Research Original Investigation
Risk Group and Death From Prostate Cancer
15. Hollander M, Wolfe D. Nonparametric Statistical Methods. New York, NY: John Wiley and Sons; 1999:106-140. 16. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481. 17. Agresti A. Categorical Data Analysis. New York, NY: John Wiley and Sons; 2013:69-112. 18. Fine J, Gray R. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496-509. 19. Klein J, Moeschberger M. Survival Analysis Techniques for Censored and Truncated Data. New York, NY: Springer; 2003:295-328.
25. Lee WR, deGuzman AF, Bare RL, Marshall MG, McCullough DL. Postimplant analysis of transperineal interstitial permanent prostate brachytherapy: evidence for a learning curve in the first year at a single institution. Int J Radiat Oncol Biol Phys. 2000;46(1):83-88. 26. Tamim H, Monfared AAT, LeLorier J. Application of lag-time into exposure definitions to control for protopathic bias. Pharmacoepidemiol Drug Saf. 2007;16(3):250-258. 27. Gaynor J, Feuer E, Tan C. On the use of cause-specific failure and conditional failure probabilities: examples from clinical oncology data. J Am Stat Assoc. 1993;88:400-409.
32. Dall’Era MA, Konety BR, Cowan JE, et al. Active surveillance for the management of prostate cancer in a contemporary cohort. Cancer. 2008;112(12): 2664-2670. 33. Ercole B, Marietti SR, Fine J, Albertsen PC. Outcomes following active surveillance of men with localized prostate cancer diagnosed in the prostate specific antigen era. J Urol. 2008;180(4):1336-1339. 34. Bul M, van den Bergh RC, Zhu X, et al. Outcomes of initially expectantly managed patients with low or intermediate risk screen-detected localized prostate cancer. BJU Int. 2012;110(11): 1672-1677.
20. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29.
28. Gray R. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141-1154.
35. Thomsen FB, Røder MA, Hvarness H, Iversen P, Brasso K. Active surveillance can reduce overtreatment in patients with low-risk prostate cancer. Dan Med J. 2013;60(2):A4575.
21. Hsieh FY, Lavori PW. Sample-size calculations for the Cox proportional hazards regression model with nonbinary covariates. Control Clin Trials. 2000;21(6):552-560.
29. Cupples LA, Gagnon DR, Ramaswamy R, D’Agostino RB. Age-adjusted survival curves with application in the Framingham Study. Stat Med. 1995;14(16):1731-1744.
36. Tosoian JJ, Trock BJ, Landis P, et al. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol. 2011; 29(16):2185-2190.
22. Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. Biometrics. 1983;39(2):499-503.
30. Godtman RA, Holmberg E, Khatami A, Stranne J, Hugosson J. Outcome following active surveillance of men with screen-detected prostate cancer. Results from the Göteborg randomised population-based prostate cancer screening trial. Eur Urol. 2013;63(1):101-107.
37. Soloway MS, Soloway CT, Eldefrawy A, Acosta K, Kava B, Manoharan M. Careful selection and close monitoring of low-risk prostate cancer patients on active surveillance minimizes the need for treatment. Eur Urol. 2010;58(6):831-835.
23. Ankerst DP, Hoefler J, Bock S, et al. Prostate Cancer Prevention Trial risk calculator 2.0 for the prediction of low- vs high-grade prostate cancer. Urology. 2014;83(6):1362-1367. 24. Russo AL, Chen M-H, Aizer AA, Hattangadi JA, D’Amico AV. Advancing age within established Gleason score categories and the risk of prostate cancer-specific mortality (PCSM). BJU Int. 2012;110 (7):973-979.
31. Selvadurai ED, Singhera M, Thomas K, et al. Medium-term outcomes of active surveillance for localised prostate cancer. Eur Urol. 2013;64(6):981987.
38. Ischia JJ, Pang CY, Tay YK, Suen CF, Aw HC, Frydenberg M. Active surveillance for prostate cancer: an Australian experience. BJU Int. 2012;109 (suppl 3):40-43.
