The impact of very high initial PSA on oncological outcomes after radical prostatectomy for clinically localized prostate cancer

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Urologic Oncology: Seminars and Original Investigations 000 (2020) 1−7

Clinical-Prostate cancer

The impact of very high initial PSA on oncological outcomes after radical prostatectomy for clinically localized prostate cancer Derya Tilki, M.D.a,b,*, Philipp Mandel, M.D.c,*, Pierre I. Karakiewicz, M.D.d, Alexander Heinze, M.D.a, Hartwig Huland, M.D.a, Markus Graefen, M.D.a, Sophie Knipper, M.D.a,d,** a

Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany b Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany c Department of Urology, University Hospital Frankfurt, Frankfurt, Germany d Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada Received 5 September 2019; received in revised form 17 December 2019; accepted 31 December 2019

Abstract Background: To analyze oncological outcomes of very high-risk patients with initial PSA 50-99.9 and ≥100 ng/ml who underwent radical prostatectomy (RP) for clinically localized prostate cancer. Methods: Overall, 2,811 RP patients (1992-2018) with negative preoperative CT-scan and bone scintigraphy were included. The impact of preoperative PSA level, categorized as 20-49.9 (n = 2,195) vs. 50-99.9 (n = 454) vs. ≥100 ng/ml (n = 162) on biochemical recurrence (BCR)-free survival, metastasis-free survival (MFS) and cancer-specific survival (CSS) was assessed using Kaplan-Meier and multivariable Cox regression models. Results: Median follow-up was 47.5 months. Ten-year BCR-free survival rates were 46.9 vs. 32.1 vs. 29.0% within PSA-categories 20-49.9 vs. 50-99.9 vs. ≥100 ng/ml, respectively (P < 0.001). Ten-year MFS rates were 78.4 vs. 67.2 vs. 37.3% within PSA-categories 20-49.9 vs. 50-99.9 vs. ≥100 ng/ml (P < 0.001). 10-year CSS rates were 93.7 vs. 85.5 vs. 66.7% within PSA-categories 20-49.9 vs. 50-99.9 vs. ≥100 ng/ml (P < 0.001). In multivariable analyses, PSA-categories 50-99.9 ng/ml and ≥100 ng/ml were independently predicting higher risk of BCR (hazard ratio [HR]: 1.3 and 1.4), metastatic progression (HR: 1.4 and 2.3), and cancer-specific mortality (CSM, HR: 1.9 and 3.4) compared with PSA-category 20-49.9 ng/ml. Conclusion: Initial PSA levels ≥50 ng/ml are associated with higher risk of BCR, metastatic progression, and CSM compared with highrisk patients with PSA of 20-49.9 ng/ml. In consequence, these patients may be counseled about a potentially increased risk of undetected metastases prior to RP possibly necessitating intensified multimodal treatments in the future. Ó 2020 Elsevier Inc. All rights reserved.

Keywords: Biochemical recurrence; Metastatic progression; Cancer-specific mortality; Prostate-specific antigen level

1. Introduction Prostate cancer (CaP) is one of the most common male malignancies worldwide. However, depending on the tumor characteristics, oncological outcomes after initial treatment, such as radical prostatectomy (RP), vary widely. *Both authors contributed equally. **Corresponding author. Tel.: +49 (0)40 7410-51300; fax: +49 (0)40 7410-51323. E-mail address: [email protected] (S. Knipper). https://doi.org/10.1016/j.urolonc.2019.12.027 1078-1439/Ó 2020 Elsevier Inc. All rights reserved.

Specifically, patients with high-risk CaP are at higher risk of biochemical recurrence after initial treatment, as well as at higher risk of metastatic progression and cancer-specific mortality in comparison to low- or intermediate-risk prostate cancer [1−5]. One of the known risk factors is a high preoperative prostate-specific antigen (PSA) level which may be caused by undetected metastases at time of RP with subsequently poorer oncological outcomes [6]. However, also very high-risk patients with potentially undetected metastases may benefit from multimodal treatment strategies including local treatment.

