Active Surveillance Follow-Up for Prostate Cancer: From Guidelines to Real-World Clinical Practice

doi:10.21203/rs.3.rs-4983571/v1

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Active Surveillance Follow-Up for Prostate Cancer: From Guidelines to Real-World Clinical Practice

https://doi.org/10.21203/rs.3.rs-4983571/v1

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Purpose

To assess active surveillance (AS) adherence for prostate cancer (PCa) in a “real-world” clinical practice.

Materials and Methods

We utilized our institutional database which was built by interrogating electronic medical records for all men who got diagnosed with PCa from 1995 to 2022. Our cohort included all patients aged < 76 years, with PCa Gleason Grade (GG) 1 or 2, ≤ cT2c, PSA ≤ 20 ng/ml at diagnosis, enrolled on AS, and with at least one biopsy after diagnosis. Patients were separated into two groups based on the monitoring intensity.Patients with at least 1 PSA/year and at least 1 biopsy every 4 years were categorized as adherent to guidelines. Univariable and Multivariable logistic regression analyses were used to examine the impact of covariates on non-adherence to guidelines. Competing risks cumulative incidence was used to depict PCSM.

Results

A total of 546 men met the inclusion criteria. Overall, 63 (11%) patients were adherent to guidelines (Group 1), while 483 (89%) were not (Group 2). Median PSAs/year and median biopsies/year were 2.3 (2.0-2.7) and 0.4 (0.3-0.6) for Group 1, and 1.2 (0.7-1.8) and 0.2 (0.1-0.2) for Group 2, respectively (both p<0.0001). At multivariable analysis, Black men had a 2.20-fold higher risk of being in Group 2 than White men (p<0.05). Patients with cT2 (OR:0.24, CI:0.11-0.52) and those with CCI ³2(OR:0.40, CCI:0.19-0.82) were less likely to be in Group 2, when compared to cT1 stage and CCI=0, respectively (both p< 0.05). At 10 years, the cumulative incidence estimate of prostate cancer-specific mortality (PCSM) for the entire cohort was 2.1%.

Conclusion

We found substantial deviations from AS monitoring guidelines, particularly in biopsy frequency, which did not seem to compromise PCSM in patients with stable PSA. Notably, our findings suggest that strict adherence to guidelines, especially in patients with cT2 at diagnosis, remains crucial.

Active Surveillance

Guideline Adherence

Practice Guideline

Prostatic Neoplasms

Prostate-Specific Antigen.

The increased use of Prostate-Specific Antigen (PSA) testing has led to more frequent detection of low-risk prostate cancer (PCa), which generally has slow progression and a favorable clinical prognosis [1–2]. To prevent overtreatment, active surveillance (AS) was suggested as a valid alternative to whole-gland treatment in these individuals [3–5].

After more than a decade since the introduction of AS to clinical guidelines, there is no consensus around the appropriate intensity of monitoring follow-up for these patients. However, all contemporary protocols share similar principles, namely regular PSA testing, combined with periodic repeats of prostate biopsy. The major guidelines including the European Association of Urology (EAU), American Urological Association (AUA), and National Comprehensive Cancer Network (NCCN), slightly vary for monitoring recommendations, but all emphasize the importance of regular follow-up. EAU advises at least 2 PSA tests per year, with a re-biopsy at least once every 3 years for a decade. AUA and NCCN both recommend up to 2 PSA tests per year. AUA advises re-biopsies ranging from every one to four years, while NCCN proposes at least biennially, not surpassing once a year [6–8].

However, given the long-term commitment that these protocols require, and the overall reluctance of patients to get periodic biopsy, it is plausible that AS protocols are not followed as strictly in daily practice as is recommended by the guidelines. A survey among European urologists supports this hypothesis, indicating that 47% of those practicing AS do not use an official AS protocol or are not involved in a clinical AS trial [9]. Furthermore, an inventory of real-world practice patterns in the United States (US), revealed that fewer than 13% underwent biopsy beyond the first 2 years [10]. Few studies evaluated the intensity of monitoring in AS follow-up in real-world practice. The largest studies are based on the SEER-Medicare database, that excludes patients younger than 66 years, which represents an important limitation considering that the median age at PCa diagnosis in the US is 66 years [10–11].

