San Camillo and Forlanini Hospitals

Rome, Italy

San Camillo and Forlanini Hospitals

Rome, Italy

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Fizazi K.,University Paris - Sud | Scher H.I.,Sloan Kettering Cancer Center | Molina A.,Janssen Research and Development | Logothetis C.J.,University of Texas M. D. Anderson Cancer Center | And 14 more authors.
The Lancet Oncology | Year: 2012

Background: Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events). Methods: Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00091442. Findings: Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4-22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8-17·0] vs 11·2 months [10·4-13·1]; hazard ratio [HR] 0·74, 95% CI 0·64-0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3-11·1, in the abiraterone group vs 6·6 months, 5·6-8·3, in the placebo group; HR 0·63, 0·52-0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6-6·5, vs 3·6 months, 2·9-5·5; HR 0·66, 0·58-0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3-4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]). Interpretation: This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up. Funding: Janssen Research & Development. © 2012 Elsevier Ltd.


Gartrell B.A.,Yeshiva University | Coleman R.E.,Weston Park Hospital | Fizazi K.,University Paris - Sud | Miller K.,University Hospital Charite | And 3 more authors.
European Urology | Year: 2014

Context Advanced prostate cancer (PCa) is associated with skeletal complications, both as a result of bone metastases and because of fractures associated with fragility due to androgen-deprivation therapy (ADT). Osteoclast inhibitors are commonly used to reduce skeletal complications but are associated with a number of potential adverse events. Objective To review clinical trials of osteoclast inhibitors in advanced PCa, to discuss the adverse event profile of these agents, and to discuss strategies to address specific adverse events. Evidence acquisition PubMed was searched for reports of clinical trials of osteoclast inhibitors in advanced PCa. As zoledronic acid and denosumab are used most commonly in this disease, these trials were the focus. The literature was reviewed to identify key publications addressing the prevention and management of adverse events associated with these drugs. Evidence synthesis The major findings of the trials and the adverse events are discussed. Prevention and management of common adverse events are addressed. Conclusions Zoledronic acid prevents loss of bone mineral density associated with ADT and delays skeletal-related events in metastatic castration-resistant PCa (mCRPC). Denosumab reduces the incidence of fragility fractures associated with ADT, delays the onset of bone metastases in nonmetastatic castration-resistant disease, and is superior to zoledronic acid in the prevention of skeletal complications in mCRPC. Adverse events associated with both agents include osteonecrosis of the jaw and hypocalcemia. Hypocalcemia is more common with denosumab. Zoledronic acid requires dose modifications for renal insufficiency, is contraindicated in severe renal insufficiency, and has been associated with deterioration of renal function. Appropriate patient selection with close attention to dental health, supplementation with calcium and vitamin D, and monitoring of laboratory values are effective strategies to minimize the impact of adverse events associated with osteoclast inhibitors in advanced PCa. © 2013 European Association of Urology.


Fizazi K.,University Paris - Sud | Scher H.I.,Sloan Kettering Cancer Center | Miller K.,Charité - Medical University of Berlin | Basch E.,University of North Carolina at Chapel Hill | And 5 more authors.
The Lancet Oncology | Year: 2014

