Combined 18F‐fluorocholine and 18F‐fluoride positron emission tomography/computed tomography imaging for staging of high‐risk prostate cancer

Study Type – Diagnosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Positron emission tomography/computed tomography (PET/CT) with choline and fluoride for the detection of metastases in patients with prostate cancer have each been evaluated, with mixed results. Choline PET/CT has been evaluated against pelvic lymphadenectomy, generally with a low sensitivity but a high specificity; however, the study populations have been heterogenous. Fluoride PET/CT has been evaluated against other imaging methods, such as bone scan, single photon emission CT and MRI, and has been shown to have high specificity as well as sensitivity for bone metastases, but there are no studies with biopsy verification. This is the first study that evaluates the clinical use of both choline and fluoride PET/CT on the same patients in a well‐defined population of patients with high‐risk prostate cancer.

OBJECTIVE

• ? To investigate how often positron emission tomography/computed tomography (PET/CT) scans, with both ¹⁸F‐fluorocholine and ¹⁸F‐fluoride as markers, add clinically relevant information for patients with prostate cancer who have high‐risk tumours and a normal or inconclusive planar bone scan.

PATIENTS AND METHODS

• ? Patients with prostate cancer with prostate specific antigen (PSA) levels between 20 and 99 ng/mL and/or Gleason score 8–10 tumours, planned for treatment with curative intent based on routine staging with a negative or inconclusive bone scan, were further investigated with a ¹⁸F‐fluorocholine and a ¹⁸F‐fluoride PET/CT.
• ? None of the patients received hormonal therapy before the staging procedures were completed.

RESULTS

• ? For 50 of the 90 included patients (56%) one or both PET/CT scans indicated metastases.
• ? ¹⁸F‐fluorocholine PET/CT indicated lymph node metastases and/or bone metastases in 35 patients (39%).
• ? ¹⁸F‐fluoride PET/CT was suggestive for bone metastases in 37 patients (41%).
• ? In 18 patients (20%) the PET/CT scans indicated widespread metastases, leading to a change in therapy intent from curative to non‐curative.
• ? Of the patients with positive scans, 74% had Gleason score 8–10 tumours. Of the patients with Gleason score 8–10 tumours, 64% had positive scans.

CONCLUSIONS

• ? PET/CT scans with ¹⁸F‐fluorocholine and ¹⁸F‐fluoride commonly detect metastases in patients with high‐risk prostate cancer and a negative or inconclusive bone scan.
• ? For 20% of the patients the results of the PET/CT scans changed the treatment plan.

     

Elasticity as a biomarker for prostate cancer: a systematic review

• To systematically review the range of methods available for assessing elasticity in the prostate and to examine its use as a biomarker for prostate cancer.

• A systematic review of the electronic database PubMed was performed up to December 2012.
• All relevant studies assessing the use of elasticity as a biomarker for prostate cancer were included except those not studying human prostates or reporting a sensitivity, specificity or quantitative elasticity value.

• There has been much interest in the use of elasticity in the detection of prostate cancer and there have been many publications using various methods of detection. The most common method of assessment is an imaging method, called sonoelastography. Further imaging methods include ultrasound (US), three‐dimensional US and magnetic resonance elastography. These methods are reviewed for sensitivity and specificity.
• The other method of assessment is the mechanical method. These use quantitative elasticity values to differentiate benign from malignant areas of the prostate. This method of assessment has shown that the elasticity changes for differing Gleason grades and T stages of disease within the prostate. Quantitative elasticity values offer the potential of using ‘threshold’ elasticity values under which the prostate is benign.

• Tissue elasticity has great potential as a diagnostic and prognostic biomarker for prostate cancer and can be assessed using various methods. Currently transrectal sonoelastography has the most evidence supporting its use in clinical practice.

     

Penile cancer: organ‐sparing techniques

• To compare the oncological safety of treating patients with penile cancer with conservative techniques developed to preserve function, cosmesis and psychological well‐being with more radical ablative strategies.

• We conducted an extensive review of the literature of penile‐preserving and ablative techniques and report on the oncological as well as functional outcomes.

• There were no randomised studies comparing penile‐preserving and ablative techniques.
• Most studies consisted of retrospective cohorts.
• The quality of evidence was level 3 at best.

• Cancer‐specific survival is similar in penile‐preserving and ablative approaches for low‐stage disease.
• Penile preservation is better for functional and cosmetic outcomes and should be offered as a primary treatment method in men with low‐stage penile cancer.

     

Single application of high‐intensity focused ultrasound as a first‐line therapy for clinically localized prostate cancer: 5‐year outcomes

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? High‐intensity focused ultrasound (HIFU) therapy has been proposed for the treatment of localized prostate cancer (PCa) for all risk levels of tumour recurrence. The study adds data on the efficacy of a single HIFU application in the treatment of PCa with different risks of recurrence. Durable cancer control was achieved in 81.7% of patients with low‐risk disease, with rates of efficacy declining in intermediate‐ and high‐risk tumours. The data suggest that the principal domain for minimal invasive HIFU should be low‐risk disease.

OBJECTIVE

• ? To report cancer control results after a single application of high‐intensity focused ultrasonography (HIFU) in patients with localized prostate cancer (PCa), stratified by tumour recurrence risk according to D'Amico risk classification.

