Diagnosis Of Castration-resistant Prostate Cancer Research Articles

Prostate-specific antigen kinetic profiles during androgen deprivation therapy as prognostic factors in castration-resistant prostate cancer

ObjectiveTo identify pretreatment prognostic factors for patients with castration-resistant prostate cancer (CRPC) undergoing docetaxel (DCT) chemotherapy. Materials and methodsWe retrospectively analyzed 102 patients with CRPC who underwent DCT chemotherapy (dosage: 60–75mg/m2) from December 2001 to August 2013. The parameters evaluated as prognostic factors were as follows: age, body mass index, Gleason score, clinical TNM stage, prior radical prostatectomy, prior radiation therapy, performance status, presence of pain, laboratory results at the start of DCT, and prostate-specific antigen (PSA) kinetics during prior androgen deprivation therapy (ADT), including PSA level at the start of ADT (PSA-ADT), PSA half-time (PSAT1/2), time to nadir, PSA level at nadir (PSA-Nadir), duration of nadir, PSA doubling time (PSADT), and PSA level at the start of DCT (PSA-DCT). Univariate and multivariate analyses were performed to identify independent prognostic factors. ResultsMedian cancer-specific survival (CSS) duration following CRPC diagnosis was 28.0 months. In univariate analyses, performance status, serum albumin, serum creatinine, PSAT1/2, time to nadir, PSA-Nadir, duration of nadir, PSADT, and PSA-DCT showed a potential association with prognosis (P<0.001–0.077). Multivariate analyses of these parameters showed that performance status (hazard ratio [HR] = 0.046; P = 0.046), serum creatinine (HR = 3.028; P = 0.036), PSAT1/2 (HR = 0.172; P = 0.007), PSA-Nadir (HR = 4.884; P = 0.033), PSADT (HR = 0.148; P<0.001), and PSA-DCT (HR = 5.222; P = 0.004) remained independent predictors of CSS in CRPC. ConclusionsPSA kinetic parameters measured during prior ADT are significant surrogate markers predicting CSS in patients undergoing DCT chemotherapy for CRPC.

The Primary Local Stage at Diagnosis Predicts Regional Symptoms Caused by Local Progression in Patients With Castration-resistant Prostate Cancer

To identify the characteristics that predict occurrence of local progression-related events (LPREs) in patients with castration-resistant prostate cancer (CRPC) to adjust its management. We retrospectively reviewed the medical records of 39 patients with CRPC. LPREs were defined as regional symptoms caused by local progression and categorized into urinary events and rectal events. Urinary events were defined as ureteral obstruction, acute urinary retention, or hematuria requiring treatment, and rectal events were rectal obstruction or rectal bleeding caused by tumor invasion. The median prostate-specific antigen level at diagnosis was 185 ng/mL. During the median follow-up period of 4.4 years, 10 patients (25.6%) had LPREs. Urinary events were observed in 8 patients (20.5%) and rectal events in 2 (5.1%). The proportion of T4 in patients with LPREs was higher than in those without LPREs (70.0% vs. 10.3%; P <.001). Stage T4 at diagnosis was an independent factor to predict LPREs in multivariate analysis (hazard ratio, 8.62; P = .004). The 5-year cumulative incidence of LPREs in patients with stage T4 was 70.0%, whereas in those with stage ≤T3, they were 3.6% (P <.001). Patients with stage T4 at diagnosis are more likely to have a risk of LPREs than those with stage ≤T3. These results indicate that patients with locally advanced prostate cancer on androgen deprivation therapy need to be closely monitored for early diagnosis of CRPC and treated with the appropriate intervention for LPREs at the appropriate time.

Real-World Treatment Patterns in Men with Castration- Resistant Prostate Cancer Receiving Docetaxel.