Background: In the AFFIRM trial of patients with metastatic castration-resistant prostate cancer after progression with docetaxel treatment, enzalutamide significantly increased overall survival compared with placebo. Here we present the prospectively defined analyses of some secondary endpoints, including occurrence of skeletal-related events, measures of pain control, and patient-reported health-related quality of life (HRQoL). Methods: In this phase 3, double-blind trial, patients were randomly assigned (2:1) to receive enzalutamide 160 mg/day or placebo orally, stratified by ECOG baseline performance status (0 or 1 vs 2) and mean pain score (Brief Pain Inventory-Short Form [BPI-SF] question 3 worst pain, score ≤3 vs ≥4). Secondary endpoints were time to first skeletal-related event (radiation therapy or surgery to bone, clinically apparent pathological bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain); change from baseline to week 13 in pain severity and interference; pain palliation and progression at week 13; time to pain progression; overall improvement in HRQoL; improvements in HRQoL domains; and time to HRQoL deterioration. Analysis was done on the intention-to-treat population for each endpoint. AFFIRM is registered with ClinicalTrials.gov, number NCT00974311. Findings: Median time to first skeletal-related event in the enzalutamide (n=800) and placebo (n=399) groups was 16·7 months (95% CI 14·6 to 19·1) and 13·3 months (95% CI 9·9 to not yet reached), respectively (hazard ratio [HR] 0·69 [95% CI 0·57-0·84]; p=0·0001). Pain progression at week 13 occurred in 174 (28%) of 625 evaluable patients in the enzalutamide group versus 101 (39%) of 259 patients in the placebo group (difference -11·2%, 95% CI -18·1 to -4·3; p=0·0018). Median time to pain progression was not yet reached in the enzalutamide group (95% CI not yet reached to not yet reached) versus 13·8 (13·8 to not yet reached) months in the placebo group (HR 0·56 [95% CI 0·41 to 0·78]; p=0·0004). Mean treatment effects for pain severity (mean change from baseline in the enzalutamide group -0·15, 95% CI -0·28 to -0·02, vs placebo 0·50, 0·29 to 0·70; difference -0·65, 95% CI -0·89 to -0·41; p<0·0001) and interference (-0·01, -0·18 to 0·16, vs 0·74, 0·47 to 1·00; respectively, difference -0·74, 95% -1·06 to -0·43; p<0·0001) were significantly better with enzalutamide than with placebo. 22 (45%) of 49 evaluable patients in the enzalutamide group reported pain palliation at week 13 versus one (7%) of 15 in the placebo group (difference 38·2%, 95% CI 19·4-57·0; p=0·0079). Overall improvement in HRQoL was reported in more patients receiving enzalutamide (275 [42%] of 652) than in those receiving placebo (36 [15%] of 248; p<0·0001). Patients in the enzalutamide group had longer median time to HRQoL deterioration than did those in the placebo group (9·0 months, 95% CI 8·3-11·1, vs 3·7 months, 95% CI 3·0-4·2; HR 0·45, 95% CI 0·37-0·55; p<0·0001). Interpretation: Our results show that, in addition to improving overall survival, enzalutamide improves wellbeing and everyday functioning of patients with metastatic castration-resistant prostate cancer. Funding: Astellas Pharma and Medivation. © 2014 Elsevier Ltd.


Sternberg C.N.,San Camillo and Forlanini Hospitals | de Bono J.S.,Institute of Cancer Research | Chi K.N.,BC Cancer Agency | Fizazi K.,University Paris - Sud | And 5 more authors.
Annals of Oncology | Year: 2014

Background: The randomized, double-blind phase III AFFIRM trial demonstrated that enzalutamide, an oral androgen receptor inhibitor, significantly prolonged overall survival (OS) [median 18.4 versus 13.6 months (hazard ratio, HR) 0.63 (95% confidence interval, CI, 0.53-0.75); P < 0.001] compared with placebo in patients with metastatic castration-resistant prostate cancer who received prior docetaxel chemotherapy. Patients and methods: A post hoc analysis was carried out to assess the efficacy and safety of enzalutamide on outcomes in younger (<75 years) and elderly (≥75 years) patients in the AFFIRM population. Statistics are presented by age group (<75 years, ≥75 years) for efficacy outcomes of OS, radiographic progression-free survival (rPFS), time to prostatespecific antigen (PSA) progression, PSA response, and safety. Results: OS was significantly improved with enzalutamide over placebo in patients <75 years [median not yet reached versus 13.6 months; HR 0.63 (95% CI 0.52-0.78), P < 0.001] and in patients ≥75 years [median 18.2 versus 13.3 months; HR 0.61 (95% CI 0.43-0.86), P ≥ 0.004], respectively. rPFS was similarly improved in both the younger [HR 0.45 (95% CI 0.38-0.53), P < 0.001] and elderly patient cohorts [HR 0.27 (95% CI 0.20-0.37), P < 0.001] relative to placebo, as were time to PSA progression and PSA response. Adverse events (AEs) were similar between the two enzalutamide age groups, with the exception of an increase in patients ≥75 years in the rates of all grade peripheral edema (22.1% versus 12.5%), fatigue (39.7% versus 31.6%), and diarrhea (26.6% versus 19.6%). The overall grade ≥3 AE rates were low with no major difference in frequency or severity between age groups or treatment arms. Five patients were reported with seizure events; three patients <75 years and two patients ≥75 years. Conclusions: Enzalutamide significantly improves outcomes in both younger (<75 years) and elderly patients (≥75 years), with comparable safety and tolerability. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Eisen T.,Addenbrookes Hospital | Sternberg C.N.,San Camillo and Forlanini Hospitals | Robert C.,Institute Gustave Roussy | Mulders P.,Radboud University Nijmegen | And 4 more authors.
Journal of the National Cancer Institute | Year: 2012

