- Email: [email protected]
Re: Effectiveness of Primary Androgen-Deprivation Therapy for Clinically Localized Prostate Cancer
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EUROPEAN UROLOGY 68 (2015) 736–741
Re: Can Clinically Significant Prostate Cancer Be Detected with Multiparametric Magnetic Resonance Imaging? A Systematic Review of the Literature Fu¨tterer JJ, Briganti A, De Visschere P, et al Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2015.01. 013 Experts’ summary: In this systematic review, the authors evaluated the diagnostic accuracy of multiparametric magnetic resonance imaging (mp-MRI) for detection of clinically significant prostate cancer (cs-PCa). The studies included in the review were heterogeneous in terms of MRI protocols, MRI target lesion reporting, the definitions used for cs-PCa, and the availability of radical prostatectomy specimens. The authors concluded that mpMRI had a diagnostic accuracy of 44–87% for cs-PCa detection, with a negative predictive value of 63–98%. These encouraging results have clinical implications in terms of routine use of MRI targets for guided biopsies and avoidance of unwanted biopsies in patients without abnormalities on MRI. Experts’ comments: Over the past decade, substantial progress in mp-MRI technology has resulted in excellent PCa localization. There is continuous robust research to improve existing techniques and MRI reporting. Sadly, the enthusiasm and investment focused on developing ultrasound (US) as a multiparametric technology are minimal. An important concern is whether we are ignoring the advantages of a basic tool over the glamour of advanced technology. Postema et al [1] recently published a systematic review of the limited literature available on mp-US. They found that addition of a lower-performing modality (combination of elastography/contrast-enhanced US [CEUS]/power Doppler) to conventional transrectal US (TRUS) biopsy via even crude methods improved TRUS sensitivity by 13–51%. In an unpublished study presented at the 2015 European Association of Urology congress, Wijkstra et al compared mp-MRI- and CEUSdetected lesions with the final histopathology for radical prostatectomy specimens and concluded that the order for overall diagnostic performance was mp-MRI + CEUS > CEUS alone > mp-MRI alone. Postema et al [2] introduced a novel quantification method for CEUS and showed that CEUS-guided targeted biopsies had a negative predictive value of 94%. Although the experience of individual centers needs to be validated, these encouraging results comparable to mp-MRI reinforce the need for intensive research to improve mp-US technology. Advances in mp-US techniques would have several specific advantages. First, US is widely available, cost-effective, simple, and less time-consuming compared to mp-MRI. Second, urologists in most worldwide centers perform TRUS, and addition of multiparametric adjuncts to TRUS could be easily accessed and interpreted by treating physicians.
Re: Effectiveness of Primary Androgen-Deprivation Therapy for Clinically Localized Prostate Cancer Potosky AL, Haque R, Cassidy-Bushrow AE, et al J Clin Oncol 2014;32:1324–30
These advantages would have a significant impact given the increasing incidence of PCa diagnoses, and could potentially eliminate tedious procedures and reduce costs and MRI waiting times, even in several developed countries. Third, TRUS images are more dynamic and real time compared to static MRI images. Technically, introduction of a multiparametric component to TRUS would provide dynamic images with real-time guidance for biopsy, which is performed separately in the case of MRI. Fourth, in spite of its high negative predictive value, several studies have shown that mp-MRI is liable to miss clinically significant high-grade prostate cancer [3]. In patients who underwent combined systematic/MRI-targeted biopsies, high-grade cancers were detected in systematic cores located at some distance from the target areas [4]. It will be very interesting to verify the mp-US imaging characteristics of these MRI-invisible cancers and assess the impact on diagnostic protocols. Fifth, confirmation of the feasibility of mp-US and mp-MRI fusion will be a significant step forward in prostate imaging [5]. This approach may not be appropriate for every patient for whom PCa is suspected, but it could represent an effective tool in downstream management of patients with equivocal findings or multiple prior negative biopsies. Sixth, with the evolving trend towards focal therapy, technical advances in mp-US can provide real-time monitoring and eventually verify the effectiveness of therapy. It is high time that we focus on improving the technology already in the hands of urologists and direct our research towards perfecting mp-US as an effective tool. mp-MRI is an excellent technology and it is possible that mp-US could establish a symbiotic co-existence in the armamentarium of prostate cancer imaging. Conflicts of interests: The authors have nothing to disclose.