To address this void, we aimed to assess AS adherence to monitoring protocols in a “real-world” setting using a diverse North American cohort, and try to identify which factors might influence deviations from the guidelines.

Data Source

We utilized our institutional database which was built by interrogating our electronic medical records (EMRs) for all men receiving care in Henry Ford Health System between 1995 and 2022. Data from EMRs was collected by trained data programmers with years of experience collecting data from these records. Of note, our system of over 50 medical centers and hospitals serves the Detroit metropolitan population which is vastly diverse in its social and racial components. Our cohort included all patients aged < 76 years, who had a diagnosis of PCa Gleason Grade (GG) 1 or 2, with clinical tumor stage ≤cT2c, N0-M0, with PSA≤20 ng/ml at diagnosis [12] , enrolled on AS. The latter was identified in the database as all patients who did not receive any treatment within 1 year of diagnosis with at least one post-diagnosis biopsy. We enrolled patients who had a diagnosis before 2022, to allow one year’s time worth of eventual treatment information in our database. The selection criteria resulted in a total of 546 assessable patients.

Variables

To account for differences in the examined cohort, we extracted the following variables for each patient: Age at diagnosis, PSA at diagnosis, Last PSA available, the difference between Last PSA available and PSA at diagnosis, Gleason Grade Group (GG) (1, 2), Clinical T stage (cT1, cT2), Race (Black, White, Other, Unknown), Charlson Comorbidity Index (CCI) (0, 1, ³2, Unknown), Family Income by census tract (below/above the median) and Bachelor’s Degree rate by census tract (below/above the median). Additionally, the following variables were extracted to account for monitoring frequency after diagnosis: count of PSA testing, ratio of PSA testing per year, count of biopsies and ratio of biopsies per year.

Patients were categorized into two groups based on the intensity of AS monitoring. This categorization was based on the most permissive frequency of PSA testing plus the most permissive frequency of biopsies among the most contemporary guidelines (EAU, AUA, and NCCN) [7-8, 12]

Group 1 (adherent to guidelines): At least 1 PSA per year and at least 1 biopsy every 4 years.
Group 2 (not-adherent to guidelines): < 1 PSA per year or less than one biopsy every 4 years.

Endpoints

Our objective was to evaluate adherence to monitoring protocols of major international guidelines for AS within the context of 'real-world' clinical practice. As secondary endpoint, we calculated our Prostate Cancer-Specific Mortality (PCSM) rate.

Statistical Analysis.

Descriptive statistics consisted of median and interquartile range (IQR) for continuous variables, while frequencies and percentages were reported for categorical variables. Patients were then stratified by the combo PSA and biopsy frequency (Group 1 vs Group 2), and the two groups were compared by the Mann-Whitney test for numerical variables and Chi-square tests for categorical variables. Univariable and Multivariable logistic regression analysis were used to examine the impact of covariates of interest on non-adherence to guidelines (being in Group 2). Competing risks cumulative incidence curves were used to estimate PCSM in the entire cohort, and also stratifying the cohort to Group 1 vs Group 2. Differences in PCSM were examined using Gray’s test. Given the limited number of events, no multivariable analysis was performed to examine the impact of guidelines adherence on PCSM.

Two-sided p values < 0.05 indicated statistical significance in univariable comparisons. The Benjamini-Hochberg p-value correction was used to control for multiple comparisons within multivariable analyses. Two-sided p-values less than their respective adjusted critical values were considered significant. All analyses were performed using SAS 9.4 (SAS Institute, Cary, North Carolina). Patients were retrospectively enrolled in HFH-IRB#12641-29. An institutional review board waiver for informed consent was obtained prior to conducting this study, in accordance with institutional regulations when dealing with de-identified previously collected data.

