Active Surveillance for Men Younger than 60 Years or with Intermediate-risk Localized Prostate Cancer. Descriptive Analyses of Clinical Practice in the Movember GAP3 Initiative.

Background: Active surveillance (AS) is a management option for men diagnosed with low-risk prostate cancer. Opinions differ on whether it is safe to include young men (≤60 yr) or men with intermediate-risk disease. Objective: To assess whether reasons for discontinuation, treatment choice after AS, and adverse pathology at radical prostatectomy (RP; N1, or ≥GG3, or ≥pT3) differ for men ≤60 yr or those with European Association of Urology (EAU) intermediate-risk disease from those for men >60 yr or those with EAU low-risk disease. Design setting and participants: We analyzed data from 5411 men ≤60 yr and 14 959 men >60 yr, 14 064 men with low-risk cancer, and 2441 men with intermediate-risk cancer, originating from the GAP3 database (21 169 patients/27 cohorts worldwide). Outcome measurements and statistical analysis: Cumulative incidence curves were used to estimate the rates of AS discontinuation and treatment choice. Results and limitations: The probability of discontinuation of AS due to disease progression at 5 yr was similar for men aged ≤60 yr (22%) and those >60 yr (25%), as well as those of any age with low-risk disease (24%) versus those with intermediate-risk disease (24%). Men with intermediate-risk disease are more prone to discontinue AS without evidence of progression than men with low-risk disease (at 1/5 yr: 5.9%/14.2% vs 2.0%/8.8%). Adverse pathology at RP was observed in 32% of men ≤60 yr compared with 36% of men >60 yr (p = 0.029), and in 34% with low-risk disease compared with 40% with intermediate-risk disease (p = 0.048). Conclusions: Our descriptive analysis of AS practices worldwide showed that the risk of progression during AS is similar across the age and risk groups studied. The proportion of adverse pathology was higher among men >60 yr than among men ≤60 yr. These results suggest that men ≤60 yr and those with EAU intermediate-risk disease should not be excluded from opting for AS as initial management. Patient summary: Data from 27 international centers reflecting daily clinical practice suggest that younger men or men with intermediate-risk prostate cancer do not hold greater risk for disease progression during active surveillance.

After ASCENDE-RT: Biochemical and survival outcomes following combined external beam radiotherapy and low-dose-rate brachytherapy for high-risk and unfavourable intermediate-risk prostate cancer, a population-based analysis.

PURPOSE: To evaluate the outcomes of unfavorable intermediate-risk (UIR) and high-risk (HR) prostate cancer patients treated with combined external beam radiation therapy (EBRT) and low-dose-rate prostate brachytherapy (LDR-PB). METHODS AND MATERIALS: A population-based cohort of 568 prostate cancer patients treated with combined EBRT and LDR-PB from 2010 to 2016 was analyzed. All patients received EBRT followed by LDR-PB boost. Outcomes were compared with the results for the brachytherapy arm of the ASCENDE-RT trial. RESULTS: The median followup was 4.5 years. Sixty-nine percent (N = 391) had HR disease. Ninety-four percent of the HR and 57% of UIR were treated with androgen deprivation therapy (ADT) with a median duration of 12 months. The 5-year K-M biochemical progression-free survival (b-PFS), metastasis-free survival (MFS), and overall survival (OS) were 84 ± 2%, 90 ± 2%, and 88 ± 2%, similar to 89 ± 5%, 94 ± 4%, and 92 ± 4% for the ASCENDE-RT LDR-PB arm. The likelihood of achieving a PSA ≤0.2 ng/mL at 4 years was 88%, similar to 86% in the ASCENDE-RT LDR-PB arm. Thirty-three men (5.8%) would have been ineligible for ASCENDE-RT due to high-risk features. The 5-year K-M b-PFS, MFS and OS estimates were 86 ± 2%, 92 ± 1% and 89 ± 2% for the ASCENDE-RT eligible versus 56 ± 10% (p < 0.001), 73 ± 8% (p < 0.001), and 77 ± 9% (p = 0.098) for the ineligible patients. CONCLUSIONS: In this population-based cohort, combining LDR-PB with pelvic EBRT (+/- ADT) achieves very favorable b-PFS that compares to the LDR-PB arm of the ASCENDE-RT, supporting the generalizability of those results. Men ineligible for ASCENDE-RT, based on prognostic features, have a much higher risk of biochemical recurrence and metastatic relapse.

