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Appropriate Candidates for Hemiablative Focal Therapy Are Infrequently Encountered Among Men Selected for Radical Prostatectomy in Contemporary Cohort
Oncology Appropriate Candidates for Hemiablative Focal Therapy Are Infrequently Encountered Among Men Selected for Radical Prostatectomy in Contemporary Cohort Basir Tareen, Alex Sankin, Guilherme Godoy, Steve Temkin, Herbert Lepor, and Samir S. Taneja OBJECTIVES
METHODS
RESULTS
CONCLUSIONS
To assess the prevalence and pathologic features of men with unilateral prostate cancer at radical prostatectomy (RP), because it has recently been proposed that men with small-volume, well-differentiated, unilateral prostate cancer can be treated with focal therapy. The records of 1467 consecutive men who underwent open RP by a single surgeon from January 2000 to June 2007 were reviewed after institutional review board approval. The RP pathologic reports were analyzed to determine the frequency of unilateral or bilateral disease, surgical margin status, presence of extracapsular extension, seminal vesicle invasion, Gleason score, percentage of tumor involvement (PTI), prostate-specific antigen (PSA) level, and prostate volume. Logistic regression analysis was performed to analyze the relationship between these factors and the detection of unilateral disease. Unilateral cancer was identified in 313 of 1467 patients (21.3%). Of these patients, 206 had a PTI of ⱕ5%, 40 had a PTI of 5%-10%, 8 had a PTI of 10%-15%, and 40 had a PTI ⬎15%. The factors significantly associated with unilateral disease on univariate analysis were PTI, PSA level, pathologic Gleason score, seminal vesicle invasion, and extracapsular extension. The PSA level and seminal vesicle invasion remained significant predictors on multivariate analysis. Overall, 163 men (11.1%) had unilateral, low-risk disease (defined as a PSA level ⬍10 ng/mL, Gleason score ⬍7, and PTI ⬍10%). Although candidates for focal therapy exist among men undergoing RP within a contemporary cohort, they represent a small minority. Before proceeding with focal therapy, the urology community must identify accurate methods of candidate selection. UROLOGY 73: 351–354, 2009. © 2009 Published by Elsevier Inc.
W
ithin the prostate-specific antigen (PSA) era, we have seen a progressive downward shift in staging. Radical prostatectomy (RP) remains the reference standard for treating localized disease in favorable risk candidates. Despite improvements in open and laparoscopic nerve-sparing techniques, potency after RP remains a legitimate concern, with most high-volume centers reporting rates of recovery of 60%-80% in experienced hands.1,2 The potency rates have been reported
B. Tareen and G. Godoy received the Bruce and Cynthia Sherman Fellowship in Urologic Oncology. From the Division of Urologic Oncology, Department of Urology, New York University Medical Center, New York, New York Reprint requests: Samir S. Taneja, M.D., Division of Urologic Oncology, Department of Urology, New York University Medical Center, 150 East 32nd Street, Suite 200, New York, NY 10016. E-mail: [email protected] Submitted: April 25, 2008, accepted (with revisions): August 5, 2008
© 2009 Published by Elsevier Inc.
to be considerably lower in the community setting, with some as low as 18%.3 Although stage migration has led to greater consideration of active surveillance, this has been slow to gain acceptance in the United States. An analysis of ⬎5300 men from the Cancer of the Prostate Strategic Urologic Research Endeavor national prostate cancer registry showed that only 7% chose active surveillance as their initial option.4 A well-defined protocol for active surveillance is still lacking, and reliable endpoints for intervention are still unknown. Focal therapy has been proposed as a method of minimizing the morbidity of whole gland treatment while still treating the cancer. Although no consensus has been reached on candidate selection, the use of focal therapy has been proposed as particularly ideal for patients with low-risk features.5-9 High-intensity focused ultrasound, cryotherapy, radiofrequency ablation, and photodynamic 0090-4295/09/$34.00 doi:10.1016/j.urology.2008.08.504
351
therapy have all emerged as potential modalities for focal treatment.10 We have considered that focal therapy could include subtotal gland ablation, hemiablative therapy (HAT), or lesion ablative therapy. The challenge in pursuing any of these focal therapy modalities lies in appropriately selecting the ideal candidates by defining the disease site and extent. Because HAT might be the most feasible form of focal therapy, given contemporary technology, we undertook this study to determine the prevalence of appropriate candidates for HAT in a contemporary RP cohort.
MATERIAL AND METHODS The records of 1467 consecutive men undergoing open RP by a single surgeon from January 2000 to June 2007 were reviewed after approval from the institutional review board. The data for all these men had previously been entered into a prospective database capturing the pre- and postoperative data. The RP pathologic reports were analyzed to determine the frequency of unilateral or bilateral disease, surgical margin status, presence of extracapsular extension and seminal vesicle invasion, Gleason score, percentage of tumor involvement (PTI), PSA level, and prostate volume. After defining low-risk disease as a PSA level of ⬍10 ng/mL, Gleason score ⬍7, and PTI ⬍10%, we further stratified the group of men with unilateral disease to isolate those with low-risk features. Logistic regression models were constructed for univariate and multivariate analyses to identify significant relationships between these factors and unilateral disease on the final RP specimen. Prostate volume and PSA level were entered into the models as continuous variables; surgical margin status, extracapsular extension, and seminal vesicle invasion were treated as dichotomous variables; and Gleason score and PTI were treated as categorical variables. All statistical analyses were performed using SPSS, version 10 (SPSS, Chicago, IL), with significance defined as P ⬍ .05.
