Prostate cancer laterality as a rationale of focal ablative therapy for the treatment of clinically localized prostate cancer

Authors

  • Vladimir Mouraviev MD, PhD,

    1. Duke Prostate Center and Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
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  • Janice M. Mayes BSc,

    1. Duke Prostate Center and Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
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  • Leon Sun MD, PhD,

    1. Duke Prostate Center and Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
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  • John F. Madden MD,

    1. Department of Pathology, Duke University Medical Center, Durham, North Carolina
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  • Judd W. Moul MD,

    1. Duke Prostate Center and Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
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  • Thomas J. Polascik MD

    Corresponding author
    1. Duke Prostate Center and Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
    • Associate Professor of Urology, Duke University Medical Center, Box 2804, Yellow Zone, Durham, NC 27710
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    • Dr. Polascik is a research consultant to Galil Medical.

    • Fax: (919) 684-5220.


Abstract

BACKGROUND.

Early detection of small-volume prostate cancer (PCa) has led to the concept of focal therapy to treat PCa as an organ-sparing, minimally invasive procedure. The authors sought to determine the frequency of unilateral cancers in the contemporary prostate-specific antigen (PSA) era to determine the percentage of patients who would be candidates for hemiablation of the prostate by using focal therapy while preserving the contralateral lobe.

METHODS.

Paraffin-embedded radical prostatectomy specimens (1184 specimens) from consecutive patients between 2002 and 2006 with pathologic organ confined PCa were analyzed. Pathologic assessment focused on tumor laterality and percentage of tumor involvement (PTI) along with other routine parameters such as pathological T-classification (pT), pathological Gleason Score (pGS), extracapsular extension (ECE), and surgical margins (SM). Clinical and pathologic parameters were analyzed by univariate and multivariate methods.

RESULTS.

Completely unilateral cancers were identified in 227 (19.2%) of 1184 patients. Of these patients, 164 (72.2%) had PTI of ≤5%, 40 (17.6%) had a PTI of 5.01%–10%, 9 (4.0%) had a PTI of 10.01%–15%, and 14 (6.2%) had a PTI of > 15%, respectively (P < .0005). African-American men had bilateral cancers more commonly that non-African-American men, eg, 90.8% versus 79.2%, respectively (P < .0005). Race, PTI, pGS, and SM were independent predictors by multivariate logistic regression (P ≤ .05).

CONCLUSIONS.

This study suggests that 1 in 5 men diagnosed with PCa have small volume, completely unilateral cancers that may be amenable to hemiablation of the prostate. Further study is needed to develop predictive models to select candidates for focal therapy. Cancer 2007; 110:906–10. © 2007 American Cancer Society.

Radical prostatectomy and whole-gland radiotherapy remain gold standards for definitive management of clinically localized prostate cancer (PCa). At present, almost all established local forms of PCa therapy aim to treat the entire gland by radiation (eg, external beam, brachytherapy), thermal therapy (eg, cryosurgery), or surgical extirpation (eg, radical prostatectomy). One potential drawback of whole-gland treatment is the host of attendant side effects associated with prostate cancer (PCa) therapy such as incontinence and impotence among others. For some patients with early detected cancers, whole-gland therapy may constitute over-treatment with excellent oncologic outcome but at the expense of diminished quality of life due to associated side effects. With the introduction and widespread acceptance of PCa screening programs, PCa specialists are witnessing a shift in PCa staging favoring early stage disease that potentially can be treated by alternative methods.1, 2 For example, if a prostate gland is found to harbor a small focus (foci) of low volume, low-grade disease that lateralizes to 1 side of the prostate, it may be conceivable to treat the affected side by minimally invasive ablative technologies, such as cryotherapy, high-intensity focused ultrasound (HIFU), or other locally ablative means.

Impotence and incontinence along with other complications of PCa therapy affects the male self-image and psyche.3, 4 Treatment of 1 lobe of the prostate with preservation of the contralateral lobe is believed to be associated with substantial improvement in the incidence of treatment-related morbidity compared with an organ-removing procedure. The goal of such treatment would be to incorporate the quality of life of the individual patient into the equation of cancer treatment, without diminishing therapeutic efficacy.

The purpose of this study was to pathologically define the frequency of unilateral PCa by final pathologic assessment of patients who underwent radical prostatectomy for localized PCa in the contemporary prostate-specific antigen (PSA) era. A secondary goal was to correlate several select demographic and/or clinical variables with those patients demonstrating unilateral PCa. This study did not intend to define those clinical variables that may accurately predict pathologic stage, and for that reason, pretreatment prostate biopsy information was not analyzed.

