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1.  Maximal Testosterone Suppression in Prostate Cancer—Free vs Total Testosterone 
Urology  2014;83(6):1217-1222.
Testosterone remains a key target in the treatment of advanced prostate cancer. The relationship of free testosterone to prostate cancer treatment and outcomes remains largely unexplored. A consensus of prostate cancer experts was convened in 2013 to review current knowledge surrounding relationship of total and free testosterone to prostate cancer, discuss the free hormone hypothesis, and highlight future avenues for therapeutics. Free testosterone may better reflect prostate cancer tissue androgen levels than serum total testosterone concentration. Free testosterone deserves more research regarding its relation to clinical outcomes.
PMCID: PMC4332796  PMID: 24713136
2.  Active Smoking May Negatively Affect Response Rate, Progression-Free Survival, and Overall Survival of Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib 
The Oncologist  2013;19(1):51-60.
An international multicenter retrospective study of sunitinib-treated metastatic renal cell carcinoma patients was performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. The results showed that active smoking may negatively affect the progression-free and overall survival of these patients.
Learning Objectives
Describe the association between risk factors for renal cell carcinoma and the outcome of sunitinib treatment for metastatic disease.Explain the impact of active smoking on the outcome of sunitinib-treated metastatic renal cell carcinoma.Discuss obesity, hypertension, and diabetes in relation to the outcome of sunitinib-treated metastatic renal cell carcinoma.
Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC).
An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors.
Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002).
Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.
PMCID: PMC3903056  PMID: 24309979
Active smoking; Metastatic renal cell carcinoma; Outcome; Sunitinib treatment
3.  Association of pretreatment neutrophil-to-lymphocyte ratio (NLR) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line docetaxel 
BJU international  2014;114(0):E11-E17.
To determine whether the pretreatment neutrophil-to-lymphocyte ratio (NLR), a measure of systemic inflammatory response, is associated with overall survival (OS) in men receiving chemotherapy with docetaxel for metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods
Records from 238 consecutive patients who were treated with first-line docetaxel-containing chemotherapy for mCRPC at a single high-volume centre from 1998 to 2010 (and who had adequate information to enable calculation of NLR) were reviewed.
Univariable and multivariable Cox regression models were used to predict OS after chemotherapy initiation.
In univariable analyses, the NLR as a discrete variable (optimal threshold 3.0) was significantly associated with OS (P = 0.001).
In multivariable analyses, a lower NLR (≤3.0) was associated with lower risk of all-cause mortality (P = 0.002).
In Kaplan-Meier analysis, the median OS was higher (18.3 vs 14.4 months) in patients that did not have an elevated NLR than in those with an elevated NLR (log-rank; P < 0.001).
Men who were treated with first-line docetaxel for mCRPC who had a low pretreatment NLR (≤3.0) had significantly longer OS.
NLR may be a potentially useful clinical marker of systemic inflammatory response in predicting OS in men with mCRPC who receive docetaxel and may be helpful to stratify patients for clinical trials.
These findings derived from a retrospective analysis need to be validated in larger populations in prospective studies, and in the context of different therapies.
PMCID: PMC4004702  PMID: 24529213
neutrophil-to-lymphocyte ratio; prostate cancer; chemotherapy; metastatic castration-resistant prostate cancer; docetaxel; overall survival
4.  Survival in Men With Nonmetastatic Prostate Cancer Treated With Hormone Therapy: A Quantitative Systematic Review 
We aimed to describe disease-free survival (DFS) and overall survival (OS) in men with localized or locally advanced prostate cancer receiving immediate hormone therapy as adjunct to radiation therapy, adjunct to radical prostatectomy, or stand-alone therapy.
Materials and Methods
A systematic literature search of MEDLINE, EMBASE, CancerLit, the Cochrane Library, and Current Contents (from 1986 to September 2006) yielded 35 high-quality clinical trials (n = 11,105 patients) which formed the evidence base. Selected studies were required to address early hormone therapy in nonmetastatic prostate cancer only. Data on DFS and OS were extracted from individual trials, summarized statistically, and displayed in graphic form.
