The Update of Active Surveillance Around the World: Utilization and Outcomes


Enrollment criteria

PSAD <0.15, clinical stage T1c, Gleason score ≤6, ≤2 positive cores, and ≤50% involvement of any core (preferred); or PSA <10, clinical stage ≤T2a, and Gleason score ≤6

Monitoring

PSA + DRE every 6 months; prostate biopsy every 1 year

Triggers for intervention

Failure to meet enrollment criteria



Outcomes from JHU were most recently reported in 2015 and described 1298 men of median age 66 years [2]. Median follow-up of the cohort was 5.0 years, with 650 men followed for at least 5 years and 184 men followed for at least 10 years. The cumulative incidence of definitive treatment with radical prostatectomy or radiotherapy was 50% at 10 years and 57% at 15 years. Freedom from metastasis was 99.4% at both 10 and 15 years, and prostate cancer-specific survival was 99.9% at both 10 and 15 years.



Sunnybrook Health Sciences Centre (Toronto, Ontario, Canada)


Also initiated in 1995 and first reporting outcomes in 2002 [24], the Sunnybrook experience provides a substantial volume of information regarding the longer-term outcomes of AS. In contrast to the JHU program, inclusion in AS at Sunnybrook has been more permissive. Prior to 2000, patients with Gleason score ≤3 + 4 and serum PSA ≤15 ng/ml were eligible for AS. Since 2000 those criteria have been modified to permit AS for GS ≤3 + 4 and PSA 10–20 ng/ml only in men with life expectancy less than 10 years (Table 18.2). Monitoring at Sunnybrook has consisted of PSA testing every 3–6 months, initial confirmatory biopsy within 1 year of diagnosis, and subsequent biopsies every 3–4 years. Intervention is recommended upon Gleason score upgrading, and, prior to 2008, in cases of PSA doubling time (PSADT) less than 3 years. Based on evidence that PSA kinetics are not reliable predictors of reclassification [35, 36], the program has since considered short PSADT an indicator for further evaluation rather than immediate intervention.


Table 18.2
AS protocol at Sunnybrook Health Sciences Centre















Enrollment criteria

Gleason score ≤6 and PSA ≤10 (low risk) or Gleason score ≤3 + 4 and PSA ≤20 if life expectancy ≤10 years (intermediate risk)

Monitoring

PSA every 3–6 months; biopsy within 1 year then every 3–4 years

Triggers for intervention

Gleason score upgrading; prior to 2008, also included PSADT <3 years

Last reported in 2015, outcomes from Sunnybrook are based on 993 men with a median follow-up of 6.4 years; 206 men were followed for more than 10 years and 50 men for more than 15 years [3]. Notably, 21% of the cohort had intermediate-risk cancer, including 13% with Gleason score ≥7. The cumulative incidence of treatment was 36% at 10 years and 45% at 15 years. During follow-up, 28 men (2.8%) developed metastatic disease , and 15 men (1.5%) died of PCa. Prostate cancer-specific survival was 98.1% at 10 years and 94.3% at 15 years.


Active Surveillance in the Göteborg Screening Trial (Göteborg, Sweden)


The AS experience in Göteborg differs from JHU and Sunnybrook most notably in how the cohort was derived. As reported in 2016 [25], this study population was composed of men diagnosed with PCa based on the Göteborg screening trial, which has been described in detail previously [37]. Importantly, management with AS was not determined based on strict inclusion criteria, but rather the use of AS was classified retrospectively in men with very low-, low-, and intermediate-risk disease who did not undergo curative treatment within 6 months of diagnosis. Similarly, the monitoring protocol was not prospectively defined, but surveillance has generally included PSA testing every 3–6 months. Early rebiopsy (≤12 months) was not standard in the cohort but was typically performed in men with limited cancer volume (<2 mm) at diagnosis to confirm suitability for AS. Additional surveillance biopsies were generally performed every 2–3 years in the absence of other worrisome findings (Table 18.3).


Table 18.3
Active surveillance in the Göteborg screening trial















Enrollment criteria

No curative treatment for PCa within 6 months of diagnosis

Monitoring

PSA every 3–6 months; biopsy within 12 months if cancer volume <2 mm, otherwise every 2–3 years in the absence of worrisome findings

Triggers for intervention

PSA progression, increased Gleason score, increased cancer volume, or clinical progression

Ultimately, the 474 patient cohorts captured a relatively wide distribution of baseline risk categorization, as it was composed of 51% VLR cancers, 27% LR cancers, and 22% intermediate-risk cancers. Median overall follow-up was 8.0 years, with 181 men followed for more than 10 years and 31 for more than 15 years. The 10- and 15-year rates of treatment were 53% and 66%, respectively. Metastasis-free survival was 99% at 10 years and 93% at 15 years. A total of six men died of PCa, with associated cancer-specific survival rates of 99.5% at 10 years and 96% at 15 years. Notably, there were no deaths among men with very low-risk prostate cancer.


