- Email: [email protected]
Beware the Risks
2566
OPPOSING VIEWS
fied as higher risk for progression and treated. In an intermediate time frame (10 years) the prostate mortality is exceptionally low. The PSA recurrence rate after selective delayed radical treatment in the most mature cohort was 50%, which represented 15% of the total surveillance cohort.5 Among the 453 patients in this group the actuarial 10-year prostate cancer survival is 97%. Mortality from other causes is the cause of death in most men on surveillance. With a median followup of 8 years, the relative risk of nonprostate cancer death was 19 times higher than the risk of prostate cancer mortality.5 Prostate and nonprostate mortality will increase with further study maturity, and so it is plausible that this ratio will remain relatively constant. Better prediction of the likely risk of disease progression for the individual patient would further improve the appeal of surveillance. Improved imaging and biopsy strategies, and molecular characterization of higher risk disease based on multiplex analysis of biopsy specimens and/or somatic singlenucleotide polymorphisms hold the promise of more accurate characterization of disease aggressivity
and, therefore, better patient selection in the near future. Perfection in medicine is rarely achieved and comes at a high cost. Active surveillance spares the majority of patients the risk of treatment associated morbidity. In most instances the minority of patients who are reclassified as higher risk with time can still benefit from definitive treatment. A sustained rapid increase in PSA and/or significant upgrading on repeat biopsy clearly identifies a group at increased risk for failure. However, the relatively high PSA failure rate in these patients should be interpreted in the context of the overall group. The fraction with posttreatment PSA recurrence is 10% to 15%, which is similar to series of radical treatment of favorable risk disease. Active surveillance is the most rational approach currently available to address the overdiagnosis associated with prostate cancer screening. Laurence Klotz Division of Urology Sunnybrook Health Sciences Centre Toronto, Ontario,Canada
REFERENCES 1. Welch HG, Schwartz LM and Woloshin S: Prostate-specific antigen levels in the United States: implications of various definitions for abnormal. J Natl Cancer Inst 2005; 97: 1132. 2. Welch HG and Albertsen PC: Prostate cancer diagnosis and treatment after the introduction of
prostate-specific antigen screening: 1986 –2005. J Natl Cancer Inst 2009; Epub ahead of print.
4. Bill-Axelson A and Holmberg L: Radical prostatectomy versus watchful waiting (update). N Engl J Med.2005; 352: 1977.
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.
5. Klotz LH, Nam R, Lam A et al: Clinical results of long-term follow-up of a large active surveillance cohort. J Urol, suppl., 2009; 181: 606, abstract 1682.
BEWARE THE RISKS “Risk comes from not knowing what you are doing” —Warren Buffet
CONSIDERATION of active surveillance for men with favorable prostate cancer is based on 5 sequential assumptions and, unfortunately, current evidence behooves us to tread cautiously on all of them. Assumption 1: The diagnosed cancer is insignificant or indolent. Existing clinical, biopsy and biomarker based criteria to predict insignificant or indolent vs aggressive disease are woefully inaccurate. Most prediction models for indolent cancer are associated with an error rate of 25% that makes 1 of every 4 patients who chose active surveillance unsuitable for this approach. Multiple definitions of low risk or favorable disease as well as variable selection criteria for entry in different active surveillance protocols confound the existing pool of patients eligible for this approach.1
Assumption 2: Cancer progression can be reliably monitored. There is no uniformity in following patients on active surveillance. While significant variability exists in the tools used during followup as well as the frequency of followup, the duration of followup is potentially indefinite. It is worthwhile to note that none of the clinical (PSA, PSA kinetics, digital rectal examination), radiological (transrectal ultrasound or endorectal coil magnetic resonance imaging) or repeat biopsy criteria have been reliably accurate to predict cancer progression.2,3 Conflicting results have been reported on the role of PSA kinetics as a reliable marker for disease progression. The only prospective randomized trial between surgery and watchful waiting highlighted the failure of any single PSA kinetic to
OPPOSING VIEWS
predict disease progression in the watchful waiting cohort.4 The burden of morbidity of frequent (every 12 to 18 months) prostate biopsies in these patients is not trivial. How many biopsies will a healthy 65-yearold man diagnosed with favorable prostate cancer end up having? If we apply the current guidelines for repeat biopsy adopted in active surveillance protocols, he will have to undergo 9 to 18 biopsies in his lifetime, assuming he has no progression based on his average life expectancy of 18 years. This number will increase significantly in younger men. Will frequent biopsies trigger inflammation and compromise future quality of delayed treatment if needed in these patients? Can repeated biopsies induce a change in the already existing cancer phenotype via inflammation? At present, we simply do not have answers to these