Oncology: Prostate/Testis/Penis/Urethra

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1 Oncology: Prostate/Testis/Penis/Urethra Impact of the U.S. Preventive Services Task Force Recommendations against Prostate Specific Antigen Screening on Prostate Biopsy and Cancer Detection Rates Bimal Bhindi,*, Muhammad Mamdani, Girish S. Kulkarni, Antonio Finelli, Robert J. Hamilton, John Trachtenberg, Alexandre R. Zlotta, Andrew Evans, Theodorus H. van der Kwast, Ants Toi and Neil E. Fleshner From the Division of Urology, Department of Surgery (BB, GSK, AF, RJH, JT, ARZ, NEF), Department of Medical Imaging (AT) and Department of Pathology (AE, THvdK), University Health Network, and Institute for Clinical Evaluative Sciences (GSK), University of Toronto, and Applied Health Research Centre, St. Michael s Hospital (MM), Toronto, Ontario, Canada Purpose: We determined if the USPSTF recommendation against prostate specific antigen screening was associated with a change in biopsy and cancer detection rates. Materials and Methods: We conducted a time series analysis (October 28 to June 213) of prostate biopsies performed at University Health Network (Toronto). Biopsies for active surveillance or solely targeting magnetic resonance imaging detected lesions were excluded from study. Interventional ARIMA models with step functions were used to examine changes in the number of biopsies performed and cancers detected per month. Low risk prostate cancer was defined as no Gleason pattern 4 or greater, 3 or fewer cores involved, or 1/3 or less of the total number of cores involved, and no core with greater than 5% cancer involvement. Intermediate to high grade prostate cancer was defined as Gleason 7-1. Results: A total of 3,48 biopsies were performed and 1,61 (47.%) prostate cancers were detected (low risk prostate cancer 563 [16.5%], intermediate to high grade prostate cancer 914 [26.8%]). The median number of biopsies per month decreased from 58. (IQR 54.5e63.) before the recommendations to 35.5 (IQR 27.e41.) afterward (p¼.3), while the median number of patients undergoing first-time biopsy decreased from 42.5 (IQR 37.5e45.5) to 24. (IQR 19.e32.5, p¼.25). The median number of low risk prostate cancers detected per month decreased from 8.5 (IQR 6.5e1.5) to 5.5 (IQR 4.e7., p¼.12), while the median number of intermediate to high grade prostate cancers per month decreased from 17.5 (IQR 14.5e21.5) to 1. (IQR 9.e12., p <.1). Conclusions: After the USPSTF recommendation the number of biopsies performed (total and first-time), based on referrals from our catchment area, has decreased. This is likely due to decreased use of prostate specific antigen screening. Although it is encouraging that fewer low risk prostate cancers are being diagnosed, the sudden decrease in the detection rate of Gleason 7-1 prostate cancers is concerning. Key Words: early detection of cancer, prostate, biopsy, prostatic neoplasms Abbreviations and Acronyms ARIMA ¼ autoregressive integrated moving average DRE ¼ digital rectal examination I-HGPC ¼ intermediate to high grade prostate cancer LRPC ¼ low risk prostate cancer PC ¼ prostate cancer PCP ¼ primary care practitioner PSA ¼ prostate specific antigen USPSTF ¼ U.S. Preventive Services Task Force Accepted for publication November 26, 214. Study received institutional research ethics approval. * Correspondence: Division of Urology, Department of Surgery, Princess Margaret Hospital, University Health Network, 61 University Ave. 3-13, Toronto, Ontario, Canada M5G 2M9 (telephone: ; FAX: ; bimal.bhindi@mail.utoronto.ca). Nothing to disclose. Financial interest and/or other relationship with Sanofi-Aventis, GSK, Pierre Fabre Medicaments, Amgen and Sanofi-Pasteur. Financial interest and/or other relationship with University Health Network, Amgen, Janssen, Astellas, Bayer, Sanofi, AbbVie, Ferring, Lilly, Bio-Advantex Pharma, Canadian Cancer Society Research Institute, Prostate Cancer Canada and Canadian Institute for Health Research. For another article on a related topic see page SINCE its rapid uptake approximately 25 years ago, controversy has surrounded the use of serum PSA for the early detection of prostate cancer. 1,2 With the aim of resolving the controversy, 3 large randomized PC Editor s Note: This article is the fourth of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1732 and /15/ / THE JOURNAL OF UROLOGY 215 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH,INC. Vol. 193, , May 215 Printed in U.S.A. j 1519