MATERIALS AND METHODS

Population

The study cohort comprised 1184 consecutive men with pathologic organ-confined disease who underwent a radical prostatectomy (retropubic, perineal or robotic) at Duke University Medical Center between January 2002 and June 2006. Excluded were patients who had a diagnostic PSA level ≥10, clinical stage ≥T3, seminal vesicle invasion (SVI), or lymph node involvement verified by surgical pathology, prior transurethral resection of the prostate (TURP), or prior exposure to hormonal therapy, chemotherapy, or radiation therapy. Demographic information and clinical characteristics were collected.

Each prostatectomy specimen was weighed, measured, inked, and fixed in 10% neutral formalin. After fixation, the apex and base were amputated and serially sectioned at 3 mm intervals in the vertical parasagittal plane. Paraffin-embedded radical prostatectomy specimens were sectioned at 5 μm thickness and stained with hematoxylin-eosin (H&E). The seminal vesicles were sectioned parallel to their junction with the prostate and entirely submitted for evaluation. The remaining specimen was serially sectioned perpendicular to the long axis of the gland from the apex to the base. Pathologic assessment had particular attention directed to laterality and percentage of tumor involvement (PTI) along with other routine parameters such as pathological T classification (pT), pathologic Gleason Score (pGS), extracapsular extension (ECE), and positive surgical margins (+SM). Based on PTI, all cancer foci were ranked in 4 groups: ≤5%, 5.01%–10%, 10.01%–15%, and >15% PTI. Foci of adenocarcinoma were considered distinct if they were separated by >4 mm.5 Tumors were classified as unilateral if all foci were confined to either the left or right side of the prostate, with respect to the urethra representing the dividing line. This study was approved by our institutional review board (No: 7404-06-7R0ER).

Statistical analysis

Clinical and pathologic parameters were analyzed by univariate (chi-square test) and multivariate (logistic regression model) methods. The statistical program SPSS, version 12, (SPSS, Chicago, Ill) was used.

RESULTS

Patient demographics and tumor characteristics are presented in Table 1. Analysis of the frequency of multifocality showed that a potential “therapeutic window” for focal therapy sequentially decreased with increasing PTI. Completely unilateral cancers were identified in 227 (19.2%) of 1184 patients. Of these patients, 164 (72.2%) had a PTI of ≤5%, 40 (17.6%) had a PTI of 5.01%–10%, 9 (4.0%) had a PTI of 10.01%–15%, and 14 (6.2%) had a PTI of >15% (P < .0005), Table 2. Among unilateral cancers, the pGS distribution favored less severe cancers with 138 (61.1%) cases having a pGS of <7, 74 (32.7%) cases having a pGS of 7, and 14 (6.2%) cases having a pGS of >7 (Fig. 1). African-American men had bilateral cancers more commonly than non-African-American men, 90.8% versus 79.2%, respectively (P < .0005). Comparative analysis of the frequency of unilaterality versus bilaterality showed a decrease of unilateral tumors from 33.2% versus 66.8% for small-sized lesions with PTI of ≤5% to 5.5% versus 94.5% in larger tumor volumes that had a PTI of >15%, respectively (Fig. 2).

Figure 1.

Pathologic Gleason score distribution among unilateral tumors.

Figure 2.

Percentage of tumor involvement (PTI) distribution among unilateral and bilateral tumors.

Table 1. Patient Demographics And Tumor Characteristics
ParametersNo.%
  1. PSA indicates prostate-specific antigen; PTI, percentage of tumor involvement.

Race
 African-American16313.8
 non-African-American99884.3
 Unknown231.9
Median age (range)61.4 y (34.6–78.9) 
Tumor laterality
 Unilateral22719.2
 Bilateral95780.8
Median diagnostic PSA (range)5.3 ng/mL (0.4–9.98) 
Clinical T-classification
 T1C92978.4
 T223419.8
 Unknown211.8
Biopsy Gleason score
 <787473.8
 723219.6
 >75.2 
 Unknown171.4
Median prostate weight (range)38.7 grams (12.7–183.2) 
PTI
 ≤549441.7
 5.01–1030125.4
 10.01–1513411.3
 >1525521.6
Pathologic T-classification
 T294679.9
 T3A23820.1
Pathologic Gleason score
 <759149.9
 751843.7
 >7665.6
 Unknown90.8
Margin status
 Negative85071.8
 Positive33428.2
Extracapsular extension of tumor
 Negative95080.2
 Positive23419.8
Table 2. Univariate Analysis of Clinical and Pathologic Variables to Predict Tumor Unilaterality
 No. (%) unilateralNo. (%) bilateralP
  1. AA indicates African Americans; Non-AA, non-African Americans, DxPSA, PSA at time of diagnosis; BxGS, biopsy Gleason score; PTI, percentage of tumor involvement; pT, pathologic T-classification; pGS, pathologic Gleason Score; ECE, extracapsular extension on the side of the unilateral tumor.

