UROLOGICAL ONCOLOGY Prostate Specific Antigen Nadir After Radical Cystoprostatectomy in Patients with Benign Prostatic Tissue: A Benchmark to Define Biochemical Recurrence After Radical Prostatectomy Seyed Yousef Hosseini1, Mohsen Alemi2 *, Erfan Amini3, Naser Riazi4 Purpose: Biochemical failure after radical prostatectomy has been defined based on retrospective studies in men who underwent RP for localized prostate cancer. Nevertheless, retrospective strategy and possibility of extra-pros- tatic extension overshadowed the accurateness of the aforementioned cut-off value. To define a more precise PSA nadir value, we estimated serum PSA after cystoprostatectomy in cases with bladder urothelial cancer and no evidence of prostate cancer. Materials and Methods: Study population consists of 52 subsequent patients who underwent radical cystoprosta- tectomy for muscle-invasive bladder cancer between December 2010 and December 2013. Patients with prostate adenocarcinoma and/or high grade prostate intraepithelial neoplasia were excluded from enrollment. Other ex- clusion criteria were prostate involvement with urothelial carcinoma, neoadjuvant or adjuvant chemotherapy and radiation therapy. Between all cases, 41 were enrolled for study. Serum PSA level was measured using immuno- chemiluminescence method from 6 months to 3 years after operation in study participants. Results: Forty-one patients with mean age of 66.4 ± 8.9 years were assessed in this study. Average serum PSA lev- el after radical cysto-prostatectomy was: 037 ± .031 ng/mL (from .002 to .1). Serum PSA level was not impressed with type of diversion or interval between operation and PSA measurement. Average serum PSA level in this study was meaningfully lesser than .2 ng/mL which is contemplated as PSA nadir value after RP. Conclusion: Serum PSA level of 0.2 ng/mL as the definition for biochemical recurrence after RP may delay sal- vage treatment. Our results showed that cut off value of （0.1 ng/mL may be more precise in the era of early salvage treatment. Keywords: biochemical recurrence; nadir; prostate specific antigen; radical cystectomy; radical prostatectomy. INTRODUCTION With the advent of prostate specific antigen (PSA) in 1980, clinicians were able to recognize pros- tate cancer at an early stage when the disease is amena- ble to definitive treatments.(1) PSA is also a valuable biomarker for early detection of disease recurrence after initial definitive treatment i.e. radical prostatec- tomy and radiation therapy. PSA increase to a certain threshold after radical prostatectomy, biochemical re- currence, may predict local or distant recurrence in fu- ture. The natural history after biochemical recurrence is variable and biochemical recurrence does not translate to metastatic disease and death in all patients.(2) The median time from biochemical recurrence to metastatic disease has been reported to be 8 years.(3) Definition of biochemical recurrence may be of utmost importance in the diagnosis of treatment failure and timely use of salvage treatments. Some investigators have proposed a cut-off value of .4 ng/mL for definition of biochemical recurrence.(4,5) According to American Urological As- 1Department of Urology, Shahid Modarres Hospital, and Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2Urology and Nephrology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran. 3Department of Urology, Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran. 4Department of Urology, Shahid Mohammadi Hospital, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. *Correspondence: Department of Urology, Shahid Beheshti hospital, Hamadan University of Medical Sciences, Hamadan, Iran. Telefax:+98-8138380155, E-mail: mohsenalemi@yahoo.com. Received April 2018 & Accepted March 2019 sociation and American Society of Clinical Oncology guidelines an initial and confirmatory PSA value of ≥ .2 ng/mL after radical prostatectomy is considered as bio- chemical recurrence.(6) National Comprehensive Cancer Network has defined biochemical failure as a detecta- ble PSA (while it was undetectable after surgery) and 2 subsequent rises. However there is no definition of detectable PSA.