and several other followup related questions for patients undergoing active surveillance. Assumption 3: If cancer progresses, it will still be curable. The rate of misclassification (pathological upgrading to Gleason 7 or higher and up staging) varies from 39% to 56% depending on the entry criteria for active surveillance.5 Of those who seek delayed treatment 20% to 25% will be incurable.1 Although a significant number of these patients have pathologically upgraded and up staged disease that may make them potentially incurable with active monotherapy, long-term data about secondary therapy as well as hormonal therapy are lacking to date. Making the selection criteria more stringent will result in decreased misclassification rates but will lead to a significant reduction in the number of patients eligible for active surveillance. Assumption 4: Treatment will not be required at all or significantly delayed. The premise of the strategy of active surveillance is to avoid treatment and treatment related morbidity for as long as possible. However approximately 25% of patients seek active treatment within the first 5 years of being on active surveillance.1 This number expectedly goes up with every passing year. The lack of followup beyond 10 years in patients on active surveillance severely limits our ability to make long-term predictions about the need for delayed treatment. Assumption 5: Morbidity, and oncological and functional outcomes will be similar for patients undergoing delayed treatment to those choosing active treatment at initial diagnosis. It is striking that, to my knowledge, no data have been reported on the level of difficulty in performing surgery (due to multiple biopsies, pathological upgrading and up staging) as well as functional outcomes for patients on active surveillance who un-
2567
dergo delayed treatment. It is plausible that issues of cancer control and aversion to treatment related morbidity, which drive men with presumed favorable cancer towards active surveillance, may be compromised with passage of time. The untested approach of active surveillance mandates lifelong patient compliance along with added anxiety of living with untreated cancer. Lack of progression in the initial years on active surveillance may induce an element of complacency in patients as well as physicians that may be detrimental for a cancer with a usually prolonged natural history. One of the main presumptions of active surveillance, that active treatment is invariably associated with treatment related morbidity, is simply not true. During the last decade better understanding of the surgical and functional anatomy of the prostate, has translated into superior oncological and functional outcomes. Similarly, advances in the field of radiation oncology have facilitated more precise delivery of high dose radiation with improved outcomes. While the treatment related goal of achieving the “trifecta” of oncological efficacy, urinary continence and sexual function is not possible in all patients, we are more close to attaining it than we have ever been in the history of treating prostate cancer. The concept of active surveillance is appealing and in select patients will undoubtedly be a viable management option. Advent of novel biomarkers that can differentiate indolent from aggressive cancers will vastly improve the selection criteria for entry into active surveillance protocols. However, we will have to wait for the results of prospective randomized clinical trials, such as START (Standard Treatment Against Restricted Treatment), PRIAS (Prostate Cancer Research International: Active Surveillance) and ProtecT (Prostate Testing for Cancer and Treatment) comparing active surveillance with active treatment as well as the multiinstitutional PASS (Prostate Cancer Active Surveillance Study), before we can safely recommend active surveillance as a standard of care for patients with favorable prostate cancer. At the center of this entire debate of active surveillance vs active treatment lies the patient along with his degree of risk aversion to either cancer or treatment related morbidity and mortality. Our goal as urologists should be to counsel patients while presenting a balanced approach on various treatment options available to help them make an educated and informed decision. Dipen J. Parekh Department of Urology University of Texas Health Sciences Center at San Antonio San Antonio, Texas
2568
OPPOSING VIEWS
REFERENCES 1. Bastian PJ, Carter BH, Bjartell A et al: Insignificant prostate cancer and active surveillance: from definition to clinical implications. Eur Urol 2009; 55: 1321. 2. Miyamoto RK and Thompson IM: The reliability of digital rectal exam, PSA, repeat prostate biopsy and endorectal MRI for following patients with
clinically localized prostate cancer on active surveillance. J Urol, suppl., 2008; The Journal of Urology 179: 154, abstract 435.
4. Fall K, Garmo H, Andren O et al: Prostate-specific antigen levels as a predictor of lethal prostate cancer. J Natl Cancer Inst 2007; 99: 526.
3. van den Bergh RC, Roemeling S, Roobol MJ et al: Prostate-specific antigen kinetics in clinical decision-making during active surveillance for early prostate cancer—a review. Eur Urol 2008; 54: 505.
5. Suardi N, Capitanio U, Chun FK et al: Currently used criteria for active surveillance in men with low-risk prostate cancer: an analysis of pathologic features. Cancer 2008; 113: 2068.
