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Figure.
Risk of Grade Group (GG)≥3 Disease at Radical Prostatectomy for Patients With Very Low-Risk (VLR), Low-Risk (LR), and “Favorable” Low-Volume Intermediate-Risk (LVIR) Prostate Cancer on Biopsy
Risk of Grade Group (GG)≥3 Disease at Radical Prostatectomy for Patients With Very Low-Risk (VLR), Low-Risk (LR), and “Favorable” Low-Volume Intermediate-Risk (LVIR) Prostate Cancer on Biopsy
Table 1.  
Distribution of Grade Groups (GGs) and Adverse Pathologic Findings After Radical Prostatectomy (RP) for Patients by Preoperative Risk Classification
Distribution of Grade Groups (GGs) and Adverse Pathologic Findings After Radical Prostatectomy (RP) for Patients by Preoperative Risk Classification
Table 2.  
Univariable and Multivariable Logistic Regression Evaluating Preoperative Factors in Men With LVIR Disease as Well as All Included Patients to Predict Adverse Pathologic Findings At Radical Prostatectomy
Univariable and Multivariable Logistic Regression Evaluating Preoperative Factors in Men With LVIR Disease as Well as All Included Patients to Predict Adverse Pathologic Findings At Radical Prostatectomy
1.
Mohler  JL, Armstrong  AJ, Bahnson  RR,  et al.  Prostate cancer, version 1.2016.  J Natl Compr Canc Netw. 2016;14(1):19-30.PubMedGoogle ScholarCrossref
2.
Tosoian  JJ, Carter  HB, Lepor  A, Loeb  S.  Active surveillance for prostate cancer: current evidence and contemporary state of practice.  Nat Rev Urol. 2016;13(4):205-215.PubMedGoogle ScholarCrossref
3.
Hamdy  FC, Donovan  JL, Lane  JA,  et al; ProtecT Study Group.  10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer.  N Engl J Med. 2016;375(15):1415-1424.PubMedGoogle ScholarCrossref
4.
Epstein  JI, Zelefsky  MJ, Sjoberg  DD,  et al.  A Contemporary prostate cancer grading system: a validated alternative to the Gleason score.  Eur Urol. 2016;69(3):428-435.PubMedGoogle ScholarCrossref
5.
Zumsteg  ZS, Spratt  DE, Pei  I,  et al.  A new risk classification system for therapeutic decision making with intermediate-risk prostate cancer patients undergoing dose-escalated external-beam radiation therapy.  Eur Urol. 2013;64(6):895-902.PubMedGoogle ScholarCrossref
6.
Raldow  AC, Zhang  D, Chen  MH, Braccioforte  MH, Moran  BJ, D’Amico  AV.  Risk group and death from prostate cancer: implications for active surveillance in men with favorable intermediate-risk prostate cancer.  JAMA Oncol. 2015;1(3):334-340.PubMedGoogle ScholarCrossref
7.
Klotz  L.  Active surveillance for prostate cancer: patient selection and management.  Curr Oncol. 2010;17(suppl 2):S11-S17.PubMedGoogle Scholar
8.
Epstein  JI, Feng  Z, Trock  BJ, Pierorazio  PM.  Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades.  Eur Urol. 2012;61(5):1019-1024.PubMedGoogle ScholarCrossref
9.
Eggener  SE, Scardino  PT, Walsh  PC,  et al.  Predicting 15-year prostate cancer specific mortality after radical prostatectomy.  J Urol. 2011;185(3):869-875.PubMedGoogle ScholarCrossref
10.
Tosoian  JJ, Sundi  D, Trock  BJ,  et al.  Pathologic outcomes in favorable-risk prostate cancer: comparative analysis of men electing active surveillance and immediate surgery.  Eur Urol. 2016;69(4):576-581.PubMedGoogle ScholarCrossref
11.
Patel  HD, Humphreys  E, Trock  BJ, Han  M, Carter  HB.  Practice patterns and individual variability of surgeons performing radical prostatectomy at a high volume academic center.  J Urol. 2015;193(3):812-819.PubMedGoogle ScholarCrossref
12.
Wilt  TJ, Brawer  MK, Jones  KM,  et al; Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group.  Radical prostatectomy versus observation for localized prostate cancer.  N Engl J Med. 2012;367(3):203-213.PubMedGoogle ScholarCrossref
13.
Bill-Axelson  A, Holmberg  L, Garmo  H,  et al.  Radical prostatectomy or watchful waiting in early prostate cancer.  N Engl J Med. 2014;370(10):932-942.PubMedGoogle ScholarCrossref
14.
Musunuru  HB, Yamamoto  T, Klotz  L,  et al.  Active surveillance for intermediate risk prostate cancer: survival outcomes in the Sunnybrook experience.  J Urol. 2016;196(6):1651-1658. doi:10.1016/j.juro.2016.06.102PubMedGoogle ScholarCrossref
15.
Godtman  RA, Holmberg  E, Khatami  A, Pihl  CG, Stranne  J, Hugosson  J.  Long-term results of active surveillance in the Göteborg randomized, population-based prostate cancer screening trial.  Eur Urol. 2016;70(5):760-766.PubMedGoogle ScholarCrossref
Brief Report
January 2018

