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Japanese Journal of Clinical Oncology Advance Access originally published online on April 24, 2009
Japanese Journal of Clinical Oncology 2009 39(6):387-393; doi:10.1093/jjco/hyp032
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© The Author (2009). Published by Oxford University Press. All rights reserved

Risk Stratification of High-grade Prostate Cancer Treated with Antegrade Radical Prostatectomy with Intended Wide Resection

Shinya Yamamoto1, Satoru Kawakami1, Junji Yonese1, Yasuhisa Fujii1, Tetsuro Tsukamoto1, Yuhei Ohkubo1, Yoshinobu Komai1, Yuichi Ishikawa2 and Iwao Fukui1

1 Department of Urology, Japanese Foundation for Cancer Research, Cancer Institute Hospital
2 Department of Pathology, Japanese Foundation for Cancer Research, Cancer Institute Hospital, Tokyo, Japan

For reprints and all correspondence: Shinya Yamamoto, Department of Urology, Japanese Foundation for Cancer Research, Cancer Institute Hospital, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan. E-mail: shinya.yamamoto{at}jfcr.or.jp

Received January 4, 2009; accepted March 5, 2009


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Conflict of interest statement
 References
 
Objective: The aim of this study was to assess the surgical outcome of high-grade prostate cancer (PCA) treated with antegrade radical prostatectomy with intended wide resection (aRP) and to establish the risk stratification.

Methods: A consecutive 77 Japanese patients with Gleason score 8–10 PCA were treated with aRP alone and excluding patients with persistently elevated prostate-specific antigen (PSA), prospectively observed without any treatment until PSA failure was confirmed. PSA failure-free, cancer-specific and overall survival curves were generated with Kaplan–Meier method and the difference between groups was assessed with log-rank test. Cox's proportional hazards model was used to elucidate predictors of PSA failure.

Results: During a median follow-up of 6 years, PSA failure was observed in 41 (53%) of the 77 patients. Five- and 10-year PSA failure-free survival rates of the entire cohort were 44.6% and 40.1%, respectively. Both overall and cancer-specific survival rates of the entire cohort at 5 and 10 years were 96.8% and 87.9%, respectively. In a multivariate analysis, PSA (P = 0.008), specimen confinement (SC) (P = 0.006) and persistently elevated PSA after aRP were identified as significant and independent predictors of PSA failure. When stratifying patients into three risk groups according to PSA level and SC status, PSA failure-free survival rate in patients with PSA < 10 ng/ml and specimen-confined disease (SCD) was significantly better than that in those of any other groups.

Conclusions: Good prognosis can be expected in patients with high-grade PCA treated with aRP alone when PSA < 10 ng/ml and the tumor was removed as an SCD.

Key Words: antegrade radical prostatectomy • high-grade prostate cancer • prostate-specific antigen • specimen-confined disease


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Conflict of interest statement
 References
 
Radical prostatectomy (RP) is a gold standard of treatment with curative intent for clinically localized prostate cancer (PCA). Approximately one-third of the PCA patients treated with RP, however, have prostate-specific antigen (PSA) failure and substantial proportion of them have death related to PCA eventually (1). In the PSA era, surgical outcome of high-grade PCA has been improved rapidly (2). This is partly due to the fact that the widespread use of PSA screening and modern imaging modalities allows earlier detection of high-grade PCA (3). Because RP with intended wide resection of the vascular pedicles might also contribute to the surgical outcome improvement, surgical curability of high-grade PCA detected at earlier stage is one of the most enthusiastic issues in the current oncological management of clinically localized PCA (3). By establishing the optimal management strategy for patients with high-grade PCA on RP specimen, the following two questions are to be answered: who would be cured by surgery alone? and to whom adjuvant treatment should be indicated?