Small cell carcinoma of the bladder: A population-based analysis of long-term outcomes after radical cystectomy and bladder conservation with chemoradiotherapy.

INTRODUCTION: We aimed to describe the oncological outcomes after radical cystectomy and chemo-radiation for localized small cell bladder cancer (SCBC). METHODS: This population-based analysis of localized SCBC from 1985-2018 in British Columbia included an analysis (analysis 1) of cancer-specific survival (CSS) and overall survival (OS) of patients treated with curative-intent radical cystectomy (RC) and radiation (RT), and an analysis (analysis 2) of CSS and OS in patients treated with RC and chemoRT consistent with the SCBC Canadian consensus guideline. RESULTS: Seventy-seven patients who were treated with curative intent were identified: 33 patients had RC and 44 had RT. For analysis 1, five-year OS was 29% and 39% for RC and RT, respectively (p=0.51), and five-year CSS was 35% and 52% for RC and RT, respectively (p=0.29). On multivariable analysis, higher Charlson comorbidity index (CCI) and the lack of neoadjuvant chemotherapy (NAC) were associated with worse OS, while higher CCI and Eastern Cooperative Oncology Group (ECOG) were associated with worse CSS. For analysis 2, five-year OS was 56% and 58% for the RC and chemoRT groups, respectively (p=0.90), and five-year CSS was 56% for RC and 71% for chemoRT (p=0.71). Four of 42 (9.5%) chemoRT patients had RC at relapse. CONCLUSIONS: SCBC is a rare entity with a poor prognosis. RC and chemoRT offer similar CSS and OS for localized SCBC, even when focusing the analysis on patients treated according to the modern consensus guidelines. NAC should be considered for eligible patients. Both chemoRT and RC treatment options should be discussed with patients with SCBC.

Outcome of limited-stage nodular lymphocyte-predominant Hodgkin lymphoma and the impact of a PET-adapted approach.

Radiotherapy (RT) is typically incorporated into the treatment of limited-stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), although it remains unknown whether chemotherapy alone may be suitable in select patients. We evaluated outcomes of limited-stage NLPHL at BC Cancer on the basis of era-specific guidelines: routine RT era, 1995 to 2005 (n = 36), combined modality with 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by RT or RT alone; positron emission tomography (PET) era, after 2005 (n = 63), ABVD alone (4 cycles) if the PET scan after the second cycle of ABVD (PET2) is negative, or treatment is changed to RT if PET2 is positive. Median age of patients was 38 years (range, 16-82 years), 73% were male, and 43% had stage II. With a median follow-up of 10.5 years for all patients, 5-year progression-free survival (PFS) was 91% [corrected] and was 97% for overall survival (OS), with no difference by treatment era (PFS, P = .15; [corrected] OS, P = .35). For the 49 patients who had a PET2 scan, 86% were PET negative and 14% were PET positive by Deauville criteria with 5-year PFS rates of 92% and 80% (P = .87) [corrected], respectively. This is the largest study of a PET-adapted approach in NLPHL and supports that ABVD alone may be a viable option in select patients with a negative PET2 scan, with consideration of acute and long-term toxicities.

Long-term results of PET-guided radiation in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP.

Consolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) remains controversial, with routine practice continuing to include RT in patients with initial bulky disease or residual masses. Positron emission tomography (PET)-computed tomography is a sensitive modality for detecting the presence of residual disease at the end of treatment (EOT). A PET-guided approach to selectively administering RT has been the policy in British Columbia since 2005. Patients with advanced-stage DLBCL diagnosed from 1 January 2005 to 1 March 2017 and treated with at least 6 cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab), who underwent EOT PET, were included in this analysis. Those with complete metabolic response (PET-negative [PET-NEG]) were observed; those with PET-positive (PET-POS) scans were offered consolidative RT, when feasible. Of the patient records reviewed, 723 were identified, with median follow-up of 4.3 years: 517 (72%) were PET-NEG; 206 (28%) were PET-POS. Time to progression (TTP) and overall survival (OS) at 3 years were 83% vs 56% and 87% vs 64%, in patients with PET-NEG and PET-POS scans, respectively. PET-POS patients with nonprogressing disease treated with consolidative RT (109 and 206; 53%) had outcomes approaching those of PET-NEG patients, with 3-year estimates of 76% and 80% for TTP and OS. PET-NEG patients who had bulky disease (≥10 cm) at diagnosis had outcomes indistinguishable from those without bulk, despite the omission of RT. These data suggest that patients with advanced-stage DLBCL who are PET-NEG at EOT and receive no RT have excellent outcomes. 18F-fluorodeoxyglucose-PET can reliably guide selective administration of consolidative RT, even in patients with initially bulky disease.

