More Evidence Backs Active Surveillance for Low-Risk Prostate Cancer | MedPage Today
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The Long-Term Risks of Metastases in Men on Active Surveillance for Early Stage Prostate Cancer |
Summary
The study analyzed the long-term outcomes of 2,155 men with favorable-risk prostate cancer managed with active surveillance in the Canary Prostate Active Surveillance Study (PASS). Key findings after 10 years of follow-up include:
- 43% of patients had biopsy grade reclassification, and 49% received treatment.
- Patients treated after confirmatory biopsies (median 1.5 years) had a 5-year recurrence rate of 11%, while those treated after subsequent surveillance biopsies (median 4.6 years) had a recurrence rate of 8%.
- 21 patients (1%) developed metastatic cancer, and 3 died of prostate cancer.
- The estimated unfavorable outcomes were:
- overall mortality was (5.1%)
- 10-year rates of metastasis (1.4%),
- prostate cancer-specific mortality (0.1%)
The results suggest that protocol-directed active surveillance with regular PSA exams and prostate biopsies is a safe and effective management strategy for favorable-risk prostate cancer. Delayed treatment during surveillance did not lead to worse outcomes compared to earlier treatment, alleviating concerns about missing a window of curability.
Questions
Based on the findings of this study, there are several important questions you should consider asking your physician if you are a candidate for active surveillance (AS):
1. What is the protocol for active surveillance at your practice, and how closely does it align with the one used in the Canary PASS study?
2. How often will I need to undergo PSA testing and prostate biopsies during active surveillance?
3. What criteria will be used to determine if my cancer has progressed or if I need to consider treatment?
4. If I do eventually need treatment, what are the potential risks and benefits of delaying treatment while on active surveillance?
5. How do the outcomes of patients in this study compare to those who chose immediate treatment?
6. Are there any additional tests, such as multiparametric prostate MRI or biomarker tests, that could help monitor my cancer during active surveillance?
7. Based on my individual characteristics and the specifics of my cancer, what is your estimate of the likelihood that I will eventually need treatment?
8. If I do need treatment after a period of active surveillance, what are the chances of recurrence or metastasis compared to having immediate treatment?
9. How will active surveillance affect my quality of life, and what symptoms should I be aware of that might indicate the need for further evaluation or treatment?
10. Are there any lifestyle changes or interventions that I can make to optimize the success of active surveillance in my case?
Remember, every patient's case is unique, and your physician should be able to provide personalized answers based on your specific situation and medical history.
Answers
When discussing active surveillance with your physician, you should expect detailed and personalized answers based on your specific case. However, based on the findings of the Canary PASS study, here are some general answers you might expect:
1. The practice's AS protocol should include regular PSA testing and prostate biopsies, similar to the Canary PASS study.
2. You will likely need PSA tests every 3-6 months and prostate biopsies every 1-2 years, depending on your risk factors and PSA levels.
3. Criteria for progression or need for treatment may include increased PSA levels, changes in biopsy results (such as increased Gleason score or volume of cancer), or changes in imaging results if MRI is used.
4. The study suggests that delayed treatment does not lead to worse outcomes compared to earlier treatment, but individual factors should be considered.
5. The outcomes of patients in this study are generally favorable, with low rates of metastasis and prostate cancer-specific mortality at 10 years.
6. Additional tests like multiparametric prostate MRI or biomarker tests may be used to supplement regular monitoring, depending on the practice's protocol and your individual case.
7. The likelihood of eventually needing treatment will depend on factors such as your age, PSA levels, Gleason score, and volume of cancer at diagnosis.
8. If treatment is needed after a period of AS, the chances of recurrence or metastasis appear to be similar to those of patients who had immediate treatment, based on this study.
9. Active surveillance should have a minimal impact on quality of life, but you should be aware of symptoms like difficulty urinating, pelvic pain, or bone pain that could indicate the need for further evaluation.
10. Your physician may recommend lifestyle changes such as maintaining a healthy diet, exercising regularly, and managing stress to support overall health during AS.
Remember, these are general expectations based on the study, and your physician should provide more specific answers tailored to your individual situation.