Invited Commentary
Active Surveillance in Prostate Cancer How Far Should We Go? Fred Saad, MD
The risk of overtreatment in localized prostate cancer has become a subject of paramount importance and is one of the major reasons behind some of the negative perceptions of screening. Although treatment today has less morbidity than in the past, there is still significant risk associated with all available treatment options. To Related article page 334 dissociate screening from treatment, the concepts of watchful waiting (WW) and active surveillance (AS) have gained widespread attention and appeal. The concept of WW implies that patients are followed up without intervention until symptoms manifest or clinical or metastatic progression becomes apparent. The concept of WW has become less attractive, especially for younger patients, given that a large randomized clinical trial demonstrated that radical prostatectomy significantly improved metastasisfree and overall survival compared with WW.1 A compromise between WW and immediate intervention has given rise to the concept of AS. Given the low risk of 10-year cancer-specific mortality, AS has become a recom340
mended option for selected patients diagnosed with apparently low-risk cancer. 2,3 Low-risk disease is generally defined as Gleason grade 6 cancers with prostate-specific antigen (PSA) findings below 10 ng/mL and nothing more than clinical T2a disease on digital rectal examination (DRE). The subclassification of very-low-risk cancer is defined as 2 or fewer positive biopsy findings with less than 50% of any core being cancerous.2 These cases are often considered optimal for AS. Patients under AS are followed up regularly with PSA measurements and DREs and usually rebiopsied at variable time points. The plan is to intervene if and when progression to a more aggressive phenotype occurs.3,4 Whether we can safely expand the concept of AS to some patients with intermediate-risk prostate cancers has become a subject of interest to both physicians and patients. The study in this issue of JAMA Oncology by Raldow et al5 compares lowrisk to favorable intermediate-risk prostate cancer and shows that brachytherapy was equally effective, with a very low risk of mortality, in both groups.5 According to the authors, the findings suggest that some intermediate-risk patients may actu-
JAMA Oncology June 2015 Volume 1, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://oncology.jamanetwork.com/ by a Yale University User on 07/22/2015
jamaoncology.com
Risk Group and Death From Prostate Cancer
Original Investigation Research
ally be good candidates for AS. This suggestion is interesting but requires careful reflection. It is true that in the past 10 years there has been a certain degree of grade migration, where Gleason grade 3 cancers are sometimes reclassified to grade 4.4 This may suggest that historical studies showing very low progression of grade 3 cancers might in fact have included favorable-looking grade 4 disease by today’s standards. However, it is clear that the duration of follow-up of the cohort in the study by Raldow et al5 is short in terms of prostate cancer timelines. It is also important to note that the authors are reviewing outcomes of patients who were treated rather than observed. The authors concede that they cannot be sure whether the results obtained would have been the same if the patients had been under AS. This reality, combined with the risk of undergrading and understaging documented Gleason grade 4 cancers, makes AS risky, to be undertaken with extreme caution. There is also evidence from studies such as PIVOT7 and other cohorts6 suggesting that patients with intermediaterisk prostate cancer have worse outcomes under AS. The large ProtecT study8 will hopefully help answer some of these questions and help identify the profile of patients that can be safely managed with active surveillance. ARTICLE INFORMATION Author Affiliation: Department of Surgery, University of Montreal, Montreal, Quebec, Canada. Corresponding Author: Fred Saad, MD, Department of Surgery, University of Montreal, 1058 St Denis, Montreal, QC H2X 3J4, Canada ([email protected]). Published Online: February 19, 2015. doi:10.1001/jamaoncol.2015.103. Conflict of Interest Disclosures: None reported. REFERENCES 1. Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med. 2014;370(10):932-942. doi:10.1056/NEJMoa1311593. 2. Mohler JL, Kantoff PW, Armstrong AJ, et al; National Comprehensive Cancer Network. Prostate cancer, version 2.2014. J Natl Compr Canc Netw. 2014;12(5):686-718. 3. Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a large active surveillance
Another important factor that may reduce the generalizability of the results reported by Raldow et al5 is pathology expertise. Studies have shown that there is significant cancer upgrading when pathologic findings of non–prostate experts are reexamined by prostate experts.4 So what will it take for physicians and patients to be more comfortable with AS? Obviously, a better understanding of the biology of the cancer at hand would be very helpful. Efforts in that area are being made with the use of magnetic resonance imaging as well as the search for reliable tissue, serum, and urine biomarkers to help stratify disease.9,10 These are the areas where we need to focus our research efforts because simply repeating biopsies has its share of inconvenience and limitations even beyond the alarming increase in the risk of sepsis. So what can we learn from this study by Raldow et al?5 One of the most important findings is that favorable intermediaterisk cancers can be very well controlled with brachytherapy. This is very worthwhile information. What about expanding the indications for AS? Although I am a urologist who has been practicing active surveillance for most of my low-risk patients for many years, I suggest that we continue to be very cautious, and extremely selective, in offering AS to patients with any features of intermediate-risk prostate cancer.
