Identifying intermediate-risk candidates for active surveillance of prostate cancer

doi:10.1016/j.urolonc.2017.06.048

Urologic Oncology: Seminars and Original Investigations

Volume 35, Issue 10, October 2017, Pages 605.e1-605.e8

https://doi.org/10.1016/j.urolonc.2017.06.048 Get rights and content

Highlights

•
A total of 144 patients with IR prostate cancer followed by active surveillance for a median of 4.5 years.
•
AS maintained in 50% of Intermediate-risk group at 5 years.
•
Treatment rates were significantly lower for VLR group compared to LR or IR group.
•
In the IR group, percentage of biopsy cores involved was an independent predictor of who would cease AS.

Abstract

Purpose

Although already established for very-low and low-risk (LR) prostate cancer (PCa), controversy remains around offering active surveillance (AS) to men with intermediate-risk (IR) PCa. As IR represents a broad spectrum of disease biology, there is a critical need to define eligibility criteria that will enable both patient and physician to accept AS as the best balance of competing risks. In this study, we aimed to identify predictors of progression to enable optimal patient selection.

Materials and methods

In our AS cohort, men were assigned to risk categories according to the National Comprehensive Cancer Network (NCCN favorable and NCCN unfavorable) and the CAPRA classifications. Clinical, biochemical and pathological characteristics, progression to definitive invasive treatment, and pathologic progression on follow-up biopsies were compared among these groups. A multivariate Cox regression model was used to identify independent predictors of progression on AS.

Results

AS was the initial management option for 651 men, including 144 with IR PCa. During the median follow-up of 4.5 years (range: 0.6–19.1), 259 patients (39.7%) underwent definitive treatment. Further, 5- and 10-year predicted rates of intervention for IR patients were 50% and 66%, respectively. Treatment rates were no different between the NCCN LR and NCCN IR groups, but were higher in CAPRA IR compared to CAPRA LR groups (P = 0.025). NCCN unfavorable IR patients had a twofold increased risk of definitive intervention compared to favorable IR (hazard ratio [HR] = 2.07; 95% CI: 1.17–3.65; P = 0.01). In the entire cohort, the percentage of biopsy cores positive (continuous variable; P = 0.006) and ISUP grade 2 or higher on initial biopsy (P = 0.027) were independent predictors of cessation of AS on multivariate analysis. In the intermediate group, only the percentage of positive biopsy cores was an independent predictor (P = 0.021) of AS cessation. Only 1 IR patient developed metastatic disease (0.7%). Actuarial overall survival at 5 and 10 years was 98.6% and 94.1%, respectively. There were 2 PCa deaths at 18.7 and 19.1 years of follow-up.

Conclusion

In all AS, increasing percentage of core involvement and presence of Gleason pattern 4 are predictors of increased risk of progression. For IR patients, the NCCN favorable criteria and CAPRA score predict those more likely to remain on AS.

Introduction

Active surveillance (AS) is widely recommended as a standard initial management option for men diagnosed with very low and low risk (LR), apparently localized prostate cancer (PCa) [1], [2], [3]. Its role in IR PCa [4], [5], [6] remains controversial, and many clinicians believe that all IR cases should be managed early because of an increased risk of metastatic disease, despite the fact that in many cases AS avoids overtreatment and associated morbidity [7], [8]. However, the PIVOT trial demonstrated that for men treated with radical prostatectomy for IR, screen detected PCa had no overall survival advantage compared to men treated with observation alone, suggesting the feasibility of a modern surveillance protocol in this patient group as well [9].

In this retrospective review, we describe our 21-year experience with AS in a cohort of men with very low-, low-, or intermediate-risk (IR) PCa managed in a tertiary referral center. We hypothesize that some men with IR disease can be safely monitored with AS if they are carefully selected . We have offered AS to men with IR disease with the knowledge that some will prove to have clinically insignificant cancers, whereas others with more aggressive disease will be uncovered and are only deferring therapeutic intervention for a period of time. In our series, we have analyzed the use of National Comprehensive Cancer Network (NCCN) favorable/unfavorable risk criteria and CAPRA score, as well as clinical, biochemical, and pathological parameters as predictors of progression in LR and IR candidates.

