785
EUROPEAN UROLOGY 66 (2014) 784–789
a
Zachary Klaassena, John M. DiBiancob, Qiang Lia, Martha K. Terrisa,*
*Corresponding author. Section of Urology, Medical College of
Section of Urology, Medical College of Georgia – Georgia Regents
Room BA 8414, Augusta, GA 30912-4050, USA.
University, Augusta, GA, USA
E-mail address: [email protected] (M.K. Terris).
b
Georgia – Georgia Regents University, 1120 Fifteenth Street,
Ross University School of Medicine, Roseau, Commonwealth of Dominica, West Indies
Re: Clinical Outcomes for Patients with Metastatic Renal Cell Carcinoma Treated with Alternative Sunitinib Schedules Atkinson BJ, Kalra S, Wang X, et al. J Urol 2014;191:611–8 Expert’s summary: The authors retrospectively evaluated patients treated with sunitinib for metastastic renal cell carcinoma (mRCC). A traditional schedule (TS; 4 wk on and 2 wk off treatment) was compared with alternative schedules (ASs; 2 wk on and 1 wk off or 1 wk on and 3–4 d off). An AS was indicated either up front or after toxicity while on TS. Progression-free survival (PFS) and overall survival (OS) probabilities were defined as end points, supplemented by multivariable Cox regression models. Approximately half of the 187 patients continually received TS, whereas the other half received some form of AS. Median PFS was 9 mo and median OS was 25.6 mo for the whole population. Comparing TS and AS showed a median PFS of 4.3 mo versus 14.5 mo and OS of 17.7 mo versus 33 mo in favor of AS. On multivariable analysis, TS independently predicted decreased OS. Expert’s comments: While other smaller series focused mainly on decreased toxicity with regimens of 2 wk on and 1 wk off [1,2], this present larger series, consisting of a routine clinical population, also showed improved outcomes from AS. PFS and OS were slightly inferior to the sunitinib phase III trial [3] (PFS: 9 mo vs 11 mo; OS: 25.6 mo vs 28 mo); however, differences between TS and AS regarding both PFS and OS were tremendous. Hazard ratios for AS regarding OS were 0.49 on univariable analysis and 0.55 on multivariable analysis. Now, if survival can be doubled by administering AS, does that mean we had chosen a suboptimal schedule for years? In this regard, the results should be interpreted with caution. It has been shown that side effects like hypertension [4] and hypothyroidism [5] may serve as surrogates for favorable treatment outcome. In this study, the main indication for switching from TS to AS was toxicity. Consequently, it appears plausible that the observed survival difference may represent a selection of patients showing better treatment
Re: Enzalutamide in Metastatic Prostate Cancer Before Chemotherapy Beer TM, Armstrong AJ, Rathkopf DE, et al.; PREVAIL Investigators N Engl J Med 2014;371:424-33
http://dx.doi.org/10.1016/j.eururo.2014.07.047
response, which was reflected by increased toxicity. This variable, however, was not adjusted for in the multivariable analysis. If included, toxicity would probably remain an independent predictor, whereas AS would vanish. This study shows that either side effects or change of treatment schedule by itself may predict improved survival; however, the observed survival differences were highly relevant. This study is hypothesis generating in two respects: Would either treating to toxicity or changing treatment schedule be the way to go to improve the outcome of mRCC patients under sunitinib? The observed results certainly deserve evaluation in prospective trials. Conflicts of interest: Richard Zigeuner is a paid speaker for Amgen, Bayer, GSK, Novartis, Pfizer, and Roche and an advisory board member for Pfizer and receives travel support from Amgen, Astellas, Bayer, GSK, Novartis, Pfizer, Roche, and Takeda.
References [1] Najjar YG, Mittal K, Elson P, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer 2014;50:1084–9. [2] Kondo T, Takagi T, Kobayashi H, et al. Superior tolerability of altered dosing schedule of sunitinib with 2-weeks-on and 1-week-off in patients with metastatic renal cell carcinoma–comparison to standard dosing schedule of 4-weeks-on and 2-weeks-off. Jpn J Clin Oncol 2014;44:270–7. [3] Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–24. [4] Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2011;103:763–73. [5] Schmidinger M, Vogl UM, Bojic M, et al. Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 2011;117: 534–44. Richard Zigeuner* Department of Urology, Medical University of Graz, Graz, Austria *Department of Urology, Medical University of Graz, Auenbruggerplatz 5/6, A-8036 Graz, Austria. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.eururo.2014.07.048
Experts’ summary: PREVAIL is a multinational, double-blind, randomised trial comparing enzalutamide, which is an oral androgen receptor inhibitor, and placebo. Beer et al. demonstrated that enzalutamide in chemotherapy-naı¨ve patients with metastatic castration-resistant prostate cancer (mCRPC) had significant clinical benefits including better rates of
EUROPEAN UROLOGY 66 (2014) 784–789
a
Zachary Klaassena, John M. DiBiancob, Qiang Lia, Martha K. Terrisa,*
*Corresponding author. Section of Urology, Medical College of
Section of Urology, Medical College of Georgia – Georgia Regents
Room BA 8414, Augusta, GA 30912-4050, USA.
