Evaluation of prognostic factors after radical prostatectomy in pt3b prostate cancer patients in Japanese population

Japanese Journal of Clinical Oncology, 2015, 45(8) 780 784 doi: 10.1093/jjco/hyv077 Advance Access Publication Date: 15 May 2015 Original Article Original Article Evaluation of prognostic factors after radical prostatectomy in pt3b prostate cancer patients in Japanese population Takahiro Inoue 1, *, Hidefumi Kinoshita 2, Naoki Terada 1, Takashi Kobayashi 1, Toshinari Yamasaki 1, Yoshiyuki Matsui 1, Tomomi Kamba 1, Hidekazu Inui 2, Motohiko Sugi 2, Tadashi Matsuda 2, and Osamu Ogawa 1 1 Department of Urology, Kyoto University Graduate School of Medicine, Sakyoku, Kyoto, and 2 Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka, Japan *For reprints and all correspondence: Takahiro Inoue, Department of Urology, Kyoto University Graduate School of Medicine, 54 Kawaharacho Shogoin, Sakyokou, Kyoto 6058507, Japan. E-mail: takahi@kuhp.kyoto-u.ac.jp Received 23 March 2015; Accepted 24 April 2015 Abstract Objective: The purpose of the current study was to evaluate prognostic factors after radical prostatectomy for prostate cancer patients with seminal vesicle invasion (pt3b) in the Japanese population. Methods: Between January 2005 and December 2011, 814 patients underwent radical prostatectomy without neoadjuvant hormonal therapy at our institutions. Among these patients, 31 were (3.8%) presented with pt3b. Kaplan Meier method was used to determine biochemical recurrence-free, disease-specific and overall survival of patients in this group. Proportional hazards models were used to determine predictors of biochemical recurrence-free survival. Results: The median follow-up period was 60 months (range, 9 108 months). During follow-up, 23 patients (74.2%) experienced biochemical recurrence, and the overall 3-year probability of freedom from biochemical recurrence was 29%. However, only one patient died of the disease, and the 5-year overall survival was 92%. In multivariate analysis, age at the time of surgery was the only significant variable for predicting biochemical recurrence after radical prostatectomy (P =0.0356, hazard ratio = 0.92, 95% confidence interval = 0.851 0.994). Conclusions: Patients with seminal vesicle invasion of pathological specimens after radical prostatectomy have high biochemical recurrence, but the survival was favorable especially in light of current multimodal treatment regimens. However, patients with younger age at the time of surgery, in particular, should receive multimodal treatments to improve their outcome. Key words: pt3b prostate cancer, biochemical recurrence, prognostic factors Introduction The prevalence of prostate-specific antigen (PSA) testing in the clinical field has led to an increase in morbidity of prostate cancer (PCa) in Japan, as well as allowing detection of earlier clinical and pathological stages, with most patients now presenting with localized disease (1). Therefore, PCa patients who underwent radical prostatectomy (RP) have an overall good prognosis. However, at present, there still exist locally advanced cases, particularly cases with seminal vesicle invasion determined pathologically after RP. The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 780

Jpn J Clin Oncol, 2015, Vol. 45, No. 8 781 Recently, retrospective studies evaluating the surgical procedure as a part of multimodal treatments for the management of high-risk PCa have revealed that cancer-specific survival and overall survival rates after RP are equivalent to or much better than those observed after external-beam radiotherapy plus androgen-deprivation therapy (ADT) (2,3). Thus, RP in the treatment of high-risk PCa patients needs to be reevaluated. As there have been few reports on pt3b PCa in the Japanese population, we assessed the clinical outcomes of pt3b PCa in high-volume centers and evaluated predictors of biochemical recurrence (BCR) in this high-risk disease. Patients and methods We performed a retrospective review of the medical records and found that between January 2005 and December 2011, 814 patients underwent RP without neoadjuvant hormonal therapy for the treatment of PCa at our institutions. Among these patients, 31 (3.8%) were determined to have seminal vesicle invasion pathologically (pt3b). Their clinical and pathological findings are listed in Table 1. The following data were analyzed: patient age, pre-biopsy serum PSA, percentages of positive biopsy cores, clinical and pathologic T stage (based on TNM 7th edition, 2010), lymph node status, surgical margin status and the biopsy and pathologic Gleason score. Surgical specimens were