Site of positive surgical margins influences biochemical recurrence after radical prostatectomy

OBJECTIVE

To determine whether the number and location of positive surgical margins (PSMs) in radical prostatectomy (RP) surgical specimens affect biochemical recurrence (BCR) rates.

PATIENTS AND METHODS

The locations of PSMs were recorded for 1308 consecutive men who underwent RP between October 2000 and December 2006. BCR was defined as three consecutive prostate‐specific antigen (PSA) level rises with the peak level ≥0.15 ng/mL. Multivariate regression analyses were used to identify preoperative predictors of PSMs and BCR. The estimated 5‐year risk of BCR was calculated using the Kaplan–Meier method.

RESULTS

In all, 128 (9.8%) men had one or more PSMs. The mean body mass index, mean preoperative serum PSA level, the distributions of clinical stage and biopsy Gleason scores, and the presence or absence of biopsy perineural invasion were significantly different between men with or with no PSMs. In multivariate analysis, baseline serum PSA level, Gleason score and perineural invasion were independent preoperative predictors of PSMs. The 5‐year actuarial BCR rates were dependent on the site of the PSM (P = 0.035) and not the number of PSMs (P = 0.18). The rank order of estimated 5‐year BCR rates according to the site of PSMs were base > anterior > posterolateral > apex ≈ posterior.

CONCLUSIONS

About half of the men with PSMs in the RP surgical specimen in our prospective series did not develop BCR. The risk of BCR was dependent on the site and not the number of PSMs. Adjuvant therapy should be considered in cases with anterior and basilar PSMs due to the very high risk of BCR.     

Prostate specific antigen recurrence rates are low after radical retropubic prostatectomy and positive margins

PURPOSE: Treatment in patients with a positive surgical margin after radical retropubic prostatectomy is controversial. Options are observation, radiation therapy and early hormone therapy. Making the appropriate choice should be based on an understanding of the risk of recurrence without treatment. MATERIALS AND METHODS: We reviewed the records of 1,383 patients after radical retropubic prostatectomy was performed by a single surgeon. All specimens were analyzed by a single pathologist. Of the patients 936 met criteria for analysis. RESULTS: Mean followup in these 936 patients was 45.8 months (minimum 12). The overall PSA biochemical recurrence rate was 11.5% (108 of 936 cases). Of the 936 patients 350 (37%) had tumor at an inked margin. These patients had a recurrence rate of 19% (67 of 350), while patients with negative margins had a recurrence rate of 7% (41 of 586). This difference was statistically significant (p <0.01). Multivariate HR analysis revealed that significant risk factors for recurrence in the 936 patients were PSA greater than 20 ng/ml, clinical stage T2 or greater, Gleason 7 or greater, seminal vesicle involvement, extraprostatic extension, a visual estimate of prostate cancer volume of greater than 9.1% and positive surgical margins. Statistically significant risk factors for recurrence in patients with a positive margin on multivariate HR analysis were PSA greater than 20 ng/ml, Gleason score 7 or greater and seminal vesicle involvement. CONCLUSIONS: Although the positive margin rate in this series was 37%, the recurrence rate in these patients was only 19%. It is important to consider other factors, such as PSA, Gleason score, seminal vesicle involvement and extraprostatic extension, when making treatment decisions.     

Percent of cores positive for cancer is a better preoperative predictor of cancer recurrence after radical prostatectomy than prostate specific antigen

