The impact of age on prostate cancer progression and quality of life in active surveillance patients

Abstract Objectives To evaluate the impact of age on overall survival (OS), freedom from distant metastasis (FDM), rates of therapeutic intervention (TI), and quality of life (QOL) in active surveillance (AS) prostate cancer patients. Materials and methods Three hundred and five consecutive, prospectively evaluated AS patients who underwent a staging transperineal template‐guided mapping biopsy (TTMB) prior to enrollment on AS were evaluated and stratified by age. Evaluated outcomes included OS, FDM, TI, and QOL to include urinary, bowel, sexual function, and depression. Post void residual (PVR) urine measurements were also followed. Repeat biopsy was based on PSA kinetics, abnormal digital rectal examination or patient preference. Results Of the 305 patients, 290 (95.1%) were Gleason 3 + 3 and 15 patients (4.9%) were Gleason 3 + 4. The median follow‐up was 5.5 years (range 1‐14 years). At 10 years, TI was 0%, 1.0%, and 11.4% for patients ≤59, 60‐69, and ≥70 years of age (P < .001). No patient has developed distant metastasis. The median time to TI was 4.71 years. No statistical differences in urinary function, bowel function, or depression were noted. Potency preservation was dependent on patient age. Conclusion Within the confines of the follow‐up of our series, younger patients were less likely to proceed to therapeutic intervention. In addition, patient age did not adversely impact QOL outcomes.

long life expectancy. Although younger patients may potentially be at greater risk for prostate cancer death without local therapy, they also are at greater risk for adverse QOL outcomes to include urinary, bowel, and sexual function when compared to older patients. 6 Leapman and colleagues evaluated 1,433 AS patients with the conclusion that at 5 years patients ≤60 years of age were less likely to require therapeutic intervention. 7 Mahal et al in an evaluation of the Surveillance, Epidemiology and End Results (SEER) database reported that young men are increasingly managed with active surveillance with AS rates increasing from 22% in 2010 to 58% in 2015. 8 The 5 year prostate cancer specific mortality rates were <0.30% across all age cohorts regardless of upfront treatment management strategies. 8 Transperineal biopsy techniques systematically map the prostate gland and provide more accurate information regarding prostate cancer grade, volume, spatial distribution of cancer, and decrease the infectious morbidity of transrectal ultrasound (TRUS) biopsy.
The possibility of missed high-grade prostate cancer at initial biopsy poses the greatest risk to AS patients in terms of lost opportunity for cure. 9 Approximately 1/3 of AS patients proceed to therapeutic intervention within the first few years of diagnosis, most likely a result of sampling error due to TRUS biopsy. TTMB has been demonstrated to accurately identify high-grade cancers when compared to wholemount radical prostatectomy (RP) pathology. 10 The majority of clinically significant prostate cancers that are missed at TRUS biopsy are located in the anterior prostate. 11,12 Previously, in a TTMB staging series we reported that Gleason score is upgraded in 39% of patients with upgrading most common in the anterior prostate and apex. 13,14 In our series, all patients undergo a transperineal template-guided mapping biopsy (TTMB) prior to AS enrollment. 4 In the current study, we evaluated the impact of patient age on AS outcomes to include overall survival (OS), freedom from distant metastases (FDM), therapeutic intervention (TI), post void residual urine (PVR) and urinary, bowel, sexual, and depressive quality of life parameters. Previously, the TTMB technique has been described in great detail. 13,14 All biopsies were performed by a single operator (GSM). Two days prior to TTMB tamulosin (0.8 mg daily) was initiated and continued for 2 weeks. TTMB was performed in the operating room with the patient in dorsal lithotomy position under general anesthesia.

| MATERIAL S AND ME THODS
All patients received peri-operative antibiotics. The prostate gland was scanned from the proximal seminal vesicles/base of the prostate gland to the apex. A volumetric ultrasonographic evaluation was obtained to determine prostate size. In addition, the prostate gland and transition zone (TZ) volumes were estimated as an ellipsoid with the formula: length × width × height × π/6. Transperineal biopsies were obtained through template apertures corresponding to the 24 regional biopsy locations. 13 All IIEF scores were obtained without pharmacologic or mechanical assistance. Potency was defined as an IIEF >12. CES-D was integrated into our patient evaluation in September 2011.
Patients were evaluated by one of three age groups (≤59, 60-69, and ≥70 years). A one-way Anova was utilized to determine the differences across the three age groups for continuous variables and Chi-square analysis was used to determine the differences of the categorical variables. OS and potency preservation was evaluated with a Kaplan-Meier survival curve and competing risk analysis was used to determine TI. For all tests a P value ≤.05 was considered statistically significant. Statistical analysis was performed using STATA (Version 15.0, STATA Corp, LP, College Station, Texas).

