These guidelines cover a wide range of topics from prostate cancer epidemiology to palliative care. Questions arising in daily clinical practice have been extracted and formulated as clinical ...questions. In the 4 years since the previous edition, there have been major changes – for example, robot‐assisted prostatectomy has rapidly come into widespread use, and new hormones and anticancer drugs have been developed for castration‐resistant prostate cancer. In response to these developments, the number of fields included in this guideline was increased from 11 in the 2012 edition to 16, and the number of clinical questions was increased from 63 to 70. The number of papers identified in searches of the existing literature increased from 4662 in the first edition, published in 2006, to 10 490 in the 2012 edition. The number of references has reached 29 448 just during this review period, indicating the exponential increase in research on the topic of prostate cancer. Clinical answers have been prepared based on the latest evidence. Recommendation grades for the clinical answers were determined by radiologists, pathologists, and other specialists in addition to urologists in order to reflect the recent advances and diversity of prostate cancer treatment. Here, we present a short English version of the original guideline, and overview its key clinical issues.
Abstract Background The Prostate Cancer Research International Active Surveillance (PRIAS) study was initiated a decade ago to study the most optimal selection and follow-up of men on active ...surveillance (AS). Objective We report on 10 yr of follow-up of men on AS in the PRIAS study and evaluate if criteria used to recommend a switch to active treatment truly predict unfavorable outcome on subsequent radical prostatectomy (RP). Design, setting, and participants Men with low-risk prostate cancer were included and followed prospectively on AS. Follow-up consisted of regular prostate-specific antigen (PSA) tests, digital rectal examinations, and biopsies. Men with Gleason >3 + 3, more than two positive biopsy cores, or stage higher than cT2 were advised to switch to active treatment (until 2014, a PSA doubling time PSA DT of 0–3 yr was also used). Outcome measurements and statistical analysis Reclassification rates, treatment after discontinuation, and outcome on RP after discontinuing AS were reported. Regression analysis on the outcome of RP was used to evaluate the predictive value of criteria currently used to recommend a switch to active treatment. Kaplan-Meier and competing risk analysis were used to report discontinuation rates over time and long-term oncologic end points. Results and limitations A total of 5302 men were included in PRIAS across 18 countries. Reclassification rates remained stable on all subsequent biopsies, with 22–33% of men having either Gleason >3 + 3 or more than two positive cores on any repeat biopsy. At 5 and 10 yr of follow-up, 52% and 73% of men, respectively, had discontinued AS, most of them because of protocol-based reclassification. A third of men undergoing subsequent RP had favorable pathologic tumor features (Gleason 3 + 3 and pT2). Of the criteria used to recommend a switch to active treatment, more than two positive cores and a PSA DT of 0–3 yr were not predictive of unfavorable pathologic outcome on RP. Conclusions A substantial group of men discontinued AS without subsequent unfavorable tumor features on RP; therefore, we propose Gleason upgrading and cT3 as the only indicators for an immediate switch to active treatment. Surrogate indicators (eg, more than two positive cores and a fast-rising PSA) should not trigger immediate active treatment but rather further investigation to confirm the suspicion of higher risk disease. Patient summary We confirmed the safety of active surveillance as a treatment option for men with low-risk prostate cancer; however, some changes could be made to the follow-up protocol to safely increase the number of men who remain on active surveillance.