Race  <.0005
 AA15 (9.2)148 (90.8) 
 Non-AA208 (20.8)790 (79.2) 
Age, y  .7950
 ≤6096 (19.4)398 (80.6) 
 60–6554 (19.2)227 (80.8) 
 >6566 (17.7)307 (82.3) 
DxPSA  .0960
 ≤459 (22.8)200 (77.2) 
 4.01–10158 (18.1)713 (81.9) 
Clinical T-classification  .8430
 T1C180 (19.4)749 (80.6) 
 T244 (18.8)190 (81.2) 
BxGS  .1200
 <7179 (20.5)695 (79.5) 
 735 (15.1)197 (84.9) 
 >79 (14.8)52 (85.2) 
Prostate weight, grams  .0340
 ≤3587 (19.5)360 (80.5) 
 35–4545 (14.4)268 (85.6) 
 >4587 (22.0)308 (78.0) 
PTI  <.0005
 ≤5164 (33.2)330 (66.8) 
 5.01–1040 (13.3)261 (86.7) 
 10.01–159 (6.7)125 (93.3) 
 >1514 (5.5)241 (94.5) 
pT  .0500
 T2192 (20.3)754 (79.7) 
 T3A35 (14.7)203 (85.3) 
pGS  .0010
 <7138 (23.4)453 (76.6) 
 774 (14.3)444 (85.7) 
 >714 (21.2)52 (78.8) 
Margin  <.0005
 −191 (22.5)659 (77.5) 
 +36 (10.8)298 (89.2) 
ECE  .0670
 −192 (20.2)758 (79.8) 
 +35 (15.0)199 (85.0) 

Univariate analysis determined significant variables to be race, prostate weight, pT classification, PTI, pGS, and +SM (Table 2). However, only race, pGS, PTI, and SM were independent predictors on multivariate logistic regression (P ≤ .05; Table 3).

Table 3. Multivariate Analysis of Clinical and Pathologic Variables to Predict Tumor Unilaterality
VariableOdds ratio95% CIP
LowerUpper
  1. PTI indicates percentage of tumor involvement; pGS, pathologic Gleason Score; pT, pathologic stage.

Race0.420.240.75.0030
PTI   <.0005
PTI ≤ 50.130.070.24<.0005
PTI 5.01–100.420.220.80.0080
PTI 10.01–150.850.362.05.7250
PTI > 151.00 (control)   
pGS   .0500
pGS < 71.830.903.75.0970
pGS = 72.321.144.73.0210
pGS > 71.00 (control)   
pT1.380.872.19.1750
Margin Status0.560.370.86.0080

DISCUSSION

Focal therapy, or targeting malignant elements within an organ while sparing benign tissue, is an evolving concept for the treatment of localized PCa in select patients. The first hemiablation with contralateral nerve-sparing cryotherapy for biopsy-proven unilateral disease was described by Onik et al. in a pilot study of 9 patients.6 After a mean follow-up of 3 years, 7 patients remained in the study, and all had a stable PSA level and negative biopsies. In another study, Ohori et al.7 examined maps of nearly 1000 early stage PCa patients treated with radical prostatectomy in the PSA era to determine the frequency and characteristics of multifocal lesions. In patients with PSA levels <10 ng/mL treated with radical prostatectomy, only 18% of cancers were unifocal, but the largest focus of cancer represented a mean of 80% of the volume of all cancer present. In more than 90% of these patients, ECE, if present, arose from the largest focus. These data suggest that it may be reasonable to target therapy to a focus of cancer identified by systemic biopsy. If the largest focus of cancer could be eradicated, the tumor burden would be conceptually reduced by 80%, and the focus giving rise to ECE would be controlled in > 90% of patients.7 Although this study was mainly focused on volumetric characteristics of the largest focus that has a high likelihood of ECE, the authors did not report the Gleason differentiation of clinically significant versus nonsignificant tumors. In addition, the study by Ohori et al. did not segregate whether these unifocal cancers lateralized to 1 lobe of the prostate and would be conceptually treatable with hemiablation of the prostate.7

