What Is the “True” Incidence of Active Surveillance and Brachytherapy Candidates in Men Undergoing Robot-Assisted Radical Prostatectomy?

Abstract

Purpose:

To correlate clinical low-risk prostate cancers with pathologic outcomes in men who are considered for active surveillance (AS), interstitial radiation therapy, or radical prostatectomy (RP).

Patients and Methods

: Clinical and pathologic data of 76 consecutive patients who underwent RP by a single surgeon between October 2001 and July 2008 were reviewed. The retrospective review identified men with clinical low-risk disease—defined as a prostate-specific antigen (PSA) level <10 ng/mL, no Gleason pattern >3, no >2 cores positive, and no core >50%—who would also have been considered for AS and/or brachytherapy based on these features. Pathologic specimens were examined for Gleason primary, secondary, and tertiary patterns, perineural invasion, capsular involvement, margins, nodal disease, and seminal vesicle involvement.

Results:

Of the patients who underwent RP, 42/76 (55%) had low-risk clinical staging; 8/76 (19%) had low-risk features on final pathologic staging. Fifty-four of 76 (71%) were pT_2c; 10% were pT₃. Gleason 6 was seen in 41/76 (53%) of RP specimens; Gleason 7 and 8 in 41% and 4%, respectively. Favorable brachytherapy parameters were identified in 63% of those who underwent surgery, but 39 of 48 (81%) would have been inappropriately selected based on features of the pathologic specimen.

Conclusion

: Clinical staging based on PSA level and biopsy findings correlates poorly with pathologic outcome when stratifying for low-risk features in men who may be candidates for brachytherapy and/or AS.

Introduction

T he incidence of prostate cancer has increased, with a downward migration in clinical and pathologic stage, since the introduction of prostate-specific antigen (PSA) screening in the late 1980s.^1,2 Detection and management of lower grade tumors has improved postprostatectomy biochemical recurrence-free periods and surrogate and actual markers for survival. The role of surveillance, brachytherapy, and radical prostatectomy (RP) continues to be a challenging debate in low-risk patients.^3,4 Clinical staging before initiation of treatment has become increasingly important as the number of nonsurgical modalities has increased. Brachytherapy and active surveillance (AS) have become two of the most commonly selected treatment options for patients with low-risk disease.

Preoperative nomograms use validated parameters to predict 5- and 10-year risk after prostatectomy.⁵ PSA level, Gleason score, and clinical stage have correlated with final pathology findings and have proven to accurately predict unfavorable outcomes.⁶ In 1998, Kattan and associates⁷ published a widely accepted nomogram that used these variables to predict biochemical recurrence after RP. This was updated in 2006 to include the recently published finding that the number of cores positive on systematic biopsy was a significant predictor of pathologic stage and biochemical failure.^8

–11 These and other factors, including percentage of each biopsy core containing cancer, have been used to guide patient selection for more conservative treatment modalities.

For AS, many such guidelines exist. Among the most widely accepted are the Epstein criteria: PSA density <0.15, ≤2 cores positive, no core >50%, and Gleason ≤6.¹² Other suggested criteria include those by Choo and colleagues,¹³ which proposed stage T_1b to T_2b, Gleason score ≤7, and PSA level of 15 ng/mL or less.

In selecting patients for brachytherapy, perhaps the most widely accepted criteria are those of the American Brachytherapy Society (ABS). For brachytherapy as monotherapy, the society recommends stage T₁ to T_2a, Gleason sum 2 to 6, and PSA level <10 ng/mL.¹⁴ Both the ABS guidelines and the various AS criteria attempt to solve a similar problem: How to predict low-volume, low-stage, clinically favorable prostate cancer. In selecting a treatment when no definitive pathology will be available, this process becomes paramount.

How accurate these criteria are in predicting clinically favorable disease remains uncertain. The gold standard for staging prostate cancer is the prostatectomy specimen. By reviewing a series of robot-assisted radical prostatectomy (RARP) specimens, we attempted to discern how many patients who were eligible for management with AS or brachytherapy would have been properly selected based on these preoperative criteria and the final pathologic staging.

Patients and Methods

After obtaining Institutional Review Board approval, we reviewed the records of 91 consecutive patients who underwent RARP by a single surgeon between October 2001 and April 2007. Fifteen patients were excluded from analysis because of inadequate biopsy or preoperative clinical information. Seventy-six patients were available for analysis with complete clinical and biopsy data.

All preoperative samples were obtained using 8 to 12 core ultrasonography-guided prostate biopsy. Biopsy specimens were examined for clinical stage, Gleason score, number of cores positive, and maximum percentage of each core positive. The preoperative PSA value was also recorded. Because the majority of patients were referred to our tertiary referral center, all biopsies were reread at our institution by genitourinary pathologists.