University, Augusta, GA, USA
E-mail address: [email protected] (M.K. Terris).
b
Georgia – Georgia Regents University, 1120 Fifteenth Street,
Ross University School of Medicine, Roseau, Commonwealth of Dominica, West Indies
Re: Clinical Outcomes for Patients with Metastatic Renal Cell Carcinoma Treated with Alternative Sunitinib Schedules Atkinson BJ, Kalra S, Wang X, et al. J Urol 2014;191:611–8 Expert’s summary: The authors retrospectively evaluated patients treated with sunitinib for metastastic renal cell carcinoma (mRCC). A traditional schedule (TS; 4 wk on and 2 wk off treatment) was compared with alternative schedules (ASs; 2 wk on and 1 wk off or 1 wk on and 3–4 d off). An AS was indicated either up front or after toxicity while on TS. Progression-free survival (PFS) and overall survival (OS) probabilities were defined as end points, supplemented by multivariable Cox regression models. Approximately half of the 187 patients continually received TS, whereas the other half received some form of AS. Median PFS was 9 mo and median OS was 25.6 mo for the whole population. Comparing TS and AS showed a median PFS of 4.3 mo versus 14.5 mo and OS of 17.7 mo versus 33 mo in favor of AS. On multivariable analysis, TS independently predicted decreased OS. Expert’s comments: While other smaller series focused mainly on decreased toxicity with regimens of 2 wk on and 1 wk off [1,2], this present larger series, consisting of a routine clinical population, also showed improved outcomes from AS. PFS and OS were slightly inferior to the sunitinib phase III trial [3] (PFS: 9 mo vs 11 mo; OS: 25.6 mo vs 28 mo); however, differences between TS and AS regarding both PFS and OS were tremendous. Hazard ratios for AS regarding OS were 0.49 on univariable analysis and 0.55 on multivariable analysis. Now, if survival can be doubled by administering AS, does that mean we had chosen a suboptimal schedule for years? In this regard, the results should be interpreted with caution. It has been shown that side effects like hypertension [4] and hypothyroidism [5] may serve as surrogates for favorable treatment outcome. In this study, the main indication for switching from TS to AS was toxicity. Consequently, it appears plausible that the observed survival difference may represent a selection of patients showing better treatment
Re: Enzalutamide in Metastatic Prostate Cancer Before Chemotherapy Beer TM, Armstrong AJ, Rathkopf DE, et al.; PREVAIL Investigators N Engl J Med 2014;371:424-33
http://dx.doi.org/10.1016/j.eururo.2014.07.047
response, which was reflected by increased toxicity. This variable, however, was not adjusted for in the multivariable analysis. If included, toxicity would probably remain an independent predictor, whereas AS would vanish. This study shows that either side effects or change of treatment schedule by itself may predict improved survival; however, the observed survival differences were highly relevant. This study is hypothesis generating in two respects: Would either treating to toxicity or changing treatment schedule be the way to go to improve the outcome of mRCC patients under sunitinib? The observed results certainly deserve evaluation in prospective trials. Conflicts of interest: Richard Zigeuner is a paid speaker for Amgen, Bayer, GSK, Novartis, Pfizer, and Roche and an advisory board member for Pfizer and receives travel support from Amgen, Astellas, Bayer, GSK, Novartis, Pfizer, Roche, and Takeda.
References [1] Najjar YG, Mittal K, Elson P, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer 2014;50:1084–9. [2] Kondo T, Takagi T, Kobayashi H, et al. Superior tolerability of altered dosing schedule of sunitinib with 2-weeks-on and 1-week-off in patients with metastatic renal cell carcinoma–comparison to standard dosing schedule of 4-weeks-on and 2-weeks-off. Jpn J Clin Oncol 2014;44:270–7. [3] Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–24. [4] Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2011;103:763–73. [5] Schmidinger M, Vogl UM, Bojic M, et al. Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 2011;117: 534–44. Richard Zigeuner* Department of Urology, Medical University of Graz, Graz, Austria *Department of Urology, Medical University of Graz, Auenbruggerplatz 5/6, A-8036 Graz, Austria. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.eururo.2014.07.048
Experts’ summary: PREVAIL is a multinational, double-blind, randomised trial comparing enzalutamide, which is an oral androgen receptor inhibitor, and placebo. Beer et al. demonstrated that enzalutamide in chemotherapy-naı¨ve patients with metastatic castration-resistant prostate cancer (mCRPC) had significant clinical benefits including better rates of