Since high Gleason score (GS) on RP specimen is one of the strongest predictors of unfavorable prognosis (4,5), adjuvant treatment has been often added to patients with this feature. It should be noted that, however, in a randomized clinical trial of adjuvant radiation therapy for pathologically confirmed locally advanced PSA following RP, Thompson et al. (6) reported an increased incidence of adverse effects in patients in the adjuvant treatment arm. It is rational, therefore, to assume that some patients with high-grade PCA would be cured by surgery alone and therefore would not benefit from any adjuvant treatment. We have been adopting a departmental policy that patients are followed with watchful observation after RP as far as possible and ever reported some risk stratifications of patients with adverse pathological findings to justify the policy (7,8).

In the current study, our interest was solely focused on patients with high-grade PCA treated primarily with antegrade RP with intended wide resection (aRP) (9). By analyzing the surgical outcome of these patients, we assessed prognostic impact of aRP monotherapy on these patients and aimed at stratifying them according to distinct risk of PSA failure.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 Conflict of interest statement
 References
 
Patient Population
We retrospectively reviewed clinical records of a consecutive 442 Japanese patients diagnosed with clinically localized or locally advanced PCA treated with aRP and bilateral lymphadenectomy limited to the obturator region without neoadjuvant treatment between February 1994 and December 2006 at Cancer Institute Hospital, Tokyo, Japan. Of the 442 patients, 77 patients (17.4%) had a GS 8 or 9 on RP specimen, whereas no patient had a GS 10 disease.

Staging and Follow-up
The median value and quartile range of age and PSA of the 77 patients were 68 years (47–77) and 13.0 ng/ml (2.2–123.0), respectively. Clinical stage was T1c, T2 and T3 in 18, 48 and 11, respectively, accordingly to the 1997 TNM classification (10) (Table 1). To measure serum PSA level, Tandem-R Test (Beckman–Coulter, San Diego, CA, USA) was used until July 2003, and AxSYM kit (Abbot Laboratories, Japan) was used thereafter. aRP was performed as reported previously throughout this study period (9). aRP is a synonym for ‘antegrade radical retropubic prostatectomy with preliminary ligation of vascular pedicles’ as we described previously (9). In the current study, we used the term to emphasize an ‘intended wide resection’. There are two important technique points in the aRP. One is to ligate two main vascular pedicles, the dorsal vein complex and the postero-lateral prostatic pedicles, before initiating the manipulation of malignant tissue. Another is to remove the prostatic pedicles and the bladder neck as widely as possible. Surgical technique reported by Serni et al. (11) with intended preservation of the bladder neck is different from ours mainly in the latter point. Wide resection of the postero-lateral vascular pedicle was not performed on the nerve sparing side of the 10 patients treated with unilateral nerve sparing surgery. After the aRP, PSA measurements were performed at least every 3 months during year 2, every 6 months during years 3–5 and yearly thereafter.


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  		Table 1. Clinical characteristics of the study cohort

 
PSA failure was defined as a PSA level >0.2 ng/ml on two consecutive measurements. Various imaging studies were performed when PSA failure was confirmed. In patients with persistently elevated PSA after aRP, the day of the surgery was assigned to the day of PSA failure. Of the 77 patients, 16 patients with persistently elevated PSA after aRP received adjuvant hormonal treatment, whereas the remaining 61 patients were prospectively observed without any treatment until PSA failure was confirmed.

Pathologic Examination
aRP specimens were processed as reported previously (12). Histopathological grading of the aRP specimen was performed according to the GS system by a single pathologist (Y.I.). When multiple cancer lesions were identified in an aRP specimen, GS was decided as primary plus secondary Gleason grade (GG) in the index cancer, the largest cancer focus in the aRP specimen. GS 8 and 9 disease was assigned to 19 and 41 of the 60 index cancers, respectively. Of the 19 patients with a GS 8 disease, 3, 12 and 4 patients had a GS 3 + 5, 4 + 4 and 5 + 3, respectively. Of the 41 patients with a GS 9 disease, 32 and 9 patients had a GS 4 + 5 and 5 + 4, respectively. In the current study, the 60 index cancers were categorized into two groups, 45 cancers with GS 9 or GS 5 + 3 (primary GG 5) and 15 cancers with GS 3 + 5 or 4 + 4 (primary GG 4 or less). Organ-confined disease (OCD) was defined as pT2 disease with negative surgical margin (NSM). Specimen-confined disease (SCD) was defined as pT2 or pT3a disease with NSM. Maximum tumor dimension (MTD) was defined as the maximum length of the index cancer on the glass slide and used instead of index cancer volume (8).