PURPOSE: We examined the prognostic significance of clinical and pathological variables on outcome following radical retropubic prostatectomy (RRP) in a cohort of patients in the post-prostate specific antigen (PSA) era. MATERIALS AND METHODS: We reviewed the clinical and pathological data on a cohort of 476 patients who underwent RRP for localized prostate cancer between January 1990 and July 2001 by 1 urologist (WCD). Median age, preoperative PSA and followup were 61 years, 5.8 ng/ml and 49 months, respectively. We used Cox proportional hazard modeling to evaluate the prognostic significance of clinical and pathological variables for cancer recurrence, defined as 2 successive PSA determinations 0.3 ng/ml or greater. RESULTS: Of the 476 patients 53 (11%) had recurrence. Estimated cancer nonprogression probability was 86% (95% CI 83 to 90) and 76% (95% CI 68 to 86) at 5 and 10 years, respectively. Two multivariate analyses were performed. The first analysis, using only preoperative indicators, found that the percent of biopsy cores positive for cancer and biopsy Gleason score were the best predictive indicators of recurrence. The second multivariate analysis, using preoperative and postoperative indicators, found that the percent of biopsy cores positive for cancer, RRP Gleason score and the combined pathological stage/margin status variable were the best predictive indicators of recurrence. PSA was not found to be an important predictor of recurrence on either multivariate analysis. Patients with a percent of biopsy cores in the upper half of the distribution (greater than 28% positive) were at significantly increased risk for recurrence compared with those in the lower half of the distribution (28% or less positive) (HR 3.86, p <0.001). CONCLUSIONS: The percent of cores positive for cancer was a better predictor of cancer recurrence than PSA in this post-PSA era RRP series. In addition, surgical Gleason score and pathological stage/surgical margins were also independent predictors of cancer recurrence after RRP. These 3 predictors are displayed in a nomogram-type format to summarize estimated 5 and 10-year recurrence-free probabilities.     

Long-term benefits of elective radiotherapy after prostatectomy for patients with positive surgical margins

PURPOSE: The benefit of adjuvant radiotherapy after prostatectomy for patients with pathological risk factors but with an undetectable postoperative PSA remains controversial. In this retrospective study we define the benefits of elective postoperative radiotherapy in this setting. MATERIALS AND METHODS: A total of 44 patients received elective postoperative radiotherapy at a single institution in the PSA era (1989 to 1995) for positive surgical margins and undetectable postoperative PSA. Radiotherapy was delivered to a median dose of 60 Gy. Clinical target volume included the prostate bed. Pelvic nodes were not treated. The four-field box technique with customized blocking of bladder, rectum and small bowels was used and defined the planning target volume. The patients were then compared to a contemporaneous group of 189 patients with positive surgical margins who underwent radical prostatectomy without any adjuvant therapy. Failure was defined as biochemical (PSA) recurrence and was timed from first detectable PSA. RESULTS: The 5 and 10-year biochemical no evidence of disease was 90.9% and 90.9% for the elective postoperative radiotherapy group, and 66.4% and 54.5% for the observation group, respectively (p = 0.0012). Median time to biochemical failure was also longer in the elective postoperative radiotherapy group (88.6 months) compared to the observation group (43.5 months) (p <0.001). Risk factors for biochemical recurrence on multivariate analysis were Gleason score greater than 7 (p = 0.017), established extracapsular extension (p = 0.002) and lack of elective postoperative radiation (p = 0.001). CONCLUSIONS: This is one of the longest followup studies showing that elective postoperative radiation therapy is associated with improved bNED and prolonged time to recurrence. Combined radical prostatectomy and elective postoperative radiotherapy should be considered in the management of high risk prostate cancer, especially in the presence of positive surgical margins despite undetectable PSA.     

Biochemical recurrence after radical prostatectomy in black and white American men with a positive or negative family history of prostate cancer

PURPOSE: We investigated the impact of a family history of prostate cancer on predicting biochemical recurrence in black and white American men. MATERIAL AND METHODS: Between January 1991 and December 1996, 910 men underwent radical retropubic prostatectomy for clinically localized prostate cancer, of whom 676 had data available on prostate cancer family history. Statistical analysis was performed to identify any correlation among the known predictors of biochemical outcome and family history in each race. RESULTS: Median followup was 34 months (range 2 to 103). We identified 355 (52%) and 321 (48%) white and black American men, respectively, for whom data were available on prostate cancer family history, including 177 (26%) with a positive and 499 (74%) with a negative history. Family history was positive in 94 black (29%) and 83 white (23%) men. No significant difference was noted in the incidence of familial prostate cancer in the 2 races (p = 0.10). In black men the biochemical failure rate was 32% and 26% in those with a positive and negative history (log rank test p = 0.51), while in white men the rate was 17% and 18%, respectively (log rank test p = 0.79). A family history positive for prostate cancer was not associated with biochemical failure in either race. CONCLUSIONS: Biochemical recurrence was not significantly worse in patients with a family history of prostate cancer than in those with nonfamilial disease in either race.     