cohort of patients with prostate cancer. J Clin Oncol. 2015;33(3):272-277. 4. Montironi R, Hammond EH, Lin DW, et al. Consensus statement with recommendations on active surveillance inclusion criteria and definition of progression in men with localized prostate cancer: the critical role of the pathologist. Virchows Arch. 2014;465(6):623-628. 5. Raldow AC, Zhang D, Chen M-H, Braccioforte MH, Moran BJ, D’Amico AV. Risk group and death from prostate cancer: implications for active surveillance in men with favorable intermediate-risk prostate cancer [published online February 19, 2015]. JAMA Oncology. doi:10.1001/jamaoncol.2014 .284. 6. Ploussard G, Isbarn H, Briganti A, et al; Members of the Prostate Cancer Working Group of the Young Academic Urologists Working Party of the European Association of Urology. Can we expand active surveillance criteria to include biopsy Gleason 3+4 prostate cancer? multi-institutional study of 2,323 patients [published online August 14, 2014]. Urol Oncol. doi:10.1016/j.urolonc.2014.07.007.
jamaoncology.com
7. Wilt TJ, Brawer MK, Jones KM, et al; Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367(3):203-213. 8. Lane JA, Donovan JL, Davis M, et al; ProtecT study group. Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial. Lancet Oncol. 2014;15(10):1109-1118. 9. Loeb S, Bruinsma SM, Nicholson J, et al. Active surveillance for prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification [published online October 31, 2014]. Eur Urol. doi:10.1016/j.eururo .2014.10.010. 10. Schoots IG, Petrides N, Giganti F, et al. Magnetic resonance imaging in active surveillance of prostate cancer: a systematic review [published online November 15, 2014]. Eur Urol. doi:10.1016/j .eururo.2014.10.050.
(Reprinted) JAMA Oncology June 2015 Volume 1, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://oncology.jamanetwork.com/ by a Yale University User on 07/22/2015
341
Risk Group and Death From Prostate Cancer
15. Hollander M, Wolfe D. Nonparametric Statistical Methods. New York, NY: John Wiley and Sons; 1999:106-140. 16. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481. 17. Agresti A. Categorical Data Analysis. New York, NY: John Wiley and Sons; 2013:69-112. 18. Fine J, Gray R. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496-509. 19. Klein J, Moeschberger M. Survival Analysis Techniques for Censored and Truncated Data. New York, NY: Springer; 2003:295-328.
25. Lee WR, deGuzman AF, Bare RL, Marshall MG, McCullough DL. Postimplant analysis of transperineal interstitial permanent prostate brachytherapy: evidence for a learning curve in the first year at a single institution. Int J Radiat Oncol Biol Phys. 2000;46(1):83-88. 26. Tamim H, Monfared AAT, LeLorier J. Application of lag-time into exposure definitions to control for protopathic bias. Pharmacoepidemiol Drug Saf. 2007;16(3):250-258. 27. Gaynor J, Feuer E, Tan C. On the use of cause-specific failure and conditional failure probabilities: examples from clinical oncology data. J Am Stat Assoc. 1993;88:400-409.
32. Dall’Era MA, Konety BR, Cowan JE, et al. Active surveillance for the management of prostate cancer in a contemporary cohort. Cancer. 2008;112(12): 2664-2670. 33. Ercole B, Marietti SR, Fine J, Albertsen PC. Outcomes following active surveillance of men with localized prostate cancer diagnosed in the prostate specific antigen era. J Urol. 2008;180(4):1336-1339. 34. Bul M, van den Bergh RC, Zhu X, et al. Outcomes of initially expectantly managed patients with low or intermediate risk screen-detected localized prostate cancer. BJU Int. 2012;110(11): 1672-1677.
20. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29.
28. Gray R. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141-1154.
35. Thomsen FB, Røder MA, Hvarness H, Iversen P, Brasso K. Active surveillance can reduce overtreatment in patients with low-risk prostate cancer. Dan Med J. 2013;60(2):A4575.
21. Hsieh FY, Lavori PW. Sample-size calculations for the Cox proportional hazards regression model with nonbinary covariates. Control Clin Trials. 2000;21(6):552-560.
