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The objective of the current research was to explore the potential prognostic value of readily available clinical and pathologic variables in bladder cancer. The novel association found between cholesterol levels and prognosis may provide the rationale for exploring novel treatments. Patients included had histologically confirmed urothelial bladder cancer and were treated with at least 3 cycles of cisplatin-based neoadjuvant chemotherapy before radical cystectomy with lymphadenectomy. A total of 245 patients at low, intermediate and high risk, presenting with 0-1, 2 or 3-4 risk factors, including positive lymph nodes, Hb 12.8, NLR ≥2.7 and cholesterol levels ≥199, were included. Five-year cancer-specific survival rate was 0.67, 0.78 and 0.94 at high, intermediate and low risk, respectively. Total cholesterol levels at the time of cystectomy may represent a commonly assessable prognostic factor and may be incorporated in a clinically meaningful risk-group classification model.Lay abstract This present study assessed a large group of patients with urothelial bladder cancer treated with chemotherapy followed by radical cystectomy, to capture the predictive power of commonly collected clinical, pathological and biochemical factors. The design of the study highlighted that higher cholesterol levels at the time of cystectomy were associated with shorter cancer-specific survival. This finding suggests that high blood-cholesterol levels truly have a negative influence on surviving cancer. In conclusion, total cholesterol levels at the time of cystectomy may represent a commonly assessable prognostic factor and could be incorporated into a clinically meaningful and valuable risk-group classification model.

Despite relevant medical advancements, metastatic breast cancer remains an uncurable disease. HER2 signaling conditions tumor behavior and treatment strategies of HER2 expressing breast cancer. Cancer treatment guidelines uniformly identify dual blockade with pertuzumab and trastuzumab plus a taxane as best first line and trastuzumab emtansine as preferred second line choice. However, there is no prospectively designed available study focusing on the sequence and outcomes of patients treated with T-DM1 following the triplet. In the following report, data concerning a wide series of patients treated in a real-life setting are presented. Results obtained in terms of response and median progression free survival suggests a significant role for T-DM1 in disease control of metastatic HER2 expressing breast cancer.

Background This multi-institutional retrospective real life study was conducted in 22 Italian Oncology Centers and evaluated the role of Axitinib in second line treatment in not selected mRCC patients. Methods 148 mRCC patients were evaluated. According to Heng score 15.5%, 60.1% and 24.4% of patients were at poor risk, intermediate and favorable risk, respectively. Results PFS, OS, DCR and ORR were 7.14 months, 15.5 months, 70.6% and 16.6%, respectively. The duration of prior sunitinib treatment correlated with a longer significant mPFS, 8.8 vs 6.3 months, respectively. Axitinib therapy was safe, without grade 4 adverse events. The most frequent toxicities of all grades were: fatigue (50%), hypertension (26%), and hypothyroidism (18%). G3 blood pressure elevation significantly correlated with longer mPFS and mOS compared to G1-G2 or no toxicity. Dose titration (DT) to 7 mg and 10 mg bid was feasible in 24% with no statistically significant differences in mPFS and mOS. The sunitinib-axitinib sequence was safe and effective, the mOS was 41.15 months. At multivariate analysis, gender, DCR to axitinib and to previous sunitinib correlated significantly with PFS; whereas DCR to axitinib, nephrectomy and Heng score independently affected overall survival. Conclusions Axitinib was effective and safe in a not selected real life mRCC population. Trial registration INT – Napoli – 11/16 oss. Registered 20 April 2016. http://www.istitutotumori.na.it

Prostate cancer (PC) is a major health issue in developed countries, with, on the one hand, men suffering from sequelae related to unnecessary treatment of non-lethal PC, and, on the other hand, still dying because of advanced PC that progresses to castration-resistant disease. Systemic treatment is the mainstay of therapy of castration-resistant PC (CRPC). To date, a multitude of systemic agents have been tested and many of these have failed to provide a clinically meaningful benefit in CRPC, while others have been approved by the US Food and Drug Administration and/or the European Medicines Agency, including antiandrogen hormonal drugs (abiraterone, enzalutamide, apalutamide), chemotherapy (docetaxel and cabazitaxel), immunotherapy (Sipuleucel-T), and radiopharmaceutical (Radium-223) agents. In this review, systemic treatments regarded as most likely to have an impact in clinical practice are presented and discussed. In addition to the pivotal clinical studies, selected retrospective and non-randomized clinical trials are also discussed if deemed to have an impact on clinical practice or future research. A comprehensive appraisal of the expanding landscape of systemic therapies for advanced PC is provided from an expert perspective, with a focus on novel classification and diagnostic tools that have been paving the way for the development of precision medicine in PC.

The term "hemp" refers to Cannabis sativa cultivars grown for industrial purposes that are characterized by lower levels of tetrahydrocannabinol (THC), the active principle responsible for Cannabis psychotropic effects. Hemp is an extraordinary crop, with enormous social and economic value, since it can be used to produce food, textiles, clothing, biodegradable plastics, paper, paint, biofuel, and animal feed, as well as lighting oil. Various parts of the hemp plant represent a valuable source of food and ingredients for nutritional supplements. While hemp inflorescence is rich in nonpsychoactive, yet biologically active cannabinoids, such as cannabidiol (CBD), which exerts potent anxiolytic, spasmolytic, as well as anticonvulsant effects, hempseed has a pleasant nutty taste and represents a valuable source of essential amino acids and fatty acids, minerals, vitamins, and fibers. In addition, hempseed oil is a source of healthy polyunsaturated fatty acids, and hemp sprouts are rich in antioxidants. This review article aims to provide a comprehensive outlook from a multidisciplinary perspective on the scientific evidence supporting hemp beneficial properties when consumed as food or supplement. Marketing of hemp-derived products is subjected to diversified and complex regulations worldwide for several reasons, including the fact that CBD is also the active principal of pharmaceutical agents and that regulatory bodies in some cases ban Cannabis inflorescence regardless of its THC content. Some key regulatory aspects of such a complex scenario are also analyzed and discussed in this review article.

Although both docetaxel and androgen-receptor-axis-targeted (ARAT) agents have yielded survival improvements in combination with androgen deprivation therapy (ADT) compared to ADT alone in metastatic castration-sensitive prostate cancer (mCSPC) patients, the optimal therapeutic choice remains to be established. We analyzed estimates of the hazard ratios for death (OS-HRs) in patients treated in the first-line setting enrolled in the GETUG-AFU15, CHAARTED, STAMPEDE, LATITUDE, ENZAMET, and TITAN trials. Overall, men with mCSPC receiving ADT with vs. without either an ARAT agent or docetaxel as first-line systemic therapy showed a pooled OS-HR of 0.69 (95 % CI: 0.61−0.78), with significant heterogeneity (p = 0.045, I2 = 52.5 %). Network meta-analysis showed an OS-HR in patients receiving an ARAT agent vs. docetaxel of 0.78 (95 %CI: 0.67−0.91). In conclusion, the evidence analysed indicates that an ARAT agent may provide improved OS outcomes compared to docetaxel. Prospective randomized trials are warranted.

