Asian Journal of Andrology

ORIGINAL ARTICLE
Year
: 2016  |  Volume : 18  |  Issue : 3  |  Page : 480--484

Prostate-specific antigen density predicts favorable pathology and biochemical recurrence in patients with intermediate-risk prostate cancer


Ho Won Kang1, Hae Do Jung2, Joo Yong Lee2, Jong Kyou Kwon3, Seong Uk Jeh4, Kang Su Cho5, Won Sik Ham2, Young Deuk Choi6,  
1 Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea
2 Department of Urology, Severance Hospital, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea
3 Department of Urology, Inje University Haeundae Paik Hospital, Busan, Korea
4 Department of Urology, Gyeongsang National University School of Medicine, Jinju, Korea
5 Department of Urology, Gangnam Severance Hospital, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea
6 Department of Urology, Severance Hospital, Urological Science Institute, Yonsei University College of Medicine, Seoul; Robot and Minimal Invasive Surgery Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

Correspondence Address:
Dr. Young Deuk Choi
Department of Urology, Severance Hospital, Urological Science Institute, Yonsei University College of Medicine, Seoul; Robot and Minimal Invasive Surgery Center, Severance Hospital, Yonsei University College of Medicine, Seoul
Korea

Abstract

This study was designed to identify clinical predictors of favorable pathology and biochemical recurrence (BCR) in patients with intermediate-risk prostate cancer (IRPCa). Between 2006 and 2012, clinicopathological and oncological data from 203 consecutive men undergoing robot-assisted radical prostatectomy (RARP) for IRPCa were reviewed in a single-institutional retrospective study. Favorable pathology was defined as Gleason score ≤6 and organ-confined cancer as detected by surgical pathology. Logistic regression analysis was used to determine predictive variables of favorable pathology, and the Kaplan-Meier and multivariate Cox regression model were used to estimate BCR-free survival after RARP. Overall, 38 patients (18.7%) had favorable pathology after RARP. Lower quartile prostate-specific antigen density (PSAD) was associated with favorable pathology compared to the highest quartile PSAD after adjusting for preoperative PSA, clinical stage and biopsy Gleason score (odds ratio, 5.42; 95% confidence interval, 1.01-28.97; P = 0.048). During a median 37.8 (interquartile range, 24.6-60.2) months of follow-up, 66 patients experienced BCR. There were significant differences with regard to BCR free survival by PSAD quartiles (log rank, P = 0.003). Using a multivariable Cox proportion hazard model, PSAD was found to be an independent predictor of BCR in patients with IRPCa after RARP (hazard ratio, 4.641; 95% confidence interval, 1.109-19.417; P = 0.036). The incorporation of the PSAD into risk assessments might provide additional prognostic information and identify some patients in whom active surveillance would be appropriate in patients with IRPCa.



How to cite this article:
Kang HW, Jung HD, Lee JY, Kwon JK, Jeh SU, Cho KS, Ham WS, Choi YD. Prostate-specific antigen density predicts favorable pathology and biochemical recurrence in patients with intermediate-risk prostate cancer .Asian J Androl 2016;18:480-484


How to cite this URL:
Kang HW, Jung HD, Lee JY, Kwon JK, Jeh SU, Cho KS, Ham WS, Choi YD. Prostate-specific antigen density predicts favorable pathology and biochemical recurrence in patients with intermediate-risk prostate cancer . Asian J Androl [serial online] 2016 [cited 2021 Jan 17 ];18:480-484
Available from: https://www.ajandrology.com/text.asp?2016/18/3/480/154313


Full Text

 Introduction



Prostate cancer (PCa) is the most common solid organ malignancy in men in many western countries including the United States and is the fifth most common in Korean males. [1],[2],[3] PCa shows an extremely heterogeneous clinical course, ranging from indolent and organ-confined to aggressive, metastatic lethal disease, leading to the overtreatment of men with relatively indolent disease and the undertreatment of those with aggressive tumors. [4],[5] Consequently, there is a great need to accurately assess the tumor characteristics of PCa so that appropriate treatment options can be considered.