29. Cupples LA, Gagnon DR, Ramaswamy R, D’Agostino RB. Age-adjusted survival curves with application in the Framingham Study. Stat Med. 1995;14(16):1731-1744.
36. Tosoian JJ, Trock BJ, Landis P, et al. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol. 2011; 29(16):2185-2190.
22. Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. Biometrics. 1983;39(2):499-503.
30. Godtman RA, Holmberg E, Khatami A, Stranne J, Hugosson J. Outcome following active surveillance of men with screen-detected prostate cancer. Results from the Göteborg randomised population-based prostate cancer screening trial. Eur Urol. 2013;63(1):101-107.
37. Soloway MS, Soloway CT, Eldefrawy A, Acosta K, Kava B, Manoharan M. Careful selection and close monitoring of low-risk prostate cancer patients on active surveillance minimizes the need for treatment. Eur Urol. 2010;58(6):831-835.
23. Ankerst DP, Hoefler J, Bock S, et al. Prostate Cancer Prevention Trial risk calculator 2.0 for the prediction of low- vs high-grade prostate cancer. Urology. 2014;83(6):1362-1367. 24. Russo AL, Chen M-H, Aizer AA, Hattangadi JA, D’Amico AV. Advancing age within established Gleason score categories and the risk of prostate cancer-specific mortality (PCSM). BJU Int. 2012;110 (7):973-979.
31. Selvadurai ED, Singhera M, Thomas K, et al. Medium-term outcomes of active surveillance for localised prostate cancer. Eur Urol. 2013;64(6):981987.
38. Ischia JJ, Pang CY, Tay YK, Suen CF, Aw HC, Frydenberg M. Active surveillance for prostate cancer: an Australian experience. BJU Int. 2012;109 (suppl 3):40-43.
Invited Commentary
Active Surveillance in Prostate Cancer How Far Should We Go? Fred Saad, MD
The risk of overtreatment in localized prostate cancer has become a subject of paramount importance and is one of the major reasons behind some of the negative perceptions of screening. Although treatment today has less morbidity than in the past, there is still significant risk associated with all available treatment options. To Related article page 334 dissociate screening from treatment, the concepts of watchful waiting (WW) and active surveillance (AS) have gained widespread attention and appeal. The concept of WW implies that patients are followed up without intervention until symptoms manifest or clinical or metastatic progression becomes apparent. The concept of WW has become less attractive, especially for younger patients, given that a large randomized clinical trial demonstrated that radical prostatectomy significantly improved metastasisfree and overall survival compared with WW.1 A compromise between WW and immediate intervention has given rise to the concept of AS. Given the low risk of 10-year cancer-specific mortality, AS has become a recom340
mended option for selected patients diagnosed with apparently low-risk cancer. 2,3 Low-risk disease is generally defined as Gleason grade 6 cancers with prostate-specific antigen (PSA) findings below 10 ng/mL and nothing more than clinical T2a disease on digital rectal examination (DRE). The subclassification of very-low-risk cancer is defined as 2 or fewer positive biopsy findings with less than 50% of any core being cancerous.2 These cases are often considered optimal for AS. Patients under AS are followed up regularly with PSA measurements and DREs and usually rebiopsied at variable time points. The plan is to intervene if and when progression to a more aggressive phenotype occurs.3,4 Whether we can safely expand the concept of AS to some patients with intermediate-risk prostate cancers has become a subject of interest to both physicians and patients. The study in this issue of JAMA Oncology by Raldow et al5 compares lowrisk to favorable intermediate-risk prostate cancer and shows that brachytherapy was equally effective, with a very low risk of mortality, in both groups.5 According to the authors, the findings suggest that some intermediate-risk patients may actu-
JAMA Oncology June 2015 Volume 1, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://oncology.jamanetwork.com/ by a Yale University User on 07/22/2015
jamaoncology.com
Risk Group and Death From Prostate Cancer
Original Investigation Research