2 152 IMPACT OF USPSTF PROSTATE SPECIFIC ANTIGEN SCREENING RECOMMENDATIONS screening trials were recently reported. 3e5 The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial failed to detect a difference in PC related mortality between men randomized to annual PSA based screening and controls receiving usual care, although high rates of PSA screening in the control arm may have biased results toward the null. 3,6 Conversely, the European Randomized Study of Screening for Prostate Cancer (ERSPC) 4,7 and Goteborg 5 screening trials (which shared a considerable number of patients) reported a reduction in PC related mortality with screening, although the number needed to screen (ERSPC 1,55; Goteborg 293) and number needed to detect (ie manage expectantly or treat actively, ERSPC 37, Goteborg 12) to prevent 1 PC related death were high. After appraisal of the evidence, the USPSTF released a recommendation statement in May 212 against PSA based screening for PC. This statement carried a Grade D recommendation, conveying that according to their assessment, there is moderate to high certainty that the service has no net benefit or that the harms outweigh the benefits. 8 Along with extensive media coverage that captured the attention of the lay public and health care practitioners, the release of this recommendation was met with polarized opinions and criticisms, emphasizing the lack of agreement in the interpretation of the trials. 9e12 Based on diverging opinions regarding the relative benefits and harms of PC screening, the impact of the USPSTF recommendation statement on clinical practice remains unclear. Therefore, we evaluated whether our prostate biopsy rates and cancer detection rates (based on referrals from our catchment area) changed after the USPSTF recommendation statement using a time series analysis. METHODS Study Design, Patients and Data Collection Patients who underwent transrectal ultrasound guided prostate biopsy from October 1, 28 to June 3, 213 were identified from our institutional Genitourinary BioBank Project at University Health Network in Toronto, Canada (census metropolitan area population 5.58 million). All biopsy referrals to our network of academic hospitals are centralized and performed by 2 high volume radiologists. The BioBank approaches all men before prostate biopsy and has a 94.7% consent rate for inclusion. Institutional research ethics approval was obtained and patient consent was sought for inclusion in the database. The majority of men (approximately 6%) were referred by the 13 academic urologists in our network while the remainder was referred by community urologists (approximately 3%) or directly by PCPs (approximately 1%) in our catchment area. Of note, the Canadian health care system requires referral from another physician (usually a PCP) before specialist consultation. Therefore, screening is conventionally performed by PCPs and urologist consultation is only sought if they are concerned (eg elevated PSA or abnormal DRE). First-time biopsies generally involved 1 to 12 cores while repeat biopsies involved 13 to 18 cores. All biopsies were read by genitourinary pathologists. Biopsies for active surveillance (1,14) or biopsies solely targeting lesions detected on magnetic resonance imaging (22) were excluded from analysis. Clinical data were obtained through patient questionnaires (patient reported ethnicity, family history of PC, use of certain medications) and electronic chart review (serum PSA, DRE findings and biopsy pathology results). Exposure and Outcome Measures The event of interest (ie the intervention) was the release of the USPSTF recommendation statement on May 22, 212. Taking into account slight delays between the referral and the actual biopsy date, June 212 was considered the first month after intervention. To evaluate the impact of the USPSTF recommendations on the monthly biopsy rate, we evaluated the total number of prostate biopsies performed per month (primary outcome) and the number of first-time biopsies performed per month (secondary outcome). The former was chosen because it is thought to reflect overall rates of ongoing PSA based PC screening. The latter was chosen because patients without prior biopsy are most likely to be newly referred by PCPs and, thus, this measure likely reflects the rates of PSA screening among PCPs. We then evaluated the impact of the USPSTF recommendations on absolute (number of cancers per month) and relative (number of cancers per month per 1 biopsies performed) cancer detection rates as additional secondary outcomes (see supplementary figure, jurology.com/). The absolute and relative numbers of low risk PCs detected per month were evaluated. Low risk PC was defined as no Gleason pattern 4 or greater, 3 or fewer cores involved, or 1/3 or less of the total number of cores involved, and no core with more than 5% cancer involvement, representing cancers that are generally most appropriate for surveillance rather than radical therapy. 