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Expectant Management of Localized Prostate Cancer—Who, What, When, Where and How?
Expectant Management of Localized Prostate Cancer—Who, What, When, Where and How? MEN with localized prostate cancer face difficult decisions regarding the management of their disease due to a paucity of randomized trials comparing various treatments. In a 2008 review, “Comparative Effectiveness and Harms of Treatments for Clinically Localized Prostate Cancer” prepared for the AHRQ (Agency for Healthcare Research and Quality), the panel concluded that the “assessment of the comparative effectiveness and harms of localized prostate cancer treatments is difficult because of limitations in the evidence.”1 Concurrently United States health care reform focusing on the quality and increasing costs of medical care collided with 2 randomized controlled prospective studies on prostate cancer screening with conflicting results.2,3 Finally, despite a unified declaration by prostate cancer survivors and urologists, the USPSTF (U.S. Preventive Services Task Force) recommended against prostate specific antigen (PSA) based screening for prostate cancer in asymptomatic men regardless of age, and suggested that the harms of intervention were equal to or outweighed the benefits. It is clear that the greatest risk of screening is over detection of indolent disease and the greatest risks of over detection are the consequences of unnecessary treatment. Therefore, accompanying prostate cancer screening with a selective approach to treating localized prostate cancer with active surveillance offers an attractive management strategy to reduce the burden of overtreatment. Since the introduction of PSA screening, the lifetime risk of being diagnosed with prostate cancer has doubled from 8% to 17%.4 The sharp increase in the incidence of prostate cancer ushered an era of expanding treatment options for localized disease. Specifically it seems the adoption of new technology affects regional treatment decisions for early stage prostate cancer, inducing patients who would have otherwise opted for expectant management approaches to undergo surgery, even in the absence of evidence of superior clinical outcomes.5 The contentious USPSTF recommendations should refocus efforts in prostate cancer research to personalize management by improving risk stratification and enabling effective treatment allocation in which active surveil0022-5347/12/1883-0696/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
696
www.jurology.com
AND
RESEARCH, INC.
lance, focal therapy and radical surgery or radiotherapy lie on a continuum of complementary therapies. The challenge begins with accurate risk stratification. The rate of upgrading and up staging in radical prostatectomy specimens in patients who would have been candidates for expectant management is not trivial. In a retrospective series reporting various clinical criteria for active surveillance, 3% to 4% had pathological Gleason score 8 or greater disease, 15% to 18% had extracapsular extension and 3% to 4% had seminal vesicle invasion.6 These data emphasize the importance of accurate clinical risk stratification. One approach is to perform immediate confirmatory repeat transrectal ultrasound (TRUS) guided prostate needle biopsy, which has been shown to result in 28% improvement in discriminating the best candidates for active expectant management.7 In this issue of The Journal Barzell et al (page 762) compare repeat TRUS biopsy with template prostate mapping (TPM).8 In men with low risk prostate cancer undergoing confirmatory biopsy with repeat TRUS biopsy and TPM at a single sitting under general anesthesia, TPM reclassified 52% of cases compared with TRUS guided biopsy. Importantly the repeat TRUS guided biopsy was directed at regions of previously detected cancer and compounded the probability of not detecting a lesion missed on initial biopsy. Despite these limitations, TPM demonstrated the most utility in identifying high risk tumors, underscoring the importance of anteriorly sampling the prostate. Despite the increased incidence of prostate cancer, the detection of clinically significant disease remains elusive. Also in this issue Kaplan et al (page 757) provide a solution for men with persistently increased PSA and negative previous biopsies.9 The authors report the results of a 2-phase study identifying changes in PSA kinetics after the initiation of a 5␣-reductase inhibitor in the first phase, and evaluating this threshold prospectively to trigger a TRUS guided biopsy in the second phase. Using 0.4 ng/ml as the PSA nadir change triggering prostate biopsy, 26.8% of patients underwent biopsy and of http://dx.doi.org/10.1016/j.juro.2012.06.049 Vol. 188, 696-697, September 2012 Printed in U.S.A.