RESULTS The mean patient age was 58.7 years (range 37-77), and the mean preoperative PSA level was 6.53 ng/dL (range 0.18-70). A total of 1069 patients (84.4%) had Stage T1c disease. Overall, unilateral cancer was identified in 313 of 1467 surgical specimens (21.2%). Detailed baseline patient clinical information is presented in Table 1. Of the men with unilateral disease, 206 had a PTI of ⱕ5%, 40 had a PTI of 5%-10%, 8 had a PTI of 10%15%, and 40 had a PTI of ⬎15%. When evaluating PTI as a variable predictive of unilateral cancer in 5% increments of disease volume, an inverse association was found between PTI and unilateral cancer on univariate analysis (P ⫽ .001). Of the men with unilateral disease, 38 (12.1%) also had extracapsular extension. Only 163 men (11.1%) were found to have low-risk unilateral cancer, with a serum PSA level of ⬍10, Gleason score ⬍7, and PTI ⬍10%. Of these men, only 2 (1.2%) had extracapsular extension on final pathologic examination. 352
Table 1. Patient demographics and tumor characteristics Parameter
Patients (n)
Tumor laterality (n ⫽ 1467) Unilateral Bilateral Clinical stage (n ⫽ 1266) T1c T2 Pathologic Gleason score (n ⫽ 1421) ⬍7 7 ⬎7 Tumor involvement (%) (n ⫽ 1385) ⬍5 5.01-10 10.01-15 ⬎15 Margin status (n ⫽ 1434) Negative Positive ECE (n ⫽ 1423) None Unilateral Bilateral
311 (21.2) 1156 (78.8) 1069 (84.4) 197 (15.5) 737 (51.8) 610 (42.9) 74 (5.2) 614 (44.3) 291 (21) 55 (3.9) 425 (30.6) 1274 (88.8) 160 (11.1) 1154 (81.1) 217 (15.2) 52 (3.6)
ECE, extracapsular extension. Data in parentheses are percentages.
Table 2. Prediction of unilateral disease by univariate logistic regression analysis Parameter PSA Prostate volume PTI ⱕ5% Gleason score ⱕ6 SVI ECE Positive margins
OR
95% CI
P Value
0.945 1.003 1.558 1.485 0.239 0.576 0.853
0.912-0.979 0.997-1.008 1.201-2.019 1.148-1.921 0.096-0.597 0.400-0.828 0.487-1.495
.002 .344 .001 .003 .002 .003 .578
OR, odds ratio; CI, confidence interval; PSA, prostate-specific antigen; PTI, percentage of tumor involvement; SVI, seminal vesicle invasion; ECE, extracapsular extension.
On univariate analysis, all pathologic factors, except for prostate volume and positive surgical margins, were predictive of the likelihood of unilateral cancer (Table 2). A lower pathologic Gleason score predicted for an increased likelihood of unilateral disease (odds ratio 1.485; 95% confidence interval 1.148-1.921; P ⫽ .003). The presence of extracapsular extension correlated negatively with the likelihood of unilateral cancer (odds ratio 0.576, 95% confidence interval 0.400-0.828, P ⫽ .003). Surgical margin status was not associated with unilateral disease (P ⫽ .578). On multivariate analysis, correcting for the effect of all factors combined, only seminal vesicle invasion (P ⫽ .018) and serum PSA level (P ⫽ .027) remained as independent predictors of the likelihood of unilateral prostate cancer (Table 3).
COMMENT Focal therapy represents a potential compromise between active surveillance and radical therapy, offering a middle UROLOGY 73 (2), 2009
Table 3. Prediction of unilateral disease by multivariate logistic regression analysis Parameter PSA Prostate volume PTI ⱕ5% Gleason score ⱕ6 SVI ECE Positive margins*
OR
95% CI
P Value
0.957 1.004 1.291 1.173 0.239 0.727 —
0.920-0.995 0.998-1.011 0.975-1.710 0.884-1.555 0.073-0.782 0.487-1.087 —
.027 .198 .075 .269 .018 .120 —
Abbreviations as in Table 2. * Not included in model because numerous missing values.