PATIENTS AND METHODS

• ? In a retrospective single‐centre study, we analysed the outcomes of patients with localized PCa who were treated with curative intent between December 2002 and October 2006 using an Ablatherm HIFU device (EDAP‐TMS, France).
• ? Transurethral resection of the prostate or adenomectomy were performed before HIFU to downsize large prostate glands.
• ? Oncological failure was determined by the occurrence of biochemical relapse, positive biopsy and/or metastasis. Biochemical relapse was defined as a PSA nadir +1.2 ng/mL (Stuttgart definition), or as a rise in PSA level to ≥0.5 ng/mL if PSA doubling time was ≤6 months. Kaplan–Meier analysis was performed for survival estimates.

RESULTS

• ? A total of 191 consecutive patients were included in the study. The median (range) patient age was 69.7 (51–82) years, and 38, 34 and 28% of these patients were in the low‐, intermediate‐ and high‐risk groups, respectively.
• ? The median (range) follow‐up was 52.8 (0.2–79.8) months.
• ? At 5 years, overall and cancer‐specific survival rates were 86.3% and 98.4%, respectively.
• ? Stratified by risk group, negative biopsy rates were 84.2%, 63.6%, and 67.5% (P = 0.032), 5‐year biochemical‐free survival rates were 84.8%, 64.9% and 54.9% (P < 0.01), and 5‐year disease‐free survival rates were 81.7%, 53.2% and 51.2% (P < 0.01), respectively.

CONCLUSION

• ? Single‐session HIFU is recommended as a curative approach in elderly patients with low‐risk PCa. Patients at higher risk of tumour progression should be counselled regarding the likely need for salvage therapy, including repeat HIFU.

     

Good quality white-light transurethral resection of bladder tumours (GQ-WLTURBT) with experienced surgeons performing complete resections and obtaining detrusor muscle reduces early recurrence in new non-muscle-invasive bladder cancer: validation across time and place and recommendation for benchmarking

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Staging of patients with prostate cancer is the cornerstone of treatment. However, after curative intended therapy a high portion of patients relapse with local and/or distant recurrence. Therefore, one may question whether surgical lymph node dissection (LND) is sufficiently reliable for staging of these patients. Several imaging methods for primary LN staging of patients with prostate cancer have been tested. Acceptable detection rates have not been achieved by CT or MRI or for that matter with PET/CT using the most common tracer fluoromethylcholine (FCH). Other more recent metabolic tracers like acetate and choline seem to be more sensitive for assessment of LNs in both primary staging and re‐staging. However, previous studies were small. Therefore, we assessed the value of [¹⁸F]FCH PET/CT for primary LN staging in a prospective study of a larger sample and with a ‘blinded’ review. After a study period of 3 years and >200 included patients, we concluded that [¹⁸F]FCH PET/CT did not reach an optimal detection rate compared with LND, and, therefore, it cannot replace this procedure. However, we did detect several bone metastases with [¹⁸F]FCH PET/CT that the normal bone scans had missed, and this might be worth pursuing.

OBJECTIVES

• ? To assess the value of [¹⁸F]fluoromethylcholine (FCH) positron emission tomography/computed tomography (PET/CT) for lymph node (LN) staging of prostate cancer.
• ? To evaluate if FCH PET/CT can replace LN dissection (LND) for LN staging of prostate cancer, as about one‐third of patients with prostate cancer who receive intended curative therapy will have recurrence, one reason being undetected LN involvement.

PATIENTS AND METHODS

• ? From January 2008 to December 2010, 210 intermediate‐ or high‐risk patients had a FCH PET/CT scan before regional LND.
• ? After dissection, the result of histological examination of the LNs (gold standard) was compared with the result of FCH PET/CT obtained by ‘blinded review’.
• ? Sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of FCH PET/CT were measured for detection of LNe metastases.

RESULTS

• ? Of the 210 patients, 76 (36.2%) were in the intermediate‐risk group and 134 (63.8%) were in the high‐risk group. A medium (range) of 5 (1–28) LNs were removed per patient.
• ? Histological examination of removed LNs showed metastases in 41 patients. Sensitivity, specificity, PPV, and NPV of FCH PET/CT for patient‐based LN staging were 73.2%, 87.6%, 58.8% and 93.1%, respectively.
• ? Corresponding values for LN‐based analyses were 56.2%, 94.0%, 40.2%, and 96.8%, respectively.
• ? The mean diameter of the true positive LN metastases was significantly larger than that of the false negative LNs (10.3 vs 4.6 mm; P < 0.001).
• ? In addition, FCH PET/CT detected a high focal bone uptake, consistent with bone metastases, in 18 patients, 12 of which had histologically benign LNs.

CONCLUSIONS

• ? Due to a relatively low sensitivity and a correspondingly rather low PPV, FCH PET/CT is not ideal for primary LN staging in patients with prostate cancer.
• ? However, FCH PET/CT does convey important additional information otherwise not recognised, especially for bone metastases.