Percent carcinoma in prostatectomy specimen is associated with risk of recurrence after radical prostatectomy in patients with pathologically organ confined prostate cancer

PURPOSE: We evaluated tumor size, measured as the percent of the prostate involved by cancer, as a predictor of tumor recurrence after radical prostatectomy in patients with pathologically organ confined prostate cancer. MATERIALS AND METHODS: One of us (WJC) performed radical retropubic prostatectomy in 1,850 men who had pathologically organ confined prostate cancer with tumor size recorded between January 1988 and February 2003. The percent of prostate tissue involved by carcinoma in the radical prostatectomy specimen was estimated by visual inspection. We compared clinicopathological characteristics in patients who did and did not have tumor recurrence and stratified them by percent of tumor in the prostatectomy specimen. We also evaluated the relationship between percent of cancer and biochemical evidence of cancer recurrence. RESULTS: Patients who had recurrence were slightly older (mean age 62 vs 60 years, p = 0.004), and had higher mean preoperative prostate specific antigen (8.6 vs 6.3 ng/ml, p <0.0001) and a higher proportion of poorly differentiated tumors (Gleason grades 8 to 10) (7% vs 1%, p = 0.001). The mean percent of cancer was higher in men with recurrence (11% vs 7%, p <0.0001). Men with 10% or greater of the gland involved by cancer had a 10% recurrence rate compared with a 5% rate in men in whom cancer involved less than 10% of the gland (p = 0.001). The 5-year recurrence-free survival rate was 94%, 91% and 82% in patients with less than 10%, 10% to 20% and greater than 20% of the gland involved. The multivariate Cox model indicated that the percent of cancer involvement of the prostate provides unique predictive information about the risk of cancer recurrence (p = 0.0001). The estimated 5-year recurrence-free survival rate based on the Cox model indicated that patients with greater than 20% of the gland involved by tumor, clinical stage T2/T3 and Gleason sum >/=7 were at substantial risk of cancer recurrence. CONCLUSIONS: Tumor size measured as the percent of cancer is an independent predictor of cancer recurrence after radical prostatectomy in patients with pathologically organ confined prostate cancer.     

Lymph node positive prostate cancer: long-term survival data after radical prostatectomy

PURPOSE: We retrospectively reviewed the outcome in our patients with prostate cancer and regional positive lymph nodes who underwent prostatectomy. MATERIALS AND METHODS: Between January 1984 and December 2002, 147 men were found to have local lymph node metastases after surgery, of whom 135 underwent further androgen ablation, including 88% within 6 weeks after prostatectomy. We especially determined overall, cancer specific and progression-free survival rates. RESULTS: Median patient age was 63.2 years (range 46 to 75 years). Postoperative followup was up to 214 months (median 41.9). There was 1 death secondary to surgery. To date 49 patients (33.3%) had disease progression, including 6 with a prostate specific antigen increase later than 100 months after surgery, and 36 (24.5%) died, including 22 of prostate cancer and 14 of other causes. Overall and cause specific survival probabilities at 5, 10 and 15 years were 76.6% and 86.5%, 60.1% and 73.7%, and 47.2% and 57.9%, respectively. Median overall survival was 144 months and median cancer specific survival was greater than 145 months. Overall progression-free probabilities at 5, 10 and 15 years were 72.7%, 49.8% and 31.6%, respectively. Biochemical progression-free survival rates were 77.4% after 5, 53.0% after 10 and 33.7% after 15 years. CONCLUSIONS: Since three-quarters of our patients were likely not to die of prostate cancer within the 10 years after surgery despite histological evidence of lymph node metastases, radical prostatectomy with or without hormonal therapy is a viable option for patients with local lymph node involvement, particularly in view of long-term survival.     