ground between the anxiety and uncertainty of expectant management and avoiding the urinary and sexual side effects of whole gland treatment. Although focal therapy is still considered investigational, numerous investigators have reported the early results with HAT in men diagnosed with early-stage organ-confined unilateral prostate cancer. Onik et al.,8 in 2002, first reported hemi-cryoablation of unilateral prostate cancer in 9 patients. Recently, in an updated series of 55 men with ⱖ12 months of follow-up and a mean follow-up of 3.6 years, they reported a 95% PSA progression-free rate using the American Society for Therapeutic Radiology and Oncology criteria. Of these men, 86% retained potency after treatment.6 Bahn et al.11 reported a similar experience with HAT for suspected unilateral prostate cancer in 31 men. They reported a biochemical disease-free survival rate of 92.8% at a mean follow-up of 70 months using the American Society for Therapeutic Radiology and Oncology criteria, with potency preservation in 88% of the men.11 The greatest challenge in implementing focal therapy in clinical practice remains candidate selection. The criteria for candidate selection will be determined by the treatment approach. If HAT is planned, the selection of men with true unilateral prostate cancer is most desirable. Mouraviev et al.12 proposed that approximately 1 in 5 men who undergo RP would be a candidate for focal therapy according to the final surgical pathologic findings. This was based on the assumption that all men with unilateral disease will have a favorable disease outcome, a low likelihood of extraprostatic disease, and a small likelihood of contralateral recurrence. The additional assumption was made that if cancer were to eventually develop on the contralateral “normal” side, it would either be insignificant or, assuming adequate follow-up, could be eradicated at a future point, if necessary. It has previously been suggested that disease biology and clinical outcome are best predicted by the dominant focus of the disease rather than the total focality.13 Wise et al.13 evaluated 486 prostatectomy specimens by 3-mm step sections and found multifocal disease in 83% of the patients. In addition to the dominant focus, a mean of 2.9 additional cancers were observed, with a mean collective volume of only 0.63 cm2. The group found that progresUROLOGY 73 (2), 2009
sion-free survival was associated with the index cancer volume but not with that of the secondary tumor foci. The high incidence of multifocality on serial step section has demonstrated the very low incidence of true unilateral disease, but, more importantly, suggests that HAT could be performed in men with a unilateral dominant focus of tumor and minimal disease on the contralateral side. Bahn et al.11 made similar conclusions regarding index tumors. They evaluated 1832 whole mount RP specimens and found that in those men with multifocal disease, 80% of the total tumor burden was from the dominant index tumor. In those with extracapsular extension, 92% arose from the dominant cancer focus. It remains unclear whether one can predict the laterality of the index tumor, and whether such tumors could be effectively treated by focal ablation. It has been proposed that the tumor volume is the single most important factor in predicting cancer progression.14,15 Villamon-Fort et al.16 recently showed that the percentage of cancer and risk of biochemical failure were also significant when evaluating information from the prostate biopsy. This relationship has also been demonstrated when evaluating the clinical characteristics and tumor volume. Master et al.17 found that men with a lower PSA level, lower percentage of positive cores, and lower Gleason score had a smaller mean tumor volume. Because of the relationship between tumor volume and prognostic outcome, we questioned whether a large focus of unilateral disease would truly be ideal for HAT. An ideal candidate for focal therapy should be one with low-risk disease features and a low risk of extraprostatic extension. Although, similar to the findings of Mouraviev et al.,12 21% of our patients were found to have unilateral disease, not all of these men could truly be considered low risk; 12.1% were found to have extracapsular disease at surgery. We selected as low risk those men with a PSA level ⬍10 ng/mL, Gleason score ⬍7, and PTI ⬍10%. We found that only one half of the patients with unilateral disease could be included in this more selective low-risk group (11.1% of total). Only 2 of these men (1.2%) had extracapsular disease at the final pathologic examination. Although it is not known whether extracapsular disease could be adequately treated by focal approaches, it would seem that men with organ-confined disease are ideal candidates, given that the fundamental premise of focal therapy is disease treatment with minimal damage to the periprostatic structures. We are not aware of any data suggesting that focal ablative treatments are effective in men with Stage T3 disease. It was not the intent of this study to define the selection criteria for focal therapy. The parameters on which we stratified the likelihood of unilateral disease were postoperative parameters that would not be available at the prostate cancer diagnosis. It does appear, however, that in selecting patients for focal therapy, if unilateral ablation is the intent 353
of therapy, it would be most appropriate to select individuals with low-risk disease features.18,19 Prostate cancer has traditionally been considered a multifocal disease.20 Pathologic studies of even smallvolume, low-risk disease have demonstrated a high likelihood of multifocality and bilateral gland involvement.21 One limitation of our study was that we did not prospectively capture the size and location of the individual tumor foci. Because of the retrospective nature of our study, and the absence of baseline mapping data on pathologic evaluation, we could not determine how many men had a single dominant lesion and a contralateral minimal volume or “insignificant” disease. These men could certainly represent a suitable cohort for focal approaches, particularly HAT or subtotal gland ablation. If such patients were included, the number of candidates appropriate for focal therapy might be substantially greater than our data have suggested. Using our data alone, we could not determine whether focal therapy is appropriate for men with bilateral disease. Future studies to address this are warranted. Because our study evaluated men who chose RP as a treatment modality, our cohort might have included some men with higher risk parameters than would be selected for focal therapy. Nonetheless, given that men with locally advanced disease or very high risk disease are usually excluded from the selection for RP, it would seem that the fraction of those diagnosed with prostate cancer who have true unilateral disease would be small and that most men who undergo RP for localized disease would be suitable candidates for focal therapy as determined by the clinical information.