Abstract Context Active surveillance (AS) is an important strategy to reduce prostate cancer overtreatment. However, the optimal criteria for eligibility and predictors of progression while on AS are ...debated. Objective To review primary data on markers, genetic factors, and risk stratification for patient selection and predictors of progression during AS. Evidence acquisition Electronic searches were conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 2014 for original articles on biomarkers and risk stratification for AS. Evidence synthesis Patient factors associated with AS outcomes in some studies include age, race, and family history. Multiple studies provide consistent evidence that a lower percentage of free prostate-specific antigen (PSA), a higher Prostate Health Index (PHI), a higher PSA density (PSAD), and greater biopsy core involvement at baseline predict a greater risk of progression. During follow-up, serial measurements of PHI and PSAD, as well as repeat biopsy results, predict later biopsy progression. While some studies have suggested a univariate relationship between urinary prostate cancer antigen 3 (PCA3) and transmembrane protease, serine 2 – v-ets avian erythroblastosis virus E26 oncogene homolog gene fusion ( TMPRSS2 : ERG ) with adverse biopsy features, these markers have not been consistently shown to independently predict AS outcomes. No conclusive data support the use of genetic tests in AS. Limitations of these studies include heterogeneous definitions of progression and limited follow-up. Conclusions There is a growing body of literature on patient characteristics, biopsy features, and biomarkers with potential utility in AS. More data are needed on practical applications such as combining these tests into multivariable clinical algorithms and long-term outcomes to further improve AS in the future. Patient summary Several PSA–based tests (free PSA, PHI, PSAD) and the extent of cancer on biopsy can help to stratify the risk of progression during active surveillance. Investigation of several other markers is under way.
Abstract Background Overdiagnosis and subsequent overtreatment are important side effects of screening for, and early detection of, prostate cancer (PCa). Active surveillance (AS) is of growing ...interest as an alternative to radical treatment of low-risk PCa. Objective To update our experience in the largest worldwide prospective AS cohort. Design, setting, and participants Eligible patients had clinical stage T1/T2 PCa, prostate-specific antigen (PSA) ≤10 ng/ml, PSA density <0.2 ng/ml per milliliter, one or two positive biopsy cores, and Gleason score ≤6. PSA was measured every 3–6 mo, and volume-based repeat biopsies were scheduled after 1, 4, and 7 yr. Reclassification was defined as more than two positive cores or Gleason >6 at repeat biopsy. Recommendation for treatment was triggered in case of PSA doubling time <3 yr or reclassification. Outcome measurements and statistical analysis Multivariate regression analysis was used to evaluate predictors for reclassification at repeat biopsy. Active therapy–free survival (ATFS) was assessed with a Kaplan-Meier analysis, and Cox regression was used to evaluate the association of clinical characteristics with active therapy over time. Results and limitations In total, 2494 patients were included and followed for a median of 1.6 yr. One or more repeat biopsies were performed in 1480 men, of whom 415 men (28%) showed reclassification. Compliance with the first repeat biopsy was estimated to be 81%. During follow-up, 527 patients (21.1%) underwent active therapy. ATFS at 2 yr was 77.3%. The strongest predictors for reclassification and switching to deferred treatment were the number of positive cores (two cores compared with one core) and PSA density. The disease-specific survival rate was 100%. Follow-up was too short to draw definitive conclusions about the safety of AS. Conclusions Our short-term data support AS as a feasible strategy to reduce overtreatment. Clinical characteristics and PSA kinetics during follow-up can be used for risk stratification. Strict monitoring is even more essential in men with high-risk features to enable timely recognition of potentially aggressive disease and offer curative intervention. Limitations of using surrogate end points and markers in AS should be recognized. Trial registration The current program is registered at the Dutch Trial Register with ID NTR1718 ( http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1718 ).
Abstract
Objectives
This study was conducted to evaluate the effect of low-dose chlormadinone acetate, an antiandrogen agent, on the persistence rate of active surveillance in patients with low-risk ...prostate cancer.
Methods
The study was a multicenter, placebo-controlled, double-blind, randomized controlled trial conducted at 38 sites in Japan. Low-risk prostate cancer patients were randomly assigned to the chlormadinone group or the placebo group and the persistence rate of active surveillance was evaluated for 3 years.
