Observation versus treatment among men with favorable risk prostate cancer in a community-based integrated health care system: a retrospective cohort study

Observation versus treatment among men with favorable risk prostate cancer in a community-based... Background: The objective of this study was to describe overall survival and the management of men with favorable risk prostate cancer (PCa) within a large community-based health care system in the United States. Methods: A retrospective cohort study was conducted using linked electronic health records from men aged ≥40 years with favorable risk PCa (T1 or 2, PSA ≤15, Gleason ≤7 [3 + 4]) diagnosed between January 2005 and October 2013. Cohorts were defined as receiving any treatment (IMT) or no treatment (OBS) within 6 months after index PCa diagnosis. Cohorts’ characteristics were compared between OBS and IMT; monitoring patterns were reported for OBS within the first 18 and 24 months. Cox Proportional Hazards models were used for multivariate analysis of overall survival. Results: A total of 1425 men met the inclusion criteria (OBS 362; IMT 1063). The proportion of men managed with OBS increased from 20% (2005) to 35% (2013). The OBS group was older (65.6 vs 62.8 years, p < 0.01), had higher Charlson comorbidity index scores (CCI ≥2, 21.5% vs 12.2%, p < 0.01), and had a higher proportion of low-risk PCa (65.2% vs 55.0%, p < 0.01). For the OBS cohort, 181 of the men (50%) eventually received treatment. Among those remaining on OBS for ≥24 months (N = 166), 88.6% had ≥1 follow-up PSA test and 26.5% received ≥1 follow-up biopsy within the 24 months. The unadjusted mortality rate was higher for OBS compared with IMT (2.7 vs 1.3/100 person-years [py]; p < 0.001). After multivariate adjustment, there was no significant difference in all-cause mortality between OBS and IMT groups (HR 0.73, p = 0.138). Conclusions: Use of OBS management increased over the 10-year study period. Men in the OBS cohort had a higher proportion of low-risk PCa. No differences were observed in overall survival between the two groups after adjustment of covariates. These data provide insights into how favorable risk PCa was managed in a community setting. Keywords: Prostate cancer, Active surveillance, Overall survival, Monitoring patterns * Correspondence: fkariburyo@statinmed.com STATinMED Research, 211 N. Fourth Avenue, Suite 2B, Ann Arbor, MI 48104, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kariburyo et al. BMC Urology (2018) 18:55 Page 2 of 12 Background Patient identification The widespread adoption of prostate-specific antigen Men aged ≥40 years and diagnosed with favorable risk (PSA)-based screening has led to a substantial increase PCa (International Classification of Diseases [ICD]-O3 in the detection of favorable risk prostate cancer (PCa) site code C61.9 and morphology 81,403, T1 or 2, PSA [1]. PSA-based screening has been shown to reduce ≤15 ng/mL, Gleason score ≤ 7 [3 + 4]) identified from prostate-specific mortality by 21–30% [2, 3]. However, January 2005–October 2013 and active in the GHS the use of PSA screening has resulted in considerable ≥12 months prior to and ≥ 18 months post-index date over-diagnosis and over-treatment, with 15–20% of men were selected. The first PCa diagnosis date was defined receiving a PCa diagnosis during their lifetime but only as the index date. Patient data were assessed until the 3% dying from the disease [4]. earlier of death or April 2015. Observation strategies (OBS) such as active surveil- Patients with evidence of a previous cancer diagnosis lance (AS) and watchful waiting (WW) are alternatives ≤5 years prior to the initial PCa diagnosis (except for to immediate treatment (IMT) for men diagnosed with non-melanoma skin cancer), any PCa treatment before favorable risk PCa. The primary motivation for these the index PCa diagnosis, or other cancer diagnosis within strategies is to avoid or delay treatment-related adverse 6 months after the initial PCa diagnosis (identified using events [5]. ICD-O3-codes) were excluded. AS strategies also reduce immediate health care PCa and other cancer diagnoses, Gleason score, and expenditures by avoiding aggressive treatment costs, tumor stage were extracted from the oncology registry. including treatment complications, but they imply recur- Demographic, encounter, and PSA testing information rent costs for biopsies and other tests that accumulate were retrieved from EMR data. Cohorts were defined as over the patient’s lifetime [5]. The risk vs benefit consid- receiving any PCa treatment (IMT) or no treatment eration of AS also includes the possibility of disease within 6 months (OBS) after index PCa diagnosis date. progression to the point that a cure is less likely or not Prostate cancer risk categories were defined by D’Amico possible. classification [9]: low (T1-T2A, PSA level ≤ 10 ng/mL, and Recent studies indicate increased adoption of AS. How- Gleason score ≤ 6) [10] or intermediate (T1 or T2, PSA ever, most published reports are from academic centers level > 10 and ≤ 20 ng/mL, and Gleason score = 7). [6] or prospective trials with defined AS protocols. Some studies have examined updated observational strategies, IRB approval finding that those who chose to undergo OBS tended to All patient information was de-identified at the source in be older with lower risk disease. The number of men diag- accordance with 45 CFR 164.514(a) and (b) (Code of nosed with low-risk PCa who chose AS in these studies Federal Regulations Title 45, Public Welfare) and there- was low, suggesting that AS may have been underused in fore independent review board approval was not required. the management of very low-risk PCa [7, 8]. The objec- tives of this study were to compare overall survival and Study variables the clinical characteristics and management trends (OBS vs IMT) among men with favorable risk PCa from a large Clinical characteristics Charlson Comorbidity Index community practice, as well as to identify factors associ- (CCI) scores during the 12 months prior to index PCa ated with choosing OBS and to describe monitoring diagnosis were measured. PCa-related characteristics were patterns used for OBS. captured at the time of PCa diagnosis including tumor grade, Gleason score, and risk category based on the D’Amico risk classification. The index PSA was defined as Methods the last PSA value before or on the index biopsy date. Data source A retrospective study was conducted from January Monitoring patterns Monitoring patterns included PSA 2004 to April 2015 using linked electronic medical test, biopsy, and urology visits. records (EMRs), oncology registry data, and enrollment information from the Geisinger Health System (GHS) – Overall survival Overall survival was estimated per 100 a community-based integrated health care organization person-years (PY). serving residents in central, south, and northeast Pennsylvania. The EMR infrastructure contains longitu- Statistical methods dinal clinical patient data including patient demograph- Clinical characteristics were examined descriptively and ics and encounter details from inpatient, outpatient, compared between the OBS and IMT cohorts. Chi-square and office-based settings such as diagnoses, medica- and t-tests were used to calculate p-values, respectively, for tions orders, procedures, and laboratory results. categorical and continuous variables. Logistic regression Kariburyo et al. BMC Urology (2018) 18:55 Page 3 of 12 was used to determine odds ratios and 95% confidence in- vs 80.9%; p < 0.01) and more Medicare beneficiaries tervals (CIs) of factors associated with the selection of OBS (32.3% vs 24.2%; p < 0.01) (Table 1). The OBS cohort also versus IMT. Based on model fitting and clinical rationale, had a lower proportion with Gleason score = 3 + 4 at diag- covariates adjusted in the model included age, race, marital nosis (22.9% vs 35.5%, p < 0.01), and a higher proportion status, insurance status, family history of PCa, prior diagno- of low-risk