Margin involvement at prostatectomy for clinically localized prostate cancer: Does a low-risk group exist?

doi:10.1016/j.prro.2014.04.005

Practical Radiation Oncology

Volume 5, Issue 1, January–February 2015, Pages e31-e36

https://doi.org/10.1016/j.prro.2014.04.005 Get rights and content

Abstract

Purpose

To determine whether additional pathology details may provide risk stratification for patients with involved surgical margins at radical prostatectomy (RP).

Methods and materials

Eligible patients underwent RP between 2003 and 2010. Patients with preoperative prostate-specific antigen (PSA) ≥ 20, follow-up < 12 months, lymph node or seminal vesicle involvement, or who received radiation therapy or hormone therapy prior to PSA relapse were excluded. Surgical specimens were reviewed by a study pathologist, blinded to outcomes. Survival analysis methods were employed to assess disease control and survival rates, as well as association of patient-, tumor-, and treatment-specific factors for endpoints.

Results

Of 355 RP cases, 279 patients were eligible for the present analysis. At a median follow-up of 53 months (range, 16-127), 31/114 (27%) of patients with involved surgical margins experienced PSA relapse, as compared with 7/165 (4%) for negative margins (hazard ratio, 4.997; 95% confidence interval, 2.425-10.296; P < .0001). Detailed pathology review demonstrated associations between PSA relapse and Gleason score at RP, extent of margin involvement (width), capsule penetration, and perineural invasion. Subgroup analysis identified low risk (4%) of 5-year PSA relapse for patients with Gleason ≤ 6 mm and margin width ≤ 4 mm (single maximal or cumulative). All subgroups with higher Gleason score or wider margin were associated with > 20% risk of PSA relapse at 5 years.

Conclusions

Within the present study, Gleason score, 6 patients with margin width ≤ 4 mm appear to have low rates of early PSA relapse following RP. Low-grade cases with larger extent of margin involvement or higher risk Gleason score patients with any margin involvement have high rates of early PSA relapse.

Introduction

An involved surgical margin at prostatectomy has long been established as a risk factor for prostate cancer recurrence.[1], [2] While phase 3 randomized trials have demonstrated improved disease control,[3], [4], [5] disease-specific survival,⁶ and distant metastasis-free survival⁶ benefits for immediate postoperative (adjuvant) radiation therapy in the setting of high-risk features (including involved margin), even these studies demonstrated an estimated 30%-40% of patients who did not have prostate-specific antigen (PSA) relapse at 10 years postprostatectomy.[6], [7] Thus, some patients may not require adjuvant therapy and may be safely observed; however, at present, identification of this “low-risk” subset remains to be determined. The present investigation seeks to determine whether additional pathology details concerning the involved margin(s) may permit substratification of patients without other high-risk features (seminal vesicle or lymph node involvement) into low- and high-risk groups for specifying postoperative management.

Section snippets

Methods and materials

Following institutional review board approval at the study institution, a research database was created with study-specific patient, treatment, and outcome data fields. Eligible cases were identified by review of medical records and quality assurance database. After selection for prostate adenocarcinoma cases, a review of patient records was performed in order to eliminate patients with advanced or metastatic disease at diagnosis (including preprostatectomy evidence of seminal vesicle or pelvic

Results

Between January 2003 and December 2010, 355 patients diagnosed with adenocarcinoma of the prostate underwent radical prostatectomy at the study institution. Of these, 279 were eligible for inclusion in the present study. Reasons for exclusion were involved seminal vesicles or nodes (n = 37), postprostatectomy follow-up < 12 months (18), prostatectomy outside study period (5), hormone therapy prior to prostatectomy (6), missing records (3), PSA ≥ 20 (6), and adjuvant radiation therapy (1). Patient

Discussion

Involvement of a surgical margin at prostatectomy has long been associated with increased risk of PSA failure.[1], [2] Despite presence of tumor cells at the margin, however, not all patients will experience PSA failure within 5-10 years postprostatectomy. Presently, consensus guidelines recommend consideration of adjuvant radiation therapy in the setting of high-risk pathologic features, including involved margin,⁹ based upon large, mature randomized trials demonstrating 50% reduction in risk

Conclusions

Within the present study, Gleason score 6 patients with margin width ≤ 4 mm appear to have low rates of early PSA relapse following radical prostatectomy. Low-grade cases with wider margin(s) or higher risk Gleason score patients with any margin involvement have high rates of early PSA relapse.