Background: Docetaxel has been a standard of care for castration-resistant prostate cancer (CRPC) in the United States since 2004, yet little has been reported on its patterns of use in routine practice. To help understand these patterns, a retrospective study was conducted and is reported here. Methods: Medical records from 394 patients treated in the United States were reviewed. Data were collected by 48 physicians from oncology (patient N=344) and 8 physicians from urology (patient N=50) practices. Inclusion criteria were: CRPC diagnosed between 2004 and 2010; received docetaxel; discontinued docetaxel due to rising prostate-specific antigen (PSA), progression of bone lesions, or progression of nodal or visceral metastases. Data were collected from physicians using an internet-based case report form. We evaluated patient demographics, characteristics of the docetaxel regimen, and other treatments used until docetaxel discontinuation. Results: Patients had a mean [±SD] age of 66.5 [8.9] years, the majority (63%) were white, and geographic dispersion was similar to the US population. The majority of patients initiated docetaxel between 2008 and 2010. After CRPC diagnosis, 8% of patients had initiated another cancer-directed therapy before starting docetaxel. Most (78.9%) patients initiated docetaxel with prednisone, while 18.5% initiated docetaxel alone and 2.6% initiated with other medications. Half of patients initiated docetaxel within 1 month after CRPC diagnosis, while 25% started ≥6 months later. Other non-chemotherapy treatments used with docetaxel were hormonal therapy (22.8%), radiotherapy (17.3%), and surgery (4.1%). Most patients (75%) received ≥4 docetaxel cycles, half received ≥6 cycles, 25% received ≥8 cycles and 10% received ≥10 cycles. Increased tumor mass, with/without new bone lesions or rising PSA, was the most common reason for docetaxel discontinuation (74% of patients). Conclusions: Concordant with guidelines, docetaxel and prednisone was the preferred first-line chemotherapy regimen in CRPC patients reviewed for this study. However, one quarter of patients did not initiate docetaxel until ≥6 months after CRPC diagnosis and total exposure varied considerably, with only 10% receiving ≥10 cycles. Future studies are needed to describe specific reasons explaining timing of docetaxel initiation and duration of exposure in some CRPC patients.

Practice Patterns and Predictors of Followup Imaging after a Negative Bone Scan in Men with Castration Resistant Prostate Cancer: Results from the SEARCH Database

We investigated imaging practice patterns in men with nonmetastatic (M0) castration resistant prostate cancer. We analyzed data on 247 patients with documented M0 CRPC from the SEARCH database. Patients were selected regardless of primary treatment modality and all had a negative bone scan after a castration resistant prostate cancer diagnosis. Cox models were used to test associations of time to a second imaging test with several demographic and clinical factors. During a median followup of 29.0 months (IQR 12.9-43.5) after a post-castration resistant prostate cancer bone scan was negative, 190 patients (77%) underwent a second imaging test. On univariable analysis patients with higher prostate specific antigen (HR 1.13, p = 0.016), shorter prostate specific antigen doubling time (HR 0.79, p < 0.001) and faster prostate specific antigen velocity (HR 1.01, p < 0.001) were more likely to undergo a second imaging test. Treatment center was also a significant predictor of a second imaging test (p = 0.010). No other factor was a significant predictor. Results were similar on multivariable analysis. It was estimated that approximately 20% of men with a prostate specific antigen doubling time of less than 3 months did not undergo an imaging test in the first year after a post-castration resistant prostate cancer negative bone scan. However, 50% of patients with prostate specific antigen doubling time 15 months or greater underwent a second imaging test in the first year. Clinicians use some known predictors of positive imaging tests to determine which patients with M0 castration resistant prostate cancer undergo a second imaging test . However, there may be under imaging in those at high risk and over imaging in those at low risk. Further studies are needed to identify risk factors for metastasis and form clear imaging guidelines in patients with M0 castration resistant prostate cancer.

Oral ethinylestradiol in castration-resistant prostate cancer: a 10-year experience.