EXPECTANT MANAGEMENT OF LOCALIZED PROSTATE CANCER
these men 54.2% were found to have prostate cancer. Importantly 76.9% of these patients were diagnosed with Gleason score 7 or greater disease and it remains unclear whether 5␣-reductase inhibitor therapy enhanced the detection of clinically significant tumors or contributed to the progression of disease. Beyond the accurate selection of men with low risk disease to undergo expectant management, the challenges are to avoid excessive delay in definitively treating those who appear to be at higher risk for progression and to avoid overtreatment of the remainder based on transient changes in PSA kinetics. However, whether men with low risk disease on active surveillance will remain compliant with followup is unknown. Furthermore, the psychological effects of living for many years with untreated cancer are a potential concern and emphasize the importance of patient education to correct misconceptions regarding the risks of disease. In another article in this issue Ritchey et al (page 769) evaluate the quality of care in patients with prostate cancer undergoing expectant management.10 Quality of care was quantified by a previously validated set of clinical indicators assessing processes of care developed by RAND for localized prostate cancer.11 Compliance with structural indicators, including staffing and specialized services, was adequate in the majority of hospitals. By contrast, compliance with the process indicators varied greatly, and patient followup after 2 visits decreased below 32%. Therefore, patient education and physician communication are important tar-
697
gets for improvement. It was encouraging that age, race or insurance status did not predict compliance with the process. Despite limitations with retrospective studies evaluating administrative data that may measure medical documentation rather than the true delivery of care, the study inspires future collaborative research targeting hospitals to assess quality of care. The treatment of men with early stage prostate cancer has become an important public health issue, and offers urologists an opportunity to seize this pivotal moment and collaborate to evaluate the effectiveness and value in the treatment of our patients. Real problems in systematic errors with routine TRUS guided biopsy need to be improved, and the infectious and bleeding complications associated with expanded biopsy strategies represent an imperfect solution. The use of imaging for targeting biopsies would bring prostate cancer diagnosis into line with the biopsy technique used for the detection of almost all other solid tumors, and improve the detection of significant cancers and the prediction of insignificant disease.12 Finally, focusing efforts to improve the education of our patients will be essential to alleviate the stress associated with over detection and to improve the quality of care we deliver to patients. Behfar Ehdaie Department of Surgery Memorial Sloan-Kettering Cancer Center New York, New York
REFERENCES 1. Agency for Healthcare Research and Quality: Comparative Effectiveness of Therapies for Clinically Localized Prostate Cancer, 2008. Available at www.effectivehealthcare.ahrq.gov. Accessed June 1, 2012. 2. Andriole GL, Crawford ED, Grubb RL 3rd et al: Mortality results from a randomized prostatecancer screening trial. N Engl J Med 2009; 360: 1310. 3. Schröder FH, Hugosson J, Roobol MJ et al: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009; 360: 1320. 4. National Cancer Institute: SEER Cancer Statistics Review 1975-2008: Lifetime Risk (Percent) of Being Diagnosed with Cancer by Site and Race/ Ethnicity: Males, 17 SEER Areas, 2006 –2008 (Table 1.15) and Females, 17 SEER Areas, 2006 – 2008 (Table 1.16), 2011. Available at http://
seer.cancer.gov/csr/1975_2008/results_merged/ topic_lifetime_risk_diagnosis.pdf. Accessed June 1, 2012. 5. Makarov DV, Yu JB, Desai RA et al: The association between diffusion of the surgical robot and radical prostatectomy rates. Med Care 2011; 49: 333. 6. Thaxton CS, Loeb S, Roehl KA et al: Treatment outcomes of radical prostatectomy in potential candidates for 3 published active surveillance protocols. Urology 2010; 75: 414. 7. Berglund RK, Masterson TA, Vora KC et al: Pathological upgrading and up staging with immediate repeat biopsy in patients eligible for active surveillance. J Urol 2008; 180: 1964. 8. Barzell WE, Melamed MR, Cathcart P et al: Identifying candidates for active surveillance: an evaluation of the repeat biopsy strategy for men with
favorable risk prostate cancer. J Urol 2012; 188: 762. 9. Kaplan SA, Lee RK, Chung DE et al: Prostate biopsy in response to a change in nadir prostate specific antigen of 0.4 ng/ml after treatment with 5␣-reductase inhibitors markedly enhances the detection rate of prostate cancer. J Urol 2012; 188: 757. 10. Ritchey J, Gay EG, Spencer BA et al: Assessment of the quality of medical care among patients with early stage prostate cancer undergoing expectant management in the United States. J Urol 2012; 188: 769. 11. Spencer BA, Steinberg M, Malin J et al: Qualityof-care indicators for early-stage prostate cancer. J Clin Oncol 2003; 21: 1928. 12. Shukla-Dave A, Hricak H, Akin O et al: Preoperative nomograms incorporating magnetic resonance imaging and spectroscopy for prediction of insignificant prostate cancer. BJU Int 2012; 109: 1315.
