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2.  ESMO / ASCO Recommendations for a Global Curriculum in Medical Oncology Edition 2016 
Dittrich, Christian | Kosty, Michael | Jezdic, Svetlana | Pyle, Doug | Berardi, Rossana | Bergh, Jonas | El-Saghir, Nagi | Lotz, Jean-Pierre | Österlund, Pia | Pavlidis, Nicholas | Purkalne, Gunta | Awada, Ahmad | Banerjee, Susana | Bhatia, Smita | Bogaerts, Jan | Buckner, Jan | Cardoso, Fatima | Casali, Paolo | Chu, Edward | Close, Julia Lee | Coiffier, Bertrand | Connolly, Roisin | Coupland, Sarah | De Petris, Luigi | De Santis, Maria | de Vries, Elisabeth G E | Dizon, Don S | Duff, Jennifer | Duska, Linda R | Eniu, Alexandru | Ernstoff, Marc | Felip, Enriqueta | Fey, Martin F | Gilbert, Jill | Girard, Nicolas | Glaudemans, Andor W J M | Gopalan, Priya K | Grothey, Axel | Hahn, Stephen M | Hanna, Diana | Herold, Christian | Herrstedt, Jørn | Homicsko, Krisztian | Jones, Dennie V | Jost, Lorenz | Keilholz, Ulrich | Khan, Saad | Kiss, Alexander | Köhne, Claus-Henning | Kunstfeld, Rainer | Lenz, Heinz-Josef | Lichtman, Stuart | Licitra, Lisa | Lion, Thomas | Litière, Saskia | Liu, Lifang | Loehrer, Patrick J | Markham, Merry Jennifer | Markman, Ben | Mayerhoefer, Marius | Meran, Johannes G | Michielin, Olivier | Moser, Elizabeth Charlotte | Mountzios, Giannis | Moynihan, Timothy | Nielsen, Torsten | Ohe, Yuichiro | Öberg, Kjell | Palumbo, Antonio | Peccatori, Fedro Alessandro | Pfeilstöcker, Michael | Raut, Chandrajit | Remick, Scot C | Robson, Mark | Rutkowski, Piotr | Salgado, Roberto | Schapira, Lidia | Schernhammer, Eva | Schlumberger, Martin | Schmoll, Hans-Joachim | Schnipper, Lowell | Sessa, Cristiana | Shapiro, Charles L | Steele, Julie | Sternberg, Cora N | Stiefel, Friedrich | Strasser, Florian | Stupp, Roger | Sullivan, Richard | Tabernero, Josep | Travado, Luzia | Verheij, Marcel | Voest, Emile | Vokes, Everett | Von Roenn, Jamie | Weber, Jeffrey S | Wildiers, Hans | Yarden, Yosef
ESMO Open  2016;1(5):e000097.
The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies.
PMCID: PMC5070299  PMID: 27843641
Global curriculum; clinical training; medical oncology; didactic principles; learning objectives
3.  Phase II Study of Dasatinib in Patients with Metastatic Castration-Resistant Prostate Cancer 
Clinical Cancer Research  2009;15(23):7421-7428.
Antiproliferative and antiosteoclastic activity from preclinical models show potential for dasatinib, an oral SRC and SRC family kinase inhibitor, as a targeted therapy for patients with prostate cancer. This phase II study investigated the activity of dasatinib in patients with metastatic castration-resistant prostate cancer (CRPC).
Experimental Design
Chemotherapy-naive men with CRPC and increasing prostate-specific antigen were treated with dasatinib 100 or 70 mg twice daily. Endpoints included changes in prostate-specific antigen, bone scans, measurable disease (Response Evaluation Criteria in Solid Tumor), and markers of bone metabolism. Following Prostate Cancer Working Group 2 guidelines, lack of progression according to Response Evaluation Criteria in Solid Tumor and bone scan was determined and reported at 12 and 24 weeks.
