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Background Cabozantinib, a potent multi-tyrosine kinases inhibitor (TKI), has demonstrated overall survival (OS) benefit over everolimus in patients previously treated with VEGFR TKI for metastatic Renal Cell Carcinoma (mRCC). The efficacy of systemic treatments after cabozantinib failure has not been investigated. Methods We conducted a retrospective study on patients receiving systemic treatment after cabozantinib failure in heavily pre-treated patient with mRCC. We assessed Time to Treatment Failure (TTF), OS and objective response rate (ORR). Results Among 150 patients treated with cabozantinib in our institution, 56 (37.3%) received subsequent systemic therapy and were eligible for the analysis. IMDC prognostic group was good, intermediate and poor in 11 (19.6%), 24 (42.9%) and 11 (19.6%) patients, respectively. Cabozantinib was administered mainly as a second (41.1%), or third (33.9%) line treatment. axitinib or immune-checkpoint inhibitors were the subsequent treatment in 18 (34.8%) patients for each everolimus (n:16, 28.6%), other angiogenesis inhibitors (n:4, 7.1%) TTF and OS from subsequent systemic therapy after cabozantinib failure were 2.8 months (95%CI 1.9-3.7) and 7.7 months (95%CI 4.4-10.8), respectively. ORR was 8.7% and two patients with axitinib and two patients treated with Immune checkpoint inhibitors achieved a partial response. Conclusions Overall, activity of systemic therapies after cabozantinib was limited. Micro abstract We performed a retrospective analysis on 56 patients with metastatic renal cell carcinoma who received at least 1 systemic treatment line after cabozantinib. Median OS after cabozantinib was 7.7 months, while median TTF after cabozantinib was 2.8 months. Further investigation is needed in this clinical context

Background: To date, no prospective study has been conducted to investigate the role of socioeconomic status (SES) on clinical outcome of glioblastoma (GBM) in Italy, where there is a National Health Service that provides universal coverage regardless of the patient's economic status. Methods: We performed a prospective observational study investigating the association between SES and survival in GBM patients at our institution, a hub centre for brain cancer research and treatment. We included GBM patients who underwent medical treatment or chemo-radiation between April 2017 and December 2017. The SES was measured using the income-brackets, attributed by the Italian Ministry of Finance on the basis of the income of the fiscal family unit, referring to the previous year. Results: One hundred and six patients were included in the study. In multivariate analysis, overall survival (OS) correlated significantly with higher-income (HR = 0.623.95% CI 0.467–0.832; p = 0.001) and MGMT methylation status (HR = 0.158.95% CI 0.082–0.304; P < 0.001). When adjusted for age, performance status and extension of surgery, survival benefit remained superior for higher-income HR = 0.641 (95% CI 0.478–0.858; p = 0.003) and MGMT methylated tumours HR = 0.167 (95% CI 0.084–0.331; p < 0.001). Conclusions: SES is an important determinant of prognosis in GBM even in the Italian National Health Service, which provides universal, largely free and relatively comprehensive healthcare. Despite aspirations to achieve equality in healthcare, socioeconomic differences exist and may impact the clinical outcome.

The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria have been largely adopted in clinical practice. In a recent retrospective study, we assessed that the addition of the first site of metastatic disease to brain, bone, and liver improves prognostic stratification of patients with metastatic renal cell carcinoma (mRCC). Here, we performed an external validation in patients with mRCC. Our aim was to evaluate if the addition of a new independent variable could improve IMDC prognosis prediction and reduce heterogeneity within risk categories.We selected all 1073 patients treated at a single institution for mRCC and included in the Institute Gustave Roussy Renal Cell Carcinoma database. All patients included received at least 1 line of targeted therapy or immune checkpoint inhibitors. Univariate and multivariate analyses (Cox regression model) were performed. Bootstrap validation of the final model was also carried out for internal validation. The IMDC modified classification was defined by the addition of the seventh variable, and we defined the modified IMDC good-risk criteria as 0 risks, intermediate-risk as 1 to 2 risks, and poor-risk as 3 or more risks.The presence of brain, bone, and/or liver as the first site of metastatic disease plus the other variables included in the IMDC score were statistically significant variables associated with overall survival (OS) after univariate and multivariate analysis and bootstrap validation. Finally, 122 (15%) patients had a modification of their initial risk category. The median OS in the poor-, intermediate-, and favorable-risk groups was 10, 26, and 52 months, respectively (P .001). The bias-corrected concordance index in patients receiving immune checkpoint inhibitors (n = 241) was 0.71.The addition of brain, bone, and/or liver metastases as an additional variable to the other IMDC variables improves the prognostic predictive power of the model.

