Author's Accepted Manuscript

Utilization of Active Surveillance as Initial Management for Newly DiagnosedProstate Cancer: Data from the Pennsylvania Urologic Regional Collaborative

Mahesh Botejue , Daniel Abbott , John Danella , Claudette Fonshell , SergeGinzburg , Thomas J. Guzzo , Thomas Lanchoney , Bret Marlowe , Jay D. Raman ,Marc Smaldone , Jeffrey J. Tomaszewski , Edouard J. Trabulsi , Robert G. Uzzo ,Adam C. Reese

PII: S0022-5347(18)44027-XDOI: https://doi.org/10.1016/j.juro.2018.10.018Reference: JURO 15866

To appear in: The Journal of UrologyAccepted Date: 20 October 2018

Please cite this article as: Botejue M, Abbott D, Danella J, Fonshell C, Ginzburg S, Guzzo TJ,Lanchoney T, Marlowe B, Raman JD, Smaldone M, Tomaszewski JJ, Trabulsi EJ, Uzzo RG, ReeseAC, Utilization of Active Surveillance as Initial Management for Newly Diagnosed Prostate Cancer: Datafrom the Pennsylvania Urologic Regional Collaborative, The Journal of Urology® (2018), doi: https://doi.org/10.1016/j.juro.2018.10.018.

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Utilization of Active Surveillance as Initial Management for Newly Diagnosed Prostate Cancer:

Data from the Pennsylvania Urologic Regional Collaborative

Mahesh Botejue1, Daniel Abbott

1, John Danella

2, Claudette Fonshell

3, Serge Ginzburg

4, Thomas

J. Guzzo5, Thomas Lanchoney

6, Bret Marlowe

3, Jay D. Raman

7, Marc Smaldone

8, Jeffrey J.

Tomaszewski9, Edouard J. Trabulsi

10, Robert G. Uzzo

8, Adam C. Reese

1

1The Lewis Katz School of Medicine at Temple University, Philadelphia, PA

2Geisinger Medical Center, Danville, PA

3The Health Care Improvement Foundation, Philadelphia, PA

4Einstein Healthcare Network, Philadelphia PA

5The University of Pennsylvania, Philadelphia, PA

6Urology Health Specialists, Bryn Mawr, PA

7Penn State Milton S. Hershey Medical Center, Hershey, PA

8Fox Chase Cancer Center, Philadelphia, PA

9Cooper University, Camden, NJ

10Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia PA

Running Head: Active surveillance in the Pennsylvania Urologic Regional Collaborative (PURC)

Key Words: active surveillance; expectant management; prostatic neoplasms; quality

improvement collaborative

Total Word Count: 2417

Abstract Word Count: 240

Tables: 4

Figures: 3

Address for Correspondence:

Adam C. Reese

Department of Urology

Temple University School of Medicine

3401 North Broad St., Suite 340

Philadelphia, PA 19140

Phone: 215-707-9122

Fax: 215-707-4758

E-mail: adam.reese@tuhs.temple.edu

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Abstract

Purpose: We aimed to describe contemporary active surveillance (AS) utilization and variation

in a regional prostate cancer collaborative, and to identify demographic and disease-specific

factors associated with the use of AS for men with newly diagnosed prostate cancer.

Materials and Methods: We analyzed data from the Pennsylvania Urologic Regional

Collaborative (PURC), a cooperative effort of urology practices in Southeastern Pennsylvania

and New Jersey. Among men with newly diagnosed NCCN very low, low, or intermediate

prostate cancer, rates of AS were determined and compared among participating practices and

providers. Univariate and multivariable analyses were used to identify factors associated with

AS utilization.

Results: 1880 men met inclusion criteria. Of men with NCCN very-low or low risk prostate

cancer, 57.4% underwent active surveillance as initial management strategy. Increasing age

was significantly associated with AS utilization (p<0.001), whereas adverse clinicopathologic

variables were associated with decreased use of AS. Substantial variation in AS utilization was

observed among practices and providers.

Conclusions: Over 50% of men with low risk disease in the PURC collaborative were managed

with AS, however substantial variation in AS rates were observed among practices and

providers in both academic and community settings. Advanced age and favorable

clinicopathologic factors were strongly associated with the use of AS. Analysis of regional

collaboratives such as PURC may allow for the development of strategies to better standardize

treatment for men with prostate cancer and to offer AS in a more uniform and systematic

fashion.