Immunotherapy based on anti PD-1/PD-L1 inhibitors has proven to be more effective than sunitinib in the first-line setting of advanced renal cell carcinoma (RCC). RCC patients with sarcomatoid histology (sRCC) have a poor prognosis and limited therapeutic options. We performed a systematic review and a meta-analysis of randomized-controlled trials (RCTs) of first-line anti PD-1/PDL-1 agents vs. sunitinib, presenting efficacy data in the sub-group of sRCC patients. The systematic research was conducted on Google Scholar, Cochrane Library, PubMed and Embase and updated until 31th January, 2020. Abstracts from ESMO and ASCO (2010−2019) were also reviewed. Full texts and abstracts reporting about RCTs testing first-line anti-PD-1/ PD-L1 agents vs. sunitinib in RCC were included if sRCC sub-group analyses of either PFS (progression-free survival), OS (overall survival) or radiological response rate were available. Pooled data from 3814 RCC patients in the ITT (intention-to-treat) population and from 512 sRCC patients were included in the quantitative synthesis. In the sRCC sub-group vs. the ITT population, pooled estimates of the PFS-HRs were 0.57 (95%: 0.45−0.74) vs. 0.79 (95% CI: 0.70−0.89), respectively, with a statistically meaningful interaction favoring the sRCC sub-group (pooled ratio of the PFS-HRs = 0.64; 95% CI: 0.50−0.82; p < 0.001). Pooled estimates of the difference in CR-R (complete response-rate) achieved with anti-PD-1/PDL-1 agents vs. sunitinib were + 0.10 (95% CI: 0.04−0.16) vs. + 0.04 (95% CI: 0.00−0.07) in the sRCC vs. the non-sRCC sub groups, with a statistically meaningful difference of + 0.06 (95% CI: 0.02−0.10; p = 0.007) favoring the sRCC sub-group. Sarcomatoid histology may be associated with improved efficacy of anti PD-1/PDL-1 agents vs. sunitinib in terms of PFS and CR-R.

Colorectal cancer (CRC) represents one of the most commonly diagnosed cancers worldwide. It is the second leading cause of cancer death in Western Countries. In the last decade, the survival of patients with metastatic CRC has improved dramatically. Due to the advent of new drugs (irinotecan and oxaliplatin) and target therapies (i.e. bevacizumab, cetuximab, panitumab, aflibercept and regorafenib), the median overall survival has risen from about 12 mo in the mid nineties to 30 mo recently. Molecular studies have recently widened the opportunity for testing new possible markers, but actually, only few markers can be recommended for practical use in clinic. In the next future, the hope is to have a complete panel of clinical biomarkers to use in every setting of CRC disease, and at the same time: 1) to receive information about prognostic significance by their expression and 2) to be oriented in the choice of the adequate treatment. Moreover, molecular analyses have shown that the natural history of all CRCs is not the same. Individual patients with same stage tumors may have different long-term prognosis and response to therapy. In addition, some prognostic variables are likely to be more important than others. Here we review the role of serum and tissue markers according to the recently published English literature. This paper is an extension of the article "Biological and clinical markers in colorectal cancer: state of art" by Cappellani A published in Jan 2010.

Simple Summary The management of metastatic renal cell carcinoma (mRCC) represents a clinical challenge. Progression or toxicity may occur during first-line treatments and many patients require a second-line option. Given the expanding options for second-line therapies clinicians are faced with the challenge to individualize treatment. We performed a systematic review in order to summarize available evidences about the clinicopathological profile of mRCC patients who receive a second-line therapy. We identified twenty-nine studies enrolling 7650 patients. Discontinuation of first-line therapy was due to progression in the majority of patients with 77.8% patients harboring ≥2 metastatic sites. Most patients had a good performance status, their age ranged from 55 to 70 years and their prognostic profile revealed a good or intermediate disease in most cases. Tailoring of second-line treatment strategies based on these features is strongly advocated. Abstract A high percentage of patients with metastatic renal cell carcinoma (mRCC) require a second-line option. We aimed to summarize available evidences about the clinicopathological profile of mRCC patients who receive a second-line therapy. A systematic review was performed in August 2020. We included papers that met the following criteria: original research; English language; human studies; enrolling mRCC patients entering a second-line therapy. Twenty-nine studies enrolling 7650 patients (73.5% male, mean age: 55 to 70 years) were included. Clear cell histology was reported in 74.4% to 100% of cases. Tyrosine kinase inhibitors, immunotherapy, bevacizumab, mTOR inhibitors, and chemotherapy were adopted as first line option in 68.5%, 29.2%, 2.9%, 0.6%, and 0.2% of patients, respectively. Discontinuation of first-line therapy was due to progression and toxicity in 18.4% to 100% and in 17% to 48.8% of patients, respectively. Eastern Cooperative Oncology Group performance status score was 0 or 1 in most cases. Most prevalent prognostic categories according to the International Metastatic RCC Database Consortium and Memorial Sloan–Kettering Cancer Centre score were intermediate and good. About 77.8% of patients harboured ≥2 metastatic sites. In conclusion, patients who enter a second-line therapy are heterogeneous in terms of a clinical-pathological profile. Tailoring of second-line treatment strategies is strongly advocated.

Introduction: While the majority of the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors currently used for the therapy of metastatic renal cell carcinoma (mRCC) are small molecule agents inhibiting multiple targets, monoclonal antibodies are inhibitors of specific targets, which may decrease off-target effects while preserving on-target activity. A few monoclonal antibodies have already been approved for mRCC (bevacizumab, nivolumab), while many others may play an important role in the therapeutic scenario of mRCC. Areas covered: This review describes emerging monoclonal antibodies for treating RCC. Currently, bevacizumab, a VEGF monoclonal antibody, is approved in combination with interferon for the therapy of metastatic RCC, while nivolumab, a Programmed Death (PD)-1 inhibitor, is approved following prior VEGF inhibitor treatment. Other PD-1 and PD-ligand (L)-1 inhibitors are undergoing clinical development. Expert opinion: Combinations of inhibitors of the PD1/PD-L1 axis with VEGF inhibitors or cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors have shown promising efficacy in mRCC. The development of biomarkers predictive for benefit and rational tolerable combinations are both important pillars of research to improve outcomes in RCC.

