- Email: [email protected]
Effective Management of Localized Prostate Cancer: First, Do No Harm
EUROPEAN UROLOGY 64 (2013) 379–380
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 372–378 of this issue
Effective Management of Localized Prostate Cancer: First, Do No Harm Behfar Ehdaie a,b, James A. Eastham a,* a
Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; b Health Outcomes Research Group,
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
The diagnosis of prostate cancer (PCa) is a difficult reality, regardless of age, health status, or disease risk, and management decisions for localized disease are complex because of the paucity of evidence comparing various treatment options. In a 2008 review, ‘‘Comparative Effectiveness and Harms of Treatments for Clinically Localized Prostate Cancer,’’ prepared for the US 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]. The results of the recent randomized trial comparing observation and definitive treatment in men with localized PCa (Prostate Cancer Intervention Versus Observation Trial [PIVOT]) have further complicated management decisions [2]. However, recommendations for treatment of localized PCa should be individualized to patient characteristics, including health status, life expectancy, and treatment preference. In a shared-decision model, prognosis and life expectancy are difficult concepts for physicians and patients. Importantly, physician estimates of healthadjusted life expectancy are imprecise [3]. In the PIVOT trial, patients were enrolled if their life expectancy was estimated to be >10 yr; however, 48.4% and 47% of patients in the surgery and observation groups, respectively, died at 12 yr, and only 7.1% of deaths were attributed to PCa. Life expectancy estimations are a key component of treatment decisions for localized PCa, as shown by the inclusion of a 10-yr life expectancy benchmark in the recommendations of the American Urological Association [4] and the National Comprehensive Cancer Network guidelines [5].
Chronological age is a standard tool used to estimate life expectancy because it is readily available for physicians. However, comorbidity has a significant impact on health status and treatment tolerance. Identifying comorbidity and health status in a patient enables physicians to individualize treatment recommendations based on biologic age. Importantly, the association between age and comorbidity with cancer diagnosis is well established, and an estimated 68% of patients diagnosed with cancer have comorbidity. The frequency of comorbidity is increased in elderly and African American patients [6], thus many comorbidity assessment tools have been developed and validated in clinical practice. The Charlson comorbidity index is one of the most wellknown validated tools and predicts 1-yr mortality for hospitalized patients [7]. In addition, it has been shown to be a significant independent predictor of survival in patients with clinically localized PCa [8]. The validity of any comorbidity prognostic tool assumes an accurate assessment of comorbidity severity. In this issue of European Urology, Nepple and colleagues evaluate the impact of treatment on prostate cancer mortality (PCM) and overall mortality (OM) in men with localized PCa [9]. In this retrospective multi-institutional observational study, the authors focus on improving the accuracy of their comparisons among treatment options and mitigating the impact of medical comorbidity by restricting their analysis to men with no documented comorbidities. The authors studied a group of healthy men diagnosed with localized PCa who would benefit most from effective treatment. In men without recorded medical comorbidity, external-beam radiation therapy (ERBT) was
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2013.03.005. * Corresponding author. Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA. Tel. +1 646 735 8141; Fax: +1 646 735 0011. E-mail address: [email protected] (J.A. Eastham). 0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eururo.2013.03.035
380
EUROPEAN UROLOGY 64 (2013) 379–380
associated with an increased risk of PCM compared with radical prostatectomy (RP) after adjusting for patient and tumor characteristics. However, a competing risks model failed to demonstrate a difference in PCM between men treated with either brachytherapy (BT) or EBRT compared with RP. In comparison with RP, both EBRT and BT were associated with an increased risk of OM. The study emphasizes the difficulty in making comparisons among treatment options in localized PCa in the absence of randomization [9]. Despite the use of restriction analysis to minimize the effect of confounding bias, we agree with the authors’ conclusion that an imbalance of unmeasured factors may have contributed to the failure to demonstrate a significant difference in PCM among treatments. The competing-risks analysis is critical for a disease such as PCa with a long latency period. The disparate results indicating the impact of treatment with EBRT on PCM between the competing-risks model and other statistical analyses highlights the importance of accurately recording cause-of-death data because the error can differ based on treatment modality and confound the assessment of PCM. Androgen deprivation therapy (ADT), for example, is used more commonly with EBRT for the primary management of localized high PCa and is associated with incident coronary artery disease, diabetes, and thromboembolic events, thereby increasing the risk of mortality [10,11]. In addition, EBRT is associated with increased risk of secondary malignancies that may be recorded as othercause mortality and affect the results of a competing-risks model, thereby confounding the evaluation of PCM. Surrogate end points such as metastases are similarly complex to evaluate because of the latent natural history of localized PCa and the timing or use of salvage therapy [12]. Despite the limitations in the current study by Nepple and colleagues [9], we agree with the authors’ conclusions that their results suggest that healthy men with PCa treated with either form of radiation therapy (RT) have an increased risk of OM than men treated with RP. What remains unclear is why. Several possibilities can be postulated. Surgery carries more immediate risk than RT, so perhaps surgeons are more conservative than radiation oncologists in classifying men as having no comorbidities. Perhaps surgery provides better loco-regional cancer control than RT or enables early detection of recurrence and early institution of more effective secondary therapy. Finally, radiation may increase OM either directly or indirectly through the use of ADT. Future studies are needed to confirm or refute the findings in this study. In addition, improved tools for
assessment of comorbidity and health status need to be developed to better assist physicians and patients in shared decision making regarding primary treatment for localized PCa. Conflicts of interest: The authors have nothing to disclose.
