-overexpressing tumour vessels. Maximum-tolerated dose (MTD) of NGR–hTNF was previously established at 45 μg m−2 as 1-h infusion, with dose-limiting toxicity being grade 3 infusion-related reactions. We explored further dose escalation by slowing infusion rate (2-h) and using premedication (paracetamol).Methods:Four patients entered each of 12 dose levels (n=48; 60–325 μg m−2). Pharmacokinetics, soluble TNF receptors (sTNF-R1/sTNF-R2), and volume transfer constant (Ktrans) by dynamic imaging (dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)) were assessed pre- and post-treatment.Results:Common related toxicity included grade 1/2 chills (58%). Maximum-tolerated dose was not reached. Both Cmax (P<0.0001) and area under the plasma concentration–time curve (P=0.0001) increased proportionally with dose. Post-treatment levels of sTNF-R2 peaked significantly higher than sTNF-R1 (P<0.0001). Changes in sTNF-Rs, however, did not differ across dose levels, suggesting a plateau effect in shedding kinetics. As best response, 12/41 evaluable patients (29%) had stable disease. By DCE-MRI, 28/37 assessed patients (76%) had reduced post-treatment Ktrans values (P<0.0001), which inversely correlated with NGR–hTNF Cmax (P=0.03) and baseline Ktrans values (P<0.0001). Lower sTNF-R2 levels and greater Ktrans decreases after first cycle were associated with improved survival.Conclusion:asparagine–glycine–arginine–hTNF can be safely escalated at doses higher than MTD and induces low receptors shedding and early antivascular effects.

Phase I pharmacokinetic and pharmacodynamic study of lapatinib in combination with sorafenib in patients with advanced refractory solid tumors.

BACKGROUND The epidermal growth factor receptor (EGFR) and ERBB2 (HER2) pathways and vascular endothelial growth factor (VEGF)-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and implicated in acquired resistance to targeted therapies making them attractive candidates for joined targeting. We undertook this phase I trial to assess the safety, the recommended dose for phase II trials (RPTD), pharmacokinetics (PK), pharmacodynamics (PD), and the preliminary antitumour activity of the combination of lapatinib and sorafenib in patients with advanced refractory solid tumours. METHODS Four cohorts of at least three patients each received lapatinib once daily and sorafenib twice daily together on a continuous schedule. Doses of lapatinib and sorafenib were escalated based on dose-limiting toxicities (DLTs) in the first treatment cycle following a traditional 3+3 design until the RPTD was reached. Additional patients were treated at the RPTD to characterise PK profiles of this combination and to investigate the potential interaction between lapatinib and sorafenib. Serum samples were collected at baseline and then prospectively every two cycles to assess changes in PD parameters. This trial is registered with ClinicalTrials.gov, number NCT00984425. FINDINGS Thirty patients with advanced refractory solid tumours were enroled. DLTs were grade three fatigue and grade 3 atypical skin rash observed at dose levels 3 and 4, respectively. The higher dose level explored (lapatinib 1250mg/day and sorafenib 400mg twice daily) represented the RPTD of the combination. The most common drug-related adverse events were fatigue (68%), hypocalcemia (61%), diarrhoea (57%), lymphopaenia (54%), anorexia (50%), rash (50%), and hypophosphatemia (46%). PK analysis revealed no significant effect of sorafenib on the PK profile of lapatinib. Of the 27 assessable patients for clinical activity, one achieved a confirmed complete response, four (15%) had a partial response, and 12 (44%) achieved disease stabilisation. The disease control rate overall was 63%. INTERPRETATION Combination treatment with lapatinib and sorafenib was feasible with promising clinical activity and without significant PK interactions. Long term tolerability seems to be challenging.

Comorbidity, postoperative morbidity and survival in patients undergoing radical surgery for malignant pleural mesothelioma.

OBJECTIVES We examined a series of malignant pleural mesothelioma (MPM) patients who underwent radical surgery to explore relationships among comorbidity, postoperative morbidity and survival. METHODS A retrospective analysis was carried out of all MPM patients operated on in a single centre from 2000 to 2015. The Charlson Comorbidity Index (CCI) was used to classify patients according to their underlying condition. Postoperative complications were scored according to WHO-derived criteria. Survival comparisons were performed by Cox analysis. RESULTS Ninety-one patients underwent extrapleural pneumonectomy (EPP), 47 underwent pleurectomy decortication (PD) and 25 underwent palliative pleurectomy. The mean CCI of PD patients was significantly higher compared with that of EPP patients (P= 0.044). The frequency of grade 3+ complications was similar between EPP and PD (27 vs 26%). However, EPP patients had a 6-fold higher frequency of pleural sepsis (24 vs 4%, P= 0.002) occurring up to 695 days postoperatively. Median overall survival was 19 months (95% CI 13-25) after EPP, 30 months (95% CI 20-35) after PD and 13 months (95% CI 5-32) after palliative pleurectomy. At multivariate analysis, CCI (P< 0.001), histology (P= 0.014) and pleural sepsis (P= 0.001), but not complete resection, were significantly associated with survival. There was a trend in favour of PD over palliative resection after adjusting for histology and CCI. CONCLUSIONS The CCI is an independent predictor of survival in MPM patients undergoing radical surgery. Owing to its significant frequency and adverse impact, pleural sepsis may contribute to a reduced life expectancy after EPP. Surgical treatment of MPM remains debatable.