Statistical Analysis
The differences in variables between patient groups were analyzed by {chi}2 test and Mann–Whitney U test. Univariate and multivariate Cox's proportional hazard analyses were used to assess the association of variables to PSA failure. Age (<68 vs. ≥68), PSA (<10 vs. ≥10 ng/ml), lymphovascular invasion (LVI) (negative vs. positive), extraprostatic extension (ECE) (negative vs. positive), seminal vesicle involvement (SVI) (negative vs. positive), pathological categories [organ confinement (OC) vs. non-OC and specimen confinement (SC) vs. non-SC], MTD (<20 vs. ≥20 mm), RP GS (4 + 4 or 3 + 5 vs. 9 or 5 + 3) and persistently elevated PSA after aRP (yes vs. no) were evaluated as possible predictors of PSA failure after aRP. PSA failure-free, cancer-specific and overall survival curves were generated with Kaplan–Meier method and the difference between groups was assessed with log-rank test. All P values were two-sided. A P value of <0.05 was considered statistically significant. Statistical analyses were performed with JMP version 5.1.1 (SAS Institute Inc., Cary, NC, USA).


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 Conflict of interest statement
 References
 
Oncological Outcome
During a median follow-up of 6 years (quartile range 0.3–14.3), PSA failure was observed in 41, including the 16 patients with persistently elevated PSA after aRP, of the 77 patients (53%) and 7 (9%) have died of PCA as on November 2008. As shown in Fig. 1, 5- and 10-year PSA failure-free survival rates of the entire cohort were 44.6% and 40.1%, respectively. Both overall and cancer-specific survival rates of the entire cohort were 96.8% at 5 years and 87.9% at 10 years, respectively.


Figure 1
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  		Figure 1. Kaplan–Meier PSA failure-free (a), cancer-specific (b) and overall survival (c) curves in patients with high-grade PCA treated with RP alone. Numbers of patients at risk are shown on the horizontal axis at 0, 5 and 10 years. PSA, prostate-specific antigen; RP, radical prostatectomy.

 
Predictors of PSA Failure
Table 2 showed univariate and multivariate analyses of association of perioperative clinico-pathological variables with PSA failure. Among the nine variables evaluated, PSA (P = 0.008), SC (P = 0.006) and persistently elevated PSA after aRP (P = 0.001) were identified as significant and independent predictors of PSA failure, whereas age, LVI, ECE, SVI, MTD and GS on RP specimen were not (Fig. 2). Other GS categorization, such as GS 8 vs. GS 9 or GG 5 absent vs. GG 5 present, did not improve prognostic impact of GS (data not shown).


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  		Table 2. Univariate and multivariate analyses of predictors of PSA failure in patients with high-grade PCA treated with RP

 

Figure 2
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  		Figure 2. Kaplan–Meier PSA failure-free survival curves according to PSA level (a) (PSA < 10 and ≥10 ng/ml) and SC (b) (SCD and non-SCD) in patients with high-grade PCA treated with RP alone. Numbers of patients at risk are shown on the horizontal axis at 0 and 5 years. SC, specimen confinement; SCD, specimen-confined disease.

