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Active surveillance in favorable intermediate-risk prostate cancer patients: Predictors of deferred intervention and treatment choice

Introduction: Active surveillance (AS) is increasingly used for favorable intermediate-risk (FIR) prostate cancer (PCa). Our objective was to determine oncological and sociodemographic predictors of deferred definitive therapy and decision for radical prostatectomy (RP) vs. radiotherapy (XRT). Methods: The Surveillance, Epidemiology, and End Results Prostate with Watchful Waiting database was used to identify all FIR PCa diagnosed between 2010 and 2015 opting for AS for at least one year following diagnosis. We sought to determine predictors of treatment and treatment type using multivariable logistic regression. Results: A total of 20 334 patients were identified. An annual decrease in incident FIR patients managed initially with AS between 2010 (4061) and 2015 (2947) was noted (p for trend <0.001); 17 895 (88.0%) patients underwent deferred RP and/or XRT. Patients with higher baseline cancer volume and clinical stage were significantly more likely to discontinue AS. Patients of higher socioeconomic status were more likely to undergo deferred therapy, with increased odds CUAJ – Original Research Sayyid et al Deferred intervention in favorable-risk AS


Introduction
Active surveillance (AS) is currently the standard of care for very low-and low-risk prostate cancer (PCa). 1,2 This management strategy has proven its long-term oncologic safety in these cohorts and simultaneously maintains patient quality of life, 3,4 and thus there has been increased interest in expanding the indications for AS to the intermediate risk cohort. This is supported by results from the Prostate Testing for Cancer and Treatment (ProtecT) trial demonstrating that low-and intermediate-risk PCa patients managed conservatively with active monitoring had long-term PCa-mortality outcomes similar to those managed with radical prostatectomy (RP) or radiotherapy (XRT). 5 Furthermore, a large, multinational autopsy study demonstrated that more than half of Asian men with incidental PCa at autopsy harbored evidence of Grade Group (GG) two disease or worse, confirming the indolent nature of a subset of this risk group. 6 These findings have contributed to multiple governing bodies supporting AS use for patients with favorable intermediate risk (FIR) PCa, 1,2 defined per the National Comprehensive Cancer Network (NCCN) as predominant GG1 disease, percentage of positive biopsy cores <50%, and a single NCCN intermediate risk factor. 7 These recommendations have been reflected in an increased uptake of AS for patients with intermediate-risk disease, with a recent analysis of the Surveillance, Epidemiology, and End Results (SEER) Prostate with Watchful Waiting (WW) database demonstrating that use of AS for such patients has significantly increased over time, from 3.7% in 2010 to 7.3% in 2015. 8 With the increased uptake of AS for FIR PCa patients, understanding the factors influencing the decision to discontinue AS in favor of deferred definitive intervention, as part of a shared decision-making process between the patient and physician, becomes important. Our objective was thus to evaluate both oncologic and sociodemographic predictors of undergoing deferred definitive intervention after a period of AS, and in patients undergoing deferred intervention, choice of RP versus XRT.

Results
Of 357,140 men with PCa in the SEER WW database, we identified 20,334 men with NCCN FIR PCa who were managed with AS for at least one year following diagnosis. Of these 20,334 men, 9,224 (45.4%), 2,552 (12.6%), and 8,558 (42.1%) were in the GG2, PSA 10-20 ng/ml, and cT2b-c groups, respectively ( Figure 1). Baseline sociodemographic and oncologic characteristics for the overall cohort and by FIR group are presented in Table 1  .9% versus 0-12.5%: 1.33 and 2.10, p=0.008 and p<0.001, respectively) and more advanced clinical stage in all three FIR groups (OR: 3.00 and 5.26 for cT2a versus cT1, p<0.001 in the GG2 and PSA 10-20 ng/ml groups respectively, and OR: 15.5 for cT2c versus cT2b in the cT2bc group, p<0.001).
With regards to baseline sociodemographic variables, patients of higher SES were significantly more likely to undergo definitive therapy in all three FIR groups (ORs for highest versus lowest quartiles: 1.72, 1.50, and 1.60, p<0.001, 0.013, and 0.03 for the GG2, PSA 10-20 ng/ml and cT2b-c groups, respectively). In the GG2 group, African American patients (versus Caucasian OR: 0.83, p=0.03) and those diagnosed in a Western region (versus Northeastern OR: 0.81, p=0.014) had significantly lower odds of undergoing definitive therapy, whereas patients who were not married were significantly more likely to opt for definitive therapy (OR: 1.43, p<0.001). In the cT2b-c group, older patients (OR for 70-79 versus 30-49: 0.16, p=0.004), those who were uninsured (versus insured OR: 0.18, p=0.009), and those diagnosed in a Southeastern region (versus Northeastern OR: 0.42, p=0.022) all had significantly lower odds of undergoing definitive therapy (Table 2).
Among patients who underwent deferred definitive therapy, patients with larger tumor volume at time of diagnosis were significantly more likely to opt for definitive XRT over RP in all FIR groups (OR for 37.6-49.9% versus 0-12.5%: 0.34, 0.21, and 0.33, p<0.001, p=0.014, and p<0.001 for the GG2, PSA 10-20 ng/ml and cT2b-c groups, respectively). Conversely, patients with a more advanced clinical stage were significantly more likely to opt for RP (OR: 167.2 and 239.8 for cT2a versus cT1, p<0.001 in the GG2 and PSA 10-20 ng/ml groups respectively, and OR: 38.6 for cT2c versus cT2b in the cT2b-c group, p<0.001). In the GG2 group, patients with a PSA of 5-10 ng/ml (OR 1.60, p=0.033) and no prior non-PCa malignancy (OR 1.60, p=0.033) were both significantly more likely to opt for RP over definitive XRT. With regards to sociodemographic variables, older patients (ORs for 70-79 versus 30-49: 0.034 and 0.027, p<0.001 for the GG2 and cT2b-c groups, respectively) and those of higher SES in the GG2 (OR for 2 nd versus lowest: 0.63, p=0.013) and cT2b-c groups (OR for 3 rd versus lowest:0.32, p =0.034) were significantly more likely to choose XRT over RP. Similarly, African American patients in the GG2 and PSA 10-20 ng/ml groups were significantly more likely to undergo XRT (OR versus Caucasian: 0.58 and 0.34, p=0.003 and 0.012, respectively). Conversely, patients who were not married were significantly more likely to undergo RP versus XRT in the GG2 (OR: 1.39, p=0.016) and cT2b-c groups (OR: 2.45, p<0.001, Table 3, Supplementary Table 2).