CONCLUSIONS We found that although 21.1% of men undergoing RP had unilateral disease, only 11.1% had true low-risk unilateral prostate cancer. Although candidates for focal therapy exist among men undergoing RP within a contemporary cohort, they appear to represent a small minority. Before proceeding with focal therapy as a standard of care within the treatment armamentarium, the urologic community must identify accurate and reproducible methods of identifying men with true low-risk disease, small-volume disease.
5. Eggener SE, Scardino PT, Carroll PR, et al. Focal therapy for localized prostate cancer: a critical appraisal of rationale and modalities. J Urol. 2007;178:2260-2267. 6. Onik G, Vaughan D, Lotenfoe R, et al. “Male lumpectomy”: focal therapy for prostate cancer using cryoablation. Urology. 2007;70: 16-21. 7. Jones JS. Focal or subtotal therapy for early stage prostate cancer. Curr Treat Options Oncol. 2007;8:165-172. 8. Onik G, Narayan P, Vaughan D, et al. Focal “nerve-sparing” cryosurgery for treatment of primary prostate cancer: a new approach to preserving potency. Urology. 2002;60:109-114. 9. Lambert EH, Bolte K, Masson P, et al. Focal cryosurgery: encouraging health outcomes for unifocal prostate cancer. Urology. 2007; 69:1117-1120. 10. Bahn DK, Silverman P, Lee F Sr, et al. Focal prostate cryoablation: initial results show cancer control and potency preservation. J Endourol. 2006;20:688-692. 11. Bahn DK, Lee F, Badalament R, et al. Targeted cryoablation of the prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology. 2002;60:3-11. 12. Mouraviev V, Mayes JM, Sun L, et al. Prostate cancer laterality as a rationale of focal ablative therapy for the treatment of clinically localized prostate cancer. Cancer. 2007;110:906-910. 13. Wise AM, Stamey TA, McNeal JE, et al. Morphologic and clinical significance of multifocal prostate cancers in radical prostatectomy specimens. Urology. 2002;60:264-269. 14. Stamey TA, McNeal JE, Freiha FS, et al. Morphometric and clinical studies on 68 consecutive radical prostatectomies. J Urol. 1988;139:1235-1241. 15. Bostwick DG, Graham SD Jr, Napalkov P, et al. Staging of early prostate cancer: a proposed tumor volume-based prognostic index. Urology. 1993;41:403-411. 16. Villamon-Fort R, Martinez-Jabaloyas JM, Soriano-Sarria P, et al. Percentage of cancer in prostate biopsies as prognostic factor for staging and postoperative biochemical failure after radical prostatectomy. Urol Int. 2007;78:328-333. 17. Master VA, Chi T, Simko JP, et al. The independent impact of extended pattern biopsy on prostate cancer stage migration. J Urol. 2005;174:1789-1793. 18. Sofer M, Savoie M, Kim SS, et al. Biochemical and pathological predictors of the recurrence of prostatic adenocarcinoma with seminal vesicle invasion. J Urol. 2003;169:153-156. 19. Pelzer AE, Colleselli D, Bektic J, et al. Pathological features of Gleason score 6 prostate cancers in the low and intermediate range of prostate-specific antigen level: is there a difference? BJU Int. 2008;101:822-825. 20. Epstein JI, Carmichael MJ, Partin AW, et al. Small high grade adenocarcinoma of the prostate in radical prostatectomy specimens performed for nonpalpable disease: pathogenetic and clinical implications. J Urol. 1994;151:1587-1592. 21. Cheng L, Jones TD, Pan CX, et al. Anatomic distribution and pathologic characterization of small-volume prostate cancer (⬍0.5 ml) in whole-mount prostatectomy specimens. Mod Pathol. 2005;18:10221026.
References 1. Catalona WJ, Basler JW. Return of erections and urinary continence following nerve sparing radical retropubic prostatectomy. J Urol. 1993;150:905-907. 2. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention 1982. J Urol. 2002;167:10051010. 3. Talcott JA, Rieker P, Propert KJ, et al. Patient-reported impotence and incontinence after nerve-sparing radical prostatectomy. J Natl Cancer Inst. 1997;89:1117-1123. 4. Harlan SR, Cooperberg MR, Elkin EP, et al. Time trends and characteristics of men choosing watchful waiting for initial treatment of localized prostate cancer: results from CaPSURE. J Urol. 2003;170:1804-1807.