 
PSA Failure Risk Stratification
The aim of this study was to evaluate the risk of PSA failure soon after the aRP. In patients with persistently elevated PSA, we do not have to evaluate the risk of PSA failure, because PSA failure would be assigned to them as definition and PSA failure risk would be 100%. Therefore, predictors of PSA failure were analyzed in the remaining 61 patients. Since PSA and SC remained as independent and significant predictors of PSA failure even when persistently elevated PSA after aRP was excluded from the multivariate analysis, we stratified the remaining 61 patients into the following three risk groups according to the two variables: Group 1, PSA < 10 ng/ml and SCD; Group 2, PSA < 10 ng/ml and non-SCD or PSA ≥ 10 ng/ml and SCD; Group 3, PSA ≥ 10 ng/ml and non-SCD. Fourteen (23%), 27 (43%) and 20 (33%) patients were assigned to the Group 1, 2 and 3, respectively. As shown in Fig. 3, this stratification discriminated the risk of PSA failure with statistical significance (P < 0.001). Five-year PSA failure-free survival rate of the Group 1 patients was 100%, whereas that of the Group 3 patients was only 19.8%. As shown in Table 3, Group 1 patients had significantly lower pathological T stage (P < 0.001) and smaller MTD (P = 0.005) than any other groups.


Figure 3
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  		Figure 3. Kaplan–Meier PSA failure-free survival curves according to three risk groups according to PSA level and SC (Group 1, PSA < 10 ng/ml and SCD; Group 2, PSA < 10 ng/ml and non-SCD or PSA ≥ 10 ng/ml and SCD; Group 3: PSA ≥ 10 ng/ml and non-SCD) in patients with high-grade PCA treated with RP alone. Numbers of patients at risk are shown on the horizontal axis at 0 and 5 years. PCA, prostate cancer.

 

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  		Table 3. Patient characteristics of three risk groups

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 Conflict of interest statement
 References
 
Oncological Control of High-grade PCA by Surgery
To date, five studies have been reported on high-grade PCA patients treated with RP (2,13,14,16,17). Oncological outcome of high-grade PCA treated with RP alone [three previous studies (2,14,16) and current one] and RP with adjuvant treatment [two studies (13,17)] was compared in Table 4. Patient cohorts treated with RP alone and followed by watchful observation until PSA failure would be ideal subjects to assess the actual contribution of RP to the oncological control of high-grade PCA. In this regard, there have been not plenty information available. The current series, the newest in surgical years with the longest follow-up period, might better reflect contemporary surgical outcome of high-grade PCA.


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  		Table 4. Oncological outcome of RP in patients with high-grade PCA

 
The current study demonstrated almost same cancer-specific survival rate compared with that reported by Lau et al. (13). Considering that all other patients except the patients with persistently elevated PSA after aRP received salvage treatment only when PSA failure was confirmed and patients in the study by Lau et al. (13) received adjuvant treatment uniformly, this comparison might support the notion that adjuvant treatment after RP might not provide any survival benefit to all patients with high-grade PCA.

SC as a Prognostic Factor
We demonstrated that aRP can be curative for patients with high-grade PCA when pre-operative PSA was <10 ng/ml and the prostate was surgically removed as an SCD. PSA value, surgical margin status and pathological stage have been indicated as predictors of PSA failure in patients with high-grade PCA treated with RP (13–16). Mian et al. (2) showed that non-SC is a sole predictor of PSA failure in patients with high-grade PCA treated with RP.

Since the mid-1990s, the detection of patients with high-grade PCA at an earlier stage has resulted in their excellent pathological results of RP (Table 3). Mian et al. (2) reported that OC and SC rates in patients with high-grade PCA treated with RP alone after 1995 are largely improved when compared with those before 1995. Recently, Serni et al. (17) also reported that in a series of 116 patients with high-grade PCA who underwent RP, positive surgical margin rate was 9.9%. In our series, patients who underwent aRP after 2002 had significantly higher OC and SC rates when compared with those before 2002, showing a tendency similar to those of the aforementioned studies (data not shown). In addition to the earlier diagnosis, advance of surgical skill might also contributed to the increased SC rate. In the current series, 7 (29%) of the 24 pT3a tumors were extirpated as SCD.