     

Salvage high-dose-rate brachytherapy for local prostate cancer recurrence after radiotherapy - preliminary results

Study Type – Prognostic (case series) Level of Evidence 4 What's known on the subject? and What does the study add? There have been no reports on the application of HDR‐BT in Japan as salvage therapy for recurrence following radiotherapy. Our data showed that salvage HDR‐BT is effective as an option for treatment of local prostate cancer recurrence after radiotherapy. OBJECTIVE

• ? To assess the preliminary clinical results of salvage high‐dose‐rate brachytherapy (HDR‐BT) applied in cases of suspected local recurrence or of residual tumour after radiotherapy.

PATIENTS AND METHODS

• ? The subjects were 11 patients who met the above conditions and underwent salvage HDR‐BT between December 2006 and January 2009. The T stage at the initial treatment was T1c in three patients, T2 in three patients and T3 in five patients.
• ? Ten patients received HDR‐BT ± electron beam radiation therapy and one patient received proton beam irradiation.
• ? Follow‐up after the completion of salvage HDR‐BT lasted 18–41 months (mean 29 months). A dose of 11.0 Gy radiation was delivered twice (22.0 Gy in total), separated by a 6‐h interval, on the day the applicators were inserted.

RESULTS

• ? Seven of the 11 cases remained in a biochemical non‐evidence of disease state.
• ? The prostate‐specific antigen (PSA) level continuously rose after salvage HDR‐BT in three of the four other cases. Hormone administration was initiated in the four cases of PSA recurrence.
• ? No G3 or more severe events occurred, and the incidence of G2 was low during this study period.

CONCLUSION

• ? Of the 11 cases treated with salvage HDR‐BT, PSA levels remained low in seven cases and the incidence of complications was also low. This suggests that salvage HDR‐BT is effective as an option for treatment of local prostate cancer recurrence after radiotherapy.

     

Long‐term radical prostatectomy outcomes among participants from the European Randomized Study of Screening for Prostate Cancer (ERSPC) Rotterdam

Study Type – Therapy (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Radical prostatectomy was previously shown to improve long‐term outcomes among men with clinically‐detected prostate cancer. Our data suggests that radical prostatectomy is also associated with improved outcomes in men with screen‐detected prostate cancer.

OBJECTIVE

• ? To examine the long‐term outcomes of radical prostatectomy (RP) among men diagnosed with prostate cancer from the screening and control arms of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC).

PATIENTS AND METHODS

• ? Among 42 376 men randomised during the period of the first round of the trial (1993–1999), 1151 and 210 in the screening and control arms were diagnosed with prostate cancer, respectively.
• ? Of these men, 420 (36.5%) screen‐detected and 54 (25.7%) controls underwent RP with long‐term follow‐up data (median follow‐up 9.9 years).
• ? Progression‐free (PFS), metastasis‐free (MFS) and cancer‐specific survival (CSS) rates were examined, and multivariable Cox proportional hazards models were used to determine whether screen‐detected (vs control) was associated with RP outcomes after adjusting for standard predictors.

RESULTS

• ? RP cases from the screening and control arms had statistically similar clinical stage and biopsy Gleason score, although screen‐detected cases had significantly lower prostate‐specific antigen (PSA) levels at diagnosis.
• ? Men from the screening arm had a significantly higher PFS (P= 0.003), MFS (P < 0.001) and CSS (P= 0.048).
• ? In multivariable models adjusting for age, PSA level, clinical stage, and biopsy Gleason score, the screening group had a significantly lower risk of biochemical recurrence (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.23–0.83, P= 0.011) and metastasis (HR 0.18, 95% CI 0.06–0.59, P= 0.005).
• ? Additionally adjusting for tumour volume and other RP pathology features, there was no longer a significant difference in biochemical recurrence between the screening and control arms.
• ? Limitations of the present study include lead‐time bias and non‐randomised treatment selection.

CONCLUSIONS

• ? After RP, screen‐detected cases had significantly improved PFS, MFS and CSS compared with controls within the available follow‐up time.
• ? The screening arm remained significantly associated with lower rates of biochemical recurrence and metastasis after adjusting for other preoperative variables.
• ? However, considering also RP pathology, the improved outcomes in the screening group appeared to be mediated by a significantly lower tumour volume.

     

Targeting castration‐induced tumour hypoxia enhances the acute effects of castration therapy in a rat prostate cancer model

What’s known on the subject? and What does the study add? Castration therapy has rather modest effects on cell death in tumours but can be enhanced by other treatments targeting tumour stroma and vasculature. This study shows that the prostate becomes hypoxic following castration and that targeting hypoxic cells during castration therapy potently enhances the effects of castration.

OBJECTIVE

• ? To explore the effects of castration therapy, the standard treatment for advanced prostate cancer, in relation to tumour hypoxia and to elicit its importance for the short‐ and long‐term therapeutic response.

MATERIAL AND METHODS

• ? We used the androgen‐sensitive rat Dunning H prostate tumour model that transiently responds to castration treatment followed by a subsequent relapse, much like the scenario in human patients.
• ? Tumour tissues were analysed using stereological methods in intact, 1 and 7 days after castration therapy.

RESULTS

• ? Hypoxia was transiently up‐regulated after castration therapy and correlated with the induction of tumour cell apoptosis.
• ? When castration therapy was combined with tirapazamine (TPZ), a drug that targets hypoxic cells and the vasculature, the effects on tumour cell apoptosis and tumour volume were enhanced in comparison to either castration or TPZ alone.