Prostatectomy specimens were examined by staff pathologists and classified using TNM staging. Prostate volume at RP was used to calculate PSA density (Table 1).

Table 1.

Prostate Volume and Preoperative Prostate-Specific Antigen Level

	PSA	Volume	PSAD
Mean	8.689211	56.99342	0.168684
SD	14.2917	23.01951	6.481087

PSA = prostate-specific antigen; PSAD = prostate-specific antigen density; SD = standard deviation.

Candidacy for AS or brachytherapy was determined by Epstein criteria (PSA density <0.15, ≤2 cores positive, no core >50%, and Gleason ≤6) and ABS guidelines (stage T₁ to T_2a, Gleason sum 2 to 6, and PSA level <10 ng/mL). Postoperatively, patients were deemed inappropriate for these modalities if upstaged to Gleason ≥7 or stage ≥pT_2c based on the prostatectomy specimen (Table 2). Statistical analysis was performed for categorical variables without parametric assumptions, using a P value < 0.05 to indicate significance. Logistic regression was performed to consider whether clinical and pathologic parameters correlated to determine candidacy for brachytherapy.

Table 2.

Pathologic Staging and Gleason Grade

Pathologic stage	No. patients	%	Gleason sum	No. patients	%
pT_2a	11	14.47	Gleason 6	41	53.95
pT_2b	2	2.63	Gleason 7	32	42.11
pT_2c	54	71.05	Gleason 8	3	3.95
pT_3a	6	7.89	Gleason 9	0	0
pT_3b	2	2.63	Gleason 10	0	0
pT_3c	1	1.32

Results

AS

Of the 76 patients analyzed, 42/76 (55%) qualified for AS by the Epstein criteria. In reviewing postoperative pathology findings, 8 of the 42 (19%) continued to be candidates for AS, while 34 of 42 (81%) would have been inappropriately selected.

Twenty-six of 34 (76%) became ineligible because of upstaging to ≥pT_2c, 2 of 34 (6%) were upgraded to Gleason ≥7, and 6 of 34 (18%) were both upstaged and upgraded. Overall, 24% of patients who qualified initially for AS were upgraded to Gleason ≥7 (Table 3).

Table 3.

Patients Qualifying for Modalities and Reasons for Inappropriate Selection

	Qualify preoperatively	Qualify postoperatively	Upstage	Upgrade	Both
Active surveillance	42/76 (55%)	8/42 (19%)	76%	6%	18%
Brachytherapy	48/76 (63%)	9/48 (19%)	64%	5%	31%

Brachytherapy

Of the 76 patients analyzed, 48/76 (63%) qualified for brachytherapy as monotherapy by ABS guidelines. In reviewing the pathology findings, 9 of those 48 (19%) continued to be candidates for brachytherapy, while 39 of the 48 (81%) would have been inappropriately selected.

Twenty-five of 39 (64%) became ineligible because of upstaging to ≥pT_2c, 2 of 39 (5%) were upgraded to Gleason ≥7, and 12 of 39 (31%) were both upstaged and upgraded. Overall, 36% of patients who qualified initially for brachytherapy were upgraded to Gleason ≥7 (Table 3).

Logistic regression was used to analyze correlation of biopsy and RP specimens. For the n = 76 cases, candidacy for brachytherapy based on clinical features did not correlate with candidacy based on pathologic features (P > 0.05). Preoperative biopsy grading correlated well with pathologic grading (R = .60, P < 0.01)

Discussion

Counseling patients with newly diagnosed prostate cancer involves a discussion of the patient's risk profile.^8,15 Selecting the appropriate treatment is paramount, because both undertreating locally advanced disease and overtreating indolent cancer may cause harm. Not every prostate cancer needs to be treated, and it has been difficult to prove survival benefit for early screening. A recent study published in the New England Journal of Medicine demonstrated no survival benefit to PSA screening.¹⁶ In the same issue, however, a European group published a 20% reduction in prostate cancer mortality with PSA screening.¹⁷

For patients who are considered at low risk, watchful waiting and brachytherapy are often advocated.^14,18,19 When choosing either AS or brachytherapy, no true accurate pathologic data are available to verify the patient's risk profile. Instead, both modalities need the use of clinical criteria as an adjunct to make this determination.

AS in men with clinically localized disease has been validated in the literature.²⁰ The criteria for inclusion in AS, however, have yet to be standardized and need extensive discussions between physician and patient. Patient selection for expectant management and patient understanding of the rigors involved are central to this approach. Many authors suggest deferring treatment in men with a life expectancy of <10 years.²¹ In addition to patient age, Gleason score, and PSA level, the Epstein criteria use PSA density, number of cores positive, and percentage of each core positive in an attempt to better characterize a patient's risk profile.

