|Year : 2015 | Volume
| Issue : 4 | Page : 646-652
Outcome of radical prostatectomy as primary treatment for high-risk prostate cancer patients
JN Kulkarni, VS Gunavanthe, A Dhale
Department of Urology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India
|Date of Web Publication||10-Mar-2016|
V S Gunavanthe
Department of Urology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
CONTEXT: Recently, there has been considerable interest in the role of radical prostatectomy (RP) in men with high-risk prostate cancer. AIMS: The objective of our study is to report the outcome of upfront RP in our patients with high-risk prostate cancer (Stage ≥ cT2c, a pre-operative serum prostate specific antigen >20 ng/ml or a biopsy Gleason score [GS] 8-10). SUBJECTS AND METHODS: From 1996 to 2010, 208 patients of prostate cancer (high risk category D'Amico's criteria) underwent open RP with bilateral pelvic lymphadenectomy. STATISTICAL ANALYSIS USED: The data was statistically analyzed using Kaplan Meier method and log rank test to calculate progression free, metastasis free survival (MFS) and cancer specific survival (CSS). Furthermore multivariate analysis (MVA) was carried out using SPSS 14 software. (IBM company). RESULTS: At 7 and 10 years, prostate cancer-specific survival (PCSS) was found to be 79.7% and 65%, respectively, biochemical recurrence free survival (BRFS) was 42.4% and 36.7%, respectively and the MFS was 71.1% and 64.4% respectively. High GS was highly predictable of PCSS, BRFS and MFS. Node positivity was the single poor risk factor on MVA whereas biopsy GS, pStage (P = 0.016) and seminal vesicle invasion (P = 0.045) had statistical significance in predicting the MFS. CONCLUSIONS: RP provides accurate pathologic staging of patients with high risk prostate cancer, allows better stratification of patients for further adjuvant therapy and either as an initial approach or part of a multimodal regimen, can provide durable local control and provides excellent CSS.
Keywords: High-risk prostate cancer, radical prostatectomy, D'Amico criteria
|How to cite this article:|
Kulkarni J N, Gunavanthe V S, Dhale A. Outcome of radical prostatectomy as primary treatment for high-risk prostate cancer patients. Indian J Cancer 2015;52:646-52
|How to cite this URL:|
Kulkarni J N, Gunavanthe V S, Dhale A. Outcome of radical prostatectomy as primary treatment for high-risk prostate cancer patients. Indian J Cancer [serial online] 2015 [cited 2019 Dec 12];52:646-52. Available from: http://www.indianjcancer.com/text.asp?2015/52/4/646/178446
| » Introduction|| |
Although in the western countries there has been stage migration in the incidence toward low stage prostate cancer, in India high-risk prostate cancer is still a major part of the organ confined cancer of the prostate., D'Amico had defined high-risk prostate cancer as one having stage equal to or greater than clinically T2c, a pre-operative serum prostate specific antigen (PSA) value >20 ng/ml or a biopsy Gleason score (GS) 8-10. Of the various definitions, this is the most widely used stratification system. Traditionally hormone therapy in combination with radiotherapy (RT) has been used in managing localized high-risk prostate cancer patients. However it is not clear whether this approach translates into absolute benefit over radical prostatectomy (RP). Further, recently there has been considerable interest in reporting the outcome of RP as an initial therapy in selected patients if not in all., Encouraged by these reports we analyzed our data of over 600 RPs and found that a cohort of 208 patients belonged to the high-risk group which forms the basis of this report. In addition, we have tried to analyze and focus on the factors responsible for poor outcome which could help us to optimize therapy in this setting.
| » Subjects and Methods|| |
Data of 604 patients who underwent open RP with bilateral pelvic lymphadenectomy for prostate cancer between 1996 and 2010, performed by our senior author (JNK), was analyzed retrospectively. Of them 208 were sub categorized into the high risk category as per D'Amico's criteria. Data included the demographic parameters such as age, history of previous transurethral resection of the prostate (TURP), PSA, biopsy GS, clinical stage, pre-operative continence and potency. Pathological specimens were classified as per TNM staging.