CONCLUSION

• ? The present study suggests that castration‐induced tumour hypoxia is a novel target for therapy.

     

A post‐radical‐prostatectomy nomogram incorporating new pathological variables and interaction terms for improved prognosis

Study Type – Prognosis (systematic review)
Level of Evidence 2a What’s known on the subject? and What does the study add? Nomograms are commonly used by urologists to assess a patient’s risk of developing biochemical failure (PSA recurrence) after radical prostatectomy. The nomograms currently available on websites and in the published literature do not take into account recent developments in pathological reporting which may improve our ability to more accurately predict patient prognosis. Furthermore, currently available nomograms treat all clinical predictors as independent variables without considering the possibility that these factors may be interlinked, which may alter their predictive value. Our study assesses the predictive value of several new pathological variables and demonstrates that the per cent of Gleason patterns 4 and/or 5 (% 4/5), intraductal prostatic carcinoma and prostate weight significantly improve the predictive value of a model based on established pathological variables. We also show that consideration of interactions between % 4/5, surgical margin status and extracapsular extension further improves our accuracy in predicting patient PSA recurrence. Finally, we find that published nomograms based on PSA recurrence defined as ≥0.4 ng/mL provide over‐optimistic predictions for prostate cancer patients where PSA recurrence was defined as ≥0.2 ng/mL.

OBJECTIVE

• ? To evaluate new variables in prostate pathology reporting including, the per cent of Gleason patterns 4 and/or 5 (% 4/5), presence or absence of intraductal carcinoma of the prostate (IDCP), tumour volume and the prostatic zone of tumour origin as predictors of post‐radical‐prostatectomy (RP) biochemical recurrence (BCR).
• ? To develop an optimal postoperative nomogram for patients with prostate cancer.

PATIENTS AND METHODS

• ? Our study cohort was 1939 eligible patients from the Abbott West Australian Prostatectomy Database.
• ? Multivariate Cox proportional hazard regression models were developed to predict BCR which was defined as prostate‐specific antigen (PSA) ≥0.2 ng/mL.
• ? Our models and the 2009 Kattan postoperative nomogram were compared in terms of discrimination and calibration, with internal validation of our final model performed using bootstrapping methods. Our final model is presented as a nomogram.

RESULTS

• ? The Kattan nomogram was accurate in discriminating our patients according to risk (concordance index: 0.791) but calibration analysis indicated underestimation of patient risk, particularly for high‐risk disease.
• ? Our nomogram incorporates % 4/5, IDCP and prostate weight plus interaction terms between % 4/5, positive surgical margins and extracapsular extension, giving improved predictive accuracy (concordance index: 0.828) and calibration.

CONCLUSIONS

• ? Nomograms that predict risk of BCR defined as PSA ≥0.4 ng/mL may not be optimal for patient cohorts where BCR is defined as PSA ≥0.2 ng/mL.
• ? If our findings are validated in other populations, current post‐RP nomograms may be improved to a modest degree by incorporating the new variables prostate weight, IDCP and % 4/5, and by considering interactions between predictive variables.

     

Influence of obesity on tumour volume in patients with prostate cancer

Study Type – Prognosis (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Obesity is associated with more aggressive prostate cancer. Prostate cancer tumour volume is affected by excess weight, after adjustment for all possible clinical and pathological confounders.

OBJECTIVE

• ? To investigate the association between body mass index and tumour volume at radical prostatectomy in a large European population.

PATIENTS AND METHODS

• ? Recent data support the hypothesis that the hormonal environment in overweight and obese men may alter androgen‐dependent prostate growth. Body mass index (BMI) has been implicated in prostate cancer pathophysiology.
• ? We analysed 1275 patients with prostate cancer who underwent radical prostatectomy at a single tertiary care institution. Mean tumour volume (TV) was evaluated according to BMI WHO categories (normal <25 kg/m² vs overweight 25–30 kg/m² vs obese 30–35 kg/m² vs severely obese >35 kg/m²).
• ? Univariable linear regression analyses targeted the association between BMI and TV at radical prostatectomy. Multivariable analyses were adjusted for age, prostate‐specific antigen value, biopsy Gleason sum, clinical stage and prostate volume.

RESULTS

• ? Mean BMI was 26.3 kg/m² (median 26; range 16.7–42.0). Mean TV was 5.6 mL (median 3.3; range 0.1–61.2). The mean prostate‐specific antigen value was 10.3 ng/dL (median 6.6; range 0.3–327).
• ? The mean TV was 5.0, 5.8, 6.3 and 9.2 mL in normal, overweight, obese and severely obese patients, respectively (P= 0.03). TVs in men with a normal BMI were 84% smaller than in severely obese men (5.0 vs 9.2 mL).
• ? On univariable analysis, BMI was correlated with TV at radical prostatectomy (P < 0.001). On multivariable analysis, BMI reached the independent predictor status after adjustment for age, prostate‐specific antigen value, biopsy Gleason score, clinical stage and prostate volume (P= 0.03).