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In consequence, we examined the impact of initial PSA levels of 50-99.9 and ≥100 ng/ml on biochemical recurrence (BCR)-free survival, metastasis-free survival (MFS), and cancer-specific survival (CSS) after RP. We hypothesized that higher PSA levels (50-99.9 and ≥100 ng/ml) represent independent predictors of worse outcomes as a proxy for undetected metastases compared with patients with lower PSA levels (20-49.9 ng/ml). We also hypothesized that nevertheless promising results may be achieved, even in these very-high risk patients. 2. Patients and methods 2.1. Study population A total of 29,976 consecutive patients treated with RP for clinically localized CaP in a single high-volume European center between 1992 and 2018 were evaluated for this study. Of these, 3,081 were excluded because of missing data on follow-up. Moreover, all patients with initial PSA values <20 ng/ml were excluded (n = 24,084) leading to a final cohort of 2,811 patients with initial PSA values ≥20 ng/ml. All patients had preoperative computed tomography (CT)-scans and bone scintigraphy without evidence of visceral or bone metastases. The study was approved by the institutional review board in Hamburg, Germany. In accordance with federal and institutional guidelines, all men signed an institutional review board-approved, protocol-specific informed consent form before study entry. This permits collection of deidentified patient data at baseline and followup, which were entered into a secure, password-protected database for subsequent analysis. Questionnaires and death reports of the National Cancer Registry were used annually for follow-up. All data were prospectively stored in an institutional database (FileMaker Pro 10; FileMaker, Inc., Santa Clara, CA). 2.2. Covariates and endpoints Initial PSA was stratified in 3 categories, namely 2049.9 vs. 50-99.9 vs. ≥100 ng/ml. Patient follow-up consisted of periodical PSA testing and postoperative imaging studies, which were performed according to PSA level and further symptoms by the referring urologists. Initial BCR was defined as PSA ≥0.2 ng/ml and rising after RP only or after RP with adjuvant RT. Metastatic progression was defined as radiological sign of metastases in further performed imaging studies. Cancer-specific mortality (CSM) was defined as death attributable to prostate cancer. Follow-up time was defined as time (months) between surgery and BCR/metastatic progression/CSM or last follow-up. 2.3. Statistical analyses Descriptive statistics included frequencies and proportions for categorical variables (biopsy Gleason Score [GS], clinical

T-stage, neoadjuvant hormonal therapy, pathological GS, pathological T-stage, pathological N-stage, surgical margin status, postoperative treatments). Means, medians, and ranges were reported for continuously coded variables (age, year of surgery, and PSA). The Chi-square tested the statistical significance in proportions differences. The t-test and KruskalWallis test examined the statistical significance of means and median differences. Kaplan-Meier plots graphically depicted BCR-free survival, MFS, and cancer-specific survival (CSS). Univariable and multivariable Cox regression models tested the relationship between oncological outcomes (BCR, metastatic progression, and CSM) and PSA categories. Additional adjustment was made for clinical T-stage (cT1 vs. cT2 vs. cT3), biopsy GS (GS ≤6 vs. 7a vs. 7b vs. ≥8), and age at surgery (continuously coded). Since the PSA level might be affected by GS, an interaction term consisting of biopsy GS and PSA level was tested (GS ≤6 vs. 7a vs. 7b vs. ≥8 and PSA 20-49.9 vs. 50-99.9 vs. ≥100 ng/ml). For all statistical analyses R software environment for statistical computing and graphics (version 3.4.3) was used. All tests were 2 sided with a level of significance set at P < 0.05. 3. Results Overall, 2,811 clinically localized CaP patients with initial PSA ≥20 ng/ml were identified. Of those, 454 (16.2%) patients had a PSA of 50-99.9 ng/ml and 152 (5.8%) had a PSA of ≥100 ng/ml. Clinicopathologic characteristics of the overall cohort are described in Table 1. Patients with PSA ≥50 ng/ml were younger, more likely to receive neoadjuvant hormonal therapy, had higher biopsy GS and more advanced clinical T-stages at presentation. Moreover, they harbored more aggressive disease, as evidenced by higher pathological GS, pT- and pN-stages. Additionally, patients with PSA ≥50 ng/ml received more often adjuvant and/or salvage treatment. Overall, BCR was recorded in 1,146 (40.8%) patients, metastases occurred in 297 (10.6%) patients, and cancerspecific death was observed in 119 (4.2%) patients. Median follow-up was 47.5 months (interquartile range: 17.6-85.2 months). 3.1. Oncological outcomes In Kaplan-Meier analyses within the overall cohort, after stratification of 10-year BCR-free survival by PSA categories, median BCR-free survival was 86.7 vs. 35.7 vs. 24.6 months and 10-year BCR-free survival rates were 46.9 vs. 32.1 vs. 29.0% in PSA categories 20-49.9 vs. 50-99.9 vs. ≥100 ng/ml, respectively (P < 0.001, Fig. 1). In Kaplan-Meier analyses within the overall cohort, after stratification of 10-year MFS by PSA-categories, 10-year MFS rates were 78.4 vs. 67.2 vs. 37.3% in PSA categories 20-49.9 vs. 50-99.9 vs. ≥100 ng/ml (P < 0.001, Fig. 2).