Adverse Pathologic Findings for Men Electing Immediate Radical Prostatectomy: Defining a Favorable Intermediate-Risk Group

Author Affiliations
  • 1The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 2Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
JAMA Oncol. 2018;4(1):89-92. doi:10.1001/jamaoncol.2017.1879
Key Points

Question  Is there a subset of men with Gleason 3 + 4 = 7 intermediate-risk prostate cancer with favorable characteristics to minimize risk of adverse pathologic findings at surgery?

Findings  In this large cohort study, 25% of men with low-volume, Gleason 3 + 4 prostate cancer on biopsy were found to harbor adverse surgical pathologic findings, a rate 4 to 5 times higher than for men with low-risk and very low-risk prostate cancer, which does not support the presence of a “favorable” subgroup.

Meaning  Men with Gleason 3 + 4 = 7 prostate cancer otherwise eligible for curative intervention should be fully informed as to the avoidable risk associated with use of active surveillance.

Abstract

Importance  Active surveillance is recommended for patients with very low-risk (VLR) and low-risk (LR) prostate cancer. Despite controversy, recent clinical guidelines state surveillance may be considered for men with low-volume intermediate-risk (LVIR) disease.

Objective  To compare rates of adverse pathologic findings among VLR, LR, and LVIR men electing immediate radical prostatectomy and evaluate criteria to define if a favorable intermediate-risk group minimizing risk exists.

Design, Setting, and Participants  This was a cohort study of men (2005-July 2016) with clinically localized VLR (1264 patients), LR (4849 patients), and LVIR (608 patients) (1-2 cores, Gleason 3 + 4 = 7, prostate-specific antigen [PSA] level <20 ng/mL) prostate cancer undergoing radical prostatectomy evaluated retrospectively at Johns Hopkins Hospital.

Interventions  Radical prostatectomy.

Main Outcomes and Measures  The proportions of men found to have at least Gleason 4 + 3 = 7 disease and other adverse pathologic features were compared by risk group. Log-binomial regression calculated relative risk (RR) of adverse pathologic findings in the LVIR cohort compared with VLR and LR cohorts. Analyses were repeated in subgroups of the LVIR population who otherwise met criteria for VLR (T1c, PSA density [PSAD] <0.15 ng/mL/cm3, ≤50% cancer in any core) and LR (≤T2a, PSA level <10 ng/mL) disease. Rates of adverse pathologic findings within the LVIR group were calculated based on various clinical thresholds, and univariable and multivariable logistic regression analyses were performed to identify predictors of adverse pathologic findings.

Results  The rate of adverse pathologic findings was significantly higher for LVIR disease (150 of 608 patients [24.7%]; RR, 4.50; 95% CI, 3.73-5.43; P < .001) compared with LR disease (280 of 4849 [5.8%]), and LVIR disease (RR, 5.14; 95% CI, 3.84-6.89; P < .001) compared with men with VLR disease (60 of 1264 [4.7%]). Restriction of LVIR men to additional criteria did not significantly affect results. There were no preoperative clinical or pathologic criteria that could identify a subgroup of the LVIR population with rates of adverse pathologic findings comparable with those of the VLR and LR cohorts. PSAD was a significant predictor of adverse pathologic findings, but Gleason score had the largest effect (odds ratio, 4.30 (95% CI, 3.40-5.44; P < .001).

Conclusions and Relevance  Nearly 25% of men (150 of 608) electing immediate radical prostatectomy with low-volume, Gleason 3 + 4 prostate cancer on biopsy are found to harbor adverse surgical pathologic findings. These data do not support the presence of a “favorable” subgroup among included patients and could have important implications for active surveillance in similar patients with Gleason 3 + 4 = 7 prostate cancer.