Forty-seven patients were enrolled and received dasatinib (initial dose 100 mg twice daily, n = 25; 70 mg twice daily, n = 22), of whom 41 (87%) had bone disease. Lack of progression was achieved in 20 (43%) patients at week 12 and in 9 (19%) patients at week 24. Of 41 evaluable patients, 21 (51%) patients achieved ≥40% reduction in urinary N-telopeptide by week 12, with 33 (80%) achieving some level of reduction anytime on study. Of 15 patients with elevated urinary N-telopeptide at baseline, 8 (53%) normalized on study. Of 40 evaluable patients, 24 (60%) had reduction in bone alkaline phosphatase at week 12 and 25 (63%) achieved some reduction on study. Dasatinib was generally well tolerated and treatment-related adverse events were moderate.
This study provides encouraging evidence of dasatinib activity in bone and reasonable tolerability in chemotherapy-naive patients with metastatic CRPC.
PMCID: PMC3394097  PMID: 19920114
4.  An open-label, dose-finding study of the combination of satraplatin and gemcitabine in patients with advanced solid tumors 
Frontiers in Oncology  2012;2:175.
Purpose: Satraplatin is a third generation oral platinum, which has demonstrated antitumor activity. The aim of this phase I study was to determine the maximum tolerated dose (MTD) of the combination of satraplatin and gemcitabine in patients previously treated with chemotherapy and in patients without prior chemotherapy. Patients and Methods: Two separate MTDs were planned in two different patient groups (those with and without prior chemotherapy treatment). Dose escalations were planned in cohorts of three patients. Tumor measurements were obtained every two cycles. Assessment of response was performed according to Response Evaluation Criteria in Solid Tumors (RECIST criteria v.1.0). Results: Thirty subjects were enrolled. A MTD of gemcitabine 1000 mg/m2 days 1 and 8 plus satraplatin 60 mg/m2 days 1–3, every 21 days was determined in the prior chemotherapy group. No MTD could be determined for the no prior chemotherapy group treated with this schedule. Five patients completed 12 treatment cycles; 22 serious adverse events (SAE) were observed. Although not an entry criteria, overall confirmed response was observed in 17 (24%) evaluable patients (complete response, CR = 1 and partial response, PR = 3) and in 3/7 (43%) patients with measure prostate cancer lesions. Conclusions: In this phase Ib study, the combination of satraplatin and gemcitabine demonstrated to be safe and efficacious in particular in patients with prostate cancer.
PMCID: PMC3504330  PMID: 23189269
satraplatin; oral platinum; phase I study; prostate cancer; solid tumors; chemotherapy
5.  Toxicities Following Treatment with Bisphosphonates and Receptor Activator of Nuclear Factor-κB Ligand Inhibitors in Patients with Advanced Prostate Cancer 
European urology  2013;65(2):278-286.
Advanced prostate cancer(PCa) is associated withskeletal 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.
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.
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.
PMCID: PMC4744484  PMID: 23706567
Prostate cancer; Systematic review; Bone-targeted agents; Bisphosphonates; Denosumab; Adverse events
6.  Enzalutamide for the treatment of metastatic castration-resistant prostate cancer 
In recent years, several nonhormonal and hormonal agents, including enzalutamide, have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC) on the basis of improved overall survival in prospective clinical trials. The incorporation of these agents has revolutionized the treatment of CRPC but has also raised the question of what is the ideal sequence of administering them. Enzalutamide is a nonsteroidal second-generation antiandrogen that has been approved for the treatment of metastatic CRPC both in the post-docetaxel and chemotherapy-naïve settings. This article reviews the pharmacological characteristics of enzalutamide, the efficacy studies which led to its approval, its safety profile, and quality of life-related parameters as well as its place in the sequential treatment and management of metastatic prostate cancer.
PMCID: PMC4492664  PMID: 26170619
enzalutamide; antiandrogen; ADT; androgen receptor; castration resistant prostate cancer; overall survival
7.  Hormonal therapy and chemotherapy in hormone-naive and castration resistant prostate cancer 
The management of advanced castration resistant prostate cancer (CRPC) has been rapidly changing and is still evolving. In the last years, there has been an increasing knowledge of prostate cancer biology. New therapeutic agents and approaches have been evaluated demonstrating benefits in survival and quality of life in patients with metastatic prostate cancer.