Of the 208 patients, 120 were diagnosed as having carcinoma prostate following a 6-12 core biopsy for either raised PSA (threshold used by us was >4 ng/ml) or abnormal DRE. The remaining 88 were diagnosed by the histopathologic specimen analysis of TURP chips, in patients with lower urinary symptoms with prostatic enlargement. All the patients underwent RP and standard bilateral pelvic node dissection in a single sitting. Operative parameters such as blood loss, time of catheter removal, early and late complications that were recorded meticulously, were obtained.
Patients who had positive surgical margins (PSMs) were given adjuvant RT, while those who had positive seminal vesicle (SV) invasion and/or positive nodes were given adjuvant hormone therapy. Post-operatively the patients were followed-up with serum PSA and DRE every 3 monthly for 2 years and later every 6 monthly until 5 years and then annually. Biochemical recurrence (BCR) was defined as the serum PSA levels >0.2 ng/ml from the nadir value on two occasions at a 3-month interval. These patients were subjected to local imaging such as computed tomography scan or magnetic resonance imaging and Bone scan. Further treatment, i.e. salvage radiation or hormone therapy, was deferred until documented relapse occurred (as seen by imaging or biopsy). Patients who progressed while on hormonal therapy were given additional chemotherapy.
Statistical analysis of the data was conducted by Kaplan Meier (KM) method to calculate progression free, metastasis free survival (MFS) and cancer specific survival (CSS) and the data was analyzed using the log rank test. Cox proportional hazards models were used to evaluate the three risk factors, i.e. GS, PSA and T stage to identify sub groups of risk factors (single, two or all three) leading to poor outcome. SPSS 14 software (IBM company) was used to perform statistical multivariate analysis (MVA).
| » Results|| |
The median age of patients in our series was 63 years with a range of 43-73 years [Table 1]. Apart from 38 patients who were asymptomatic, all the others had obstructive or other voiding symptoms. Of the 208 patients, 88 had a prior TURP with a clinical diagnosis of benign prostatic enlargement and carcinoma was a surprise at histology. PSA was >20 ng/ml in 97 patients and <20 ng/ml in 111 patients. Biopsy GS was <7 in 89 patients, 7a (3 + 4) or 7b (4 + 3) in 59 and 8-10 in 60 patients. Clinically, 93 had stage <T2c tumors while remaining 115 patients had stage T2c or greater tumors. Examination of the RP specimen revealed specimen-confined disease in 48 patients (pT2), extra-capsular extension (pT3a) in 38 patients, SV invasion (pT3b) with negative nodes in 66, whereas total 56 patients had positive pelvic lymph nodes.
|Table 1: Demographic data of our patients with high--risk prostate cancer|
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[Table 2] gives the comparison between clinical variables and pathological findings. The pre-operative serum PSA level, clinical stage and biopsy GS were compared with the pathological findings. The clinical stage and PSA were insignificant while biopsy GS was found to be highly significant in predicting the pathology accurately.
Survival outcome analysis showed better outcome in post 2002 era [Figure 1], [Table 3]. Further At 7 and 10 years of follow-up, prostate cancer-specific survival (PCSS) was found to be 79.7% and 65%, respectively, biochemical recurrence free survival (BRFS) was 42.4% and 36.7%, respectively and the MFS was 71.1% and 64.4% respectively, as calculated by using KM method. We also calculated the survival in relation to the clinical factors and pathological findings [Table 4], [Figure 1][Figure 2][Figure 3][Figure 4][Figure 5]. Further as a single criterion only GS was significant. Clinical stage and PSA as criteria combined together were significant and all the three criteria had worst histology and outcome. Positive pelvic lymph nodes had added adversities in contrast to negative nodes [Figure 5]. Among the biopsy GS, 3 + 4 versus 4 + 3 and 8 versus 9-10 had different outcomes with respect to pathology and survival. Further 4 + 3 and 8 had slightly favorable outcome than 9-10. Another interesting finding was that high GS was highly predictable of PCS, BRFS and MFS in patients undergone TURP.