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Cited by (7)

A Recursive Partitioning Analysis Demonstrating Risk Subsets for 8-Year Biochemical Relapse After Margin-Positive Radical Prostatectomy Without Adjuvant Hormone or Radiation Therapy
2021, Advances in Radiation Oncology
Citation Excerpt :
To our knowledge, this is the only study to implement RPA stratification to identify potential low- and high-risk cohorts with more than 200 margin-positive patients and median follow-up over 8 years. The bRFS at 8 years of those with GG1 disease with cumulative margin 2 mm or less was historically comparable (92%) to those with negative margins.6,19 Additionally, approximately 50% of patients with GG2 and positive margins experienced biochemical failure at 8 years.
The cohort of patients with locally advanced prostate cancer (PC) and positive surgical margin(s) at radical prostatectomy (RP) who would benefit from salvage or adjuvant treatment is unclear. This study examines the risk of prostate-specific antigen (PSA) relapse in a large population of men with PC after margin-positive RP.
Using a multi-institutional database, patients with clinically localized PC who underwent RP between 2002 and 2010 with recorded follow-up PSA were retrospectively selected. Patients were excluded for pathologic seminal vesicle or lymph node involvement, metastatic disease, pre-RP PSA ≥ 30, or adjuvant (nonsalvage) radiation therapy or hormone therapy. The primary endpoint was biochemical relapse free survival (bRFS), where PSA failure was defined as PSA > 0.10 ng/mL and rising, or at salvage intervention. The Kaplan-Meier method was employed for bRFS estimates; recursive partitioning analysis using cumulative or single maximal margin extent (ME) and Gleason grade (GG) at RP was applied to identify variables associated with bRFS.
At median follow-up of 105 months, 210 patients with positive margins at RP were eligible for analysis, and 89 had experienced PSA relapse. Median age was 61 years (range, 43-76), and median pre-RP PSA 5.8 ng/mL (1.6-26.0). Recursive partitioning analysis yielded 5 discrete risk groups, with the lowest risk group (GG1, ≤ 2 mm ME) demonstrating a bRFS of 92% at 8 years compared with the highest risk group (GG3-5, ≥ 3 mm ME) of 11%.
This retrospective study suggests that it may be possible to risk-stratify patients undergoing margin-positive RP using commonly acquired clinical and pathologic variables. Patients with low-grade tumors and minimally involved margins have a very low recurrence risk and may be able to forego postprostatectomy radiation. Meanwhile, those with higher grade and greater involvement could benefit from adjuvant or early salvage radiation therapy.
Gleason Score ≤ 6 Prostate Cancer at Radical Prostatectomy: Does a High-Risk Setting Truly Exist? A Recursive Partitioning Analysis
2017, Clinical Genitourinary Cancer
Citation Excerpt :
Further, the benefit of adjuvant RT appears to be maintained in the setting of the bladder base as the sole site of margin involvement.19 The extent of involvement at the margin site(s) has also been evaluated, and linear extent of the margin has consistently shown an inverse association with bRFS,14,20-22 even within G6PC specifically.20 The association between longer interval between biopsy to RP and PSA relapse in multivariable analysis was interesting.
The purpose of this study was to determine whether a “high-risk” subpopulation of low-grade (Gleason score ≤6) prostate cancer defined by lower prostate-specific antigen (PSA) relapse-free survival (bRFS) might be identified within a large population of men who underwent radical prostatectomy (RP) alone, with mature follow-up.
Patients were retrospectively identified for inclusion by cT1-2 prostate cancer managed with RP alone. Exclusion criteria were: Gleason score ≥7 at RP, any pre- or post-RP radiotherapy or hormone therapy, or PSA follow-up <12 months. The Kaplan–Meier method was used for survival estimates; recursive partitioning by conditional inference analysis was applied to identify variables associated with bRFS.
From 2002 through 2010, 284 eligible patients were identified. Median age was 60 years (range, 44-76 years), 233 (82%) were cT1c, and median PSA was 5.3 ng/dL (92% ≤10). The median biopsy to RP interval was 50 days (range, 11-410, with 97% <180 days). Eighty patients (28%) had positive margin (M+). At a median follow-up of 92.6 months (range, 16.9-160.9, with 45% followed ≥ 8 years), 32 patients (11%) had PSA failure, with an estimated 8-year bRFS rate of 89%. In univariate analysis, M+, extraprostatic extension, detectable initial post-RP PSA, and longer biopsy to RP interval were significantly associated with lower bRFS. M+ and longer biopsy to RP interval remained significant in multivariable analysis. Recursive partitioning analysis identified M+ as the only stratification factor, with 8-year bRFS estimates of 74% versus 95% for M+ versus margin-negative.
Gleason score ≤6 prostate cancer managed using RP alone is associated with high rates of bRFS; however, margin positivity predicts early PSA failure rates in >20% of patients.
Individualization of Adjuvant Therapy after Radical Prostatectomy for Clinically Localized Prostate Cancer: Current Status and Future Directions
2016, Clinical Genitourinary Cancer
Citation Excerpt :