A total of 546 men met the inclusion criteria (Figure 1), with a median age at diagnosis of 65 (IQR 60-69). Median PSA at diagnosis was 5.0 (4.2-6.5) ng/ml. The most represented GG and clinical tumor stage were GG1 (81%) and cT1 (90%). Categorizing the cohort, 63 (11%) patients were in Group 1, and 483 (89%) were in Group 2. Follow-up time was 5.3 (2.2-7.0) years for Group 1 and 9.3 (6.8-12.2) years for Group 2 (p<0.0001). The median difference between the last PSA and the PSA at diagnosis was 0.0 (-4.6, 1.7) for Group 1 and -0.5 (-4.3, 0.7) for Group 2 (p = 0.4). Median PSAs testing per year and median biopsies per year were 2.3 (2.0-2.7) and 0.4 (0.3-0.6) for Group 1, and 1.2 (0.7-1.8) and 0.2 (0.1-0.2) for Group 2, respectively (both p<0.0001). All the other descriptive statistics are illustrated in Table 1.

At multivariable analysis (Table 2), Black patients had a 2.20-fold higher risk of being in the non-adherent to guidelines group (Group 2) when compared to their White counterparts (p<0.05). Patients with cT2 disease (OR:0.24, CI:0.11-0.52) and those with high comorbidity (CCI ³2) (OR:0.40, CCI:0.19-0.82) were less likely to be in the non-adherent to guidelines group, when compared to the cT1 stage and CCI=0, respectively (both p< 0.05).

Cumulative incidence curves are represented in Figure 2. At 10 years, the cumulative incidence estimate of PCSM for the entire cohort was 2.1%, and it was 8.4% vs 1.6% for Group 1 vs Group 2 (p= 0.0003).

Over a decade has passed since the introduction of AS to clinical guidelines, and yet there is no consensus on the optimal intensity of monitoring follow-up for these patients. The most contemporary protocols adhere to the same principles: regular PSA testing, combined with periodic repeats of prostate biopsy. However, in clinical practice, urologists and patients often do not adhere to AS protocols as delineated in clinical trials and recommended by guidelines [9]. Furthermore, few studies evaluated AS monitoring in a diverse cohort such as the American population, and the majority of studies available rely on the SEER-Medicare database, which excludes patients younger than 66 years [10–11]. To fill this gap, our study sought to evaluate adherence to AS monitoring protocols in a 'real-world' context, hypothesizing that in clinical practice, the frequency of PSA testing and biopsy will be less frequent than what is recommended in the guidelines.

Several of our findings are worth highlighting. First, we observed that 89% of patients in our AS cohort do not adhere to the guideline’s recommendations, even the most permissive ones available. However, these patients had a median PSA testing frequency of 1.2 per year (0.7–1.8), which aligns with the recommendations of both AUA and NCCN (at least one PSA per year), suggesting that the defining factor placing these patients 'out of guidelines' is not the frequency of PSA testing, but rather the frequency of biopsies. Indeed, the median (IQR) number of biopsies/year was 0.2 (0.1–0.2), which indicates that 75% of these patients underwent one biopsy every five years or more, which significantly diverges from even the most permissive guidelines, such as the AUA, which advise re-biopsies ranging from one to four years. The lower utilization of biopsies compared to PSA testing has been known for some years, for example Loeb et al. reported that among 5,192 patients on AS in the SEER-Medicare database, over 80% underwent annual PSA testing, while less than 13% had a biopsy after the first two years [10].

Second, the median difference between the last available PSA and PSA at diagnosis for the group of patients who didn’t adhere to guidelines was − 0.5 (-4.3–0.7), indicating that at least 75% of these patients experienced a PSA increase inferior to 0.7 ng/ml over the study period. Consequently, their PSA levels remained relatively stable over a median (IQR) follow-up of 9.3 years (6.8-12.29). This stability in PSA over time may partly explain why patients forego biopsies, which besides being unpleasant for patients, do also carry risks of infection and bleeding [13–14]. Moreover, without a notable increase in PSA, urologists might be less persuasive in justifying the need for a repeat biopsy.