Section snippets

Data source and patient selection

Since 1993, men with clinically localized PCa have been offered AS at the Vancouver Prostate Centre (VPC). Their clinical data have been collected in an Institutional Review Board–approved, prospectively accrued database. Men have been followed with a well-defined protocol including digital rectal examination and prostate-specific antigen (PSA) measurements every 6 months, restaging confirmatory transrectal ultrasound (TRUS)–guided prostate biopsy within 18 months of first diagnosis and

Results

The clinical and pathological characteristics of the 651 patients meeting inclusion criteria are shown in Table 1. Mean age and PSA at diagnosis were 64.3 years and 5.7 ng/ml, respectively. Median follow-up for all groups was 4.5 years, with a range of 0.6 to 19.1 years (Table 1). More than 10-year follow-up was achieved in 54 men (8.2%) and more than 5-year follow-up in 293 men (45%).

Discussion

This study describes a 21-year experience of AS in a large cohort of patients with very low-, low- and intermediate-risk PCa. Most men with IR disease were “favorable” IR and were selected for AS because of individual priorities of sexual function and continence that outweighed the patient’s (and physician’s) concerns about the risk of imminent disease progression. Our results show extremely low rates of metastasis and PCa death in each of the very low-, low-, and intermediate-risk groups.

The

Conclusion

Parameters that predict for a lower risk of progression in patients with IR disease include the NCCN favorable IR criteria, a low CAPRA score, and a low percentage of biopsy cores involved. However, until we have a better biologically or image-based method of separating the “good actors” from the “bad actors,” the patient and physician should accept that selecting AS is better considered “AS with probable delayed intervention.” In our experience, the risks of progression to incurable PCa and

Acknowledgments

The authors would like to acknowledge the contribution of Mr. Kenny Lynch and Drs. Antonio Hurtado-Coll and Michael Peacock in data collation and resource management.

References (22)

I. Thompson et al.
Guideline for the management of clinically localized prostate cancer: 2007 update
J Urol
(2007)
A. Heidenreich et al.
EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013
Eur Urol
(2014)
H.B. Musunuru et al.
Active surveillance for intermediate risk prostate cancer: survival outcomes in the Sunnybrook experience
J Urol
(2016)
J.I. Epstein et al.
A contemporary prostate cancer grading system: a validated alternative to the Gleason score
Eur Urol
(2016)
M.R. Cooperberg et al.
The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy
J Urol
(2005)
L.F. Newcomb et al.
Outcomes of active surveillance for clinically localized prostate cancer in the prospective, multi-institutional canary PASS cohort
J Urol
(2016)
N.J. van As et al.
Predicting the probability of deferred radical treatment for localised prostate cancer managed by active surveillance
Eur Urol
(2008)
T.H. Van der Kwast
The trade-off between sensitivity and specificity of clinical protocols for identification of insignificant prostate cancer
Eur Urol
(2012)
C.M. Moore et al.
Standards of reporting for MRI-targeted biopsy studies (START) of the prostate: recommendations from an International Working Group
Eur Urol
(2013)
J.L. Mohler et al.
Prostate cancer, Version 1.2016
J Natl Compr Cancer Netw
(2016)

M.R. Cooperberg et al.

Outcomes of active surveillance for men with intermediate-risk prostate cancer

J Clin Oncol

(2011)

Cited by (23)

