Prediction of A Positive Surgical Margin and Biochemical Recurrence After Robot-Assisted Radical Prostatectomy 

Abstract

A positive surgical margin (PSM) detected in a prostatectomy specimen is associated with poor oncotherapeutic outcomes. Certain aspects regarding the determination of surgical margins and their effects on biochemical recurrence (BCR) remain unclear. This study investigated the predictive factors for PSM and BCR. We prospectively included 419 robot-assisted radical prostatectomy cases. The number of PSM cases was 126 (30.1%), stratified as 22 (12.2%) in stage T2 and 103 (43.6%) in stage T3. Preoperative prostate-specific antigen (PSA) > 10 ng/mL (p = 0.047; odds ratio [OR] 1.712), intraoperative blood loss > 200 mL (p = 0.006; OR 4.01), and postoperative pT3 stage (p < .001; OR 6.901) were three independent predictors for PSM in multivariate analysis. PSA > 10 ng/mL (p < 0.015; hazard ratio [HR] 1.8), pT3 stage (p = 0.012; HR 2.264), ISUP grade > 3 (p = 0.02; HR 1.964), and PSM (p = 0.027; HR 1.725) were four significant predictors for BCR in multivariate analysis. Among PSM cases, ISUP grade > 3 (p = 0.002; HR 2.689) was a significant BCR predictor. These results indicate that PSA level and pathological stage markedly influence the PSM and BCR.

Introduction

Up to 2019, an estimated 4986 robotic systems have been installed in medical centers worldwide, of which 561 are located in Asian countries ¹. Robot-assisted radical prostatectomy (RARP) has become a standard approach for localized prostate cancer (PCa) treatment ². This method yields comparable oncological outcomes as previous open and laparoscopic methods, primarily with respect to positive surgical margin (PSM) and biochemical recurrence (BCR), along with enhancements in functional outcomes, including urinary continence and recovery of erectile potency ^3–5.

PSM detected in radical prostatectomy (RP) specimens is considered a poor oncological outcome ⁶; however, its long-term effect on mortality remains uncertain ⁷. Previous studies have reported several predictors for PSM, including prostate-specific antigen (PSA) concentration, prostate weight ⁸, obesity ⁹, the histopathological findings from biopsy and RP specimens ¹⁰, surgeon experience ¹¹, pathologist interpretation ¹², surgical approach ¹³, and surgical method ^14–17, may potentially influence postoperative PSM. However, data from Asian countries regarding the prediction of PSM and BCR are still lacking owing to differences in PCa phenotypes between individuals in Asian and Western countries ¹⁸. It remains difficult for surgeons to determine the risk of PSM before surgery and the effect of PSM on the BCR rate after surgery. In this study, we used case-cohort data from an Asian medical center to further the current understanding of PSM and BCR after RARP.

Results

Discussion

RARP offers potential benefits such as a low PSM rate compared with open RP owing to better visibility and less blood loss ^19,20. In our series, the overall PSM rate was 30.1%, which is a higher rate than that reported in high-volume RARP studies, in which the range typically was 10.8–22% ²¹. This may be attributable to a much higher percentage (56.6%) of patients in the pT3 stage in our study than in other studies, where the percentage of pT3 stage patients ranged from 9.3 to 37.5% ²¹.

We determined the major preoperative predictor for the PSM rate to be PSA > 10 ng/mL. The predictors of the ISUP score upon biopsy and the cT stage defined through MRI did not exhibit a positive correlation in multivariate analysis. Liss et al. assessed 216 cases of RARPs and concluded, similar to us, that the preoperative predictive factor of PSM was PSA level instead of cT stage and ISUP score ²². The author explained this phenomenon because a portion of patients was transferred from other hospitals; thus, biopsy methods and MRI outcomes were not standardized, potentially yielding different results. Another reason we proposed may be the high pathological ISUP (43%) and T stage (30.2%) upgrading rate from biopsy to prostatectomy in our database. These factors may limit the precise prediction of the postoperative PSM rate through the use of the preoperative cT stage and ISUP grade.

