- Email: [email protected]
Re: Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma
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Re: Nephron-sparing Techniques Independently Decrease the Risk of Cardiovascular Events Relative to Radical Nephrectomy in Patients with a T1a–T1b Renal Mass and Normal Preoperative Renal Function Capitanio U, Terrone C, Antonelli A, et al Eur Urol 2015;67:683–9 Expert’s summary: Capitanio et al [1] report the association between a type of treatment (nephron sparing surgery [NSS] vs radical nephrectomy [RN]) and the risk of cardiovascular events (CVEs) in a large multi-institutional dataset of 1331 patients with a clinical T1a–T1b renal mass and normal preoperative renal function. CVEs included new coronary artery disease, cardiomyopathy, vasculopathy, hypertension, heart failure, dysrhythmias, and cerebrovascular disease. After accounting for the baseline cardiovascular profile, NSS patients showed a significantly lower risk of CVEs compared with RN patients. The 10-yr CVE rates in the NSS and RN groups were 20.2% and 25.9%, respectively. Overall, the study demonstrated a strong correlation between nephron preservation and cardiovascular benefits.
One study suggested an explanation for the underlying mechanism associated with NSS and CVE, demonstrating that NSS is associated with increased blood pressure and progression of hypertension [5]. Despite the preliminary results, this study suggests that partial nephrectomy (such as renal injury) increases the risk of CVE in some patients like renal injury. There is no doubt that NSS is beneficial for preserving renal function. However, the effect of NSS on CVEs leading to overall survival should be shown in a prospective randomized study. Otherwise, we may need to pay attention on the overuse or aggressive application of NSS. Conflicts of interest: The author has nothing to disclose.
References [1] Capitanio U, Terrone C, Antonelli A, et al. Nephron-sparing techniques independently decrease the risk of cardiovascular events relative to radical nephrectomy in patients with a T1a-T1b renal mass and normal preoperative renal function. Eur Urol 2015;67:983–9. [2] Smaldone MC, Egleston B, Uzzo RG, Kutikov A. Does partial ne-
Expert’s comments: Despite the strengths of its large cohort size and adjustment of the analysis by baseline cardiovascular risk, the study still has the limitation of its retrospective nature. The CVE rate curves show early splitting immediately after initiation of follow-up, and the differences would seem to be constant throughout the duration of follow-up. Because the benefit of renal preservation on CVE could be expected to be acquired over time, this could reflect selection bias for well-conditioned patients to NSS, as shown in an administrative cohort study [2]. The results are in conflict with those of the European Organization for Research and Treatment of Cancer 30904 trial, the only prospective study comparing NSS and RN, which included randomization of 541 patients with renal masses 5 cm. NSS was associated with reduced overall survival and a slightly higher rate (statistically insignificant) of CVErelated death (9.3%) compared with that of RN (7.3%); although, postoperative renal function was better in NSS patients [3,4]. A better understanding of these conflicting results is needed to better manage patients with renal tumors.
Re: Nivolumab versus Everolimus in Advanced RenalCell Carcinoma Motzer RJ, Escudier B, McDermott DF, et al N Engl J Med. In press. http://dx.doi.org/10.1056/ NEJMoa1510665 Experts’ summary: This trial is the first phase 3 study of a therapeutic immune checkpoint blockade in metastatic renal cell carcinoma (mRCC) [1]. It proves the superiority of the programmed cell death-1 receptor antibody nivolumab versus everolimus in mRCC patients after prior antiangiogenic therapy. The trial
phrectomy result in a durable overall survival benefit in the Medicare population? J Urol 2012;188:2089–94. [3] Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomized EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011;59:543–52. [4] Scosyrev E, Messing EM, Sylvester R, Campbell S, Van Poppel H. Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904. Eur Urol 2014;65:372–7. [5] Inoue M, Fujii Y, Yokoyama M, Saito K, Numao N, Kihara K. Progression of hypertension after partial nephrectomy in patients with renal tumors: a preliminary report. Int J Urol 2015;22:797–8. Kazutaka Saito* Department of Urology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan *Department of Urology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2015.12.024