PCa (65.2% vs 55.0%, p < 0.01) (Table 2). sis of chronic obstructive pulmonary disease, CCI score, and D’Amico risk categories. The use and frequency of Factors associated with the selection of OBS vs IMT monitoring patterns were assessed for patients utilizing Figure 2 shows the factors associated with OBS vs IMT OBS before switching to active treatment during the first, using a logistic regression model. Older age (65–74 years; second, and third years following their index PCa diagnosis. OR = 1.6 or 75+ years; OR = 4.3), marital status (single; Unadjusted Kaplan-Meier (KM) and log rank tests OR = 1.6 or divorce/separated; OR = 1.9), high CCI score were used to compare survival rates in OBS and IMT (≥2; OR = 1.6), and low-risk PCa (intermediate-risk vs cohorts. Multivariate Cox proportional hazards models low-risk, OR = 0.5) were significant predictors of choosing were used to examine Hazard Ratio (HR), and 95% CI of OBS over IMT, after adjusting for other covariates. overall survival. Statistical analyses were performed using SAS Version Prostate Cancer management trends 9.3 (Cary, NC) with p-value < 0.05 considered significant. The proportion of men managed with OBS increased Standardized differences and clinical relevance were also from 20% in 2005 to 35 and 52% in 2013 for patients considered. with favorable risk PCa, or low-risk PCa, respectively (Fig. 3). A similar increase was observed in patients with Subgroup analyses intermediate-risk PCa up to 2012 (from 19% in 2005 to A subgroup analysis was conducted by reporting monitor- 30% in 2012) but the proportion decreased to 14% in ing patterns among men whose treatment was managed 2013 (Fig. 3). with OBS: 1) for those who remained on OBS for at least 18 months and had ≥1 urologist visit (a proxy for active Time to active treatment patient management), and 2) for those who remained on The median time to treatment of all OBS patients was ~ OBS for ≥24 months. 4 years (Fig. 4). Of 181 OBS patients who switched to active treatment, the average time from initial PCa diag- Chart review nosis to treatment was 459 days (1.3 years). Manual examination of de-identified EMR chart data was For the subgroup analysis according to D’Amico risk undertaken to explore why some OBS patients did not classification: 29% (236/821) of low-risk versus 20% (117/ have follow-up visits. Charts were reviewed for all OBS 578) of intermediate-risk PCa patients received OBS. patients without a follow-up visit in the urology depart- Among men managed by OBS, 50% of low-risk versus ment within the first year after PCa diagnosis (N =57). 53% of intermediate-risk PCa patients eventually received The reasons were categorized as follow-up by another treatment during the follow-up period. clinical department (eg, oncology), delayed treatment based on patients’ preference, complicating comorbidities, Monitoring patterns for men managed with OBS and limited follow-up data. Monitoring patterns were assessed among the patients remaining on OBS in year 1 (n = 239), year 2 (n =166) and Results year 3 (n =116) (Fig. 5). In the OBS cohort, the percentage Patient characteristics of patients with at least one urology visit decreased during A total of 3342 men diagnosed with PCa and aged the first 3 years post-index PCa diagnosis from 86.6% in ≥40 years were identified from the oncology registry. year 1 to 65.1% in year 2 and 54.3% in year 3. However, After applying the exclusion criteria, the remaining 1425 PSA testing rates remained similar in the first 3 years of men in this analysis included 362 patients (25.5%) in the diagnosis, with approximately 70% of men receiving ≥1 OBS cohort vs 1063 patients (74.5%) in the IMT cohort PSA test each year. Approximately 7.1, 18.7, and 10.3% of (Fig. 1) with a median follow-up of 5 years. men in the OBS cohort received a prostate biopsy in the There were no significant differences between the OBS first, second, and third year, respectively (Fig. 5). and IMT groups in index PSA result, tumor stage, or body Among men remaining on OBS for ≥18 months and with mass index (Tables 1 and 2). The OBS group was older ≥1urology visit(N = 212), 85.8% received ≥1PSA testsand (65.6 vs 62.8 years; p < 0.01), had higher CCI scores (CCI 19.3% were administered one biopsy within the 18 months. score ≥ 2: 21.5% vs 12.2%, p <0.01), more patients whose Among those remaining on OBS for ≥24 months (N = 166), marital status was “divorced” (9.1% vs 5.7%; p =0.03), 88.6% received ≥1 PSA tests and 26.5% received one biopsy fewer patients whose marital status was “married” (72.9% within the 24 months. A chart review of 57 patients in the Kariburyo et al. BMC Urology (2018) 18:55 Page 4 of 12 Fig. 1 Patient Selection Flow Chart. PSA: prostate specific antigen; PCa: prostate cancer; ICD: international classification of diseases; OBS: observation strategies; IMT: immediate treatment. *Cohorts were defined as receiving any treatment (IMT) or no treatment (OBS) within 6 months after index PCa diagnosis OBS cohort without follow-up urology visits within the first all-cause mortality rate was higher for OBS compared 360 days post-diagnosis indicated that in 49 of 57 cases with IMT (2.7 vs 1.3/100 PY; p <0.001). The cumulative (86%) of PCa-related care by other GHS departments were hazard plot for overall survival indicated that after the identified with oncology as the most common specialty. sixth year of PCa diagnosis, the risk of all-cause mortality was higher in the OBS cohort than in the IMT cohort Overall survival (Fig. 6). However, after multivariate adjustment, there was Median follow-up time from PCa diagnosis in the entire no significant difference in all-cause mortality between the study cohort was approximately 5 years. The unadjusted OBS and IMT cohorts (IMT vs OBS, HR = 0.73, p =0.138; Kariburyo et al. BMC Urology (2018) 18:55 Page 5 of 12 Table 1 Socio-demographic characteristics of men with favorable risk PCa in OBS vs IMT cohorts OBS IMT (n = 362) (n = 1063) N/Mean %/SD N/Mean %/SD P-value Standardized difference Age (Mean) 65.6 9 62.8 8 <.01 33.10 Age Group 40–64 166 45.9% 601 56.5% <.01 21.47 65–74 137 37.9% 390 36.7% 0.69 2.39 75+ 59 16.3% 72 6.8% <.01 21.47 Race White 347 95.9% 1044 98.2% 0.01 13.91 Black or African American 14 3.9% 11 1.0% <.01 18.37 Native Hawaiian 1 0.3% 4 0.4% 0.78 1.75 Asian 0 0.0% 1 0.1% 0.56 4.34 Unknown 0 0.0% 3 0.3% 0.31 7.52 Marital Status Single 33 9.1% 68 6.4% 0.08 10.17 Married 264 72.9% 860 80.9% <.01 18.99 Widow 30 8.3% 67 6.3% 0.20 7.63 Divorced 33 9.1% 61 5.7% 0.03 12.89 Separated 2 0.6% 7 0.7% 0.83 1.37 Insurance Status Medicare 117 32.3% 257 24.2% <.01 18.15 Veterans Affairs 2 0.6% 2 0.2% 0.26 5.99 Medicaid 8 2.2% 19 1.8% 0.61 3.02 Commercial 227 62.7% 782 73.6% <.01 23.44 Other 4 1.1% 3 0.3% 0.05 9.91 Unknown 4 1.1% 0 0.0% <.01 14.93 OBS observation, IMT immediate treatment, SD standard deviation, CCI Charlson Comorbidity Index SD = standardized difference (SD is defined as the difference in sample means or proportions divided by standard error; reported as 100*|actual standardize difference|. Standardize differences >|10| are considered significant Fig. 7). Multivariate analysis also indicated that older age, In the current analysis, we found that patients who were divorce or separated status; prior diagnosis of COPD, and managed by OBS strategies were on average over age congestive heart failure were risk factors for all-cause 65 years and had higher CCI scores when compared to mortality. patients who received definitive treatment after index PCa diagnosis. Factors associated with the selection of OBS were similar with Liu et al. [11]. Similarly, prior research Discussion has reported that OBS strategies focus on deferring PCa In this study, we described overall survival and the charac- treatment in older, sicker patients diagnosed with a teristics and management patterns in men with favorable prostate tumor that is less aggressive than their underlying risk PCa within a large community-based health care sys- comorbidities [10, 12]. tem in the United States. While no single source provides Because of these known demographic and clinical differ- comprehensive data for most US patients, the major ences in patients who were managed by OBS compared to strength of this study is its large community-based setting. those who underwent IMT, the unadjusted all-cause In addition to the real-world use of EMR, the claims mortality rate was higher in OBS patients compared to oncology registry and unstructured information from IMT. These findings are similar to a previously published charts maximized the available data for each patient, while study comparing radical prostatectomy with WW in early also yielding a large sample size. Each of the data sources PCa patients [13]. After adjusting for these known differ- provided complementary information. ences in baseline demographic and clinical characteristics Kariburyo et al. BMC Urology (2018) 18:55 Page 6 of 12 Table 2 Clinical characteristics of men with favorable risk PCa in OBS vs IMT cohorts OBS IMT (n = 362) (n = 1063) N% N% p-value Standardized difference Comorbid Indices (CCI) 0 225 62.2% 750 70.6% <.01 17.83 1 59 16.3% 183 17.2% 0.69 2.45 2+ 78 21.6% 130 12.2% <.01 25.04 Comorbid Conditions Hypertension 153 42.3% 405 38.1% 0.16 8.50 Diabetes 61 16.9% 134 12.6% 0.04 11.99 COPD 43 11.9% 82 7.7% 0.02 14.03 Congestive Heart Failure 13 3.6% 27 2.5% 0.30 6.09 Dementia 0 0.0% 3 0.3% 0.31 7.52 Benign Prostatic Hyperplasia 130 35.9% 388 36.5% 0.84 1.22 Body Mass Index Underweight (< 18.5) 1 0.3% 5 0.5% 0.62 3.18 Normal (18.5–24.9) 42 11.6% 102 9.6% 0.27 6.52 Overweight (25.0–29.9) 118 32.6% 342 32.2% 0.88 0.90 Obese (≥30) 112 30.9% 336 31.6% 0.81 1.44 Unknown 89 24.6% 278 26.2% 0.56 3.60 Family History of Prostate Cancer Yes 74 20.4% 262 24.7% 0.10 10.07 No 208 57.5% 598 56.3% 0.69 2.43 Unknown 80 22.1% 203 19.1% 0.22 7.42 Family History of Cancer 109 30.1% 339 31.9% 0.53 3.85 Prostate Cancer Characteristics Index PSA (Mean, SD) 5.8 2.5 5.7 2.5 0.31 6.31 < 4 ng/mL 69 19.1% 208 19.6% 0.83 1.28 4–10 ng/mL 256 70.7% 758 71.3% 0.83 1.30 > 10 ng/mL 30 8.3% 77 7.2% 0.52 3.90 Unknown 7 1.9% 20 1.9% 0.95 0.38 Index Clinical Stage Stage 1 303 83.7% 855 80.4% 0.17 8.52 Stage 2 55 15.2% 184 17.3% 0.35 5.73 Unknown 4 1.1% 24 2.3% 0.17 8.97 Index Total Gleason Score = 3 + 4 83 22.9% 377 35.5% <.01 27.82 Risk Category Low-risk 236 65.2% 585 55.0% <.01 20.84 Intermediate-risk 117 32.3% 461 43.4% <.01 22.91 Unknown 9 2.5% 17 1.6% 0.28 6.27 OBS observation, IMT immediate treatment, SD standard deviation, COPD chronic obstructive pulmonary disease SD = standardized difference (SD is defined as the difference in sample means or proportions divided by standard error; reported as 100*|actual standardize difference|. Standardize differences >|10| are considered significant Clinical stage: anatomic Extent of the disease based on the clinical T, N and M element Risk Categories: Low risk (T1-T2A, PSA level ≤ 10 ng/mL, and Gleason score ≤ 6) and intermediate-risk (T1 or T2, PSA level > 10 and ≤ 20 ng/mL, and Gleason score = 7) Kariburyo et al. BMC Urology (2018) 18:55 Page 7 of 12 Fig. 2 Logistic Regression: Risk Factors Associated with OBS vs IMT. CCI: Charlson comorbidity index; CI: confidence interval; COPD: chronic obstructive pulmonary disease; VA: veterans affairs between the OBS and IMT cohorts in a multivariate PCa-specific mortality in favorable risk cancer is relatively analysis, there was no longer a significant difference in low and we do not have sufficient numbers of patients all-cause mortality between the OBS and IMT cohorts. followed for a long enough period to appreciate the differ- However, longer follow-up is needed to more convincingly ences between the OBS and IMT groups. assess all-cause mortality. We also evaluated deaths due to Other studies have shown that the presence of signifi- PCA or complication from PCa. However, the results were cant others in a patient’s life often influences treatment not conclusive because we could not identify the cause of decisions and our results suggest that even adjusting for death with certainty. There were a total of nine patients other factors such as race and type of insurance, that men (2.5%) with deaths possibly or probably due to PCa in the who were divorced or separated (or single) were more OBS group vs 15 deaths (1.4%) possibly or probably due likely to be treated with OBS vs IMT. However, in this to PCa in the IMT group (results not shown). In addition, study, marital status was only captured as single, married, Kariburyo et al. BMC Urology (2018) 18:55 Page 8 of 12 Fig. 3 Annual Prostate Cancer Management Trends for Favorable Risk and Low Risk PCa Patients. PCa: prostate cancer; OBS: observation strategies widow, divorced, and separated, and data on whether men consistent with American Urological Association (AUA) who were divorced, separated, or single were actually guideline changes and was similar with the trend in the living alone or living with a significant other was not adoption of AS/WW from a large US national registry captured [14]. In addition, health insurance plans were population with low-risk PCa [15]. Our study also identified from the data including Medicare, commercial, indicated that patients who switched from OBS to IMT Medicaid, self/other, Veterans Affairs, and unknown. We (64.6 years) were, on average, younger than patients who observed from our study that the risk of choosing OBS remained in the OBS (66.3 years) cohort with a median was significantly lower among the patients enrolled in follow-up period of 5 years. Moreover, 50% of the men commercial/other types of health insurance plans (34.5%) on OBS received active treatment eventually which is compared to those enrolled in Medicare/VA/Medicaid higher than in other studies [16–20]. This might be health insurance plans. because the benefits of AS were not clearly discussed or Regarding the adoption of OBS, we found an increased due to lesser adoption of AS in community settings as use of OBS in the GHS over time. This trend was opposed to academic institutions. This percentage is Fig. 4 Kaplan Meier for Time to Active Treatment in Men with Favorable Risk PCa Managed with OBS. OBS: observation strategies Kariburyo et al. BMC Urology (2018) 18:55 Page 9 of 12 Fig. 5 Monitoring Patterns for PCa Patients Managed with OBS. PSA: prostate specific antigen plausible given that during the timeframe of the study treatment date due to comorbid medical conditions to be (January 2004 to April 2015), there were no existing AS addressed prior to surgery or to better align with personal guidelines to inform decisions on conversion of patients commitments such as a seasonal work schedule. to active treatment. Several AS schedules for the management of favorable The proportion of OBS patients converting to treatment risk PCa have been used in various studies including the within the first 12 months and the second 12 months after 2017 National Comprehensive Cancer Network NCCN the index date is substantial. The most likely reason for guideline [21] and Cancer Care Ontario’s guideline on the large drop during the first 12 months is patients AS for the management of favorable risk PCa endorsed simply deferred treatment. A chart review of 20 by the American Society of Clinical Oncology (ASCO) randomly-selected OBS patients showed that 10 of 20 [22]. In comparison to these guidelines, we found that (50%) patients were considered for IMT. One additional serial monitoring in GHS was relatively low. patient received brachytherapy 10 months after diagnosis, Among the OBS patients who were active in the GHS but there were limited encounters with urology; therefore, for ≥2 years and who remained on OBS treatment in the details of the complete treatment plan were not available. first 2 years, only 61.5% had 3 or more PSA tests and Eight of these 11 men (73%) had intentional delays in their only 26.5% had a prostate biopsy, which differs from Fig. 6 Kaplan Meier Curve for Overall Survival Among