Background Several models are adopted in clinical practice to estimate prognosis of patients with metastatic renal cell carcinoma (mRCC); however, none of these models have evaluated patients treated by immune-checkpoint inhibitors. The aim of this study was to investigate if the site of initial metastasis could be a parameter able to stratified prognosis among patients with mRCC among different risk groups defined by the International Metastatic Renal Cell Database Consortium (IMDC) model. The site of initial metastasis was defined as the primary tissue or organ in which metastasis was diagnosed in the course of the medical history of the disease. Patients and Methods A total of 134 patients treated between January 2010 and December 2018 in our institution were retrospectively evaluated. The primary outcome was overall survival (OS) defined as the time from initiation of first-line therapy to death from any cause. Of note, 26 (19.4%) patients received immune-checkpoint inhibitors. Univariable analysis was performed through the log-rank test to estimate the effect of number of metastatic sites and site of initial metastasis on OS. Subsequently, a Cox regression proportional hazards model was employed in multivariable analysis. Results Of the 12 variables analyzed, 4 were statistically associated to worse OS in univariable analysis (number of metastases and liver, bone, or central nervous system metastases). Multivariate analysis confirmed that bone (hazard ratio [HR], 1.92; 95% confidence interval [CI], 1.17-3.13), liver (HR, 2.65; 95% CI, 1.59-4.42), and central nervous system (HR, 3.3; 95% CI, 1.62-6.74) initial metastases were independent parameters related to worse OS. The presence of 1 or more of the selected sites recognized specific populations of patients associated to worse prognosis in both good (P = .003) and intermediate (P = .047) risk groups. Conclusion The site of initial metastasis defines specific populations of patients associated with worse prognosis in the good and intermediate IMDC groups.

In the past few years several hormonal agents have been tested in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) leading to an impressive improvement in terms of metastases-free survival (MFS). We performed a meta-analysis aimed to: (1) estimate the pooled effect of new hormonal compounds in terms of MFS, overall survival (OS) in overall and specific subpopulations; and (2) estimate the effect of high-grade toxicities of these drugs. We identified 881 studies published between January 1, 2010 and February 16, 2018 on PubMed/Medline, Cochrane Library, and Scopus. Three randomized placebo controlled clinical trials were selected (PROSPER, SPARTAN, and ARAMIS). Because of the absence of individual data, all of the analyses performed were made on aggregated data provided in selected studies. We used the inverse variance technique for the meta-analysis of the hazard ratios collected for MFS and OS analysis. Fixed and randomized models were used. Relative risk and 95% confidence intervals and risk difference were estimated considering the number of Grade 3 adverse events in treatment and control arms. Administration of new hormonal compounds in nmCRPC patients led to a significant benefit in MFS in the overall population and in all subgroups analyzed. These agents might also improve OS but longer follow-up is needed to confirm this hypothesis. Indeed results of OS analysis should be carefully evaluated because none of the studies selected provided mature OS data. Administration of these agents resulted in a significant increased risk of treatment-related death, high cardiovascular toxicity, hypertension, fractures, and falls. Administration of new hormonal compounds prolongs the time of metastases occurrence and might prolong also survival in patients with nmCRPC. Treatment-related toxicity is an important issue because these agents increase the risk of death, cardiovascular toxicity, hypertension, fractures, and risk of falls.