Currently, pathological analyses (including clinical stage and tumor grade in biopsy as measured by the Gleason score) and serum prostate-specific antigen (PSA) levels are key determinants for risk assessment and therapeutic decision-making. [6] However, none of the histological criteria or biomarkers reported to date show sufficient sensitivity or specificity for detecting, monitoring, and determining the prognosis of PCa. D'Amico et al. [7] were the first to combine the use of preoperative PSA levels, clinical stage, and biopsy Gleason score to stratify patients with PCa into low-, intermediate-, and high-risk groups. Even within a given risk group, significant clinical heterogeneity remains, particularly for those with intermediate-risk PCa (IRPCa). [8],[9] Biochemical recurrence (BCR) rates following definitive primary treatment for IRPCa are variable, with 5-year rates ranging from 2% to 70%. [10],[11] Given this clinical heterogeneity, a uniform treatment paradigm is unlikely to be an optimal approach for IRPCa. The optimal treatment for IRPCa is controversial; radical surgery, brachytherapy, external beam radiotherapy, hormone suppression, and combinations of these modalities are all feasible treatment options. [12] Recently, several investigators have reported the appropriateness of active surveillance (AS) in select men with IRPCa, demonstrating favorable outcomes. [13],[14] Thus, there is a critical need for methods capable of precise risk stratification and identifying some patients in whom AS would be appropriate in patients with IRPCa. To address these issues, we investigated preoperative variables associated with favorable pathology and BCR after RARP in IRPCa.

 Materials And Methods



We retrospectively reviewed the data of 1086 patients who underwent robot-assisted radical prostatectomy (RARP) for PCa at Severance Hospital between January 2006 and December 2012. Of the total RARP cases, 19.6% of patients (n = 213) met the criteria of IRPCa according to the D'Amico classification, defined as clinical stage T2b or PSA levels between 10 and 20 or Gleason score of 7. Patients who received neo-adjuvant treatment (n = 8) or adjuvant radiotherapy (n = 6, four patients also received neo-adjuvant treatment) were excluded. As a result, 203 subjects satisfied the final inclusion criteria.

RARP was carried out using our standardized extraperitoneal technique by a single surgeon (YDC). [15] The study was carried out in agreement with applicable laws and regulations, good clinical practices, and ethical principles as described in the Declaration of Helsinki. The Institutional Review Board of the hospital approved the present study protocol (Approval number: 4-2014-0619). Favorable pathology was defined as a Gleason score ≤6 and organ-confined cancer as detected by surgical pathology. BCR was defined as two sequential PSA values ≥0.2 ng ml−[1] after prostatectomy.

Continuous variables are shown as the median and IQR. Differences in variables with a continuous distribution across dichotomous categories were assessed using the Mann-Whitney U-test. The Fisher exact test was used to evaluate the association between categorical variables. PSAD was categorized into approximate quartiles within the nested subcohort, with the highest quartile assigned as the reference group. Survival analyses were conducted according to the Kaplan-Meier method, and survival characteristics were compared using the log-rank test. Univariate and multivariate Cox regression model was used to identify the independent prognostic factors for BCR following RARP. Variables of P < 0.1 on univariate analysis included in the multivariate analysis. Statistical significance was considered at P < 0.05, and all reported P values are two-sided. Analysis was performed using SPSS 20.0 software (SPSS Inc., Chicago, IL, USA).

 Results



Baseline characteristics

[Table 1] lists the baseline characteristics of the 203 IRPCa cases. The median prebiopsy PSA and PSAD were 7.92 (IQR 5.59-11.93) ng ml−1 and 0.27 (IQR 0.19-0.38) ng ml−1 g−1 , respectively. The majority of men had a biopsy Gleason score 7 (69.9%); of those, 65 patients had a primary Gleason pattern of 4.