Survival probabilities were extracted from 16 trials (n = 5,987 patients) addressing hormone therapy as an adjunct to radiation therapy, 11 trials (n = 1,885 patients) investigating hormone therapy as an adjunct to prostatectomy, and 10 trials (n = 3,233 patients) evaluating hormone therapy alone. In men receiving hormones and radiation, estimated 5-year DFS and OS were 52% and 82%, whereas median DFS and OS were 5.4 years and more than 7 years, respectively. In men receiving hormones and surgery, 5-year DFS and OS were 64% and 90%, whereas median DFS and OS were more than 6 years and more than 7 years, respectively. In men receiving hormones alone, 5-year DFS and OS were 57% and 70%, whereas median DFS and OS were 6.0 years and more than 7 years, respectively.
This systematic review provides a new baseline for expected DFS and OS in patients treated with hormone therapy for nonmetastatic prostate cancer. Survival in these men may be longer than estimated previously.
PMCID: PMC4133788  PMID: 17971600
5.  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
6.  Preclinical and Clinical Studies with the Multi-Kinase Inhibitor CEP-701 as Treatment for Prostate Cancer Demonstrate the Inadequacy of PSA Response as a Primary Endpoint 
Cancer biology & therapy  2007;6(9):1360-1367.
CEP-701 is a potent inhibitor of trk receptors that causes cell death in prostate cancer (PC) models. CEP-701 binds to serum proteins and a preprostatectomy study was performed to assess prostate tissue penetration and clinical response to CEP-701.
Growth assays and Western blot analyses were performed to evaluate CEP-701 kinase inhibition. In a preprostatectomy study, patients received CEP-701 for five days prior to prostatectomy and prostate tissue analyzed for CEP-701 levels. A phase II dose escalation study was performed in patients with hormone refractory PC with rising PSA and no metastases. Endpoints included PSA response and safety.
CEP-701 binds to serum proteins limiting tissue penetration. An oral dose of 40 mg bid of CEP-701 for five days produced levels of 219 ± 38 nM in prostate at time of prostatectomy. No patients in the Phase II study met the primary response criteria of >50% PSA decline. Seven/9 patients had increase in PSA slope on CEP-701 compared to PSA slope prestudy. Five/9 patients had a decrease in PSA levels after stopping CEP-701. Laboratory studies showed increased PSA production by CEP-701 growth arrested human PC cells in vitro and in vivo.
Evaluation of PSA response is an inadequate indicator of response in CEP-701 treated PC patients. Therefore, the effectiveness of CEP-701 as treatment for prostate cancer has not been adequately tested. Based on a strong preclinical rationale, further clinical studies with CEP-701 using alternative endpoints are indicated.
PMCID: PMC4124640  PMID: 17786033
prostate cancer; PSA; kinase; peceptor; CEP-701
8.  Penile Cancer 
Squamous cell carcinoma of the penis represents approximately 0.5% of all cancers among men in the United States and other developed countries. Although rare, it is associated with significant disfigurement, and only half of the patients survive beyond 5 years. Proper evaluation of both the primary lesion and lymph nodes is critical, because nodal involvement is the most important factor of survival. The NCCN Clinical Practice Guidelines in Oncology for Penile Cancer provide recommendations on the diagnosis and management of this devastating disease based on evidence and expert consensus.
PMCID: PMC4042432  PMID: 23667209
9.  Does short-term ADT before and during radiation therapy improve outcomes in locally advanced prostate cancer? 
This Practice Point discusses the 10-year data of the RTOG 8610 trial, published by Roach III and colleagues, which suggest that a short, 4-month course of neoadjuvant–concomitant androgen deprivation therapy (ADT) might be sufficient to improve clinically relevant long-term outcomes in men with bulky, locally advanced prostate cancer. The results show that patients randomized to receive short-term ADT before and during radiation therapy (RT), rather than RT alone, had improved long-term disease-specific mortality, freedom from distant metastases, disease-free survival, freedom from biochemical failure, and possibly even overall survival. Importantly, no increase in the risk of fatal cardiac events was seen. The study did not, however, address the issue of the optimum duration of ADT; recent data suggest that longer courses of ADT (≥2 years), when added to RT, might further improve disease-free and even overall survival, especially in patients with high-grade disease.
PMCID: PMC4036454  PMID: 18665153
androgen deprivation therapy; disease-free survival; locally advanced prostate cancer; overall survival; radiation therapy
10.  Novel targeted therapeutics for metastatic castration-resistant prostate cancer 
Cancer letters  2009;291(1):1-13.
Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard of care for these patients and is associated with a modest prolongation of survival, there is an urgent need for novel treatment strategies for metastatic prostate cancer. In the last several years, great strides have been made in our understanding of the biological and molecular mechanisms driving prostate cancer growth and progression, and this has resulted in widespread clinical testing of numerous new targeted therapies. This review discusses some of the key therapeutic agents that have emerged for the treatment of metastatic castration-resistant prostate cancer in the last 5 years, with an emphasis on both molecular targets and clinical trial design. These agents include mammalian target of rapamycin (mTOR) pathway inhibitors, anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, insulin-like growth factor (IGF) pathway inhibitors, apoptosis-inducing drugs, endothelin receptor antagonists, receptor activator of nuclear factor κB (RANK) ligand inhibitors, vitamin D analogues, cytochrome P17 enzyme inhibitors, androgen receptor modulators, epigenetic therapies, vaccine therapies, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 blocking agents.
PMCID: PMC4029098  PMID: 19717225
Metastatic castration-resistant prostate; cancer; Targeted therapies; Immune therapies; Molecular targets; Clinical trials; Drug development
11.  Is abiraterone acetate well tolerated and effective in the treatment of castration-resistant prostate cancer? 
This Practice Point commentary discusses the findings of the first phase I trial to evaluate abiraterone acetate (an inhibitor of the androgen-regulating enzyme CYP17) in the treatment of castration-resistant prostate cancer. This open-label, dose-escalation study by Attard et al. showed that abiraterone was well tolerated but often induced a syndrome of secondary mineralocorticoid excess that improved with eplerenone (a mineralocorticoid receptor antagonist). Abiraterone is a potent suppressor of adrenal androgen synthesis, and produced lasting prostate-specific antigen responses in approximately half of the patients. A few patients had partial regression of distant metastases. Although promising, these results should be interpreted with caution owing to the small sample size and because the study was not primarily designed to examine drug efficacy. Multi-institutional, prospective trials should provide additional information on the tolerability and activity of this compound and further define the population most likely to benefit from this endocrine approach.
PMCID: PMC4014058  PMID: 18957947
abiraterone acetate; castration-resistant prostate cancer; CyP17 enzyme; efficacy; tolerability
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.  Unmet Needs in the Prediction and Detection of Metastases in Prostate Cancer 
The Oncologist  2013;18(5):549-557.
Despite advances in therapy options, few guidelines or reviews address the optimal timing or methodology for the radiographic detection of metastatic disease in patients with advanced prostate cancer. This review discusses the current status of predicting the presence of metastatic disease, with a particular emphasis on the detection of the M0 to M1 transition, and reviews current data on newer imaging technologies that are changing the way metastases are detected.
The therapeutic landscape for the treatment of advanced prostate cancer is rapidly evolving, especially for those patients with metastatic castration-resistant prostate cancer (CPRC). Despite advances in therapy options, the diagnostic landscape has remained relatively static, with few guidelines or reviews addressing the optimal timing or methodology for the radiographic detection of metastatic disease. Given recent reports indicating a substantial proportion of patients with CRPC thought to be nonmetastatic (M0) are in fact metastatic (M1), there is now a clear opportunity and need for improvement in detection practices. Herein, we discuss the current status of predicting the presence of metastatic disease, with a particular emphasis on the detection of the M0 to M1 transition. In addition, we review current data on newer imaging technologies that are changing the way metastases are detected. Whether earlier detection of metastatic disease will ultimately improve patient outcomes is unknown, but given that the therapeutic options for those with metastatic and nonmetastatic CPRC vary, there are considerable implications of how and when metastases are detected.
PMCID: PMC3662846  PMID: 23650019
Imaging; Lymph nodes; Magnetic resonance imaging; Neoplasm metastasis; Prostatic neoplasms; Radionuclide imaging
14.  Pretreatment Neutrophil-to-Lymphocyte Ratio in Metastatic Castration-Resistant Prostate Cancer Patients Treated With Ketoconazole: Association with Outcome and Predictive Nomogram 
The Oncologist  2012;17(12):1508-1514.
Association between the pretreatment neutrophil-to-lymphocyte ratio and outcome of patients with metastatic castration-resistant prostate cancer treated with ketoconazole was assessed. The pretreatment neutrophil-to-lymphocyte ratio and prostate-specific antigen doubling time, and prior response to androgen-deprivation therapy, were associated with the progression-free survival interval in these patients.
The neutrophil-to-lymphocyte ratio (NLR), an inflammation marker, is prognostic in several cancers. We assessed the association between the pretreatment NLR and outcome of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the CYP17 inhibitor ketoconazole.