was prematurely stopped in July 2015 after the recommendation of the data monitoring committee at the planned interim analysis due to the demonstrated superiority in overall survival: hazard ratio 0.73 (98.5% confidence interval [CI], 0.57–0.93; p = 0.002) with a median overall survival (OS) of 25.0 mo with nivolumab (95% CI 21.8 to not reported) versus everolimus with 19.6 mo (95% CI 17.6–23.1). Progression-free survival showed no difference with 4.6 mo (nivolumab, 95% CI 3.7–5.4) versus 4.4 mo (everolimus, 95% CI, 3.7–5.5, p = 0.11) and the median time to response was 3.5 mo versus 3.7 mo with 103 (25%) patients responding in the nivolumab arm and 22 (5%) patients in the everolimus arm. Thirty-two patients (31%) in the nivolumab group had an ongoing response for
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12 mo or longer. The safety profile demonstrated a rate of grade 3 or grade 4 treatment-related adverse events in 76 of the 406 patients (19%) in the nivolumab arm and 145 of the 397 patients (37%) in the everolimus arm. The most common adverse events were fatigue (2%) with nivolumab and anaemia (8%) with everolimus. Experts’ comments: This trial demonstrates a prolongation of overall survival in mRCC after prior antiangiogenic therapy. Most of the responses occurred between wk 8 and wk 16. Interestingly, nivolumab induced responses that lasted 12 mo or longer in 31% of the responding patients. This raises hope to induce long-term responders as observed in a small proportion of patients treated with cytokines, but not observed in patients treated with targeted therapy in mRCC [1]. The final OS results of CheckMate 25, which are expected later, will prove this question to be true or not. In general, nivolumab was well tolerated and safe with fewer grade 3 or grade 4 adverse events than everolimus. Interestingly, there was no difference in the OS benefit within the subgroups according to the Memorial Sloan Kettering Cancer Centre stratification for nivolumab, all favouring nivolumab. This is remarkable in the Memorial Sloan Kettering Cancer Centre poor prognosis patients, which represent a subgroup of patients for whom effective therapy is not available. Probably a higher rate of mutations with the formation of neoantigens in the poor prognosis group might render these patients prone to checkpoint blockade [2]. In addition, programmed death-ligand 1 expression status was not a predictor of the response to nivolumab in this mRCC trial, contradicting the results of studies in other entities like bladder carcinoma [3]. This fact underlines the clinical need for predictive biomarkers, apparently still missing in mRCC patients.
Re: Genomic Classifier Identifies Men with Adverse Pathology After Radical Prostatectomy Who Benefit from Adjuvant Radiation Therapy Den RB, Yousefi K, Trabulsi EJ, et al J Clin Oncol 2015;33:944–51 Experts’ summary: Den et al report a validation study on use of the GenomeDx Decipher test to predict the occurrence of clinical metastasis and patients who might spared from early postoperative radiotherapy (RT). The cohort consisted of 188 patients who underwent adjuvant RT (ART) or salvage RT (SRT) following radical prostatectomy (RP). The ART and SRT criteria were PSA levels of 0.2 and >0.2 ng/ml, respectively, before RT. Some 30% of the patients received androgen deprivation therapy (ADT) with RT. Clinical metastasis was detected by computed tomograpy or a bone scan. The 5-yr cumulative incidence of metastasis after RT was 0%, 9%, and 29% for patients with low, average, and high genomic classifier (GC) scores, respectively. For patients with higher GC scores, the 5-yr metastasis incidence was 6% following ART and 23% following SRT. By
Since 2005 several tyrosine kinase and mammalian target of rapamycin inhibitors have changed the treatment paradigm in mRCC with a prolongation of progression-free survival displacing unspecific immunotherapy with cytokines [4]. The presented trial of checkpoint blockade of the programmed cell death-1 receptor with nivolumab renders immunotherapy back into the centre of systemic treatment of mRCC, maybe turning the switch from the unspecificity of cytokines to a well-defined mode of action in immunotherapy with nivolumab being the first agent within this new class of checkpoint inhibitors. Conflicts of interest: Stenzl and Bedke were investigators of the Checkmate 025 Nivolumab trial.