Introduction

The current treatment paradigm for men with localized prostate cancer involves risk stratification to distinguish men whose disease can be safely treated under active surveillance (AS) from those more likely to benefit from immediate curative intervention.1 The National Comprehensive Cancer Network (NCCN) recommends AS as a first-line treatment option for most men diagnosed as having low-risk (LR) and very low-risk (VLR) disease based on a body of data demonstrating acceptably low rates of metastasis and prostate cancer–specific mortality over the intermediate term.1,2 Recent results from the ProtecT trial, which includes some men with Gleason score 7 cancer, noted similar prostate cancer–specific survival for active monitoring, surgery, and radiotherapy.3 However, it remains unclear which subset of intermediate-risk (IR) patients with Gleason score 7 cancers can be safely treated with AS.

Several groups have attempted to identify a “favorable” IR population including those with Gleason score 7 disease. The prognostic significance of pathologic grade has been demonstrated and validated to separate Gleason 3 + 4 (grade group [GG] 2) and Gleason 4 + 3 (GG3) disease in a multi-institutional analysis.4 Therefore, potential favorable IR cohorts have invariably been restricted to men with Gleason 3 + 4 (GG2) cancers.5,6 However, the original definition of favorable IR was based on survival outcomes in men treated with radiation therapy; such a population does not represent untreated patients on AS and does not allow for evaluation of true underlying pathologic abnormalities.

Despite controversy, NCCN guidelines now suggest that AS may be an option for men with some IR cancers, prompting a pressing need to understand pathologic correlates and better define this risk group.1 Expanding AS criteria to include higher-risk cancers may place these patients at undue risk of harm. We therefore sought to assess pathologic outcomes among men with VLR, LR, and limited-volume intermediate-risk (LVIR) prostate cancer. LVIR candidates included men with only 1 or 2 cores of Gleason score 3 + 4 = 7 cancer detected at biopsy. Risk-stratification was performed to identify a subgroup of LVIR candidates at minimal risk of harboring adverse pathologic findings who may be appropriate for AS.

Methods
Patient Population, Variables, and Outcomes

With institutional review board approval from Johns Hopkins Hospital, we identified all men with clinically localized NCCN VLR, LR, and LVIR (Gleason 3 + 4 (GG2), 1 or 2 biopsy cores showing cancer, prostate-specific antigen (PSA) level <20 ng/mL) prostate cancer who underwent radical prostatectomy by 15 surgeons at the Johns Hopkins Hospital (January 2005–July 2016) (see eMethods and eReferences in the Supplement for detailed definitions). The primary outcome was adverse pathologic findings at radical prostatectomy, defined as Gleason score of at least 4 + 3 = 7 (GG≥3), seminal vesicle invasion (pT3b), or lymph node metastasis (pN1); this outcome was selected based on universal acceptance that AS is inappropriate for patients harboring such features.7

Statistical Analysis

Distributions of grade group and adverse surgical pathologic findings were tabulated among the VLR, LR, and LVIR populations. Log-binomial regression was used to calculate relative-risk (RR) of adverse pathologic findings. Analyses were repeated in subgroups of the Gleason 3 + 4 = 7 (GG2) population that met all other (ie, non–Gleason score) VLR (T1c, PSA density [PSAD] <0.15 ng/mL/cm3, ≤50% cancer in any core) and LR criteria (≤T2a, PSA level <10 ng/mL).1

For the LVIR group, clinical and pathologic factors were compared among men who did and did not have adverse pathologic findings. To identify clinically useful cut points for risk stratification, we calculated the rates of adverse pathologic findings based on various thresholds of PSA level, PSA density (PSAD), and cancer volume at diagnosis (see eMethods in the Supplement). Univariable and multivariable logistic regression analyses were performed to identify predictors of adverse pathologic findings. Akaike information criterion was evaluated for each model. Statistical analyses were performed using Stata software (version 12.0; StataCorp).

Results
Adverse Pathologic Findings Among VLR, LR, and LVIR Groups

A total of 1264 VLR, 4849 LR, and 608 LVIR men underwent radical prostatectomy during the study period. For reference, 1248 LR men, with 804 meeting VLR, criteria were followed on AS during the same time period with IR men excluded. The rate of adverse pathologic findings was notably higher for LVIR patients (150 of 608 [24.7%]) compared with LR patients (280 of 4849 [5.8%]; RR, 4.50; 95% CI, 3.73-5.43; P < .001) or VLR patients (60 of 1264 [4.7%]; RR, 5.14; 95% CI, 3.84-6.89; P < .001) (Table 1). Most adverse pathologic findings were driven by the rate of disease with Gleason scores of at least 4 + 3 = 7 (GG≥3) (Table 1; Figure). Among 508 LVIR men (83.6%) who met all LR criteria other than biopsy grade, 108 (21.3%) were found to harbor adverse pathologic findings (RR, 3.68; 95% CI, 3.01-4.51; P < .001). Similarly, considering the 271 LVIR men (44.6%) who met all VLR criteria beside biopsy grade, 50 men (18.5%) demonstrated adverse surgical pathologic findings (RR, 3.89; 95% CI, 2.73-5.52; P < .001).