Background: Single-agent taxanes are commonly used as salvage systemic therapy for patients with advanced urothelial carcinoma (UC). Objective: To study the impact of combination chemotherapy delivering a taxane plus other chemotherapeutic agents compared with single-agent taxane as salvage therapy. Design, setting, and participants: Individual patient-level data from phase 2 trials of salvage systemic therapy were used. Interventions: Trials evaluating either single agents (paclitaxel or docetaxel) or combination chemotherapy (taxane plus one other chemotherapeutic agent or more) following prior platinum-based therapy were used. Outcome measurements and statistical analysis: Information regarding the known major baseline prognostic factors was required: time from prior chemotherapy, hemoglobin, performance status, albumin, and liver metastasis status. Cox proportional hazards regression was used to evaluate the association of prognostic factors and combination versus single-agent chemotherapy with overall survival (OS). Results and limitations: Data were available from eight trials including 370 patients; two trials (n = 109) evaluated single-agent chemotherapy with docetaxel (n = 72) and cremophor-free paclitaxel (n = 37), and six trials (n = 261) evaluated combination chemotherapy with gemcitabine-paclitaxel (two trials, with n = 99 and n = 24), paclitaxel-cyclophosphamide (n = 32), paclitaxel-ifosfamide-nedaplatin (n = 45), docetaxelifosfamide-cisplatin (n = 26), and paclitaxel-epirubicin (n = 35). On multivariable analysis after adjustment for baseline prognostic factors, combination chemotherapy was independently and significantly associated with improved OS (hazard ratio: 0.60; 95% confidence interval, 0.45-0.82; p = 0.001). The retrospective design of this analysis and the trial-eligible population were inherent limitations. Conclusions: Patients enrolled in trials of combination chemotherapy exhibited improved OS compared with patients enrolled in trials of single-agent chemotherapy as salvage therapy for advanced UC. Prospective randomized trials are required to validate a potential role for rational and tolerable combination chemotherapeutic regimens for the salvage therapy of advanced UC. Patient summary: This retrospective study suggests that a combination of chemotherapy agents may extend survival compared with single-agent chemotherapy in selected patients with metastatic urothelial cancer progressing after prior chemotherapy. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Background: Glioblastoma multiforme (GBM) is a rare and deadly disease, with a reported average incidence rate of 3.19 cases per 100,000 inhabitants. Fotemustine, a third-generation nitrosourea with an alanine phosphor carrier that facilitates cellular penetration, has been extensively investigated in the setting of recurrent/progressive disease after initial treatment. Fotemustine is usually administered following a schedule consisting of 3 doses every week, followed by maintenance doses administered every 3 weeks. Methods: In this phase I/II trial, we aimed to assess whether the use of a biweekly regimen allowed administration of higher dose than the standard 100 mg/m2 dose approved per label indication in a population of patients with recurrent GBM. In this phase I/II trial, fotemustine was administered intravenously over 1 hour every 2 weeks at either 120 or 140 mg/m2 doses for up to 1 year, until disease progression, unacceptable toxicity, or patient's request to withdraw from the study. The phase I part of the trial was conducted following the classic 3+3 study design. The phase II part of the trial was a single-arm study. The primary efficacy endpoint was the percentage of patients who had not progressed after 24 weeks (PFS-24). Results: Thirty-seven patients were enrolled in this phase I/II trial from August 2006 to November 2011. Treatment was well tolerated in the overall population. Main severe toxicity was grades 3 and 4 thrombocytopenia, which occurred in 4 of 6 patients treated at the 140 mg/m2 dose level and in 3 of 31 patients treated at 120 mg/m2. Median PFS and overall survival were 12.1 (1–40.2) weeks and 19.7 (1–102) weeks, respectively. Conclusion: We conclude that fotemustine can be safely administered at 120 mg/m2 biweekly. The efficacy of such modified schedule and doses should be compared to the biweekly schedule at 80 mg2 and the standard weekly schedule at 80 to 100 mg/m2.

Sunitinib is the most commonly prescribed drug for advanced renal cell carcinoma in the first-line setting and has been associated with multiple adverse events related to its on–and off–target effects, including hand and foot syndrome and fatigue. It was hypothesized that sunitinib-induced fatigue may be related to off target inhibition of the AMPK enzyme, which results in impairment of energy-producing processes at a systemic level. Quercetin is a naturally occurring flavonol with established AMPK-stimulating activity. While clinical use of quercetin is limited by its poor bio-availability, quercetin-3-O-β-d-glucopyranoside, that is isoquercetin, has an improved pharmacokinetic profile. On the grounds of the in vitro stimulatory activity with respect to AMPk, we hypothesized that oral isoquercetin could improve fatigue in kidney cancer patients receiving sunitinib. Given the lack of data on the safety of isoquercetin given concomitantly with sunitinib, we conducted a phase I trial to assess the safety of GMP manufactured isoquercetin given at two dose levels (450 and 900 mg a day). In the 12-patient study cohort included in this study, isoquercetin was administered concomitantly with 50 mg sunitinib for a median 81 days (IQR, 75.5, 86.5). None of the 12 patients required isoquercetin suspension or isoquercetin dose reduction because of adverse events. No abnormalities in ECG, heart or lower limbs doppler ultrasound were detected. A statistically significant improvement was reported for the FACIT fatigue score (6.8 points; 95% CI: 2.8–10.8; p = 0.002) and for the FACIT Adverse Events score (18.9 points; 95% CI: 9.1–28.8; p < 0.001) after isoquercetin consumption vs. baseline. In this phase I trial, isoquercetin was remarkably safe, with a preliminary signal of activity in terms of improvement of sunitinib adverse events.

// Jacob A. Gordon 1, * , Carlo Buonerba 2, 3, * , Gregory Pond 4 , Daniel Crona 5 , Silke Gillessen 6 , Giuseppe Lucarelli 7 , Sabrina Rossetti 8 , Tanya Dorff 9 , Salvatore Artale 10 , Jennifer A. Locke 1 , Davide Bosso 2 , Matthew Ivan Milowsky 5 , Mira Sofie Witek 6 , Michele Battaglia 7 , Sandro Pignata 11 , Cyrus Cherhroudi 12 , Michael E. Cox 1 , Pietro De Placido 2 , Dario Ribera 2 , Aurelius Omlin 6 , Gaetano Buonocore 13 , Kim Chi 14 , Christian Kollmannsberger 14 , Daniel Khalaf 14 , Gaetano Facchini 8 , Guru Sonpavde 15 , Sabino De Placido 2 , Bernhard J. Eigl 14, # and Giuseppe Di Lorenzo 2, # 1 Vancouver Prostate Center, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada 2 Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy 3 Istituto Zooprofilattico Sperimentale del Mezzogiorno, Portici, Italy 4 McMaster University, Hamilton, Ontario, Canada 5 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA 6 Department of Medical Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland 7 Department of Emergency and Organ Transplantation, Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy 8 S.S.D Oncologia Clinica Sperimentale Uro-Andrologica, Dipartimento Corp-S Assistenziale dei Percorsi Oncologici Uro-Genitale, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy 9 University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California, USA 10 Oncology Department, Ospedale di Gallarate ASST Valle Olona, Gallarate, Italy 11 Division of Medical Oncology, Department of Uro-Gynecologi cal Oncology, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy 12 Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada 13 Hospital Directorate, Azienda Ospedaliera Universitaria Federico II of Naples, Naples, Italy 14 BC Cancer, Vancouver, British Columbia, Canada 15 Genitourinary Oncology Section, Dana Farber Cancer Institute, Boston, Massachusetts, USA * These two authors equally contributed to this work # These two authors share equal senior authorship Correspondence to: Giuseppe Di Lorenzo, email: dilorengiuseppe@gmail.com Keywords: prostate cancer; abiraterone; enzalutamide; statins Received: February 01, 2018 Accepted: February 27, 2018, 2018 Published: April 13, 2018 ABSTRACT Background: Statins may potentiate the effects of anti-hormonal agents for metastatic castration-resistant prostate cancer (mCRPC) through further disruption of essential steroidogenic processes. We investigated the effects of statin use on clinical outcomes in patients with mCRPC receiving abiraterone or enzalutamide. Materials and methods: This was a retrospective multicenter study including patients that received abiraterone or enzalutamide for mCRPC. The effect of concurrent statin use on outcomes was evaluated. The associations of statins with early (≤12 weeks) prostate-specific antigen (PSA) declines (> 30%), cancer-specific survival and overall survival (OS) were evaluated after controlling for known prognostic factors. Results: Five hundred and ninety-eight patients treated with second-line abiraterone or enzalutamide after docetaxel for mCRPC were included. A total of 199 men (33.3%) received statins during abiraterone/enzalutamide treatment. Median OS was 20.8 months (95% CI = 18.3–23.2) for patients who received statins, versus 12.9 months (95% CI = 11.4–14.6) for patients who did not receive statins ( P 30% PSA decline within the first 12 weeks of treatment (OR = 1.63; 95% CI = 1.03–2.60; P = 0.039). Conclusions: In this retrospective cohort, statin use was significantly associated with both prolonged OS and cancer-specific survival and increased early > 30% PSA declines. Prospective validation is warranted.