PMCID: PMC4708230  PMID: 26816835
Prostate cancer; chemotherapy; hormonal therapy
8.  Six-Month Progression-Free Survival as the Primary Endpoint to Evaluate the Activity of New Agents as Second-line Therapy for Advanced Urothelial Carcinoma 
Clinical genitourinary cancer  2013;12(2):130-137.
This study examined the association of progression-free survival at 6 months with overall survival in the context of second-line therapy of advanced urothelial carcinoma in pooled patient-level data from 10 phase II trials and then externally validated in a large phase III trial. Progression-free survival at 6 months was significantly correlated with overall survival and is an innovative primary endpoint to evaluate new agents in this setting.
Second-line systemic therapy for advanced urothelial carcinoma (UC) has substantial unmet needs, and current agents show dismal activity. Second-line trials of metastatic UC have used response rate (RR) and median progression-free survival (PFS) as primary endpoints, which may not reflect durable benefits. A more robust endpoint to identify signals of durable benefits when investigating new agents in second-line trials may expedite drug development. PFS at 6 months (PFS6) is a candidate endpoint, which may correlate with overall survival (OS) at 12 months (OS12) and may be applicable across cytostatic and cytotoxic agents.
Ten second-line phase II trials with individual patient outcomes data evaluating chemotherapy or biologics were combined for discovery, followed by external validation in a phase III trial. The relationship between PFS6/RR and OS12 was assessed at the trial level using Pearson correlation and weighted linear regression, and at the individual level using Pearson chi-square test with Yates continuity correction.
In the discovery dataset, a significant correlation was observed between PFS6 and OS12 at the trial (R2 = 0.55, Pearson correlation = 0.66) and individual levels (82%, Қ = 0.45). Response correlated with OS12 at the individual level less robustly (78%, Қ = 0.36), and the trial level association was not statistically significant (R2 = 0.16, Pearson correlation = 0.37). The correlation of PFS6 (81%, Қ = 0.44) appeared
PMCID: PMC4142680  PMID: 24220220
Advanced urothelial carcinoma; Intermediate endpoint; Overall survival; Progression-free survival at 6 months; Second-line treatment
9.  Prognostic Model Predicting Metastatic Castration-Resistant Prostate Cancer Survival in Men Treated With Second-Line Chemotherapy 
Several prognostic models for overall survival (OS) have been developed and validated in men with metastatic castration-resistant prostate cancer (mCRPC) who receive first-line chemotherapy. We sought to develop and validate a prognostic model to predict OS in men who had progressed after first-line chemotherapy and were selected to receive second-line chemotherapy.
Data from a phase III trial in men with mCRPC who had developed progressive disease after first-line chemotherapy (TROPIC trial) were used. The TROPIC was randomly split into training (n = 507) and testing (n = 248) sets. Another dataset consisting of 488 men previously treated with docetaxel (SPARC trial) was used for external validation. Adaptive least absolute shrinkage and selection operator selected nine prognostic factors of OS. A prognostic score was computed from the regression coefficients. The model was assessed on the testing and validation sets for its predictive accuracy using the time-dependent area under the curve (tAUC).
The nine prognostic variables in the final model were Eastern Cooperative Oncology Group performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of hormonal use, hemoglobin, prostate specific antigen, and alkaline phosphatase. The tAUCs for this model were 0.73 (95% confidence interval [CI] = 0.72 to 0.74) and 0.70 (95% CI = 0.68 to 0.72) for the testing and validation sets, respectively.
A prognostic model of OS in the postdocetaxel, second-line chemotherapy, mCRPC setting was developed and externally validated. This model incorporates novel prognostic factors and can be used to provide predicted probabilities for individual patients and to select patients to participate in clinical trials on the basis of their prognosis. Prospective validation is needed.
PMCID: PMC3833929  PMID: 24136890
10.  Time from Prior Chemotherapy Enhances Prognostic Risk Grouping in the Second-line Setting of Advanced Urothelial Carcinoma: A Retrospective Analysis of Pooled, Prospective Phase 2 Trials 
European urology  2012;63(4):717-723.