References [1] Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. In press. http://dx.doi.org/10.1056/NEJMoa1510665 [2] Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014;515:577–81. [3] Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515:558–62. [4] Kruck S, Bedke J, Kuczyk MA, Merseburger AS. Second-line systemic therapy for the treatment of metastatic renal cell cancer. Expert Rev Anticancer Ther 2012;12:777–85. Jens Bedke, Arnulf Stenzl* Department of Urology, Eberhard Karls University, Tu¨bingen, Germany *Corresponding author. Department of Urology, Eberhard Karls University, Hoppe-Seyler-Straße 3, Tu¨bingen 72076, Germany. E-mail address: [email protected] (A. Stenzl). http://dx.doi.org/10.1016/j.eururo.2015.12.025
contrast, ART did not decrease the incidence of metastasis in patients with a low GC score. The authors conclude that patients with low GC scores are best spared ART and treated with SRT as needed, while those with high GC scores benefit from ART. Experts’ comments: This study describes a genomic test that could potentially replace or serve as an adjunct to PSA kinetics, imaging, and validated instruments such as the Stephenson nomogram [1] and CAPRA-S score [2] to guide the use of post-RP RT. However, use of this test as suggested by the authors may not be where it could have the greatest value. A primary endpoint of metastasis at 5 yr may be inadequate as a basis for management decisions considering that the median actuarial time from a rising PSA after RP to metastasis is 8 yr [3]. Perhaps GC scores may hold greater promise in selecting patients for whom RT alone might be inadequate. A high GC score may suggest that such patients require ADT in addition to post-RP RT. This notion is supported by a recent decision impact study in which the biggest change in treatment recommendations for radiation oncologists occurred when they were faced with
EUROPEAN UROLOGY 69 (2016) 536–540
Re: Nephron-sparing Techniques Independently Decrease the Risk of Cardiovascular Events Relative to Radical Nephrectomy in Patients with a T1a–T1b Renal Mass and Normal Preoperative Renal Function Capitanio U, Terrone C, Antonelli A, et al Eur Urol 2015;67:683–9 Expert’s summary: Capitanio et al [1] report the association between a type of treatment (nephron sparing surgery [NSS] vs radical nephrectomy [RN]) and the risk of cardiovascular events (CVEs) in a large multi-institutional dataset of 1331 patients with a clinical T1a–T1b renal mass and normal preoperative renal function. CVEs included new coronary artery disease, cardiomyopathy, vasculopathy, hypertension, heart failure, dysrhythmias, and cerebrovascular disease. After accounting for the baseline cardiovascular profile, NSS patients showed a significantly lower risk of CVEs compared with RN patients. The 10-yr CVE rates in the NSS and RN groups were 20.2% and 25.9%, respectively. Overall, the study demonstrated a strong correlation between nephron preservation and cardiovascular benefits.
One study suggested an explanation for the underlying mechanism associated with NSS and CVE, demonstrating that NSS is associated with increased blood pressure and progression of hypertension [5]. Despite the preliminary results, this study suggests that partial nephrectomy (such as renal injury) increases the risk of CVE in some patients like renal injury. There is no doubt that NSS is beneficial for preserving renal function. However, the effect of NSS on CVEs leading to overall survival should be shown in a prospective randomized study. Otherwise, we may need to pay attention on the overuse or aggressive application of NSS. Conflicts of interest: The author has nothing to disclose.
References [1] Capitanio U, Terrone C, Antonelli A, et al. Nephron-sparing techniques independently decrease the risk of cardiovascular events relative to radical nephrectomy in patients with a T1a-T1b renal mass and normal preoperative renal function. Eur Urol 2015;67:983–9. [2] Smaldone MC, Egleston B, Uzzo RG, Kutikov A. Does partial ne-
Expert’s comments: Despite the strengths of its large cohort size and adjustment of the analysis by baseline cardiovascular risk, the study still has the limitation of its retrospective nature. The CVE rate curves show early splitting immediately after initiation of follow-up, and the differences would seem to be constant throughout the duration of follow-up. Because the benefit of renal preservation on CVE could be expected to be acquired over time, this could reflect selection bias for well-conditioned patients to NSS, as shown in an administrative cohort study [2]. The results are in conflict with those of the European Organization for Research and Treatment of Cancer 30904 trial, the only prospective study comparing NSS and RN, which included randomization of 541 patients with renal masses 5 cm. NSS was associated with reduced overall survival and a slightly higher rate (statistically insignificant) of CVErelated death (9.3%) compared with that of RN (7.3%); although, postoperative renal function was better in NSS patients [3,4]. A better understanding of these conflicting results is needed to better manage patients with renal tumors.
Re: Nivolumab versus Everolimus in Advanced RenalCell Carcinoma Motzer RJ, Escudier B, McDermott DF, et al N Engl J Med. In press. http://dx.doi.org/10.1056/ NEJMoa1510665 Experts’ summary: This trial is the first phase 3 study of a therapeutic immune checkpoint blockade in metastatic renal cell carcinoma (mRCC) [1]. It proves the superiority of the programmed cell death-1 receptor antibody nivolumab versus everolimus in mRCC patients after prior antiangiogenic therapy. The trial