Liproca Depot: A New Antiandrogen Treatment for Active Surveillance Patients
2022, European Urology Focus
There is increasing interest in nonmorbid treatments for low- and intermediate-risk prostate cancer with fewer side effects than surgery or radiotherapy.
To investigate the tolerability, safety, and antitumor effects of the intraprostatic NanoZolid depot formulation Liproca Depot (LIDDS AB, Uppsala, Sweden) with antiandrogen 2-hydroxyflutamide (2-HOF) in men with low- or intermediate-risk localized prostate cancer managed with active surveillance.
This clinical phase 2b trial, LPC-004, involved 61 patients. The 2-HOF-containing formulation Liproca Depot was injected transrectally into the prostate under ultrasound guidance. A single dose of 35% or 45% of the prostate volume (study part 1) and a fixed dose of 16 or 20 ml (study part 2) of the formulation were evaluated.
The primary endpoints were tolerability and the reduction in serum prostate-specific antigen (PSA) 5 mo after injection. Antitumor effects were evaluated with magnetic resonance imaging (MRI) and prostate biopsies. Quality of life was assessed using a validated questionnaire (International Prostate Symptom Score).
All doses were safe and well tolerated, without hormonal side effects. In part 2 of the study, the PSA reduction was greatest for the group receiving 16 ml, with an average decrease of 14%, and 95% of patients had a PSA reduction. Some 78% of patients showed a prostate volume decrease compared to baseline. Prostate MRI and biopsies confirmed stable or reduced lesion size. However, post treatment biopsies were performed at the discretion of the investigator, and not routinely. Most patients were amenable to a second injection.
PSA and prostate volume decreased in most patients. Indications of efficacy were shown by post-treatment MRI and biopsies demonstrating stabilization or regression in the majority of cases.
Liproca Depot is a safe, minimally invasive treatment that offers the potential for cancer control in patients with intermediate-risk prostate cancer. Further clinical evaluation is warranted.
Regional differences in patient age and prostate cancer characteristics and rates of treatment modalities in favorable and unfavorable intermediate risk prostate cancer across United States SEER registries
2021, Cancer Epidemiology
Citation Excerpt :
D’Amico intermediate risk (IR) prostate cancer (PCa) is a highly heterogeneous entity and accounts for the majority of PCa patients [1–4].
Intermediate risk (IR) prostate cancer (PCa) is a highly heterogeneous entity and can be distinguished into favorable and unfavorable IR PCa according to biopsy, PSA and cT-stage characteristics. These differences may translate into differences in treatment type.
We tested for differences in PCa tumor characteristics and differences in active treatment rates (radical prostatectomy [RP], external beam radiotherapy [EBRT]) according to Surveillance, Epidemiology and End Results (SEER) registry (2010−2015) in favorable and unfavorable IR PCa. Data were stratified according to individual SEER registries. Further analyses additionally adjusted for PCa baseline characteristics (PSA, cT stage, biopsy Gleason group grading [GGG], percentage of positive biopsy cores).
Tabulations according to SEER registries showed that, in favorable IR vs. unfavorable IR, the rates of RP and EBRT respectively ranged from 30.0 to 54.3% vs. 30.3–55.5 % and 8.3–44.7 % vs. 11.5–45.5 %. Differences in age and baseline PCa tumor characteristics also existed in both favorable and unfavorable IR across SEER registries. After adjustment for those baseline patient and PCa characteristics (PSA, cT stage, GGG, percentage of positive biopsy cores), RP and EBRT rates exhibited virtually no residual differences across individual SEER registries, in both favorable (36.0–41.0 % and 26.8–28.1 %) and unfavorable IR PCa (39.2−42.0% and 31.1–33.5 %).
Important differences may be identified in treatment rates within the examined 18 SEER registries in favorable and in unfavorable IR PCa. However, the observed differences are virtually entirely explained by differences in baseline PCa characteristics.
Defining and Measuring Adherence in Observational Studies Assessing Outcomes of Real-world Active Surveillance for Prostate Cancer: A Systematic Review
2021, European Urology Oncology
Citation Excerpt :
Eligibility criteria also changed over time in certain long-term studies, reflecting a general trend in the evolution of AS protocols [9,22–26]. Most studies reported follow-up time on AS; however, the measure varied based on when investigators determined that follow-up began (eg, upon diagnosis or agreement to enroll into an AS program) and ended (eg, upon study completion, movement to active treatment, or other censorship) [9,10,12–19,21–24,27–44]. Median follow-up time ranged from 16.9 mo [33] to 6.7 yr [31,33].
Evidence-based guidelines for active surveillance (AS), a treatment option for men with low-risk prostate cancer, recommend regular follow-up at periodic intervals to monitor disease progression. However, gaps in monitoring can lead to delayed detection of cancer progression, leading to a missed window of curability.
We aimed to identify the extent to which real-world observational studies reported adherence to monitoring protocols among prostate cancer patients on AS. When reported, we sought to characterize definitions of adherence.