Outcomes for patients in the second-line setting of advanced urothelial carcinoma (UC) are dismal. The recognized prognostic factors in this context are Eastern Cooperative Oncology Group (ECOG) performance status (PS) >0, hemoglobin level (Hb) <10 g/dl, and liver metastasis (LM).
The purpose of this retrospective study of prospective trials was to investigate the prognostic value of time from prior chemotherapy (TFPC) independent of known prognostic factors. Design, setting, and participants: Data from patients from seven prospective trials with available baseline TFPC, Hb, PS, and LM values were used for retrospective analysis (n = 570). External validation was conducted in a second-line phase 3 trial comparing best supportive care (BSC) versus vinflunine plus BSC (n = 352).
Outcome measurements and statistical analysis
Cox proportional hazards regression was used to evaluate the association of factors, with overall survival (OS) and progression-free survival (PFS) being the respective primary and secondary outcome measures.
Results and limitations
ECOG-PS >0, LM, Hb <10 g/dl, and shorter TFPC were significant prognostic factors for OS and PFS on multivariable analysis. Patients with zero, one, two, and three to four factors demonstrated median OS of 12.2, 6.7, 5.1, and 3.0 mo, respectively (concordance statistic = 0.638). Setting of prior chemotherapy (metastatic disease vs perioperative) and prior platinum agent (cisplatin or carboplatin) were not prognostic factors. External validation demonstrated a significant association of TFPC with PFS on univariable and most multivariable analyses, and with OS on univariable analyses. Limitations of retrospective analyses are applicable.
Shorter TFPC enhances prognostic classification independent of ECOG-PS>0, Hb<10 g/ dl, and LM in the setting of second-line therapy for advanced UC. These data may facilitate drug development and interpretation of trials.
PMCID: PMC4127896  PMID: 23206856
Urothelial carcinoma; Second line; Prognosis; Time from prior chemotherapy; Hemoglobin; Liver metastasis; Performance status
11.  Adjuvant Leuprolide With or Without Docetaxel in Patients With High-Risk Prostate Cancer After Radical Prostatectomy (TAX-3501) 
Cancer  2013;119(20):3610-3618.
The current trial evaluated 2 common therapies for patients with advanced prostate cancer, docetaxel and hormonal therapy (HT), in the surgical adjuvant setting.
TAX-3501 was a randomized, phase 3, adjuvant study post-radical prostatectomy (RP) in high-risk patients with prostate cancer (n = 228) comparing 18 months of HT with (CHT) without docetaxel chemotherapy either immediately (I) or deferred (D). High-risk disease was defined as a 5-year freedom-from-disease-progression rate of ≤60% as predicted by a post-RP nomogram. Progression-free survival (PFS), including prostate-specific antigen disease recurrence, was the primary endpoint. The authors also assessed the accuracy of the nomogram and analyzed testosterone recovery in 108 patients treated with HT who had at least 1 posttreatment testosterone value.
Between December 2005 and September 2007, 228 patients were randomized between the treatment cohorts. TAX-3501 was terminated prematurely because of enrollment challenges, leaving it underpowered to detect differences in PFS. After a median follow-up of 3.4 years (interquartile range, 2.3–3.8 years), 39 of 228 patients (17%) demonstrated PSA disease progression, and metastatic disease progression occurred in 1 patient. The median time to baseline testosterone recovery after the completion of treatment was prolonged at 487 days (95% confidence interval, 457–546 days). The nomogram’s predicted versus observed freedom from disease progression was significantly different for the combination D(HT) and D(CHT) group (P < .00001).
TAX-3501 illustrated several difficulties involved in conducting postoperative adjuvant systemic trials in men with high-risk prostate cancer: the lack of consensus regarding patient selection and treatment, the need for long follow-up time, nonvalidated intermediate endpoints, evolving standard approaches, and the need for long-term research support. Except for selected patients at very high-risk of disease recurrence and death, surgical adjuvant trials in patients with prostate cancer may not be feasible.
PMCID: PMC4124610  PMID: 23943299
prostate cancer; adjuvant therapy; docetaxel; leuprolide; testosterone recovery
12.  Design and End Points of Clinical Trials for Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group 
To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.
A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.
The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as “new lesions” or “no new lesions,” changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.
PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.
PMCID: PMC4010133  PMID: 18309951
13.  Treatment patterns and characteristics of European patients with castration-resistant prostate cancer 
BMC Urology  2013;13:58.
European treatment guidelines recommend the use of hormonal therapy for the treatment of advanced prostate cancer, including castration-resistant prostate cancer (CRPC), but there is little understanding of how common practices in prostate cancer treatment compare across Europe. The aim of this analysis was to evaluate the management of CRPC patients across five European countries (France, Germany, Italy, Spain and the UK).
Data were drawn from the Adelphi Real World Prostate Cancer Disease Specific Programme (DSP), a cross-sectional survey of patients undertaken between December 2009 and May 2010. The study is based on physician interviews, physician-completed detailed patient record forms, and a patient-completed questionnaire.
A total of 348 physicians (191 urologists and 157 oncologists) reported on 3477 patients with prostate cancer. Of the 3477 patients, 1405 (40%) were categorised as having CRPC, and 1119 of these had metastatic CRPC. Bone metastases were the most common (78%), followed by liver (37%) and lung (30%). The mean age of CRPC patients was 71 years, 35% were current or ex-smokers and 10% had a family history of prostate cancer. CRPC patients had a mean of 1.8 comorbidities; 66% had hypertension and 32% had diabetes. Most physicians estimated their patients would stop responding to initial hormone therapy after 19–24 months. Overall, addition of an anti-androgen to a luteinising-hormone-releasing hormone (LHRH) agonist was the most commonly prescribed therapy when patients failed initial LHRH agonist therapy, although there were considerable variations between countries. While 72% of physicians in Europe would choose chemotherapy as the next treatment option after diagnosis of CRPC, 31% of this group would initially prescribe this without an LHRH agonist.
Results from this analysis highlight inconsistencies in common hormonal therapy treatment patterns for CRPC and hormonal therapy across the EU.
PMCID: PMC4226263  PMID: 24206580
Castrate-resistant prostate cancer; CRPC; treatment; hormonal therapy; Anti-androgen; LHRH; Chemotherapy; Survey
14.  Optimal approach for renal cancer 
EJC Supplements  2013;11(2):159.
PMCID: PMC4041554
15.  Contemporary Role of Androgen Deprivation Therapy for Prostate Cancer 
European urology  2011;61(1):11-25.
Androgen deprivation therapy (ADT) for prostate cancer (PCa) represents one of the most effective systemic palliative treatments known for solid tumors. Although clinical trials have assessed the role of ADT in patients with metastatic and advanced locoregional disease, the risk–benefit ratio, especially in earlier stages, remains poorly defined. Given the mounting evidence for potentially life-threatening adverse effects with short- and long-term ADT, it is important to redefine the role of ADT for this disease.
Review the published experience with currently available ADT approaches in various contemporary clinical settings of PCa and reported serious treatment-related adverse events. This review addresses the level of evidence associated with the use of ADT in PCa, focusing upon survival outcome measures. Furthermore, this paper discusses evolving approaches targeting androgen receptor signaling pathways and emerging evidence from clinical trials with newer compounds.
Evidence acquisition
A comprehensive review of the literature was performed, focusing on data from the last 10 yr (January 2000 to July 2011) and using the terms androgen deprivation, hormone treatment, prostate cancer and adverse effects. Abstracts from trials reported at international conferences held in 2010 and 2011 were also evaluated.
Evidence synthesis
Data from randomized controlled trials and population-based studies were analyzed in different clinical paradigms. Specifically, the role of ADT was evaluated in patients with nonmetastatic disease as the primary and sole treatment, in combination with radiation therapy (RT) or after surgery, and in patients with metastatic disease. The data suggest that in men with nonmetastatic disease, the use of primary ADT as monotherapy has not shown a benefit and is not recommended, while ADT combined with conventional-dose RT (<72 Gy) for patients with high-risk disease may delay progression and prolong survival. The postoperative use of ADT remains poorly evaluated in prospective studies. Likewise, there are no trials evaluating the role of ADT in patients with biochemical relapses after surgery or RT. In patients with metastatic disease, there is a clear benefit in terms of quality of life, reduction of disease-associated morbidity, and possibly survival. Treatment with bilateral orchiectomy, luteinizing hormone–releasing hormone agonist therapy, with and without antiandrogens has been associated with various serious adverse events, including cardiovascular disease, diabetes, and skeletal complications that may also affect mortality.