Men With Favorable Risk PCa Kariburyo et al. BMC Urology (2018) 18:55 Page 10 of 12 Fig. 7 Multivariate Cox Regression Model for All-cause Mortality Among. Men With Favorable Risk PCa. PCa: prostate cancer; VA: veterans affairs; CCI: Charlson comorbidity index; COPD: chronic obstructive pulmonary disorder; PSA: prostate specific antigen; CI: confidence interval ASCO guidelines and most prospective AS protocols. were in the OBS group and 8.75% of the patients with Our data also showed a relatively stable PSA testing rate IMT had prostate-related MRI during the follow-up but a decrease in urology visits over time. In our study, period (results not shown). It is worth mentioning that 7.7, 20.5, and 10.8% of patients had one prostate biopsy MRI, including mpMRI, was not routinely used during in the first, second, and third year, respectively. Magnetic the timeframe of this study (January 2004 to April resonance imaging (MRI) use is an increasingly import- 2015). Although MRI was not routinely carried out in ant tool in clinical practice for the diagnosis and moni- the management of PCa in these patients, we do not be- toring of PCa patients, especially the multi-parametric lieve that any of these patients had their cancer manage- (mp) MRI [23]. Using Current Procedural Terminology ment affected by not using mpMRI. (CPT) codes to identify MRI use during the study The low monitoring rates observed in this study may period, we observed that only 8.56% of the patients who reflect a greater proportion of WW versus AS, which we Kariburyo et al. BMC Urology (2018) 18:55 Page 11 of 12 are unable to distinguish in our OBS population. In but were older and had higher CCI scores. However, no addition, a large proportion of patients included in this differences were observed in overall survival between the analysis were managed or treated prior to 2010 when AS two groups after covariates adjustment. These data was not yet widely adopted as a management strategy for provide insights into management patterns for favorable patients with clinically-localized PCa and there were no risk PCa within a community setting. consensus/guidelines for monitoring of AS or WW. Low Analysis of monitoring patterns within the OBS cohort monitoring rates for AS and WW in the community showed relatively low rates of repeat clinic visits and setting have been reported by Herden and Weissbach [24] testing. Further research is necessary to focus on verifying and Auffenberg et al. [25] as well, suggesting a need for the appropriate monitoring schedule to optimize patient research into the factors associated with departure from outcomes and to encourage the adoption of AS in com- guideline-recommended monitoring practices. munity settings. This study was a retrospective review of community prac- Abbreviations tice intended to reflect the real-world implementation of AS: Active surveillance; ASCO: American Society of Clinical Oncology; routine management. The inclusion and exclusion criteria CCI: Charlson comorbidity index; CPT: Current procedural terminology; EMR: Electronic medical records; GHS: Geisinger Health System; were primarily based on the patient having a lower-risk, IMT: Immediate treatment; mpMRI: Multi-Parametric magnetic resonance early stage of cancer at diagnosis. To achieve the observa- imaging; MRI: Magnetic resonance imaging; OBS: Observation strategies; tional nature of the study, no requirements or exclusions PSA: Prostate specific antigen; PY: person years; WW: Watchful waiting were made based upon management protocol including the Acknowledgements use of imaging data or biopsy results to address diagnosis Editorial assistance was provided by Michael Moriarty of STATinMED or treatment among favorable risk PCa patients. research. In sum, our data reveal significant opportunities for Funding improvement in management strategies for favorable risk This study was funded by Roche Molecular Systems. prostate cancer within our large community group setting. Educational activities should promote increased adoption Availability of data and materials The datasets supporting the conclusions of this article were obtained from of AS among favorable risk PCa patients as well as a clear linked electronic medical records (EMRs), oncology registry data, and distinction between AS and WW in individual patients. enrollment information from the Geisinger Health System, but restrictions Community-based AS strategies should also focus on apply to the availability of these data, which were used under license for the current study, and so therefore are not publicly available. Data however are appropriate monitoring of patients placed on AS. available upon request and with permission from the Geisinger Health System. Requests regarding data availability should be directed to Eric Limitations Meadows (es_meadows@yahoo.com). All patients without definitive treatment in the first Authors’ contributions 6 months after PCa diagnosis were temporarily classified as IC and DM conceptualized and designed the study. MFK and YW, LX, EM, JD, receiving OBS. However, the OBS strategies, AS or WW, and MC verified and analyzed the data. MFK, YW, IC, LW, DM, LX, EM, MC and JD substantially contributed to the interpretation of the data, wrote were not prospectively collected or always clearly noted by the manuscript and/or substantially contributed to critical revisions of the practitioners in the patient medical records. Therefore, we intellectual content. All authors read and approved the final manuscript. were not able to clearly distinguish between AS or WW Ethics approval and consent to participate from these real-world data. This limitation was also noted Since the core study herein did not involve the collection, use, or transmittal of from other studies (Cooperberg et al., 2015) [15]. Further- individual identifiable data, Institutional Review Board (IRB) approval to conduct more, there also was some apparent misclassification in this study was not required. Both the datasets and the security of our offices to keep the dataset meet the requirements of the Health Insurance Portability and assigning patients to OBS strategies versus IMT by the Accountability Act (HIPAA) of 1996. 6-month threshold, as some patients planned for definitive treatment but waited longer than6monthsbeforereceiving Competing interests FK, YW, and LX are paid employees of STATinMED Research which is treatment. An additional limitation is that Geisinger serves a paid consultant to Roche Molecular Systems. LW is a paid employee patients in Central and Northeastern Pennsylvania; there- of Genentech which is a member of the Roche group. DM is a paid fore, the study results may not be generalizable to the entire employee of Roche Diagnostics Operations. IC is a paid employee of Roche Molecular Systems. EM and JD are paid employees of Geisinger US PCa population. Finally, some patients may have re- Health System which is a paid consultant to Roche Molecular Systems. ceived care outside of GHS. MC has no conflicts to declare. Conclusion Publisher’sNote The proportion of men managed by OBS increased over Springer Nature remains neutral with regard to jurisdictional claims in the 10-year study period although the rate of adoption published maps and institutional affiliations. might have been slightly slower in this large community Author details setting compared with prospective AS protocols. Men in 1 STATinMED Research, 211 N. Fourth Avenue, Suite 2B, Ann Arbor, MI 48104, the OBS cohort had a higher proportion of low-risk PCa USA. Diagnostics Information Solutions, F. Hoffmann-La Roche AG, Basel, Kariburyo et al. BMC Urology (2018) 18:55 Page 12 of 12 3 4 Switzerland. Genentech, Inc, South San Francisco, CA, USA. Roche 19. 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The influence of psychosocial constructs on the adherence to active surveillance for localized prostate cancer in a prospective, population- based cohort. Urology. 2017;103:173–8. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Urology Springer Journals