13 Then the absolute and relative numbers of I-HGPC (defined as Gleason score 7-1) detected per month were evaluated. These cancers represent potential threats to survival 14 and are most likely to benefit from early intervention. 15,16 Statistical Analysis Statistical analyses were performed using SASÒ v9.3 with the Time Series Forecasting System. Characteristics were compared between biopsies performed in the months before vs after the release of the USPSTF recommendations using standardized differences. To assess for significant changes after the release of the USPSTF recommendations, interventional ARIMA models with step functions were used. 17,18 This technique offers several advantages compared to simpler before vs after comparisons. Most notably, the model intrinsically

3 IMPACT OF USPSTF PROSTATE SPECIFIC ANTIGEN SCREENING RECOMMENDATIONS 1521 accounts for confounders that gradually change with time, measured and unmeasured (eg trends in practice patterns) and, therefore, multivariable adjustment is generally not necessary. It is only susceptible to temporal confounding from other discrete events that occur in close proximity to the event of interest. In the present study there are none to the best of our knowledge. Model selection was guided by the autocorrelation, partial autocorrelation and inverse autocorrelation plots. Autocorrelation was assessed using the Ljung-Box chisquare statistic and stationarity was assessed using the augmented Dickey-Fuller test. All tests were 2-sided with p <.5 considered statistically significant. Time series are presented graphically. From June 212 onward, observed outcomes measurements are compared to expected projections for each outcome measure based on pre-intervention data using exponential smoothing models. RESULTS Our study cohort included 3,48 biopsies overall and 2,43 first-time biopsies performed in 3,221 patients. Cohort characteristics are summarized in table 1. Mean age at biopsy was 63.4 years. A lower proportion of older men underwent prostate biopsy over time, with the proportion of men 7 years old or older decreasing gradually with time (21.9% before June 212 vs 16.% from June 212 onward). Men who underwent biopsy from June 212 onward more commonly had a family history of PC (24.3% vs 18.8%), but differences in rates of DRE abnormality and median serum PSA were not meaningful (standardized difference less than.1). Overall and first-time biopsy rates by month are shown in figure 1. There was a spike in the number of biopsies performed in 29 around the time of publication of the screening trials, followed by a general stabilization of biopsy rates until May 212. Subsequently the median number of biopsies per month decreased from 58 (IQR 54.5e63.) in the year preceding the USPSTF recommendations to 35.5 (IQR 27.e41.) in the year after (p¼.3). Meanwhile, the median number of first-time biopsies decreased from 42.5 per month (IQR 37.5e57.5) in the year preceding the USPSTF recommendations to 24. per month (IQR 19.e32.5) in the year after (p¼.25). Overall 1,61 PCs (47.%) were detected, including 687 Gleason 6 (2.2%), 767 Gleason 7 (22.5%) and 147 Gleason 8-1 (4.3%). Among men who underwent biopsy there were no significant differences in relative cancer detection rates in the year after vs the year before the release of the USPSTF recommendations (table 2). Time series analyses did not reveal any significant differences in the proportion of biopsies showing LRPC (p¼.9) or Gleason 7-1 PC (p¼.17) following the USPSTF recommendations (see supplementary figure, jurology.com/). Conversely, the absolute rates of cancer detection per month decreased after the USPSTF recommendation statement (table 3). While there was a significant decrease in the median number of LRPCs detected per month (from 8.5, IQR 6.5e1.5 to 5.5, IQR 4.e7.) (p¼.12, fig. 2, A), there was also a significant decrease in the absolute number of Gleason 7-1 PCs detected per month (from 17.5, IQR 14.5e21.5 to 1., IQR 9.e12.) (p <.1, fig. 2, B). DISCUSSION After the initial publication of the PC screening trials in 29 to 21, 3e5 the guidelines put forth by the ACS (American Cancer Society), CUA (Canadian Urological Association) and EAU (European Urological Association) in 21 to 211 all took a relatively neutral stance, emphasizing the involvement of patients in shared decision making regarding whether to screen for PC, after discussing the benefits of prevention of metastatic disease and Table 1. Cohort characteristics Overall October 28 e May 212 June 212eJune 213 Standardized Difference p Value No. biopsies 3,48 2, Mean age (SD): 63.4 (8.2) 63.5 (8.2) 62.6 (8.).1.4 Less than (5.3) 151 (5.1) 3 (6.9) e (26.9) 797 (26.8) 121 (27.7) 6e69 1,588 (46.6) 1,372 (46.2) 216 (49.4) 7þ 721 (21.2) 651 (21.9) 7 (16.) No. ethnicity (%): European descent 2,45 (7.6) 2,13 (7.8) 32 (69.1).8.83 African descent 221 (6.5) 191 (6.4) 3 (6.9) Asian descent 341 (1.) 