Estimated blood loss > 200 mL is a significant intraoperative predictor of the PSM rate, and we speculated that intraoperative bleeding would hinder clear visualization from identifying prostate margins and prolonging the surgical time. In our study, further analysis found the operative time was longer among patients with an estimated blood loss of > 200 mL than in those with an estimated blood loss of ≤ 200 mL (mean: 303 min vs. 235 min, respectively). Kim et al. determined that higher blood loss was associated with larger prostate size in a series of 1168 RARPs. Nevertheless, the final PSM rate did not significantly differ among divided-size subgroups ²³. Tamhankar et al. reviewed 1406 RARPs to determine the steepness of the surgical learning curve reflected by the extent of blood loss and reported a 70% reduction in blood loss from the start to the end of the training period. However, the surgical time and the number of cases were not associated with the risk of PSM ²⁴.

Individualized surgical experiences may influence RARP performance. Several studies have reported that the PSM rate is inversely proportional to the number of surgical cases ^25–28. In our study, a single surgeon with extensive prior experience in laparoscopic surgery performed the surgeries; consequently, the PSM rate was almost the same at approximately 30% per 100 cases. This finding suggests that the surgeon’s previous experience in minimally invasive surgery can minimize the risk of PSMs when using a robotic surgical approach. White et al. reported a single-urologist case series and revealed that extensive previous experience in ORP might potentially prevent an increase in the PSM rate during the initial learning curve in RARP ²⁹.

The pT3 stage predictor was significantly correlated with a high PSM rate according to previous reports ^{21,22,30−33}. Ficarra et al. studied 322 RARPs and reported that the pathological findings of extraprostatic extension (EPE) were the only relevant PSM predictor ³⁴. Previous studies have reported that T upstaging rates varied widely from 4.5–68% of cases ^35,36. In this study, T upstaging occurred in one-third of cases, suggesting that preoperative understaging data may result in underresection of prostate tumors. In particular, the ISUP grade at RP is not considered an independent predictor, implying that total resection of high-grade tumors can be accomplished without leaving positive margins. A Partin table is a useful tool developed at John Hopkins Hospital for evaluating the risk of EPE before prostatectomy on the basis of preoperative PSA, ISUP, and clinical stage ³⁷. However, in our data, only preoperative PSA level was significantly associated with EPE in multivariate analysis. The discrepancy of preoperative ISUP and clinical stage in pathological reports of RP specimens may reduce the utility of preoperative parameters for predicting postoperative PSM.

Kang et al. reported the distribution of surgical margins in high-risk PCa, with positive rates of 16.2% in the apex, 14.7% in the bladder neck, 38.2% in posterolateral regions, and 26.5% in multifocal regions ³⁰. For our study, the majority of PSM is 73.8% in the posterolateral, 27.7% in apical and 13.5% in bladder neck regions. Previous studies have reported that the high PSM rate occurs in the posterolateral area, especially for high-risk pT3 diseases ^30,38. Eastham et al. reported large amounts of neurovascular tissue over the posterolateral region, potentially enhancing tumor cell migration and promoting local invasion ³⁹; furthermore, the BCR rate was higher among individuals with posterolateral PSM than in those with NSM (HR: 2.80). The NS procedure is associated with the PSM in the posterolateral region ^22,40, potentially explaining the high technical skill needed for successful dissection of the correct planes of fascia. However, the current results demonstrated that the NS group had a lower risk of PSM in the posterolateral region than the non-NS group did (3% vs. 20%). This is probably because of the higher percentage of patients in the pT3 stage than in the pT2 stage in the non-NS group (79% vs. 21%), which may be more influential than NS techniques.

Previous studies have been reported the apex is the most frequent region of PSM in RP specimens ^31,41. This is attributable to the unclear prostate capsular margins, which are difficult to identify in pT2 and pT3 stages ³⁸. More other studies have reported that apical PSM is correlated with the surgeon’s approach and skills rather than the tumor stage ^21,26,41. The surgeon in this study has extensive laparoscopic experience, explaining the relatively low rate of PSM in the apex. The estimated blood loss was significantly higher among patients with apical PSM, which implies potential bleeding from the dorsal vein complex upon dissection of the apical prostate ⁴². Coelho et al. reported that high BMI was a predictor for apical PSM in a cohort study involving 876 RARPs ³¹, and our study determined that high BMI was significantly associated with higher odds of PSMs at multifocal regions (p = 0.025) but not apical regions.