In 2002, Carter and colleagues²² reported their preliminary results for an AS program. Eighty-one men who qualified for surveillance by the Epstein criteria were followed for a median of 23 months with semiannual PSA level determinations and digital rectal examinations, and annual prostate biopsies. They found that 31% of men had disease progression, defined as Gleason ≥7 or >2 positive cores, at a median of 14 months. Of those who progressed, 72% were uncovered in the first 2 years of surveillance. This suggests that the initial biopsy underestimated both the tumor volume and grade in the vast majority of men with progression. The authors recommended that men considering AS undergo a repeated biopsy with wide area sampling to reduce the incidence of understaging and inappropriate inclusion. They estimated that 20% to 30% of men have more extensive disease, underrepresented by biopsy. Our data suggest, using the gold standard of RP specimens, that the number may be closer to 80%.

Inappropriate inclusion in AS can cause emotional and physical distress. Choo and coworkers¹³ and Carter and colleagues²³ both showed that patient anxiety contributes to high rates of abandoning this approach. Penson and Litwin²⁴ reported that the stress associated with delaying treatment adversely affected patient quality of life. Our study suggests that the clinical factors currently used may not provide an accurate prediction of true pathologic stage or grade. As a result, determining a patient's true risk profile may be difficult.

AS may lead to more than psychological consequences. The group from Johns Hopkins reported that of the 25 men with disease progression who underwent RP, 1 had advanced and potentially incurable disease.²² Furthermore, in a randomized trial of 695 men with low-risk prostate cancer, Holmberg and associates²⁵ showed that RP significantly reduced disease-specific mortality compared with the surveillance group.

Despite the risks of failure, men withdrawing from AS may still enjoy a favorable prognosis.^26,27 Using inclusion criteria similar to those in this article, Hardie and associates²⁶ published an 80% rate of continuation with AS at a median of 42 months. In all, 11 patients withdrew from AS. Of the seven patients who completed radical therapy, all remained biochemically controlled at a median of 20 months.

In a series of 40 men with clinically localized prostate cancer, Albertsen and coworkers¹⁹ demonstrated a 5-year rate of continuing surveillance of 73%. Of the nine men who withdrew, most were because of a rising PSA level and patient anxiety. Of the men undergoing definitive therapy, none had biochemical failure after radiation therapy.

The exponential rise in the number of patients receiving brachytherapy is a reflection in part of the increased detection of early cancer. The ABS states that patients with a high probability of low-stage, organ-confined disease are appropriate candidates for permanent radionuclide implantation.¹⁴ Our data suggest that the parameters that are used currently to predict low-stage, low-grade prostate cancer may not be accurate and that these patients may be understaged. Thirty-nine of 48 (81%) patients who qualified for brachytherapy based on ABS guidelines had pathologic features that were incompatible with radionuclide implantation as monotherapy. Understaging prostate cancer and inappropriate treatment can lead to increased cost of treatment and increased risk of biochemical failure.²⁸

Limitations of our study include the fact that not all of our biopsies were 12-core biopsies. One could argue that performing a standardized 12-core template could provide more accurate clinical staging. Unfortunately, the tertiary nature of our center did not allow this analysis.

Many attempts have been made to improve clinical staging using MRI or CT. Because the majority of patients were referred for surgery to our tertiary referral center, staging studies (CT, bone scan) were typically performed by community urologists and not standardized to allow adequate evaluation. Advances in endorectal MRI technology someday may allow greater precision in staging. Whether this will be readily accessible by patients and community urologists remains to be seen.

Ideally, we would be able to evaluate a matched cohort of brachytherapy and AS patients to evaluate whether oncologic outcomes in men who were undergoing AS or brachytherapy truly differed from men who underwent RP.

We do concede that the majority of patients with low-risk prostate cancer may not ultimately die of their disease. Unfortunately, survival data in most prostate cancer studies are limited, given the lack of 15- to 20-year follow-up. That said, survival is not the only pertinent end point, because men with recurrence after brachytherapy or with progressive disease on AS may experience significant medical and psychological morbidity.

While our review is retrospective and involves a small cohort of patients, we believe that our findings are significant and certainly merit further investigation. Our data showed that 81% of patients who would have qualified for AS or brachytherapy would have been inappropriately selected.

Conclusion

There appears to be little predictive value in the biopsy and preoperative criteria used currently to define a patient's risk profile when compared with the gold standard of pathologic staging. Caution should be used in selecting patients for AS or brachytherapy monotherapy. Further study is needed to validate selection criteria for patients who are not undergoing RP.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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