|Table 4: Univariate analysis assessing impact of various clinical and pathological variables on PCS, BRFS and MFS at 5, 7 and 10 years of follow--up|
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[Table 5] gives the impact of variables on survival on MVA. Among the various factors node positivity was the single poor risk factor on MVA while biopsy GS (P = 0.046), pathological stage (P = 0.016) and SV involvement (P = 0.045) had statistical significance in predicting the MFS. However age (P = 0.007) and pathological stage (P = 0.001) were predictable for BRFS. PSA, clinical stage, previous TURP and presence of positive cut margins did not show any impact. In addition pathological factors such as pathological stage and pathological GS had some impact. Further, lymph node positivity had a significant impact while PSM did not. Lastly we avoided adjuvant therapy in 25% (pT2N0M0) patients.
|Table 5: Multivariate analysis of variables of high--risk prostate cancer patients that had an impact on post--radical prostatectomy outcome|
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| » Discussion|| |
Historically, radical retropubic prostatectomy has been popular for low grade, low stage organ confined prostate cancer. Many non-randomized studies , have shown significant durable local control and prolonged disease free survival after RP in them. However patients with high risk prostate cancer have been thought to have a higher incidence of harboring clinically occult metastases at the time of diagnosis and hence were considered incurable by RP alone., Further, some argued that the morbidity associated with RP such as urinary incontinence and erectile dysfunction, were not justifiable and that RT  or primary androgen-deprivation therapy  be considered better therapeutic options for such patients.
More recent reports suggest that upfront RP with curative intent is a viable option in selected cases of high-risk prostate cancer., Moreover, multimodal treatment strategies including neo adjuvant androgen deprivation and chemotherapeutic regimens are being investigated. It has been shown that RP not only helps in local control and long-term PCSS in a subset of patients with high-risk prostate cancer, but also provides accurate pathologic information. This information may aid in the differentiation of patients who may benefit from adjuvant therapies  from patients who may not, thus avoiding their harmful effects. Thus, it appears that optimum treatment of high-risk clinically localized prostate cancer is still evolving. The most important issue is the identification of clinical variables which will predict the accurate histology and have an impact on PCSS, BRFS and MFS. The sole aim of these efforts is to identify those patients who can be cured with surgery alone, thus avoiding unnecessary adjuvant treatment.
The Shared Equal Access Regional Cancer Hospital database noted that disease progression in patients with high-risk prostate cancer was significantly influenced by capsular penetration on histopathology of the specimen resected by RP, when both pre-operative and post-operative variables were analyzed. Some studies have reported pathologic tumor stage as the most significant predictor of disease recurrence after RP in patients with a GS of 8-10., Do et al. assessing RP or RT either as monotherapy or in combination for patients with a GS of 8-10 found that a pre-treatment PSA level of >20 ng/ml and SV invasion (pT3b) predicted BCR, although only SV invasion predicted systemic failure. Further they reported that pre-operative PSA level >20 ng/ml was found to predict BCR, but was not associated with systemic progression or CSS. Finally, they  found improved 5-year rates of biochemical and clinical progression-free survival in their patients with a GS of 8-10 treated with RP plus post-operative RT (65% and 80%) compared with RP (20% and 35%) or RT (30% and 60%) alone, thus suggesting the value of multimodal approach in high-grade prostate cancer.