References [1] Minnesota Evidence-based Practice Center Investigators; Wilt TJ, Shamliyan T, Taylor B, et al. Comparative effectiveness of therapies for clinically localized prostate cancer [AHRQ publication no. 08EHC010-EF]. US Agency for Healthcare Research and Quality Web site. http://www.effectivehealthcare.ahrq.gov/repFiles/2008_0204 ProstateCancerFinal.pdf. Published February 2008. [2] Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012;367: 203–13. [3] Wilson JR, Clarke MG, Ewings P, et al. The assessment of patient lifeexpectancy: how accurate are urologists and oncologists? BJU Int 2005;95:794–8. [4] Prostate cancer. Guideline for the management of clinically localized prostate cancer: 2007 update. American Urological Association Web site. http://www.auanet.org/content/guidelines-and-qualitycare/clinical-guidelines/main-reports/proscan07/content.pdf. [5] NCCN clinical practice guidelines in oncology: prostate cancer. National Comprehensive Cancer Network Web site. http://www. nccn.org/professionals/physician_gls/pdf/prostate.pdf. Updated 2013. [6] Ogle KS, Swanson GM, Woods N, et al. Cancer and comorbidity: redefining chronic diseases. Cancer 2000;88:653–63. [7] Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83. [8] Kastner C, Armitage J, Kimble A, et al. The Charlson comorbidity score: a superior comorbidity assessment tool for the prostate cancer multidisciplinary meeting. Prostate Cancer Prostatic Dis 2006; 9:270–4. [9] Nepple KG, Stephenson AJ, Kallogjeri D, et al. Mortality after prostate cancer treatment with radical prostatectomy, external beam radiation therapy, or brachytherapy in men without comorbidity. Eur Urol 2013;64:372–8. [10] Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006;24:4448–56. [11] Ehdaie B, Atoria CL, Gupta A, et al. Androgen deprivation and thromboembolic events in men with prostate cancer. Cancer 2012;118: 3397–406. [12] Zelefsky MJ, Eastham JA, Cronin AM, et al. Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. J Clin Oncol 2010;28:1508–13.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 372–378 of this issue
Effective Management of Localized Prostate Cancer: First, Do No Harm Behfar Ehdaie a,b, James A. Eastham a,* a
Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; b Health Outcomes Research Group,
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
The diagnosis of prostate cancer (PCa) is a difficult reality, regardless of age, health status, or disease risk, and management decisions for localized disease are complex because of the paucity of evidence comparing various treatment options. In a 2008 review, ‘‘Comparative Effectiveness and Harms of Treatments for Clinically Localized Prostate Cancer,’’ prepared for the US 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]. The results of the recent randomized trial comparing observation and definitive treatment in men with localized PCa (Prostate Cancer Intervention Versus Observation Trial [PIVOT]) have further complicated management decisions [2]. However, recommendations for treatment of localized PCa should be individualized to patient characteristics, including health status, life expectancy, and treatment preference. In a shared-decision model, prognosis and life expectancy are difficult concepts for physicians and patients. Importantly, physician estimates of healthadjusted life expectancy are imprecise [3]. In the PIVOT trial, patients were enrolled if their life expectancy was estimated to be >10 yr; however, 48.4% and 47% of patients in the surgery and observation groups, respectively, died at 12 yr, and only 7.1% of deaths were attributed to PCa. Life expectancy estimations are a key component of treatment decisions for localized PCa, as shown by the inclusion of a 10-yr life expectancy benchmark in the recommendations of the American Urological Association [4] and the National Comprehensive Cancer Network guidelines [5].