Penile cancer is a rare disease, with an incidence that is higher in less developed countries and is in the range of 1 - 10 per 100000 men worldwide. Early diagnosis is essential for cure, as 5 year cancer-specific survival is 90 - 100 % in patients with intraepithelial neoplasms and in those with low-grade superficial tumors without lymphovascular invasion, but it drops to 30% in men with multiple mobile or bilateral inguinal lymph nodes. The EGFR family plays a major role in penile cancer biology, with distinct receptors being involved in HPV-positive and -negative tumors. A number of anti-EGFR agents were used in penile cancer patients outside the context of a clinical trial, mainly as a salvage treatment after failure of first-line chemotherapy. A total of 28 patients received anti-EGFR monoclonal antibodies, with 50% of them showing a response to treatment, and a median PFS of ∼ 3 months. The rarity of the disease poses great challenge in terms of education and awareness of the general population, planning of preventive measures on a large scale, as well as conduction of prospective trials and approval of high-cost biological therapy.

In the METEOR study [3], cabozantinib appeared to be superior to everolimus in terms of objective response rate (21 vs 5%; p < 0.001) and PFS, with a statistically significant hazard ratio for progres sion or death of 0.58. A planned interim analysis showed that overall survival was longer with cabozantinib with respect to everolimus (hazard ratio for death: 0.67; 95% CI: 0.51–0.89; p = 0.005), although the p-value did not cross the prespecified boundary for statistical significance. Conversely, in the CheckMate 025 trial [4], the median overall survival associated with the use of nivolumab versus everolimus was 25.0 months (95% CI: 21.8–not estimable) versus 19.6 months (95% CI: 17.6–23.1), with a hazard ratio for death of 0.73 (98.5% CI: 0.57–0.93; p = 0.002), which did meet the prespecified criterion for superiority (p ≤ 0.0148). While the objective response rate was greater with nivolumab than with everolimus (25 vs 5%; p < 0.001), there was no difference in “Differently from everolimus and axitinib, both cabozantinib, a multityrosine kinasis inhibitor, and nivolumab, an anti-PD-1 agent, did yield an advantage in overall survival when compared with everolimus...”

Background: Cabazitaxel is a second-generation taxane that is approved for use with concomitant low dose daily prednisone in metastatic castration resistant prostate cancer (mCRPC) after docetaxel failure. Since the role of daily corticosteroids in improving cabazitaxel efficacy or ameliorating its safety profile has not been adequately investigated so far, we compared outcomes of patients receiving cabazitaxel with or without daily corticosteroids in a retrospective single-Institution cohort of mCRPC patients. Patients and methods: Medical records of deceased patients with documented mCRPC treated with cabazitaxel following prior docetaxel between January, 2011 and January, 2017 were reviewed at the single participating center. Patients who were receiving daily doses of systemic corticosteroids other than low dose daily prednisone or prednisolone (30% PSA decline at 12 weeks. Prednisone use was not significantly prognostic for overall survival or PSA decline ≥30% rates on regression analyses. Importantly, a >30% PSA decline at 12, but not at 3, 6, 9 weeks, was prognostic for improved survival at multivariate analysis Conclusions: The data presented here support the hypothesis that omitting daily corticosteroids in cabazitaxel-treated patients has no negative impact on either survival or safety profile. In the large prospective trial CABACARE, cabazitaxel-treated patients will be randomized to receive or not receive daily prednisone. The CABACARE (EudraCT n. 2016-003646-81) study is currently ongoing at University Federico II of Naples and at other multiple participating centers in Italy.

TPS345 Background: In the TROPIC trial, cabazitaxel (CAB) plus daily prednisone (PDN) was associated with a significant advantage in OS and PFS in docetaxel (DOC)-pretreated patients (Pts). Whether daily PDN may significantly contribute to CAB efficacy or improve its safety profile is unknown. In the CHARTEED trial, DOC was administered without daily PDN with no concerns about the lack of efficacy or greater toxicity. Safety data about CAB without PDN are scarce. Corticosteroids present multiple biological effects, which may potentially be either positive, such as those mediated by adrenal androgen and cytokine suppression, or detrimental, such as those associated with the activation of the glucocorticoid receptor (GR) and of the androgen receptor (AR). Furthermore, PDN is a CYP3A4 inducer and can potentially negatively affect CAB clearance. Finally, AR-V7 positivity in circulating tumor cells and retinoblastoma (RB) loss/inactivation have been identified as potential mechanisms of resistance to hormonal and chemotherapy treatments in prostate cancer. For this reason, we also aim to evaluate if CAB activity is related to such biomarkers. Methods: CABACARE (EudraCT 2016-005251-25) is a randomized, phase II, open label, multi-center study comparing CAB at 25 mg/m2 q21 plus daily PDN (10 mg) vs CAB at 25 mg/m2 q21 alone in mCRPC pts progressed during or after DOC treatment. The study is designed to test non inferiority in terms of PFS, according PCWG-2, of CAB alone vs CAB plus PDN assuming that the two arms are equally effective (non-inferiority HR = 1.4). Main secondary objectives are: safety, QoL, pain assessment, overall response rate (ORR), PSA response, time to PSA progression, Time to radiological progression; OS; time to skeletal related events . The influence of AR-V7 and RB status measured in circulating epithelial cells at baseline on CAB activity will also be evaluated. A total of 35 Italian centers have started / will start recruiting pts in the CABACARE trial. Of the 220 pts required by the trial design, 43 pts have been enrolled since 30th Nov , 2017 until 2nd Oct, 2018 in 10 different Italian Institutions. Clinical trial information: 2016-005251-25.

Current therapy for metastatic clear cell renal cell carcinoma (RCC) consists of the serial administration of single agents. Combinations of VEGF and mTOR inhibitors have been disappointing in previous randomized trials. However, the combination of lenvatinib, a multitargeted agent that inhibits VEGF as well as FGF receptors, and everolimus demonstrated promising results in a randomized phase II trial. Moreover, the emergence of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors has spawned the investigation of combinations of these agents with VEGF inhibitors and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors. These ongoing phase III trials in conjunction with the development of predictive biomarkers and agents inhibiting novel therapeutic targets may provide much needed advances in this still largely incurable disease.

Introduction and objectives: Metastatic penile squamous cell carcinoma (PSCC) is associated with dismal outcomes with median overall survival (OS) of 6–12 months in the first-line and

Cabazitaxel provided a survival advantage compared with mitoxantrone in patients with castration-resistant prostate cancer refractory to docetaxel. Grade 3 to 4 (G3–4) neutropenia and febrile neutropenia were relatively frequent in the registrative XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC) trial, but their incidence was lower in the Expanded Access Program (EAP). Although cumulative doses of docetaxel are associated with neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this retrospective review of prospectively collected data, the authors assessed “per cycle” incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel. The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant adverse events identified was assessed using a Generalized Estimating Equations model at univariate and multivariate analysis. “Per cycle” incidence of G 3 to 4 neutropenia was 8.7%, whereas febrile neutropenia was reported in 0.9% of cycles. All events of febrile neutropenia occurred during the first 3 cycles. Multivariate logistic regression analysis showed that higher prior dose of cabazitaxel was associated with decreased odds of having G3 to 4 neutropenia (OR = 0.90; 95% CI: 0.86–0.93; P 2 m2 presented increased odds of having G 3 to 4 neutropenia (OR = 0.93; 95% CI: 0.86–1; P = 0.07), but decreased odds of having G3 to 4 anemia. Among the toxicities assessed, the authors did not identify any that appeared to be associated with a higher number of cabazitaxel cycles delivered. Prior cumulative dose was associated with reduced G3 to 4 neutropenia and anemia. The apparent protective effect associated with higher doses of cabazitaxel is likely to be affected by early dose reduction and early toxicity-related treatment discontinuation. Because this analysis is limited by its retrospective design, prospective trials are required to assess the optimal duration of cabazitaxel treatment.