References [1] Postema A, et al. World J Urol. In press. http://dx.doi.org/10.1007/ s00345-015-1523-6 [2] Postema A, et al. BJU Int. In press. http://dx.doi.org/10.1111/bju. 13116 [3] Isebaert S, et al. J Magn Reson Imaging 2013;37:1392–401. [4] Schoots IG, et al. Eur Urol. In press. http://dx.doi.org/10.1016/j. eururo.2014.11.037 [5] Brock M. J Urol 2015;193:1191–7. Arjun Sivaraman, Rafael Sanchez-Salas* Institute Mutualiste Montsouris, Paris, France *Corresponding author. Urology Department, Institute Mutualiste Montsouris, 42 Boulevard Jourdan, Paris 75014, France. E-mail address: [email protected] (R. Sanchez-Salas). http://dx.doi.org/10.1016/j.eururo.2015.06.033
Experts’ summary: In this retrospective cohort study from three integrated health care systems composed of 15 170 men diagnosed with localized prostate cancer between 1995 and 2008 who were not treated with curative intent, the authors found that primary
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EUROPEAN UROLOGY 68 (2015) 736–741
androgen deprivation therapy (PADT) was not associated with a reduced risk of all-cause, prostate cancer–specific, or cardiovascular mortality, with a median follow-up period of approximately 5 yr. In subgroup analysis, PADT was associated with a slightly reduced risk of all-cause mortality in the high-risk subgroup (hazard ratio [HR]: 0.88; 95% CI: 0.78– 0.97; p = 0.02) and a slightly increased risk among the low-risk men (HR: 1.41; 95% CI: 0.99–1.82; p = 0.02); however, prostate cancer–specific mortality did not differ among the low, intermediate, and high-risk groups. Experts’ comments: Although the use of PADT as the sole treatment of localized prostate cancer is not endorsed by clinical guidelines or approved by the US Food and Drug Administration [1], it is still commonly prescribed. An estimated 23% of men with localized prostate cancer in this study from Kaiser Permanente and Henry Ford Health System used PDAT. Previous work using Surveillance Epidemiology and End Results (SEER)–Medicare data also demonstrated considerable use of androgen deprivation therapy (ADT) as primary treatment for localized prostate cancer, even after Medicare reimbursement rates for certain forms of ADT declined [2]. The potential adverse effects of ADT are widely publicized, yet that has not halted its use as primary therapy for men with localized prostate cancer. This study provides more strong evidence that PADT does not improve all-cause or prostate cancer–specific mortality in men with localized prostate cancer. The reduced overall mortality risk in the high-risk subgroup and increased overall mortality risk in the low-risk subgroup should be interpreted cautiously, as residual confounding and lack of adjustment for multiple comparisons could account for these findings. There are limitations to this retrospective nonrandomized study, but the compelling data add to the argument against using PADT for the treatment of localized prostate cancer, especially when one considers the known metabolic,
Re: Risk of Myocardial Infarction in Older Men Receiving Testosterone Therapy Baillargeon J, Urban RJ, Kuo YF, et al Ann Pharmacother 2014;48:1138–44 Experts’ summary: In a retrospective cohort study of 6335 Medicare patients aged 66 yr and treated with intramuscular testosterone supplementation, testosterone therapy did not increase the risk of a cardiovascular event. In a subgroup of men from this cohort with elevated risk of myocardial infarction before treatment, testosterone therapy even decreased the risk of a major cardiovascular event (MACE). Experts’ comments: Hypogonadism is an independent biomarker for cardiovascular events and is associated with cardiovascular-related mortality [1]. Patients with cardiovascular diseases have lower levels of testosterone [2]. It would be expected that testosterone
cognitive, cardiovascular, and sexual-function side effects of ADT [3,4]. Potosky and colleagues reaffirmed that PADT, when compared with no therapy, likely has little to no impact on improving survival in men with localized prostate cancer. As urologic health care providers, we should carefully consider the risks, costs, and lack of proven efficacy before prescribing PADT to our patients with localized prostate cancer. Conflicts of interest: The authors have nothing to disclose.