Chronological age is a standard tool used to estimate life expectancy because it is readily available for physicians. However, comorbidity has a significant impact on health status and treatment tolerance. Identifying comorbidity and health status in a patient enables physicians to individualize treatment recommendations based on biologic age. Importantly, the association between age and comorbidity with cancer diagnosis is well established, and an estimated 68% of patients diagnosed with cancer have comorbidity. The frequency of comorbidity is increased in elderly and African American patients [6], thus many comorbidity assessment tools have been developed and validated in clinical practice. The Charlson comorbidity index is one of the most wellknown validated tools and predicts 1-yr mortality for hospitalized patients [7]. In addition, it has been shown to be a significant independent predictor of survival in patients with clinically localized PCa [8]. The validity of any comorbidity prognostic tool assumes an accurate assessment of comorbidity severity. In this issue of European Urology, Nepple and colleagues evaluate the impact of treatment on prostate cancer mortality (PCM) and overall mortality (OM) in men with localized PCa [9]. In this retrospective multi-institutional observational study, the authors focus on improving the accuracy of their comparisons among treatment options and mitigating the impact of medical comorbidity by restricting their analysis to men with no documented comorbidities. The authors studied a group of healthy men diagnosed with localized PCa who would benefit most from effective treatment. In men without recorded medical comorbidity, external-beam radiation therapy (ERBT) was
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2013.03.005. * Corresponding author. Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA. Tel. +1 646 735 8141; Fax: +1 646 735 0011. E-mail address: [email protected] (J.A. Eastham). 0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eururo.2013.03.035
380
EUROPEAN UROLOGY 64 (2013) 379–380
associated with an increased risk of PCM compared with radical prostatectomy (RP) after adjusting for patient and tumor characteristics. However, a competing risks model failed to demonstrate a difference in PCM between men treated with either brachytherapy (BT) or EBRT compared with RP. In comparison with RP, both EBRT and BT were associated with an increased risk of OM. The study emphasizes the difficulty in making comparisons among treatment options in localized PCa in the absence of randomization [9]. Despite the use of restriction analysis to minimize the effect of confounding bias, we agree with the authors’ conclusion that an imbalance of unmeasured factors may have contributed to the failure to demonstrate a significant difference in PCM among treatments. The competing-risks analysis is critical for a disease such as PCa with a long latency period. The disparate results indicating the impact of treatment with EBRT on PCM between the competing-risks model and other statistical analyses highlights the importance of accurately recording cause-of-death data because the error can differ based on treatment modality and confound the assessment of PCM. Androgen deprivation therapy (ADT), for example, is used more commonly with EBRT for the primary management of localized high PCa and is associated with incident coronary artery disease, diabetes, and thromboembolic events, thereby increasing the risk of mortality [10,11]. In addition, EBRT is associated with increased risk of secondary malignancies that may be recorded as othercause mortality and affect the results of a competing-risks model, thereby confounding the evaluation of PCM. Surrogate end points such as metastases are similarly complex to evaluate because of the latent natural history of localized PCa and the timing or use of salvage therapy [12]. Despite the limitations in the current study by Nepple and colleagues [9], we agree with the authors’ conclusions that their results suggest that healthy men with PCa treated with either form of radiation therapy (RT) have an increased risk of OM than men treated with RP. What remains unclear is why. Several possibilities can be postulated. Surgery carries more immediate risk than RT, so perhaps surgeons are more conservative than radiation oncologists in classifying men as having no comorbidities. Perhaps surgery provides better loco-regional cancer control than RT or enables early detection of recurrence and early institution of more effective secondary therapy. Finally, radiation may increase OM either directly or indirectly through the use of ADT. Future studies are needed to confirm or refute the findings in this study. In addition, improved tools for
assessment of comorbidity and health status need to be developed to better assist physicians and patients in shared decision making regarding primary treatment for localized PCa. Conflicts of interest: The authors have nothing to disclose.
References [1] Minnesota Evidence-based Practice Center Investigators; Wilt TJ, Shamliyan T, Taylor B, et al. Comparative effectiveness of therapies for clinically localized prostate cancer [AHRQ publication no. 08EHC010-EF]. US Agency for Healthcare Research and Quality Web site. http://www.effectivehealthcare.ahrq.gov/repFiles/2008_0204 ProstateCancerFinal.pdf. Published February 2008. [2] Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012;367: 203–13. [3] Wilson JR, Clarke MG, Ewings P, et al. The assessment of patient lifeexpectancy: how accurate are urologists and oncologists? BJU Int 2005;95:794–8. [4] Prostate cancer. Guideline for the management of clinically localized prostate cancer: 2007 update. American Urological Association Web site. http://www.auanet.org/content/guidelines-and-qualitycare/clinical-guidelines/main-reports/proscan07/content.pdf. [5] NCCN clinical practice guidelines in oncology: prostate cancer. National Comprehensive Cancer Network Web site. http://www. nccn.org/professionals/physician_gls/pdf/prostate.pdf. Updated 2013. [6] Ogle KS, Swanson GM, Woods N, et al. Cancer and comorbidity: redefining chronic diseases. Cancer 2000;88:653–63. [7] Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83. [8] Kastner C, Armitage J, Kimble A, et al. The Charlson comorbidity score: a superior comorbidity assessment tool for the prostate cancer multidisciplinary meeting. Prostate Cancer Prostatic Dis 2006; 9:270–4. [9] Nepple KG, Stephenson AJ, Kallogjeri D, et al. Mortality after prostate cancer treatment with radical prostatectomy, external beam radiation therapy, or brachytherapy in men without comorbidity. Eur Urol 2013;64:372–8. [10] Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006;24:4448–56. [11] Ehdaie B, Atoria CL, Gupta A, et al. Androgen deprivation and thromboembolic events in men with prostate cancer. Cancer 2012;118: 3397–406. [12] Zelefsky MJ, Eastham JA, Cronin AM, et al. Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. J Clin Oncol 2010;28:1508–13.