Although tyrosine kinase inhibitors (TKIs) are widely used in the metastatic setting, they have shown more limited effectiveness in the adjuvant setting. Despite multiple clinical trials, there has been no improvement in overall survival (OS) with the use of these agents as adjuvant therapy, and conflicting data on disease-free survival (DFS). We carried out a meta-analysis of available phase III randomized clinical trials on adjuvant TKIs in clear-cell renal cell carcinoma (RCC). Primary end points of our study were the effect of adjuvant TKIs on OS and DFS in the overall population. Furthermore, we investigated if use of adjuvant TKIs resulted in improved DFS among patients with different risk of tumor relapse. Higher-risk patients were patients with 1 or more of the following features: positive nodes (N+), T4 tumors and T3 tumors, with higher Fuhrman grades (3-4). We adopted Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to carry out our study. In the overall population, the pooled hazard ratio (HR) of OS and DFS was 0.89 (95% confidence interval [CI], 0.76-1.04) and 0.84 (95% CI, 0.76-0.93), respectively. In the low- and high-risk populations, the pooled DFS HR was 0.98 (95% CI, 0.82-1.17) and 0.85 (95% CI, 0.75-0.97), respectively. Adjuvant use of TKIs do not appear to provide a statistically significant OS benefit. However, a benefit in DFS has been observed in overall and high-risk populations, suggesting that better selection of patients might be important for the evaluation of adjuvant therapies in RCC.

Chemotherapy has represented the standard therapy for unresectable or metastatic urothelial carcinoma for more than 20 years. The growing knowledge of the interaction between tumour and immune system has led to the advent of new classes of drugs, the immune-checkpoints inhibitors, which are intended to change the current scenario. To date, immunotherapy is able to improve the overall responses and survival. Moreover, thanks to its safety profile immune-checkpoint inhibitors could be proposed also to patients unfit for standard chemotherapy. No doubts that these agents have started a revolution expected for years, but despite this encouraging results it appears clear that not all subjects respond to these agents and requiring the development of reliable predictive response factors able to isolate patients who can more benefit from these treatments as well as new strategies aimed to improve immunotherapy clinical outcome. In this review we describe the active or ongoing clinical trials involving Programmed Death Ligand 1 (PD-L1), Programmed Death receptor 1 (PD-1) and Cytotoxic-T Lymphocyte Antigen 4 (CTLA 4) inhibitors in urothelial carcinoma focusing our attention on the developing new immune-agents and combination strategies with immune-checkpoint inhibitors.

Background anaplastic lymphoma kinase (ALK) overexpression and gene alterations have been detected in several malignancies, with prognostic and therapeutic implications. However, few studies investigated the correlation between ALK altered expression and prognosis in patients with glioblastoma (GBM). Methods We performed an evaluation of ALK overexpression and structural/quantitative chromosome alterations through immune-histochemical assay (IHC with D5F3 antibody) and fluorescent in situ hybridization (FISH) in patients with isocitrate dehydrogenase (IDH) wild type (wt) GBM. Assuming an ALK overexpression in 20 % of patients we planned a sample of 44 patients to achieve a probability of 90 % to include from 10 % to 30 % of patients with ALK alterations. Results We evaluated 44 patients with IDH wt GBM, treated in our institution and dead due to GBM progression in 2017. ALK overexpression obtained by a composed score (the product of IHC intensity staining and rate of positive cells) was observed in 19 (43 %) patients. FISH analysis showed that 11 patients (25 %) had gene deletion, 2 patients (4.5 %) had monosomy and one patient (2.3 %) presented polysomy. Only one patient (2.3 %) demonstrated ALK rearrangement. There was no statistical difference in median OS between patients with ALK-positive (mOS = 18.9 months) and ALK-negative IHC (mOS = 18.0 months). Conclusion We identified some rare previously unreported alterations of ALK gene in patients with IDH wt GBM. In these patients, the ALK overexpression does not influences survival.