Observation versus treatment among men with favorable risk prostate cancer in a community-based integrated health care system: a retrospective cohort study

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Medicine & Public Health; Urology; Internal Medicine
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Abstract

Background: The objective of this study was to describe overall survival and the management of men with favorable risk prostate cancer (PCa) within a large community-based health care system in the United States. Methods: A retrospective cohort study was conducted using linked electronic health records from men aged ≥40 years with favorable risk PCa (T1 or 2, PSA ≤15, Gleason ≤7 [3 + 4]) diagnosed between January 2005 and October 2013. Cohorts were defined as receiving any treatment (IMT) or no treatment (OBS) within 6 months after index PCa diagnosis. Cohorts’ characteristics were compared between OBS and IMT; monitoring patterns were reported for OBS within the first 18 and 24 months. Cox Proportional Hazards models were used for multivariate analysis of overall survival. Results: A total of 1425 men met the inclusion criteria (OBS 362; IMT 1063). The proportion of men managed with OBS increased from 20% (2005) to 35% (2013). The OBS group was older (65.6 vs 62.8 years, p < 0.01), had higher Charlson comorbidity index scores (CCI ≥2, 21.5% vs 12.2%, p < 0.01), and had a higher proportion of low-risk PCa (65.2% vs 55.0%, p < 0.01). For the OBS cohort, 181 of the men (50%) eventually received treatment. Among those remaining on OBS for ≥24 months (N = 166), 88.6% had ≥1 follow-up PSA test and 26.5% received ≥1 follow-up biopsy within the 24 months. The unadjusted mortality rate was higher for OBS compared with IMT (2.7 vs 1.3/100 person-years [py]; p < 0.001). After multivariate adjustment, there was no significant difference in all-cause mortality between OBS and IMT groups (HR 0.73, p = 0.138). Conclusions: Use of OBS management increased over the 10-year study period. Men in the OBS cohort had a higher proportion of low-risk PCa. No differences were observed in overall survival between the two groups after adjustment of covariates. These data provide insights into how favorable risk PCa was managed in a community setting. Keywords: Prostate cancer, Active surveillance, Overall survival, Monitoring patterns * Correspondence: fkariburyo@statinmed.com STATinMED Research, 211 N. Fourth Avenue, Suite 2B, Ann Arbor, MI 48104, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kariburyo et al. BMC Urology (2018) 18:55 Page 2 of 12 Background Patient identification The widespread adoption of prostate-specific antigen Men aged ≥40 years and diagnosed with favorable risk (PSA)-based screening has led to a substantial increase PCa (International Classification of Diseases [ICD]-O3 in the detection of favorable risk prostate cancer (PCa) site code C61.9 and morphology 81,403, T1 or 2, PSA [1]. PSA-based screening has been shown to reduce ≤15 ng/mL, Gleason score ≤ 7 [3 + 4]) identified from prostate-specific mortality by 21–30% [2, 3]. However, January 2005–October 2013 and active in the GHS the use of PSA screening has resulted in considerable ≥12 months prior to and ≥ 18 months post-index date over-diagnosis and over-treatment, with 15–20% of men were selected. The first PCa diagnosis date was defined receiving a PCa diagnosis during their lifetime but only as the index date. Patient data were assessed until the 3% dying from the disease [4]. earlier of death or April 2015. Observation strategies (OBS) such as active surveil- Patients with evidence of a previous cancer diagnosis lance (AS) and watchful waiting (WW) are alternatives ≤5 years prior to the initial PCa diagnosis (except for to immediate treatment (IMT) for men diagnosed with non-melanoma skin cancer), any PCa treatment before favorable risk PCa. The primary motivation for these the index PCa diagnosis, or other cancer diagnosis within strategies is to avoid or delay treatment-related adverse 6 months after the initial PCa diagnosis (identified using events [5]. ICD-O3-codes) were excluded. AS strategies also reduce immediate health care PCa and other cancer diagnoses, Gleason score, and expenditures by avoiding aggressive treatment costs, tumor stage were extracted from the oncology registry. including treatment complications, but they imply recur- Demographic, encounter, and PSA testing information rent costs for biopsies and other tests that accumulate were retrieved from EMR data. Cohorts were defined as over the patient’s lifetime [5]. The risk vs benefit consid- receiving any PCa treatment (IMT) or no treatment eration of AS also includes the possibility of disease within 6 months (OBS) after index PCa diagnosis date. progression to the point that a cure is less likely or not Prostate cancer risk categories were defined by D’Amico possible. classification [9]: low (T1-T2A, PSA level ≤ 10 ng/mL, and Recent studies indicate increased adoption of AS. How- Gleason score ≤ 6) [10] or intermediate (T1 or T2, PSA ever, most published reports are from academic centers level > 10 and ≤ 20 ng/mL, and Gleason score = 7). [6] or prospective trials with defined AS protocols. Some studies have examined updated observational strategies, IRB approval finding that those who chose to undergo OBS tended to All patient information was de-identified at the source in be older with lower risk disease. The number of men diag- accordance with 45 CFR 164.514(a) and (b) (Code of nosed with low-risk PCa who chose AS in these studies Federal Regulations Title 45, Public Welfare) and there- was low, suggesting that AS may have been underused in fore independent review board approval was not required. the management of very low-risk PCa [7, 8]. The objec- tives of this study were to compare overall survival and Study variables the clinical characteristics and management trends (OBS vs IMT) among men with favorable risk PCa from a large Clinical characteristics Charlson Comorbidity Index community practice, as well as to identify factors associ- (CCI) scores during the 12 months prior to index PCa ated with choosing OBS and to describe monitoring diagnosis were measured. PCa-related characteristics were patterns used for OBS. captured at the time of PCa diagnosis including tumor grade, Gleason score, and risk category based on the D’Amico risk classification. The index PSA was defined as Methods the last PSA value before or on the index biopsy date. Data source A retrospective study was conducted from January Monitoring patterns Monitoring patterns included PSA 2004 to April 2015 using linked electronic medical test, biopsy, and urology visits. records (EMRs), oncology registry data, and enrollment information from the Geisinger Health System (GHS) – Overall survival Overall survival was estimated per 100 a community-based integrated health care organization person-years (PY). serving residents in central, south, and northeast Pennsylvania. The EMR infrastructure contains longitu- Statistical methods dinal clinical patient data including patient demograph- Clinical characteristics were examined descriptively and ics and encounter details from inpatient, outpatient, compared between the OBS and IMT cohorts. Chi-square and office-based settings such as diagnoses, medica- and t-tests were used to calculate p-values, respectively, for tions orders, procedures, and laboratory results. categorical and continuous variables. Logistic regression Kariburyo et al. BMC Urology (2018) 18:55 Page 3 of 12 was used to determine odds ratios and 95% confidence in- vs 80.9%; p < 0.01) and more Medicare beneficiaries tervals (CIs) of factors associated with the selection of OBS (32.3% vs 24.2%; p < 0.01) (Table 1). The OBS cohort also versus IMT. Based on model fitting and clinical rationale, had a lower proportion with Gleason score = 3 + 4 at diag- covariates adjusted in the model included age, race, marital nosis (22.9% vs 