Results
Seventy-one patients in the chlormadinone group and 72 patients in the placebo group were analyzed. The persistence rate of active surveillance 95% CI at 3 years was 75.5% 62.5–84.6 in the chlormadinone group and 50.1% 36.7–62.2 in the placebo group, showing a significant difference between the groups (P = 0.0039). The hazard ratio 95% CI of the chlormadinone group to the placebo group for discontinuation of active surveillance was 0.417 0.226–0.770. The chlormadinone group showed a significant decrease in prostate specific antigen level, testosterone level and prostate volume. The number of positive cores at 12 and 36 months biopsy was significantly lower in the chlormadinone group. The incidence of adverse events was 43.7% in the chlormadinone group and 12.5% in the placebo group. The most common adverse event in the chlormadinone group was constipation in 22.5%, followed by hepatobiliary disorders in 9.9%.
Conclusions
In patients with low-risk prostate cancer, low-dose chlormadinone showed a reduced number of positive cores and prostate volume, and an increased persistence rate of active surveillance (UMIN000012284).
Data from patients with low-risk prostate cancer, chlormadinone, an antiandrogenic agent showed a reduced number of positive cores and prostate volume, and an increased persistence rate of active surveillance.
Objective: To assess the morbidity secondary to ultrasound‐guided systematic prostate biopsy in Japan.
Methods: Five hundred and forty‐eight principal urological training institutions certified by ...the Japanese Urological Association participated in the survey. A retrospective analysis of complications after prostate biopsy was conducted.
Results: Medical records of 212 065 procedures carried out between 2004 and 2006 were reviewed. Seventy‐six percent of procedures had been carried out transrectally, and 23% transperineally. Hematuria, rectal bleeding and hematospermia occurred in 12%, 5.9% and 1.2% of cases, respectively. Voiding symptoms were reported after biopsy in 1.9% of cases and urinary retention in 1.1%. Fever (>38°C) was observed in 1.1% and sepsis occurred in 0.07%. Hospitalization was required in 0.69% of cases for the treatment of biopsy‐related complications.
Conclusions: Overall, contemporary ultrasound‐guided systematic prostate biopsy is safely carried out in Japan. However, minor complications are not infrequent, whereas major ones remain very rare but life‐threatening if they occur. Thus, adequate information should be provided to patients undergoing prostate biopsy.
Background
Based on results from Japanese post-marketing surveillance, exploratory analyses were performed to investigate real-world outcomes of radium-223 for metastatic CRPC (mCRPC) according to ...patient characteristics.
Methods
This non-interventional, prospective study enrolled mCRPC patients selected for radium-223 treatment in clinical practice. Six-month safety and effectiveness were evaluated in subgroups who had/had not received prior chemotherapy (prior-chemo/no prior-chemo groups), and a subgroup who had not received concomitant androgen-receptor axis-targeted agents (ARATs).
Results
In the overall population (
n
= 296), the prior-chemo group (
n
= 126) tended to have more bone metastases, more analgesic use, and higher prostate-specific antigen values than the no prior-chemo group (
n
= 170). Incidences of treatment-emergent adverse events (TEAEs), drug-related TEAEs, and ≥ grade 3 drug-related hematological TEAEs were 47% vs. 53%, 25% vs. 29%, and 4% vs. 7% in the no prior-chemo and prior-chemo groups, respectively. Incidences of TEAEs (61%), drug-related TEAEs (36%), and ≥ grade 3 drug-related hematological events (12%) were numerically higher in 33 patients who had received two lines of prior chemotherapy. Multivariate analysis showed that two lines of prior chemotherapy, and hemoglobin, platelet, and lactate dehydrogenase values were baseline factors significantly related to ≥ grade 2 platelet count decreased. Safety and effectiveness in patients without concomitant ARATs (
n
= 201) were similar to those in the overall population.
Conclusion
In a real-life setting, radium-223 was well tolerated irrespective of prior chemotherapy, but relatively higher incidences of TEAEs and hematotoxicities were suggested in patients with two lines of prior chemotherapy, possibly reflecting more advanced disease. Radium-223 safety and effectiveness in patients without concomitant ARATs were favorable.