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More Evidence Backs Active Surveillance for Low-Risk Prostate Cancer | MedPage Today
— Half of patients did not have grade reclassification or treatment after 10 years of follow-up
by Charles Bankhead , Senior Editor, MedPage Today May 30, 2024
Half of men with low-risk prostate cancer remained free from progression or treatment 10 years after diagnosis when followed in a protocol-directed active surveillance program.
At 10 years, 43% of more than 2,000 patients had biopsy grade reclassification, and 49% had treatment for prostate cancer. Patients who received treatment after confirmatory or subsequent surveillance biopsies had a low rate of recurrence and distant metastasis, suggesting that delayed treatment did not lead to worse outcomes versus earlier treatment.
The results added to evidence for active surveillance in selected patients with favorable-risk prostate cancer, reported Lisa F. Newcomb, PhD, of Fred Hutchinson Cancer Center in Seattle, and co-authors in opens in a new tab or windowJAMAopens in a new tab or window.
"Our study showed that using active surveillance that includes regular PSA exams and prostate biopsies is a safe and effective management strategy for favorable-risk prostate cancer," Newcomb said in a statement from JAMA. "An important finding was that adverse outcomes such as recurrence or metastasis do not seem worse in people treated after several years of surveillance versus 1 year of surveillance, alleviating concern about losing a window of curability."
"We hope that this study encourages the national acceptance of active surveillance instead of immediate treatment for prostate cancer," she added.
Although active surveillance has emerged as the preferred management strategy for low-grade prostate cancer, only about 60% of eligible patients undergoopens in a new tab or window surveillance. Reasons for the low uptake are multifaceted but include fear of undertreatment and missing a window of curability for cancers that initially appear indolent but exhibit aggressive features during surveillance, the authors noted. Additionally, current clinical guidelines provide little guidance for an optimal approach to surveillance.
Increased use of active surveillance requires a better understanding of how to achieve an optimal balance between avoidance of overtreatment and prevention of undertreatment. To address that issue, Newcomb and colleagues analyzed data from the Canary Prostate Active Surveillance Studyopens in a new tab or window (PASS), a collaborative observational study involving 10 North American centers that enrolled patients with favorable-risk prostate cancer from 2008 through 2022.
The study's primary objective was to describe long-term oncologic outcomes of patients enrolled in Canary PASS. Primary endpoints were biopsy grade reclassification, treatment, metastasis, prostate cancer mortality, overall mortality, and recurrence after treatment following a first or subsequent surveillance biopsies.
The analysis included 2,155 men who had a median age of 63 and a median follow-up of 7.2 years. The patients had grade group 1 diseaseopens in a new tab or window in 90% of cases, and median prostate-specific antigen was 5.2 ng/mL.
Medical News from Around the Web
The results showed that 927 patients had biopsy grade reclassification at 10 years. Treatment occurred after a confirmatory biopsy (median 1.5 years) in 425 cases and after subsequent surveillance biopsies (median 4.6 years) in 396 cases. Patients treated early during active surveillance had a 5-year recurrence rate of 11%, whereas later treatment was associated with a recurrence rate of 8% at 5 years.
Progression to metastatic cancer occurred in 21 study participants, and three patients died of prostate cancer. The estimated 10-year rates of metastasis or prostate cancer-specific mortality were 1.4% and 0.1%, respectively. The 10-year overall mortality was 5.1%.
The authors noted that the Canary PASS cohort had high adherence to biopsy schedules, as 88% of participants had a first follow-up biopsy within 2 years of diagnosis and 97% within 5 years. High adherence to the biopsy schedule might have contributed to the low rates of metastasis, as compared with other studies that did not require regular biopsies.
"These results are consistent with the premise that surveillance with regular monitoring is a safe management strategy for favorable-risk prostate cancer," they stated
Newcomb and co-authors acknowledged that enrollment in the study began before the introduction of multiparametric prostate MRI and biomarker tests beyond PSA and continued through the adoption phase of the diagnostic advances. The study's current protocol requires MRI before biopsy, and about half of the cohort has undergone MRI. Continued early use of MRI might lead to further reductions in recurrence and metastasis.