35.5%, p < 0.01), and a higher proportion status, insurance status, family history of PCa, prior diagno- of low-risk PCa (65.2% vs 55.0%, p < 0.01) (Table 2). sis of chronic obstructive pulmonary disease, CCI score, and D’Amico risk categories. The use and frequency of Factors associated with the selection of OBS vs IMT monitoring patterns were assessed for patients utilizing Figure 2 shows the factors associated with OBS vs IMT OBS before switching to active treatment during the first, using a logistic regression model. Older age (65–74 years; second, and third years following their index PCa diagnosis. OR = 1.6 or 75+ years; OR = 4.3), marital status (single; Unadjusted Kaplan-Meier (KM) and log rank tests OR = 1.6 or divorce/separated; OR = 1.9), high CCI score were used to compare survival rates in OBS and IMT (≥2; OR = 1.6), and low-risk PCa (intermediate-risk vs cohorts. Multivariate Cox proportional hazards models low-risk, OR = 0.5) were significant predictors of choosing were used to examine Hazard Ratio (HR), and 95% CI of OBS over IMT, after adjusting for other covariates. overall survival. Statistical analyses were performed using SAS Version Prostate Cancer management trends 9.3 (Cary, NC) with p-value < 0.05 considered significant. The proportion of men managed with OBS increased Standardized differences and clinical relevance were also from 20% in 2005 to 35 and 52% in 2013 for patients considered. with favorable risk PCa, or low-risk PCa, respectively (Fig. 3). A similar increase was observed in patients with Subgroup analyses intermediate-risk PCa up to 2012 (from 19% in 2005 to A subgroup analysis was conducted by reporting monitor- 30% in 2012) but the proportion decreased to 14% in ing patterns among men whose treatment was managed 2013 (Fig. 3). with OBS: 1) for those who remained on OBS for at least 18 months and had ≥1 urologist visit (a proxy for active Time to active treatment patient management), and 2) for those who remained on The median time to treatment of all OBS patients was ~ OBS for ≥24 months. 4 years (Fig. 4). Of 181 OBS patients who switched to active treatment, the average time from initial PCa diag- Chart review nosis to treatment was 459 days (1.3 years). Manual examination of de-identified EMR chart data was For the subgroup analysis according to D’Amico risk undertaken to explore why some OBS patients did not classification: 29% (236/821) of low-risk versus 20% (117/ have follow-up visits. Charts were reviewed for all OBS 578) of intermediate-risk PCa patients received OBS. patients without a follow-up visit in the urology depart- Among men managed by OBS, 50% of low-risk versus ment within the first year after PCa diagnosis (N =57). 53% of intermediate-risk PCa patients eventually received The reasons were categorized as follow-up by another treatment during the follow-up period. clinical department (eg, oncology), delayed treatment based on patients’ preference, complicating comorbidities, Monitoring patterns for men managed with OBS and limited follow-up data. Monitoring patterns were assessed among the patients remaining on OBS in year 1 (n = 239), year 2 (n =166) and Results year 3 (n =116) (Fig. 5). In the OBS cohort, the percentage Patient characteristics of patients with at least one urology visit decreased during A total of 3342 men diagnosed with PCa and aged the first 3 years post-index PCa diagnosis from 86.6% in ≥40 years were identified from the oncology registry. year 1 to 65.1% in year 2 and 54.3% in year 3. However, After applying the exclusion criteria, the remaining 1425 PSA testing rates remained similar in the first 3 years of men in this analysis included 362 patients (25.5%) in the diagnosis, with approximately 70% of men receiving ≥1 OBS cohort vs 1063 patients (74.5%) in the IMT cohort PSA test each year. Approximately 7.1, 18.7, and 10.3% of (Fig. 1) with a median follow-up of 5 years. men in the OBS cohort received a prostate biopsy in the There were no significant differences between the OBS first, second, and third year, respectively (Fig. 5). and IMT groups in index PSA result, tumor stage, or body Among men remaining on OBS for ≥18 months and with mass index (Tables 1 and 2). The OBS group was older ≥1urology visit(N = 212), 85.8% received ≥1PSA testsand (65.6 vs 62.8 years; p < 0.01), had higher CCI scores (CCI 19.3% were administered one biopsy within the 18 months. score ≥ 2: 21.5% vs 12.2%, p <0.01), more patients whose Among those remaining on OBS for ≥24 months (N = 166), marital status was “divorced” (9.1% vs 5.7%; p =0.03), 88.6% received ≥1 PSA tests and 26.5% received one biopsy fewer patients whose marital status was “married” (72.9% within the 24 months. A chart review of 57 patients in the Kariburyo et al. BMC Urology (2018) 18:55 Page 4 of 12 Fig. 1 Patient Selection Flow Chart. PSA: prostate specific antigen; PCa: prostate cancer; ICD: international classification of diseases; OBS: observation strategies; IMT: immediate treatment. *Cohorts were defined as receiving any treatment (IMT) or no treatment (OBS) within 6 months after index PCa diagnosis OBS cohort without follow-up urology visits within the first all-cause mortality rate was higher for OBS compared 360 days post-diagnosis indicated that in 49 of 57 cases with IMT (2.7 vs 1.3/100 PY; p <0.001). The cumulative (86%) of PCa-related care by other GHS departments were hazard plot for overall survival indicated that after the identified with oncology as the most common specialty. sixth year of PCa diagnosis, the risk of all-cause mortality was higher in the OBS cohort than in the IMT cohort Overall survival (Fig. 6). However, after multivariate adjustment, there was Median follow-up time from PCa diagnosis in the entire no significant difference in all-cause mortality between the study cohort was approximately 5 years. The unadjusted OBS and IMT cohorts (IMT vs OBS, HR = 0.73, p =0.138; Kariburyo et al. BMC Urology (2018) 18:55 Page 5 of 12 Table 1 Socio-demographic characteristics of men with favorable risk PCa in OBS vs IMT cohorts OBS IMT (n = 362) (n = 1063) N/Mean %/SD N/Mean %/SD P-value Standardized difference Age (Mean) 65.6 9 62.8 8 <.01 33.10 Age Group 40–64 166 45.9% 601 56.5% <.01 21.47 65–74 137 37.9% 390 36.7% 0.69 2.39 75+ 59 16.3% 72 6.8% <.01 21.47 Race White 347 95.9% 1044 98.2% 0.01 13.91 Black or African American 14 3.9% 11 1.0% <.01 18.37 Native Hawaiian 1 0.3% 4 0.4% 0.78 1.75 Asian 0 0.0% 1 0.1% 0.56 4.34 Unknown 0 0.0% 3 0.3% 0.31 7.52 Marital Status Single 33 9.1% 68 6.4% 0.08 10.17 Married 264 72.9% 860 80.9% <.01 18.99 Widow 30 8.3% 67 6.3% 0.20 7.63 Divorced 33 9.1% 61 5.7% 0.03 12.89 Separated 2 0.6% 7 0.7% 0.83 1.37 Insurance Status Medicare 117 32.3% 257 24.2% <.01 18.15 Veterans Affairs 2 0.6% 2 0.2% 0.26 5.99 Medicaid 8 2.2% 19 1.8% 0.61 3.02 Commercial 227 62.7% 782 73.6% <.01 23.44 Other 4 1.1% 3 0.3% 0.05 9.91 Unknown 4 1.1% 0 0.0% <.01 14.93 OBS observation, IMT immediate treatment, SD standard deviation, CCI Charlson Comorbidity Index SD = standardized difference (SD is defined as the difference in sample means or proportions divided by standard error; reported as 100*|actual standardize difference|. Standardize differences >|10| are considered significant Fig. 7). Multivariate analysis also indicated that older age, In the current analysis, we found that patients who were divorce or separated status; prior diagnosis of COPD, and managed by OBS strategies were on average over age congestive heart failure were risk factors for all-cause 65 years and had higher CCI scores when compared to mortality. patients who received definitive treatment after index PCa diagnosis. Factors associated with the selection of OBS were similar with Liu et al. [11]. Similarly, prior research Discussion has reported that OBS strategies focus on deferring PCa In this study, we described overall survival and the charac- treatment in older, sicker patients diagnosed with a teristics and management patterns in men with favorable prostate tumor that