RRM1-an important DNA replication/repair enzyme-is the primary molecular gemcitabine (GEM) target. High RRM1-expression associates with gemcitabine-resistance in various cancers and RRM1 inhibition ...may provide novel cancer treatment approaches. Our study elucidates how RRM1 inhibition affects cancer cell proliferation and influences gemcitabine-resistant bladder cancer cells. Of nine bladder cancer cell lines investigated, two RRM1 highly expressed cells, 253J and RT112, were selected for further experimentation. An RRM1-targeting shRNA was cloned into adenoviral vector, Ad-shRRM1. Gene and protein expression were investigated using real-time PCR and western blotting. Cell proliferation rate and chemotherapeutic sensitivity to GEM were assessed by MTT assay. A human tumor xenograft model was prepared by implanting RRM1 highly expressed tumors, derived from RT112 cells, in nude mice. Infection with Ad-shRRM1 effectively downregulated RRM1 expression, significantly inhibiting cell growth in both RRM1 highly expressed tumor cells. In vivo, Ad-shRRM1 treatment had pronounced antitumor effects against RRM1 highly expressed tumor xenografts (
< 0.05). Moreover, combination of Ad-shRRM1 and GEM inhibited cell proliferation in both cell lines significantly more than either treatment individually. Cancer gene therapy using anti-RRM1 shRNA has pronounced antitumor effects against RRM1 highly expressed tumors, and RRM1 inhibition specifically increases bladder cancer cell GEM-sensitivity. Ad-shRRM1/GEM combination therapy may offer new treatment options for patients with GEM-resistant bladder tumors.
Differentiation between lethal and non-lethal prostate cancer subtypes has become a very important issue in avoiding excessive treatment in an era when prostate-specific antigen (PSA) screening has ...reduced the rate of prostate cancer deaths by more than 20%. However, it is difficult to determine the patients who may or may not benefit from immediate treatment interventions at the time of the initial diagnosis. The selection of candidate patients who can postpone immediate treatment and undergo follow-ups with a specific surveillance program, or 'active surveillance,' is a practical way to minimize overtreatment. In this review, the benefits and risks of active surveillance are discussed. Future perspectives, including imaging and new biomarkers for improving the outcomes of active surveillance programs, are also discussed.
Purpose
Active surveillance (AS) is one potential solution to avoiding the overtreatment of favorable prostate cancer. By handling the AS strategy more safely, tumor aggressiveness may be evaluated ...more accurately. The aim of the present study was to evaluate the predictive impact of baseline prostate-specific antigen (PSA) isoform −2proPSA (p2PSA)-related indices on the pathological reclassification at 1 year during an AS program.
Methods
Between 2002 and 2003, 134 males diagnosed with low-risk prostate cancer were registered in the Japanese multicenter study cohort as candidates for AS, and 118 (88 %) males actually proceeded to AS. Of the 118 patients, the 67 that underwent protocol biopsy at 1 year after beginning AS were enrolled in the present study. The predictive significance of various baseline clinicopathological features and p2PSA-related indices on pathological reclassification at 1 year after beginning AS were investigated.
Results
The pathological reclassification rate was 37.3 %. According to the univariate analysis, prostate volume (
p
= 0.049), number of biopsy cores (
p
= 0.047), percentage of positive biopsy cores (
p
= 0.023), p2PSA to free PSA ratio (%p2PSA) (
p
= 0.003) and prostate health index (phi) (
p
= 0.010) at baseline were significantly different between the reclassification and non-reclassification groups. By multivariate logistic regression analysis, baseline %p2PSA (
p
= 0.008) and phi (
p
= 0.008) were the only independent predictive factors for pathological upgrade at 1 year after AS commencement.
Conclusions
Baseline %p2PSA and phi may predict the pathological reclassification at 1 year after starting AS, which could be due to the under detection of clinically significant prostate cancer at AS enrollment.
PDF
![The impact of baseline [−2]...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0171-5216_1432-1335/small "The impact of baseline [−2]proPSA-related indices on the prediction of pathological reclassification at 1 year during active surveillance for low-risk prostate cancer: the Japanese multicenter study cohort")