Another method by which to evaluate involved surgical margins is to measure the linear extent of disease at the surgical margin. One investigation of 114 adjuvant therapy-naive patients with involved surgical margins identified the linear extent of the positive margin to be significantly associated with early PSA recurrence.17 Additionally, when stratified by the Gleason score at prostatectomy, a subset of patients with a low risk of early recurrence was identified.
Radiation therapy indications in the postprostatectomy setting are evolving. Several retrospective series have identified a number of “high-risk” pathologic features associated with an elevated risk of disease recurrence after radical prostatectomy. More recently, several randomized phase III trials demonstrated superior biochemical relapse-free survival for adjuvant radiation therapy after prostatectomy for patients with these high-risk pathologic features, including positive margin status, extraprostatic extension, and/or seminal vesicle invasion. These series further suggested improvement in distant metastasis control and overall survival after 15 years. However, not all patients with high-risk features experience disease recurrence after surgery alone, and some subsets of patients experience suboptimal disease control and survival despite immediate postoperative radiotherapy. Furthermore, some patients without high-risk features will develop recurrence. The present review discusses the current data and potential future directions to improve individualization of therapy after prostatectomy.
Margin details matter: The prognostic significance of pseudocapsule invasion at the site of involved margin in prostatectomy specimens
2015, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
This aligns well with 33% to 60% reported elsewhere in the literature [4,5,8,9]. Further, these findings build on previously-reported experiences of pathology-determined subset creation, including extent of margin involvement (particularly when analyzed by Gleason score of the prostatectomy specimen) [6,7]. In 1 retrospective series, investigators from the University of Western Ontario (Canada) described outcomes for patients with node-negative/seminal vesicle-uninvolved prostatectomy with EPE and involved margins [7].
An involved surgical margin at prostatectomy has long been associated with elevated risk of prostate cancer recurrence; however, not all patients with an involved margin will relapse, and thus details of the involved margin may provide an opportunity for risk subset stratification. The present investigation seeks to determine whether a difference exists in recurrence rates when the margin involvement is at a site of prostate pseudocapsule invasion vs. within the prostate parenchyma proper.
Patients were retrospectively identified for inclusion by clinically localized disease and prostate-specific antigen (PSA) level of<30 ng/ml at diagnosis, managed with prostatectomy alone and identified to have involvement of surgical margin(s). Exclusion criteria were: pT3b or pN1 disease, immediate/nonsalvage postoperative radiation or hormone therapy, or insufficient follow-up (<12 mo). Pathology slides were reviewed by a pathologist blinded to outcome, for determination of pseudocapsule invasion at a site of margin involvement. Disease recurrence was defined as PSA level of≥0.2 ng/ml and rising, per contemporary guidelines. Kaplan-Meier method was used for construction of disease control estimate confidence intervals; Cox Proportional Hazards Model was used to compare disease control across groups.
Between 2003 and 2010, 155 patients were identified for inclusion in the present study. The median age was 61 years, and all had clinical stage T1 and T2 disease (75% T1c). At diagnosis, the Gleason score was 6, 7, and 8–9 for 103 (66%), 42 (27%), and 10 (6%) patients, respectively, with median PSA level of 5.6 ng/ml (85%≤10). For 149 patients with reviewable margin site data, 51 (34%) demonstrated involvement within or beyond the pseudocapsule. At a median follow-up of 68 months (range: 13–137), 62 patients had experienced PSA relapse. The estimated 5-year PSA relapse rates for patients with an involved margin at the site of pseudocapsule invasion vs. prostate parenchyma were 49% vs. 34%, respectively (P = 0.017; hazard ratio = 1.853).
Early PSA relapse rates are high for patients with involved surgical margin(s) without seminal vesicle or node involvement at prostatectomy; however, for patients who are followed without immediate adjuvant therapy, presence of tumor cells at the margin in a site of pseudocapsule invasion or penetration confers a higher risk of recurrence.
Biochemical Relapse in Low-risk Prostate Cancer Treated with Radical Prostatectomy and Bilateral Pelvic Lymphadenectomy
2022, Urologia Colombiana
Biochemical Relapse in Low Risk Prostate Cáncer Treated with Radial Prostatectomy and Pelvic Lymphadenectomy
2020, Urologia Colombiana

View all citing articles on Scopus

: Conflicts of interest: None.

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Original ReportMargin involvement at prostatectomy for clinically localized prostate cancer: Does a low-risk group exist?

Abstract

Purpose

Methods and materials

Results

Conclusions

Introduction

Section snippets

Methods and materials

Results

Discussion

Conclusions

J Urol

J Urol

Lancet

J Urol

Lancet

J Urol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Original Report
Margin involvement at prostatectomy for clinically localized prostate cancer: Does a low-risk group exist?