We systematically reviewed observational studies assessing outcomes of prostate cancer patients on AS, published before March 22, 2019 in PubMed, Embase, and CENTRAL. Adherence definitions were considered time bound if they included prespecified time and binary if adherence was assessed but did not specify a time interval. We assessed study quality using the Strengthening the Reporting of Observational Studies in Epidemiology checklist.
Forty-five studies met our inclusion criteria. Eleven studies did not report any data on adherence to AS protocols. Twenty-five studies did not explicitly measure adherence, but provided relevant data (eg, number of patients who received a repeat biopsy). Six studies reported adherence using a time-bound definition, while three studies used a binary definition. Twenty-three studies provided information on patients lost to follow-up.
Most studies reporting outcomes of patients on AS did not measure or report adherence. When reported, adherence was often not time specific. As some AS patients will benefit from maintaining a window of curability, clinical practices and future studies should track and report adherence and associated factors.
We reviewed real-world observational studies examining outcomes of prostate cancer patients on active surveillance. Most studies did not clearly define or report adherence to monitoring protocols, which is important to consider for appropriate disease management.
Active Surveillance for Intermediate-Risk Prostate Cancer: Systematic Review and Meta-analysis of Current Protocols and Outcomes
2020, Clinical Genitourinary Cancer
Citation Excerpt :
The selected articles had some differences in inclusion criteria. Only 3 included patient characteristics that met the EAU criteria of intermediate cancer risk (stage ≤ T2b disease, prostate-specific antigen [PSA] < 20 ng/mL, Gleason ≤7).20,21,27 Thirteen articles used the intermediate-risk characteristics from the original article from D’Amico et al30: the inclusion of the T2c stage patients is indicated, or the T2 stage was not divided into subgroups.13-15,17-19,22-26,28,29
Current guidelines allow active surveillance for intermediate-risk prostate cancer patients but do not provide comprehensive recommendations for selection. We performed a systematic review and meta-analysis of outcomes for active surveillance in intermediate- and low-risk groups.
We performed a systematic literature search of intermediate-risk localized prostate cancer patients undergoing active surveillance using 3 literature search engines (Medline, Web of Science, and Scopus) over the past 10 years. The primary outcome was the percentage of patients who remain under surveillance. Secondary outcomes included cancer-specific survival, overall survival, and metastasis-free survival. For articles including both low- and intermediate-risk patients undergoing active surveillance, comparisons between the two groups were made.
The proportion of patients who remained on active surveillance was comparable between the low- and intermediate-risk groups after 10 and 15 years’ follow-up (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.83–1.14; and OR, 0.86; 95% CI, 0.65–1.13). Cancer-specific survival was worse in the intermediate-risk group after 10 years (OR, 0.47; 95% CI, 0.31–0.69) and 15 years (OR, 0.34; 95% CI, 0.2–0.58). The overall survival rate showed no statistical difference at 5 years’ follow-up (OR, 0.84; 95% CI, 0.45–1.57) but was worse in the intermediate-risk group after 10 years (OR, 0.43; 95% CI, 0.35–0.53). Metastases-free survival did not significantly differ after 5 years (OR, 0.55; 95% CI, 0.2–1.53) and was worse in the intermediate-risk group after 10 years (OR, 0.46; 95% CI, 0.28–0.77).
Active surveillance could be offered to patients with intermediate-risk prostate cancer. However, they should be informed of the need for regular monitoring and the possibility of discontinuation as a result of a higher rate of progression. Available data indicate that 5-year survival rates between intermediate- and low-risk patients do not differ; 10-year survival rates are worse. To assess the long-term effectiveness and safety of active surveillance, it is necessary to develop unified algorithms for patient selection and management, and to prospectively conduct studies with long-term surveillance.
MR Imaging–Guided Focal Treatment of Prostate Cancer: An Update
2018, Radiologic Clinics of North America
Active surveillance should be considered for select men with Grade Group 2 prostate cancer
2023, BMC Urology

View all citing articles on Scopus

View full text

Original articleIdentifying intermediate-risk candidates for active surveillance of prostate cancer

Highlights

Abstract

Purpose

Materials and methods

Results

Conclusion

Introduction

Section snippets

Data source and patient selection

Results

Discussion

Conclusion

Acknowledgments

J Urol

Eur Urol

J Urol

Eur Urol

J Urol

J Urol

Eur Urol

Eur Urol

Eur Urol

Prostate cancer, Version 1.2016

J Natl Compr Cancer Netw

Outcomes of active surveillance for men with intermediate-risk prostate cancer

J Clin Oncol

Original article
Identifying intermediate-risk candidates for active surveillance of prostate cancer