354
EDITORIAL COMMENT The study by Taneja et al. examines in a contemporary cohort of men undergoing radical prostatectomy the likelihood of the presence of unilateral disease as a surrogate marker for the incidence of men suitable for focal therapy. They found that only 21.3% had unilateral cancer, concluding that only a small minority of men would be candidates for focal therapy. What is not provided are detailed characteristics of these men’s tumor on biopsy and the tumor volume and grade of the bilateral tumor. Candidates for focal therapy should have unilateral cancer on biopsy that is not high grade and not high volume. UROLOGY 73 (2), 2009
METHODS
RESULTS
CONCLUSIONS
To assess the prevalence and pathologic features of men with unilateral prostate cancer at radical prostatectomy (RP), because it has recently been proposed that men with small-volume, well-differentiated, unilateral prostate cancer can be treated with focal therapy. The records of 1467 consecutive men who underwent open RP by a single surgeon from January 2000 to June 2007 were reviewed after institutional review board approval. The RP pathologic reports were analyzed to determine the frequency of unilateral or bilateral disease, surgical margin status, presence of extracapsular extension, seminal vesicle invasion, Gleason score, percentage of tumor involvement (PTI), prostate-specific antigen (PSA) level, and prostate volume. Logistic regression analysis was performed to analyze the relationship between these factors and the detection of unilateral disease. Unilateral cancer was identified in 313 of 1467 patients (21.3%). Of these patients, 206 had a PTI of ⱕ5%, 40 had a PTI of 5%-10%, 8 had a PTI of 10%-15%, and 40 had a PTI ⬎15%. The factors significantly associated with unilateral disease on univariate analysis were PTI, PSA level, pathologic Gleason score, seminal vesicle invasion, and extracapsular extension. The PSA level and seminal vesicle invasion remained significant predictors on multivariate analysis. Overall, 163 men (11.1%) had unilateral, low-risk disease (defined as a PSA level ⬍10 ng/mL, Gleason score ⬍7, and PTI ⬍10%). Although candidates for focal therapy exist among men undergoing RP within a contemporary cohort, they represent a small minority. Before proceeding with focal therapy, the urology community must identify accurate methods of candidate selection. UROLOGY 73: 351–354, 2009. © 2009 Published by Elsevier Inc.
W
ithin the prostate-specific antigen (PSA) era, we have seen a progressive downward shift in staging. Radical prostatectomy (RP) remains the reference standard for treating localized disease in favorable risk candidates. Despite improvements in open and laparoscopic nerve-sparing techniques, potency after RP remains a legitimate concern, with most high-volume centers reporting rates of recovery of 60%-80% in experienced hands.1,2 The potency rates have been reported
B. Tareen and G. Godoy received the Bruce and Cynthia Sherman Fellowship in Urologic Oncology. From the Division of Urologic Oncology, Department of Urology, New York University Medical Center, New York, New York Reprint requests: Samir S. Taneja, M.D., Division of Urologic Oncology, Department of Urology, New York University Medical Center, 150 East 32nd Street, Suite 200, New York, NY 10016. E-mail: [email protected] Submitted: April 25, 2008, accepted (with revisions): August 5, 2008
© 2009 Published by Elsevier Inc.
to be considerably lower in the community setting, with some as low as 18%.3 Although stage migration has led to greater consideration of active surveillance, this has been slow to gain acceptance in the United States. An analysis of ⬎5300 men from the Cancer of the Prostate Strategic Urologic Research Endeavor national prostate cancer registry showed that only 7% chose active surveillance as their initial option.4 A well-defined protocol for active surveillance is still lacking, and reliable endpoints for intervention are still unknown. Focal therapy has been proposed as a method of minimizing the morbidity of whole gland treatment while still treating the cancer. Although no consensus has been reached on candidate selection, the use of focal therapy has been proposed as particularly ideal for patients with low-risk features.5-9 High-intensity focused ultrasound, cryotherapy, radiofrequency ablation, and photodynamic 0090-4295/09/$34.00 doi:10.1016/j.urology.2008.08.504
351
therapy have all emerged as potential modalities for focal treatment.10 We have considered that focal therapy could include subtotal gland ablation, hemiablative therapy (HAT), or lesion ablative therapy. The challenge in pursuing any of these focal therapy modalities lies in appropriately selecting the ideal candidates by defining the disease site and extent. Because HAT might be the most feasible form of focal therapy, given contemporary technology, we undertook this study to determine the prevalence of appropriate candidates for HAT in a contemporary RP cohort.
MATERIAL AND METHODS The records of 1467 consecutive men undergoing open RP by a single surgeon from January 2000 to June 2007 were reviewed after approval from the institutional review board. The data for all these men had previously been entered into a prospective database capturing the pre- and postoperative data. The RP pathologic reports were analyzed to determine the frequency of unilateral or bilateral disease, surgical margin status, presence of extracapsular extension and seminal vesicle invasion, Gleason score, percentage of tumor involvement (PTI), PSA level, and prostate volume. After defining low-risk disease as a PSA level of ⬍10 ng/mL, Gleason score ⬍7, and PTI ⬍10%, we further stratified the group of men with unilateral disease to isolate those with low-risk features. Logistic regression models were constructed for univariate and multivariate analyses to identify significant relationships between these factors and unilateral disease on the final RP specimen. Prostate volume and PSA level were entered into the models as continuous variables; surgical margin status, extracapsular extension, and seminal vesicle invasion were treated as dichotomous variables; and Gleason score and PTI were treated as categorical variables. All statistical analyses were performed using SPSS, version 10 (SPSS, Chicago, IL), with significance defined as P ⬍ .05.