To describe our 10-year experience with the use of oral ethinylestradiol in the treatment of metastatic castration-resistant prostate cancer. From February 2000 to April 2010, 116 patients with a metastatic castration-resistant prostate cancer were prospectively submitted to oral ethinylestradiol monotherapy. Inclusion criteria were: diagnosis of castration-resistant prostate cancer after failure of at least two lines of androgen deprivation therapy and radiological evidence of metastases. Exclusion criteria were: symptomatic cases with a European Cooperative Oncology Group score >2 and severe or uncontrolled cardiovascular diseases. At inclusion in the study, all patients discontinued the previous androgen deprivation therapy and started oral ethinylestradiol at the daily dose of 1 mg. Aspirin (100 mg/daily) was concomitantly given. The median ethinylestradiol therapy duration was 15.9 months (range 8-36 months), whereas the median follow up of patients was 28 months (range 13-36 months). During ethinylestradiol therapy, a confirmed prostate-specific antigen response was found in 79 patients (70.5%). The median time to prostate-specific antigen progression was 15.10 months (95% confidence interval 13.24-18.76 months). A toxicity requiring treatment cessation was observed in 26 patients (23.2%) at a median time of 16 months (mainly thromboembolism). Our 10-year experience shows that ethinylestradiol provides a prostate-specific antigen response in a high percentage of patients with metastatic castration-resistant prostate cancer. Cardiovascular toxicity can be managed through accurate patient selection, close follow up and a concomitant anticoagulation therapy.

MiR-663 Induces Castration-Resistant Prostate Cancer Transformation and Predicts Clinical Recurrence

Castration-resistant prostate cancer (CRPC) and its treatment are challenging issues in prostate cancer management. Here, we report that miR-663 is upregulated in CRPC tissues. Overexpression of miR-663 in prostate LNCaP cells promotes cell proliferation and invasion, neuroendocrine differentiation, and reduction in dihydrotestosterone-induced upregulation of prostate-specific antigen expression. Furthermore, results of in situ hybridization show that miR-663 expression is correlated with Gleason score and TNM stage and is an independent prognostic predictor of clinical recurrence. Together, these findings suggest that miR-663 is a potential oncomiR for CRPC and may serve as a tumor biomarker for the early diagnosis of CRPC.

Treatment patterns and characteristics of European patients with castration-resistant prostate cancer

BackgroundEuropean 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).MethodsData 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.ResultsA 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.ConclusionsResults from this analysis highlight inconsistencies in common hormonal therapy treatment patterns for CRPC and hormonal therapy across the EU.

Androgen receptor co-regulatory networks in castration-resistant prostate cancer

Androgen and the androgen receptor (AR) are critical effectors of prostate cancer. Consequently, androgen deprivation therapy is typically employed as a first-line treatment for prostate cancer patients. While initial responses are generally positive, prostate tumors frequently recur and progress to a lethal form known as castration-resistant prostate cancer (CRPC). Recently, considerable effort has been directed toward elucidating the molecular mechanisms of CRPC. Results from both preclinical and clinical studies suggest that AR-mediated signaling persists and remains functionally important in CRPC despite the elimination of androgens. Understanding the role of this pathway in the development of resistance will therefore be critical to identify alternative diagnostic markers as well as more effective therapies for the treatment of CRPC. Using next-generation sequencing and other high-throughput approaches, numerous groups are beginning to identify the key differences in the transcriptional regulatory and gene expression programs between androgen-dependent and CRPC. A number of mechanisms have been proposed for the differences and these mostly involve alterations to components of the AR co-regulatory network. In this review, we summarize current knowledge on co-regulators of the AR and discuss their potential roles in CRPC. It is anticipated that a deeper understanding of these factors will undercover new targets that can assist in the diagnosis and treatment of CRPC.

Raman spectroscopy, a potential tool in diagnosis and prognosis of castration-resistant prostate cancer

We evaluated the feasibility of Raman spectroscopy (RS) in diagnosis and prognosis of castration-resistant prostate cancer (CRPC) in patients with prostate cancer (PC). Raman spectra are detected from PC cell lines (LNCaP and C4-2) and tissues using a Labram HR 800 RS. Then, principal component analysis (PCA) and support vector machine (SVM) are applied for prediction. A leave-one-out cross-validation is used to train and test the SVM. There are 50 qualified patients, including 33 with androgen-dependent prostate cancer (ADPC) and 17 with CRPC. The spectral changes at 1126, 1170, 1315 to 1338, and 1447 cm-1 between CRPC and ADPC are detected in both cells and tissues models, which are assigned to specific amino acids and DNA. PCA/SVM algorithm provided a sensitivity of 88.2% and a specificity of 87.9% for diagnosing CRPC tissues. Furthermore, 14 patients with ADPC progressed to CRPC within 12 months. These patients are separated into two groups depending on whether their cancers progressed to CRPC within 12 months. PCA/SVM could differentiate these two groups with a sensitivity of 85.7% and a specificity of 88.9%. RS has the potential in diagnosis and prognosis of CRPC in clinical practice.