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![author['full_name']](https://clf1.medpagetoday.com/media/images/author/charlesBankhead_188.jpg)
Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007.
Disclosures
The study was supported by Canary Foundation, NIH, and the Institute for Prostate Cancer Research.
Newcomb reported no relevant financial disclosures. Co-authors disclosed relationships with PatientApps, Janssen, Pfizer, and Merck.
Abbreviations and Acronyms
| AS |
active surveillance |
| CAPRA |
Cancer of the Prostate Risk Assessment score |
| GG |
Grade Group |
| GPS |
Genomic Prostate Score |
| HT |
hormonal therapy |
| mpMRI |
multiparametric magnetic resonance imaging |
| PCa |
prostate cancer |
| PI-RADS® |
Prostate Imaging Reporting and Data System |
| PSA |
prostate specific antigen |
| PSAD |
PSA density |
| PSAV |
PSA velocity |
| RP |
radical prostatectomy |
| RT |
radiation therapy |
| TRUS |
transrectal ultrasound |
| UCSF |
University of California San Francisco |
Active surveillance is generally accepted as the standard of care for those with low risk prostate cancer and in well selected patients with intermediate risk disease.1–5 The goal of active surveillance is to avoid or delay the side effects of treatment in men with favorable risk disease without compromising long-term outcomes such as survival or metastasis.6–9
Despite the widespread use of AS, there is still uncertainty regarding optimal candidates and surveillance strategies as well as the long-term risks. There is limited information on longer‐term outcomes, such as metastases and death, because of the low risk of progression and lengthy followup needed to assess such events.7–11 We aimed to assess the long-term outcomes from a large prospective cohort of men diagnosed with low and intermediate risk PCa initially managed on AS, and determine the clinical prognostic factors that may predict the risk of metastases.
Methods
Data were obtained prospectively on men who enrolled on AS at the University of California, San Francisco. Strict AS eligibility criteria included organ confined disease with biopsy Gleason GG1, 33% or less positive biopsy cores and PSA density less than 0.15 ng/ml/cm3, although carefully selected men with other clinical characteristics also were enrolled. Patients for this analysis were diagnosed between 1990 and 2018 with low or intermediate risk disease, defined as clinical stage T1-2, PSA less than 20 ng/ml, and biopsy GG1 or GG2, and underwent at least 1 biopsy after enrollment. All participants provided written informed consent to participate in research under supervision by the UCSF institutional review board (study 11-05226).
Independent sociodemographic (age, race, relationship status, family history of PCa) and clinical variables at diagnosis (PSA, prostate volume on TRUS, PSAD [defined as PSA divided by prostate volume], clinical stage, biopsy Gleason GG, number of biopsy cores dissected, percentage of positive cores, mpMRI PI-RADS v2, clinical CAPRA score12 and year) were assessed. Patients were classified into 3 groups for analysis based on the clinical characteristics diagnostic GG1 with PSAD less than 0.15 ng/ml/cm3, diagnostic GG1 with PSAD 0.15 ng/ml/cm3 or greater, and GG2 with any PSAD. Genomic Prostate Score (GPS, or OncotypeDx®) was reported when available. Findings at surgical pathology (pathological GG, stage and margins) were reported for a subset of men who underwent delayed radical prostatectomy. PSA velocity, computed as slope from PSA at diagnosis to last PSA before date of metastases or last followup, was used for multivariate analysis.
The primary outcome event was metastatic PCa detected on imaging (magnetic resonance imaging, computerized tomography, positron emission tomography, or bone scan) or at surgical pathology in those who underwent delayed RP. Secondary clinical outcome events were upgrade on surveillance biopsy GG2 or greater for patients who began with GG1, and GG3 or greater for patients who began with GG2, and receipt of active treatment. Lastly, PCa specific and overall survival outcomes were assessed.
Independent variables were reported with means, medians and frequency tables. Groups were compared with ANOVA for means, Kruskal-Wallis test for medians and Pearson chi-square for categorical variables. Life table product limit estimates were used to estimate event-free survival. Cox proportional hazards regression models were used to test associations between independent variables and risk of metastases. Cox models were adjusted for characteristics at diagnosis (age, biopsy GG and percentage of positive cores, prostate volume on TRUS and year), high PI-RADS 4-5 on first mpMRI versus no mpMRI, and PSAV. All analyses were performed with SAS® 9.4 for Windows®.