Efficacy of Palliative Radiation Therapy (RT) for Chemotherapy Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Population-Based Retrospective Review.

PURPOSE: The study objective was to investigate the effectiveness of palliative radiation therapy (RT) for patients with diffuse large B-cell lymphoma (DLBCL) and to identify factors, such as chemotherapy relapsed/refractory (R/R) disease, that may influence RT outcomes. METHODS AND MATERIALS: Patients with DLBCL who received palliative RT from 2001 to 2015 in British Columbia were reviewed for patient characteristics, treatment details, and outcomes. Univariable and multivariable analyses for response and local progression were performed. RESULTS: Three-hundred and seventy courses of palliative RT in 217 patients were identified. Median equivalent dose in 2 Gy fractions was 19 Gy (range, 2-42 Gy). Clinical and/or radiologic response occurred in 230 (83%) of the 276 courses with response data available. Local control following palliative RT at 6 months was 66.7%. On univariable analysis, R/R disease was not associated with lower clinical response rates but had higher risk of progression (hazard ratio [HR], 0.5; P = .040). On multivariable analyses, patients with R/R disease who did not require concurrent steroids had greater response compared with those who received upfront palliative RT (odds ratio, 3.5; P = .011). Response to first-line chemotherapy and smaller lesion size were associated with improved local progression rates (HR, 0.2; P < .001 and HR, 0.5; P = .020, respectively). RT dose fractionation factors were not significant on any analyses. CONCLUSIONS: Palliative RT for DLBCL is effective for symptom improvement, including in the chemotherapy R/R setting. Not requiring concurrent steroids, response to first-line chemotherapy, and smaller lesion size predicted better RT outcomes. There was no association between dose fractionation and response rates or local control to suggest that higher RT doses are more effective for palliation.

Current topics in radiotherapy for genitourinary cancers: Consensus statements of the Genitourinary Radiation Oncologists of Canada.

INTRODUCTION: The biennial meeting of the Genitourinary Radiation Oncologists of Canada (GUROC) took place November 22-23, 2019. A consensus-building session was held during the meeting addressing topics of emerging interest or controversy in the management of genitourinary malignancies. METHODS: Draft statements were debated among all meeting attendees in an open forum with anonymous live voting. Statements for which there was at least 75% agreement among attendees were adopted as GUROC consensus. RESULTS: Four evidence-based consensus statements were developed. First, the use of prostate radiotherapy is recommended in the setting of de novo low-volume metastatic hormone-sensitive prostate cancer to improve overall survival. Second, the support of ongoing randomized trials evaluating metastasis-directed ablative local therapy in oligometastatic prostate cancer is recommended; where such trials are available, off-trial use of oligometastasis-directed ablative radiotherapy at this time is strongly discouraged. Third, routine use of prostate-rectal hydrogel spacer devices in patients with localized prostate cancer planned to receive external beam radiotherapy is not recommended; instead, selective use in patients at highest risk of rectal toxicity may be considered. Finally, multidisciplinary consultation is recommended for all patients with newly diagnosed localized muscle-invasive bladder cancer. CONCLUSIONS: The GUROC consensus statements provide practical guidance to clinicians in areas of current controversy in the management of prostate and bladder cancer, and it is hoped that their implementation will contribute to improved outcomes in real-world practice and greater support of clinical trials.

Prostate brachytherapy intraoperative dosimetry using a combination of radiographic seed localization with a C-arm and deformed ultrasound prostate contours.