Koizumi et al. reported that employing the RARP approach has a higher likelihood of leading to PSM at the bladder neck than either ORP or LARP do ²⁹. This is possible because of the excessive preservation of bladder neck tissue to secure postoperative urinary continence ¹⁵. Furthermore, the presence of a prominent median lobe during surgery might increase the risk of PSM over the bladder neck (p = 0.047), indicating the challenging task of identifying surgical margins between the protruding prostatic lobe and bladder neck.

Several studies have reported patients who underwent prostatectomy with a 5-year BCR-free survival rate ranging from 74–87% and a median PSA recurrence time of 2.6 years ^43–45. In this study, the 5-year BCR-free survival rate was 66.7%, which was lower than that reported in other studies; this is probably owing to the higher ratio (53%) of aggressive pT3 disease at the outset of the accumulation of RARP cases. Evidence supports the characterization of PSM as a strong predictor of disease progression ^46–48. Our data indicate that the hazard ratio for PSM with BCR is 1.725 (p = 0.027). Recently, Zhang et al. performed a systematic review and meta-analysis, wherein they included 38000 patients and determined PSM to be an independent factor with higher BCR in multivariate analysis (p < 0.001, pooled HR 1.35) ⁶. Ploussard et al. analyzed a prospective study including 1943 RPs with a mean follow-up of 68 months and suggested that PSM was a significant predictor of BCR, the need for salvage therapy, and even cancer-related death. However, PSM was significantly correlated with BCR at stage pT2 and pT3a disease but not pT3b stage disease ⁴⁸. PSM's effect on BCR in stage pT3b disease was reportedly weak owing to a markedly higher risk of micrometastatic lesions, which are more influential than PSM is. Similarly, our study's PSM effect was nonsignificant in the pT3 stage compared with the other two predictors, PSA and ISUP grade.

In particular, among men who underwent RARP with postoperative PSM, an ISUP grade > 3 at RP (p = 0.002, HR 2.689) was the sole predictor of BCR-free survival regardless of pT stage and PSA concentration. Karakiewicz et al. reported similar results among 5831 RPs, indicating that the PSM group had a 3.7-fold higher risk of progression, particularly in the group with tumors at an ISUP grade > 2 in PSM ⁴⁷. Furthermore, Kang et al. reported that pathological ISUP grade > 3 was a predictor for BCR (p = 0.047, HR 4.180). These results suggest that disease progression depends on the PCa tumor grade in surgical margins ⁴⁹. Moreover, Stephensen et al. reported the effect of the number and extent of PSM on BCR, indicating that a mildly increased risk of BCR is significantly correlated with multifocal and extensive PSM ⁵⁰. However, we did not analyze the effect of PSM's extent; the current evidence is inadequate to differentiate the effect of unifocal and multifocal PSM on BCR-free survival. The residual low-grade tumors on PSM may not increase the BCR rate. Our study’s surgeon used electrocautery methods when dissecting the prostate fascia, thus indirectly decreasing the residual tumors on margins and reducing PSA recurrence risk. Furthermore, in Asian countries, the incidence of PCa is relatively low; however, the type of PCa typical to Asia is more aggressive than that in Western countries ^18,51. A high percentage of PCa patients have pT3 stage disease in prostatectomy, which may reduce the influence of PSM in terms of PCa progression.

Limitations

First, since we retrospectively obtained clinical data, there may have been an inherent selection bias in the analysis. Second, the lack of standardized MRI and pathological interpretations from other hospitals may affect the results in prostatectomy. Third, the results were obtained from a single experienced surgeon; thus, the technical details regarding NS methods and the determination of prominent prostate median lobes may have led to subjective bias. Fourth, we determined prostate size by using the data from RP specimens instead of presurgical imaging, which may have restricted the clinical application of this method for preoperative assessment. Finally, some cases were lost to follow-up early during the study, and some clinically significant diseases recurred after five years. The current follow-up duration was limited for the prediction of the final endpoint of BCR.

