Original Article Japanese Journal of Clinical Oncology Advance Access published January 17, 2008 Jpn J Clin Oncol doi:10.1093/jjco/hym135 Prognostic Value of Surgical Margin Status for Biochemical Recurrence Following Radical Prostatectomy Kohei Hashimoto 1, Naoya Masumori 1, Fumiyasu Takei 1, Fumimasa Fukuta 1, Atsushi Takahashi 3, Naoki Itoh 1, Tadashi Hasegawa 2 and Taiji Tsukamoto 1 1 Department of Urology, 2 Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo and 3 Department of Urology, Hakodate Goryokaku Hospital, Hakodate, Hokkaido, Japan Received June 4, 2007; accepted September 19, 2007 Objective: We evaluated the preoperative parameters to predict a positive surgical margin (SM) at radical prostatectomy for patients with prostate cancer. In addition, the prognostic factors for biochemical recurrence were determined in patients with positive SMs. Methods: We retrospectively analysed 238 patients with prostate cancer who underwent retropubic radical prostatectomy and bilateral pelvic lymph node dissection from May 1985 to July 2005 in our hospital. Biochemical recurrence was defined as an increase of undetectable prostate-specific antigen (PSA) to 0.2 ng/ml or greater. Results: Of the 238, 82 patients (34.4%) had positive SMs. On multivariate analysis, preoperative PSA (10 ng/ml), clinical T stage (T2a) and the positive core rate (35%) were parameters that could predict a positive SM. During the median follow-up of 31.2 months, 48 patients (20.2%) developed biochemical recurrence. The 5-year biochemical progression-free survival rates were 81.7% and 62.6% in patients with negative and positive SMs, respectively (P, 0.001). In the Cox proportional hazards model, preoperative PSA of 20 ng/ml and a pathological T stage of pt3a/pt3b were significant risk factors for biochemical recurrence in patients with positive SMs. Conclusions: SM status at radical prostatectomy depends on preoperative PSA, clinical stage and the positive core rate. Patients with a positive SM had a higher risk for biochemical recurrence than those with a negative one. Patients with a positive margin had a higher risk for biochemical recurrence if they exhibited preoperative PSA of 20 ng/ml and/or pathological T stage of pt3a/pt3b. Key words: prostate cancer radical prostatectomy surgical margin recurrence INTRODUCTION Although radical prostatectomy is a standard treatment for clinically localized prostate cancer, recent studies have reported that 5 43% of patients show a positive surgical margin (SM) in their specimens (1). A positive SM defined as the extension of cancer to the surface of the removed specimen generally indicates incomplete resection. The cause of a positive SM is multifactorial, and includes clinical and pathological features of cancer as well as inadequate surgical skill or careless incision (2). Identifying preoperative For reprints and all correspondence: Naoya Masumori, Department of Urology, Sapporo Medical University School of Medicine, S1, W16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: masumori@sapmed.ac.jp factors to predict a positive SM may contribute to a decrease of the rate by selection of appropriate candidates and more prudent surgical management. Many studies have indicated that a positive SM at radical prostatectomy is an independent risk factor for biochemical recurrence (1,3 6). However, this still remains controversial (7 10), suggesting that the outcome of the patients with a positive SM might be determined by other clinical and pathological parameters. In this study, we evaluated the preoperative parameters to predict a positive SM at radical prostatectomy for patients with prostate cancer. In addition, the prognostic factors for biochemical recurrence were determined in patients with a positive SM. # The Author (2008). Published by Oxford University Press. All rights reserved.