Although ADT is an effective treatment of PCa, consistent long-term benefits in terms of quality and quantity of life are predominantly evident in patients with advanced/metastatic disease or when ADT is used in combination with RT (<72 Gy) in patients with high-risk tumors. Implementation of ADT should be evidence based, with special consideration to adverse events and the risk–benefit ratio.
PMCID: PMC3483081  PMID: 21871711
Prostate cancer; Androgen deprivation; Hormone treatment; Adverse effects
16.  Abiraterone and Increased Survival in Metastatic Prostate Cancer 
The New England journal of medicine  2011;364(21):1995-2005.
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group.
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 number, NCT00638690.)
PMCID: PMC3471149  PMID: 21612468
17.  Once-daily Dasatinib: Expansion of Phase II Study Evaluating Safety and Efficacy of Dasatinib in Patients With Metastatic Castration-resistant Prostate Cancer 
Urology  2011;77(5):1166-1171.
To determine the activity and tolerability of 100-mg once-daily (QD) dasatinib in patients with metastatic castration-resistance prostate cancer (CRPC). Dasatinib, an oral Src family kinase inhibitor, has demonstrated both preclinical and clinical activity with twice-daily dosing in patients with metastatic CRPC.
Chemotherapy-naive men with metastatic CRPC and increasing prostate-specific antigen levels were treated with dasatinib 100 mg QD. The primary measurement was a composite lack of disease progression, according to the Prostate Cancer Working Group 2 criteria, determined every 12 weeks during the study. The other analyses included changes in the prostate-specific antigen level, bone lesions, soft tissue disease, and bone turnover markers (urine N-telopeptide and bone alkaline phosphatase).
The present trial was designed before the publication of the recent Prostate Cancer Working Group 2 criteria; however, the analyses are presented to conform to the updated guidelines. A total of 48 patients received dasatinib. A lack of disease progression was observed in 21 patients (44%) at week 12 and in 8 (17%) at week 24. Urine N-telopeptide was reduced by ≥40% from baseline in 22 (51%) of 43 patients, and bone alkaline phosphatase was decreased in 26 (59%) of 44 patients. Dasatinib was well-tolerated, with only 6 patients (13%) with drug-related grade 3–4 adverse events and 3 (6%) with grade 3 adverse events. The most common treatment-related adverse events (≥20%) were fatigue, nausea, diarrhea, headache, and anorexia.
Dasatinib 100 mg QD has a favorable safety profile and maintains a similar degree of activity as the previously reported twice-daily dosing schedules. These data support additional study of dasatinib 100 mg QD for metastatic CRPC.
PMCID: PMC3394099  PMID: 21539969
18.  Androgen Deprivation Therapy for the Treatment of Prostate Cancer: Consider Both Benefits and Risks 
European urology  2008;55(1):62-75.
Androgen deprivation therapy (ADT) is increasingly used for the treatment of prostate cancer (PCa), even in clinical settings in which there is no evidence-based proof of prolonged overall survival (OS). ADT, however, may be associated with numerous side effects, including an increased therapy-related cardiovascular mortality.
To discuss different clinical settings in which ADT is currently used and to critically weigh the benefits of ADT against its possible side effects.
Evidence acquisition
A MEDLINE search was conducted to identify original articles and review articles addressing the efficacy and side effects of ADT for the treatment of PCa. Keywords consisted of prostate cancer, hormonal therapy, adverse effects, radical prostatectomy, and radiotherapy. The articles with the highest level of evidence for the various examined end points were identified with the consensus of all authors and were reviewed.
Evidence synthesis
Even short-term use of ADT may lead to numerous side effects, such as osteoporosis, obesity, sarcopenia, lipid alterations, insulin resistance, and increased risk for diabetes and cardiovascular morbidity. Despite these side effects, ADT is commonly used in various clinical settings in which a clear effect on improved OS has not been shown.