PURPOSE: The purpose of the study was to assess the feasibility of performing intraoperative dosimetry for permanent prostate brachytherapy by combining transrectal ultrasound (TRUS) and fluoroscopy/cone beam CT [CBCT] images and accounting for the effect of prostate deformation. METHODS AND MATERIALS: 13 patients underwent TRUS and multiview two-dimensional fluoroscopic imaging partway through the implant, as well as repeat fluoroscopic imaging with the TRUS probe inserted and retracted, and finally three-dimensional CBCT imaging at the end of the implant. The locations of all the implanted seeds were obtained from the fluoroscopy/CBCT images and were registered to prostate contours delineated on the TRUS images based on a common subset of seeds identified on both image sets. Prostate contours were also deformed, using a finite-element model, to take into account the effect of the TRUS probe pressure. Prostate dosimetry parameters were obtained for fluoroscopic and CBCT-dosimetry approaches and compared with the standard-of-care Day-0 postimplant CT dosimetry. RESULTS: High linear correlation (R2 > 0.8) was observed in the measured values of prostate D90%, V100%, and V150%, between the two intraoperative dosimetry approaches. The prostate D90% and V100% obtained from intraoperative dosimetry methods were in agreement with the postimplant CT dosimetry. Only the prostate V150% was on average 4.1% (p-value <0.05) higher in the CBCT-dosimetry approach and 6.7% (p-value <0.05) higher in postimplant CT dosimetry compared with the fluoroscopic dosimetry approach. Deformation of the prostate by the ultrasound probe appeared to have a minimal effect on prostate dosimetry. CONCLUSIONS: The results of this study have shown that both of the proposed dosimetric evaluation approaches have potential for real-time intraoperative dosimetry.

Outcome of primary mediastinal large B-cell lymphoma using R-CHOP: impact of a PET-adapted approach.

Cure rates for primary mediastinal large B-cell lymphoma (PMBCL) have improved with the integration of rituximab. However, the type of primary therapy and role of radiotherapy (RT) remains ill-defined. Herein, we evaluated the outcome of PMBCL primarily treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and the impact of an end-of-treatment (EOT) 18F-fluorodeoxyglucose positron emission tomography (PET) scan to guide consolidative RT. Patients ≥18 years of age with PMBCL treated with curative intent rituximab-chemotherapy were identified. Prior to 2005, patients were recommended to receive R-CHOP + RT (RT era). Beginning in 2005, EOT PET was used to guide RT and only those with a PET-positive scan received RT (PET era). In total, 159 patients were identified, 94% were treated with R-CHOP and 44% received RT (78% in RT era, 28% in PET era). The 5-year time to progression (TTP) and overall survival (OS) for the entire cohort were 80% and 89%, respectively, similar across treatment eras. Overall, 10% had refractory disease. In total, 113 patients had an EOT PET scan: 63% negative and 37% positive with a 5-year TTP of 90% vs 71% and 5-year OS of 97% vs 88%, respectively. For those with Deauville (D)-scored PET scans (n = 103), the 5-year TTP for PET-negative cases by Deauville criteria (D1-D3, DX) was 91%, with inferior outcomes for D5 vs D4 (5-year TTP 33% vs 87%, P = .0002). Outcomes for PMBCL treated with RCHOP are favorable and use of a PET-adapted approach reduces RT in the majority of patients. A small proportion have refractory disease and may benefit from an alternate treatment.

Testosterone Breakthrough Rates during Androgen Deprivation Therapy for Castration Sensitive Prostate Cancer.

PURPOSE: Androgen deprivation therapy is an established therapy for castration sensitive prostate cancer and recent studies have observed that patients whose testosterone levels are suppressed below 0.7 nmol/l have improved outcomes. Testosterone breakthrough, or a rise in testosterone above a target threshold after the first month of androgen deprivation therapy, is generally associated with treatment deficiency. The purpose of this review is to summarize breakthrough rate data and explore the relationship to clinical outcomes in patients with castration sensitive prostate cancer receiving androgen deprivation therapy. MATERIALS AND METHODS: Our systematic search identified 45 studies with a total of 52 cohorts representing 6,047 total patients reporting testosterone breakthrough rates or derivative measures above the thresholds of 1.7 nmol/l (51 cohorts, 6,015 patients) or 0.7 nmol/l (15 cohorts, 2,495 patients). RESULTS: Significantly higher weighted mean breakthrough rates were seen for the 0.7 nmol/l threshold compared to 1.7 nmol/l (41.3% vs 6.9%, p <0.0001). A significant association between breakthrough rates and worse clinical outcomes overall was not found, although when larger trials (sample size greater than 100) and higher event rates (greater than 50%) were considered for the lowest threshold, significant associations between breakthrough rates and clinical outcomes were observed. Clinical factors such as administration and monitoring frequency, type of testosterone assay and type of androgen deprivation therapy did not significantly affect breakthrough rates, although nonvalidated assays were associated with a large degree of variability. CONCLUSIONS: Results from our analysis indicate that testosterone breakthroughs likely result in worse clinical outcomes and should be avoided. Moreover, there is a need to standardize assessment of testosterone levels both clinically and in the research context to better inform treatment decisions and improve the reliability and comparability of results across studies.

Consistent Biopsy Quality and Gleason Grading Within the Global Active Surveillance Global Action Plan 3 Initiative: A Prerequisite for Future Studies.