Results
Of the 2,112 men enrolled on AS at UCSF from 1990 to 2018, a total of 1,450 met the inclusion criteria (fig. 1). The clinical and demographic characteristics at diagnosis are summarized in table 1.
Figure 1. CONSORT diagram of patient selection
| Median age (IQR) | 62 (57–67) |
| No. ethnicity (%): | |
| Native American | 3 (less than 1) |
| Asian/Pacific islander | 60 (5) |
| African American | 39 (3) |
| Caucasian | 1,193 (92) |
| Mixed | 4 (less than 1) |
| Missing | 151 |
| No. relationship status (%): | |
| Single/widowed | 301 (22) |
| Married/partnered | 1,068 (78) |
| Missing | 81 |
| No. family history of PCa (%): | |
| Yes | 317 (22) |
| No | 1,133 (78) |
| Median yr of diagnosis (IQR) | 2010 (2006–2013) |
| Median ng/ml PSA (IQR) | 5.4 (4.2–7.3) |
| Median cm3 prostate vol (IQR) | 38 (28–52) |
| Median ng/ml/cm3 PSAD (IQR) | 0.13 (0.09–0.18) |
| No. clinical T stage (%): | |
| cT1 | 756 (55) |
| cT2 | 624 (45) |
| No. biopsy Gleason GG (%): | |
| GG1 | 1,303 (90) |
| GG2 | 147 (10) |
| No. combination of GG+PSAD (%): | |
| GG1 with PSAD less than 0.15 ng/ml/cm3 | 832 (57) |
| GG1 with PSAD 0.15 ng/ml/cm3 or greater | 471 (32) |
| GG2 with any PSAD | 147 (10) |
| Median No. biopsy sessions (IQR) | 3 (2–4) |
| Median No. biopsy cores taken (IQR) | 14 (12–17) |
| Median % biopsy cores pos (IQR) | 13 (8–22) |
| Mean±SD GPS | 25.4±12.0 |
| No. diagnostic biopsy at UCSF (%): | |
| Yes | 394 (27) |
| No | 1,056 (73) |
| No. any neg biopsy during AS (%): | |
| Yes | 387 (27) |
| No | 1,063 (73) |
| No. clinical CAPRA risk category (%): | |
| Low (0–2) | 1,234 (85) |
| Intermediate (3–5) | 216 (15) |
| No. met UCSF AS eligibility criteria (%): | |
| Yes | 749 (52) |
| No | 701 (48) |
| No. first mpMRI PI-RADS score v2 (%): | |
| 1–2 | 208 (14) |
| 3 | 118 (8) |
| 4–5 | 346 (24) |
| No mpMRI | 778 (54) |
| Median mos total followup (IQR) | 77 (49–114) |
Our institution's strict AS criteria were met by 52% patients. Median age at diagnosis was 62 (IQR 57–67) years. Median PSA at biopsy was 5.4 ng/ml (IQR 4.2–7.3) and median PSAD was 0.13 ng/ml/cm3 (IQR 0.09–0.18). A total of 1,303 patients (90%) were initially diagnosed with GG1 and 147 (10%) with GG2, and 85% of patients had clinical CAPRA 0-2 and 15% had CAPRA 3-5. More than half (57%) of cases were classified as GG1 with PSAD less than 0.15 ng/ml/cm3, 32% as GG1 with PSAD 0.15 ng/ml/cm3 or greater and 10% as GG2 with any PSAD. The supplementary table (https://www.jurology.com) shows characteristics at diagnosis according to this stratification. Mean GPS was 25 (SD 12.0) for the 34% of men who underwent genomic testing. Overall, 46% of men underwent mpMRI and 24% had PI-RADS 4-5. Median followup for men at risk for upgrading was 78 months (IQR 48–118) and median time from PCa diagnosis to last followup or death was 77 months (IQR 49–114). Overall 266 (19%) men have been observed for 10 to 15 years and 58 (4%) for more than 15 years.