Prostate Cancer Research International Active Surveillance (PRIAS)


The PRIAS study was initiated in 2006 and represents a departure from the conventional, single-institution approach to AS [38]. In contrast, PRIAS includes participants from academic, nonacademic, and private practices derived from over 150 centers across 18 countries. Patient data are prospectively entered through the PRIAS website, allowing for efficient provision of recommendations and data collection across several sites. Initial patient selection criteria included clinical stage ≤T2c, PSA ≤10 ng/ml, PSAD <0.20 ng/ml/cc, Gleason score ≤6, ≤2 positive biopsy cores, and fitness for curative treatment (Table 18.4). In recent years, these criteria have been adapted to include select Gleason score 3 + 4 = 7 patients and to accommodate changes in practice secondary to the use of saturation or magnetic resonance imaging (MRI)-guided biopsies [26]. The initial 2 years of follow-up include PSA testing every 3 months and DRE every 6 months, and subsequent monitoring includes PSA testing every 6 months and DRE every 1 year. Surveillance biopsies are scheduled at years 1, 4, 7, and 10 from diagnosis; additional interval biopsies are recommended if PSADT is <10 years. Active treatment is recommended upon detection of Gleason score >6, more than two positive biopsy cores, or clinical stage >T2.


Table 18.4
AS protocol in Prostate Cancer Research International Active Surveillance (PRIAS)















Enrollment criteria

Clinical stage ≤T2c, PSA ≤10 ng/ml, PSAD <0.20 ng/ml/cc, Gleason score ≤ 6, and ≤2 positive biopsy cores (or ≤15% of total cores positive); or Gleason score 3 + 4 = 7, ≤ 2 positive biopsy cores, ≤10% cancer involvement in any core, and age ≥70; all patients must be fit for curative treatment

Monitoring

PSA every 3–6 months; DRE every 6–12 months; scheduled biopsy at years 1, 4, 7, and 10, with additional biopsies recommended if PSADT <10 years

Triggers for intervention

Gleason score >6, >2 positive biopsy cores, or clinical stage >T2

As a relatively young study with an innovative, online approach for widely capturing data, PRIAS has reported on 5302 men, of which 3379 underwent at least one surveillance biopsy and 622 were followed for >5 years. At 5 and 10 years of follow-up, 48% and 27% of the cohort remained on AS, respectively. During follow-up, 30 men underwent biochemical recurrence (BCR) after prostatectomy or radiotherapy, 10 developed local recurrences, 8 developed metastatic disease, and 1 man died of PCa. Given the low event rate and limited follow-up, the authors reported a composite endpoint including BCR, local recurrence, metastasis, and PCa death. Cumulative incidence of this outcome was 2% at 5 years and 6% at 10 years following diagnosis.


University of California, San Francisco (UCSF ; San Francisco, California, USA)


UCSF has prospectively collected clinical data in men diagnosed with PCa who did not undergo active treatment for at least 6 months for many years [27]. This active surveillance cohort has evolved with time in terms of patient inclusion and monitoring criteria. As of 2015, strict inclusion criteria included serum PSA ≤10 ng/ml, clinical stage T1/2, biopsy Gleason score ≤6, ≤33% of biopsy cores positive, and ≤50% cancer involvement of any core (Table 18.5). Recommended monitoring has included PSA testing every 3 months, transrectal ultrasound (TRUS) every 6 months, and an initial confirmatory biopsy within 12 months of diagnosis. Subsequent prostate biopsies have been recommended every 1–2 years according to clinical risk. Indications for treatment include biopsy, Cancer of the Prostate Risk Assessment (CAPRA) risk, or clinical stage reclassification.


Table 18.5
AS protocol at University of California, San Francisco (UCSF)















Enrollment criteria

PSA ≤10 ng/ml, clinical stage T1/2, biopsy Gleason score ≤6, ≤33% of biopsy cores positive, and ≤50% cancer involvement of any core

Monitoring

PSA every 3 months; TRUS every 6 months; biopsy within 12 months then every 1–2 years based on clinical risk

Triggers for intervention

Biopsy reclassification (Gleason score >6, >33% of biopsy cores positive, >50% cancer involvement of any core), CAPRA risk reclassification, or clinical stage reclassification

Clinical data were reported in 2015. A total of 810 men consented to study inclusion and had accrued at least 6 months of follow-up, of which 556 (69%) met inclusion criteria. Over a median follow-up of 60 months, including over 200 men with at least 7.5 years of follow-up, the authors observed metastatic disease in only 1 man (0.12%) and prostate cancer death in none. Five-year treatment-free survival was 60%. Additional time-specific outcomes were not reported.