OPPOSING VIEWS
fied as higher risk for progression and treated. In an intermediate time frame (10 years) the prostate mortality is exceptionally low. The PSA recurrence rate after selective delayed radical treatment in the most mature cohort was 50%, which represented 15% of the total surveillance cohort.5 Among the 453 patients in this group the actuarial 10-year prostate cancer survival is 97%. Mortality from other causes is the cause of death in most men on surveillance. With a median followup of 8 years, the relative risk of nonprostate cancer death was 19 times higher than the risk of prostate cancer mortality.5 Prostate and nonprostate mortality will increase with further study maturity, and so it is plausible that this ratio will remain relatively constant. Better prediction of the likely risk of disease progression for the individual patient would further improve the appeal of surveillance. Improved imaging and biopsy strategies, and molecular characterization of higher risk disease based on multiplex analysis of biopsy specimens and/or somatic singlenucleotide polymorphisms hold the promise of more accurate characterization of disease aggressivity
and, therefore, better patient selection in the near future. Perfection in medicine is rarely achieved and comes at a high cost. Active surveillance spares the majority of patients the risk of treatment associated morbidity. In most instances the minority of patients who are reclassified as higher risk with time can still benefit from definitive treatment. A sustained rapid increase in PSA and/or significant upgrading on repeat biopsy clearly identifies a group at increased risk for failure. However, the relatively high PSA failure rate in these patients should be interpreted in the context of the overall group. The fraction with posttreatment PSA recurrence is 10% to 15%, which is similar to series of radical treatment of favorable risk disease. Active surveillance is the most rational approach currently available to address the overdiagnosis associated with prostate cancer screening. Laurence Klotz Division of Urology Sunnybrook Health Sciences Centre Toronto, Ontario,Canada
REFERENCES 1. Welch HG, Schwartz LM and Woloshin S: Prostate-specific antigen levels in the United States: implications of various definitions for abnormal. J Natl Cancer Inst 2005; 97: 1132. 2. Welch HG and Albertsen PC: Prostate cancer diagnosis and treatment after the introduction of
prostate-specific antigen screening: 1986 –2005. J Natl Cancer Inst 2009; Epub ahead of print.
4. Bill-Axelson A and Holmberg L: Radical prostatectomy versus watchful waiting (update). N Engl J Med.2005; 352: 1977.
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.
5. Klotz LH, Nam R, Lam A et al: Clinical results of long-term follow-up of a large active surveillance cohort. J Urol, suppl., 2009; 181: 606, abstract 1682.
BEWARE THE RISKS “Risk comes from not knowing what you are doing” —Warren Buffet
CONSIDERATION of active surveillance for men with favorable prostate cancer is based on 5 sequential assumptions and, unfortunately, current evidence behooves us to tread cautiously on all of them. Assumption 1: The diagnosed cancer is insignificant or indolent. Existing clinical, biopsy and biomarker based criteria to predict insignificant or indolent vs aggressive disease are woefully inaccurate. Most prediction models for indolent cancer are associated with an error rate of 25% that makes 1 of every 4 patients who chose active surveillance unsuitable for this approach. Multiple definitions of low risk or favorable disease as well as variable selection criteria for entry in different active surveillance protocols confound the existing pool of patients eligible for this approach.1
Assumption 2: Cancer progression can be reliably monitored. There is no uniformity in following patients on active surveillance. While significant variability exists in the tools used during followup as well as the frequency of followup, the duration of followup is potentially indefinite. It is worthwhile to note that none of the clinical (PSA, PSA kinetics, digital rectal examination), radiological (transrectal ultrasound or endorectal coil magnetic resonance imaging) or repeat biopsy criteria have been reliably accurate to predict cancer progression.2,3 Conflicting results have been reported on the role of PSA kinetics as a reliable marker for disease progression. The only prospective randomized trial between surgery and watchful waiting highlighted the failure of any single PSA kinetic to
OPPOSING VIEWS
predict disease progression in the watchful waiting cohort.4 The burden of morbidity of frequent (every 12 to 18 months) prostate biopsies in these patients is not trivial. How many biopsies will a healthy 65-yearold man diagnosed with favorable prostate cancer end up having? If we apply the current guidelines for repeat biopsy adopted in active surveillance protocols, he will have to undergo 9 to 18 biopsies in his lifetime, assuming he has no progression based on his average life expectancy of 18 years. This number will increase significantly in younger men. Will frequent biopsies trigger inflammation and compromise future quality of delayed treatment if needed in these patients? Can repeated biopsies induce a change in the already existing cancer phenotype via inflammation? At present, we simply do not have answers to these and several other followup