Skeletal-related events (SRE) and bone-targeted agents for metastatic prostate cancer: Are we changing outcomes?

e16074 Background: Bone-targeted agents (BTA) have been extensively studied in patients (pts) with prostate cancer (PC) and bone metastases (BM). Relatively little is known about the impact of BTAs on skeletal morbidity in the non-trial setting. We evaluated the impact BTAs on SRE and survival at a large Canadian cancer centre. Methods: Electronic heath records were reviewed for PC pts referred for further management from January 2008-June 2012. Demographic, clinical, and treatment data including: date of CRPC, occurrence of SRE, and BTA use were collected and analyzed. Results: A total of 141 pt charts were examined and were included in the analysis. Median age was 74 years (IQR 63-82), and 95% were stage IV at time of referral. Consequences of BMs included:101 pts had at least one SRE (72%), 58 (40%) pts had ≥1 SRE and 39% were hospitalised due to an SRE. Median overall survival from diagnosis of BM was 35.4 months (m) (IQR 16.1-65.9). Overall, 74 pts (52%) developed castration resistant PC (CRPC). In the CRPC group, the use of imaging to assess BM was highly variable, ranging from only once (12%) to every 1-2 m (4%), however the mode was every 3-5 m (43%). Sixty one percent (45/74) received a BTA, primarilyzoledronic acid (ZA). Despite having CRPC and BM, 39% never received a BTA, mainly because it was not offered (64%), or due to patient’s refusal (29%). Median time from diagnosis of CRPC to start of BTA was 1 month. Sixty-nine percent of pts had BTA discontinued, mainly due to progression of disease and pts deterioration. Osteonecrosis of the jaw occurred in 4% (2/45). In 39 pts (53%) the first SRE occurred prior to CRPC diagnosis, and 62 pts (84%) had at least 1 SRE after CRPC diagnosis. Forty seven percent (21/45) had a new SRE after starting BTA. Conclusions: BM have significant consequences for pts with PC irrespective of hormone sensitivity. Even for pts with CRPC the use of BTAs is highly variable. This reflects physician’s belief in the efficacy of BTAs, tailored by the expected benefits to each pt according to performance status and extent of disease. Interestingly in the CRPC group 53% have had an SRE prior to CRPC diagnosis. Strategies to optimise the care of pts with BM are clearly warranted.

Improved Survival in a Cohort of Trial Participants with Metastatic Castration-resistant Prostate Cancer Demonstrates the Need for Updated Prognostic Nomograms

BackgroundMedian overall survival (OS) in men with metastatic castration-resistant prostate cancer (CRPC) was 13–16 mo in the predocetaxel era. Prognostic nomograms for survival estimation in CRPC were constructed prior to the introduction of docetaxel and other novel treatments. ObjectiveTo examine whether prognostic models still accurately reflect survival in a large cohort of trial participants. Design, setting, and participantsSurvival analysis of 442 men with CRPC sequentially treated in clinical trials at our institution from June 2003 to December 2011. Outcome measures and statistical analysisPredicted survival by Halabi and Smaletz nomograms was compared to observed survival. Cox model multivariate analysis (MVA) used variables at referral, including performance status (PS); levels of prostate-specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), haemoglobin (Hb), and albumin; presence of visceral disease, and metastatic disease at diagnosis. Results and limitationsFrom point of referral, chemotherapy-naïve patients had a median OS of 30.6 mo (95% confidence interval [CI], 27.6–36.5 mo). In contrast, predicted survival using the Halabi and Smaletz models was 21 and 18 mo, respectively. In these patients, poor PS, lower Hb level, and increasing LDH level were the strongest predictors in the MVA. In patients referred after chemotherapy, survival from referral was 17.5 mo (95% CI, 16.0–19.5 mo) and increasing LDH level and presence of visceral metastases were the strongest predictors of survival. Median OS from diagnosis of CRPC was 40.7 mo in the overall cohort (95% CI, 36.8–44.0 mo). Clinical trial participation was safe, with low mortality rate.This cohort of men participated in phase 1, 2 and 3 trials and expanded access programs; their data may not reflect survival in all CRPC patients. ConclusionsDue to the impact of highly effective novel therapies on survival, prognostic nomograms in current use require revalidation regarding their ability to predict survival in CRPC.