With the advent of targeted agents for the treatment of renal cell carcinoma (RCC), overall survival has improved, and patients are being treated continuously for increasingly long periods of time. This has raised challenges in the management of adverse events (AEs) associated with the six targeted agents approved in RCC-sorafenib, sunitinib, pazopanib, bevacizumab (in combination with interferon alpha), temsirolimus, and everolimus. Suggestions for monitoring and managing AEs have been published, but there are few consensus recommendations. In addition, there is a risk that patients will be subjected to multiple unnecessary investigations. In this review, we aimed to identify the level of supporting evidence for suggested AE management strategies to provide practical guidance on essential monitoring and management that should be undertaken when using targeted agents. Five databases were systematically searched for relevant English language articles (including American Society of Clinical Oncology abstracts) published between January 2007 and March 2011; European Society of Medical Oncology congress abstracts were hand searched. Strategies for AE management were summarized and categorized according to the level of recommendation. A total of 107 articles were identified that describe a large number of different investigations for monitoring AEs and interventions for AE management. We identify and summarize clear recommendations for the management of dermatologic, gastrointestinal, thyroid, cardiovascular, and other AEs, based predominantly on expert opinion. However, because the evidence for the suggested management strategies is largely anecdotal, there is a need for further systematic investigation of management strategies for AEs related to targeted therapies for RCC. © 2012 The Author.


Agarwal N.,University of Utah | Sonpavde G.,Texas Oncology | Sonpavde G.,Baylor College of Medicine | Sternberg C.N.,San Camillo and Forlanini Hospitals
European Urology | Year: 2012

Context: Improved understanding of mechanisms underlying metastatic castration-resistant prostate cancer (mCRPC) progression has led to the recognition of multiple molecular targets and advances in the therapeutic landscape. The addition of abiraterone acetate, sipuleucel-T, cabazitaxel, and denosumab to the therapeutic armamentarium and the impending addition of MDV-3100 and radium-223 underscore the importance of androgen pathway inhibition, immunotherapy, tubulin antagonism, and pathophysiology of bone metastasis. Objective: Review the next generation of molecular targets in mCRPC. Evidence acquisition: Medline databases were searched for >100 original articles published as of October 18, 2011, with the search terms metastatic castration-resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy. Proceedings from the last 5 yr of conferences of the American Society of Clinical Oncology, American Urological Association, European Society of Medical Oncology, and the European Association of Urology were also searched. We included novel and promising drugs that have reached clinical trial evaluation. Evidence synthesis: The major findings were addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed. Conclusions: mCRPC is a disease with multiple molecular drivers. Molecular pathways being targeted in ongoing phase 3 trials are androgen signaling (MDV3100, TAK700), immunoregulatory pathways (ipilimumab, Prostvac-VF-TRICOM), Src (dasatinib), Met (cabozantinib), clusterin (custirsen), and angiogenesis (aflibercept, tasquinimod). The strides made in identifying multiple other novel molecular targets offer potential opportunities for further improving outcomes. © 2011 European Association of Urology.


Tran H.T.,University of Houston | Liu Y.,Glaxosmithkline | Zurita A.J.,University of Houston | Lin Y.,Glaxosmithkline | And 8 more authors.
The Lancet Oncology | Year: 2012