is less aggressive than their underlying risk PCa within a large community-based health care sys- comorbidities [10, 12]. tem in the United States. While no single source provides Because of these known demographic and clinical differ- comprehensive data for most US patients, the major ences in patients who were managed by OBS compared to strength of this study is its large community-based setting. those who underwent IMT, the unadjusted all-cause In addition to the real-world use of EMR, the claims mortality rate was higher in OBS patients compared to oncology registry and unstructured information from IMT. These findings are similar to a previously published charts maximized the available data for each patient, while study comparing radical prostatectomy with WW in early also yielding a large sample size. Each of the data sources PCa patients [13]. After adjusting for these known differ- provided complementary information. ences in baseline demographic and clinical characteristics Kariburyo et al. BMC Urology (2018) 18:55 Page 6 of 12 Table 2 Clinical characteristics of men with favorable risk PCa in OBS vs IMT cohorts OBS IMT (n = 362) (n = 1063) N% N% p-value Standardized difference Comorbid Indices (CCI) 0 225 62.2% 750 70.6% <.01 17.83 1 59 16.3% 183 17.2% 0.69 2.45 2+ 78 21.6% 130 12.2% <.01 25.04 Comorbid Conditions Hypertension 153 42.3% 405 38.1% 0.16 8.50 Diabetes 61 16.9% 134 12.6% 0.04 11.99 COPD 43 11.9% 82 7.7% 0.02 14.03 Congestive Heart Failure 13 3.6% 27 2.5% 0.30 6.09 Dementia 0 0.0% 3 0.3% 0.31 7.52 Benign Prostatic Hyperplasia 130 35.9% 388 36.5% 0.84 1.22 Body Mass Index Underweight (< 18.5) 1 0.3% 5 0.5% 0.62 3.18 Normal (18.5–24.9) 42 11.6% 102 9.6% 0.27 6.52 Overweight (25.0–29.9) 118 32.6% 342 32.2% 0.88 0.90 Obese (≥30) 112 30.9% 336 31.6% 0.81 1.44 Unknown 89 24.6% 278 26.2% 0.56 3.60 Family History of Prostate Cancer Yes 74 20.4% 262 24.7% 0.10 10.07 No 208 57.5% 598 56.3% 0.69 2.43 Unknown 80 22.1% 203 19.1% 0.22 7.42 Family History of Cancer 109 30.1% 339 31.9% 0.53 3.85 Prostate Cancer Characteristics Index PSA (Mean, SD) 5.8 2.5 5.7 2.5 0.31 6.31 < 4 ng/mL 69 19.1% 208 19.6% 0.83 1.28 4–10 ng/mL 256 70.7% 758 71.3% 0.83 1.30 > 10 ng/mL 30 8.3% 77 7.2% 0.52 3.90 Unknown 7 1.9% 20 1.9% 0.95 0.38 Index Clinical Stage Stage 1 303 83.7% 855 80.4% 0.17 8.52 Stage 2 55 15.2% 184 17.3% 0.35 5.73 Unknown 4 1.1% 24 2.3% 0.17 8.97 Index Total Gleason Score = 3 + 4 83 22.9% 377 35.5% <.01 27.82 Risk Category Low-risk 236 65.2% 585 55.0% <.01 20.84 Intermediate-risk 117 32.3% 461 43.4% <.01 22.91 Unknown 9 2.5% 17 1.6% 0.28 6.27 OBS observation, IMT immediate treatment, SD standard deviation, COPD chronic obstructive pulmonary disease SD = standardized difference (SD is defined as the difference in sample means or proportions divided by standard error; reported as 100*|actual standardize difference|. Standardize differences >|10| are considered significant Clinical stage: anatomic Extent of the disease based on the clinical T, N and M element Risk Categories: Low risk (T1-T2A, PSA level ≤ 10 ng/mL, and Gleason score ≤ 6) and intermediate-risk (T1 or T2, PSA level > 10 and ≤ 20 ng/mL, and Gleason score = 7) Kariburyo et al. BMC Urology (2018) 18:55 Page 7 of 12 Fig. 2 Logistic Regression: Risk Factors Associated with OBS vs IMT. CCI: Charlson comorbidity index; CI: confidence interval; COPD: chronic obstructive pulmonary disease; VA: veterans affairs between the OBS and IMT cohorts in a multivariate PCa-specific mortality in favorable risk cancer is relatively analysis, there was no longer a significant difference in low and we do not have sufficient numbers of patients all-cause mortality between the OBS and IMT cohorts. followed for a long enough period to appreciate the differ- However, longer follow-up is needed to more convincingly ences between the OBS and IMT groups. assess all-cause mortality. We also evaluated deaths due to Other studies have shown that the presence of signifi- PCA or complication from PCa. However, the results were cant others in a patient’s life often influences treatment not conclusive because we could not identify the cause of decisions and our results suggest that even adjusting for death with certainty. There were a total of nine patients other factors such as race and type of insurance, that men (2.5%) with deaths possibly or probably due to PCa in the who were divorced or separated (or single) were more OBS group vs 15 deaths (1.4%) possibly or probably due likely to be treated with OBS vs IMT. However, in this to PCa in the IMT group (results not shown). In addition, study, marital status was only captured as single, married, Kariburyo et al. BMC Urology (2018) 18:55 Page 8 of 12 Fig. 3 Annual Prostate Cancer Management Trends for Favorable Risk and Low Risk PCa Patients. PCa: prostate cancer; OBS: observation strategies widow, divorced, and separated, and data on whether men consistent with American Urological Association (AUA) who were divorced, separated, or single were actually guideline changes and was similar with the trend in the living alone or living with a significant other was not adoption of AS/WW from a large US national registry captured [14]. In addition, health insurance plans were population with low-risk PCa [15]. Our study also identified from the data including Medicare, commercial, indicated that patients who switched from OBS to IMT Medicaid, self/other, Veterans Affairs, and unknown. We (64.6 years) were, on average, younger than patients who observed from our study that the risk of choosing OBS remained in the OBS (66.3 years) cohort with a median was significantly lower among the patients enrolled in follow-up period of 5 years. Moreover, 50% of the men commercial/other types of health insurance plans (34.5%) on OBS received active treatment eventually which is compared to those enrolled in Medicare/VA/Medicaid higher than in other studies [16–20]. This might be health insurance plans. because the benefits of AS were not clearly discussed or Regarding the adoption of OBS, we found an increased due to lesser adoption of AS in community settings as use of OBS in the GHS over time. This trend was opposed to academic institutions. This percentage is Fig. 4 Kaplan Meier for Time to Active Treatment in Men with Favorable Risk PCa Managed with OBS. OBS: observation strategies Kariburyo et al. BMC Urology (2018) 18:55 Page 9 of 12 Fig. 5 Monitoring Patterns for PCa Patients Managed with OBS. PSA: prostate specific antigen plausible given that during the timeframe of the study treatment date due to comorbid medical conditions to be (January 2004 to April 2015), there were no existing AS addressed prior to surgery or to better align with personal guidelines to inform decisions on conversion of patients commitments such as a seasonal work schedule. to active treatment. Several AS schedules for the management of favorable The proportion of OBS patients converting to treatment risk PCa have been used in various studies including the within the first 12 months and the second 12 months after 2017 National Comprehensive Cancer Network NCCN the index date is substantial. The most likely reason for guideline [21] and Cancer Care Ontario’s guideline on the large drop during the first 12 months is patients AS for the management of favorable risk PCa endorsed simply deferred treatment. A chart review of 20 by the American Society of Clinical Oncology (ASCO) randomly-selected OBS patients showed that 10 of 20 [22]. In comparison to these guidelines, we found that (50%) patients were considered for IMT. One additional serial monitoring in GHS was relatively low. patient received brachytherapy 10 months after diagnosis, Among the OBS patients who were active in the GHS but there were limited encounters with urology; therefore, for ≥2 years and who remained on OBS treatment in the details of the complete treatment plan were not available. first 2 years, only 61.5% had 3 or more PSA tests and Eight of these 11 men (73%) had intentional delays in