After RARP, pathologic organ-confined disease was found in 103 (50.7%) cases and Gleason scores ≤6, 3 + 4, 4 + 3, and ≥8 were found in 53 (26.1%), 76 (37.4%), 60 (29.6%), and 14 (6.9%) cases, respectively. Overall, 38 patients (18.7% of IRPCa cohort) had favorable pathology after RARP [Table 1].{Table 1}

Clinical variables associated with favorable pathology in patients with IRPCa

Preoperative PSAD and CAPRA score were significantly associated with favorable pathology after RARP (P = 0.017, P = 0.013, respectively). However, there were no significant differences among the favorable and unfavorable pathology groups with respect to other preoperative variables, including age, BMI, preoperative PSA, and clinical stage and grade [Table 2].{Table 2}

When PSAD was categorized into quartiles, the lower quartile PSAD group was associated with favorable pathology compared with the highest quartile PSAD group after adjusting for PSA, clinical stage, and biopsy Gleason score (odds ratio, 5.42; 95% confidence interval [CI], 1.01-28.97; P = 0.048) [Table 3]. {Table 3}

Prediction of BCR after radical prostatectomy in patients with IRPCa

During a median 37.8 (interquartile range 24.6-60.2) months of follow-up, 66 patients (32.5% of the IRPCa cohort) experienced BCR and the majority of BCR (95.5%) were occurred in unfavorable pathology group. One- and 3-year BCR-free survival rates were 94.6% and 91.8% for patients with favorable pathology, whereas 78.9% and 63.9% for patients with unfavorable pathology.

Kaplan-Meier analysis exhibits significantly different BCR-free survival by PSAD quartiles (log-rank P = 0.003) [Figure 1]. [Table 4] shows results from univariate and multivariate Cox proportion hazard analysis for prediction of BCR after RARP. In univariate analyses, lower preoperative PSA, PSAD, CAPRA score, LVI and positive surgical margins were associated with BCR after RARP. When multivariate analysis with PSAD, PSAD (hazard ratio [HR], 4.641; 95% CI, 1.109-19.417; P = 0.036), LVI (HR, 3.734; 95% CI, 1.644-8.482; P = 0.002) and positive surgical margins (HR, 1.842; 95% CI, 1.108-3.061; P = 0.018) were independent predictors of BCR after RARP.{Figure 1}{Table 4}

 Discussion



The current study investigated the preoperative variables of favorable pathology and the risk of BCR in patients with IRPCa. Our study showed that approximately 20% of patients with IRPCa had a favorable pathology as detected by final pathology. Preoperative PSAD was not only associated with favorable pathology, but also an independent predictor of BCR in patients with IRPCa after prostatectomy. PSAD might be an additional tool for stratifying men with IRPCa and identifying some patients in whom AS would be appropriate in this setting.

PCa shows an extremely heterogeneous clinical course, ranging from indolent and organ-confined to aggressive, metastatic lethal disease. [16],[17],[18] Moreover, we acknowledge that patients in each risk group have significant clinical heterogeneity, particularly IRPCa. [8],[9] The original research concerning within-group heterogeneity by Reese et al. [9] revealed heterogeneous pathologic and biochemical outcomes among men within a single NCCN risk group. In their study, BCR-free survival rates were superior in men classified as intermediate-risk by clinical stage compared with those assigned by biopsy Gleason score or PSA level. Interestingly, comparing men who met only one intermediate-risk criterion with low-risk men, no significant differences were found in terms of 10-year BCR-free survival by clinical stage. These authors also found that the BCR-free survival rates also differed according to the number of intermediate-risk criteria. Additional clinical factors have been proposed for stratifying men with IRPCa, including the proportion of positive biopsy cores, pretreatment PSA velocity, and primary Gleason pattern. [19],[20],[21] Series from the Mayo Clinic and Johns Hopkins University showed a statistically significant difference in biochemical and progression-free outcomes in patients with a total Gleason score of 7, when stratified according to primary Gleason pattern. [22],[23] Recently, Zumsteg et al. [8] proposed a new risk stratification system for patients with IRPCa treated with dose-escalated, external-beam radiation therapy. They defined unfavorable IRPCa as any intermediate-risk patient with a primary Gleason pattern of 4, percentage of positive biopsy cores greater than or equal to 50%, or multiple intermediate-risk factors. Despite being significantly more likely to receive ADT, patients classified with unfavorable IRPCa had worse BCR-free survival, local failure, distant metastases, and CSM than patients with favorable IRPCa. Similarly, our study cohorts showed heterogeneous pathologic outcomes. Although 18.7% of the entire cohort had a favorable outcome after radical prostatectomy, a significant proportion of patients showed a high-grade advanced stage of disease.