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Introduction

In contemporary urologic practice, there is little doubt regarding the potential harms of

widespread PSA screening and resultant prostate cancer overdiagnosis and overtreatment.

Several decades of research now support active surveillance (AS) as a safe and effective

management strategy for men with low risk prostatic malignancies1, 2

, with the potential to

decrease patient morbidity caused by overtreatment of clinically indolent tumors. As such, AS

is now endorsed by most published guidelines as a preferred management strategy for men

with low risk disease3-5

, and several recent publications have shown an increase in AS utilization

in recent years6-8

.

Nonetheless, the utilization of AS is known to vary widely on both a national and regional level,

and even within individual urology practices.9-11

The reasons for this variation are likely

multifactorial, but likely are at least partially explained by variability in criteria used to identify

men eligible for AS, physician beliefs and biases regarding AS, and patient concerns for both

cancer control and preservation of quality of life.

In the current study, we analyzed a regional prostate cancer collaborative encompassing

multiple urology practices throughout Central and Southeastern Pennsylvania and Southern

New Jersey. The participating groups comprise both academic centers and community

urologists. We aimed to characterize AS utilization and to identify factors associated with the

use of AS within this collaborative. Such information may offer insight into the factors

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underlying the regional and practice-level variation in the practice of AS, as well as provide

avenues to promote standardization of this management strategy.

Material and Methods

Patients

The Pennsylvania Urologic Regional Collaborative (PURC), founded in 2015, is a voluntary

cooperative effort of both academic and community urology practices in Southeastern

Pennsylvania and New Jersey aimed at advancing the quality of diagnosis and care for men with

prostate cancer. PURC was initially formed as a collaborative of 6 practices (Einstein Health

Network, Jefferson Urology Associates, Fox Chase Cancer Center, Temple University Hospital,

The University of Pennsylvania, and Urology Health Specialists) and expanded in November

2016 to add three additional practices (Geisinger Health System, MD Anderson at Cooper

University Hospital, and Penn State Milton S. Hershey Medical Center). The initial cohort of

PURC practices was composed primarily of large academic medical centers. PURC has

subsequently been open to all urology practices in the region, with participation largely

dependent on the interest of the individual practice. Currently, there are 117 providers who

manage men with prostate cancer across these 9 PURC practices.

PURC collects data on all men with prostate cancer managed at participating sites. At each

clinical site, data are collected by trained data abstractors via manual review of the electronic

medical record. Following a diagnosis of prostate cancer, data abstractors read all subsequent

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clinic notes and only record initial management strategy once it has been documented by the

provider in the electronic medical record. Abstractors are trained to differentiate active

surveillance (with the potential for delayed definitive treatment) from watchful waiting, and

record these as separate management strategies in the PURC database. Periodic audits are

performed by the PURC coordinating center to ensure data accuracy.

With approval from the Institutional Review Board (IRB), as well as PURC, we retrospectively

identified all patients diagnosed with very-low, low, or intermediate risk prostate cancer, as

defined by the National Comprehensive Cancer Network (NCCN)5, between January 2015 and

November 2017. We excluded men in whom initial management strategy was unknown, or

those who were initially managed with primary androgen deprivation therapy or watchful

waiting.

For men meeting inclusion criteria, demographic (age, race/ethnicity) and clinicopathologic

variables (family history of prostate cancer, clinical T-stage, biopsy grade group, PSA, percent of

positive biopsy cores, and maximum percent biopsy core positive) were identified. Trained

data abstractors then determined the initial prostate cancer management strategy used in

these men via review of the electronic medical record, differentiating those who underwent

active surveillance from those undergoing definitive management strategies (radical

prostatectomy, external beam radiation therapy, brachytherapy, high intensity focused

ultrasound).

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Statistical Analysis

Univariate associations between demographic/ clinicopathologic variables and AS utilization

were determined using chi-squared analysis. Multivariable logistic regression was then used to

identify factors associated with AS utilization while controlling for potential confounders. We

also assessed trends in active surveillance utilization over time, with patients stratified by NCCN

disease risk. Finally we characterized variation by urology practice and by individual

practitioner in the percentage of patients undergoing AS as initial management strategy.