Within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative, 25 centers across the globe collaborate to standardize active surveillance (AS) protocols for men with low-risk prostate cancer (PCa). A centralized PCa AS database, comprising data of more than 15000 patients worldwide, was created. Comparability of the histopathology between the different cohorts was assessed by a centralized pathology review of 445 biopsies from 15 GAP3 centers. Grade group 1 (Gleason score 6) in 85% and grade group ≥2 (Gleason score ≥7) in 15% showed 89% concordance at review with moderate agreement (κ=0.56). Average biopsy core length was similar among the analyzed cohorts. Recently established highly adverse pathologies, including cribriform and/or intraductal carcinoma, were observed in 3.6% of the reviewed biopsies. In conclusion, the centralized pathology review of 445 biopsies revealed comparable histopathology among the 15 GAP3 centers with a low frequency of high-risk features. This enables further data analyses-without correction-toward uniform global AS guidelines for men with low-risk PCa. PATIENT SUMMARY: Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative combines data from 15000 men with low-risk prostate cancer (PCa) across the globe to standardize active surveillance protocols. Histopathology review confirmed that the histopathology was consistent with low-risk PCa in most men and comparable between different centers.

A Population-Based Study of Palliative Radiation Therapy for Bone Metastases in Patients Dying of Prostate Cancer.

PURPOSE: Increasing the survival of patients with metastatic prostate cancer (PCa) may affect the demand for palliative radiation to bone (PRTB). Our aim was to characterize the use of PRTB in patients who died of PCa in British Columbia between 2003 and 2015. METHODS AND MATERIALS: All patients with a diagnosis of PCa who died during the study period (n = 23,260) were identified from a population-based provincial registry. Patient and treatment characteristics were analyzed. PRTB utilization rate was calculated by year and location. Survival was calculated from the first and the last course of PRTB. RESULTS: A total of 5701 patients died of PCa, with a median survival from diagnosis of 5.2 years. The overall PRTB utilization rate was 38.6%, with an increasing trend over time. Multiple courses of PRTB were frequent, with 51% of patients receiving ≥2 courses of PRTB. Of the patients who died of PCa (15.2% of the PRTB cohort), 5.4% received PRTB within the last 4 weeks of life, 60% of whom received multiple fractions. Rural areas had a lower referral rate and lower use of PRTB. Patients with longer survival tended to receive multiple courses of treatment. The median survival after the first course of PRTB increased from 8.2 months in 2003 to 2004 to 9.4 months in 2013 to 2014 (P = .04). CONCLUSIONS: PRTB is only used in a minority of patients dying of PCa. The majority who die of PCa after PRTB do so within a year of their first course. The use of multifractionation was common in the last 4 weeks of life. Survival after first PRTB increased minimally over time, and additional research is required to identify its association with recent changes in practice. The referral rate and PRTB utilization rate differ between rural and nonrural locations, underlying the importance of accessibility and referral for utilization of PRTB. Investigating other barriers and ensuring equitable access to radiation are needed.

Using a surgical prostate-specific antigen threshold of >0.2 ng/mL to define biochemical failure for intermediate- and high-risk prostate cancer patients treated with definitive radiation therapy in the ASCENDE-RT randomized control trial.

PURPOSE: To compare biochemical failure using a prostate-specific antigen (PSA) threshold of >0.2 ng/mL to that using Phoenix threshold (nadir+2 ng/mL). METHODS AND MATERIALS: Androgen suppression combined with elective nodal and dose-escalated radiation therapy (the ASCENDE-RT trial) is a randomized control trial in which 276 high-risk and 122 intermediate-risk patients were randomized to (1) a standard arm with 12 months of androgen deprivation therapy, pelvic external beam radiation therapy (EBRT) to 46 Gy, and an EBRT boost (dose-escalated EBRT [DE-EBRT]) to 78 Gy, or (2) an experimental arm which substituted a low-dose-rate prostate brachytherapy boost (LDR-PB). The primary endpoint was biochemical progression-free survival (b-PFS) using the Phoenix threshold. In this reanalysis of ASCENDE-RT, the b-PFS using phoenix is compared to the surgical PSA threshold of >0.2 ng/mL. RESULTS: Compared to nadir+2 ng/mL, the >0.2 ng/mL PSA threshold doubled the number of relapse events from 69 to 139. However, the increase was confined to the DE-EBRT subjects. The 7-year Kaplan-Meier b-PFS after DE-EBRT declined from 76% using nadir+2 ng/mL to 38% using the >0.2 ng/mL threshold (p < 0.001). Among the LDR-PB subset, there was no significant difference in b-PFS; the 7-year Kaplan-Meier b-PFS was 85% (>0.2 ng/mL) versus 88% (nadir+2 ng/mL) (p = 0.319). CONCLUSIONS: Replacing Phoenix with a surgical threshold greatly increased biochemical failure after DE-EBRT boost but had no effect after LDR-PB. As a result of this finding, PSA outcomes after surgery or brachytherapy can be directly compared by using the surgical definition of PSA failure. In this context, a brachytherapy boost appears to produce superior b-PFS compared to contemporary surgical series.