Conclusion

This study is the most up-to-date study in an Asian population to assess the predictors of PSM and BCR on RARP. Our results indicated that PSA level, pT stage, and estimated blood loss were the significant predictors of the PSM rate. Regarding the 5-year BCR-free survival, PSA, pT stage, ISUP grade, and PSM were identified as clinically significant predictors in multivariate analysis. In pT3 stage disease, PSM was less significant than PSA and ISUP grade for predicting PSA recurrence. Nevertheless, in cases of PSM observed after prostatectomy, ISUP grade > 3 was the sole predictor of PSA recurrence.

Material And Methods

Patients and study design

A medical record of 419 patients who underwent RARP from December 2010 to January 2018 at Taipei Veterans General Hospital, Taiwan, were analyzed retrospectively in this study. The research protocol was approved, and the need for informed consent was agreed to be waived by the Institutional Review Board and Human Research Protection Center of Taipei Veterans General Hospital (No.: 2020-05-001BC). The patient records were anonymized and de-identified before analysis. All study procedures involving data collection and management were in accordance with relevant guidelines and regulations. The indication for prostatectomy was clinically localized prostate cancer revealed through prostate biopsy. Most patients had undergone MRI for presurgical clinical-stage evaluation. We preoperatively collected the following clinical data: age, BMI, PSA, ISUP grade, and cT stage (defined through MRI). The following intraoperative parameters were noted: surgical time, estimated blood loss, previous TURP, previous abdominal surgery, prominent prostate median lobe (observed by the surgeon), number of surgical cases, and the use or nonuse of NS methods. The following postoperative parameters were recorded: margin status, ISUP at RP specimens, pT stage, prostate weight, Clavien complication grades, and the point of PSA recurrence within five years (defined as PSA level ≥ 0.2 ng/mL in two separate measurements). The locations of PSM were classified as apical, bladder neck, posterolateral, unifocal, and multifocal areas to evaluate the predictive risks. At least two qualified pathologists interpreted the final RP pathological reports.

Exclusion criteria: patients with a history of neoadjuvant hormone therapy or any focal treatment, including radiotherapy, cryotherapy, high-intensity focused ultrasound therapy, and salvage prostatectomy, were excluded. Furthermore, patients lost to follow-up within two months of RARP, and those who received adjuvant therapy owing to adverse pathological outcomes before PSA relapse were excluded.

Preoperative PSA levels were determined immediately before the prostate biopsy, and postoperative PSA levels were determined within 1-month post-biopsy and then at 3-month intervals until PSA recurrence was confirmed. Time zero marked the date of RARP, and patients without BCR did not present PSA recurrence on the most recent follow-up evaluation before the end of 2019. An increase in serum PSA levels was identified twice, and other factors potentially elevating PSA levels were excluded.

RARP

All RARPs were performed by a single urologist (H.J.C) who had > 15 years’ experience in laparoscopic urological surgery. For RARP, the transperitoneal approach was adopted, employing the Intuitive Surgical da Vinci® Surgical System Si or Xi with six ports. The prostatic anterior fat pad was removed to visualize the prostatic boundaries. The bladder neck was opened and separated from the prostate. By dividing the vesicoprostatic muscle, the vas deferens and seminal vesicles were exposed. Bilateral vas deferens were transected and then pulled anteriorly to facilitate the dissection of seminal vesicles. The Denonvilliers’ fascia was identified, and the posterior plane was carefully dissected from the base to the prostate apex to preserve neurovascular bundles. The prostatic apex was dissected, thus maximally preserving the urethral stump. The apex was laterally dissected from the anteromedial components of the levator ani. The urethra was posteriorly incised, and the prostate was removed. The vesicourethral anastomosis was conducted using a continuous suture. Finally, the incised detrusor apron was reapproximated.

Declarations

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