(7) Therefore, there is no consensus on the definition of biochemical recurrence after radical prostatectomy in the literature; in addition, the presence of benign prostatic tissue after radical prostatectomy, and extra-prostatic sources of PSA may interfere with postoperative PSA measurements and precise definition of biochemical recurrence. We conducted this study to assess postoperative PSA in men who underwent rad- ical cystoprostatectomy for urothelial bladder cancer and no pathological evidence of prostate cancer. The distribution of PSA values in this population can be used as a benchmark for determining the optimal nadir value as well as defining detection threshold in the era of ultrasensitive PSA. Urology Journal/Vol 16 No. 6/ November-December2019/ pp. 563-566. [DOI: 10.22037/uj.v0i0.4551] MATERIALS AND METHODS All consecutive patients who underwent radical cysto- prostatectomy with curative intent between December 2010 and December 2013 were considered for enroll- ment in this prospective cohort. Patients with prostate adenocarcinoma or high grade intraepithelial neoplasia in the final cystoprostatectomy specimen were exclud- ed from enrollment. Additional exclusion criteria were prostate involvement with urothelial carcinoma, neoad- juvant or adjuvant chemotherapy and radiation therapy. It should be noted that all surgeries were performed by or under supervision of one urologist (SYH). Histo- pathological evaluation of prostatic tissue in cysto- prostatectomy specimens was performed in slices with 3 micrometers in thickness. Any evidence of prostatic adenocarcinoma and/or high grade prostatic intraepi- thelial neoplasia were considered as exclusion criteria. A total of 41 patients were eligible for the study. The se- rum PSA level was measured by ECLIA (Electro chemi luminesence immunoassay) between 6 months and 3 years after surgery. Institutional review board approved the study and written informed consent was obtained from all participants. Statistical analysis Statistical Analysis was performed using SPSS version 16 (SPSS Inc., Chicago, IL, USA). Frequency of pa- tients with undetectable PSA was determined. Different cut-off values were used to define undetectable PSA. Using t-test, mean value of serum PSA after cysto- prostatectomy was compared to 0.2 as the threshold of biochemical recurrence. In addition, the effect of age, disease stage, and time elapsed from surgery as well as type of urinary diversion on postoperative serum PSA was evaluated. P value of less than 0.05 was considered as statistically significant. RESULTS A total of 41 patients with mean age of 65.1 ± 8.7 (range from 48 to 83) were evaluated in this study. Mean se- rum PSA after radical cystoprostatectomy was .037 ± .031 ng/mL ranging from .002 to .1. When compared to cut off values .1 and .2 (current definition of bio- chemical recurrence after radical prostatectomy), the mean value of serum PSA after cystoprostatectomy was significantly lower (p < .001, one sample T-test). Nei- ther of patients had serum PSA above .1 and 30 of 41 patients (73.2%) had serum PSA less than .05. We also noted that 20 (48.8%) and 13 (31.7%) patients had PSA ≤ .03 and ≤ .01 respectively. No correlation was found between postoperative PSA value and interval between surgery and PSA measurement (r = .036, p = .821; Pear- son correlation). To assess the effect of age on postoper- ative serum PSA level, patients were dichotomized into 2 groups (younger and older than 65). Mean serum PSA was comparable between different age groups (Table 1). Similarly, we did not find any association between either pathologic stage of urothelial cancer or type of urinary diversion and serum PSA level (Table 1). DISCUSSION According to our findings the majority of patients af- ter cystoprostatectomy have undetectable serum PSA level and applying ultrasensitive PSA assay showed that more than 70% of patients had PSA less than .05 and neither of patients had PSA greater than .1 ng/mL. Based on these findings we expect similar PSA nadir values in patients with localized prostate cancer who undergo radical prostatectomy. Therefore, applying ul- trasensitive PSA to detect biochemical recurrences after radical prostatectomy provides an opportunity to initi- ate early salvage treatment in eligible patients. Despite improvements in surgical methods and case selection, about 25% to 41% of patients will show prostate spe- cific antigen (PSA) relapse 10 years after operation. (8-10) The likelihood of recurrence is even higher when radical prostatectomy is performed in patient with high risk advanced prostate cancer. Therefore, a significant proportion of patients after radical prostatectomy re- quire adjuvant treatment and determining proper cut off values for initiation of salvage treatment is of utmost importance. A measureable PSA level after operation may be secondary to residual benign tissue rather than residual malignancy or existence of micrometastatic disease.