Page 2 of 5 Surgical margin in radical prostatectomy METHODS We retrospectively reviewed the outcomes of 305 patients who underwent retropubic radical prostatectomy and bilateral pelvic lymph node dissection from May 1985 to July 2005 in our institute. A total of 67 patients were excluded from the analysis, consisting of 44 with neoadjuvant hormonal treatment, 19 with adjuvant hormonal treatment, 3 with pathologically proven lymph node metastasis and 1 with no evidence of cancer in the surgical specimen. All patients had preoperative serum prostate-specific antigen (PSA) determination (Tandem-R). Systematic prostate biopsy was done using an 18-gage needle under the guidance of transrectal ultrasound and a total of 6 14 (median: 7) biopsy cores were taken for each patient. The positive core rate was calculated as the number of cancer-positive cores divided by total biopsy cores 100. was determined by digital rectal examination, transrectal ultrasound, abdominal computed tomography, chest X-ray and bone scan. Radical prostatectomy was done using a standard retropubic approach with limited pelvic lymph node dissection. Each neurovascular bundle was preserved if there was no positive core on each side or only well-differentiated cancer was detected in the biopsy specimens. Ultimately whether to preserve the neurovascular bundles was determined by the patients preference because of the lack of validated criteria for nerve-sparing radical prostatectomy. The nerve-sparing procedure was performed as described by Walsh (11) with minor modifications. The surgical specimens were sectioned at 5 mm intervals and provided for pathological analysis. Stage and histological grade were assigned using the 1997 UICC-American Joint Committee on Cancer TNM system and the Gleason system, respectively. Stage and histological grade were according to the pathologists reports. After surgery, serum PSA measurement was performed every 3 months throughout the follow-up period. Biochemical recurrence was defined as an increase of undetectable PSA (,0.2 ng/ml) to 0.2 ng/ml or greater. If the patients failed to achieve undetectable PSA levels after radical prostatectomy, the time to biochemical recurrence was defined as 0 days. The chi-square test and logistic regression analysis were performed to test relationships between various clinical parameters and a positive SM. Biochemical progression-free survival was calculated using the Kaplan Meier method, and the differences between biochemical progression-free survival rates were assessed by the log-rank test. The Cox proportional hazards model was used to estimate the risk of biochemical recurrence. Tree-based recursive partitioning was performed to identify a cut-off for PSA, which optimally stratified cases according to the risk for a positive SM and biochemical recurrence. The level of statistical significance was considered to be P, 0.05 in all analyses. We used the computer program StatView 5.0 for Windows (SAS Institute, Cary, NC, USA) for statistical analyses. RESULTS Table 1 shows clinical and pathological characteristics of the 238 patients evaluated in this study. Their ages were distributed from 44 to 74 years with mean age of 65.6 years (median: 66 years). The mean follow-up period was 42.8 months (median: 31.2 months), ranging from 1 to 210 months. Preoperative PSA ranged from 1.1 to 143 ng/ml with a mean of 12.1 ng/ml (median: 8.2 ng/ml). A positive SM was found in 82 patients (34.4%), and the rate increased with the extension of pathological disease. It was 25.8% in patients with pathologically organ-confined disease, but increased to 64.7% in those with pt3a and 59.1% in those with pt3b. In 55 (67.0%) of 82 patients with a positive SM, the disease was found in the apex of the prostate. The positive SM rate in the apex was similar for T1 (57.6%) and T2/3 (73.5%) diseases (P ¼ 0.501). Multivariate analysis demonstrated that the preoperative PSA level (10 ng/ml), clinical stage (T2a) and positive core rate (35%) were independently significant factors to predict a positive SM (Table 2). Table 1. Clinical and pathological features of 238 patients treated with radical prostatectomy Features Number of patients (%) T1 133 (55.9) T2 103 (43.3) T3 2 (0.8) Gleason sum on biopsy 6 106 (45.5) 7 100 (42.0) 8 17 (7.2) unclear 15 (6.3),35% 132 (55.4) 35 65% 49 (20.6) 65% 39 (16.4) undetectable T1a, T1b 18 (7.6) Nerve-sparing procedure 97 (40.8) Gleason sum on prostatectomy 6 75 (31.5) 7 136 (57.1) 8 27 (11.3) Positive surgical margin 82 (34.4) Pathological stage T2 182 (76.5) T3a 34 (14.3) T3b 22 (9.2)