ally be good candidates for AS. This suggestion is interesting but requires careful reflection. It is true that in the past 10 years there has been a certain degree of grade migration, where Gleason grade 3 cancers are sometimes reclassified to grade 4.4 This may suggest that historical studies showing very low progression of grade 3 cancers might in fact have included favorable-looking grade 4 disease by today’s standards. However, it is clear that the duration of follow-up of the cohort in the study by Raldow et al5 is short in terms of prostate cancer timelines. It is also important to note that the authors are reviewing outcomes of patients who were treated rather than observed. The authors concede that they cannot be sure whether the results obtained would have been the same if the patients had been under AS. This reality, combined with the risk of undergrading and understaging documented Gleason grade 4 cancers, makes AS risky, to be undertaken with extreme caution. There is also evidence from studies such as PIVOT7 and other cohorts6 suggesting that patients with intermediaterisk prostate cancer have worse outcomes under AS. The large ProtecT study8 will hopefully help answer some of these questions and help identify the profile of patients that can be safely managed with active surveillance. ARTICLE INFORMATION Author Affiliation: Department of Surgery, University of Montreal, Montreal, Quebec, Canada. Corresponding Author: Fred Saad, MD, Department of Surgery, University of Montreal, 1058 St Denis, Montreal, QC H2X 3J4, Canada ([email protected]). Published Online: February 19, 2015. doi:10.1001/jamaoncol.2015.103. Conflict of Interest Disclosures: None reported. REFERENCES 1. Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med. 2014;370(10):932-942. doi:10.1056/NEJMoa1311593. 2. Mohler JL, Kantoff PW, Armstrong AJ, et al; National Comprehensive Cancer Network. Prostate cancer, version 2.2014. J Natl Compr Canc Netw. 2014;12(5):686-718. 3. Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a large active surveillance
Another important factor that may reduce the generalizability of the results reported by Raldow et al5 is pathology expertise. Studies have shown that there is significant cancer upgrading when pathologic findings of non–prostate experts are reexamined by prostate experts.4 So what will it take for physicians and patients to be more comfortable with AS? Obviously, a better understanding of the biology of the cancer at hand would be very helpful. Efforts in that area are being made with the use of magnetic resonance imaging as well as the search for reliable tissue, serum, and urine biomarkers to help stratify disease.9,10 These are the areas where we need to focus our research efforts because simply repeating biopsies has its share of inconvenience and limitations even beyond the alarming increase in the risk of sepsis. So what can we learn from this study by Raldow et al?5 One of the most important findings is that favorable intermediaterisk cancers can be very well controlled with brachytherapy. This is very worthwhile information. What about expanding the indications for AS? Although I am a urologist who has been practicing active surveillance for most of my low-risk patients for many years, I suggest that we continue to be very cautious, and extremely selective, in offering AS to patients with any features of intermediate-risk prostate cancer.
cohort of patients with prostate cancer. J Clin Oncol. 2015;33(3):272-277. 4. Montironi R, Hammond EH, Lin DW, et al. Consensus statement with recommendations on active surveillance inclusion criteria and definition of progression in men with localized prostate cancer: the critical role of the pathologist. Virchows Arch. 2014;465(6):623-628. 5. Raldow AC, Zhang D, Chen M-H, Braccioforte MH, Moran BJ, D’Amico AV. Risk group and death from prostate cancer: implications for active surveillance in men with favorable intermediate-risk prostate cancer [published online February 19, 2015]. JAMA Oncology. doi:10.1001/jamaoncol.2014 .284. 6. Ploussard G, Isbarn H, Briganti A, et al; Members of the Prostate Cancer Working Group of the Young Academic Urologists Working Party of the European Association of Urology. Can we expand active surveillance criteria to include biopsy Gleason 3+4 prostate cancer? multi-institutional study of 2,323 patients [published online August 14, 2014]. Urol Oncol. doi:10.1016/j.urolonc.2014.07.007.
jamaoncology.com
7. Wilt TJ, Brawer MK, Jones KM, et al; Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367(3):203-213. 8. Lane JA, Donovan JL, Davis M, et al; ProtecT study group. Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial. Lancet Oncol. 2014;15(10):1109-1118. 9. Loeb S, Bruinsma SM, Nicholson J, et al. Active surveillance for prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification [published online October 31, 2014]. Eur Urol. doi:10.1016/j.eururo .2014.10.010. 10. Schoots IG, Petrides N, Giganti F, et al. Magnetic resonance imaging in active surveillance of prostate cancer: a systematic review [published online November 15, 2014]. Eur Urol. doi:10.1016/j .eururo.2014.10.050.
(Reprinted) JAMA Oncology June 2015 Volume 1, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://oncology.jamanetwork.com/ by a Yale University User on 07/22/2015
341