UNLABELLED What's known on the subject? and What does the study add? Metastatic or locally advanced squamous cell carcinoma of the penis (SCCP) is generally incurable, but it can be palliated with systemic chemotherapy. Two retrospective studies, involving

Guidelines on the treatment of metastatic squamous cell carcinoma of the penis are limited to a few prospective trials. Cisplatin-based regimens represent the standard of treatment with promising activity of taxanes. Recently, epidermal growth factor receptor overexpression has been shown in these patients. We treated an elderly man with a docetaxel-cetuximab combination after failure of the cisplatin regimen. We observed a necrosis of the inguinal lymph nodes and a reduction of (18)F-fluorodeoxyglucose uptake at PET/CT scan. Only mild mucositis and skin toxicity had been detected. Our case report, the first in the literature, shows that this combination is active and well tolerated in penile squamous cell carcinoma.

What's known on the subject? and What does the study add? Sipuleucel-T is known to be very well tolerated and to prolong overall survival, but not progression-free survival, measured according to prostate-specific antigen variations and radiographic progression. Its exact mechanism is unknown. Although the article does not present new data, a new way of assessing immunotherapy efficacy is proposed. This involves measuring ‘consecutive’ times to progression, in an attempt to capture the delayed effects of immunotherapy. OBJECTIVE • To propose a new way of assessing immunotherapy efficacy. Since 2010, the therapeutic armamentarium for prostate cancer has expanded to include the potent taxane agent cabazitaxel, the CYP17A1 inhibitor abiraterone and the novel immunotherapy agent sipuleucel-T (Provenge®. Demdreon, Seattle, WA, USA). • Sipuleucel-T is an antigen-specific active immunotherapy agent, which is not designed to be directly toxic to tumour cells, but to help the immune system to selectively attack cancerous cells. We aimed to provide a comprehensive review of available safety and efficacy data about Sipuleucel-T. METHODS • A systematic analysis of the literature was conducted using the terms ‘Sipuleucel-T’ and ‘Provenge’. PUBMED was the main search engine, but abstracts published by the American Society of Clinical Oncology and the European Society of Medical Oncology, as well as press releases and product monographs, were also considered for inclusion. • Reference lists of key articles were searched for further leads. Articles providing safety and efficacy data were included in this review. RESULTS • Sipuleucel-T is based on autologous dendritic cells, which are collected by leukapheresis of peripheral blood, co-cultured with a modified PAP protein, and then re-injected intravenously. It is the first agent of its kind to obtain Food and Drug Administration approval for any kind of malignant tumour. • Its approval was determined by the results of a placebocontrolled, randomized trial (the IMPACT trial), conducted in 512 asymptomatic or minimally symptomatic mean with metastatic castration-resistant prostate cancer. • Although no difference in time to progression or PSA response rate was reported, a statistically meaningful 4.1-month improvement in median survival was achieved in the active arm with respect to the placebo arm (25.8 months vs 21.7 months). • After Food and Drug Administration approval in April 2010, in view of the high economic cost of sipuleucel-T and the not completely flawless study design of the IMPACT trial, a national coverage analysis of sipuleucel-T was conducted by the Centers for Medicare and Medicaid Services. Such analysis has recently concluded that sipuleucel-T is a ‘necessary and reasonable’ treatment. CONCLUSION • Sipuleucel-T is an effective treatment for prostate cancer, although its widespread use is uncertain for complex social and economic reasons.

Thymic epithelial tumors (TETs) are rare tumors of the mediastinum, with an estimated incidence of about 3 cases per 100,000 inhabitants. Although anthracycline- and platinum-based chemotherapy is an active treatment for TETs, novel systemic therapeutic options are especially needed for metastatic disease, which is virtually incurable. On the basis of the radiographic response obtained with imatinib (Novartis Pharma, Basel, Switzerland) in a patient with thymic carcinoma harboring the V560del c-KIT mutation, a phase II trial was initiated at the Department of Molecular and Clinical Oncology and Endocrinology of University “Federico II of Naples” with the purpose to test imatinib in TETs. Imatinib was daily delivered at the dose of 400 mg to patients affected by TETs, who had progressed after at least one chemotherapy regimen. Positivity of c-KIT on immunohistochemistry was not mandatory for study entry. Radiographic responses were measured by CT scans performed every 3 months, according to the RECIST criteria. Toxicity was graded according to the Common Toxicity Criteria of the National Cancer Institute, version 3.0. Fifteen patients with advanced TETs were enrolled from March 2008 to May 2010. Three patients presented with thymic carcinomas. Two of these three patients presented c-kit expression on immunohistochemistry. No patient harbored a known c-kit activating mutation. Imatinib was very well tolerated, with no toxicity-related death. Diarrhea and migraine were the most frequent events, occurring both in 20% of patients, but were manageable and mild. No radiographic responses were recorded. Median progression-free survival was 3 months (interquartile range, 2.5–4). Median overall survival was not reached. The study was terminated before it reached its target accrual of 42 patients, because of the lack of responses and low accrual rate. This trial indicates the lack of effectiveness of imatinib in unselected patients with thymic epithelial tumors. Nevertheless, imatinib may represent a valuable option in selected patients with TETs, such as those harboring the V560del c-KIT mutation.

Objective: To date, no trial data exist comparing treatment outcomes for everolimus versus sorafenib. The current analysis indirectly compares the overall survival (OS) benefit of everolimus and sorafenib as second-line treatment options. Research design and methods: A single-arm sorafenib study is selected as a basis to match an everolimus sunitinib-refractory subpopulation of the RECORD-1 trial. Only patients with clear cell histology are included. An adjusted matching approach is taken where 1000 repeated random samples matched to the sorafenib population on risk score distribution are produced, and a 95% CI around the mean of all sampled median OS is generated. Main outcome measures: The main outcome measures include adjusted median OS and progression-free survival. Results: In all, 45 clear cell histology sorafenib patients and 1000 samples of N = 41 sunitinib-refractory everolimus patients are considered for analysis. After adjusted matching, the estimated median OS benefit is 32.7 weeks (95% CI: 22...

Study Type – Therapy (cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? We show that (i) docetaxel re-treatment, after a treatment-free interval, preserves activity; (ii) the treatment is especially well tolerated in patients who were effectively pretreated with docetaxel; and (iii) it could be speculated that combining docetaxel with other agents in this setting might be safe and result in greater activity. OBJECTIVE To determine the activity and tolerability of docetaxel re-treatment after first-line therapy with docetaxel in castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS Between November 2005 and January 2009, 45 patients initially responding to docetaxel and then experiencing disease progression after a period of biochemical remission of at least 5 months were enrolled in a prospective multicenter study and re-treated with docetaxel. The primary endpoint was the biochemical response (biochemical partial response defined as >50% prostate-specific antigen [PSA] decline); secondary endpoints were objective response, toxicity, progression-free survival (PFS) and overall survival (OS). RESULTS Partial PSA responses were observed in 11 patients (24.5%), 4 (25%) of whom also had an objective response. The treatment was well tolerated, with grade 1–2 neutropenia, thrombocytopenia, vomiting and peripheral neuropathy noted in 18 (40%), 11 (24.5%), 8 (17.8%), and 6 (13.3%) patients, respectively. The most common grade 3 toxicity was neutropenia, which was observed in 8 patients (17.8%). Median PFS was 5 months and median OS was 13 months. CONCLUSIONS Docetaxel re-treatment preserves anti-tumour activity and is well tolerated in a selected population of pretreated patients with CRPC. Further randomized trials are needed to confirm our preliminary results.