Best practices for the management of thymic epithelial tumors: A position paper by the Italian collaborative group for ThYmic MalignanciEs (TYME)

Thymic epithelial tumors (TETs) are a heterogenous group of rare tumors, with a complex histopatological classification. Furthermore, the recent introduction of the first TNM staging system, that is scheduled to replace the Masaoka-Koga system, may create further difficulties in TET management, that remains challenging. Several guidelines for treatment of TETs are available and provide recommendations based mainly on non randomized trials and retrospective or limited series. Often the lack of evidence leads to formulation of indications based on expert opinions. As for other rare cancers it is crucial to create networks to coordinate the work among centres involved in treatment of these diseases in order to offer the best diagnostic and therapeutic tools. For this purpose, in 2014 a network named TYME (ThYmic MalignanciEs), was founded in Italy with the aim of improving care and research in TETs. In September 2017 a panel of multidisciplinary experts from TYME network and from other Italian centres strongly involved in TET diagnosis and treatment convened a first Italian Expert meeting together with representatives of association for patients affected by rare thoracic cancers Tu.To.R, to explore how these tumors are managed in the different centres of Italy compared to ESMO guidelines. In this paper we summarize the issues discussed during that meeting and we propose recommandations based on Masaoka Koga and the new TNM staging system.

Hypofractionated radiation therapy (HFRT) versus conventional fractionated radiation therapy (CRT) for newly diagnosed glioblastoma patients. A propensity score matched analysis

BACKGROUND The current treatment for newly diagnosed glioblastoma consists of surgery followed by conventional radiotherapy (CRT) with concomitant and adjuvant chemotherapy. Hypofractionated radiation therapy (HFRT) has been investigated and it resulted feasible and safe. The aim of this study was to evaluate whether HFRT can be comparable to CRT. MATERIALS AND METHODS The analysis included newly diagnosed glioblastoma patients treated with CRT 60 Gy/30 fractions or HFRT 60 Gy/15 fractions. A propensity score matching analysis (PSM) was performed using a logistic regression that considered age, KPS, extent of surgery, MGMT and IDH status. RESULTS A total of 267 patients were included; before PSM 169 were in CRT-group and 98 in HRFT-group. After 1:1 matching, 82 patients resulted in each group. The median OS time was 17.9 months for the CRT-group and 16.7 months for the HFRT-group; the 1, 2, 3-year OS rates were 75.6%, 32.7%, and 15.5% for the CRT-group, and 75.6%, 33.3%, and 18.9% for the HFRT-group (p value = 0.8). No statistically significant differences were recorded between the two radiation therapy treatments performed. CONCLUSIONS A short course of radiation therapy would seem comparable to CRT in terms of outcome and less burdensome for these poor prognosis patients.

Prognostic and predictive role of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with unresectable malignant pleural mesothelioma (MPM) treated with up-front pemetrexed-based chemotherapy

The aim of this study was to evaluate the role of metabolic parameters analyzed at baseline and at interim FDG‐PET in predicting disease outcome in unresectable MPM patients receiving pemetrexed‐based chemotherapy. A consecutive series of MPM patients treated between February 2004 and July 2013 with first‐line pemetrexed‐based chemotherapy, and evaluated by FDG‐PET and CT scan at baseline and after two cycles of chemotherapy, was reviewed. Best CT scan response was assessed according to modified RECIST criteria. Progression‐free survival (PFS) and overall survival (OS) were correlated with FDG‐PET parameters, such as maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and percentage changes in SUVmax (∆SUV) and TLG (∆TLG). Overall, 142 patients were enrolled; 77 (54%) received talc pleurodesis before chemotherapy. Baseline SUVmax and TLG showed a statistically significant correlation with PFS and OS (P < 0.05) in both group of patients (treated and untreated with pleurodesis). In 65 patients not receiving pleurodesis, SUVmax reduction ≥25% (∆SUV ≥ 25%) and TLG reduction ≥30% (∆TLG ≥ 30%) were significantly associated with longer PFS (P < 0.05). Patients showing both ∆SUV ≥ 25% and ∆TLG ≥ 30% responses had a significant reduction in the risk of disease progression (HR:0.31, P < 0.001) and death (HR:0.52, P = 0.044). Neither ∆SUV nor ∆TLG showed similar association with survival outcomes in patients treated with pleurodesis. Our study confirmed the prognostic role of baseline FDG‐PET in a large series of MPM patients treated with first‐line pemetrexed‐based chemotherapy. Moreover, use of ∆SUV ≥ 25% and ∆TLG ≥ 30% as cut‐off values to define early metabolic response supported the role of FDG‐PET in predicting disease outcome and treatment response in patients not receiving pleurodesis.

Outcome evaluation of patients with newly diagnosed anaplastic gliomas treated in a single institution

AIM To evaluate the outcome of newly diagnosed anaplastic glioma patients treated in our institution in relation to the 2016 WHO classification suggestions. METHODS This retrospective study included patients who underwent surgery plus adjuvant chemotherapy alone or concomitant and adjuvant chemoradiotherapy. Response was recorded using the Response Assessment in Neuro-Oncology criteria. RESULTS 123 patients were analyzed. The median progression-free survival time and the 2, 3 and 5 years progression-free survival rate were 27 months, 65.5, 21.2 and 21.2%; the 2, 3 and 5 years overall survival rate were 89.7, 83.0 and 58.4%. From the univariate/multivariate analysis, the factors conditioning survival were Karnofsky performance scale, extent of resection, IDH1 mutation status and presence of 1p/19q codeletion. CONCLUSION The choice of adjuvant treatment have to consider molecular assessment and, in our experience, the extent of surgical resection.