Testosterone suppression in the treatment of recurrent or metastatic prostate cancer - A Canadian consensus statement.

Testosterone suppression, achieved through orchiectomy or medically induced androgen-deprivation therapy (ADT), is a standard treatment for men with recurrent and metastatic prostate cancer. Current assay methods demonstrate the capacity for testosterone suppression to <0.7 nmol/l, and clinical data support improved outcomes from ADT when lower levels are achieved. Practical clinical guidelines are warranted to facilitate adoption of 0.7 nmol/l as the new standard castrate testosterone level.A pan-Canadian group of experts, representing diverse clinical specialties, identified key clinical issues, searched and reviewed relevant literature, and developed consensus statements on testosterone suppression for the treatment of prostate cancer. The expert panel found that current evidence supports the clinical benefit of achieving low testosterone levels during ADT, and encourage adoption of ≤0.7 nmol/l as a new castrate level threshold. The panel recommends regular monitoring of testosterone (e.g., every 3-6 months) and prostate-specific antigen (PSA) levels as clinically appropriate (e.g., every 3-6 months) during ADT, with reassessment of therapeutic strategy if testosterone is not suppressed or if PSA rises regardless of adequate testosterone suppression. The panel also emphasizes the need for greater awareness and education regarding testosterone assay specifications, and strongly promotes the use of mass spectrometry-based assays to ensure accurate measurement of testosterone at castrate levels.

Can active surveillance really reduce the harms of overdiagnosing prostate cancer? A reflection of real life clinical practice in the PRIAS study.

BACKGROUND: Active surveillance (AS) for low-risk prostate cancer (PCa) appears to provide excellent long-term PCa-specific and overall survival. The choice for AS as initial treatment is mainly based on avoiding side effects from invasive treatment; but AS entails regular check-ups and the possibility of still having to switch or deciding to switch to invasive treatment. Here, we assessed the long-term follow-up data from AS in real life clinical practices. METHODS: Data from the first 500 men, enrolled in PRIAS before July 2008 by 30 centers across 8 countries, were analyzed to provide long-term follow-up results. Men were advised to be regularly examined with prostate-specific antigen (PSA) tests, digital rectal examinations, and prostate biopsies. Men were advised to switch to invasive treatment if they had disease reclassification [Gleason score (GS) ≥3+4 on biopsy, more than two positive biopsy cores, a stage higher than cT2] or a PSA-doubling time of 0-3 years. We assessed time on AS, outcomes and reasons for discontinuing AS, and rates of potential unnecessary biopsies and treatments. RESULTS: The median follow-up time was 6.5 years. During this period, 325 (65%) men discontinued after a median of 2.3 years and 121 (24%) men had no recent (>1 year) data-update after a median of 7.3 years. The remaining 54 (11%) men were confirmed to be still on AS. Most men discontinued based on protocol advice; 38% had other reasons. During follow-up, 838 biopsy sessions were performed of which 79% to 90% did not lead to reclassification, depending on the criteria. Of the 325 discontinued men, 112 subsequently underwent radical prostatectomy (RP), 126 underwent radiotherapy, 57 switched to watchful waiting (WW) or died, and 30 had another or unknown treatment. RP results were available of 99 men: 34% to 68%, depending on definition, had favorable outcomes; 50% of unfavorable the outcomes occurred in the first 2 years. Of the 30 (6%) men who died, 1 man died due to PCa. CONCLUSIONS: These data, reflecting real life clinical practice, show that more than half of men switched to invasive treatment within 2.3 years, indicating limitations to the extent in which AS is able to reduce the adverse effects of overdiagnosis. Therefore, despite guidelines stating that PCa diagnosis must be uncoupled from treatment, it remains important to avoid overdiagnosing PCa as much as possible.