ADT is associated with an increased risk of multiple side effects that may reduce quality of life and/or OS. Consequently, these issues should be discussed in detail with patients and their families before initiation of ADT. ADT should be used with knowledge of its potential long-term side effects and with possible lifestyle interventions, especially in settings with the highest risk–benefit ratio, to alleviate comorbidities.
PMCID: PMC3090670  PMID: 18945543
Prostate cancer; Hormonal therapy; Adverse effects; Radical prostatectomy; Radiotherapy
19.  Enzalutamide in European and North American men participating in the AFFIRM trial 
Bju International  2014;115(1):41-49.
To explore any differences in efficacy and safety outcomes between European (EU) (n = 684) and North American (NA) (n = 395) patients in the AFFIRM trial (NCT00974311).
Patients and Methods
Phase III, double-blind, placebo-controlled, multinational AFFIRM trial in men with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel. Participants were randomly assigned in a 2:1 ratio to receive oral enzalutamide 160 mg/day or placebo. The primary end point was overall survival (OS) in a post hoc analysis.
Enzalutamide significantly improved OS compared with placebo in both EU and NA patients. The median OS in EU patients was longer than NA patients in both treatment groups. However, the relative treatment effect, expressed as hazard ratio and 95% confidence interval, was similar in both regions: 0.64 (0.50, 0.82) for EU and 0.63 (0.47, 0.83) for NA. Significant improvements in other end points further confirmed the benefit of enzalutamide over placebo in patients from both regions. The tolerability profile of enzalutamide was comparable between EU and NA patients, with fatigue and nausea the most common adverse events. Four EU patients (4/461 enzalutamide-treated, 0.87%) and one NA patient (1/263 enzalutamide-treated, 0.38%) had seizures. The difference in median OS was related in part to the timing of development of mCRPC and baseline demographics on study entry.
This post hoc exploratory analysis of the AFFIRM trial showed a consistent OS benefit for enzalutamide in men with mCRPC who had previously progressed on docetaxel in both NA- and EU-treated patients, although the median OS was higher in EU relative to NA patients. Efficacy benefits were consistent across end points, with a comparable safety profile in both regions.
PMCID: PMC4312486  PMID: 25123978
androgen receptor inhibitor; enzalutamide; metastatic castration-resistant prostate cancer
20.  Management of prostate cancer in older men: recommendations of a working group of the International Society of Geriatric Oncology 
Bju International  2010;106(4):462-469.
Prostate cancer is the most prevalent cancer in men and predominantly affects older men (aged ≥70 years). The median age at diagnosis is 68 years; overall, two-thirds of prostate cancer-related deaths occur in men aged ≥75 years. With the exponential ageing of the population and the increasing life-expectancy in developed countries, the burden of prostate cancer is expected to increase dramatically in the future. To date, no specific guidelines on the management of prostate cancer in older men have been published. The International Society of Geriatric Oncology (SIOG) conducted a systematic bibliographic search based on screening, diagnostic procedures and treatment options for localized and advanced prostate cancer, to develop a proposal for recommendations that should provide the highest standard of care for older men with prostate cancer. The consensus of the SIOG Prostate Cancer Task Force is that older men with prostate cancer should be managed according to their individual health status, which is mainly driven by the severity of associated comorbid conditions, and not according to chronological age. Existing international recommendations (European Association of Urology, National Comprehensive Cancer Network, and American Urological Association) are the backbone for localized and advanced prostate cancer treatment, but need to be adapted to patient health status. Based on a rapid and simple evaluation, patients can be classified into four different groups: 1, ‘Healthy’ patients (controlled comorbidity, fully independent in daily living activities, no malnutrition) should receive the same treatment as younger patients; 2, ‘Vulnerable’ patients (reversible impairment) should receive standard treatment after medical intervention; 3, ‘Frail’ patients (irreversible impairment) should receive adapted treatment; 4, Patients who are ‘too sick’ with ‘terminal illness’ should receive only symptomatic palliative treatment.
PMCID: PMC3258484  PMID: 20346033
elderly; guidelines; localized disease; metastatic; prostate cancer

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