LVIR Cohort and Predictors of Adverse Pathologic Findings

Among the 150 LVIR men with adverse surgical pathologic findings, 141 (94%) harbored disease with Gleason score of at least 4 + 3 = 7 (GG≥3); only 9 additional patients were identified owing solely to seminal vesicle invasion (n = 8 [5.3%]) or lymph node positivity (n = 1 [0.7%]). Patients with and without adverse pathologic findings did not differ by age, race, family history of prostate cancer, or volume of cancer on biopsy (eTable 1 in the Supplement).

Stratified analyses of PSA level and PSAD revealed a consistent 2-fold difference in rate of adverse pathologic findings regardless of selected cutoffs (eTable 2 in the Supplement). Detailed stratification by cancer volume revealed no statistically significant thresholds to aid in further risk stratification (eTable 3 in the Supplement). Univariable analyses of adverse pathologic findings revealed associations with PSA level, PSAD, and year of surgery for LVIR patients (Table 2). Multivariable analysis of the overall cohort showed Gleason score exerted the largest effect (odds ratio, 4.30; 95% CI, 3.40-5.44; P < .001).

Discussion

Active surveillance seems to be a safe treatment option in most men with Gleason 6 (GG1) prostate cancer, but it remains unclear whether AS should be considered in the population of men with limited Gleason 3 + 4 = 7 (GG2) disease. Existing literature has demonstrated that pathologic grade of at least 4 + 3 = 7, seminal vesicle invasion, and lymph node metastasis are the strongest predictors of long-term outcomes after surgery.7-10 Therefore, it is reasonable to propose that a subgroup of Gleason 3 + 4 = 7 (GG2) cancers at minimal risk of harboring these features could be monitored with AS to avoid harms of overtreatment. Our findings, however, revealed 1 in 4 men with low-volume Gleason 3 + 4 = 7 (GG2) disease on biopsy harbored adverse surgical pathologic findings. Indeed, the rate of adverse pathologic findings was more than 4-fold higher than observed in the VLR and LR populations and remained high even when limited to all other VLR and LR criteria. Furthermore, no clinical or pathological parameters could distinguish a population of LVIR men with pathologic outcomes comparable with the VLR or LR cohorts.

The goal of AS is to reduce overtreatment of prostate cancer for patients unlikely to benefit from intervention.2 The traditional focus has been on LR disease, where urologists vary widely in selecting patients for AS and treatment.11 Patients followed with AS for LR and VLR disease who undergo delayed surgery have similar rates of increased grade and other adverse pathologic findings compared with patients receiving immediate surgery.10 Patients with IR prostate cancer represent a very different and heterogeneous population compared with those with LR prostate cancer. Randomized clinical trials have generally suggested that IR men derive the greatest benefit from radical prostatectomy.12,13 In addition, recent reports from 2 large AS programs have revealed that even carefully selected men with IR cancer fared poorly compared with LR men, largely driven by presence of Gleason 7 disease.14,15

Limitations

Limitations of the present study include the use of a retrospective cohort undergoing radical prostatectomy. However, all men were risk-stratified according to NCCN criteria, the same inclusion criteria used for our prospective AS cohort for LR and VLR men. We avoided performing survival analyses in treated men, which can bias conclusions, and instead used a validated pathologic surrogate. Another limitation of the study is that magnetic resonance imaging and molecular and/or genetic tests were not performed routinely enough to include in analyses that could further stratify patients. Finally, the analysis is limited to 1 institution with dedicated expert genitourinary pathologists.

Conclusions

Approximately 1 in 4 men with low-volume, Gleason 3 + 4 = 7 (GG2) prostate cancer on biopsy undergoing prostatectomy were found to harbor adverse pathologic findings. Traditional clinical and pathologic criteria were not useful in identifying a “favorable” subset. Our observations suggest use of AS may place similar men with Gleason 3 + 4 = 7 (GG2) cancer at risk of adverse outcomes that could have potentially been avoided with immediate intervention. This study could have important implications for men with LVIR prostate cancer electing AS, and further study is clearly needed.