processed as follows: after marking the surgical specimens, the apical and basal parts were removed by making transverse cuts 5 mm from the distal and proximal margins, respectively. The apical and proximal parts were dissected parasagittally at 5 mm intervals perpendicular to the marked surface. The specimens Table 1. Demographic features of patients with pt3b in our cohort Characteristics n =31 Age (years) Median 67 Range 55 75 PSA level (ng/ml) Median 11.82 Range 5.54 42.63 Biopsy Gleason score 6 3 7 15 8 6 9 5 10 2 Percentage of positive biopsy Median 42 Range 5.6 88 Clinical T stage 1a/c 9 2a 9 2b 5 2c 0 3a 8 Whole-mount Gleason score 6 1 7 7 8 4 9 19 Positive lymph node (n) 6 Positive surgical margin (n) 19 PSA, prostate-specific antigen. were step-sectioned at 5 mm intervals to the apical basal axis of the gland. Seminal vesicle invasion was diagnosed under a standard protocol, with seminal vesicle invasion defined as tumor invading the muscular wall of the seminal vesicle. Of note, the route of invasion was not consistently documented and was not considered in this analysis. All the biopsies and RP specimens were evaluated by experienced uropathologists. We defined BCR as two consecutive measurements of PSA levels 0.2 ng/ml, and the date of BCR as the time of the first measurement of PSA level 0.2 ng/ml. When PSA levels after surgery did not decrease to <0.2 ng/ml, we defined the date of BCR as the time of surgery. The post-operative follow-up protocol included PSA measurements performed every 3 months after surgery. Computed tomography and bone scans were obtained at the physician s discretion. No adjuvant treatment was administered, and the treatment options after BCR were determined according to the physician s preference. Survival probabilities were estimated using the Kaplan Meier method and compared groups with the log-rank test. Multivariate analysis using Cox proportional hazards models was performed for age, pre-operative PSA, pathological lymph node and surgical margin status. Moreover, the stepwise regression procedure (reduced model) was conducted to identify important factors within these explanatory variables. Results were presented as the hazard ratio (HR) with 95% confidence interval (CI). Age and PSA values were entered as continuous covariates and others as categorized covariates. Times to all events were calculated from the date of surgery. Values of P < 0.05 were considered statistically significant. Statistical analysis was carried out using R statistical software (http://www.okada.jp.org/rwiki/). Results The median follow-up period was 60 months (range, 9 108 months). Out of 31 patients, 12 underwent open RP and 19 underwent laparoscopic RP. Lymph node dissection was performed in 24 patients (77.4%) with external iliac and obturator lesions. Lymph node metastasis was found in six patients (25%). Total number of cases with each surgical margin positive site was the following: apex, 10; posterior or lateral, 7; bladder neck, 6; seminal vesicle, 1. The PSA levels of 12 patients (38.7%) did not decrease to <0.2 ng/ml after surgery. At follow-up, BCR had occurred in 23 patients (74.2%) and PCa death in 1 patient. The patient who died of the disease experienced BCR at 3 months and received combined androgen blockage therapy but eventually developed castration-resistant disease. Docetaxel treatment was administered at 75 months after surgery, but the patient died 80 months after undergoing RP. Eighteen patients (78.3%) received ADT and 3 patients (13%) received radiation therapy (RT) as the primary therapy after BCR. The median time to BCR was 3 months, and the estimated BCR-free survival at 12, 36 and 60 months after surgery was 42, 29 and 29%, respectively (Fig. 1). The estimated overall survival at 60 and 84 months was 92 and 78.9, respectively. During follow-up, two patients died from gastric cancer, in addition to the above-mentioned patient, at 40 and 41 months after RP, but these patients did not have BCR at the time of their deaths. In order to evaluate prognostic factors for BCR after surgery, Cox proportional hazards regression analysis was conducted with preoperative and post-operative parameters, and the results are presented in Table 2. Age at the time of surgery (P = 0.010, HR = 0.875, 95% CI = 0.790 0.969) and surgical margin status (P = 0.041, HR = 2.72, 95% CI = 1.04 7.11) was significant predictors of BCR in a full model. On the other hand, only age was an independent significant