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Table 1 Descriptive characteristics of 2,811 radical prostatectomy patients, treated between 1992 and 2018 in a tertiary referral center, stratified according to prostatespecific antigen (PSA) category (20-49.9 vs. 50-99.9 vs. ≥100 ng/ml) Variables

Age at surgery Year of surgery PSA Neoadjuvant HT Biopsy GS/ GG

Clinical T-stage

Pathological GS/GG

Pathological T-stage

Pathological N-stage

Surgical margin status

Postoperative treatment

Median IQR Median IQR Median IQR No Yes ≤6/I 7a/II 7b/III ≥8/IV-V Unknown cT1c cT2 cT3 Unknown ≤6/I 7a/II 7b/III ≥8/IV-V Unknown pT2 pT3a pT3b pT4 Unknown N0 N1 NX R0 R1 Unknown no RT adjRT salvRT adjHT salvHT

PSA 20-49.9 ng/ml

PSA 50-99.9 ng/ml

PSA ≥100 ng/ml

2,195 (78.1) 65.1 59.8−69.5 2012 2008−2015 27 22.8−34.4 1,991 (90.7) 204 (9.3) 537 (24.5) 520 (23.7) 424 (19.3) 661 (30.1) 53 (2.4) 1,355 (61.7) 744 (33.9) 62 (2.8) 34 (1.5) 192 (8.7) 850 (38.7) 717 (32.7) 432 (19.7) 4 (0.2) 741 (33.8) 640 (29.2) 770 (35.1) 42 (1.9) 2 (0.1) 1,444 (65.8) 613 (27.9) 138 (6.3) 1270 (57.9) 897 (40.9) 28 (1.3) 1,369 (62.4) 312 (14.2) 514 (23.4) 136 (6.2) 400 (18.2)

454 (16.2) 64.6 59.4−68.9 2013 2009.2−2015 64 56−77.5 364 (80.2) 90 (19.8) 64 (14.1) 83 (18.3) 89 (19.6) 206 (45.4) 12 (2.6) 237 (52.2) 174 (38.3) 36 (7.9) 7 (1.5) 22 (4.8) 112 (24.7) 178 (39.2) 141 (31.1) 1 (0.2) 84 (18.5) 97 (21.4) 250 (55.1) 23 (5.1) 0 (0) 225 (49.6) 214 (47.1) 15 (3.3) 170 (37.4) 278 (61.2) 6 (1.3) 226 (49.8) 100 (22.0) 128 (28.2) 60 (13.2) 116 (25.6)

162 (5.8) 64.5 58.3−68.5 2014 2010−2016 148.5 119−214.7 107 (66.0) 55 (34.0) 22 (13.6) 16 (9.9) 28 (17.3) 94 (58.0) 2 (1.2) 86 (53.1) 59 (36.4) 15 (9.3) 2 (1.2) 7 (4.3) 23 (14.2) 51 (31.5) 81 (50.0) 0 (0) 21 (13.0) 22 (13.6) 107 (66.0) 12 (7.4) 0 (0) 47 (29.0) 105 (64.8) 10 (6.2) 45 (27.8) 115 (71.0) 2 (1.2) 80 (49.4) 42 (25.9) 40 (24.7) 39 (24.1) 40 (24.7)

GG = grade group; GS = Gleason score; HT= hormonal treatment; IQR= interquartile range; RT = radiotherapy.