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Article Information

Corresponding Author: Hiten D. Patel, MD, MPH, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, 600 N Wolfe St, Marburg 144, Baltimore, MD 21287 (hitenpatel@jhmi.edu).

Accepted for Publication: May 8, 2017.

Published Online: July 13, 2017. doi:10.1001/jamaoncol.2017.1879

Author Contributions: Drs Patel and Epstein had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Patel and Tosoian are co–first authors.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Patel, Tosoian, Epstein.

Statistical analysis: Patel, Tosoian.

Study supervision: Carter, Epstein.

Conflict of Interest Disclosures: None reported.

References
1.
Mohler  JL, Armstrong  AJ, Bahnson  RR,  et al.  Prostate cancer, version 1.2016.  J Natl Compr Canc Netw. 2016;14(1):19-30.PubMedGoogle ScholarCrossref
2.
Tosoian  JJ, Carter  HB, Lepor  A, Loeb  S.  Active surveillance for prostate cancer: current evidence and contemporary state of practice.  Nat Rev Urol. 2016;13(4):205-215.PubMedGoogle ScholarCrossref
3.
Hamdy  FC, Donovan  JL, Lane  JA,  et al; ProtecT Study Group.  10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer.  N Engl J Med. 2016;375(15):1415-1424.PubMedGoogle ScholarCrossref
4.
Epstein  JI, Zelefsky  MJ, Sjoberg  DD,  et al.  A Contemporary prostate cancer grading system: a validated alternative to the Gleason score.  Eur Urol. 2016;69(3):428-435.PubMedGoogle ScholarCrossref
5.
Zumsteg  ZS, Spratt  DE, Pei  I,  et al.  A new risk classification system for therapeutic decision making with intermediate-risk prostate cancer patients undergoing dose-escalated external-beam radiation therapy.  Eur Urol. 2013;64(6):895-902.PubMedGoogle ScholarCrossref
6.
Raldow  AC, Zhang  D, Chen  MH, Braccioforte  MH, Moran  BJ, D’Amico  AV.  Risk group and death from prostate cancer: implications for active surveillance in men with favorable intermediate-risk prostate cancer.  JAMA Oncol. 2015;1(3):334-340.PubMedGoogle ScholarCrossref
7.
Klotz  L.  Active surveillance for prostate cancer: patient selection and management.  Curr Oncol. 2010;17(suppl 2):S11-S17.PubMedGoogle Scholar
8.
Epstein  JI, Feng  Z, Trock  BJ, Pierorazio  PM.  Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades.  Eur Urol. 2012;61(5):1019-1024.PubMedGoogle ScholarCrossref
9.
Eggener  SE, Scardino  PT, Walsh  PC,  et al.  Predicting 15-year prostate cancer specific mortality after radical prostatectomy.  J Urol. 2011;185(3):869-875.PubMedGoogle ScholarCrossref
10.
Tosoian  JJ, Sundi  D, Trock  BJ,  et al.  Pathologic outcomes in favorable-risk prostate cancer: comparative analysis of men electing active surveillance and immediate surgery.  Eur Urol. 2016;69(4):576-581.PubMedGoogle ScholarCrossref
11.
Patel  HD, Humphreys  E, Trock  BJ, Han  M, Carter  HB.  Practice patterns and individual variability of surgeons performing radical prostatectomy at a high volume academic center.  J Urol. 2015;193(3):812-819.PubMedGoogle ScholarCrossref
12.
Wilt  TJ, Brawer  MK, Jones  KM,  et al; Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group.  Radical prostatectomy versus observation for localized prostate cancer.  N Engl J Med. 2012;367(3):203-213.PubMedGoogle ScholarCrossref
13.
Bill-Axelson  A, Holmberg  L, Garmo  H,  et al.  Radical prostatectomy or watchful waiting in early prostate cancer.  N Engl J Med. 2014;370(10):932-942.PubMedGoogle ScholarCrossref
14.
Musunuru  HB, Yamamoto  T, Klotz  L,  et al.  Active surveillance for intermediate risk prostate cancer: survival outcomes in the Sunnybrook experience.  J Urol. 2016;196(6):1651-1658. doi:10.1016/j.juro.2016.06.102PubMedGoogle ScholarCrossref
15.
Godtman  RA, Holmberg  E, Khatami  A, Pihl  CG, Stranne  J, Hugosson  J.  Long-term results of active surveillance in the Göteborg randomized, population-based prostate cancer screening trial.  Eur Urol. 2016;70(5):760-766.PubMedGoogle ScholarCrossref
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