| RE SULTS
The study population consisted of 305 consecutive, prospectively evaluated AS patients. All patients underwent TTMB as a staging procedure for a TRUS or transperineal diagnosed Gleason score 6 (3+3) adenocarcinoma of the prostate gland, a persistently elevated PSA and/or the presence of ASAP ( When TRUS and TTMB biopsies cores were combined, a mean of 71 cores were obtained with a mean of three positive cores. Younger patients (≤59 years of age) presented with a lower pre-diagnosis PSA, a smaller prostate volume, a higher incidence of Gleason score 6 histology, a lower positive core percentage and were less likely to present with hypertension, coronary artery disease, diabetes or hypercholestoremia.
OS at 10 years was 100%, 84.6%, and 78.3% in patients ≤59, 60-69, and ≥70 of age (P = .082) ( Figure 1A). Therapeutic intervention at 10 years was 0%, 1%, and 11.4% for patients ≤59, 60-69, and ≥70 years of age (P < .001) ( Figure 1B) In terms of quality of life, no significant change in IPSS, urinary QOL, PVR, rectal function, or depression scores were noted throughout the duration of the study (Figure 2). At 8 years, 77.5%, 64.9%, and 35.1% of patients ≤59, 60-69, and ≥70 years of age remained potent (P < .001) (IIEF>12 without pharmacologic or mechanical assistance) ( Figure 3). for AS patient selection because of its ability to accurately identify high-grade prostate cancers. 10 The majority of clinically significant prostate cancers missed at TRUS biopsy are located in the anterior gland which is a region easily accessible by TTMB. 13,14 AS is an appealing strategy in younger patients because these patients have better baseline urinary and sexual function compared to older patients. Until recently, younger patients with favorable prostate cancer were most likely treated with definitive local therapy. However, recent trends demonstrate an increased acceptance of AS management in these younger patients. 8 It has been reported that younger men managed with AS are not at increased risk for progression. 7, 21 Druskin and colleagues reported a 5 year incidence of biopsy grade reclassification to grade group 3 or greater of 4%, 7%, and 14% in men younger than 60, 60-69, and 70 years of age or older (P < .001). 21 This is consistent with the incidence of therapeutic intervention in our series. Figure 1B illustrates therapeutic intervention rates of 0%, 1.0% and 11.4% of men ≤ 59, 60-69, and ≥ 70 of age at 10 years (P ≤ .001).

| D ISCUSS I ON
Recent AS studies demonstrate that PSA kinetics predict follow-up biopsy outcomes in selected situations. 22 Importantly, a review of Gleason score 6 radical prostatectomy (RP) specimens confirmed the absence of metastatic potential in these lesions. 25 Following RP with Gleason score 6 histology a 0.2% cancer death rate was reported.
A possible shortcoming of our AS protocol is the absence of routine follow-up prostate biopsies. In our series, repeat TTMB Surveillance) series followed for more than 4 years had undergone all of the biopsies recommended by study protocol. 26 In the future, genomic testing and MRI will play greater roles in patient selection and follow-up.
Strengths of our study include its prospective nature, all patients underwent the same intensive initial biopsy procedure prior to AS enrollment and underwent consistent and complete follow-up.
Weaknesses of our study is that prostate cancer has a long natural history and additional follow-up of this cohort will be mandatory to determine durability. The necessity of general anesthesia and operating room time has limited the widespread adoption of TTMB.
In addition, consistent with the John's Hopkins study our series is enriched with white patients (97.7%). As such, our results may not be applicable to minority patients. 4

| CON CLUS IONS
Within the confines of the follow-up of our series, younger patients were less likely to proceed to therapeutic intervention. In addition, patient age did not adversely impact QOL outcomes.