782 Prognostic factors of pt3b prostate cancer predictor of BCR (P = 0.0356, HR = 0.92, 95% CI = 0.851 0.994) in a reduced model. When we stratified the patients according to the median age (67 years), patients with younger ages ( 67 years) were found to have significantly higher rates of BCR than elderly patients (>67 years) (P = 0.041) (Fig. 2). We also stratified patients with pn0 (n = 18) according to the same age, excluding pn1 and pn patients, and the result was the same as patients with younger ages ( 67 years) were found to have significantly higher rates of BCR than elderly patients (>67 years) (P = 0.041). Discussion Historically, patients with high-risk PCa have been treated most often either with a combination of external RT and ADT or either of the two alone (2,3). However, a growing body of evidence in support of surgery seems to be transforming historical treatment patterns, because current trends reflect an increase in the number of these high-risk patients being treated with surgery. Therefore, it seems to be crucial to know the clinical outcomes of these high-risk patients, especially patients with seminal vesicle invasion confirmed after RP (pt3b), as it is a strong predictor of BCR and cancer-specific mortality after RP. In addition, understanding the outcomes of pt3b patients will focus Figure 1. Kaplan Meier curves for biochemical recurrence-free survival in 31 patients with seminal vesicle invasion after radical prostatectomy. our attention on individualizing multimodal approaches for these high-risk patients, especially in the Japanese population. Recently, Pierorazio et al. (4) have investigated contemporary outcomes in men with pt3b disease using a large comprehensive database from Johns Hopkins. In their cohort, the rate of seminal vesicle invasion was 3.9% among men who underwent RP at their institution in the contemporary PSA era. The 3-year and 5-year BCR-free survival rates were 55.0 and 36.1, respectively, and the cancer-specific survival rates were 96.6 and 91.3%, respectively. Their BCR-free survival rate is superior to that of our cohort, but they excluded patients with PCa involving pelvic lymph nodes, and 5.1% of the patients in their study received adjuvant RT. Six patients (25%) in our cohort were pathologically positive for pelvic lymph nodes and five of these patients experienced BCR. In addition, four of these patients had a detectable post-operative PSA level. Furthermore, the median PSA values (7.2 vs. 11.8 ng/ml) and percentage of patients with Gleason score of surgically removed whole-mount sections >7 (38.1% vs. 74.2%) might be the factors accounting for this difference. In another recent study, Forgues et al. (5) reported that 6% of the patients who received minimally invasive RP were identified to have seminal vesicle invasion pathologically. The 5-year BCR-free survival was 55.8% and only two patients died, one from PCa and one from cardiac disease. Among 129 patients with pt3b, they excluded from their analysis 25 patients who had a post-operative detectable PSA level and received adjuvant therapy. When we excluded 12 patients with a detectable PSA level after surgery, the 5-year BCR-free survival rate in our study was 47.4%, which is comparable to the findings of Forgues et al. (5). Yamamoto et al. (6) investigated the clinical outcomes of pt3b Japanese PCa patients. The 3-year BCR-free survival rate was 48%, with a short median follow-up period of 34 months, which was more favorable in comparison to that of our cohort. However, their study excluded patients with lymph node positive disease, and the percentage of patients with a Gleason score of surgically removed wholemount sections >7 in their study was lower in comparison to that of our cohort (48.1% vs. 74.2%). Considering prognostic factors for BCR of pt3b patients, Gleason score of surgically removed whole-mount sections, surgical margin status, pre-operative PSA and clinical stage have been considered as independent predictors (4,5,7,8). In this investigation, we only selected four variables considering our small sample size. Gleason score of surgically removed whole-mount sections in most of our cases was eight and over, we did not include in our multivariate model. Moreover, determination of clinical stage depend basically upon digital rectal examination of prostate by each physician, which was relatively subjective, Table 2. Multivariate analysis of predictors of BCR Covariate Multivariate full model Multivariate reduced model HR 95% CI P HR 95% CI P Age (years) 0.875 0.790 0.969 0.010 0.92 0.851 0.994 0.0356 PSA (ng/ml) 1 0.945 1.07 0.91 pn 0 1 (ref) 1 1.63 0.517 5.15 0.404 X 0.319 0.085 1.20 0.091 Surgical margin Negative 1 (ref) positive 2.72 1.04 7.11 0.041 BCR, biochemical recurrence; CI, confidence interval; HR, hazard ratio.