Jpn J Clin Oncol 2007 Page 3 of 5 Table 2. Univariate and multivariate analyses of preoperative factors predicting positive surgical margins after radical prostatectomy Preoperative parameters Preoperative PSA (ng/ml) PSM rate: % (number of patients with PSM/total number of patients),10 24.5 (36/147) 10 50.5 (46/ 91) T1 24.6 (33/134) T2 47.1 (49/104) Gleason sum on biopsy 6 31.1 (33/106) 7 38.5 (45/117),35% 24.2 (32/132) 35% 54.5 (48/ 88) Nerve-sparing procedure Yes 26.8 (26/ 97) No 39.7 (56/141) Chi-square test: P value PSM, positive surgical margin; PSA, prostate-specific antigen. Logistic regression analysis: P value,0.001 0.002,0.001 0.026 0.997 0.578,0.001,0.001 0.039 0.778 Figure 1. Kaplan Meier curve estimates of prostate-specific antigen (PSA) progression-free survival of patients treated with radical prostatectomy according to surgical margin status (P, 0.001). SM, surgical margin. Table 3. Cox proportional hazards model of factors predicting biochemical recurrence in patients with positive surgical margin after radical prostatectomy Variables Hazard ratio (95% CI) P value Preoperative PSA,20 ng/ml 1.0 20 ng/ml 3.37 (1.33 8.54) 0.010 T1 1.0 T2 1.42 (0.59 3.42) 0.433,35% 1.0 35% 1.14 (0.46 2.87) 0.775 Nerve-sparing procedure Yes 1.0 No 2.37 (0.80 7.05) 0.121 Gleason sum on radical prostatectomy 7 1.0 8 1.29 (0.47 3.56) 0.625 Pathological stage T2 1.0 T3a 3.36 (1.10 10.24) 0.033 T3b 7.13 (2.10 24.21) 0.002 CI, confidence interval. positive SM (62.6%) than in those with a negative SM (81.7%) (P, 0.001, Fig. 1). The Cox proportional hazards model revealed that preoperative PSA and pathological stage were significant risk factors for biochemical recurrence in patients with a positive SM (Table 3). The preoperative PSA level and pathological T stage were used to construct risk categories for patients with a positive SM. If the preoperative PSA level was 20 ng/ml or higher, or the pathological T stage was pt3a, score 1 was given. If the pathological T stage was pt3b, score 2 was given. The sum of scores determined the risk scores, ranging from 0 to 3. The estimated 3-year biochemical progression-free survival rate was 81.8% in patients with a risk score of 0 or 1. However, those with scores 2 or 3 had a markedly lower rate of survival (20.7%) (P, 0.001, Fig. 2). During the median follow-up period of 31.2 months, 48 patients (20.2%) developed biochemical recurrence. Of them, 15 failed to achieve undetectable PSA levels after radical prostatectomy. There was one (0.4%) who died of prostate cancer and six (2.5%) who died of other diseases. The estimated 5-year and 10-year biochemical progressionfree survival rates were 75.0% and 71.0%, respectively. According to the SM status, the 5-year biochemical progression-free survival was lower in the patients with a DISCUSSION Several variables can affect SM status at radical prostatectomy. A positive SM occurs either as a result of incising into prostate cancer that extends beyond the prostatic capsule or anterior side of the apex lacking the prostate capsule, or from incising into an intracapsular cancer by an inadequate procedure. Considering this consensus, it is not surprising that the surgical technique and pathological stage can affect
Page 4 of 5 Surgical margin in radical prostatectomy Figure 2. Kaplan Meier curve estimates of PSA progression-free survival according to risk scores (RS) in 82 patients with positive surgical margins after radical prostatectomy. RS 0 versus 1: P ¼ 0.300; RS 0 versus 2: P, 0.001; RS 0 versus 3: P, 0.001; RS 1 versus 2: P ¼ 0.029; RS 1 versus 3: P ¼ 0.005, RS 2 versus 3: P ¼ 0.190. Three-year PSA progression-free survival for RS 0-1 versus 2 3: 81.8% versus 20.7%, P, 0.001. SM status (1 3,5,12,13). However, if any technical effort in surgery can contribute to decreasing the likelihood of a positive SM, it would be necessary to identify the preoperative parameters to predict the positive SM. In the present study, preoperative PSA (10 ng/ml), clinical stage (T2a) and a positive core rate (35%) were significant factors to predict a positive SM. A positive SM may represent aggressive features of cancer in patients with these risk factors. Previous studies have demonstrated that the preoperative parameters, including preoperative PSA, Gleason score on biopsy specimens and clinical stage, influence SM status (14 16). Although it was beyond the scope of this study to determine whether patients with these risks are really appropriate candidates for radical prostatectomy, sufficient resection of the tissue surrounding the prostate, as extensively as possible, will contribute to decreasing the likelihood of a positive SM. A positive SM generally indicates that cancerous tissue is not completely removed. However, whether all patients with a positive SM will develop progression following radical prostatectomy remains to be determined and the prognostic impact of a positive margin on the clinical course is controversial. Several studies demonstrated that SM status was not an independent prognostic factor for recurrence in organconfined disease or in disease with seminal vesicle involvement (7,8). Likewise, it has been reported that, regardless of SM status, patients with extraprostatic extension have a similar risk for biochemical recurrence (9,10). On the other hand, the present study demonstrated that PSA progressionfree survival was worse in patients with a positive SM than in those with a negative one, which was supported by other studies (1,3 6). A recent large multi-institutional cohort analysing 5813 patients clearly demonstrated