In Kaplan-Meier analyses within the overall cohort, after stratification of 10-year CSS by PSA categories, 10-year CSS rates were 93.7 vs. 85.5 vs. 66.7% in PSA categories 20-49.9 vs. 50-99.9 vs. ≥100 ng/ml (P < 0.001, Fig.3). In multivariable analyses, PSA 50-99.9 ng/ml, as well as PSA ≥100 ng/ml were independently predicting higher risk of BCR (hazard ratio [HR]: 1.3 and 1.4), metastatic progression (HR: 1.4 and 2.3), and CSM (HR: 1.9 and 3.4) compared with patients with PSA 20-49.9 ng/ml (Table 2). No statistically significant interaction between GS and PSA level was identified. 4. Discussion High PSA levels are known to be a risk factor for poorer oncological outcomes as they might be a surrogate for

potentially undetected metastases [6,7]. However, also veryhigh risk patients with potentially undetected metastases may benefit from multimodal treatment strategies including local treatment [8−10]. Unfortunately, no randomized data for RP is available in this setting. Moreover, only few retrospective series addressed the oncological outcomes of nonmetastatic CaP patients with very high (≥50 ng/ml) PSA level prior to RP [11−15]. These studies however suffer from small sample sizes and historical data. In consequence, we aimed at examining the impact of initial PSA levels of 50-99.9 and ≥100 ng/ml on oncological outcomes after RP in a large cohort. We hypothesized that high PSA levels represent independent predictors of worse outcomes compared with patients with lower PSA levels. We also hypothesized that nevertheless satisfying results can be achieved, even in these very-high risk patients, when treated surgically.

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Fig. 1. Kaplan-Meier analyses depicting biochemical recurrence (BCR)-free survival rates in 2,811 radical prostatectomy patients, treated between 1992 and 2018 in a tertiary referral center, stratified according to prostate-specific antigen (PSA) categories 20-49.9 vs. 50-99.9 vs. ≥100 ng/ml.

Our analyses demonstrated several noteworthy findings. First, we identified important differences in age, clinical stage, biopsy GS characteristics between patients with PSA 20-49.9 vs. ≥50 ng/ml. In general, patients with higher initial PSA were younger and had more aggressive disease characteristics than their lower PSA counterparts. This is mainly in agreement with previous retrospective studies, who also reported more aggressive disease characteristics in patients with higher PSA levels [12]. Second, our analyses demonstrated significantly lower BCR-free survival rates, MFS rates, and CSS rates in PSA categories 5099.9 and ≥100 ng/ml vs. PSA category 2049.9 ng/ml. This was confirmed in multivariable analyses, where PSA 50-99.9 ng/ml, as well as PSA ≥100 ng/ml was independently predicting higher risk of BCR, metastatic progression and CSM compared with patients with PSA 2049.9 ng/ml. This is only partly corroborating previous findings. Gontero et al. reported on 137 and 48 patients with PSA levels

of 50.1-99 and ≥100 ng/ml with a significantly worse 10-year CSS of 85.4 and 79.8%, respectively, compared with 90.9% in 527 patients with PSA 20.1-50 ng/ml [12]. However, no multivariable analyses were performed in this study. Brandli et al. reported on 11 patients with PSA ≥50 ng/ml compared with 39 patients with PSA 20 to 49 ng/ml. Here, overall BCRfree survival was 48% at 5 years [11]. However, in their multivariable analyses, PSA was not predictive for higher risk of BCR. Tai et al. reported on 7 RP patients with PSA 5099.9 ng/ml and 85 RP patients with PSA 20-49.9 ng/ml, within their series across all treatment modalities [13]. Here, 10-year CSS was 57 vs. 84%. However, no multivariable analyses according to PSA levels were performed. Makino et al. compared 31 RP patients with PSA ≥50 ng/ml (14 of those with PSA ≥100 ng/ml) to 47 patients with hormonal therapy alone (of those 24 with PSA ≥100 ng/ml) [15]. They reported a median BCR-free survival of 20 months and a 10-year CSS of 81% in the RP group. In their multivariable analyses, higher

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Fig. 2. Kaplan-Meier analyses depicting metastasis-free survival (MFS) rates in 2,811 radical prostatectomy patients, treated between 1992 and 2018 in a tertiary referral center, stratified according to prostate-specific antigen (PSA) categories 20-49.9 vs. 50-99.9 vs. ≥100 ng/ml.