This was an international, retrospective study of 156 mCRPC patients treated with ketoconazole. The independent effect of the pretreatment NLR and factors associated with treatment outcome were determined by multivariate analysis.
Seventy-eight patients (50%) had a ≥50% decline in prostate-specific antigen (PSA). The median progression-free survival (PFS) time was 8 months. Excluded from the analysis were 23 patients without available data on their NLR and those with a recent health event or treatment associated with a blood count change. Sixty-two patients (47%) had a pretreatment NLR >3. Risk factors associated with the PFS outcome were a pretreatment NLR >3 and PSA doubling time (PSADT) <3 months and a prior response to a gonadotropin-releasing hormone agonist of <24 months or to an antiandrogen of <6 months. The number of risk factors was used to form a predictive nomogram by patient categorization into favorable (zero or one factor), intermediate (two factors), and poor (three or four factors) risk groups.
In mCRPC patients treated with ketoconazole, the pretreatment NLR and PSADT, and prior response to androgen-deprivation therapy, may be associated with the PFS time and used to form a risk stratification predictive nomogram.
PMCID: PMC3528383  PMID: 22971522
Ketoconazole treatment; Metastatic castration-resistant prostate cancer; Neutrophil-to-lymphocyte ratio; Outcome; Predictive nomogram
15.  Improved Overall Survival Trends of Men with Newly Diagnosed M1 Prostate Cancer: A SWOG Phase III Trial Experience (S8494, S8894 & S9346) 
The Journal of urology  2012;188(4):1164-1169.
Frequent PSA testing in screening and monitoring of prostate cancer has led to significant stage migration. We evaluated if overall survival (OS) in hormone naïve, metastatic prostate cancer patients has improved during the era of PSA use. We also assessed whether any subsets of patients benefited differentially during this period.
Materials and Methods
We compared OS in three sequential phase III trials of men with hormone naïve, metastatic prostate cancer receiving similar androgen deprivation therapy (n=3096): two conducted prior to the ‘PSA era’ (S8494 and S8894), and the other during this era (S9346). OS was adjusted for patient and disease risk factors in the latter two trials. Subgroups were evaluated by interactions of risk factors with trial.
Median OS in S8494 was 30 months, 33 months in S8894; and 49 months in S9346. Adjusting for risk factors, there was a 22% lower risk of death in S9346 compared to S8894 (hazard ratio 0.78, 95% confidence interval 0.70, 0.87, p<0.001). The improvement in OS was greater in African Americans (AA) (p=0.008 for test of interaction). In both S8494 and S8894, median survival for AA was 27 months and 34 and 35 months for non-AA, respectively; this racial difference disappeared in S9346 (AA OS=48 months, non-AA OS=49 months).
Adjusting for risk factors, OS was significantly improved in the post-PSA era trial. However, attributing this solely to PSA monitoring cannot be concluded. AA men now have comparable OS to Caucasians. Current estimates of survival should be used for designing new trials in this population.
PMCID: PMC3481164  PMID: 22921015
16.  The Experience with Cytotoxic Chemotherapy in Metastatic Castration-Resistant Prostate Cancer 
PMCID: PMC3742094  PMID: 23084532
Cytotoxic chemotherapy; Metastatic castration-resistant prostate cancer; Docetaxel
17.  Biodistribution, Tumor Detection, and Radiation Dosimetry of 18F-DCFBC, a Low-Molecular-Weight Inhibitor of Prostate-Specific Membrane Antigen, in Patients with Metastatic Prostate Cancer 
Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-Lcysteine (18F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of 18F-DCFBC in men with metastatic PCa.
Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of 18F-DCFBC. Serial PET was performed until 2 h after administration. Time- activity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1.
Most vascular organs demonstrated a slow decrease in radioactivity concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (µGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 ± 1.34 µSv/MBq (mean ± SD).
Although further studies are needed for validation, our findings demonstrate the potential of 18F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for 18F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as 18F-FDG.
PMCID: PMC3742115  PMID: 23203246
prostate-specific membrane antigen; prostate cancer; 18F; urea; PET/CT
18.  The effect of clinical trial participation versus non-participation on overall survival in men receiving first-line docetaxel-containing chemotherapy for metastatic castration-resistant prostate cancer 
BJU international  2012;110(11 0 0):E575-E582.
To study differences in baseline characteristics and outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line docetaxel-containing chemotherapy on prospective clinical studies (trial participants) versus those receiving this therapy outside of a clinical study (non-participants).