Discussion
In this population-based analysis of 20,334 men with FIR PCa managed with AS for at least one year following diagnosis, we determined that most (88.0%) patients eventually discontinued AS in favor of deferred definitive therapy. This figure is significantly higher than that previously

CUAJ -Original Research
Sayyid et al Deferred intervention in favorable-risk AS 6 © 2021 Canadian Urological Association reported for low risk PCa patients from the SEER WW database (65.7%). 15 It is also higher than the proportion treated in a recent single center experience of AS in intermediate risk cancer, where it was 49% at 10 years. 16 Notably, choice of deferred definitive therapy differed by FIR risk group in our cohort. XRT was the treatment of choice for patients with GG2 and PSA 10-20 ng/ml FIR PCa (86.3% and 86.0%, respectively), whereas RP was the treatment of choice for 96.1% of patients with cT2b-c FIR PCa.
A significant annual decrease in number of FIR PCa patients managed with AS was observed for the overall cohort, which was secondary to an absolute decrease in number of PSA 10-20 ng/ml and cT2b-c FIR patients managed with AS. There was a concurrent increase in the number of GG2 FIR patients managed with AS. Despite this overall decrease, it is not possible to infer that there has been a decreased uptake of AS for FIR patients without considering the number of such patients managed with definitive therapy during the same timeframe. This decrease may in part reflect the overall decrease in PCa incidence following the 2012 United States Preventive Services Task Force recommendations. 17 Advanced clinical stage was consistently found to be strongly associated with increased odds of undergoing deferred definitive intervention, and among those who underwent intervention, RP over XRT (ORs of 38.6-239.8 across all three FIR groups). These findings may be related to the increased uptake of multiparametric magnetic resonance imaging (mp-MRI) in the follow up of AS patients since 2010, resulting in increased detection of extraprostatic extension. 18 This would plausibly trigger discontinuation of AS and may also explain the decrease in numbers of cT2b-c FIR patients managed with AS between 2010 and 2015 in our cohort.
Patients of higher SES were significantly more likely to undergo deferred definitive therapy across FIR subgroups. Patients of higher SES are known to be more likely to follow up with their physicians, 19,20 and thus be more compliant with repeat PSA, clinical exam and biopsy protocols. This increases the likelihood of detecting signs of disease progression/understaging, which act as triggers for intervention. Interestingly, such patients were also more likely to opt for definitive XRT over RP in two of the FIR groups. Similarly, FIR African American patients with GG2 or PSA 10-20 ng/ml were more likely to opt definitive XRT over RP even after controlling for baseline oncologic and sociodemographic variables such as SES and insurance status. These findings may reflect African American patients' known distrust of the medical system 21-23 and their desire to avoid invasive interventions. This is further reflected in GG2 FIR African American patients being 17% less likely to undergo definitive intervention. This is the first population-based study evaluating sociodemographic and oncologic predictors of deferred definitive therapy in AS FIR PCa patients. Our study is strengthened by our use of a large, validated, 24,25 nationally representative dataset. 9 It is important to note however that our deferred intervention rate of 88.0% is significantly higher than those previously reported in other series, which have ranged between 31 and 49% over a five to ten year follow up  16,[26][27][28] This difference is likely related in part to differences in cohort eligibility criteria with previously reported series applying stricter eligibility criteria. In these series, AS was often restricted to FIR patients older than 65 years 26,28 or a life expectancy less than ten years. 28 Furthermore, these series originated in academic tertiary centers where practice patterns are likely to differ from those seen in population-based settings. However, without follow up oncologic data (e.g. PSA changes, mp-MRI findings, GS upgrading or increased PCa volume on repeat biopsies), exact triggers for intervention, and information regarding patients' medical comorbidities it is not possible to discern the exact reasons for these disparities. AS protocols (i.e. timing of confirmatory biopsy, frequency of PSA measurements, etc.) were not available for these patients. Practice patterns have also evolved since the study time period of 2010 to 2015. There has been an increased uptake of mp-MRI 29 and prognostic genetic biomarkers 30 in the AS setting, as well as changes to the GS scoring system. 31 Thus, the results of this study must interpreted in light of these recent advances. Further limitations to this study include the absence of timing of interventions, which precluded us from performing time-to-event analyses with Cox proportional hazard modeling, and inability to differentiate patients initially managed with AS or WW. However, by excluding patients older than 80 years at time of diagnosis, we attempted to minimize the number of patients in the WW group. 10 Similar to other studies originating from population-based registries, this analysis is subject to the limitations and inherent biases characteristic of population-based registries, particularly with regards to missing data which has been found to be as high as 46% in validation studies of this dataset. 24,25 Patients in the SEER database are from population-based cancer registries covering approximately 35 percent of the US population, and thus results from this dataset may not be generalizable to the entire US population. 9