PSA (≥100 ng/ml) was also not predictive for higher risk of BCR. In consequence, our findings corroborate previous studies concerning worse univariable results in patients with higher PSA levels. Additionally, to the best of our knowledge, we are the first to report worse oncological outcomes even after multivariable adjustment. Current guidelines recommend metastatic screening with at least cross-sectional abdominopelvic imaging and bone scintigraphy as initial staging in high-risk CaP patients [16,17]. However, there is growing evidence on the improved performance of 68Gallium prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) imaging compared with conventional imaging in primary staging. Specifically, varying sensitivity (per-lesion analysis: 3392%), but good specificity (per-lesion analysis: 82-100%) has been reported for PSMA-PET imaging [18−23]. Moreover, most studies demonstrated increased detection rates of PSMA-PET imaging compared with conventional imaging

modalities, e.g. detection of microscopic involvement of normal-sized nodes (20). Although the clinical benefit of detecting metastases with these new imaging modalities at an earlier time-point still remains unclear, accurate early staging of prostate cancer is key to patient risk stratification [24]. Only with precise risk stratification, the optimum patient-specific therapeutic strategy may be determined and further treatment options, such as additional systemic treatment, may potentially be considered. Taken together, PSA levels ≥50 ng/ml at diagnosis in clinically localized patients are associated with higher risk of BCR, metastatic progression and CSM after RP compared with high-risk patients with PSA of 20-49.9 ng/ml. However, 85.5 and 66.7% of patients with PSA 50-99.9 and ≥100 ng/ml, respectively, did not experience cancer-specific mortality at 10 years of follow-up. This encourages local treatment in these high-risk patients, especially in patients with PSA 50-99.9 ng/ml.

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Fig. 3. Kaplan-Meier analyses depicting cancer-specific survival (CSS) rates in 2,811 radical prostatectomy patients, treated between 1992 and 2018 in a tertiary referral center, stratified according to prostate-specific antigen (PSA) categories 20-49.9 vs. 50-99.9 vs. ≥100 ng/ml. Table 2 Multivariable Cox regression models predicting biochemical recurrence (BCR), metastatic progression (MET), and cancer-specific mortality (CSM) at 10 years in 2,811 radical prostatectomy patients treated between 1992 and 2018 in a tertiary referral center, stratified according to prostate-specific antigen (PSA) categories 20-49.9 vs. 50-99.9 vs. ≥100 ng/ml, additionally adjusted for age at surgery Multivariable HR (95% CI) for BCR PSA 20-49.9 ng/ml 50-99.9 ng/ml ≥100 ng/ml Clinical T stage T1 T2 T3 Clinical GS GS 6 (GG I) GS 7a (GG II) GS 7b (GG III) ≥GS 8 (GG IV-V)

P value

Multivariable HR (95% CI) for MET

P value

Multivariable HR (95% CI) for CSM

P value

Ref. 1.3 (1.1−1.5) 1.4 (1.1−1.8)

<0.001 <0.01

Ref. 1.4 (1.1−1.9) 2.3 (1.6−3.5)

0.04 <0.001

Ref. 1.9 (1.2−2.9) 3.4 (1.9−6.2)

<0.01 <0.001

Ref. 1.5 (1.3−1.7) 1.7 (1.3−2.2)

<0.001 <0.001

Ref. 1.4 (1.1−1.8) 1.5 (0.9−2.5)

<0.01 0.1

Ref. 1.4 (0.9−2.0) 3.0 (1.6−5.6)

0.1 <0.001

Ref. 1.8 (1.5−2.2) 2.7 (2.2−3.3) 3.3 (2.7−4.0)

<0.001 <0.001 <0.001

Ref. 2.6 (1.5−4.3) 5.3 (3.2−8.6) 9.5 (5.9−15.1)

<0.001 <0.001 <0.001

Ref. 1.3 (0.7−2.4) 1.7 (0.9−3.3) 4.0 (2.3−6.9)

0.4 0.1 <0.001

CI = confidence interval; HR = hazard ratio; GG = grade group; GS = Gleason score.

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Several limitations of our study need to be mentioned. First and foremost are the limitations inherent to retrospective analyses. However, these limitations are shared with all previous studies addressing the comparison of different PSA levels [11−13,15]. Second, our follow-up period was moderate concerning the long natural history of CaP.

[10]

[11]

5. Conclusions Initial PSA levels ≥50 ng/ml are associated with higher risk of BCR, metastatic progression, and CSM after RP compared with high-risk patients with PSA of 20-49.9 ng/ml. In consequence, these patients may be counseled about a potentially increased risk of undetected metastases prior to RP possibly necessitating intensified multimodal treatments in the future. Conflict of interest There was no external financial support for this study. The authors declare that they have no conflict of interest.

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