Jpn J Clin Oncol, 2015, Vol. 45, No. 8 783 Figure 2. Kaplan Meier curves for biochemical recurrence-free survival in 31 patients with seminal vesicle invasion after radical prostatectomy, stratified according to age at the time of surgery. and therefore the parameter was also not included in the model. Although surgical margin status was a significant predictor in a full model of Cox regression analysis, age was the most significant BCR predictor among patients with pt3b, and younger patients had significantly lower BCR-free survival after RP than older men in our cohort. Additionally, when we excluded patients with pn1 or pnx, younger patients ( 67 years) also had significantly lower BCR-free survival after RP than older men (>67 years), despite no difference in PSA level and surgical margin status between the two groups. Freedland et al. (8) reported that in their cohort, age (<60 years) was a significant independent predictor of BCR after RP together with surgical margin status and Gleason score of surgically removed whole-mount sections on multivariate analysis. However, they did not state why younger men with seminal vesicle invasion should have unfavorable outcomes even after controlling for tumor grade and surgical margin status. Recently, Hong et al. (9) determined in their cohort that younger and older patients showed no significant differences regarding pathological parameters and BCR-free survival among all subjects who underwent RP. However, in the high-risk group, younger patients (<60 years) had a lower rate of BCR-free survival after RP compared with older patients ( 60 years) even with no significant differences observed among various known prognostic parameters between these two groups. Moreover, multivariate analysis also revealed that age was an independent predictor of BCR-free survival among the high-risk group. These previous data are supportive of our findings. In contrast, Forgues et al. (5) did not find any association between BCR and age at surgery in pt3b patients in their cohort. They found that only Gleason score of surgically removed whole-mount sections was a significant risk factor for BCR in multivariate analysis. Fairey et al. (7) also reported that Gleason score of surgically removed whole-mount sections was a significant predictor of BCR for pt3b patients who received RP. This discrepancy might be due to differences in patient characteristics as well as analyzed parameters, because 74.2% of our patients had Gleason scores 8 in surgically removed whole-mount specimens in contrast to 17.3 and 47% of patients in the previous reports, respectively (5,7). In our study, no significant differences were observed between the two age cohort (>67 years vs. 67 years) regarding PSA level, percentage of positive biopsy cores, clinical T stage, surgical margin status and Gleason score of surgically removed whole-mount sections (data not shown). Therefore, it would be difficult to give potential explanation for the observed difference in BCR outcomes based upon known prognostic variables. There might be unknown genetic or other biological factors that have contributed to our findings. Further investigation is needed to provide deep insights into biological behaviors of this high-risk disease. Despite the high rate of BCR in patients with pt3b disease, cancerspecific survival was excellent in our small series, and this favorable outcome was also confirmed by other previous reports (4 8). Although post-operative management has not been clearly defined for pt3b cases (5,10,11), multimodal treatments including radiation to the prostatic bed or hormonal therapy will allow the patients to survive for many years even after PCa growth beyond the gland. Our study has some limitations resulting from its retrospective design, small sample size and short follow-up period. Treatments after BCR were not standardized and were dependent upon physician preferences. Pelvic lymph node dissection was not performed (n = 7) if the percentage of lymph node involvement was <5% on the nomogram for the Japanese population, as previously reported in one of our institutions (12). Therefore, the cohort included pt3bpn0, pt3bpn1 and pt3bpnx patients, so we should be cautious in interpreting our data when we compare the results of pt3b outcome in our study with other previous reports. Conclusively, seminal vesicle invasion after RP betokens a poor prognosis with regard to BCR, but cancer-specific survival is largely favorable, especially in light of current multimodal treatment regimens. However, younger patients with seminal vesicle invasion had worse BCR-free survival compared with older patients, so aggressive treatments should be considered for these high-risk patients. Further investigations will be needed to evaluate the molecular mechanisms of this PCa biology, and to define preferable approaches after RP in order to prevent disease recurrence. Conflict of interest statement None declared. References 1. Onozawa M, Hinotsu S, Tsukamoto T, et al. Recent trends in the initial therapy for newly diagnosed prostate cancer in Japan. Jpn J Clin Oncol 2014;44:969 81. 2. Lee BH, Kibel AS, Ciezki JP, et al. Are biochemical recurrence outcomes similar after radical prostatectomy and radiation therapy? 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