Background: Several targeted drugs are approved for treatment of patients with metastatic renal-cell cancer, but no validated biomarkers are available for prediction of clinical outcome. We aimed to assess the prognostic and predictive associations of pretreatment plasma concentrations of cytokine and angiogenic factors (CAFs) with data from a phase 2 and a phase 3 trial of pazopanib treatment. Methods: We used a three-step approach for screening, confirmation, and validation of prospective CAF biomarkers. We screened 17 CAFs in 129 patients who had the greatest or least tumour shrinkage in a phase 2 trial of 215 patients treated with pazopanib. We confirmed associations of candidate CAFs (those identified in the screening and from previous studies) with tumour response and progression-free survival (PFS) in 215 patients from this phase 2 trial with an independent analytical platform. We validated confirmed markers in 344 patients from a randomised, placebo-controlled, phase 3 clinical study of pazopanib. Findings: Five candidate markers emerged from initial screening-interleukin 6, interleukin 8, hepatocyte growth factor (HGF), tissue inhibitor of metalloproteinases (TIMP)-1, and E-selectin. Confirmatory analyses identified associations of interleukin 6, interleukin 8, VEGF, osteopontin, E-selectin, and HGF with continuous tumour shrinkage or PFS in patients treated with pazopanib. In the validation set of samples from the phase 3 trial, patients treated with pazopanib who had high concentrations (relative to median) of interleukin 8 (p=0·006), osteopontin (p=0·0004), HGF (p=0·010), and TIMP-1 (p=0·006) had shorter PFS than did those with low concentrations. In the placebo group, high concentrations of interleukin 6 (p<0·0001), interleukin 8 (p=0·002), and osteopontin (p<0·0001) were all prognostically associated with shorter PFS. These factors were stronger prognostic markers than were standard clinical classifications (Eastern Cooperative Oncology Group, Memorial Sloan-Kettering Cancer Center, and Heng criteria). High concentrations of interleukin 6 were predictive of improved relative PFS benefit from pazopanib compared with placebo (p interaction=0·009); standard clinical classifications were not predictive of PFS benefit. Interpretation: CAF profiles could provide prognostic information beyond that of standard clinical classification and identify markers predictive of pazopanib benefit in patients with metastatic renal-cell carcinoma. Further studies of the predictive effects of these markers in different populations and with different drugs (eg, mTOR inhibitors) are warranted. Funding: GlaxoSmithKline. © 2012 Elsevier Ltd.


Sonpavde G.,Baylor College of Medicine | Sternberg C.N.,San Camillo and Forlanini Hospitals
Current Urology Reports | Year: 2012

Neoadjuvant cisplatin-based combination chemotherapy is an established standard for resectable muscleinvasive bladder cancer, a disease with a pattern of predominantly distant and early recurrences. Pathologic complete remission appears to be an intermediate surrogate for survival when employing combination chemotherapy. Moreover, baseline host and tumor tissue studies may enable the discovery of biomarkers predictive of activity. The neoadjuvant setting also provides a window of opportunity to evaluate novel biologic agents or rational combinations of biologic agents to obtain a signal of biologic activity. The residual tumor after neoadjuvant therapy may be exploited to study the mechanism of action and resistance. Cisplatinineligible patients warrant the evaluation of tolerable neoadjuvant regimens. Given that bladder cancer is characterized by initial localized presentation in the vast majority of cases, the paradigm of neoadjuvant therapy may expedite the development of novel systemic agents. © Springer Science+Business Media, LLC 2012.


Calabro F.,San Camillo and Forlanini Hospitals | Sternberg C.N.,San Camillo and Forlanini Hospitals
Current Opinion in Supportive and Palliative Care | Year: 2012

Purpose of review Although bladder cancer is considered a chemosensitive disease, the prognosis of patients with metastatic disease is still poor with median survival being approximately 12-14 months in good prognosis patients and with cure in only a minority of patients. The addition of new drugs to the standard cisplatin-based regimens has not improved these figures. The purpose of this review is to highlight the role of chemotherapy and the impact of the new targeted agents in the treatment of metastatic bladder carcinoma. Recent findings A better understanding of the biology of the molecular patterns of urothelial bladder cancer has led to the clinical investigation of several therapeutic targets such as antiangiogenics, anti-EGFR agents, and immunomodulatory agents. To date, these agents have yet to demonstrate an improvement in overall survival. The molecular alterations that drive platinum resistance and the study of the genetic profiles will help to identify the prognostic and predictive biomarkers. Summary No major advances have been achieved in the recent years in the treatment of urothelial carcinoma of the bladder. Chemotherapy remains the mainstay of treatment of metastatic disease. Several targeted agents are currently under investigation, but no major breakthroughs have been achieved with these drugs. Development of less toxic, more effective agents is crucial and clinical trial participation needs to be emphasized. © 2012 Wolters Kluwer Health | Lippincott Williams &Wilkins.


Sternberg C.N.,San Camillo and Forlanini Hospitals
European Journal of Cancer | Year: 2011

The contemporary management of metastatic castration-resistant prostate cancer (mCRPC) is evolving dramatically. Understanding the biology of this disease, positive phase III studies and approvals for 4 novel agents in the US in 2010 and shortly in Europe have dramatically changed the therapeutic landscape. © 2011 Elsevier Ltd.

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