The US FDA recently approved sipuleucel-T (Provenge(®), Dendreon, Inc., WA, USA) on the grounds of the results reported by a Phase III trial, which are presented and discussed in detail in this article. This study was conducted in 512 metastatic castration-resistant prostate cancer patients randomized in a 2:1 ratio to receive either active therapy or placebo. Although no difference in time to progression was observed, a survival advantage was achieved, with a statistically meaningful 4.1-month improvement in median survival in the active arm with respect to the placebo arm (25.8 vs 21.7 months). In view of its favorable toxicity profile and manageable route of administration, sipuleucel-T is the ideal agent to be combined with other standard treatments, which include hormonal, cytotoxic and biological agents, and radiotherapy. Sipuleucel-T opens exciting new paradigms for prostate cancer and increases the possibility of survival prolongation for men with this deadly disease.

153 ISSN 1479-6694 10.2217/FON.13.243 © 2014 Future Medicine Ltd Future Oncol. (2014) 10(2), 153–155 An unprecedented large number of agents capable of prolonging survival is presently available for patients with castrationresistant prostate cancer (CRPC) [1,2]. Survival expectancy of a patient with newly diagnosed CRPC has approximately doubled since the approval of docetaxel, although it still appears to be poor in selected populations [3,4], such as those with primary refractoriness to docetaxel [5]. US FDAand EMA-approved agents now include immunotherapy agent sipuleucel-T, CYP17A inhibitor abiraterone, antiandrogen receptor enzalutamide, cytotoxic agent cabazitaxel and radiopharmeceutical agent radium-223. These agents were approved in different settings. While sipuleucel-T was mainly tested in minimally symptomatic, chemotherapy-naive patients, abiraterone, enzalutamide and cabazitaxel were tested in patients pretreated with docetaxel. Radium-223 was approved in patients who were either ineligible to or refused or had already received docetaxel, and had symptomatic diffuse bone metastases. Although abiraterone proved to prolong progression-free survival in chemotherapy-naive patients, with a statistically significant improvement in overall survival that did not satisfy the statistical boundaries required by the study design, the potential detrimental effect on survival that postponing docetaxel in a population of metastatic CRPC might have was not adequately accounted for in this trial, and an opportunity to test sequential therapies was missed [6]. With multiple available effective agents, their optimal sequential use, their use in selected populations and the early assessment of efficacy in individual patients are three main issues. A few recently published case series showed only modest efficacy of cabazitaxel, abiraterone and enzalutamide when used as third-line agents, although prospective data are lacking. In 24 patients treated with cabazitaxel after docetaxel and abiraterone, a median of four cycles of cabazitaxel were delivered, with a median survival from initiation of cabazitaxel of 8.2 months (95% CI: 3.34–13.05) [7], and a median survival after docetaxel initiation of 32 months. In 35 patients treated with the sequence enzalutamide after docetaxel and abiraterone, a greater than 50% PSA decline was recorded in 45.7% of patients

Background Sunitinib and everolimus have been approved for first- and second-line treatment, respectively, in metastatic renal cell carcinoma (mRCC). The role of sorafenib, which is approved for second-line treatment after cytokines failure, is presently to be defined. Objective To determine whether third-line sorafenib after sequential use of sunitinib and mammalian target of rapamycin inhibitors (everolimus or temsirolimus) is feasible and effective. Design, setting, and participants One hundred fifty medical records of patients with mRCC treated with first-line sunitinib between January 2006 and January 2010 were reviewed at four participating centers. Data regarding patients treated with the sequence sunitinib–everolimus or temsirolimus–sorafenib were extracted. Central analysis of radiographic images was performed using RECIST criteria to determine progression-free survival (PFS) and overall response rate (oRR) to sorafenib treatment. Measurements PFS and oRR to sorafenib were the primary end points. Secondary outcomes were safety and overall survival (OS). Results and limitations Thirty-four patients were eligible for the study. A median PFS of 4 mo (range: 3–6 mo) and a median OS of 7 mo since sorafenib treatment (range: 6–10 mo) were reported. Of the patients, 23.5% showed response to sorafenib, with an overall disease control rate (complete responses plus partial responses plus stable disease) of 44%. Selection bias, data incompleteness, and absence of study design are inevitable limitations of the study, although central review can strengthen the quality of presented data. Conclusions Third-line sorafenib appears to be active and well tolerated in mRCC after first-line sunitinib and second-line everolimus or temsirolimus, with no patients interrupting sorafenib because of toxicity or lack of compliance. Prospective, placebo-controlled trials are completely lacking and are required in this setting.

Until very recently, docetaxel was the only approved agent in castration-resistant prostate cancer (CRPC) and other effective therapeutic options are urgently needed. In recent years, several new agents with promising activity and a favourable toxicity profile have been developed and clinically investigated in the fields of hormonal, cytotoxic, targeted and immune therapy. In particular, recent results from two large phase III trials of sipuleucel-T and cabazitaxel show that these two agents significantly prolong overall survival in CRPC. Indeed, sipuleucel-T has recently been approved by the US FDA for the treatment of CRPC. Many other pharmaceuticals, which are presented in this review, have been investigated recently or are being investigated in phase III trials and might prove to be effective in the future. Reviewed articles are discussed in light of the innovations in study design brought by the Prostate Cancer Clinical Trials Working Group (PCWG2), which updated the Prostate-Specific Antigen Working Group (PCWG1) guidelines, in order to allow better identification of potentially active drugs in clinical trials.

TPS387 Background: In the TROPIC trial, cabazitaxel (CAB) plus daily prednisone (PDN) was associated with a significant advantage in OS and PFS in docetaxel (DOC)-pretreated patients. Whether daily prednisone may significantly contribute to cabazitaxel efficacy or improve its safety profile is unknown. In the CHARTEED trial, DOC was administered without daily PDN with no concerns about the lack of efficacy or greater toxicity. Safety data about CAB without PDN are missing. Corticosteroids present multiple biological effects, which may potentially be either positive, such as those mediated by adrenal androgen and cytokine suppression, or detrimental, such as those associated with the activation of the glucocorticoid receptor (GR) and of the androgen receptor (AR). Furthermore, PDN is a CYP3A4 inducer and can potentially negatively affect cabazitaxel clearance. Finally, AR-V7 positivity in circulating tumor cells and retinoblastoma (RB) loss/inactivation have been identified as potential mechanisms of resistance to hormonal and chemotherapy treatments in prostate cancer. For this reason, we also aim to evaluate if CAB activity is related to such biomarkers. Methods: CABACARE is a randomized, phase II, open label, multi center study comparing CAB at 25 mg/m2 q21 plus daily PDN (10 mg) vs CAB at 25 mg/m2 q21 alone in mCRPC pts progressed during or after DOC treatment. The study is designed to test non inferiority in terms of PFS, according PCWG-2, of CAB alone vs CAB plus PDN assuming that the two arms are equally effective. Each arm will enroll 110 pts. Main secondary objectives are: safety, QoL, pain assessment, overall response rate (ORR), PSA response, time to PSA progression, Time to radiological progression; OS; time to skeletal related events (SRE). The influence of Arv7 and RB status on CAB activity will also be evaluated. Clinical trial information: 2016-005251-25.