298 (1.) 43 (9.8) Mixed/other 441 (12.9) 379 (12.8) 62 (14.2) No. known family history of PC (%) 666 (19.5) 56 (18.8) 16 (24.3).16.8 No. abnormal DRE (%) 886 (26.) 766 (25.8) 12 (27.5).2.46 No. history of prior neg biopsy (%) 978 (28.7) 862 (29.) 116 (26.5).4.29 Median ng/ml serum PSA (IQR) 6. (4.3e8.32) 6. (4.3e8.27) 6.15 (4.3e8.76).5.34 Median cc prostate vol (IQR) 42. (32.e57.) 42.5 (32.e58.) 42. (31.e55.).8.14

4 1522 IMPACT OF USPSTF PROSTATE SPECIFIC ANTIGEN SCREENING RECOMMENDATIONS A Number of biopsies per month Total no. of biopsies p=.3 B Number of first- me biopsies per month First- me biopsies p=.25 Oct-8 Jul-9 Oct-1 Oct-8 Jul-9 Oct-1 Figure 1. Total number (A) and first-time (B) biopsies per month in relation to release of USPSTF recommendations (vertical line) PC related mortality vs the risk of over diagnosis and overtreatment, all in the context of life expectancy. 19e21 For example, the CUA guidelines recommended that the harms and benefits of PCa screening must be explained to each patient so they understand all the factors to be considered in the shared decision making about screening. 2 Conversely, the USPSTF recommendation statement 8 was more polarized, generating much controversy and attracting considerable media attention due to its practice changing implications. Based on our data the USPSTF recommendation appears to have had an immediate impact on clinical practice, likely due to the extensive media coverage that garnered the attention of the lay public and physicians. The early release of a draft of the USPSTF recommendations in October 211 may have also increased awareness, leading to a more prompt response after the release of the final recommendation statement. Subsequent guidelines released by the American Urological Association (May 26, 213) 22 and the American College of Physicians (April 9, 213), 23 as well as updated Table 2. Comparison of relative cancer detection rates in the year before vs the year after the release of the USPSTF recommendations June 211 e May 212 (No./1 biopsies) June 212 e June 213 (No./1 biopsies) Rate Ratio (95% CI)* No Ca (.69e1.12) Gleason 6 PC (.89e1.64) Gleason 7 PC (.69e1.22) Gleason 8e1 PC (.83e2.46) I-HGPC (Gleason (.76e1.29) 7e1) NonLRPC (.84e1.41) LRPC (.79e1.54) * After USPSTF recommendations vs before. statements from the ACS (July 16, 212) 24 and EAU (October 6, 213), 25 were generally positioned in the middle ground and cannot be used to explain study observations. After the release of the USPSTF recommendations there was a significant decrease in the overall number of biopsies and first-time biopsies performed by our group, based on referrals from our catchment area. This finding suggests that there was a reduction but not a cessation in the use of PSA screening in the region serviced by our hospital network. There has been a gradual reduction in the number of older men (age 7 years or older) being referred for biopsy, suggesting decreased use of screening in an age stratum that is unlikely to benefit. 22,23 Conversely, median PSA at referral and rates of DRE abnormalities have not significantly changed. Thus, it is possible that PCPs are being more selective in who they screen, but continue to use the same threshold to consider specialist referral. The relative influence of patient vs physician views on PSA screening has yet to be well Table 3. Comparison of absolute cancer detection rates in the year before vs the year after the release of the USPSTF recommendations Absolute No./Mo Median (IQR) June 211eMay 212 June 212eJune 213 Biopsies 58. (54.5e63.) 35.5 (27.e41.) First-time biopsies 42.5 (37.5e45.5) 24. (19.e32.5) Neg biopsies 3.5 (27.5e32.5) 16.5 (12.e22.) Gleason 6 PC 1. (8.e13.) 7.5 (6.e8.5) Gleason 7 PC 14.5 (11.5e19.) 8. (6.e1.) Gleason 8e1 PC 3. (.e4.) 2. (.5e3.5) I-HGPC (Gleason 7e1) 17.5 (14.5e21.5) 1. (9.e12.) NonLRPC 19. (15.e24.5) 12.5 (1.e14.5) LRPC 8.5 (6.5e1.5) 5.5 (4.e7.)