Statistical analyses were performed with STATA 14.1 (College Station, Texas).

Results

Utilization of Active Surveillance in the PURC Collaborative

A total of 2250 men with NCCN low and intermediate risk prostate cancer were identified from

PURC. Of these men, 337 were excluded due to lack of data on initial management strategy.

An additional 33 were excluded in whom initial management strategy was primary androgen

deprivation therapy (19 men) or watchful waiting (14 men). After exclusion, 1880 men

remained for analysis. Demographic and disease-specific variables for these men are shown in

table 1.

Table 2 shows the initial management strategy for men with newly diagnosed prostate cancer,

stratified by NCCN disease risk. Of men with NCCN very-low or low risk prostate cancer, 57.4%

underwent active surveillance as initial management strategy. There was a significant decrease

in the utilization of active surveillance as disease risk increased (p<0.001), with a corresponding

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increase in the utilization of radical prostatectomy (p<0.001) and external beam radiation

therapy (p<0.001).

Univariate analysis of factors associated with AS utilization are shown in table 3. Increasing age

was significantly associated with increased utilization AS (p<0.001). For all clinicopathologic

factors analyzed, more advanced disease parameters were significantly associated with

decreased AS utilization. The use of active surveillance did not differ significantly by race

(p=0.18).

Results of a multivariable logistic regression analysis of factor associated with AS utilization are

shown in table 4. This analysis confirmed the results of the univariate analysis whereby

increasing age was significantly associated with increased AS utilization and significant inverse

associations between adverse clinicopathologic factors and the utilization of AS.

Figure 1 shows time trends in AS utilization over time in PURC since the initiation of the PURC

collaborative. In general, there has been trend towards a modest increase in AS utilization over

the time period of interest.

Variation in Active Surveillance Utilization by Urology Practice and Individual Practitioner

Figures 2a-c show practice-level variation in AS utilization, with patients stratified by disease

risk. There was substantial variation in AS rates among various practices, particularly in the

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management of men with NCCN very-low and low risk disease, where AS rates by practice

varied from 30.3% to 86.0%.

Figures 3a-c show variation in AS utilization among individual practitioners. There was marked

variation in AS rates among practitioners. AS rates varied by practitioner from 6.4% to 68.0%

for men with NCCN ≤ intermediate risk disease, from 10.0% to 100% for men with NCCN ≤ low

risk disease, and from 20.0% to 100% for men with NCCN very-low risk disease.

Discussion

In the current analysis of the Pennsylvania Urologic Regional Collaborative (PURC), a regional

prostate cancer collaborative of academic and private urology practices, we observed relatively

high rates of AS in the initial management of prostate cancer. Of men with newly-diagnosed

NCCN very-low or low risk prostate cancer, 57.4% chose AS as initial management strategy.

Furthermore, since initiation of the PURC collaborative in early 2015, we noted a modest

increase in the percentage of low risk patients managed with active surveillance over time.

These data add to a growing body of literature showing an increasing acceptance of active

surveillance as a preferred management strategy for men with low risk prostate cancer across

the United States. A prior analysis of the Michigan Urologic Surgery Collaborative (MUSIC)

found that 49% of men with low risk prostate cancer, as defined by D’Amico criteria12

, were

managed with AS in the state of Michigan.13

A study of CAPSURE, a registry of primarily

community-based U.S. urology practices, reported a 40% AS rate among men with low-risk

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disease as defined by the Cancer of the Prostate Risk Assessment Score (CAPRA).6, 14

More

recently, data from the Veterans Administration found that 48% of men with low risk disease

were managed conservatively.15

Cumulatively, these studies describe relatively high AS

utilization among diverse practice settings and geographically distant patient populations in the

United States. Although the AS rates reported in these prior studies is slightly lower than the

57% AS rate identified in PURC, AS utilization appears to be increasing with time and therefore

contemporary AS rates are likely to be comparable across these diverse patient populations.