696
www.jurology.com
AND
RESEARCH, INC.
lance, focal therapy and radical surgery or radiotherapy lie on a continuum of complementary therapies. The challenge begins with accurate risk stratification. The rate of upgrading and up staging in radical prostatectomy specimens in patients who would have been candidates for expectant management is not trivial. In a retrospective series reporting various clinical criteria for active surveillance, 3% to 4% had pathological Gleason score 8 or greater disease, 15% to 18% had extracapsular extension and 3% to 4% had seminal vesicle invasion.6 These data emphasize the importance of accurate clinical risk stratification. One approach is to perform immediate confirmatory repeat transrectal ultrasound (TRUS) guided prostate needle biopsy, which has been shown to result in 28% improvement in discriminating the best candidates for active expectant management.7 In this issue of The Journal Barzell et al (page 762) compare repeat TRUS biopsy with template prostate mapping (TPM).8 In men with low risk prostate cancer undergoing confirmatory biopsy with repeat TRUS biopsy and TPM at a single sitting under general anesthesia, TPM reclassified 52% of cases compared with TRUS guided biopsy. Importantly the repeat TRUS guided biopsy was directed at regions of previously detected cancer and compounded the probability of not detecting a lesion missed on initial biopsy. Despite these limitations, TPM demonstrated the most utility in identifying high risk tumors, underscoring the importance of anteriorly sampling the prostate. Despite the increased incidence of prostate cancer, the detection of clinically significant disease remains elusive. Also in this issue Kaplan et al (page 757) provide a solution for men with persistently increased PSA and negative previous biopsies.9 The authors report the results of a 2-phase study identifying changes in PSA kinetics after the initiation of a 5␣-reductase inhibitor in the first phase, and evaluating this threshold prospectively to trigger a TRUS guided biopsy in the second phase. Using 0.4 ng/ml as the PSA nadir change triggering prostate biopsy, 26.8% of patients underwent biopsy and of http://dx.doi.org/10.1016/j.juro.2012.06.049 Vol. 188, 696-697, September 2012 Printed in U.S.A.