Other studies showed that in patients with a GS of 8-10, surgical technique and PSMs affected the outcome due to their significantly increased association with death from prostate cancer., A study at the Mayo Clinic reported 40% patients of high-risk prostate cancer received adjuvant hormonal therapy (AHT) as a preference by the urologists  and they criticized the additional therapy as a possible confounder of the impact of RP alone on high-grade prostate cancer. The same group reported that RP provided excellent local control in high-risk prostate cancer, with a local recurrence rate of only 13% in patients who had pre op PSA >50 ng/ml. Studies that oppose upfront surgery in patients with high-risk prostate cancer propose that incomplete excision and presence of micrometastasis are responsible for failure.
A study by Zagars et al. found that RT provided only 41% 10-year MFS rate and only 64% local recurrence-free survival rate. Further post-RT biopsy studies have shown persistent prostate cancer in 14-91% of the patients. Coen et al. postulated that a biologically altered prostate cancer after RT resulted in a late wave of metastatic seeding. Similarly D'Amico et al. in their study also reported a significantly lower 10-year prostate cancer-specific mortality rate in men treated with surgery (10%) than in those who received RT (25%). Other studies in larger populations and a randomized trial suggest that RT is inferior to surgery as the primary therapy for high-risk prostate cancer., Hence, larger randomized trials comparing the two modalities head to head are certainly needed to clarify this issue.
Currently in the western countries, for the younger man with cT3 disease, RP is preferred. With increasing patient age, RT (in the age groups 50-74 years) becomes the more preferred definitive therapy and finally active surveillance becomes increasingly dominant in the elderly with adverse co-morbidity profile. For cT3 disease and high-risk prostate cancer, RP or RT alone (monotherapy) may remain inadequate and multimodal therapy may be necessary. Recent data, as compiled above suggests that RP as a single method is the most successful initial therapy as it instantly debulks the cancer load. Also, if residual loco-regional or micrometastatic disease is found subsequently, RT, AHT or other therapy may still be used. Further, a variable period of freedom from androgen deprivation or adjuvant RT is certainly possible after upfront surgery. This is important keeping in mind that these modalities too have severe consequences such as metabolic syndrome, depression, loss of libido, hot flashes, diabetes, potential cardiovascular morbidity and mortality, osteoporosis and bone fracture  from androgen deprivation therapy and fatigue, skin, rectal or vesical irritability or toxicity  following RT.
Our study has a higher proportion of cases detected by TURP, which may be due to a higher threshold of PSA used at our center (4 ng/ml) for transrectal ultrasound guided biopsies. In our study, the univariate analysis showed that amongst the clinical variables, PSA levels >20 ng/ml or a biopsy GS 8-10 had a significantly higher likelihood of having SV and/or lymph node involvement. Also, pre-operative PSA level and clinical stage were not found to be significant predictors of BCR-free or CSS. Conversely biopsy GS, pathological GS, pathological stage and cut margins were all found to be significant predictors of BCR-free, CSS and MFS.
We further noted that the presence of more than one risk factor (GS 8-10, PSA >20 ng/ml and clinical stage ≥T3a) was a significant predictor of MFS. The same data on MVA showed pathological stage alone as an independent predictor of BCR-free survival at 10 years while pathological stage, SV involvement and biopsy GS were significant predictors of MFS at 10 years. The results of our data concur with that of studies from western literature [as shown in [Table 6].
|Table 6: Various studies assessing impact of radical prostatectomy on outcome for patients with high--risk|
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| » Conclusions|| |
Primary RP in well-selected patients having clinically localized high-risk prostate cancer not only provides accurate pathologic staging, but also identifies variables that are highly significant predictors of cancer specific outcomes and allows better stratification of patients for further adjuvant therapy. Adjuvant radiation, hormonal therapy or chemotherapy, can also be added, based on the pathological findings of RP such as positive lymph nodes, PSMs and pathologic tumor stage. Thus, RP, either as an initial approach, or as part of a multimodal regimen, can provide durable local control and excellent CSS, hence it should be considered a strong option for first line management of selected men with high-risk prostate cancer.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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