- Email: [email protected]
Re: Economic Evaluation of Denosumab Compared With Zoledronic Acid in Hormone-Refractory Prostate Cancer Patients With Bone Metastases
427
EUROPEAN UROLOGY 61 (2012) 423–428
In this prospective randomized multicenter trial, O’Brien and colleagues demonstrated that a single administration of 40 mg of intravesical MMC reduces the probability of BCa occurrence within the first 12 mo following RNU. In perprotocol analyses, the absolute risk reduction with MMC was 11%, and the number of patients needed to prevent one BCa was nine. This effect was only seen in cases managed by open RNU with bladder cuff. However, this trial was not designed, and was underpowered, to detect differences according to the type of surgery. Further important limitations are an unstandardized surgical approach, including management of the distal ureter, and the fact that BCa was diagnosed by cystoscopy only, without histologic proof.
BCa risk in patients with prior BCa or in patients who were treated by segmental ureterectomy. Conflicts of interest: The authors have nothing to disclose.
References [1] Roupreˆt M, Zigeuner R, Palou J, et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Eur Urol 2011;59:584–94. [2] Boorjian SA. Postoperative intravesical therapy to prevent bladder tumor recurrence: are we ready to listen yet? Eur Urol 2011;60: 711–2. Mesut Remzia,*, Tobias Klatteb
Experts’ comments: This prospective randomized trial provides us with level 1 evidence for management of UTUC. With this evidence, our practice pattern should be changed and our guidelines should be adjusted. In every patient without prior BCa who underwent RNU for UTUC, 40 mg of intravesical MMC should be administered at the time of catheter removal. We agree with Boorjian [2] that the trial limitations do not justify the nonuse of MMC. Future trials should evaluate whether MMC reduces
Re: Economic Evaluation of Denosumab Compared With Zoledronic Acid in Hormone-Refractory Prostate Cancer Patients With Bone Metastases Xie J, Namjoshi M, Wu EQ, et al J Manag Care Pharm 2011;17:621–34 Experts’ summary: The authors tried to compare the cost effectiveness of denosumab (a human monoclonal antibody that binds to the receptor activator of nuclear factor kappa B ligand) and bisphosphonate zoledronic acid in the treatment of bone metastases in men with castration-resistant prostate cancer (CRPC). They analysed the phase 3 trial of Fizazi et al. [1]. Using the Markov model, costs and effectiveness over 1 and 3 yr were analysed. This calculation uses different assumptions in a theoretical model and so-called transition probabilities associated with experiencing the first skeletal-related event (SRE), subsequent SREs, disease progression, and death. Drug and nondrug costs with incremental costs were calculated, as well as the costs of treating adverse events. The estimated number of SREs per patient during the 1-yr period was 0.49 for denosumab and 0.60 for zoledronic acid, resulting in an incremental number of SREs of 0.11 for denosumab and incremental direct costs for denosumab of US$7813. The authors conclude that denosumab is a costly alternative to zoledronic acid that offers only a small advantage over the current standard treatment. Experts’ comments: The therapeutic spectrum in CRPC is rapidly expanding and includes inhibition of androgen biosynthesis by blocking cytochrome P450 c17 (abiraterone acetate), novel cytotoxic
a
Department of Urology, Landesklinikum Weinviertel-Korneuburg, Korneuburg, Austria
b
Department of Urology, Medical University of Vienna, Vienna, Austria *Corresponding author. LKH Weinviertel- Korneuburg, Urology, Wiener Ring 3-5, Korneuburg, 2100, Austria. E-mail address: [email protected] (M. Remzi)
DOI: 10.1016/j.eururo.2011.11.026