We found markers of disease risk at diagnosis, including serum PSA, biopsy Gleason score, and

the volume of disease on prostate biopsy, to be strongly associated with AS utilization as initial

management strategy. This finding was not surprising, as these disease-specific variables are

known to predict the risk of adverse pathology after radical prostatectomy, and therefore have

been incorporated into various AS eligibility criteria that have been proposed to identify

potential AS candidates.16-22

Likewise, advanced patient age was associated with increased use

of AS, likely due to concerns for competing comorbidities in older patients.

Our analysis did not identify a significant association between race and the adoption of AS.

Specifically, AS utilization in African American men was comparable to that of Caucasians. This

observation is noteworthy, as others have suggested that AS may carry an increased risk in

African American men compared to Caucasians.23

These concerns are largely based on prior

studies reporting a higher incidence of advanced or high-grade disease in African American men

at radical prostatectomy, even among those suspected to be low risk at diagnosis.24

A more

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recent study, however, failed to confirm these findings and there is a paucity of data

characterizing long-term outcomes of AS in minority populations.25

Despite these potential

concerns regarding AS in minority populations, our findings suggest that patient race does not

strongly influence the decision to pursue AS in our region.

Similar to prior analyses9, we noted significant variation in AS rates among low risk patients on

the both the practice and provider level. Among the practices analyzed, AS rates for NCCN very

low and low risk patient ranged from 30% to 86%. For individual providers managing at least 10

such patients, AS rates ranged from 10% to 100%. In order to address this marked variation, it

is first necessary to characterize the factors underlying these disparate AS rates, which are likely

explained by a combination of provider- and patient-related factors. For providers, it has been

hypothesized that concerns regarding the safety of AS, financial incentives associated with

definitive treatment, and personal and institutional biases have hindered the uptake of active

surveillance in the past. Patients deciding on initial management strategy must weigh a

number of factors including cancer control rates, implications of various treatment modalities

on quality of life, frequency and necessity of follow up visits, and financial considerations, all of

which may factor in to their decision whether to pursue AS.

We are hopeful that interventions specifically targeted to providers with low AS rates may

increase the overall utilization of AS across our region and decrease the observed variability

among providers. To date, PURC has not developed specific guidelines regarding the practice of

active surveillance. In the near future, however, we plan to develop more explicit protocols to

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help providers identify appropriate AS candidates and employ effective surveillance protocols.

Additionally, development of educational materials describing the long-term safety of AS may

increase patient acceptance of surveillance as a management strategy. Although the optimal

strategies to increase acceptance of AS remain unclear, we feel that collaborative efforts such

as PURC can help to better characterize the factors underlying variation in AS utilization and

develop specific strategies to offer AS in a more uniform and systematic fashion.

It should be noted that the factors predictive of adoption of AS in this study are factors that

providers within our region feel are important in differentiating men with low risk disease who

can safely pursue AS from those with higher-risk tumors that may be better served by definitive

treatment. This study does not suggest that these are the optimal factors to determined AS

eligibility. Various AS eligibility criteria have been proposed previously, which vary in their

stringency and therefore have implications on the percentage of men who would be considered

candidates for AS at the time of diagnosis.16-22

Further work is needed to identify the optimal

AS eligibility criteria, which ideally would offer AS to the maximum number of patients with

clinically indolent tumors while accurately excluding those with higher-risk disease in whom AS

may not be safe. Future analyses of large collaborative datasets such as PURC may be valuable

in defining the optimal AS eligibility criteria to achieve these goals.

There are several factors specific to PURC that may limit the generalizability of our findings.

First, these data reflect AS practice patterns in Central and Southeastern Pennsylvania and New

Jersey, and these results may not be generalizable to other regions. Second, PURC is primarily

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composed of academic medical centers, with the exception of one large urology group practice,

and therefore these results may not accurately reflect the practice of community-based

urologists in our region. Third, all providers within PURC are trained urologists, and therefore

these data may not reflect the practice of radiation or medical oncologists within our region.

Finally, several centers within PURC employ high volume surgeons, to whom patients are

referred specifically for surgery after deciding on a management strategy with their local

urologist. Such a referral practice will suppress AS rates among specific providers and their

institutions, and may explain some of the variation observed in this study.

There are additional limitations to the current study. We were unable to assess patient-related

factors underlying the decision whether or not to pursue active surveillance, and further

characterization of these factors will be important for future research efforts. Finally, imaging

and genomics data may play a role in determining initial management strategy, however we did

not include these data in our analysis as these tests are not employed uniformly across the

practices in our region.