Records from 247 consecutive chemotherapy-naive patients who were treated with docetaxel-containing chemotherapy for mCRPC at a single high-volume centre from 1998 to 2010 were reviewed.
All patients received docetaxel either as clinical trial participants (n = 142; 11 separate studies) or as non-participants (n = 105).
Univariable and multivariable Cox regression models predicted overall survival after chemotherapy initiation.
There was no significant difference between trial participation and non-participation with respect to patient age, type of primary treatment, tumour grade or clinical stage.
Multivariable analyses showed a significantly lower risk of all-cause mortality (hazard ratio 0.567; P = 0.027) among trial participants vs non-participants.
Patients that were treated with docetaxel for mCRPC showed a significantly longer overall survival when enrolled in a clinical trial.
Improved survival in trial participants may reflect the better medical oversight typically seen in patients enrolled in trials, more regimented follow-up schedules, or a positive effect on caregivers’ attitudes because of greater contact with medical services.
With the retrospective nature of this analysis and the small study population, prospective studies are needed to validate the present findings and to further investigate the relationship between clinical trial participation and outcomes.
PMCID: PMC3715077  PMID: 22702837
prostate cancer; chemotherapy; clinical trial; metastatic castration-resistant prostate cancer; docetaxel; overall survival
The Prostate  2011;72(10):1133-1139.
To evaluate the prognostic significance of six epigenetic biomarkers (AIM1, CDH1, KIF1A, MT1G, PAK3 and RBM6 promoter hypermethlation) in a homogeneous group of prostate cancer patients, following radical prostatectomy.
Patients and Methods
Biomarker analyses were performed retrospectively on tumors from 95 prostate cancer patients all with a Gleason score of 3+4=7 and a minimum follow up period of 8 years. Using Quantitative Methylation Specific PCR (QMSP), we analyzed the promoter region of six genes in primary prostate tumor tissues. Time to any progression was the primary endpoint and development of metastatic disease and/or death from prostate cancer was a secondary endpoint. The association of clinicopathological and biomolecular risk factors to recurrence was performed using the Log-rank test and Cox proportional hazards model for multivariate analysis. To identify independent prognostic factors, a stepwise selection method was used.
At a median follow-up time of 10 years, 48 patients (50.5%) had evidence of recurrence: biochemical/PSA relapse, metastases, or death from prostate cancer. In the final multivariate analysis for time to progression, the significant factors were: older age, HR=0.95 (95% CI: 0.91, 1.0) (P=0.03), positive lymph nodes HR=2.11 (95%CI: 1.05, 4.26) (P=0.04) and decreased hypermethylation of AIM1 HR=0.45 (95%CI: 0.2, 1.0) (P=0.05).
Methylation status of AIM1 in the prostate cancer specimen may predict for time to recurrence in Gleason 3+4=7 patients undergoing prostatectomy. These results should be validated in a larger and unselected cohort.
PMCID: PMC3360823  PMID: 22127895
20.  Lenalidomide Modulates IL-8 and Anti-Prostate Antibody Levels in Men with Biochemically Recurrent Prostate Cancer 
The Prostate  2011;72(5):487-498.
We retrospectively explored changes in immunological parameters in men with biochemically recurrent prostate cancer treated with either 5mg or 25mg of lenalidomide in a randomized phase 2 trial, and determined whether those changes correlated with disease progression.
Cytokine levels were compared for each patient at baseline and after 6 months of treatment with lenalidomide. Regression models for correlated data were used to assess associations of cytokine levels with lenalidomide treatment effect. Estimates were obtained using generalized estimating equations (GEE). Changes in circulating anti-prostate antibodies were evaluated using a high-throughput immunoblot technique.
Treatment with lenalidomide was associated with global changes in immune-reactivity to a number of prostate-associated antigens, as well as with changes in circulating levels of the TH2 cytokines IL-4, IL-5, IL-10 and IL-13. Disease progression in treated patients was associated with an increase in circulating IL-8 levels, while IL-8 levels decreased significantly in non-progressors.
Lenalidomide demonstrates immunomodulatory properties in patients with biochemically recurrent prostate cancer. The induction of novel anti-prostate antibodies is a potential mechanism for lenalidomide response. Changes in serum IL-8 levels may serve as a potential biomarker in treated patients. These hypotheses require formal testing in future prospective trials.