However, tumor unilaterality may play an even more significant role for more liberal treatment of 1 lobe than targeted ablation of a single focus of cancer, because the functionally intact contralateral lobe may provide these patients sufficient quality of life. Recently, Masson et al. presented 5-year outcomes of 20 patients who underwent focal cryoablation for unifocal PCa based on a minimal biopsy of 12-cores.8 At a median follow-up of 1 month to 3 months, 95% of patients returned to their baseline genitourinary function and potency. Clearly, long-term oncologic treatment efficacy will need to be determined before these approaches become standard.

Based on the natural history of PCa and autopsy series, there was a 25% prevalence of incidental, clinically unsuspected PCa with half of these designated as focal and low-grade cancers.9 The converse viewpoint is the highly heterogeneous nature of PCa.10 For example, Boccon-Gibod et al. showed that 70% of patients had multifocal microscopic cancers separate from the index tumor.11 The presence of Gleason grade 4 disease was missed by the biopsy in 50% of the cases; however, the primary grade was correctly evaluated in greater than 70% of the biopsy sets. Forty-two percent of the patients had a cancer volume <0.5 mL and 29% met the definition of insignificant and/or unimportant cancer characterized by a well-differentiated tumor (Gleason score ≤6) of low volume (<0.5 mL); however, no feature was accurately predictive of insignificant cancer.11 The use of saturation prostate biopsies (up to 24 cores) under 3-dimensional transrectal ultrasonography guidance (TRUS), computerized tomography (CT) or magnetic resonance imaging (MRI) may, with higher likelihood, delineate unilateral versus bilateral and/or monofocal versus multifocal PCa.12, 13, 14

To our knowledge, our data is the first to show that focal therapy in the form of hemiablation of the prostate may potentially be a treatment option in 1 of 5 men with clinically localized disease who would otherwise have chosen surgery. Furthermore, these results demonstrate that among those with unilateral PCa, the majority (93.4%) have Gleason score ≤7 tumors (Fig. 1). These unilaterally positioned tumors may conceivably be eradicated by novel, focal-ablative therapies. Of course, careful surveillance of both the treated and untreated sides of the prostate would be prudent, and this may require additional biopsies, serum studies, or imaging tests. To our knowledge, the distribution of Gleason scores in unilateral tumors has not been previously reported in the literature; however 1 report described the overall frequency of tumors with a Gleason score <7 among small-volume PCa (<0.5 mL) as approximately 84%.5 In the present study, non-African-American men tended to have an increased prevalence of unilateral tumors compared with African-American men at 20.8% versus 9.2%, respectively (Table 2). With an increase in tumor volume, the number of potential candidates for unilateral tumor ablation progressively decreased, eg, from 164 (33.2% of all unilateral cases with PTI of ≤5) patients to 14 (5.5% of all unilateral cases with PTI >15) patients. To increase the certainty that a tumor(s) is unilateral, a multicore prostate biopsy should be done to reduce the likelihood of a tumor focus being present in the contralateral lobe. Imaging modalities capable of detecting PCa within the prostate gland are still being developed.

A few limitations of this study deserve mention. First, the study was performed in a single institution with medical, geographic, and environmental features attributable to the Southeastern region. Second, this study was retrospective and based on pathologic assessment of prostatectomy specimens to define the frequency of unilateral PCa tumors in an effort to determine what percentage of patients undergoing surgery could potentially have been candidates for unilateral ablation of the prostate. We acknowledge that the denominator of potential candidates for unilateral ablation is likely larger when one takes into account patients electing other forms of therapy such as radiation, or those with low risk disease who are undergoing active surveillance. Nevertheless, we believe the large sample size of pathologically verified specimens allows us to estimate the prevalence of unilateral disease.

Conclusions

This study suggests that 1 in 5 men diagnosed with clinically localized PCa who would otherwise have selected surgical treatment have small-volume, completely unilateral cancers that would be amenable to focal-ablation therapy targeting 1 lobe of the prostate. Further study is needed to develop predictive models for those patients likely to have small, unilateral cancers amenable to focal therapy.

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