WS14-4 - The Clinical Role of Peptide Vaccines for Castration-Resistant Prostate Cancer

ABSTRACT Introduction Androgen deprivation therapy (ADT) is the standard treatment of metastatic prostate cancer. Although ADT achieves disease stabilization in the beginning of the treatment, most patients eventually develop castration-resistant prostate cancer (CRPC). Docetaxel (DTX)-based chemotherapy has been proved the efficacy for CRPC, however, the prognosis of patients after the induction of chemotherapy is limited. Therefore, extending the period from the diagnosis of CRPC to the induction of chemotherapy may contribute to improvement of overall survival of those patients. Immunotherapy is being developed for several malignancies including prostate cancer. We have previously carried out phase-I/II study of personalized peptide vaccination in metastatic CRPC patients, and showed the safety and effectiveness of peptide vaccination therapy. Since cancer immunotherapy may act more effectively in early stage of the disease before systemic chemotherapy, we conducted a randomized phase II study to evaluate the efficacy of the peptide vaccination therapy for chemotherapy-naive CRPC patients. Patients and methods The patients are randomly assigned to two groups; one (vaccination group) receives the combination therapy of peptide vaccines and low-dose (1 mg/day) dexamethasone (Dx) and the other receives Dx alone. In the vaccination group, maximum of four kinds of peptide from those that have been recognized by the patient-specific immune system (serum IgG antibodies) in the peripheral blood are selected as vaccines. 3mg of each peptide is administrated separately every 2 weeks. Dexamethasone 1 mg/day p.o. is started on the first day of peptide administration. The primary end point of the study is progression-free survival and secondary end points include objective response rate and subjective effects. Results Up to now, 72 CRPC patients were enrolled in this study and 60 were evaluable and analyzed in detail. Median age was 68 years old (48–80 years) and median serum PSA was 4.8 ng/ml. The patients in vaccination group showed a significantly longer PSA progression free survival (P

Prediction of survival benefit using an automated bone scan index in patients with castration‐resistant prostate cancer

What's known on the subject? and What does the study add? A bone scan index (BSI) can quantify the extent of bone involvement and response to treatment, but it has not been widely accepted, because of its time-consuming nature. The study is the first to demonstrate that automated BSI calculated with a computer-assisted diagnosis system is effective in judging the chemotherapeutic response of bone metastatic lesions in patients with castration-resistant prostate cancer. • To evaluate the value of an automated bone scan index (aBSI), calculated using a computer-assisted diagnosis system, to indicate chemotherapy response and to predict prognosis in patients with castration-resistant prostate cancer (CRPC) with bone metastasis. • Forty-two consecutive CRPC patients underwent taxane-based chemotherapy between November 2004 and March 2011 at our institution. • The aBSIs were retrospectively calculated at the diagnosis of CRPC and 16 weeks after starting chemotherapy. • Cox proportional hazards regression models were applied to multivariate analyses with and without aBSI response in addition to the basic model. • Based on the difference in the concordance index (c-index) between each model, the prognostic relevance of adding the aBSI response was determined. • A decrease in aBSI was found in 28 patients (66.7%), whereas a response was shown by bone scan in only 23.8% of patients. • Patients with a reduction in aBSI had longer overall survival (OS) in comparison with the other patients (P= 0.0157). • Multivariate analysis without aBSI response showed that performance status (P= 0.0182) and PSA response (P= 0.0375) were significant prognosticators. • By adding the aBSI response to this basic model, the prognostic relevance of the model was improved with an increase in the c-index from 0.621 to 0.660. • The aBSI reflected the chemotherapy response in bone metastasis. • The index detected small changes of bone metastasis response as quantified values and was a strong prognostic indicator for patients with CRPC.