CONCLUSION

• ? We showed that BMI is independently associated with prostate cancer volume at radical prostatectomy. The present results confirm that obesity may play a key role in prostate cancer pathophysiology.

     

Expression of integrin proteins in non‐muscle‐invasive bladder cancer: significance of intravesical recurrence after transurethral resection

Study Type – Aetiology (case control)
Level of Evidence 3b What’s known on the subject? and What does the study add? A number of studies have reported several clinicopathological factors closely associated with intravesical recurrence of non‐muscle invasive bladder cancer (NMIBC). In addition, various types of molecular markers have been shown to be useful for predicting intravesical recurrence of NMIBC following transurethral resection (TUR). Of six subunits of integrin proteins, including α2, α3, α5, α6, β1 and β4, the expression level of the β4 subunit in NMIBC, in addition to pathological T stage and concomitant carcinoma in situ appeared to be independently related to intravesical recurrence. Therefore, consideration of the expression levels of integrins, particularly that of the β4 subunit, in TUR specimens would contribute to further accurate prediction of intravesical recurrence of NMIBC.

OBJECTIVES

• ? To evaluate the expression of integrin proteins, a family of transmembrane heterodimers, in non‐muscle‐invasive bladder cancer (NMIBC).
• ? To assess the significance of these proteins as prognostic indicators in patients undergoing transurethral resection (TUR).

PATIENTS AND METHODS

• ? The present study comprised 161 patients diagnosed as having NMIBC after TUR.
• ? Expression levels of six subunits of integrin proteins, including α2, α3, α5, α6, β1 and β4, were measured in TUR specimens by immunohistochemical staining.

RESULTS

• ? Of the six proteins, expression levels of α2‐, α3‐, α6‐ and β4‐subunits were significantly associated with the incidence of intravesical recurrence. Univariate analysis identified expression levels of α3‐, α6‐ and β4‐subunits as important predictors of intravesical recurrence, while tumour size, pathological T stage and concomitant carcinoma in situ (CIS) were also important.
• ? Multivariate analysis showed that the expression level of the β4 subunit, pathological T stage and concomitant CIS are independently related to intravesical recurrence.
• ? There were significant differences in intravesical recurrence‐free survival for patients who were positive for the three independent risk factors; intravesical recurrence occurred in 10 of 49 (20.4%) patients who were negative for all risk factors, 31 of 68 who were positive for one risk factor (45.6%), and 30 of 44 who were positive for two or three risk factors (68.2%).

CONCLUSIONS

• ? Consideration of the expression levels of integrins, particularly those of the β4 subunit, in TUR specimens, in addition to conventional variables, would contribute to accurate prediction of intravesical recurrence after TUR for NMIBC patients.

     

Positive predictive value of prostate biopsy indicated by prostate‐specific‐antigen‐based prostate cancer screening: trends over time in a European randomized trial*

Study Type – Diagnosis (validating cohort) Level of Evidence 1b What's known on the subject? and What does the study add? The European Randomized study of Screening for Prostate Cancer (ERSPC) showed a reduction in prostate cancer mortality of 21% for PSA‐based screening at a median follow‐up of 11 years. In the ERSPC, men are screened at 4‐year intervals. A prostate biopsy is recommended for men with a PSA level ≥3.0 ng/mL. The study shows that the positive predictive value (PPV) of a prostate biopsy indicated by PSA‐based screening remains equal throughout consecutive screening rounds in men without a previous biopsy. In men who have previously had a benign biopsy, the PPV drops considerably, but 20% of the cancers detected still show aggressive characteristics.

OBJECTIVE

• ? To assess the positive predictive value (PPV) of prostate biopsy, indicated by a prostate‐specific antigen (PSA) threshold of ≥3.0 ng/mL, over time, in the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC).

PATIENTS AND METHODS

• ? In the Rotterdam section of the ERSPC, a total of 42 376 participants, aged 55–74 years, identified from population registries were randomly assigned to a screening or control arm.
• ? For the ERSPC men undergo PSA screening at 4‐year intervals. A total of three screening rounds were evaluated; therefore, only men aged 55–69 years at the first screening were eligible for the present study.

RESULTS

• ? PPVs for men without previous biopsy remained equal throughout the three subsequent screenings (25.5, 22.3 and 24.8% respectively).
• ? Conversely, PPVs for men with a previous negative biopsy dropped significantly (12.0 and 15.2% at the second and third screening, respectively).
• ? Additionally, in men with and without previous biopsy, the percentage of aggressive prostate cancers (clinical stage >T2b, Gleason score ≥7) decreased after the first round of screening from 44.4 to 23.8% in the second (P < 0.001) and 18.6% in the third round (P < 0.001).
• ? Repeat biopsies accounted for 24.6% of all biopsies, but yielded only 8.6% of all aggressive cancers.

CONCLUSIONS

• ? In consecutive screening rounds the PPV of PSA‐based screening remains equal in previously unbiopsied men.
• ? In men with a previous negative biopsy the PPV drops considerably, but 20% of cancers detected still show aggressive characteristics.
• ? Individualized screening algorithms should incorporate previous biopsy status in the decision to perform a repeat biopsy with the aim of further reducing unnecessary biopsies.