EXPECTANT MANAGEMENT OF LOCALIZED PROSTATE CANCER
these men 54.2% were found to have prostate cancer. Importantly 76.9% of these patients were diagnosed with Gleason score 7 or greater disease and it remains unclear whether 5␣-reductase inhibitor therapy enhanced the detection of clinically significant tumors or contributed to the progression of disease. Beyond the accurate selection of men with low risk disease to undergo expectant management, the challenges are to avoid excessive delay in definitively treating those who appear to be at higher risk for progression and to avoid overtreatment of the remainder based on transient changes in PSA kinetics. However, whether men with low risk disease on active surveillance will remain compliant with followup is unknown. Furthermore, the psychological effects of living for many years with untreated cancer are a potential concern and emphasize the importance of patient education to correct misconceptions regarding the risks of disease. In another article in this issue Ritchey et al (page 769) evaluate the quality of care in patients with prostate cancer undergoing expectant management.10 Quality of care was quantified by a previously validated set of clinical indicators assessing processes of care developed by RAND for localized prostate cancer.11 Compliance with structural indicators, including staffing and specialized services, was adequate in the majority of hospitals. By contrast, compliance with the process indicators varied greatly, and patient followup after 2 visits decreased below 32%. Therefore, patient education and physician communication are important tar-
697
gets for improvement. It was encouraging that age, race or insurance status did not predict compliance with the process. Despite limitations with retrospective studies evaluating administrative data that may measure medical documentation rather than the true delivery of care, the study inspires future collaborative research targeting hospitals to assess quality of care. The treatment of men with early stage prostate cancer has become an important public health issue, and offers urologists an opportunity to seize this pivotal moment and collaborate to evaluate the effectiveness and value in the treatment of our patients. Real problems in systematic errors with routine TRUS guided biopsy need to be improved, and the infectious and bleeding complications associated with expanded biopsy strategies represent an imperfect solution. The use of imaging for targeting biopsies would bring prostate cancer diagnosis into line with the biopsy technique used for the detection of almost all other solid tumors, and improve the detection of significant cancers and the prediction of insignificant disease.12 Finally, focusing efforts to improve the education of our patients will be essential to alleviate the stress associated with over detection and to improve the quality of care we deliver to patients. Behfar Ehdaie Department of Surgery Memorial Sloan-Kettering Cancer Center New York, New York
REFERENCES 1. Agency for Healthcare Research and Quality: Comparative Effectiveness of Therapies for Clinically Localized Prostate Cancer, 2008. Available at www.effectivehealthcare.ahrq.gov. Accessed June 1, 2012. 2. Andriole GL, Crawford ED, Grubb RL 3rd et al: Mortality results from a randomized prostatecancer screening trial. N Engl J Med 2009; 360: 1310. 3. Schröder FH, Hugosson J, Roobol MJ et al: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009; 360: 1320. 4. National Cancer Institute: SEER Cancer Statistics Review 1975-2008: Lifetime Risk (Percent) of Being Diagnosed with Cancer by Site and Race/ Ethnicity: Males, 17 SEER Areas, 2006 –2008 (Table 1.15) and Females, 17 SEER Areas, 2006 – 2008 (Table 1.16), 2011. Available at http://
seer.cancer.gov/csr/1975_2008/results_merged/ topic_lifetime_risk_diagnosis.pdf. Accessed June 1, 2012. 5. Makarov DV, Yu JB, Desai RA et al: The association between diffusion of the surgical robot and radical prostatectomy rates. Med Care 2011; 49: 333. 6. Thaxton CS, Loeb S, Roehl KA et al: Treatment outcomes of radical prostatectomy in potential candidates for 3 published active surveillance protocols. Urology 2010; 75: 414. 7. Berglund RK, Masterson TA, Vora KC et al: Pathological upgrading and up staging with immediate repeat biopsy in patients eligible for active surveillance. J Urol 2008; 180: 1964. 8. Barzell WE, Melamed MR, Cathcart P et al: Identifying candidates for active surveillance: an evaluation of the repeat biopsy strategy for men with
favorable risk prostate cancer. J Urol 2012; 188: 762. 9. Kaplan SA, Lee RK, Chung DE et al: Prostate biopsy in response to a change in nadir prostate specific antigen of 0.4 ng/ml after treatment with 5␣-reductase inhibitors markedly enhances the detection rate of prostate cancer. J Urol 2012; 188: 757. 10. Ritchey J, Gay EG, Spencer BA et al: Assessment of the quality of medical care among patients with early stage prostate cancer undergoing expectant management in the United States. J Urol 2012; 188: 769. 11. Spencer BA, Steinberg M, Malin J et al: Qualityof-care indicators for early-stage prostate cancer. J Clin Oncol 2003; 21: 1928. 12. Shukla-Dave A, Hricak H, Akin O et al: Preoperative nomograms incorporating magnetic resonance imaging and spectroscopy for prediction of insignificant prostate cancer. BJU Int 2012; 109: 1315.