RESULTS The mean patient age was 58.7 years (range 37-77), and the mean preoperative PSA level was 6.53 ng/dL (range 0.18-70). A total of 1069 patients (84.4%) had Stage T1c disease. Overall, unilateral cancer was identified in 313 of 1467 surgical specimens (21.2%). Detailed baseline patient clinical information is presented in Table 1. Of the men with unilateral disease, 206 had a PTI of ⱕ5%, 40 had a PTI of 5%-10%, 8 had a PTI of 10%15%, and 40 had a PTI of ⬎15%. When evaluating PTI as a variable predictive of unilateral cancer in 5% increments of disease volume, an inverse association was found between PTI and unilateral cancer on univariate analysis (P ⫽ .001). Of the men with unilateral disease, 38 (12.1%) also had extracapsular extension. Only 163 men (11.1%) were found to have low-risk unilateral cancer, with a serum PSA level of ⬍10, Gleason score ⬍7, and PTI ⬍10%. Of these men, only 2 (1.2%) had extracapsular extension on final pathologic examination. 352
Table 1. Patient demographics and tumor characteristics Parameter
Patients (n)
Tumor laterality (n ⫽ 1467) Unilateral Bilateral Clinical stage (n ⫽ 1266) T1c T2 Pathologic Gleason score (n ⫽ 1421) ⬍7 7 ⬎7 Tumor involvement (%) (n ⫽ 1385) ⬍5 5.01-10 10.01-15 ⬎15 Margin status (n ⫽ 1434) Negative Positive ECE (n ⫽ 1423) None Unilateral Bilateral
311 (21.2) 1156 (78.8) 1069 (84.4) 197 (15.5) 737 (51.8) 610 (42.9) 74 (5.2) 614 (44.3) 291 (21) 55 (3.9) 425 (30.6) 1274 (88.8) 160 (11.1) 1154 (81.1) 217 (15.2) 52 (3.6)
ECE, extracapsular extension. Data in parentheses are percentages.
Table 2. Prediction of unilateral disease by univariate logistic regression analysis Parameter PSA Prostate volume PTI ⱕ5% Gleason score ⱕ6 SVI ECE Positive margins
OR
95% CI
P Value
0.945 1.003 1.558 1.485 0.239 0.576 0.853
0.912-0.979 0.997-1.008 1.201-2.019 1.148-1.921 0.096-0.597 0.400-0.828 0.487-1.495
.002 .344 .001 .003 .002 .003 .578
OR, odds ratio; CI, confidence interval; PSA, prostate-specific antigen; PTI, percentage of tumor involvement; SVI, seminal vesicle invasion; ECE, extracapsular extension.
On univariate analysis, all pathologic factors, except for prostate volume and positive surgical margins, were predictive of the likelihood of unilateral cancer (Table 2). A lower pathologic Gleason score predicted for an increased likelihood of unilateral disease (odds ratio 1.485; 95% confidence interval 1.148-1.921; P ⫽ .003). The presence of extracapsular extension correlated negatively with the likelihood of unilateral cancer (odds ratio 0.576, 95% confidence interval 0.400-0.828, P ⫽ .003). Surgical margin status was not associated with unilateral disease (P ⫽ .578). On multivariate analysis, correcting for the effect of all factors combined, only seminal vesicle invasion (P ⫽ .018) and serum PSA level (P ⫽ .027) remained as independent predictors of the likelihood of unilateral prostate cancer (Table 3).
COMMENT Focal therapy represents a potential compromise between active surveillance and radical therapy, offering a middle UROLOGY 73 (2), 2009
Table 3. Prediction of unilateral disease by multivariate logistic regression analysis Parameter PSA Prostate volume PTI ⱕ5% Gleason score ⱕ6 SVI ECE Positive margins*
OR
95% CI
P Value
0.957 1.004 1.291 1.173 0.239 0.727 —
0.920-0.995 0.998-1.011 0.975-1.710 0.884-1.555 0.073-0.782 0.487-1.087 —
.027 .198 .075 .269 .018 .120 —
Abbreviations as in Table 2. * Not included in model because numerous missing values.