PSAD was initially introduced to improve the sensitivity and specificity of PSA testing for PCa screening. [24] However, some groups have also examined the role of PSAD in predicting advanced pathology after radical prostatectomy or BCR after local treatment. [25],[26] PSAD has been adopted as criteria for AS in men with low-risk PCa. The NCCN and PRIAS AS protocols include PSAD as an inclusion criterion. Furthermore, a recent study showed that PSAD was associated with an upgraded Gleason score of the prostatectomy specimen. [27],[28] While it is well-known that PSAD is a useful tool for selecting candidates for AS and prediction of BCR after definitive treatment in low-risk disease, the prognostic implications of PSAD in IRPCa have not yet been sufficiently elucidated. Our results suggest the potential utility of PSAD in predicting the favorable pathology and the risk of recurrence after surgery in IRPCa.

Recently, several investigators have reported the appropriateness of AS in select men with IRPCa, demonstrating favorable outcomes. [13],[14] The UCSF group reported that selected men with intermediate-risk features be appropriate candidates for AS, and are not necessarily more likely to progress. [29] Better risk assessment through emerging biomarkers and better integration of clinical predictors could discriminate significant from indolent tumors in men with IRPCa. PSAD might be an additional tool for appropriate selection for AS in IRPCa. Further prospective design is needed to confirm the clinical application of PSAD for AS and consequent oncologic safety assessment in intermediate-risk disease.

Our study has both strengths and limitations. It had a retrospective design, which means that there may have been some sampling bias. However, the RARP data originated at a single institution and a single surgeon, minimizing performance variability within groups and decreasing performance bias. In addition, current study cohort consisted entirely of men treated with RARP. Thus, the prognostic implications of PSAD in IRPCa patients treated with brachytherapy, external beam radiotherapy, hormone suppression, and combinations of these modalities should be validated in future studies.

 Conclusions



PSAD is associated with favorable pathology and is an independent predictor of BCR in patients with IRPCa after surgery. PSAD might be an additional tool for sub-stratifying patients with IRPCa into different prognostic groups and identifying some patients in whom AS would be appropriate in this setting.

 Author Contributions



HWK, JYL, and YDC conceived and designed the study. HDJ and JKK collected the data. SUJ, JKK, and HWK performed the statistical analyses. HWK, JYL, SUJ, and HDJ drafted the manuscript. KSC, WSH, and YDC participated in the design of the study and critical revision of the manuscript. All authors read and approved the final manuscript.

 Competing Interests



All authors declare no competing interests.

 Acknowledgments



This study was supported by a grant from the Korean Foundation for Cancer Research (CB-2011-04-02), Korea.