References [1] Lupron depot [prescribing information]. Osaka, Japan: Takeda Pharmaceutical Company Limited; 2014. US Food and Drug Administration Web site. http://www.accessdata.fda.gov/drugsatfda_docs/ label/2014/020517s036_019732s041lbl.pdf. [2] Shahinian VB, Kuo YF, Gilbert SM. Reimbursement policy and androgen-deprivation therapy for prostate cancer. N Engl J Med 2010;363:1822–32. [3] Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol 2015; 67:825–36. [4] Fossa˚ SD, Nilssen Y, Kva˚le R, Hernes E, Axcrona K, Møller B. Treatment and 5-year survival in patients with nonmetastatic prostate cancer: the Norwegian experience. Urology 2014;83:146–52. Kefu Du, Patrik Luzny, William T. Lowrance* Department of Surgery, Division of Urology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA *Corresponding author. Department of Surgery, Division of Urology, Huntsman Cancer Institute, University of Utah, 1950 Circle of Hope, #6405, Salt Lake City, UT 84112, USA. E-mail address: [email protected] (W.T. Lowrance). http://dx.doi.org/10.1016/j.eururo.2015.06.034
supplementation in these patients could potentially decrease the risk of cardiovascular incidents. Instead, two recent studies indicated a higher risk of cardiovascular events in men receiving testosterone supplementation [3,4]. Both studies have been criticized for methodological and statistical shortcomings [5]. The effects of testosterone therapy on the cardiovascular system are complex: testosterone has a positive influence on body composition, lipid profile, and insulin resistance [1], but can also cause fluid retention, increase blood pressure, and elevate hematocrit [2]. The study by Baillargeon et al has added important new data to the controversy regarding the cardiovascular safety of testosterone therapy. In a large sample of patients using testosterone and matched controls, no increase in MACE was observed. In fact, testosterone therapy reduced the risk of MACE in men with cardiovascular risk factors. Despite these reassuring results, caution in their interpretation is warranted. The authors balance the limitations of their study with the strengths, the most important being the
EUROPEAN UROLOGY 68 (2015) 736–741
Re: Can Clinically Significant Prostate Cancer Be Detected with Multiparametric Magnetic Resonance Imaging? A Systematic Review of the Literature Fu¨tterer JJ, Briganti A, De Visschere P, et al Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2015.01. 013 Experts’ summary: In this systematic review, the authors evaluated the diagnostic accuracy of multiparametric magnetic resonance imaging (mp-MRI) for detection of clinically significant prostate cancer (cs-PCa). The studies included in the review were heterogeneous in terms of MRI protocols, MRI target lesion reporting, the definitions used for cs-PCa, and the availability of radical prostatectomy specimens. The authors concluded that mpMRI had a diagnostic accuracy of 44–87% for cs-PCa detection, with a negative predictive value of 63–98%. These encouraging results have clinical implications in terms of routine use of MRI targets for guided biopsies and avoidance of unwanted biopsies in patients without abnormalities on MRI. Experts’ comments: Over the past decade, substantial progress in mp-MRI technology has resulted in excellent PCa localization. There is continuous robust research to improve existing techniques and MRI reporting. Sadly, the enthusiasm and investment focused on developing ultrasound (US) as a multiparametric technology are minimal. An important concern is whether we are ignoring the advantages of a basic tool over the glamour of advanced technology. Postema et al [1] recently published a systematic review of the limited literature available on mp-US. They found that addition of a lower-performing modality (combination of elastography/contrast-enhanced US [CEUS]/power Doppler) to conventional transrectal US (TRUS) biopsy via even crude methods improved TRUS sensitivity by 13–51%. In an unpublished study presented at the 2015 European Association of Urology congress, Wijkstra et al compared mp-MRI- and CEUSdetected lesions with the final histopathology for radical prostatectomy specimens and concluded that the order for overall diagnostic performance was mp-MRI + CEUS > CEUS alone > mp-MRI alone. Postema et al [2] introduced a novel quantification method for CEUS and showed that CEUS-guided targeted biopsies had a negative predictive value of 94%. Although the experience of individual centers needs to be validated, these encouraging results comparable to mp-MRI reinforce the need for intensive research to improve mp-US technology. Advances in mp-US techniques would have several specific advantages. First, US is widely available, cost-effective, simple, and less time-consuming compared to mp-MRI. Second, urologists in most worldwide centers perform TRUS, and addition of multiparametric adjuncts to TRUS could be easily accessed and interpreted by treating physicians.