Perineural invasion in prostate cancer biopsies is not associated with higher rates of positive surgical margins

PURPOSE: High rates of extracapsular tumor extension have been reported with biopsy perineural invasion (PNI), leading some to advocate routine resection of the ipsilateral neurovascular bundle (NVB) with radical retropubic prostatectomy (RRP) to assure negative surgical margins. The contemporary rates of extracapsular tumor extension (ECE) and margin status associated with biopsy PNI were investigated. MATERIALS AND METHODS: The prostate needle biopsies, RRP specimens, and operative reports of 452 consecutive patients undergoing RRP by a single surgeon were reviewed to determine the presence of PNI invasion, presence of ECE, margin status, and preservation of NVB. Patients were excluded from the analysis if they underwent preoperative hormonal ablation or if their original biopsy was not reviewed by the pathologists at our institution. Both univariate and multivariate analyses were performed to determine the effect of PNI on extracapsular extension, the likelihood of performing a bilateral nerve-sparing technique, and the result of a positive surgical margin. RESULTS: In the 402 evaluable cases, based on multivariate models PNI showed only a marginal association with positive surgical margin (+SM) (P = 0.10) and bilateral nerve-sparing (B-NS) (P = 0.07), but was significantly associated with organ confinement (P = 0.03). The odds ratio (OR) of PNI for +SM, although not statistically significant, was 0.36. Although showing a higher level of statistical significance, PNI for OC had an odds ratio of 0.50. Similarly, the odds ratio was 0.54 for B-NS. CONCLUSIONS: Although biopsy PNI alone was associated with a higher probability of ECE, it is not predictive of bilateral nerve-sparing technique or a positive surgical margin in an individual patient.     

Close surgical margins after radical prostatectomy mimic biochemical recurrence rates of positive margins

IntroductionThe significance of a “close” but negative surgical margin after radical prostatectomy (RP) is controversial. We evaluated the effect of a close surgical margin (CSM) on biochemical recurrence (BCR) compared to a negative margin after RP.Materials and methodsPathologic records of men who underwent RP from 2005-2011 were retrospectively reviewed. Margin status was classified as “positive” (PSM), “negative” (NSM), or “close” (<1 mm from margin). BCR was defined as 2 consecutive postoperative prostate specific antigen measurements >0.2 ng/ml. Probability of BCR was estimated using the Kaplan-Meier method and stratified by margin status. Univariable and multivariable Cox proportional hazards models were used to determine whether close margin status was associated with an increased rate of BCR.ResultsA total of 609 consecutive patients underwent RP (93% robotic) and had complete pathologic data. A total of 126 (20.7%) had PSM, 453 (74.4%) had NSM, and 30 (4.9%) had CSM (mean<0.44 mm). The 3-year BCR-free survival for patients with CSM was similar to those with PSM (70.4% vs. 74.5%, log rank P = 0.66) and significantly worse than those with NSM (90%, log rank P<0.001). On multivariable regression, positive margin status (HR = 3.26, P<0.001) was significantly associated with a higher risk of BCR, along with close margins (HR = 2.7, P = 0.04).ConclusionsBCR for patients with CSM at RP is tantamount to PSM patients. CSM <1 mm should be explicitly noted on pathology reports. Patients with this finding should be followed up closely and offered adjuvant therapy.     

Overall rate,location, and predictive factors for positive surgical margins after robot-assisted laparoscopic radical prostatectomy for high-risk prostate cancer

We report the overall rate, locations and predictive factors of positive surgical margins (PSMs) in 271 patients with high-risk prostate cancer. Between April 2008 and October 2011, we prospectively collected data from patients classified as D’Amico high-risk who underwent robot-assisted laparoscopic radical prostatectomy. Overall rate and location of PSMs were reported. Stepwise logistic regression models were fitted to assess predictive factors of PSM. The overall rate of PSMs was 25.1% (68 of 271 patients). Of these PSM, 38.2% (26 of 68) were posterolateral (PL), 26.5% (18 of 68) multifocal, 16.2% (11 of 68) in the apex, 14.7% (10 of 68) in the bladder neck, and 4.4% (3/68) in other locations. The PSM rate of patients with pathological stage pT2 was 8.6% (12 of 140), 26.6% (17 of 64) of pT3a, 53.3% (32/60) of pT3b, and 100% (7 of 7) of pT4. In a logistic regression model including pre-, intra-, and post-operative parameters, body mass index (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.01–1.19, P= 0.029), pathological stage (pT3b or higher vs pT2; OR: 5.14; 95% CI: 1.92–13.78; P = 0.001) and percentage of the tumor (OR: 46.71; 95% CI: 6.37–342.57; P< 0.001) were independent predictive factors for PSMs. The most common location of PSMs in patients at high-risk was the PL aspect, which reflects the reported tumor aggressiveness. The only significant predictive factors of PSMs were pathological outcomes, such as percentage of the tumor in the specimen and pathological stage.     