Conclusions

We observed reasonably high rates of AS as the initial management strategy for men with

newly-diagnosed NCCN very-low and low risk prostate cancer in a regional collaborative.

Receipt of AS appears to be primarily driven by patient age and disease-specific factors

associated with disease risk at the time of diagnosis. Significant variation in the utilization of AS

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exists within our region, and future efforts should focus on strategies to deploy AS in a more

uniform and systematic fashion.

Acknowledgment

Pennsylvania Urologic Regional Collaborative (PURC), managed by Health Care Improvement

Foundation (HCIF), is a quality improvement initiative in Pennsylvania that brings urology

practices together for a physician-led, data-driven collaborative aimed at improving prostate

cancer care. HCIF is an independent non-profit organization that leads healthcare initiatives

aimed at improving the safety, outcomes and care experiences of all patients. HCIF has

operated as an independent 501(c)3 organization since 2003. PURC is funded through the

Partnership for Patient Care (PPC) program, a collaboration with Independence Blue Cross and

the region’s hospitals, and participating PURC practices.

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Table 1: Patient Characteristics and Initial Management Strategy

Variable N (%)

Age < 60 644 (34.3%)

60 – 65 619 (32.9%)

> 65 617 (32.8%)

Race/Ethnicity Caucasian 1280 (68.1%)

African American 441 (23.5%)

Hispanic 66 (3.5%)

Asian and Pacific Islander 29 (1.5%)

Unknown/Other 64 (3.4%)

NCCN Disease Risk Very-Low 216 (11.5%)

Low 568 (30.2%)

Intermediate 1096 (58.3%)

Initial Management

Strategy

Active Surveillance 535 (28.5%)

Radical Prostatectomy 1105 (58.8%)

External Beam Radiation Therapy 228 (12.1%)

Brachytherapy 11 (0.6%)

High Intensity Focused Ultrasound 1 (0.1%)

Total 1880

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Table 2: Initial Management Strategy by NCCN Disease Risk

Very-Low Risk Low Risk Intermediate

Risk

All patients

Active Surveillance 179 (82.9%) 271 (47.7%) 85 (7.8%) 535 (28.4%)

Radical

Prostatectomy

29 (13.4%) 260 (45.8%) 816 (74.4%) 1105 (58.8%)

External Beam

Radiation Therapy

8 (3.7%) 36 (6.3%) 184 (16.8%) 228 (12.1%)

Brachytherapy 0 1 (0.2%) 10 (0.9%) 11 (0.6%)

High Intensity

Focused Ultrasound

0 0 1 (0.1%) 1 (0.1%)

Total 216 (11.5%) 568 (30.2%) 1096 (58.3%) 1880

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Table 3: Univariate Analysis of Factors Associated with Active Surveillance Utilization

Variable Active Surveillance p-value

Yes No

Age < 60 147 (22.8%) 497 (77.2%) <0.001

60 – 65 179 (28.9%) 440 (71.1%)

> 65 209 (33.9%) 408 (66.1%)

Race/Ethnicity Caucasian 359 (28.1%) 921 (71.9%) 0.18

African

American

118 (26.8%) 323 (73.2%)

Hispanic 26 (39.4%) 40 (60.6%)

Asian and

Pacific Islander

10 (34.5%) 19 (65.5%)

Unknown/Other 22 (34.4%) 42 (65.6%)

Family History

of Prostate

Cancer

Yes 117 (26.7%) 322 (73.4%) 0.33

No 418 (29.0%) 1022 (71.0%)

NCCN Disease

Risk

Very-Low 179 (82.9%) 37 (17.1%) <0.001

Low 271 (47.7%) 297 (52.3%)

Intermediate 85 (7.8%) 1011 (92.2%)

Clinical Stage T1a/b 13 (68.4%) 6 (31.6%) <0.001

T1c 471 (29.3%) 1138 (70.7%)

T2a 47 (25.0%) 141 (75.0%)

T2b 0 (0%) 32 (100%)

T2c 4 (12.5%) 29 (87.5%)

Biopsy Grade

Group

1 491 (55.5%) 393 (44.5%) <0.001

2 39 (5.8%) 637 (94.2%)