Re: Effectiveness of Primary Androgen-Deprivation Therapy for Clinically Localized Prostate Cancer Potosky AL, Haque R, Cassidy-Bushrow AE, et al J Clin Oncol 2014;32:1324–30
These advantages would have a significant impact given the increasing incidence of PCa diagnoses, and could potentially eliminate tedious procedures and reduce costs and MRI waiting times, even in several developed countries. Third, TRUS images are more dynamic and real time compared to static MRI images. Technically, introduction of a multiparametric component to TRUS would provide dynamic images with real-time guidance for biopsy, which is performed separately in the case of MRI. Fourth, in spite of its high negative predictive value, several studies have shown that mp-MRI is liable to miss clinically significant high-grade prostate cancer [3]. In patients who underwent combined systematic/MRI-targeted biopsies, high-grade cancers were detected in systematic cores located at some distance from the target areas [4]. It will be very interesting to verify the mp-US imaging characteristics of these MRI-invisible cancers and assess the impact on diagnostic protocols. Fifth, confirmation of the feasibility of mp-US and mp-MRI fusion will be a significant step forward in prostate imaging [5]. This approach may not be appropriate for every patient for whom PCa is suspected, but it could represent an effective tool in downstream management of patients with equivocal findings or multiple prior negative biopsies. Sixth, with the evolving trend towards focal therapy, technical advances in mp-US can provide real-time monitoring and eventually verify the effectiveness of therapy. It is high time that we focus on improving the technology already in the hands of urologists and direct our research towards perfecting mp-US as an effective tool. mp-MRI is an excellent technology and it is possible that mp-US could establish a symbiotic co-existence in the armamentarium of prostate cancer imaging. Conflicts of interests: The authors have nothing to disclose.
References [1] Postema A, et al. World J Urol. In press. http://dx.doi.org/10.1007/ s00345-015-1523-6 [2] Postema A, et al. BJU Int. In press. http://dx.doi.org/10.1111/bju. 13116 [3] Isebaert S, et al. J Magn Reson Imaging 2013;37:1392–401. [4] Schoots IG, et al. Eur Urol. In press. http://dx.doi.org/10.1016/j. eururo.2014.11.037 [5] Brock M. J Urol 2015;193:1191–7. Arjun Sivaraman, Rafael Sanchez-Salas* Institute Mutualiste Montsouris, Paris, France *Corresponding author. Urology Department, Institute Mutualiste Montsouris, 42 Boulevard Jourdan, Paris 75014, France. E-mail address: [email protected] (R. Sanchez-Salas). http://dx.doi.org/10.1016/j.eururo.2015.06.033
Experts’ summary: In this retrospective cohort study from three integrated health care systems composed of 15 170 men diagnosed with localized prostate cancer between 1995 and 2008 who were not treated with curative intent, the authors found that primary
739
EUROPEAN UROLOGY 68 (2015) 736–741
androgen deprivation therapy (PADT) was not associated with a reduced risk of all-cause, prostate cancer–specific, or cardiovascular mortality, with a median follow-up period of approximately 5 yr. In subgroup analysis, PADT was associated with a slightly reduced risk of all-cause mortality in the high-risk subgroup (hazard ratio [HR]: 0.88; 95% CI: 0.78– 0.97; p = 0.02) and a slightly increased risk among the low-risk men (HR: 1.41; 95% CI: 0.99–1.82; p = 0.02); however, prostate cancer–specific mortality did not differ among the low, intermediate, and high-risk groups. Experts’ comments: Although the use of PADT as the sole treatment of localized prostate cancer is not endorsed by clinical guidelines or approved by the US Food and Drug Administration [1], it is still commonly prescribed. An estimated 23% of men with localized prostate cancer in this study from Kaiser Permanente and Henry Ford Health System used PDAT. Previous work using Surveillance Epidemiology and End Results (SEER)–Medicare data also demonstrated considerable use of androgen deprivation therapy (ADT) as primary treatment for localized prostate cancer, even after Medicare reimbursement rates for certain forms of ADT declined [2]. The potential adverse