Treatment patterns in men with castration-resistant prostate cancer receiving docetaxel.

e15165 Background: Docetaxel has been a standard of care for castration-resistant prostate cancer (CRPC) in the US since 2004 (TAX 327), yet little has been reported on its patterns of use in routine practice. To help understand these patterns, a retrospective study was conducted and is reported here. Methods: Medical records from 394 patients treated in the US were reviewed: 48 from oncology (N=344) and 8 from urology (N=50) practices. Inclusion criteria were: CRPC diagnosed between 2004 and 2010; received docetaxel; discontinued docetaxel due to rising PSA, progression of bone lesions, or progression of nodal or visceral metastases. Data were collected from physicians using an internet-based case report form. We evaluated patient demographics, characteristics of the docetaxel regimen and other treatments used until docetaxel discontinuation. Results: Patients had a mean [±SD] age of 66.5 [8.9] years, the majority (63%) were white, and geographic dispersion was similar to the US population. The majority of patients initiated docetaxel between 2008 and 2010. After CRPC diagnosis, 8% of patients initiated another cancer-directed therapy before starting docetaxel. Most (78.9%) patients initiated docetaxel with prednisone, while 18.5% initiated docetaxel alone and 2.6% initiated with other drugs. Half of patients initiated docetaxel within 1 month after CRPC diagnosis, while 25% started ≥6 months later. Other non-chemotherapy treatments used with docetaxel were hormonal therapy (22.8%), radiotherapy (17.3%), and surgery (4.1%). Most patients (75%) received ≥4 docetaxel cycles, half received ≥6 cycles, 25% received ≥8 cycles and 10% received ≥10 cycles. Increased tumor mass, with/without new bone lesions or rising PSA, was the most common reason for docetaxel discontinuation (74% of patients). Conclusions: Concordant with guidelines, docetaxel and prednisone was the preferred first-line chemotherapy regimen in CRPC patients. However, one quarter of patients did not initiate docetaxel until ≥6 months after CRPC diagnosis and total exposure varied considerably, with only 10% receiving ≥10 cycles. Future studies are needed to describe specific reasons for docetaxel delay and sub-maximal exposure in some CRPC patients.

A validated whole-blood RNA transcript-based prognostic model that predicts survival in men with castration-resistant prostate cancer.

4516 Background: Survival for patients with castration resistant prostate cancer (CRPC) is highly variable. We developed a whole blood RNA transcript-based model as a prognostic biomarker in CRPC. Methods: Peripheral blood was collected from 62 men with CRPC in a training set and from 140 patients with CRPC in a validation set on various treatment regimens. A panel of 168 inflammation and prostate cancer-related genes was evaluated using optimized quantitative polymerase chain reaction to assess biomarkers predictive of survival. A 2-class proportional hazard model was developed from time of CRPC diagnosis and time of blood draw. Results: A 6-gene model (consisting of ABL2, SEMA4D, ITGAL, and C1QA, TIMP1, CDKN1A) separated CRPC patients into two classes: higher risk men who died within 2·2 years of developing CRPC and lower risk men who lived over 2·2 years (log rank p=0·00083). The results were similar regardless of the survival time definition (CRPC diagnosis versus blood draw) and did not depend on whether they received chemotherapy in addition to hormone treatment. The model successfully validated in an independent cohort of men with CRPC (p= 0.000001·7). Conclusions: Transcriptional profiling of whole blood yields critical prognostic information in men with CRPC independent of treatment. The 6-gene model suggests possible dysregulation of the immune system, a finding that warrants further study. This model may play an important role in patient counseling, in patient stratification for clinical trials, and potentially as a predictive biomarker for immune-based therapeutic strategies.