that a positive SM was an independent prognostic factor (4). The prognosis of the patient with a positive SM may be determined by the result of the combined clinical and pathological characteristics. In the present study, a PSA level of 20 ng/ml or greater, pt3a and pt3b were significant risk factors for biochemical recurrence in patients with a positive SM. A previous study demonstrated that patients with Gleason scores of 7 10 or lymph node involvement were at an even greater risk if a positive SM was encountered (4). Likewise, another study indicated that there were several factors increasing the possibility of recurrence in patients with a positive SM, including a PSA level of greater than 20 ng/ml, Gleason scores of 8 10 and seminal vesicle involvement (6). These findings clearly indicate that a positive SM would drive disease progression, especially together with other adverse features. Our results also suggested that the risk score determined by preoperative PSA and pathological stage was helpful to identify patients with higher risk for recurrence among those with a positive SM. For patients with these risks, an indication for adjuvant therapy should be discussed to reduce the risk of recurrence. Recently, the European Organization for Research and Treatment of Cancer (EORTC) trial 22911 study demonstrated the efficacy of adjuvant radiotherapy after radical prostatectomy for patients with pathologically advanced prostate cancer (pt2 with positive SM or pt3 with or without a positive SM) (17). Adjuvant radiation therapy significantly improved the 5-year biochemical progression-free survival compared with wait-and-see (74.0% versus 52.6%, P, 0.0001). Another randomized control study showed that adjuvant radiotherapy resulted in a significantly reduced risk of biochemical recurrence (18). In addition, the efficacy of immediate hormonal therapy was indicated in a randomized trial (n ¼ 309), in which adjuvant flutamide treatment significantly reduced the risk of disease progression compared with observation for locally advanced prostate cancer ( pt3-4) (19). Thus, subsets of patients with adverse prognostic features might benefit from adjuvant therapy. However, it remains to be determined which adjuvant therapy should be given to these patients to improve overall and diseasespecific survival. In addition, it should also be determined whether salvage therapy is equally effective as adjuvant therapy for biochemical recurrence. The present study had several limitations, including its retrospective nature, multiple surgeons and pathologists, and the relatively short follow-up period. The positive SM rate in patients with pathologically organ-confined disease was 25.8%, which was slightly higher than that of other recent studies in which it ranged from 3.2% to 18.0% (1,3,5,12). We provided patients with radical prostatectomy as one of the treatment modalities even when they had a clinically localized disease with a high PSA level. In patients with high PSA levels who may have large tumor volume, it is likely that the cancer will be incised, resulting in a positive SM even in pathologically organ-confined disease. Multivariate analyses picked up two independent parameters, the
Jpn J Clin Oncol 2007 Page 5 of 5 preoperative PSA level and pathological stage to predict biochemical recurrence in patients with a positive SM. Risk categories were constructed by the combination of these two parameters. There were only three patients with score 3, whichmeanshavingpt3bandpsa20ng/mlorhigher. Since these patients had a markedly low rate of survival compared with scores 0, 1 and 2, we believe that it is necessary to present the prognosis of these patients. In spite of these limitations, we found that patients with a positive SM could be stratified into two groups by the risk score for predicting their prognosis. Thus, we believe that the clinical implications of a positive SM after radical prostatectomy are partly elucidated in this study. CONCLUSIONS The preoperative parameters, including preoperative PSA (10 ng/ml), clinical stage (T2a) and positive core rate (35%), were significant factors to predict a positive SM at radical prostatectomy. Patients with a positive SM had a significantly higher risk for biochemical recurrence than those without a positive SM. In multivariate analysis, preoperative PSA (20 ng/ml), pt3a and pt3b were significant risk factors for biochemical recurrence in patients with a positive SM. The risk score determined by PSA and pathological T stage may be useful to predict the prognoses of these patients. Conflict of interest statement None declared. References 1. Swindle P, Eastham JA, Ohori M, Kattan MW, Wheeler T, Maru N, et al. Do margins matter? The prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 2005;174:903 7. 2. Eastham JA, Kattan MW, Riedel E, Begg CB, Wheeler TM, Gerigk C, et al. Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens. J Urol 2003;170:2292 5. 3. Pettus JA, Weight CJ, Thompson CJ, Middleton RG, Stephenson RA. 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