PMCID: PMC3248613  PMID: 21748755
prostate cancer; antibody; cytokine; IL-8; lenalidomide
21.  Changes in PSA Kinetics Predict Metastasis-Free Survival in Men with PSA-Recurrent Prostate Cancer Treated with Non-Hormonal Agents: Combined Analysis of 4 Phase II Trials 
Cancer  2012;118(6):1533-1542.
Several phase II trials in men with non-castrate PSA-recurrent prostate cancer have assessed the impact of novel non-hormonal agents on PSA kinetics. However, it is unknown whether changes in PSA kinetics influence metastasis-free survival (MFS).
We performed a retrospective post hoc analysis of 146 men treated in four phase II trials examining the investigational agents marimastat (a matrix metalloproteinase inhibitor; n=39), imatinib (a tyrosine kinase inhibitor; n=25), ATN-224 (a copper/zinc-superoxide dismutase inhibitor; n=22), and lenalidomide (an antiangiogenic/immunomodulatory drug; n=60). We investigated factors influencing MFS, including within-subject changes in PSA kinetics (PSA slope, doubling time, and velocity) before and after treatment initiation.
After a median follow-up of 16.8 months, 70 patients (47.9%) developed metastases. In multivariable Cox regression models, factors that were independently predictive of MFS after adjusting for age and other clinical prognostic variables were baseline PSA doubling time (PSADT) (P=.05), baseline PSA slope (P=.01), on-study change in PSADT (P=.02), and on-study change in PSA slope (P=.03). In a landmark Kaplan-Meier analysis, median MFS was 63.5 months (95% CI 34.6–not reached) and 28.9 months (95% CI 13.5–68.0) for men with or without any decrease in PSA slope by 6 months after treatment, respectively.
This hypothesis-generating analysis suggests that within-subject changes in PSADT and PSA slope after initiation of experimental therapy may correlate with MFS in men with biochemically-recurrent prostate cancer. If validated in prospective trials, changes in PSA kinetics may represent a reasonable intermediate endpoint for screening new agents in these patients.
PMCID: PMC3252493  PMID: 21960118
22.  Phase I rapid dose-escalation study of AGS-1C4D4, a human anti-PSCA (prostate stem cell antigen) monoclonal antibody, in patients with castration-resistant prostate cancer: a PCCTC trial 
AGS-1C4D4 is a human monoclonal antibody against prostate stem cell antigen (PSCA), a cell-surface protein expressed by most prostate cancers. AGS-1C4D4 is produced in Chinese hamster ovary (CHO) cells and has an identical sequence to AGS-PSCA, an anti-PSCA antibody produced in mouse hybridoma cells that has completed Phase I testing. Preclinical studies demonstrated comparability of AGS-1C4D4 to AGS-PSCA with respect to pharmacokinetics (PK) and tumor inhibition. However, because of differences in antibody-dependent cellular cytotoxicity between AGS-PSCA and AGS-1C4D4, a limited Phase I trial using AGS-1C4D4 was performed evaluating safety and PK.
Patients and method
Thirteen patients with metastatic castration-resistant prostate cancer were enrolled. AGS-1C4D4 was administered intravenously every 3 weeks for four planned doses at 6, 12, 24, or 48 mg/kg. Primary endpoints were safety and PK. Secondary endpoints were immunogenicity and clinical activity. Disease assessments were conducted every 12 weeks and included radiographic and PSA evaluations. Patients with stable disease could receive extended treatment beyond four infusions.
Adverse events were primarily grade 1–2, without any grade 3–4 drug-related toxicities or infusion reactions. Anti-AGS-1C4D4 antibodies were not detected. Similar to AGS-PSCA, serum AGS-1C4D4 concentrations declined biphasically and elimination was characterized by slow clearance (CL) and a long terminal half-life (t1/2). Median CL for the four dose levels ranged from 0.10 to 0.14 ml/h kg, and t1/2 ranged from 2.2 to 2.9 weeks. No PSA reductions ≥50% were observed. Six patients (46%) had radiographically stable disease, lasting a median of 24 weeks.
AGS-1C4D4 was well-tolerated and demonstrated linear PK. Despite preclinical differences in antibody-dependent cellular cytotoxicity, AGS-1C4D4 and AGS-PSCA have similar safety and PK profiles. The recommended Phase II dose is 48 mg/kg.