Median time to biopsy upgrade was 25 months (IQR 13–52). At 7 years, biopsy upgrade-free survival was 40%. Among patients diagnosed with GG1, those with PSAD less than 0.15 ng/ml/cm3 had higher 7-year upgrade-free survival (47%, 95% CI 43–52) compared to those with PSAD 0.15 ng/ml/cm3 or greater (28%, 95% CI 22–33) or GG2 disease (44%, 95% CI 29–57) (log rank p <0.01) (fig. 2).
Figure 2. Kaplan-Meier curves for biopsy upgrade-free survival by diagnostic group (GG1 with PSAD less than 0.15 ng/ml/cm3 vs GG1 with PSAD 0.15 ng/ml/cm3 or greater vs GG2 with any PSAD)
Median time to active treatment was 32 months (IQR 17–52) and 7-year active treatment-free survival was 59%. Men diagnosed with GG1 with PSAD less than 0.15 ng/ml/cm3 had higher 7-year treatment-free survival (69%, 95% CI 66–73) compared to those with GG1 and PSAD 0.15 ng/ml/cm3 or greater (46%, 95% CI 41–51) or GG2 (42%, 95% CI 32–52) (log rank p <0.01) (fig. 3).
Figure 3. Kaplan-Meier curves active treatment-free survival by diagnostic group (GG1 with PSAD less than 0.15 ng/ml/cm3 vs GG1 with PSAD 0.15 ng/ml/cm3 or greater vs GG2 with any PSAD)
During followup 562 men received active treatment, including 412 (73%) RP, 135 (24%) a form of radiation therapy, 11 (2%) hormonal therapy or other advanced systemic treatments and 4 (1%) focal therapy. Among 412 men who underwent delayed RP final pathology showed GG1 in 61 (15%), GG2 in 257 (63%) and GG3 or greater in 91 (22%) patients. In addition, 162 (38%) were pT3 or greater (34% pT3a, 4% pT3b and less than 1% pT4), 157 (38%) had extracapsular extension and 93 (23%) had positive surgical margins (most all focal in nature).
Median time to metastases was 62 months (IQR 29–104) and 7-year metastasis-free survival was 99% (fig. 4). Among 15 men who experienced metastases 2 were lost to followup and were excluded from analysis, 9/13 (69%) had metastasis in lymph nodes, 2/13 (15%) lymph nodes + bone, 1/13 (8%) bone and 1/13 (8%) bone + visceral organ (lung). Of those with metastases, 10/13 (77%) had upgrading on biopsy and all were treated after metastasis. Treatments for metastatic disease were RP monotherapy in 1/13 (8%), RT+HT in 7/13 (53%), RP and RT+HT in 3/13 (23%) and bone RT+HT in 2/13 (16%), with 2 of 4 RP cases having pN1 disease. Men diagnosed with GG2 disease had lower 7-year metastasis-free survival (96%, 95% CI 95–100) compared to those diagnosed with GG1 and PSAD less than 0.15 ng/ml/cm3 (99%, 95% CI 98–100) or 0.15 ng/ml/cm3 or greater (100%, 95% CI 98–100) (log rank p <0.01). Median (IQR) months on AS was 77 (49, 113) for men who did not have progression to metastasis.
Figure 4. Kaplan-Meier curves for metastasis-free survival by diagnostic group (GG1 with PSAD less than 0.15 ng/ml/cm3 vs GG1 with PSAD 0.15 ng/ml/cm3 or greater vs GG2 with any PSAD)
On multivariable Cox regression GG2 at diagnosis was associated with a higher risk of metastases (HR 19.8, 95% CI 4.9–79.3) compared to GG1. The wide confidence interval was due to the small number of outcome events. Other risk factors for metastases were PSAV (HR 1.4, 95% CI 1.1–1.7) and PI-RADS 4-5 lesion (HR 8.5, 95% CI 2.2–33.1) (table 2). PSAD and GPS at diagnosis were not associated with risk of metastases on multivariable analysis.