effects of ADT are widely publicized, yet that has not halted its use as primary therapy for men with localized prostate cancer. This study provides more strong evidence that PADT does not improve all-cause or prostate cancer–specific mortality in men with localized prostate cancer. The reduced overall mortality risk in the high-risk subgroup and increased overall mortality risk in the low-risk subgroup should be interpreted cautiously, as residual confounding and lack of adjustment for multiple comparisons could account for these findings. There are limitations to this retrospective nonrandomized study, but the compelling data add to the argument against using PADT for the treatment of localized prostate cancer, especially when one considers the known metabolic,
Re: Risk of Myocardial Infarction in Older Men Receiving Testosterone Therapy Baillargeon J, Urban RJ, Kuo YF, et al Ann Pharmacother 2014;48:1138–44 Experts’ summary: In a retrospective cohort study of 6335 Medicare patients aged 66 yr and treated with intramuscular testosterone supplementation, testosterone therapy did not increase the risk of a cardiovascular event. In a subgroup of men from this cohort with elevated risk of myocardial infarction before treatment, testosterone therapy even decreased the risk of a major cardiovascular event (MACE). Experts’ comments: Hypogonadism is an independent biomarker for cardiovascular events and is associated with cardiovascular-related mortality [1]. Patients with cardiovascular diseases have lower levels of testosterone [2]. It would be expected that testosterone
cognitive, cardiovascular, and sexual-function side effects of ADT [3,4]. Potosky and colleagues reaffirmed that PADT, when compared with no therapy, likely has little to no impact on improving survival in men with localized prostate cancer. As urologic health care providers, we should carefully consider the risks, costs, and lack of proven efficacy before prescribing PADT to our patients with localized prostate cancer. Conflicts of interest: The authors have nothing to disclose.
References [1] Lupron depot [prescribing information]. Osaka, Japan: Takeda Pharmaceutical Company Limited; 2014. US Food and Drug Administration Web site. http://www.accessdata.fda.gov/drugsatfda_docs/ label/2014/020517s036_019732s041lbl.pdf. [2] Shahinian VB, Kuo YF, Gilbert SM. Reimbursement policy and androgen-deprivation therapy for prostate cancer. N Engl J Med 2010;363:1822–32. [3] Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol 2015; 67:825–36. [4] Fossa˚ SD, Nilssen Y, Kva˚le R, Hernes E, Axcrona K, Møller B. Treatment and 5-year survival in patients with nonmetastatic prostate cancer: the Norwegian experience. Urology 2014;83:146–52. Kefu Du, Patrik Luzny, William T. Lowrance* Department of Surgery, Division of Urology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA *Corresponding author. Department of Surgery, Division of Urology, Huntsman Cancer Institute, University of Utah, 1950 Circle of Hope, #6405, Salt Lake City, UT 84112, USA. E-mail address: [email protected] (W.T. Lowrance). http://dx.doi.org/10.1016/j.eururo.2015.06.034
supplementation in these patients could potentially decrease the risk of cardiovascular incidents. Instead, two recent studies indicated a higher risk of cardiovascular events in men receiving testosterone supplementation [3,4]. Both studies have been criticized for methodological and statistical shortcomings [5]. The effects of testosterone therapy on the cardiovascular system are complex: testosterone has a positive influence on body composition, lipid profile, and insulin resistance [1], but can also cause fluid retention, increase blood pressure, and elevate hematocrit [2]. The study by Baillargeon et al has added important new data to the controversy regarding the cardiovascular safety of testosterone therapy. In a large sample of patients using testosterone and matched controls, no increase in MACE was observed. In fact, testosterone therapy reduced the risk of MACE in men with cardiovascular risk factors. Despite these reassuring results, caution in their interpretation is warranted. The authors balance the limitations of their study with the strengths, the most important being the