ground between the anxiety and uncertainty of expectant management and avoiding the urinary and sexual side effects of whole gland treatment. Although focal therapy is still considered investigational, numerous investigators have reported the early results with HAT in men diagnosed with early-stage organ-confined unilateral prostate cancer. Onik et al.,8 in 2002, first reported hemi-cryoablation of unilateral prostate cancer in 9 patients. Recently, in an updated series of 55 men with ⱖ12 months of follow-up and a mean follow-up of 3.6 years, they reported a 95% PSA progression-free rate using the American Society for Therapeutic Radiology and Oncology criteria. Of these men, 86% retained potency after treatment.6 Bahn et al.11 reported a similar experience with HAT for suspected unilateral prostate cancer in 31 men. They reported a biochemical disease-free survival rate of 92.8% at a mean follow-up of 70 months using the American Society for Therapeutic Radiology and Oncology criteria, with potency preservation in 88% of the men.11 The greatest challenge in implementing focal therapy in clinical practice remains candidate selection. The criteria for candidate selection will be determined by the treatment approach. If HAT is planned, the selection of men with true unilateral prostate cancer is most desirable. Mouraviev et al.12 proposed that approximately 1 in 5 men who undergo RP would be a candidate for focal therapy according to the final surgical pathologic findings. This was based on the assumption that all men with unilateral disease will have a favorable disease outcome, a low likelihood of extraprostatic disease, and a small likelihood of contralateral recurrence. The additional assumption was made that if cancer were to eventually develop on the contralateral “normal” side, it would either be insignificant or, assuming adequate follow-up, could be eradicated at a future point, if necessary. It has previously been suggested that disease biology and clinical outcome are best predicted by the dominant focus of the disease rather than the total focality.13 Wise et al.13 evaluated 486 prostatectomy specimens by 3-mm step sections and found multifocal disease in 83% of the patients. In addition to the dominant focus, a mean of 2.9 additional cancers were observed, with a mean collective volume of only 0.63 cm2. The group found that progresUROLOGY 73 (2), 2009
sion-free survival was associated with the index cancer volume but not with that of the secondary tumor foci. The high incidence of multifocality on serial step section has demonstrated the very low incidence of true unilateral disease, but, more importantly, suggests that HAT could be performed in men with a unilateral dominant focus of tumor and minimal disease on the contralateral side. Bahn et al.11 made similar conclusions regarding index tumors. They evaluated 1832 whole mount RP specimens and found that in those men with multifocal disease, 80% of the total tumor burden was from the dominant index tumor. In those with extracapsular extension, 92% arose from the dominant cancer focus. It remains unclear whether one can predict the laterality of the index tumor, and whether such tumors could be effectively treated by focal ablation. It has been proposed that the tumor volume is the single most important factor in predicting cancer progression.14,15 Villamon-Fort et al.16 recently showed that the percentage of cancer and risk of biochemical failure were also significant when evaluating information from the prostate biopsy. This relationship has also been demonstrated when evaluating the clinical characteristics and tumor volume. Master et al.17 found that men with a lower PSA level, lower percentage of positive cores, and lower Gleason score had a smaller mean tumor volume. Because of the relationship between tumor volume and prognostic outcome, we questioned whether a large focus of unilateral disease would truly be ideal for HAT. An ideal candidate for focal therapy should be one with low-risk disease features and a low risk of extraprostatic extension. Although, similar to the findings of Mouraviev et al.,12 21% of our patients were found to have unilateral disease, not all of these men could truly be considered low risk; 12.1% were found to have extracapsular disease at surgery. We selected as low risk those men with a PSA level ⬍10 ng/mL, Gleason score ⬍7, and PTI ⬍10%. We found that only one half of the patients with unilateral disease could be included in this more selective low-risk group (11.1% of total). Only 2 of these men (1.2%) had extracapsular disease at the final pathologic examination. Although it is not known whether extracapsular disease could be adequately treated by focal approaches, it would seem that men with organ-confined disease are ideal candidates, given that the fundamental premise of focal therapy is disease treatment with minimal damage to the periprostatic structures. We are not aware of any data suggesting that focal ablative treatments are effective in men with Stage T3 disease. It was not the intent of this study to define the selection criteria for focal therapy. The parameters on which we stratified the likelihood of unilateral disease were postoperative parameters that would not be available at the prostate cancer diagnosis. It does appear, however, that in selecting patients for focal therapy, if unilateral ablation is the intent 353
of therapy, it would be most appropriate to select individuals with low-risk disease features.18,19 Prostate cancer has traditionally been considered a multifocal disease.20 Pathologic studies of even smallvolume, low-risk disease have demonstrated a high likelihood of multifocality and bilateral gland involvement.21 One limitation of our study was that we did not prospectively capture the size and location of the individual tumor foci. Because of the retrospective nature of our study, and the absence of baseline mapping data on pathologic evaluation, we could not determine how many men had a single dominant lesion and a contralateral minimal volume or “insignificant” disease. These men could certainly represent a suitable cohort for focal approaches, particularly HAT or subtotal gland ablation. If such patients were included, the number of candidates appropriate for focal therapy might be substantially greater than our data have suggested. Using our data alone, we could not determine whether focal therapy is appropriate for men with bilateral disease. Future studies to address this are warranted. Because our study evaluated men who chose RP as a treatment modality, our cohort might have included some men with higher risk parameters than would be selected for focal therapy. Nonetheless, given that men with locally advanced disease or very high risk disease are usually excluded from the selection for RP, it would seem that the fraction of those diagnosed with prostate cancer who have true unilateral disease would be small and that most men who undergo RP for localized disease would be suitable candidates for focal therapy as determined by the clinical information.