References

1Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014; 64: 9-29.
2Jung KW, Won YJ, Kong HJ, Oh CM, Seo HG, et al. Cancer statistics in Korea: incidence, mortality, survival and prevalence in 2010. Cancer Res Treat 2013; 45: 1-14.
3Hong JH, Kim IY. Nonmetastatic castration-resistant prostate cancer. Korean J Urol 2014; 55: 153-60.
4Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 2010; 28: 1117-23.
5Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: 203-13.
6Eggener SE, Scardino PT, Walsh PC, Han M, Partin AW, et al. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol 2011; 185: 869-75.
7D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280: 969-74.
8Zumsteg ZS, Spratt DE, Pei I, Zhang Z, Yamada Y, et al. A new risk classification system for therapeutic decision making with intermediate-risk prostate cancer patients undergoing dose-escalated external-beam radiation therapy. Eur Urol 2013; 64: 895-902.
9Reese AC, Pierorazio PM, Han M, Partin AW. Contemporary evaluation of the National Comprehensive Cancer Network prostate cancer risk classification system. Urology 2012; 80: 1075-9.
10Grossfeld GD, Latini DM, Lubeck DP, Broering JM, Li YP, et al. Predicting disease recurrence in intermediate and high-risk patients undergoing radical prostatectomy using percent positive biopsies: results from CaPSURE. Urology 2002; 59: 560-5.
11Hernandez DJ, Nielsen ME, Han M, Partin AW. Contemporary evaluation of the D'amico risk classification of prostate cancer. Urology 2007; 70: 931-5.
12Buyyounouski MK. Prostate cancer: stratifying intermediate-risk patients for radiotherapy. Nat Rev Urol 2013; 10: 438-9.
13Abern MR, Aronson WJ, Terris MK, Kane CJ, Presti JC Jr, et al. Delayed radical prostatectomy for intermediate-risk prostate cancer is associated with biochemical recurrence: possible implications for active surveillance from the SEARCH database. Prostate 2013; 73: 409-17.
14Loeb S, Berglund A, Stattin P. Population based study of use and determinants of active surveillance and watchful waiting for low and intermediate risk prostate cancer. J Urol 2013; 190: 1742-9.
15Lee JY, Diaz RR, Cho KS, Yu HS, Chung JS, et al. Lymphocele after extraperitoneal robot-assisted radical prostatectomy: a propensity score-matching study. Int J Urol 2013; 20: 1169-76.
16Seo WI, Kang PM, Chung JI. Predictive value of the cancer of the prostate risk assessment score for recurrence-free survival after radical prostatectomy in Korea: a single-surgeon series. Korean J Urol 2014; 55: 321-6.
17Cooperberg MR, Lubeck DP, Mehta SS, Carroll PR; CaPSURE. Time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from CaPSURE). J Urol 2003; 170: S21-5.
18Killock D. Prostate cancer: substratification of intermediate-risk disease using the current NCCN criteria. Nat Rev Urol 2014; 11: 188. doi: 10.1038/nrurol. 2014.66
19Palma D, Tyldesley S, Blood P, Liu M, Morris J, et al. Pretreatment PSA velocity as a predictor of disease outcome following radical radiation therapy. Int J Radiat Oncol Biol Phys 2007; 67: 1425-9.
20Freedland SJ, Aronson WJ, Terris MK, Kane CJ, Amling CL, et al. Percent of prostate needle biopsy cores with cancer is significant independent predictor of prostate specific antigen recurrence following radical prostatectomy: results from SEARCH database. J Urol 2003; 169: 2136-41.
21Rasiah KK, Stricker PD, Haynes AM, Delprado W, Turner JJ, et al. Prognostic significance of Gleason pattern in patients with Gleason score 7 prostate carcinoma. Cancer 2003; 98: 2560-5.
22Lau WK, Blute ML, Bostwick DG, Weaver AL, Sebo TJ, et al. Prognostic factors for survival of patients with pathological Gleason score 7 prostate cancer: differences in outcome between primary Gleason grades 3 and 4. J Urol 2001; 166: 1692-7.
23Chan TY, Partin AW, Walsh PC, Epstein JI. Prognostic significance of Gleason score 3+4 versus Gleason score 4+3 tumor at radical prostatectomy. Urology 2000; 56: 823-7.
24San Francisco IF, Werner L, Regan MM, Garnick MB, Bubley G, et al. Risk stratification and validation of prostate specific antigen density as independent predictor of progression in men with low risk prostate cancer during active surveillance. J Urol 2011; 185: 471-6.
25Magheli A, Hinz S, Hege C, Stephan C, Jung K, et al. Prostate specific antigen density to predict prostate cancer upgrading in a contemporary radical prostatectomy series: a single center experience. J Urol 2010; 183: 126-31.
26Busch J, Hamborg K, Meyer HA, Buckendahl J, Magheli A, et al. Value of prostate specific antigen density and percent free prostate specific antigen for prostate cancer prognosis. J Urol 2012; 188: 2165-70.
27van den Bergh RC, Roemeling S, Roobol MJ, Aus G, Hugosson J, et al. Outcomes of men with screen-detected prostate cancer eligible for active surveillance who were managed expectantly. Eur Urol 2009; 55: 1-8.
28Mohler JL. The 2010 NCCN clinical practice guidelines in oncology on prostate cancer. J Natl Compr Canc Netw 2010; 8: 145.
29Cooperberg MR, Cowan JE, Hilton JF, Reese AC, Zaid HB, et al. Outcomes of active surveillance for men with intermediate-risk prostate cancer. J Clin Oncol 2011; 29: 228-34.