| HR | 95% CI | p Value | |
| Age at diagnosis | 0.9 | 0.9–1.1 | 0.89 |
| Diagnostic GG2 vs GG1 | 19.8 | 4.9–79.3 | <0.01 |
| % Biopsy cores pos at diagnosis | 1.0 | 0.9–1.1 | 0.60 |
| TRUS prostate vol at diagnosis (log) | 4.9 | 1.3–18.9 | 0.02 |
| PSA velocity/yr | 1.4 | 1.1–1.7 | 0.01 |
| First PI-RADS 4–5 vs no mpMRI | 8.5 | 2.2–33.1 | 0.01 |
Overall 64 men died at a median of 84 months (IQR 57–134), of whom 4 were PCa specific deaths. At 7 years overall survival was 97% in the entire cohort. Rates differed by group, with GG1 with PSAD less than 0.15 ng/ml/cm3 (98%, 95% CI 97–99), GG1 with PSAD 0.15 ng/ml/cm3 or greater (96%, 95% CI 93–98) and GG2 (87%, 95% CI 75–93) groups (log rank p <0.01). PCa specific survival was greater than 99% at 7 years for the entire cohort.
Discussion
Our aim was to determine clinical factors that may influence the risk of metastasis in an AS cohort. At 7 years 1% of men in our cohort had metastatic disease and less than 1% died of PCa.
The incidence of metastases and PCa specific mortality are consistent with prior studies on the long-term oncologic safety of AS. To date, results from a number of AS cohorts have been limited to a median followup of 5 years, with only a few studies assessing outcomes beyond 10 years.13–17 There are differences in the risk profiles in these cohorts, as well as surveillance strategies, making the identification of risk factors for metastatic events challenging.
The Sunnybrook cohort, which included 21% of patients with intermediate risk disease (defined as GG2 and/or PSA 10 to 20 ng/ml) and 1.4% with GG3, reported a metastatic rate of 2.8%.13 An update of this series showed a rate of 3.1% with 10-year and 15-year metastasis-free survival rates of 95.1% and 91.4%, respectively.18 The rate of metastasis from the Johns Hopkins series was 0.4% at 15 years with a metastasis-free survival rate of 99.4%. Notably, 71% of cases were very low risk PCa according to Epstein criteria (T1c, PSAD less than 0.15 ng/ml/cm3, GG1, 2 or fewer positive cores, and 50% or less tumor in any core), and no intermediate risk cases were included.14 An update of their cohort showed a cumulative incidence of metastasis of 0.1% at 10 and 15 years.15 Recently, Memorial Sloan Kettering published their experience of men with GG1 disease on AS, reporting a 10 and 15-year risk of metastasis of 0.6% and 1.5%, respectively.16 The same group separately analyzed data from men with GG2, and over a median followup of 3.1 years reported 2 cases with lymph node metastases (no men had distant metastases).19 These series, including the current study, although with different surveillance protocols, selection criteria and underlying clinical risk, demonstrate variable yet favorable long-term outcomes.
We found a lower rate of 7-year metastasis-free survival among men initially diagnosed with GG2 compared to those with GG1 disease. The low rate of metastasis in men with GG1 PCa is in line with those reported from large cohorts managed with surgery.20,21 On multivariable Cox regression analysis GG2 at diagnosis was associated with a higher risk of metastases (HR of 19.8, 95% CI 4.9–79.3) compared to GG1. Our results are consistent with previous studies demonstrating a significantly higher risk of metastatic progression among patients on AS with more aggressive clinical features at diagnosis.