related questions for patients undergoing active surveillance. Assumption 3: If cancer progresses, it will still be curable. The rate of misclassification (pathological upgrading to Gleason 7 or higher and up staging) varies from 39% to 56% depending on the entry criteria for active surveillance.5 Of those who seek delayed treatment 20% to 25% will be incurable.1 Although a significant number of these patients have pathologically upgraded and up staged disease that may make them potentially incurable with active monotherapy, long-term data about secondary therapy as well as hormonal therapy are lacking to date. Making the selection criteria more stringent will result in decreased misclassification rates but will lead to a significant reduction in the number of patients eligible for active surveillance. Assumption 4: Treatment will not be required at all or significantly delayed. The premise of the strategy of active surveillance is to avoid treatment and treatment related morbidity for as long as possible. However approximately 25% of patients seek active treatment within the first 5 years of being on active surveillance.1 This number expectedly goes up with every passing year. The lack of followup beyond 10 years in patients on active surveillance severely limits our ability to make long-term predictions about the need for delayed treatment. Assumption 5: Morbidity, and oncological and functional outcomes will be similar for patients undergoing delayed treatment to those choosing active treatment at initial diagnosis. It is striking that, to my knowledge, no data have been reported on the level of difficulty in performing surgery (due to multiple biopsies, pathological upgrading and up staging) as well as functional outcomes for patients on active surveillance who un-
2567
dergo delayed treatment. It is plausible that issues of cancer control and aversion to treatment related morbidity, which drive men with presumed favorable cancer towards active surveillance, may be compromised with passage of time. The untested approach of active surveillance mandates lifelong patient compliance along with added anxiety of living with untreated cancer. Lack of progression in the initial years on active surveillance may induce an element of complacency in patients as well as physicians that may be detrimental for a cancer with a usually prolonged natural history. One of the main presumptions of active surveillance, that active treatment is invariably associated with treatment related morbidity, is simply not true. During the last decade better understanding of the surgical and functional anatomy of the prostate, has translated into superior oncological and functional outcomes. Similarly, advances in the field of radiation oncology have facilitated more precise delivery of high dose radiation with improved outcomes. While the treatment related goal of achieving the “trifecta” of oncological efficacy, urinary continence and sexual function is not possible in all patients, we are more close to attaining it than we have ever been in the history of treating prostate cancer. The concept of active surveillance is appealing and in select patients will undoubtedly be a viable management option. Advent of novel biomarkers that can differentiate indolent from aggressive cancers will vastly improve the selection criteria for entry into active surveillance protocols. However, we will have to wait for the results of prospective randomized clinical trials, such as START (Standard Treatment Against Restricted Treatment), PRIAS (Prostate Cancer Research International: Active Surveillance) and ProtecT (Prostate Testing for Cancer and Treatment) comparing active surveillance with active treatment as well as the multiinstitutional PASS (Prostate Cancer Active Surveillance Study), before we can safely recommend active surveillance as a standard of care for patients with favorable prostate cancer. At the center of this entire debate of active surveillance vs active treatment lies the patient along with his degree of risk aversion to either cancer or treatment related morbidity and mortality. Our goal as urologists should be to counsel patients while presenting a balanced approach on various treatment options available to help them make an educated and informed decision. Dipen J. Parekh Department of Urology University of Texas Health Sciences Center at San Antonio San Antonio, Texas
2568
OPPOSING VIEWS
REFERENCES 1. Bastian PJ, Carter BH, Bjartell A et al: Insignificant prostate cancer and active surveillance: from definition to clinical implications. Eur Urol 2009; 55: 1321. 2. Miyamoto RK and Thompson IM: The reliability of digital rectal exam, PSA, repeat prostate biopsy and endorectal MRI for following patients with
clinically localized prostate cancer on active surveillance. J Urol, suppl., 2008; The Journal of Urology 179: 154, abstract 435.
4. Fall K, Garmo H, Andren O et al: Prostate-specific antigen levels as a predictor of lethal prostate cancer. J Natl Cancer Inst 2007; 99: 526.
3. van den Bergh RC, Roemeling S, Roobol MJ et al: Prostate-specific antigen kinetics in clinical decision-making during active surveillance for early prostate cancer—a review. Eur Urol 2008; 54: 505.
5. Suardi N, Capitanio U, Chun FK et al: Currently used criteria for active surveillance in men with low-risk prostate cancer: an analysis of pathologic features. Cancer 2008; 113: 2068.