Third, as shown in the multivariable analysis, Black patients were less likely to follow the AS monitoring guidelines compared to White patients. This observation corroborates a previous SEER-Medicare-based study, where Black men were less likely to undergo PSA testing, MRI, and re-biopsy compared to non-Black men [11]. Furthermore, from our data, it emerges that patients in poorer health (CCI ≥2 vs CCI = 0, p = 0.01) and with more advanced PCa at diagnosis (cT2 vs cT1, p < 0.05) were more likely to adhere to AS guidelines. The relationship between a higher stage at diagnosis and receiving a closer follow-up was expected, and similar to previous reports [10]. On the other hand, the higher compliance in patients with more comorbidities, is somewhat counterintuitive and different from the study mentioned above [10], where repeated biopsies were less frequent in patients with higher comorbidity. We do not have a precise explanation for this phenomenon, but it could be speculated that these patients, due to their additional comorbidities, might have been under closer overall surveillance by our healthcare system, leading to more frequent consultations with urologists.

Fourth, our patients on AS exhibited a favorable cumulative incidence of PCSM, estimated at 2.1% at 10 years, which is similar to the 1.5% reported in the PROTECT trial [15], especially considering that our study was retrospective and reflected real-world clinical practice. However, upon examining the two separate groups, those adhering to monitoring guidelines (Group 1) exhibited a PCSM rate five times higher than the group not adherent to guidelines (Group 2) (8.4% vs 1.6%, p = 0.0003). Noteworthy, due to the retrospective nature of the study, it is plausible that patients in Group 1 are those who had disease progression during surveillance, which explains the higher biopsy rate in this group. It also explains why these individuals had a shorter median (IQR) follow-up (5.3 years, 2.2-7.0) when compared to Group 2 (9.3 years, 6.8–12.2). In the future, it will be crucial to develop more sophisticated tools for identifying these individuals upfront, as they might benefit from active treatment. Moreover, caution is advised when interpreting this data, as there are relatively few patients in Group 1, and these patients presented with a significantly higher cT stage. This might explain why patients in Group 1 were well-monitored and strictly adhered to the AS monitoring guidelines. On the other hand, Group 2 had a PCa that remained stable, with a cumulative incidence of PCSM at 10 years of 1.6%, which is comparable to PCSM rate reported in clinical trials [15]. These patients underwent fewer biopsies than recommended, and this doesn’t seem to compromise their PCSM. Regrettably, due to insufficient events, a multivariate analysis on PCSM, which would be ideal, cannot be performed. Nonetheless, these findings confirm that although both groups were good candidates for AS, over time they tended to exhibit different disease courses.

To the best of our knowledge, our work is the first that evaluated AS adherence to monitoring protocols in a “real-world” setting using a cohort without age limitations. Our study adds knowledge to the existing literature analyzing how AS patients are actually monitored in clinical practice. Strengths of our data include a long median follow-up period of 8.9 years, allowing for evaluation of real-world AS monitoring patterns across a long interval. Another strength is that the data were collected up until 2022, reflecting the use of AS from its initial adoption to the present, during which its use has exponentially increased.

Although our study contributes and adds to the previous literature, it is not without limitations. Our work’s limitations include the retrospective nature of the study. Additionally, unknown confounders might also have affected our observations. A further potential limitation is that our cohort might fail to capture PSA testing performed outside of our health system; this limitation is partially mitigated by the approximately 50 locations within the health system that offer laboratory services. Additionally, some patients might have moved out of our surveillance within our institutions and were consequently lost to follow-up.

Our study represents a significant step in understanding AS adherence to monitoring protocols in a 'real-world' setting. We found substantial deviations from AS monitoring guidelines, particularly in biopsy frequency, which did not seem to compromise PCSM in patients with stable PSA levels. Notably, our findings suggest that strict adherence to guidelines, especially in patients with cT2 at diagnosis, remains crucial.

Funding: The VCORE is supported by a fund, which was started by a contribution from the Menon Foundation and the VUI Foundation. No funding was received to assist with the preparation of this manuscript. No funding was received for conducting this study.

Competing interests: None of the authors have any relevant disclosures, and none of the authors have any financial or non-financial interests that may be relevant to the submitted work.

Other acknowledgements: The funder did not play a role in any part or phase of the study. Results in this manuscript have been presented in part as abstract presentation at the European Association of Urology 2024 Congress.

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Tables 1 to 2 are available in the Supplementary Files section

No competing interests reported.

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Active Surveillance Follow-Up for Prostate Cancer: From Guidelines to Real-World Clinical Practice

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