CONCLUSIONS We found that although 21.1% of men undergoing RP had unilateral disease, only 11.1% had true low-risk unilateral prostate cancer. Although candidates for focal therapy exist among men undergoing RP within a contemporary cohort, they appear to represent a small minority. Before proceeding with focal therapy as a standard of care within the treatment armamentarium, the urologic community must identify accurate and reproducible methods of identifying men with true low-risk disease, small-volume disease.
5. Eggener SE, Scardino PT, Carroll PR, et al. Focal therapy for localized prostate cancer: a critical appraisal of rationale and modalities. J Urol. 2007;178:2260-2267. 6. Onik G, Vaughan D, Lotenfoe R, et al. “Male lumpectomy”: focal therapy for prostate cancer using cryoablation. Urology. 2007;70: 16-21. 7. Jones JS. Focal or subtotal therapy for early stage prostate cancer. Curr Treat Options Oncol. 2007;8:165-172. 8. Onik G, Narayan P, Vaughan D, et al. Focal “nerve-sparing” cryosurgery for treatment of primary prostate cancer: a new approach to preserving potency. Urology. 2002;60:109-114. 9. Lambert EH, Bolte K, Masson P, et al. Focal cryosurgery: encouraging health outcomes for unifocal prostate cancer. Urology. 2007; 69:1117-1120. 10. Bahn DK, Silverman P, Lee F Sr, et al. Focal prostate cryoablation: initial results show cancer control and potency preservation. J Endourol. 2006;20:688-692. 11. Bahn DK, Lee F, Badalament R, et al. Targeted cryoablation of the prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology. 2002;60:3-11. 12. Mouraviev V, Mayes JM, Sun L, et al. Prostate cancer laterality as a rationale of focal ablative therapy for the treatment of clinically localized prostate cancer. Cancer. 2007;110:906-910. 13. Wise AM, Stamey TA, McNeal JE, et al. Morphologic and clinical significance of multifocal prostate cancers in radical prostatectomy specimens. Urology. 2002;60:264-269. 14. Stamey TA, McNeal JE, Freiha FS, et al. Morphometric and clinical studies on 68 consecutive radical prostatectomies. J Urol. 1988;139:1235-1241. 15. Bostwick DG, Graham SD Jr, Napalkov P, et al. Staging of early prostate cancer: a proposed tumor volume-based prognostic index. Urology. 1993;41:403-411. 16. Villamon-Fort R, Martinez-Jabaloyas JM, Soriano-Sarria P, et al. Percentage of cancer in prostate biopsies as prognostic factor for staging and postoperative biochemical failure after radical prostatectomy. Urol Int. 2007;78:328-333. 17. Master VA, Chi T, Simko JP, et al. The independent impact of extended pattern biopsy on prostate cancer stage migration. J Urol. 2005;174:1789-1793. 18. Sofer M, Savoie M, Kim SS, et al. Biochemical and pathological predictors of the recurrence of prostatic adenocarcinoma with seminal vesicle invasion. J Urol. 2003;169:153-156. 19. Pelzer AE, Colleselli D, Bektic J, et al. Pathological features of Gleason score 6 prostate cancers in the low and intermediate range of prostate-specific antigen level: is there a difference? BJU Int. 2008;101:822-825. 20. Epstein JI, Carmichael MJ, Partin AW, et al. Small high grade adenocarcinoma of the prostate in radical prostatectomy specimens performed for nonpalpable disease: pathogenetic and clinical implications. J Urol. 1994;151:1587-1592. 21. Cheng L, Jones TD, Pan CX, et al. Anatomic distribution and pathologic characterization of small-volume prostate cancer (⬍0.5 ml) in whole-mount prostatectomy specimens. Mod Pathol. 2005;18:10221026.
References 1. Catalona WJ, Basler JW. Return of erections and urinary continence following nerve sparing radical retropubic prostatectomy. J Urol. 1993;150:905-907. 2. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention 1982. J Urol. 2002;167:10051010. 3. Talcott JA, Rieker P, Propert KJ, et al. Patient-reported impotence and incontinence after nerve-sparing radical prostatectomy. J Natl Cancer Inst. 1997;89:1117-1123. 4. Harlan SR, Cooperberg MR, Elkin EP, et al. Time trends and characteristics of men choosing watchful waiting for initial treatment of localized prostate cancer: results from CaPSURE. J Urol. 2003;170:1804-1807.
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EDITORIAL COMMENT The study by Taneja et al. examines in a contemporary cohort of men undergoing radical prostatectomy the likelihood of the presence of unilateral disease as a surrogate marker for the incidence of men suitable for focal therapy. They found that only 21.3% had unilateral cancer, concluding that only a small minority of men would be candidates for focal therapy. What is not provided are detailed characteristics of these men’s tumor on biopsy and the tumor volume and grade of the bilateral tumor. Candidates for focal therapy should have unilateral cancer on biopsy that is not high grade and not high volume. UROLOGY 73 (2), 2009