     

The use of estramustine phosphate in the modern management of advanced prostate cancer

What’s known on the subject? and What does the study add? Estramustine phosphate has anti‐tumour properties and it improves patient outcomes if combined with other chemotherapy agents such as doeetaxel. The efficacy of estramustine phosphate in selected patients and its safety profile, provided used with any low‐molecular‐weight heparin support its use as a second‐line treatment in hormone‐resistant prostate cancer.

OBJECTIVES

• ? Estramustine phosphate is a nitrogen mustard derivative of estradiol‐17β‐phosphate and has anti‐tumour properties.
• ? Interest in estramustine has been renewed because of the results of clinical studies showing improved patient outcomes if estramustine is combined with other chemotherapy agents such as docetaxel.

PATIENTS AND METHODS

• ? Relevant clinical studies using chemotherapy combinations including estramustine are discussed.
• ? Efficacy and safety outcomes are summarized.

RESULTS

• ? Combination therapy with estramustine and docetaxel can increase PSA response rates, improve quality of life and increase median patient survival compared with chemotherapy regimens that do not include estramustine.
• ? Although the overall tolerability of estramustine is favourable, its use can be associated with an increased risk of thromboembolic events.

CONCLUSIONS

• ? The identification of suitable patient groups and the effective management of the risk of thromboembolism with the adjunct of low‐molecular‐weight heparins support the use of estramustine as an effective second‐line treatment strategy in hormone‐resistant prostate cancer.
• ? These promising findings warrant further investigation in a randomized clinical trial.

     

The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up

Study Type – Prognosis (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Patients with biochemical recurrence after prostatectomy often develop subsequent metastases. However, the natural history of metastatic progression in men who have not received subsequent therapies before developing metastases has been understudied. Here, we describe the largest known cohort of men with PSA‐recurrent prostate cancer after prostatectomy who have not received additional treatments before metastasis. We characterize metastatic risk based on clinical variables, and we show that Gleason score and PSA doubling time are the strongest predictors of metastasis‐free survival. We present tables stratifying metastatic risk by these two variables.

OBJECTIVE

• ? 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.

PATIENTS AND METHODS

• ? 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.

RESULTS

• ? 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.

CONCLUSIONS

• ? 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.

     

Age‐related changes in prostate zonal volumes as measured by high‐resolution magnetic resonance imaging (MRI): a cross‐sectional study in over 500 patients

Study Type – Diagnosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Benign prostatic hyperplasia is the most common symptomatic disorder of the prostate and its severity varies greatly in the population. Various methods have been used to estimate prostate volumes in the past including the digital rectal examination and ultrasound measurements. High‐resolution T2 weighted MRI can provide accurate measurements of zonal volumes and total volumes, which can be used to better understand the etiology of lower urinary tract symptoms of men.

OBJECTIVE

• ? To use ability of magnetic resonance imaging (MRI) to investigate age‐related changes in zonal prostate volumes.

PATIENTS AND METHODS

• ? This Institutional Review Board approved, Health Insurance Portability and Accountability Act‐compliant study consisted of 503 patients who underwent 3 T prostate MRI before any treatment for prostate cancer.
• ? Whole prostate (WP) and central gland (CG) volumes were manually contoured on T2‐weighted MRI using a semi‐automated segmentation tool. WP, CG, peripheral zone (PZ) volumes were measured for each patient.
• ? WP, CG, PZ volumes were correlated with age, serum prostate‐specific antigen (PSA) level, International Prostate Symptom Score (IPSS), Sexual Health Inventory for Men (SHIM) scores.

RESULTS

• ? Linear regression analysis showed positive correlations between WP, CG volumes and patient age (P < 0.001); there was no correlation between age and PZ volume (P= 0.173).
• ? There was a positive correlation between WP, CG volumes and serum PSA level (P < 0.001), as well as between PZ volume and serum PSA level (P= 0.002).
• ? At logistic regression analysis, IPSS positively correlated with WP, CG volumes (P < 0.001).
• ? SHIM positively correlated with WP (P= 0.015) and CG (P= 0.023) volumes.
• ? As expected, the IPSS of patients with prostate volumes (WP, CG) in first decile for age were significantly lower than those in tenth decile.

CONCLUSIONS

• ? Prostate MRI is able to document age‐related changes in prostate zonal volumes.
• ? Changes in WP and CG volumes correlated inversely with changes in lower urinary tract symptoms.
• ? These findings suggest a role for MRI in measuring accurate prostate zonal volumes; have interesting implications for study of age‐related changes in the prostate.

     

Clinical evaluation of a novel method for the measurement of prostate-specific antigen, AccuPSA(TM) , as a predictor of 5-year biochemical recurrence-free survival after radical prostatectomy: results of a pilot study

Study Type – Diagnostic (validating cohort) Level of Evidence 1b What's known on the subject? and What does the study add? Nadir Ultrasensitive PSA levels has some value for predicting BCR following RD. AccuPSA assays lower limit of PSA quantification of <0.01 pg/ml greatly enhances sensitivity and specificity of nadir PSA to predict BCR following RP. Our pilot study shows an AccuPSA of 3 pg/ml has a sensitory and specificity of 100% and 75% respectively for predicting 5 year BCR following RP. OBJECTIVES

• ? To conduct a proof of concept study to evaluate a novel digital single molecule immunoassay (AccuPSA^TM) that detects prostate‐specific antigen (PSA) a thousandfold more sensitively than current PSA detection methods.
• ? To determine the ability of the AccuPSA^TM assay to predict 5‐year biochemical recurrence (BCR)‐free survival after radical prostatectomy (RP).