Royal Marsden (London, England, UK)


In 2002, the Royal Marsden Hospital in the United Kingdom (UK) began prospectively collecting data on men managed with AS [39]. This program differs from others in that it selectively excludes very young men and the elderly by restricting eligibility to men aged 50–80 years. Enrollment criteria include clinical stage T1/T2, PSA <15 ng/ml, Gleason score ≤6, and no more than 50% of overall biopsy cores positive (Table 18.6) [28]. Men who presented with Gleason score 3 + 4 were in some cases also enrolled if they were older than age 65. The inclusion criteria for Royal Marsden are relatively permissive in some regards; for example, there is not a specific threshold for exclusion based on elevated PSAD or high involvement of cancer within a positive biopsy core. During surveillance, PSA and DRE are performed every 3 months in year 1, every 4 months in year 2, and every 6 months thereafter; biopsies are performed approximately every 2 years. Intervention for treatment is recommended if the PSA velocity (PSAV) exceeds 1 ng/ml per year or if adverse histology is detected on repeat biopsy, defined as Gleason score ≥4 + 3 or the presence of cancer in more than 50% of biopsy cores obtained.


Table 18.6
AS protocol at Royal Marsden















Enrollment criteria

Age 50–80, clinical stage T1/T2, PSA <15 ng/ml, Gleason score ≤6 (or 3 + 4 if age > 65), and ≤50% total biopsy cores positive

Monitoring

PSA and DRE every 3 months for year 1, every 4 months for year 2, then every 6 months; biopsy every 2 years

Triggers for intervention

PSAV >1 ng/ml/year, Gleason score ≥4 + 3, or >50% positive biopsy cores

As of 2013, the Royal Marsden experience included 471 men (median age 66 years) managed with AS for a median follow-up time of 5.7 years. Of these, 383 (81.3%) were classified as low risk, while the remaining 88 (18.7%) were intermediate risk. Within the cohort, 33 men (7.0%) were diagnosed with Gleason score 3 + 4 disease. Analysis of intermediate-term outcomes from this cohort demonstrated 2- and 5-year treatment-free survival rates of 89% and 70%, respectively. The rate of adverse histology at these same time points was 6% and 22%, respectively. While rates of metastatic disease were not reported, there were two (0.4%) deaths attributed to prostate cancer over the entire follow-up period.


Additional Cohorts


As the concept of active surveillance has taken hold, numerous institutions from around the world have followed suit in reporting their respective experiences. Three additional cohorts have contributed to the literature describing outcomes over the shorter term (median follow-up <5 years).


St. Vincent’s Prostate Cancer Centre (Sydney, Australia)


The St. Vincent’s experience was initiated in 1998, with AS reserved for men with clinical stage <T2b, PSA <10 ng/ml, Gleason score ≤6, <20% of cores with cancer, and <30% cancer involvement of any positive core (Table 18.7) [29]. However, the program has also allowed for the inclusion of men with up to two higher-risk features, including age <55 years, PSA >10 ng/ml, clinical stage ≥T2b, small-volume Gleason score 3 + 4, >20% of cores with cancer, or >30% cancer involvement of any positive core. These patients were followed using PSA measurements every 3 months for 3 years and every 6 months thereafter, DRE every 6 months for 3 years and every year thereafter, and biopsies at 1 year, 2–3 years, and every 3–5 years thereafter. Intervention is recommended if there is a new diagnosis of Gleason pattern 4 cancer or, in select patients with small-volume Gleason score 3 + 4 disease, an increasing proportion of Gleason pattern 4. Other triggers for intervention include PSADT <3 years, PSAV >0.75 ng/ml, clinical stage ≥T2b, >20% of biopsy cores positive, or >40% involvement of any positive core.


Table 18.7
AS protocol at St. Vincent’s Prostate Cancer Centre














Enrollment criteria

Clinical stage <T2b, PSA <10 ng/ml, Gleason score ≤6, <20% positive biopsy cores, and <30% cancer involvement of any positive core (preferred); see text for detailed higher-risk criteria

Monitoring

PSA every 3–6 months; DRE every 6–12 months; biopsy at 1 year, 2–3 years, then every 3–5 years

Triggers for intervention

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Feb 9, 2018 | Posted by in Uncategorized | Comments Off on The Update of Active Surveillance Around the World: Utilization and Outcomes
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