Risk Stratification of High-grade PCA
A remarkable downward stage migration provides patients with high-grade PCA, an opportunity of surgical cure (3). Our results demonstrated that such an opportunity could be opened to those with pre-operative PSA <10 ng/ml. However, further requirement was indicated to the surgeon that surgical cure in these patients can be expected only when the prostate was removed as an SCD.

The current result, 100% 5-year PSA failure-free survival rate of the patients with PSA < 10 ng/ml and SCD, indicates that any adjuvant treatments would not be required for these patients. When compared with a previous large series, 5-year PSA failure-free survival rate of this group is more favorable than those of OCD (87.1%) and low-risk group of D'Amico's risk classification (87.1%), and is by far better than that of RP GS 7 (18). In contrast, considering the remarkably lower 19.8% 5-year PSA failure-free survival rate of the patients with PSA ≥ 10 ng/ml and non-SCD, contribution of aRP monotherapy for these patients would be limited.

In the current series, although patients with PSA failure were salvaged by radiotherapy and/or hormonal therapy, all two deaths caused by PCA. Freedland et al. (19) reported that in 15-year actuarial survival estimates, 77% of all deaths in patients treated with RP who experienced PSA failure caused by PCA. Our risk stratification may be useful to decide the indication of adjuvant treatment after aRP for patients with high-grade PCA treated with aRP alone. How to manage patients with either PSA ≥ 10 ng/ml or non-SCD post-operatively should be clarified.

Limitations of the Study
The major limitation of this study is its small study size. Validating our results by larger studies would be necessary. In the current series, we performed pelvic lymphadenectomy limited to the obturator lesion. Extended pelvic lymph node dissection might further contribute to the improved oncological outcome of these patients (20).


   CONCLUSIONS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
Conflict of interest statement
 References
 
aRP monotherapy can be curative in selected patients with high-grade PCA with PSA <10 ng/ml and achieved SCD by the surgery. Withholding adjuvant treatment to those patients would effectively circumvent possible complication associating with the adjuvant treatment. In contrast, contribution of aRP monotherapy for patients with PSA ≥10 ng/ml and non-SCD would be limited. Therefore, we propose risk stratification based on PSA level and SC in patients with high-grade PCA treated with aRP alone. Our results would facilitate effective patient selection in clinical trials for high-grade PCA.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Conflict of interest statement
References
 
None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Conflict of interest statement
 References
 
1 Carini M, Masieri L, Minervini A, Lapini A, Serni S. Oncological and functional results of antegrade radical retropubic prostatectomy for the treatment of clinically localized prostate cancer. Eur Urol (2008) 53:554–63.[CrossRef][Web of Science][Medline]

2 Mian BM, Troncoso P, Okihara K, Bhadkamkar V, Johnston D, Reyes AO, et al. Outcome of patients with Gleason score 8 or higher prostate cancer following radical prostatectomy alone. J Urol (2002) 167:1675–80.[CrossRef][Web of Science][Medline]

3 Poppel HV, Joniau S. An analysis of radical prostatectomy in advanced stage and high-grade prostate cancer. Eur Urol (2008) 53:253–9.[CrossRef][Web of Science][Medline]

4 Partin AW, Pound CR, Clemens JQ, Epstein JI, Walsh PC. Serum PSA after anatomic radical retropubic prostatectomy. The Johns Hopkins experience after 10 years. Urol Clin North Am (1993) 20:713–25.[Web of Science][Medline]

5 Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term biochemical disease-free and cancer specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am. (2001) 28:555–65.[CrossRef][Web of Science][Medline]

6 Thompson IM Jr, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer. A randomized clinical trial. JAMA (2006) 296:2329–35.[Abstract/Free Full Text]