(4,11) Measuring PSA after cystoprostatectomy in patients with benign prostatic tissue provides an oppor- tunity to assess the role of benign residual tissue and/or extra-prostatic sources of PSA in post radical prostatec- tomy nadir value. According to our findings remaining benign tissue and/or extraprostatic sources of PSA is not associated with values greater than .1 and remains below .05 in majority of patients. Several studies have investigated the importance of PSA nadir value after radical prostatectomy. Sokoll et al. in a study assessing 754 men who underwent radical prostatectomy showed that a lower PSA nadir value (i.e .01 vs. .1 ng/mL) is an independent predictor of biochemical recurrence.(12) Other studies also showed that in the range of .01 and .1, higher PSA nadir is associated with increased risk of biochemical relapse.(13,14) PSA nadir value has also been shown to be an independent predictor of biochem- ical recurrence in the range of .001 and .01 ng/mL. In another study Kang et al. using ultrasensitive PSA as- Table 1. Association between post-cystectomy serum PSA level and patient characteristics Patient Characteristics No. (%) Mean Serum PSA Level (ng/mL) P-value Age ≤ 65 18 (43.9) .042 ± .040 .703a > 65 23 (56.1) .034 ± .027 Type of urinary diversion Ileal conduit 18 (43.9) .033 ± .027 .906b Orthotopic neobladder 17 (41.5) .040 ± .038 Continent cutaneous pouch 6 (14.6) .042 ± .040 Pathologic stage T1 14 (34.1) .037 ± .042 .566b T2 18 (43.9) .042 ± .029 T3 9 (22.0) .030 ± .027 Abbreviations: PSA, Prostate Specific Antigen. a Mann Whitney test b Kruskal Wallis Test PSA Nadir after Radical Cystectomy-Hosseini et al. Urological Oncology 564 Vol 16 No 06 November-December2019 565 say, proposed that cut-off value of .03 is an independent predictor of biochemical recurrence. This ultrasensitive PSA relapse criterion of ≥ .03 ng/mL predicted all even- tual relapses with high sensitivity (100%) and specific- ity (96%) and provided a median 18 months lead time advantage over the standard definitions of PSA relapse. (15) Lowering the threshold and applying advanced ul- trasensitive PSA assays that detect concentrations as low as .001 ng/mL are associated with a high rate of false positive findings. In addition, it is not necessary to measure extremely low values as residual benign and malignant cells produce higher amounts of PSA. Some investigators have questioned the accuracy of ultrasen- sitive PSA at cut-off values in the .01 - .1 ng/mL range as overlap of PSA values was found in recurrent and non-recurrent patient groups.(16) Despite all limitations associated with the use of ultrasensitive PSA, current definition of PSA failure may be flawed. In the era of early salvage treatment values less than .2 ng/mL should not be considered undetectable. Using ultrasensitive assays and lowering the cut-off val- ue for the definition of biochemical recurrence provide an opportunity to detect the biochemical recurrence sooner when salvage treatment might be more effective. Mir et al. evaluating different cut off values for defining biochemical recurrence, proposed PSA ≥ .05 ng/mL as a criteria for therapy(14). Our findings also showed that majority of patients had PSA less than 0.05 after cysto- prostatectomy. One limitation in the present study was the absent of re-review of pathology slides to confirm the absence of prostate cancer in the specimens; howev- er, all specimens were assessed by a limited number of uropathologists who are expert in the field of urologic oncology. More recently there has been interest in using salvage radiation therapy instead of adjuvant treatments in patients with adverse pathologic features after radical prostatectomy. Although 3 different randomized trials showed improved outcomes in patients with adverse pathologic features who receive adjuvant radiation ther- apy compared to “wait and see” approach(17-19), recent evidence questions the benefit of adjuvant compared to salvage radiation therapy in a subset of patients. One study showed that only 17% of men with adverse patho- logic features after radical prostatectomy progressed to biochemical recurrence.(20) Therefore, applying salvage radiation instead of adjuvant treatment has the poten- tial to prevent overtreatment in a significant proportion of patients. Applying ultrasensitive PSA has also the potential to safely prevent unnecessary adjuvant treat- ments. The definition of biochemical recurrence also should be refined to prevent delays in salvage treatment. 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