5 IMPACT OF USPSTF PROSTATE SPECIFIC ANTIGEN SCREENING RECOMMENDATIONS 1523 A Number of low risk PCs diagnosed per month Low risk PCs p=.12 B Number of Gleason 7-1 PCs diagnosed per month Gleason 7-1 PCs p<.1 Oct-8 Jul-9 Oct-1 Oct-8 Jul-9 Oct-1 Figure 2. Number of low risk (A) and Gleason 7-1 (B) prostate cancers diagnosed per month characterized. In a survey of the U.S. population after the release of the draft of the USPSTF recommendation, it was reported that 54% of men would continue to get screened. 26 Black race, higher income and having a prior PSA test were all predictors of continuing to undergo screening. Meanwhile 33% were undecided at the time. However, it is unclear how these proportions might be influenced by an ensuing discussion with their physician. Moreover, to our knowledge a comparable survey has not been conducted after the release of the final USPSTF recommendation statement. We also found a decrease in the absolute number of cancers detected after the USPSTF recommendations, while no change was noted in the relative detection rates. It is encouraging that there are fewer diagnoses of low risk PC (cancers that are unlikely to result in PC related mortality and can be managed expectantly). 27 Conversely, there was also a corresponding decrease in the absolute number of I-HGPCs (Gleason 7-1) diagnosed. Assuming that the biological incidence of Gleason 7-1 PC and the size of our source population (men in our catchment area) have not meaningfully changed during the 5-year study period, this suggests that a number of significant cancers are going undiagnosed, or at least are not being diagnosed in a timely manner. This is concerning given that clinically localized Gleason 7 PC and 8-1 PC are associated with a 3% to 5% and 5% to 8% probability of PC related mortality in 1 years, respectively. 14 Given evidence that local therapies such as radical prostatectomy and radiation can improve survival in men with intermediate and high grade cancers, 15,16,28 there is concern regarding potentially missed opportunities for early intervention and cure. Aslani et al recently reported a dramatic reduction in the number of screening tests performed at academic and community hospitals in Northeastern Ohio after the release of the USPSTF recommendations. 29 Meanwhile Cohn et al noted fewer PSA tests being ordered by PCPs after the USPSTF recommendations. 3 However, neither study evaluated the downstream impact of these changes. Our study results are consistent with the findings of these studies. Strengths of our study include that beyond changes in screening practice, we assessed the downstream clinical consequences of these changes. While other studies have evaluated changes in the number of PSA tests ordered after the USPSTF recommendation, 29,3 our study is the first to our knowledge to evaluate changes in biopsy rates and cancer detection. Moreover the use of a clinical data set allowed us to better risk stratify patients based on biopsy pathology. Additionally, our analytic approach using ARIMA models intrinsically addresses various sources of measured and unmeasured confounding (eg gradual changes in the age distribution of men undergoing biopsy) that are not addressed by other analytic approaches. Limitations include that this is a study performed at a network of academic hospitals in a single payer health care system. While our results are plausible and consistent with another study in an American population, 29 further population based studies in diverse populations are warranted to evaluate generalizability. This is an observational study demonstrating a temporal association and cannot be used to establish causality. There are other factors affecting PC incidence that were not evaluated in our study, such as changes in practice

6 1524 IMPACT OF USPSTF PROSTATE SPECIFIC ANTIGEN SCREENING RECOMMENDATIONS and referral patterns, changing demographics and other unmeasured factors. Conversely, it is expected that these factors result in gradual changes in PC incidence, which are intrinsically modeled in the underlying trends with our models. Such factors do not explain the sudden change in PC biopsy rates and cancer detection rates around the time of the release of the USPSTF recommendations and, therefore, are unlikely to be meaningful confounders. In addition, we cannot discern whether the study findings are driven by changes in patient or physician behaviors, or both. Information on patient comorbidity was not available in our data set. Lastly, it is still too soon to assess the impact of the USPSTF recommendations on PC mortality. Further long-term studies are needed. CONCLUSIONS After the USPSTF recommendations there was an associated decrease in the number of biopsies performed per month (overall and first-time), likely suggesting a decrease in the use of PSA screening in our catchment area. In accordance, there were fewer detected cancers. While it is encouraging that there was a decrease in the number of diagnoses of low risk PCs (that are unlikely to benefit from radical therapy), there was also a corresponding rapid decrease in the number of Gleason 7-1 PCs being detected (which are believed to benefit from radical therapy). Further population based studies are needed to evaluate the long-term impact of the USPSTF recommendation against PSA screening on the rates of metastatic disease and PC related mortality. REFERENCES 1. Stamey TA, Yang N, Hay AR et al: Prostatespecific antigen as a serum marker for adenocarcinoma of the prostate. 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