chemotherapy (cabazitaxel), and active cellular immunotherapy (sipuleucel-T) [2]. Furthermore, bone-targeted strategies are an important part of integrated treatment with the current focus on inhibition of osteoclast-mediated bone resorption [3]. In a recent randomised double-blind study, denosumab was superior in delaying time to the first on-study SRE compared with zoledronic acid (median: 20.7 vs 17.1 mo, respectively; p = 0.008) [1]. Median prostate-specific antigen levels during the study, overall survival, and adverse events were similar between both groups. However, as in most phase 3 trials, cost effectiveness analysis has not been applied. In daily clinical practice, physicians are either not aware of or do not care much for the costs they create. Xie and colleagues try to fill this gap with the aid of the Markov model [4]. With the main parameters being similar, the key question becomes the clinical relevance of a 3.6-mo delay of first SRE compared with the US$7813 spent. This question, of course, is an ethical and socioeconomic one rather than a medical one and cannot be discussed in the framework of this short comment. However, there are some hints that denosumab is not the expected breakthrough in osteoprotective therapy. First, the profile of adverse events seems to be less favourable compared with zoledronic acid: cumulative osteonecrosis of the jaw (22 vs 12 patients, respectively), hypocalcaemia (121 vs 55 patients, respectively), and new primary malignant disease (18 vs 10 patients, respectively) [1]. The long-term influence of denosumab on the immune system is not known. Second, as of March 2013, zoledronic acid will be available in its generic form and thus will be even less expensive. Third, another study estimated an incremental cost per qualityadjusted life-year of US$1.25 million comparing denosumab
428
EUROPEAN UROLOGY 61 (2012) 423–428
and zoledronic acid use over 27 mo, using the Fizazi et al trial [5]. In conclusion, we suggest that in phase 3 studies not only the classic end points and adverse events be evaluated but also the real-life costs in each treatment arm. A sophisticated calculation based on a model, as in the Xie et al study, would therefore no longer be necessary. Conflicts of interest: The authors have nothing to disclose.
[3] Beltran H, et al. Eur Urol 2011;60:279–90. [4] Sonnenberg FA, et al. Med Decis Making 1993;13:322–38. [5] Snedecor SJ, et al. J Clin Oncol 2011;29(Suppl):4581.
Hans-Peter Schmida,*, Robert Theilerb a
Department of Urology, Kantonsspital, St. Gallen, Switzerland
b
Department of Rheumatology, Stadtspital Triemli, Zu¨rich, Switzerland
*Corresponding author. Kantonsspital, Urology, Rorschacher Strasse 95, St. Gallen, 9007, Switzerland.
References
E-mail address: [email protected] (H.-P. Schmid)
[1] Fizazi K, et al. Lancet 2011;377:813–22. [2] Mottet N, et al. Eur Urol 2011;59:572–83.
DOI: 10.1016/j.eururo.2011.11.027
EUROPEAN UROLOGY 61 (2012) 423–428
In this prospective randomized multicenter trial, O’Brien and colleagues demonstrated that a single administration of 40 mg of intravesical MMC reduces the probability of BCa occurrence within the first 12 mo following RNU. In perprotocol analyses, the absolute risk reduction with MMC was 11%, and the number of patients needed to prevent one BCa was nine. This effect was only seen in cases managed by open RNU with bladder cuff. However, this trial was not designed, and was underpowered, to detect differences according to the type of surgery. Further important limitations are an unstandardized surgical approach, including management of the distal ureter, and the fact that BCa was diagnosed by cystoscopy only, without histologic proof.
BCa risk in patients with prior BCa or in patients who were treated by segmental ureterectomy. Conflicts of interest: The authors have nothing to disclose.