7 Yamamoto S, Kawakami S, Yonese J, Fujii Y, Ohkubo Y, Suyama T, et al. Lymphovascular invasion is an independent predictor of prostate-specific antigen failure after radical prostatectomy in patients with pT3aN0 prostate cancer. Int J Urol (2008) 15:895–9.[CrossRef][Web of Science][Medline]

8 Yamamoto S, Kawakami S, Yonese J, Fujii Y, Tsukamoto T, Ohkubo Y, et al. Prognostic significance of cancer volume involving seminal vesicles in patients with pT3bpN0 prostate cancer. Urology (2008) 72:1224–8.[CrossRef][Web of Science][Medline]

9 Kawakami S, Fukui I, Yonese J, Okubo Y, Yamamoto S, Tsukamoto T, et al. Antegrade radical retropubic prostatectomy with preliminary ligation of vascular pedicles in 614 consecutive patients. Jpn J Clin Oncol (2007) 37:528–33.[Abstract/Free Full Text]

10 Sobin LH, Wittekind CH. International Union Against Cancer, Urologic Tumors, Prostate. In: TNM Classification of Malignant Tumors—Sobin LH, Wittekind CH, eds. (2002) 6th edn. New York: John Wiley & Sons. 170–3.

11 Serni S, Masieri L, Lapini A, Nesi G, Carini M. A low incidence of positive surgical margins in prostate cancer at high risk of extracapsular extension after a modified anterograde radical prostatectomy. BJU Int (2004) 93:279–83.[CrossRef][Web of Science][Medline]

12 Yamamoto S, Yonese J, Kawakami S, Ohkubo Y, Tatokoro M, Komai Y, et al. Preoperative serum testosterone level as an independent predictor of treatment failure following radical prostatectomy. Eur Urol (2007) 52:696–701.[CrossRef][Web of Science][Medline]

13 Lau WK, Bergstralh EJ, Blute ML, Slezak JM, Zincke H. Radical prostatectomy for pathological Gleason 8 or greater prostate cancer: influence concomitant pathological variables. J Urol (2002) 167:117–22.[CrossRef][Web of Science][Medline]

14 Tefilli MV, Gheiler EL, Tiguert R, Banerjee M, Sakr W, Grignon D, et al. Role of radical prostatectomy in patients with prostate cancer of high Gleason score. Prostate (1999) 39:60–6.[CrossRef][Web of Science][Medline]

15 Rodriguez-Covarrubias F, Larre S, De la Taille A, Abbou CC, Salomon L. The outcome of patients with pathological Gleason score ≥8 prostate cancer after radical prostatectomy. BJU Int (2007) 101:305–7.[CrossRef][Web of Science][Medline]

16 Perrotti M, Rabbani F, Russo P, Solomon MC, Fair WR. Early prostate cancer detection and potential for surgical cure in men with poorly differentiated tumors. Urology (1998) 52:106–10.[CrossRef][Web of Science][Medline]

17 Serni S, Masieri L, Minervini A, Lapini A, Nesi G, Carini M. Cancer progression after anterograde radical prostatectomy for pathologic Gleason score 8 to 10 and influence of concomitant variables. Urology (2006) 67:373–8.[CrossRef][Web of Science][Medline]

18 Chun FKH, Graefen M, Zacharias M, Haese A, Steuber T, Schlomm T, et al. Anatomic radical retropubic prostatectomy-long-term recurrence-free survival rates for localized prostate cancer. World J Urol (2006) 24:273–80.[CrossRef][Web of Science][Medline]

19 Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC, et al. Death in patients with recurrent prostate cancer after radical prostatectomy: prostate-specific antigen doubling time subgroups and their associated contributions to all-cause mortality. J Clin Oncol. (2007) 25:1765–71.[Abstract/Free Full Text]

20 Burkhard FC, Studer UE. The role of lymphadenectomy in high risk prostate cancer. World J Urol (2008) 26:231–6.[CrossRef][Web of Science][Medline]


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