PATIENTS AND METHODS

• ? A total of 31 frozen serum specimens were obtained from specimen logs maintained at New York University Langone Medical Center and the Johns Hopkins University School of Medicine on men who had undergone RP. Those men without evidence of BCR had a minimum of 5 years' PSA follow‐up.
• ? In all cases, preoperative and pathological information were available, as was a serum specimen 3–6 months after RP, with a PSA level of <0.1 ng/mL measured by conventional PSA methods at the time of serum collection.
• ? Specimens were tested using the AccuPSA^TM method.
• ? A Cox proportional hazard model and Kaplan–Meier analysis were used to determine whether AccuPSA^TM predicted the risk of BCR.

RESULTS

• ? Overall, 11/31 (35.5%) men developed BCR.
• ? Mean AccuPSA^TM nadir levels were significantly different (P < 0.001) between the non‐BCR group (2.27 pg/mL) and the BCR group (46.99 pg/mL).
• ? Using a multivariate Cox proportional hazard model, AccuPSA^TM nadir level was a significant predictor of BCR‐free survival (P < 0.01).
• ? Kaplan–Meier analysis of up to 5 years follow‐up showed that 100% of men with AccuPSA^TM nadir values <3 pg/mL did not develop BCR, whereas 62.5% of men with values >3 pg/mL developed BCR (P= 0.00024).
• ? The sensitivity, specificity, positive predictive value and negative predictive value of the AccuPSA^TM method was 100%, 75%, 69% and 100%, respectively.

CONCLUSIONS

• ? AccuPSA^TM assay predicts 5‐year BCR‐ free survival after RP.
• ? Identifying a reliable predictor of BCR soon after RP has important implications for frequency of PSA testing, selection of candidates for adjuvant therapy, and reassuring a large subset of men that they are not at risk of recurrence.
• ? Larger studies are needed to validate these findings.

     

Impact of surgical margin status on prostate‐cancer‐specific mortality

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Surgical margin status at radical prostatectomy (RP) has been shown to be a predictor of disease progression and the strongest predictor of benefit from adjuvant therapy, but the impact of a positive surgical margin (PSM) on long‐term prostate‐cancer‐specific survival is unknown. The PSM rate is dependent on the pathological stage of the cancer. In a recent multicentre nomogram for 15‐year prostate‐cancer‐specific mortality (PCSM) after RP, PSM was not significantly associated with PCSM, while Gleason score and pathological stage were the only significant predictors. This has not been validated in a single centre, and PSM has been shown to vary greatly with surgical technique. This is the first study on the impact of PSM on PCSM in a single surgeon's cohort. In other centres, the decision to administer adjuvant therapy may be influenced by surgical margin status. In this cohort, men routinely did not receive adjuvant therapy, affording the unique opportunity to study the long‐term implications of a PSM.

OBJECTIVE

• ? To examine the relative impact of a positive surgical margin (PSM) and other clinicopathological variables on prostate‐cancer‐specific mortality (PCSM) in a large retrospective cohort of patients undergoing radical prostatectomy (RP).

PATIENTS AND METHODS

• ? Between 1982 and 2011, 4569 men underwent RP performed by a single surgeon.
• ? Of the patient population, 4461 (97.6%) met all the inclusion criteria.
• ? The median (range) age was 58 (33–75) years and the median prostate‐specific antigen (PSA) was 5.4 ng/mL; RP Gleason score was ≤6 in 2834 (63.7%), 7 in 1351 (30.3%), and 8–10 in 260 (6.0%) patients; PSMs were found in 462 (10.4%) patients.
• ? Cox proportional hazards models were used to determine the impact of a PSM on PCSM.

RESULTS

• ? At a median (range) follow‐up of 10 years (1–29), 187 men (4.3%) had died from prostate cancer.
• ? The 20‐year prostate‐cancer‐specific survival rate was 75% for those with a PSM and 93% for those without.
• ? Compared with those with a negative surgical margin, men with a PSM were more likely to be older (median age 60 vs 58 years) and to have undergone RP in the pre‐PSA era (36.6% vs 11.8%). Additionally, they were more likely to have a higher PSA level (median 7.6 vs 5.2 ng/mL), a Gleason score of ≥7 (58.7% vs 33.7%), and a non‐organ‐confined tumour (90.9% vs 30.6% [P < 0.001 for all]).
• ? In a univariate model for PCSM, PSM was highly significant (hazard ratio [HR] 5.0, 95% confidence interval [CI] 3.7–6.7, P < 0.001).
• ? In a multivariable model, adjusting for pathological variables and RP year, PSM remained an independent predictor of PCSM (HR 1.4, 95% CI 1.0–1.9, P= 0.036) with a modest effect relative to RP Gleason score (HR 5.7–12.6) and pathological stage (HR 2.2–11.0 [P < 0.001]).