PMCID: PMC3586214  PMID: 22020316
AGS-1C4D4; Castration-resistant prostate cancer; Monoclonal antibody; Phase I; PSCA
23.  An Immunohistochemical Signature Comprising PTEN, MYC, and Ki67 Predicts Progression in Prostate Cancer Patients Receiving Adjuvant Docetaxel After Prostatectomy 
Cancer  2012;118(24):6063-6071.
Loss of the tumor suppressor PTEN is common in prostate cancer and may have prognostic significance. The authors examined PTEN and additional protein markers in primary tumors from patients with high-risk, localized prostate cancer who received adjuvant docetaxel in a prospective multicenter trial (TAX2501).
Fifty-six of 77 patients enrolled in TAX2501 had primary prostatectomy specimens available for immunohistochemical analysis of PTEN, MYC, ERG, tumor protein p53 (p53), antigen KI-67 (Ki67), and phosphorylated forms of Akt, mammalian target of rapamycin (mTOR), and S6 ribosomal protein. Protocol-defined progression included a prostate-specific antigen (PSA) level ≥0.4 ng/mL, radiologic/clinical recurrence, or death. Univariate and multivariable proportional hazards regression analyses were used to investigate the influence of PTEN status (and other protein markers) on progression-free survival (PFS).
In this exploratory, post hoc analysis, PTEN protein loss (vs presence) was observed in 61% of patients and was associated with lower preoperative PSA levels, higher clinical stage, lower Ki67 expression, the presence of p53, and the presence of ERG. In univariate analysis, the factors associated with PFS included Gleason sum, seminal vesicle invasion, PTEN status, MYC expression, and Ki67 expression. In multivariable analysis, only 3 variables emerged as independent prognostic factors for PFS: PTEN status (P = .035), MYC expression (P = .001), and Ki67 expression (P < .001). A prognostic model was constructed that incorporated clinical covariates as well as information on PTEN, MYC, and Ki67.
The current results indicated that PTEN status, MYC expression, and Ki67 expression in primary tumor samples may predict PFS more accurately than clinical factors alone in men with high-risk prostate cancer who receive adjuvant docetaxel after prostatectomy. If validated, these hypothesis-generating findings may have prognostic and therapeutic implications and may aid clinical trial design.
PMCID: PMC3572534  PMID: 22674438
PTEN; MYC; Ki67; high-risk prostate cancer; adjuvant docetaxel; progression-free survival; prognostic model
24.  Double-Blind, Randomized Trial of Docetaxel Plus Vandetanib Versus Docetaxel Plus Placebo in Platinum-Pretreated Metastatic Urothelial Cancer 
Journal of Clinical Oncology  2011;30(5):507-512.
Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy.
Patients and Methods
The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m2 intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives.
In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months.
In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal.
PMCID: PMC4104290  PMID: 22184381
25.  The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up 
BJU international  2011;109(1):32-39.
To describe metastasis-free survival (MFS) in men with prostate-specific antigen (PSA) recurrence following radical prostatectomy, and to define clinical prognostic factors modifying metastatic risk.
We conducted a retrospective analysis of 450 men treated with prostatectomy at a tertiary hospital between July 1981 and July 2010 who developed PSA recurrence (≥0.2 ng/mL) and never received adjuvant or salvage therapy before the development of metastatic disease.
We estimated MFS using the Kaplan–Meier method, and investigated factors influencing the risk of metastasis using Cox proportional hazards regression.
Median follow-up after prostatectomy was 8.0 years, and after biochemical recurrence was 4.0 years. At last follow-up, 134 of 450 patients (29.8%) had developed metastases, while median MFS was 10.0 years.
Using multivariable regressions, two variables emerged as independently predictive of MFS: PSA doubling time (<3.0 vs 3.0–8.9 vs 9.0–14.9 vs ≥15.0 months) and Gleason score (≤6 vs 7 vs 8–10).
Using these stratifications of Gleason score and PSA doubling time, tables were constructed to predict median, 5- and 10-year MFS after PSA recurrence. In different patient subsets, median MFS ranged from 1 to 15 years.
In men undergoing prostatectomy, MFS after PSA recurrence is variable and is most strongly influenced by PSA doubling time and Gleason score. These parameters serve to stratify men into different risk groups with respect to metastatic progression.
Our findings may provide the background for appropriate selection of patients, treatments and endpoints for clinical trials.
PMCID: PMC3204323  PMID: 21777360
metastasis-free survival; natural history; prostate cancer; PSA recurrence

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