Using the ERSPC (European Randomized Study of Screening for Prostate Cancer) data set Bul et al found a lower 10-year metastasis-free survival rate for men with intermediate risk (defined by PRIAS [Prostate Cancer Research International Active Surveillance] criteria as PSA 10 to 20 ng/ml, GG2-3, 3 positive biopsy cores) compared to those with low risk disease (96.4% vs 99.7%).22 Similarly, Musunuru et al showed worse metastasis-free survival at 10 and 15 years in the favorable intermediate risk group (classified as PSA 10-20, GG2-3, cT2c) compared to the low risk group (10-year 90.7% vs 95.8% and 15-year 82.2% vs 94.6%), resulting in a risk of metastases 3.14 times higher.23 Moreover, metastases were more likely to develop in GG3 compared to GG2 (HR 4.9, 95% CI 1.3–18.7) or GG1 cases (HR 7.5, 95% CI 1.5–39.2). Yamamoto et al found that intermediate risk patients had a significantly higher rate of metastases and that PSA doubling time less than 3 years (HR 3.7, 95% CI 1.4–9.4), GG2-3 (HR 3.0, 95% CI 1.2–7.3) and 3 or more positive biopsy cores (HR 2.7, 95% CI 1.1–6.8) were independent predictors of metastases.18 As the authors did not find a higher rate among men with GG1 and PSA greater than 10 ng/ml, they concluded that this subgroup could be safely managed with AS. In contrast, Nyame et al reported no significant difference in metastasis-free survival between NCCN® PCa risk categories (intermediate/high risk vs very low/low risk, HR 1.50, 95% CI 0.16–14.5).24 These results should be interpreted with caution, as there is likely considerable clinical variability in these cohorts as well as the length and intensity of followup.
Our analysis showed that 60% of patients overall experienced biopsy upgrade and 41% underwent deferred radical treatment within 7 years after diagnosis. Risk factors for reclassification and active treatment during AS, including diagnostic biopsy characteristics, PSAV, PSAD and surveillance biopsy findings, have been identified. Additionally, mpMRI and novel biomarkers may be promising tools for risk assessment in the context of AS.25–27
We found that patients diagnosed with GG1 and PSAD 0.15 ng/ml/cm3 or greater had worse upgrade-free survival compared to the entire cohort, and that men with GG2 as well as GG1 and PSAD 0.15 ng/ml/cm3 or greater had lower treatment-free survival. In our cohort 7-year metastasis-free survival rates were comparable in patients with GG1 and PSAD less than 0.15 or 0.15 ng/ml/cm3 or greater compared to those with GG2. The analysis was not sufficiently powered to evaluate PSAD within the GG2 group, and PSAD at diagnosis was not associated with the risk of metastases on multivariable analysis. In the current cohort, in addition to GG, PSAV was an independent predictor of metastatic progression (HR 1.4, 95% CI 1.1–1.7), indicating that the prognostic value of PSA kinetics may increase during long-term surveillance.
Tissue based genetic assays have been proposed to refine AS selection criteria and promising results provide the opportunity for their evaluation in predicting disease progression. In the study by Cullen et al the GPS assay was independently associated with risk of adverse pathology and biochemical recurrence and, on univariable analysis, with metastatic progression.28 In our cohort GPS was not associated with a higher likelihood of metastatic progression, possibly as a result of the relatively low number of metastatic cases.
A growing body of evidence supports the utility of mpMRI in the selection and surveillance of men on AS. Although several studies have demonstrated its ability to predict upgrade during surveillance, there is no consensus on its clinical application in AS.15,29 On multivariable analysis we found that having a PI-RADS 4-5 lesion was associated with a higher risk of metastases (HR 8.5, 95% CI 2.2–33.1) compared to not undergoing mpMRI, suggesting that incorporating mpMRI into AS protocols may provide further information for the management of patients on AS.
This study has some limitations worth noting. We lack data about histopathological features such as percentage of Gleason pattern 4 or presence of cribriform pattern on diagnostic biopsy that may provide additional meaningful prognostic information and help risk stratify men. However, our previous work suggests that those who harbor a higher volume of GG2 disease are at higher risk compared to those with more limited disease.30 The AS program at our institution has evolved over time with mpMRI and genomic testing more recently incorporated into our surveillance strategy. Not all men underwent the same diagnostic evaluation and metastases were only detected in patients undergoing surgery or imaging. Therefore, the number of patients with metastases may be underestimated. The majority of men in the cohort were Caucasian and our results may not be generalizable to other populations. Despite these limitations, the current analysis has numerous strengths due to the large sample size, length of followup and the number of predictive variables assessed.
Conclusions
In the long term AS is a safe and viable option for men with low risk and carefully selected intermediate risk PCa. However, higher risk of metastasis was associated with higher Gleason grade, PSAV, and possibly, imaging. These characteristics should be taken into account when selecting, following and counseling patients for AS.
© 2020 by American Urological Association Education and Research, Inc.
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