CONCLUSION

• ? Although a PSM has a statistically significant adverse effect on prostate‐cancer‐specific survival in multivariable analysis, Gleason grade and pathological stage were stronger predictors.

     

Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer

What's known on the subject? and What does the study add? It is known that both lactate inhibition and carbohydrate restriction inhibit tumour growth. What is unknown is whether the two work synergistically together. This study adds that though the combination of lactate inhibition and carbohydrate restriction did not synergistically slow tumour growth in our model, we confirmed that carbohydrate restriction started after tumour inoculation slowed tumour growth. Moreover, lactate inhibition resulted in changes in the tumour microenvironment that may have implications for future metabolic targeting of prostate cancer growth.

OBJECTIVE

• ? To determine if a no‐carbohydrate ketogenic diet (NCKD) and lactate transporter inhibition can exert a synergistic effect on delaying prostate tumour growth in a xenograft mouse model of human prostate cancer.

MATERIALS AND METHODS

• ? 120 nude athymic male mice (aged 6–8 weeks) were injected s.c. in the flank with 1.0 × 10⁵ LAPC‐4 prostate cancer cells.
• ? Mice were randomized to one of four treatment groups: Western diet (WD, 35% fat, 16% protein, 49% carbohydrate) and vehicle (Veh) treatment; WD and mono‐carboxylate transporter‐1 (MCT1) inhibition via α‐cyano‐4‐hydroxycinnamate (CHC) delivered through a mini osmotic pump; NCKD (84% fat, 16% protein, 0% carbohydrate) plus Veh; or NCKD and MCT1 inhibition.
• ? Mice were fed and weighed three times per week and feed was adjusted to maintain similar body weights.
• ? Tumour size was measured twice weekly and the combined effect of treatment was tested via Kruskal–Wallis analysis of all four groups. Independent effects of treatment (NCKD vs WD and CHC vs Veh) on tumour volume were tested using linear regression analysis.
• ? All mice were killed on Day 53 (conclusion of pump ejection), and serum and tumour sections were analysed for various markers. Again, combined and independent effects of treatment were tested using Kruskal–Wallis and linear regression analysis, respectively.

RESULTS

• ? There were no significant differences in tumour volumes among the four groups (P= 0.09).
• ? When testing the independent effects of treatment, NCKD was significantly associated with lower tumour volumes at the end of the experiment (P= 0.026), while CHC administration was not (P= 0.981). However, CHC was associated with increased necrotic fraction (P < 0.001).

CONCLUSIONS

• ? Differences in tumour volumes were observed only in comparisons between mice fed a NCKD and mice fed a WD.
• ? MCT1 inhibition did not have a significant effect on tumour volume, although it was associated with increased necrotic fraction.

     

Prediction of outcomes after radical prostatectomy in patients diagnosed with prostate cancer of biopsy Gleason score ≥ 8 via contemporary multi (≥ 12)-core prostate biopsy

Study Type – Prognostic (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Currently, controversy continues with regards to the efficacy of performing radical prostatectomy (RP) and the potential predictor of outcome after surgery in patients with prostate cancers of higher biopsy Gleason score. Among contemporary patients with biopsy Gleason score ≥8 who underwent RP alone, patients with pathologically organ‐confined disease demonstrated significantly better biochemical outcome than others. Serum PSA level and maximum tumour length in a biopsy core, independent predictors of organ‐confined disease, would be useful in the selection of candidates for RP among patients presenting with biopsy Gleason score ≥8.

OBJECTIVE

• ? To investigate the outcome of patients who underwent radical prostatectomy (RP) for prostate cancer of biopsy Gleason score ≥ 8 diagnosed via contemporary prostate biopsy.

PATIENTS AND METHODS

• ? We reviewed records of 151 patients who underwent RP for prostate cancer of biopsy Gleason score ≥ 8 detected via multi (≥12)‐core prostate biopsy without any neoadjuvant or adjuvant treatment.
• ? Preoperative predictors of pathologically organ‐confined disease along with biochemical recurrence‐free survival were analyzed via multivariate logistic regression and Cox proportional hazards model.

RESULTS

• ? For 151 total subjects, 5‐year estimated biochemical recurrence‐free survival rate was 41.0%. Patients with pathologically organ‐confined disease were observed to have much higher 5‐year biochemical recurrence‐free survival rate than those otherwise (72.1 vs 31.5%, P < 0.001).
• ? Serum PSA level (P= 0.031) and maximum tumour length in a biopsy core (P= 0.005) were observed to be significant preoperative predictors of having pathologically organ‐confined disease.
• ? As for biochemical recurrence‐free survival following RP, serum PSA (P= 0.023), biopsy Gleason score (P= 0.032), and percent of total tumour length in biopsy cores (P < 0.001) were observed be significant preoperative predictors on multivariate analysis.

CONCLUSION

• ? Among contemporary patients with biopsy Gleason score ≥ 8 who underwent RP alone, patients with pathologically organ‐confined disease demonstrated significantly better biochemical outcome than others. Serum PSA level and maximum tumour length in a biopsy core, independent predictors of organ‐confined disease, would be useful in the selection of candidates for RP among patients presenting with biopsy Gleason score ≥ 8.