3 5 (1.6%) 315 (98.4%)

PSA < 5 229 (31.1%) 508 (68.9%) <0.001

5 - 10 263 (29.2%) 637 (70.8%)

> 10 43 (17.7%) 200 (82.3%)

Percent of

Positive Biopsy

Cores

< 25 359 (62.2%) 218 (37.8%) <0.001

25 - 50 73 (22.5%) 251 (77.5%)

> 50 90 (9.8%) 830 (90.2%)

Data Missing 13 (22.0%) 46 (78.0%)

Maximum

Percent Biopsy

Core Positive

< 25 408 (52.4%) 370 (47.6%) <0.001

25 - 50 78 (20.0%) 313 (80.0%)

> 50 31 (5.4%) 544 (94.6%)

Data Missing 18 (13.2%) 118 (85.8%)

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Table 4: Logistic Regression Analysis of Factors Associated with Active Surveillance

Utilization

Odds Ratio (95% CI) p-value

Age < 60 Reference Reference

60 - 65 2.10 (1.44 – 3.06) <0.001

> 65 2.43 (1.66 – 3.54) <0.001

Race/Ethnicity Caucasian Reference Reference

African American 0.83 (0.57 – 1.21) 0.34

Hispanic 1.17 (0.53 – 2.59) 0.69

Asian/Pacific

Islander

0.67 (0.23 – 1.94) 0.46

Other/Unknown 2.19 (0.94 – 5.07) 0.07

Family History of

Prostate Cancer

No Reference Reference

Yes 1.05 (0.73 – 1.51) 0.78

Clinical Stage T1 Reference Reference

T2a 0.98 (0.58 – 1.66) 0.94

T2b/c 0.37 (0.09 – 1.44) 0.15

Biopsy Grade Group 1 Reference Reference

2 0.07 (0.05 – 0.11) <0.001

3 0.02 (0.01 – 0.06) <0.001

PSA < 5 Reference Reference

5 – 10 0.74 (0.54 – 1.02) 0.07

> 10 0.32 (0.19 – 0.55) <0.001

Percent of Positive

Biopsy Cores

< 25 Reference Reference

25 - 50 0.38 (0.25 – 0.58) <0.001

> 50 0.11 (0.07 – 0.15) <0.001

Maximum Percent

Biopsy Core Positive

< 25 Reference Reference

25 - 50 0.47 (0.32 – 0.68) <0.001

> 50 0.27 (0.17 – 0.43) <0.001

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Figure 1: Time Trends in Active Surveillance Utilization

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Figure 2: Practice-Level Variation in AS Utilization

Figure 2a: Practice-level variation in AS utilization for men with NCCN very-low, low, and intermediate risk prostate cancer

*Practices managing < 50 patients excluded #

Error bars represent 95% confidence interval of observed active surveillance rate

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Figure 2b: Practice-level variation in AS utilization for men with NCCN very-low and low risk prostate cancer

*Practices managing < 50 patients excluded #

Error bars represent 95% confidence interval of observed active surveillance rate

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Figure 2c: Practice-level variation in AS utilization for men with NCCN very-low risk prostate cancer

*Practices managing < 20 patients excluded #

Error bars represent 95% confidence interval of observed active surveillance rate

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Figure 3: Practitioner-Level Variation in AS Utilization

Figure 3a: Practitioner-level variation in AS utilization for men with NCCN very-low, low, and intermediate risk prostate cancer

*Practitioners managing < 10 patients excluded #

Error bars represent 95% confidence interval of observed active surveillance rate

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Figure 3b: Practitioner-level variation in AS utilization for men with NCCN very-low and low risk prostate cancer

*Practitioners managing < 10 patients excluded #

Error bars represent 95% confidence interval of observed active surveillance rate

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Figure 3c: Practitioner-level variation in AS utilization for men with NCCN very-low risk prostate cancer

*Practitioners managing < 5 patients excluded #

Error bars represent 95% confidence interval of observed active surveillance rate

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Key of Definitions for Abbreviations

AS – active surveillance

PURC – Pennsylvania Urologic Regional Collaborative

NCCN – National Comprehensive Cancer Network

MUSIC – Michigan Urologic Surgery Collaborative

CAPRA – Cancer of the Prostate Risk Assessment Score