their only 26.5% had a prostate biopsy, which differs from Fig. 6 Kaplan Meier Curve for Overall Survival Among Men With Favorable Risk PCa Kariburyo et al. BMC Urology (2018) 18:55 Page 10 of 12 Fig. 7 Multivariate Cox Regression Model for All-cause Mortality Among. Men With Favorable Risk PCa. PCa: prostate cancer; VA: veterans affairs; CCI: Charlson comorbidity index; COPD: chronic obstructive pulmonary disorder; PSA: prostate specific antigen; CI: confidence interval ASCO guidelines and most prospective AS protocols. were in the OBS group and 8.75% of the patients with Our data also showed a relatively stable PSA testing rate IMT had prostate-related MRI during the follow-up but a decrease in urology visits over time. In our study, period (results not shown). It is worth mentioning that 7.7, 20.5, and 10.8% of patients had one prostate biopsy MRI, including mpMRI, was not routinely used during in the first, second, and third year, respectively. Magnetic the timeframe of this study (January 2004 to April resonance imaging (MRI) use is an increasingly import- 2015). Although MRI was not routinely carried out in ant tool in clinical practice for the diagnosis and moni- the management of PCa in these patients, we do not be- toring of PCa patients, especially the multi-parametric lieve that any of these patients had their cancer manage- (mp) MRI [23]. Using Current Procedural Terminology ment affected by not using mpMRI. (CPT) codes to identify MRI use during the study The low monitoring rates observed in this study may period, we observed that only 8.56% of the patients who reflect a greater proportion of WW versus AS, which we Kariburyo et al. BMC Urology (2018) 18:55 Page 11 of 12 are unable to distinguish in our OBS population. In but were older and had higher CCI scores. However, no addition, a large proportion of patients included in this differences were observed in overall survival between the analysis were managed or treated prior to 2010 when AS two groups after covariates adjustment. These data was not yet widely adopted as a management strategy for provide insights into management patterns for favorable patients with clinically-localized PCa and there were no risk PCa within a community setting. consensus/guidelines for monitoring of AS or WW. Low Analysis of monitoring patterns within the OBS cohort monitoring rates for AS and WW in the community showed relatively low rates of repeat clinic visits and setting have been reported by Herden and Weissbach [24] testing. Further research is necessary to focus on verifying and Auffenberg et al. [25] as well, suggesting a need for the appropriate monitoring schedule to optimize patient research into the factors associated with departure from outcomes and to encourage the adoption of AS in com- guideline-recommended monitoring practices. munity settings. This study was a retrospective review of community prac- Abbreviations tice intended to reflect the real-world implementation of AS: Active surveillance; ASCO: American Society of Clinical Oncology; routine management. The inclusion and exclusion criteria CCI: Charlson comorbidity index; CPT: Current procedural terminology; EMR: Electronic medical records; GHS: Geisinger Health System; were primarily based on the patient having a lower-risk, IMT: Immediate treatment; mpMRI: Multi-Parametric magnetic resonance early stage of cancer at diagnosis. To achieve the observa- imaging; MRI: Magnetic resonance imaging; OBS: Observation strategies; tional nature of the study, no requirements or exclusions PSA: Prostate specific antigen; PY: person years; WW: Watchful waiting were made based upon management protocol including the Acknowledgements use of imaging data or biopsy results to address diagnosis Editorial assistance was provided by Michael Moriarty of STATinMED or treatment among favorable risk PCa patients. research. In sum, our data reveal significant opportunities for Funding improvement in management strategies for favorable risk This study was funded by Roche Molecular Systems. prostate cancer within our large community group setting. Educational activities should promote increased adoption Availability of data and materials The datasets supporting the conclusions of this article were obtained from of AS among favorable risk PCa patients as well as a clear linked electronic medical records (EMRs), oncology registry data, and distinction between AS and WW in individual patients. enrollment information from the Geisinger Health System, but restrictions Community-based AS strategies should also focus on apply to the availability of these data, which were used under license for the current study, and so therefore are not publicly available. Data however are appropriate monitoring of patients placed on AS. available upon request and with permission from the Geisinger Health System. Requests regarding data availability should be directed to Eric Limitations Meadows (es_meadows@yahoo.com). All patients without definitive treatment in the first Authors’ contributions 6 months after PCa diagnosis were temporarily classified as IC and DM conceptualized and designed the study. MFK and YW, LX, EM, JD, receiving OBS. However, the OBS strategies, AS or WW, and MC verified and analyzed the data. MFK, YW, IC, LW, DM, LX, EM, MC and JD substantially contributed to the interpretation of the data, wrote were not prospectively collected or always clearly noted by the manuscript and/or substantially contributed to critical revisions of the practitioners in the patient medical records. Therefore, we intellectual content. All authors read and approved the final manuscript. were not able to clearly distinguish between AS or WW Ethics approval and consent to participate from these real-world data. This limitation was also noted Since the core study herein did not involve the collection, use, or transmittal of from other studies (Cooperberg et al., 2015) [15]. Further- individual identifiable data, Institutional Review Board (IRB) approval to conduct more, there also was some apparent misclassification in this study was not required. Both the datasets and the security of our offices to keep the dataset meet the requirements of the Health Insurance Portability and assigning patients to OBS strategies versus IMT by the Accountability Act (HIPAA) of 1996. 6-month threshold, as some patients planned for definitive treatment but waited longer than6monthsbeforereceiving Competing interests FK, YW, and LX are paid employees of STATinMED Research which is treatment. An additional limitation is that Geisinger serves a paid consultant to Roche Molecular Systems. LW is a paid employee patients in Central and Northeastern Pennsylvania; there- of Genentech which is a member of the Roche group. DM is a paid fore, the study results may not be generalizable to the entire employee of Roche Diagnostics Operations. IC is a paid employee of Roche Molecular Systems. EM and JD are paid employees of Geisinger US PCa population. Finally, some patients may have re- Health System which is a paid consultant to Roche Molecular Systems. ceived care outside of GHS. MC has no conflicts to declare. Conclusion Publisher’sNote The proportion of men managed by OBS increased over Springer Nature remains neutral with regard to jurisdictional claims in the 10-year study period although the rate of adoption published maps and institutional affiliations. might have been slightly slower in this large community Author details setting compared with prospective AS protocols. Men in 1 STATinMED Research, 211 N. Fourth Avenue, Suite 2B, Ann Arbor, MI 48104, the OBS cohort had a higher proportion of low-risk PCa USA. Diagnostics Information Solutions, F. Hoffmann-La Roche AG, Basel, Kariburyo et al. BMC Urology (2018) 18:55 Page 12 of 12 3 4 Switzerland. Genentech, Inc, South San Francisco, CA, USA. Roche 19. 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BMC UrologySpringer Journals

Published: Jun 4, 2018

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