Severe zoledronic acid (ZOL)-associated hypophosphatemia and prognosis in patients with castration-resistant prostate cancer (CRPC).

e15180 Background: ZOL therapy is associated with severe (i.e., grade ≥ 3) hypocalcemia and hypophosphatemia in a subset of patients with metastatic CRPC. However, as opposed to the distinct clinical picture of hypocalcemia, the symptoms of hypophosphatemia are less pathognomonic. Furthermore, serum phosphate abnormalities are not regularly reported. Methods: To characterize the rate and clinical impact of severe hypophosphatemia in CRPC patients undergoing ZOL therapy, we identified CRPC patients receiving at least 3 doses of ZOL at our Centre between 01/2004 and 03/2011. Patient demographics, disease characteristics and laboratory parameters were extracted using the Oncology Symptom Control and Information Resource database, and by means of manual chart review. Results: 12 of 90 evaluable patients developed grade ≥ 3 hypophosphatemia (nadir) after 364±299 days (mean±SD) following the first dose of ZOL. While only one patient presented with concomitant severe hypocalcemia, the hypophosphatemia nadir coincided with rising PSA readings in 9 out of 11 informative patients. Severe ZOL-associated hypophosphatemia identified patients with worse outcome (median overall survival from time of CRPC diagnosis to death 685 days) compared to patients without documented hypophosphatemia (907 days, HR 0.52, p=0.049; n=42), or patients with grade 1-2 hypophosphatemia (1035 days, HR 0.44, p=0.016; n=36). Otherwise, the prognostic nomogram developed by Armstrong et al appears not to capture the poor prognosis of patients with severe ZOL-associated hypophosphatemia. Conclusions: Grade 3-4 hypophosphatemia occurs in about 15% of CRPC patients undergoing ZOL therapy and is associated with worse prognosis when compared to patients with absent or mild hypophosphatemia. The latter is usually transient and likely related to increased parathyroid hormone levels due to calcium decreases as a consequence of bisphosphonate therapy. On the other hand, the distinct clinical behavior of CRPC presenting with ZOL-associated severe hypophosphatemia suggests that secreted tumor-associated factors such as fibroblast growth factor 23 may contribute to this phenomenon.

Characterising the castration-resistant prostate cancer population: a systematic review

Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer associated with poor survival rates. However, characterisation of the disease epidemiology is hampered by use of varying terminology, definition and disease management. The aim of this review was to conduct a systematic review to provide greater clarity on the sum of the available epidemiologic evidence and to guide future research into the disease prevalence, progression, characteristics and outcome. Systematic searches of PubMed and Embase were performed in March 2010 to identify relevant observational studies relating to the epidemiology, progression and outcomes of CRPC. Further studies were identified for inclusion in our review through manual searches of the authors' bibliographical databases and the reference lists of the included articles. We identified 12 articles (10 full papers and 2 abstracts) reporting studies that included a total of 71,179 patients observed for up to 12 years for evaluation in our review. Five studies looked at the prevalence of CRPC in patients with prostate cancer. Together, the data indicate that 10-20% of prostate cancer patients develop CRPC within approximately 5 years of follow-up. Two studies reported the prevalence of bone metastases present at diagnosis of CRPC. Together, ≥ 84% were shown to have metastases at diagnosis. Of those patients with no metastases present at diagnosis of CRPC, 33% could expect to develop them within 2 years. The median survival of patients with CRPC was reported in five studies, with values varying from 9 to 30 months. A pooled, sample-weighted survival estimate calculated from the survival data included in this review is 14 months. Very few studies that met our inclusion criteria evaluated treatment patterns in CRPC. One study reported that only 37% of patients with CRPC received chemotherapy, with the remainder receiving only steroids and supportive care. The most common palliative therapies administered to patients with skeletal symptoms were radiotherapy, radionuclide therapy, bisphosphonates and opioids. This review highlights the poor prognosis of patients with CRPC, and demonstrates a survival of 9-13 months in those patients with metastatic CRPC. Furthermore, progression to CRPC is associated with deterioration in quality of life, and few therapeutic options are currently available to patients with CRPC. However, epidemiologic study of these patients is hampered by differing terminology, definitions and treatment paradigms. Our review highlights the need for further well-designed, epidemiological studies of CRPC, using standardised definitions and methods.