References [1] Roupreˆt M, Zigeuner R, Palou J, et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Eur Urol 2011;59:584–94. [2] Boorjian SA. Postoperative intravesical therapy to prevent bladder tumor recurrence: are we ready to listen yet? Eur Urol 2011;60: 711–2. Mesut Remzia,*, Tobias Klatteb
Experts’ comments: This prospective randomized trial provides us with level 1 evidence for management of UTUC. With this evidence, our practice pattern should be changed and our guidelines should be adjusted. In every patient without prior BCa who underwent RNU for UTUC, 40 mg of intravesical MMC should be administered at the time of catheter removal. We agree with Boorjian [2] that the trial limitations do not justify the nonuse of MMC. Future trials should evaluate whether MMC reduces
Re: Economic Evaluation of Denosumab Compared With Zoledronic Acid in Hormone-Refractory Prostate Cancer Patients With Bone Metastases Xie J, Namjoshi M, Wu EQ, et al J Manag Care Pharm 2011;17:621–34 Experts’ summary: The authors tried to compare the cost effectiveness of denosumab (a human monoclonal antibody that binds to the receptor activator of nuclear factor kappa B ligand) and bisphosphonate zoledronic acid in the treatment of bone metastases in men with castration-resistant prostate cancer (CRPC). They analysed the phase 3 trial of Fizazi et al. [1]. Using the Markov model, costs and effectiveness over 1 and 3 yr were analysed. This calculation uses different assumptions in a theoretical model and so-called transition probabilities associated with experiencing the first skeletal-related event (SRE), subsequent SREs, disease progression, and death. Drug and nondrug costs with incremental costs were calculated, as well as the costs of treating adverse events. The estimated number of SREs per patient during the 1-yr period was 0.49 for denosumab and 0.60 for zoledronic acid, resulting in an incremental number of SREs of 0.11 for denosumab and incremental direct costs for denosumab of US$7813. The authors conclude that denosumab is a costly alternative to zoledronic acid that offers only a small advantage over the current standard treatment. Experts’ comments: The therapeutic spectrum in CRPC is rapidly expanding and includes inhibition of androgen biosynthesis by blocking cytochrome P450 c17 (abiraterone acetate), novel cytotoxic
a
Department of Urology, Landesklinikum Weinviertel-Korneuburg, Korneuburg, Austria
b
Department of Urology, Medical University of Vienna, Vienna, Austria *Corresponding author. LKH Weinviertel- Korneuburg, Urology, Wiener Ring 3-5, Korneuburg, 2100, Austria. E-mail address: [email protected] (M. Remzi)
DOI: 10.1016/j.eururo.2011.11.026
chemotherapy (cabazitaxel), and active cellular immunotherapy (sipuleucel-T) [2]. Furthermore, bone-targeted strategies are an important part of integrated treatment with the current focus on inhibition of osteoclast-mediated bone resorption [3]. In a recent randomised double-blind study, denosumab was superior in delaying time to the first on-study SRE compared with zoledronic acid (median: 20.7 vs 17.1 mo, respectively; p = 0.008) [1]. Median prostate-specific antigen levels during the study, overall survival, and adverse events were similar between both groups. However, as in most phase 3 trials, cost effectiveness analysis has not been applied. In daily clinical practice, physicians are either not aware of or do not care much for the costs they create. Xie and colleagues try to fill this gap with the aid of the Markov model [4]. With the main parameters being similar, the key question becomes the clinical relevance of a 3.6-mo delay of first SRE compared with the US$7813 spent. This question, of course, is an ethical and socioeconomic one rather than a medical one and cannot be discussed in the framework of this short comment. However, there are some hints that denosumab is not the expected breakthrough in osteoprotective therapy. First, the profile of adverse events seems to be less favourable compared with zoledronic acid: cumulative osteonecrosis of the jaw (22 vs 12 patients, respectively), hypocalcaemia (121 vs 55 patients, respectively), and new primary malignant disease (18 vs 10 patients, respectively) [1]. The long-term influence of denosumab on the immune system is not known. Second, as of March 2013, zoledronic acid will be available in its generic form and thus will be even less expensive. Third, another study estimated an incremental cost per qualityadjusted life-year of US$1.25 million comparing denosumab
428
EUROPEAN UROLOGY 61 (2012) 423–428
and zoledronic acid use over 27 mo, using the Fizazi et al trial [5]. In conclusion, we suggest that in phase 3 studies not only the classic end points and adverse events be evaluated but also the real-life costs in each treatment arm. A sophisticated calculation based on a model, as in the Xie et al study, would therefore no longer be necessary. Conflicts of interest: The authors have nothing to disclose.
[3] Beltran H, et al. Eur Urol 2011;60:279–90. [4] Sonnenberg FA, et al. Med Decis Making 1993;13:322–38. [5] Snedecor SJ, et al. J Clin Oncol 2011;29(Suppl):4581.
Hans-Peter Schmida,*, Robert Theilerb a
Department of Urology, Kantonsspital, St. Gallen, Switzerland
b
Department of Rheumatology, Stadtspital Triemli, Zu¨rich, Switzerland
*Corresponding author. Kantonsspital, Urology, Rorschacher Strasse 95, St. Gallen, 9007, Switzerland.
References
E-mail address: [email protected] (H.-P. Schmid)
[1] Fizazi K, et al. Lancet 2011;377:813–22. [2] Mottet N, et al. Eur Urol 2011;59:572–83.
DOI: 10.1016/j.eururo.2011.11.027