Aim: This study aimed to identify predictive/prognostic factors in castration-resistant prostate cancer patients treated with cabazitaxel. Patients & methods: Patients were enrolled from March 2011 to December 2011 in an international expanded access program. In January 2012, when cabazitaxel became commercially available, a prospective study was initiated at University Federico II of Naples and at Rionero in Vulture Hospital. Results: Forty-seven patients were enrolled in this study. Patients received a median of nine cycles of cabazitaxel. Median progression-free survival was 7.0 months (95% CI: 5.7–8.0). Seventeen patients were still alive at the time of the analysis, with a median overall survival of 14 months (95% CI: 11–16). At multivariate analysis, a higher Gleason score (≥8) appeared to be associated with prolonged progression-free survival (hazard ratio: 0.36; 95% CI: 0.18–0.72); however, the higher Gleason score showed no statistical impact on overall survival. Conclusion: We hypothesize that the Gleason score has the potential to be incorporated in the clinical decision-making process for definition of treatment strategy in docetaxel-pretreated castration-resistant prostate cancer patients. We encourage further experimentation in this setting.

To identify the optimal choice for first-line chemotherapy for advanced urothelial carcinoma (UC), we investigated the outcomes between cisplatin and non-cisplatin regimens in patients with metastatic UC after perioperative cisplatin-based chemotherapy (PCBC) in a multicenter retrospective study. In patients who had undergone previous PCBC for UC, a repeat challenge with cisplatin conferred poorer overall survival, especially in those with progression in < 1 year. Introduction: The optimal choice of first-line chemotherapy for patients with relapse of urothelial carcinoma (UC) after perioperative cisplatin-based chemotherapy (PCBC) is unclear. We investigated the outcomes with cisplatin rechallenge versus a non-cisplatin regimen in patients with recurrent metastatic UC after PCBC in a multicenter retrospective study. Patients and Methods: Individual patient-level data were collected for patients who had received various first-line chemotherapy regimens for advanced UC after previous PCBC. Cox proportional hazards models were used to investigate the prognostic ability of the type of perioperative and first-line chemotherapy to independently affect overall survival (OS) and progression-free survival (PFS) after accounting for known prognostic factors. Results: Data were available for 145 patients (12 centers). The mean age was 62 years; the Eastern Cooperative Oncology Group (ECOG) performance status (PS) was > 0 for 42.0% of the patients. Of the 145 patients, 63% had received cisplatin-based first-line chemotherapy. The median time from previous chemotherapy (TFPC) was 6.2 months (range, 1-154 months). The median OS was 22 months (95% confidence interval [CI], 18-27 months), and the median PFS was 6 months (95% CI, 5-7 months). A better ECOG PS and a longer TFPC (> 12 months vs.

Evaluation of: Grunwald V, Seidel C, Fenner M, Ganser A, Busch J, Weikert S. Treatment of everolimus-resistant metastatic renal cell carcinoma with VEGF-targeted therapies. Br. J. Cancer 105(11), 1635–1639 (2011).The results achieved with targeted therapy have changed the natural course of kidney cancer not amenable to local therapy. Sunitinib, bevacizumab and pazopanib are approved in the first-line setting for patients at good/intermediate prognosis, while temsirolimus should be the first-line agent to be used in patients at poor prognosis. The oncology community has been eagerly awaiting results as far as second-line treatment is concerned. The RECORD-1 and AXIS trials provided evidence in favor of everolimus and axitinib, respectively, in patients pretreated with VEGF-directed agents. As the number of available agents grows, so does the possibility of using multiple lines of therapy with a potential benefit in overall survival. The third-line setting has been poorly investigated, and no comparative pr...

ABSTRACT: Aims: Carboplatin plus etoposide has modest efficacy in docetaxel-pretreated castration-resistant prostate cancer patients. We hypothesized that carboplatin–etoposide could still exert some therapeutic activity after docetaxel, cabazitaxel and either abiraterone or enzalutamide. Patients & methods: We enrolled 15 patients in the first step of a Phase II trial. The target sample size is 46 patients. The primary end point of the study was progression-free survival after 12 weeks. Results: The median progression-free survival was 11 weeks (range: 8–18), while median overall survival was 18 weeks (range: 12–26). Of seven patients with measurable disease, two had a partial response, two showed stable disease and the remaining three had progressive disease as the best radiological response. Five patients were considered progression-free after 12 weeks, prompting continuation of the trial. Conclusion: Our preliminary findings support the hypothesis that carboplatin plus etoposide may yield some clinical benefit in a population of patients who failed all currently approved therapeutic options for prostate cancer.

Nasopharyngeal carcinoma is rare in western countries, accounting for less than 1% of all malignancies. Despite prognosis is satisfactory for newly diagnosed, non-metastatic disease, management of recurrent disease is challenging, with a survival expectancy of approximately 6 mo with the use of chemotherapy as the sole salvage treatment. We report a case of recurrent nasopharyngeal carcinoma treated with a combination of chemotherapy, radiotherapy and surgery in the context of a multidisciplinary approach. A durable complete response was achieved.

Prostate cancer is the most common non-cutaneous malignancy for men. The skeleton is the most common metastatic site but, following an improvement in survival, metastases in uncommon sites are being found more frequently in clinical practice, especially brain metastases. Despite the new drugs now available for metastatic castration resistant prostate cancer, no clinical evidence exists about their effectiveness on brain metastases. We describe the clinical history of 3 patients treated with cabazitaxel plus whole brain radiotherapy. These case reports demonstrate that cabazitaxel is highly active and well tolerated in brain metastases.

ABSTRACT Background: A multi-institutional Phase II trial was initiated in 2005 to test the combination gemcitabine and capecitabine in patients with thymic epithelial malignancies (TETs). Patients & methods: Patients with histologic confirmation of TET diagnosis by central review who had received >1 systemic chemotherapy treatment were included. Patients received oral capecitabine (650 mg/mq twice daily on days 1–14) and intravenous gemcitabine (1000 mg/mq on days 1 and 8 every 3 weeks). Results: Of the 30 patients included (18 men, 12 women; median age: 57 years, range: 48–61 years), the majority (73%) had thymoma, and the remaining thymic carcinoma. Eight patients developed grade 3–4 neutropenia. A total of 12 patients had a response. Median progression-free survival was 11 months (range: 6.5–16.5). Conclusion: Capecitabine and gemcitabine is highly active in TETs.

Denosumab has been proven to be at least as effective with respect to zoledronic acid in preventing skeletal-related events in patients with bone metastases from solid tumors. Although denosumab can be considered to have a more favorable toxicity profile compared to zoledronic acid in terms of kidney toxicity and flu-like symptoms, hypocalcemia is twice as frequent with denosumab. Importantly, denosumab is not metabolized by the kidney and it may be employed even in patients with severe kidney failure. Like zoledronic acid, denosumab is administered with oral calcium and vitamin D. As conversion of vitamin D to its active form is progressively impaired with a creatinine clearance < 70 ml/min, we speculate that calcitriol may be a better option than vitamin D in denosumab-treated patients with impaired kidney function.