Long-term outcome following radical prostatectomy in men with clinical stage T3 prostate cancer

PURPOSE: We evaluated patients at our institution who underwent radical prostatectomy for clinical stage T3 prostate cancer to determine their long-term clinical outcomes. MATERIALS AND METHODS: We reviewed our prospective surgical database and identified 176 men who underwent radical retropubic prostatectomy for clinical stage T3 prostate cancer from 1983 to 2003. Clinical and pathological data were reviewed and evaluated in a Cox proportional hazards model to determine preoperative predictors of biochemical recurrence. Clinical progression following biochemical recurrence was evaluated and clinical failure was defined as the development of clinical metastases or progression to hormone refractory prostate cancer. RESULTS: Of the 176 patients with cT3 prostate cancer 64 (36%) received neoadjuvant hormonal therapy. At a mean followup of 6.4 years 84 (48%) patients had disease recurrence with a median time to biochemical recurrence of 4.6 years. The actuarial 10-year probability of freedom from recurrence was 44%. On multivariate analysis biopsy Gleason score, pretreatment serum prostate specific antigen and year of surgery were independent predictors of biochemical recurrence. Neoadjuvant hormonal therapy was not a significant predictor of biochemical recurrence. Following biochemical recurrence clinical failure developed in 30 of 84 (36%) men with a median time of 11 years. Overall the 5, 10 and 15-year probabilities of death from prostate cancer were 6%, 15% and 24%, respectively. CONCLUSIONS: More than half (52%) of our patients remained free of disease recurrence following radical prostatectomy. In our series neoadjuvant hormonal therapy offered no advantage with respect to disease recurrence. Radical prostatectomy remains an integral component in the treatment of select patients with clinical stage T3 prostate cancer.     

Biochemical recurrence rate in patients with positive surgical margins at radical prostatectomy with further negative resected tissue

OBJECTIVE

To determine the biochemical recurrence (BCR) rate in patients with positive surgical margins (PSMs) on the prostate specimen who have additional negative tissue resected from that site (M+ ?), compared to patients with negative margins (M?) and those with persistent PSM (M+), as those with PSM at radical prostatectomy (RP) are at greater risk of BCR, and in some instances where suspicious tissue is noted in the prostate bed or when frozen‐section analysis shows PSM, additional tissue is resected from the suspect site of the PSM.

PATIENTS AND METHODS

Between January 1999 and June 2007, 4217 consecutive patients underwent open or laparoscopic RP with no previous radiotherapy or hormonal therapy. The median (interquartile range) follow‐up was 37.4 (21.1–60.7) months.

RESULTS

Pathological organ‐confined (OC) cancer was present in 2901 men, of whom 2659 had M?, 216 had M+, and 26 had M+ ?. Extracapsular extension (ECE) alone with no seminal vesicle or lymph node involvement was present in 843 men, of whom 657 had M?, 174 had M+ and 12 had M+ ?. For patients with OC cancer, the 36‐month actuarial BCR‐free probability was 97.9% (95% confidence interval 97.3–98.5) for M?, vs 89.0 (84.1–93.9)% for M+ vs 100% for M+ ?. For patients with ECE, the 36‐month actuarial BCR‐free probability was 83.7 (80.0–87.4)% for M? vs 73.7 (66.1–81.3)% for M+ vs 90.0 (71.4–100)% for M+ ?. The main limitation of the study was its retrospective nature, with the reason for resection of additional tissue not always well documented.

CONCLUSIONS

While the few patients with PSMs and further negative resected tissue limited the statistical analysis, it would appear that in these patients the disease behaves as in those with negative margins.     

Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy

PURPOSE: Hormonal therapy (HT) is the current mainstay of systemic treatment for prostate specific antigen (PSA) only recurrence (PSAR), however, there is virtually no published literature comparing HT to observation in the clinical setting. The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational database to compare clinical outcomes in men who experienced PSAR after radical prostatectomy by early versus delayed use of HT and by a risk stratified approach. MATERIALS AND METHODS: Of 5382 men in the database who underwent primary radical prostatectomy (RP), 4967 patients were treated in the PSA-era between 1988 and December 2002. Of those patients 1352 men who had PSAR (PSA after surgery greater than 0.2 ng/ml) and had postoperative followup greater than 6 months were used as the study cohort. These patients were further divided into an early HT group in which patients (355) received HT after PSA only recurrence but before clinical metastasis and a late HT group for patients (997) who received no HT before clinical metastasis or by current followup. The primary end point was the development of clinical metastases. Of the 1352 patients with PSAR clinical metastases developed in 103 (7.6%). Patients were also stratified by surgical Gleason sum, PSA doubling time and timing of recurrence. Univariate and multivariate Cox proportional hazard models were used to evaluate the effect of early and late HT on clinical outcome. RESULTS: Early HT was associated with delayed clinical metastasis in patients with a pathological Gleason sum greater than 7 or PSA doubling time of 12 months or less (Hazards ratio = 2.12, p = 0.01). However, in the overall cohort early HT did not impact clinical metastases. Race, age at RP and PSA at diagnosis had no effect on metastasis-free survival (p >0.05). CONCLUSIONS: The retrospective observational multicenter database analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup. Further study with longer followup and randomized trials are needed to address this important issue.     

Prostate cancers scored as Gleason 6 on prostate biopsy are frequently Gleason 7 tumors at radical prostatectomy: implication on outcome

PURPOSE: Differentiation between Gleason score 6 and 7 in prostate biopsy is important for treatment decision making. Nevertheless, under grading errors compared with the actual pathological grade at radical prostatectomy are common. We compared the characteristics and outcomes of tumors that were scored 6 on prostate biopsy but were 7 on subsequent radical prostatectomy pathological evaluation to those in tumors with a consistent rating of Gleason score 6 or 7 at biopsy and surgery. MATERIALS AND METHODS: We performed a retrospective database analysis from our referral center (1989 to 2004). We compared pre-prostatectomy characteristics, radical prostatectomy pathological features and the post-radical prostatectomy prostate specific antigen failure rate, defined as any 2 consecutive detectable prostate specific antigen measurements, in 3 subgroups of patients, including 156 with matched Gleason score 6 in the prostate biopsy and radical prostatectomy, 205 with upgraded Gleason score 6/7, that is prostate biopsy Gleason score 6 and radical prostatectomy Gleason score 7, and 412 with matched Gleason score 7 in the prostate biopsy and radical prostatectomy. RESULTS: Radical prostatectomy Gleason score matched the prostate biopsy score in 38.2% of biopsy Gleason score 6 and 81.4% of biopsy Gleason score 7 cases. Higher prostate specific antigen was associated and an increased percent of cancer in the prostate biopsy was predictive of discordance between the prostate biopsy and radical prostatectomy Gleason scores (p <0.001). Margin (p = 0.0075) or seminal vesicle involvement (p = 0.0002), cancer volume (p <0.001) and the prostate specific antigen failures rate (p = 0.014) were significantly higher in under graded Gleason score 7 cancer compared to those in matched Gleason score 6 cases. However, they were comparable to those with a matched Gleason score 7 tumor grade (p = 0.66). CONCLUSIONS: Almost half of tumors graded Gleason score 6 at biopsy are Gleason score 7 at surgery. Upgraded Gleason score 6 to 7 tumors have outcomes similar to those of genuine Gleason score 7 cancer. For prostate biopsy Gleason score 6 tumors clinicians should consider the overall likelihood of tumor upgrading as well as specific patient characteristics, such as prostate specific antigen and the percent of tumor in the prostate biopsy, when contemplating treatments that are optimized for low grade tumors, including watchful waiting or brachytherapy.