To evaluate the outcomes and potential prognostic factors in patients with non-acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS).Patients with histologically proven non-AIDS-related KS treated with systemic chemotherapy were included in this retrospective analysis. In some cases, the human herpes virus 8 status was assessed by immunohistochemistry. The patients were staged according to the Mediterranean KS staging system. A multivariable model was constructed using a forward stepwise selection procedure. A P value0.05 was considered statistically significant, and all tests were two-sided.Thirty-two cases were included in this analysis. The average age at diagnosis was 70 years, with a male/female ratio of approximately 2:1. Eighty-four percent of the cases had classic KS. All patients received systemic chemotherapy containing one of the following agents: vinca alkaloid, taxane, and pegylated liposomal doxorubicin. Ten patients (31.5%) experienced a partial response, and a complete response was achieved in four patients (12.4%) and stable disease in sixteen cases (50%). Two patients (6.2%) were refractory to the systemic treatment. The median progression-free survival (PFS) was 11.7 mo, whereas the median overall survival was 28.5 mo. At multivariate analysis, the presence of nodular lesions (vs macular lesions only) was significantly related to a lower PFS (hazard ratio: 3.09; 95%CI: 1.18-8.13, P = 0.0133).Non-AIDS-related KS appears mostly limited to the skin and is well-responsive to systemic therapies. Our data show that nodular lesions may be associated with a shorter PFS in patients receiving chemotherapy.

Chemotherapy agents for patients with metastatic castration-resistant prostate cancer (mCRPC) include docetaxel and cabazitaxel. Although docetaxel is approved in the first-line treatment setting, a few studies have shown that selected patients can benefit from docetaxel rechallenge.We, here, report the case of a heavily pretreated mCRPC patient who reported clinical benefit from receiving docetaxel after previous exposure to docetaxel, cabazitaxel, abiraterone, and enzalutamide.After 4 cycles of treatment, patient's performance status had improved to 1, the hemoglobin level was 12.9 g/dL and his serum prostate specific antigen levels were reduced by >70%, with no treatment-related adverse events.Although docetaxel rechallenge is a therapeutic option for selected patients, the risk of cumulative toxicity described in literature must be carefully considered.As the risk of cabazitaxel-related cumulative toxicity is probably lower, retreatment with cabazitaxel rather than docetaxel may also be an option in the setting of heavily pretreated mCRPC patients.

Although thymic epithelial tumors (TETs) are rare in the general population, they represent the most frequently diagnosed primary malignant tumor of the anterior mediastinum. Unlike localized disease, metastatic disease is invariably fatal. While several chemotherapy agents have proven to be effective in TETs, somatostatin analogs are the only targeted agents with an established role in this disease. Everolimus is an mTOR inhibitor with multiple application in oncology. In this report, we show for the first time that everolimus was effective in two heavily pretreated patients with advanced TETs, with a progression-free survival longer than 1 year and minimal toxicity.

Prostate Cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in men in the Western World. Docetaxel-based chemotherapy has been the mainstay of treatment until a few years ago for metastatic castration resistant prostatic cancer (mCRPC). Recently, a broad range of therapeutic options has become available for mCRPC in a variety of settings, including chemotherapeutic agents (cabazitaxel), androgen synthesis inhibitors (abiraterone acetate), androgen receptor (AR) inhibitors (enzalutamide) and immunotherapy (sipuleucel-T). Multiple novel targeted agents are at an advanced stage of experimentation, including androgen synthesis inhibitors (TAK700), AR inhibitors (ARN509), radiopharmaceuticals (radium-223) and immunotherapeutic agents (poxvirus-based vaccine, ipilimumab). This review describes in detail the latest results obtained with a the most promising agents in prostate cancer, with a focus on CRPC biology and mechanism of resistance to anti-neoplastic treatment.

Non-muscle invasive bladder cancer is the most common type of bladder cancer in Western countries. The glycosaminoglycan (GAG) layer at the bladder surface non-specifically blocks the adherence of bacteria, ions and molecules to the bladder epithelium and bladder cancer cells express CD44 that binds GAG. Currently, there are few options other than cystectomy for the management of non-muscle invasive bladder cancer with intravesical chemotherapy using several drugs such as gemcitabine (GEM) and mitomycin-C (MMC) with poor prophylactic activity. In this study, we investigated the effects of the GAG chondroitin sulphate (CS) on the growth inhibition of human bladder cancer cell lines HT-1376 and effects of the combination between GEM or MMC with CS. We have found that CS, MMC and GEM induced 50% growth inhibition at 72 h. Therefore, we have evaluated the growth inhibition induced by different concentration of CS in combination with MMC or GEM, respectively, at 72 h. We have observed, at Calcusyn analysis, a synergism when HT-1376 cells were treated with CS in combination with MMC or GEM, respectively, if used at an equimolar ratio. We have also found that CS/GEM combination induced a strong potentiation of apoptosis with the consequent activation of caspases 9 and 3. On the other hand, HT-1376 cells were necrotic if exposed to the CS/MMC combination and no signs of caspase activation was observed. In conclusion, in the human bladder cancer cell line HT-1376 pharmacological combination of CS with GEM or MMC resulted in a strong synergism on cell growth inhibition.

Anaplastic thyroid carcinoma (ATC) is the rarest, but deadliest histologic type among thyroid malignancies, with a dismal median survival of 3-9 mo. Even though ATC accounts for less than 2% of all thyroid tumors, it is responsible for 14%-39% of thyroid carcinoma-related deaths. ATC clinically presents as a rapidly growing mass in the neck, associated with dyspnoea, dysphagia and vocal cord paralysis. It is usually locally advanced and often metastatic at initial presentation. For operable diseases, the combination of radical surgery with adjuvant radiotherapy or chemotherapy, using agents such as doxorubicin and cisplatin, is the best treatment strategy. Cytotoxic drugs for advanced/metastatic ATC are poorly effective. On the other hand, targeted agents might represent a viable therapeutic option. Axitinib, combretastatin A4, sorafenib and imatinib have been tested in small clinical trials of ATC, with a promising disease control rate ranging from 33% to 75%. Other clinical trials of targeted therapy for thyroid carcinoma are currently ongoing. Biological agents that are under investigation include pazopanib, gefitinib and everolimus. With the very limited therapeutic armamentarium available at the present time, targeted therapy constitutes an exciting new horizon for ATC. In future, biological agents will probably represent the standard of care for this aggressive malignancy, in the same fashion as it has recently occurred for other chemo-refractory tumors, such as kidney and hepatic cancer.

Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant glioma (MG), with a median survival time of 12-15 months, despite current best treatment based on surgery, radiotherapy and systemic chemotherapy. Many potentially active therapeutic agents are not effective by systemic administration, because they are unable to cross the blood-brain barrier (BBB). As intracerebral administration bypasses the BBB, it increases the number of drugs that can be successfully delivered to the brain, with the possibility of minor systemic toxicity and better effectiveness. This review summarizes the results of the extensive clinical research conducted on intracerebral therapy. Biodegradable drug carriers, implantable subcutaneous reservoirs and convection-enhanced delivery (CED) represent the main techniques for intracerebral delivery, while conventional chemotherapy agents, radiolabeled antibodies and receptor-targeted toxins are the main classes of drugs for intracerebral therapy. At the present time, biodegradable carmustine wafers, commercialized as Gliadel(®), are the only FDA-approved treatment for intracerebral chemotherapy of MG, but intracavitary delivery of mitoxantrone and radiolabeled antitenascin antibodies via implantable reservoirs has yielded promising results in uncontrolled trials. The pressure-driven flow generated by CED can potentially distribute convected drugs over large volumes of the brain, independently on their intrinsic diffusivity. Nevertheless, prominent technical problems, like backflow, are yet to be properly addressed and contributed to the disappointing results of two phase III trials that investigated CED of cintredekin besudotox and TransMid™ in patients with recurrent GBM.