phrectomy result in a durable overall survival benefit in the Medicare population? J Urol 2012;188:2089–94. [3] Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomized EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011;59:543–52. [4] Scosyrev E, Messing EM, Sylvester R, Campbell S, Van Poppel H. Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904. Eur Urol 2014;65:372–7. [5] Inoue M, Fujii Y, Yokoyama M, Saito K, Numao N, Kihara K. Progression of hypertension after partial nephrectomy in patients with renal tumors: a preliminary report. Int J Urol 2015;22:797–8. Kazutaka Saito* Department of Urology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan *Department of Urology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2015.12.024
was prematurely stopped in July 2015 after the recommendation of the data monitoring committee at the planned interim analysis due to the demonstrated superiority in overall survival: hazard ratio 0.73 (98.5% confidence interval [CI], 0.57–0.93; p = 0.002) with a median overall survival (OS) of 25.0 mo with nivolumab (95% CI 21.8 to not reported) versus everolimus with 19.6 mo (95% CI 17.6–23.1). Progression-free survival showed no difference with 4.6 mo (nivolumab, 95% CI 3.7–5.4) versus 4.4 mo (everolimus, 95% CI, 3.7–5.5, p = 0.11) and the median time to response was 3.5 mo versus 3.7 mo with 103 (25%) patients responding in the nivolumab arm and 22 (5%) patients in the everolimus arm. Thirty-two patients (31%) in the nivolumab group had an ongoing response for
539
EUROPEAN UROLOGY 69 (2016) 536–540
12 mo or longer. The safety profile demonstrated a rate of grade 3 or grade 4 treatment-related adverse events in 76 of the 406 patients (19%) in the nivolumab arm and 145 of the 397 patients (37%) in the everolimus arm. The most common adverse events were fatigue (2%) with nivolumab and anaemia (8%) with everolimus. Experts’ comments: This trial demonstrates a prolongation of overall survival in mRCC after prior antiangiogenic therapy. Most of the responses occurred between wk 8 and wk 16. Interestingly, nivolumab induced responses that lasted 12 mo or longer in 31% of the responding patients. This raises hope to induce long-term responders as observed in a small proportion of patients treated with cytokines, but not observed in patients treated with targeted therapy in mRCC [1]. The final OS results of CheckMate 25, which are expected later, will prove this question to be true or not. In general, nivolumab was well tolerated and safe with fewer grade 3 or grade 4 adverse events than everolimus. Interestingly, there was no difference in the OS benefit within the subgroups according to the Memorial Sloan Kettering Cancer Centre stratification for nivolumab, all favouring nivolumab. This is remarkable in the Memorial Sloan Kettering Cancer Centre poor prognosis patients, which represent a subgroup of patients for whom effective therapy is not available. Probably a higher rate of mutations with the formation of neoantigens in the poor prognosis group might render these patients prone to checkpoint blockade [2]. In addition, programmed death-ligand 1 expression status was not a predictor of the response to nivolumab in this mRCC trial, contradicting the results of studies in other entities like bladder carcinoma [3]. This fact underlines the clinical need for predictive biomarkers, apparently still missing in mRCC patients.
Re: Genomic Classifier Identifies Men with Adverse Pathology After Radical Prostatectomy Who Benefit from Adjuvant Radiation Therapy Den RB, Yousefi K, Trabulsi EJ, et al J Clin Oncol 2015;33:944–51 Experts’ summary: Den et al report a validation study on use of the GenomeDx Decipher test to predict the occurrence of clinical metastasis and patients who might spared from early postoperative radiotherapy (RT). The cohort consisted of 188 patients who underwent adjuvant RT (ART) or salvage RT (SRT) following radical prostatectomy (RP). The ART and SRT criteria were PSA levels of 0.2 and >0.2 ng/ml, respectively, before RT. Some 30% of the patients received androgen deprivation therapy (ADT) with RT. Clinical metastasis was detected by computed tomograpy or a bone scan. The 5-yr cumulative incidence of metastasis after RT was 0%, 9%, and 29% for patients with low, average, and high genomic classifier (GC) scores, respectively. For patients with higher GC scores, the 5-yr metastasis incidence was 6% following ART and 23% following SRT. By
Since 2005 several tyrosine kinase and mammalian target of rapamycin inhibitors have changed the treatment paradigm in mRCC with a prolongation of progression-free survival displacing unspecific immunotherapy with cytokines [4]. The presented trial of checkpoint blockade of the programmed cell death-1 receptor with nivolumab renders immunotherapy back into the centre of systemic treatment of mRCC, maybe turning the switch from the unspecificity of cytokines to a well-defined mode of action in immunotherapy with nivolumab being the first agent within this new class of checkpoint inhibitors. Conflicts of interest: Stenzl and Bedke were investigators of the Checkmate 025 Nivolumab trial.
References [1] Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. In press. http://dx.doi.org/10.1056/NEJMoa1510665 [2] Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014;515:577–81. [3] Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515:558–62. [4] Kruck S, Bedke J, Kuczyk MA, Merseburger AS. Second-line systemic therapy for the treatment of metastatic renal cell cancer. Expert Rev Anticancer Ther 2012;12:777–85. Jens Bedke, Arnulf Stenzl* Department of Urology, Eberhard Karls University, Tu¨bingen, Germany *Corresponding author. Department of Urology, Eberhard Karls University, Hoppe-Seyler-Straße 3, Tu¨bingen 72076, Germany. E-mail address: [email protected] (A. Stenzl). http://dx.doi.org/10.1016/j.eururo.2015.12.025
contrast, ART did not decrease the incidence of metastasis in patients with a low GC score. The authors conclude that patients with low GC scores are best spared ART and treated with SRT as needed, while those with high GC scores benefit from ART. Experts’ comments: This study describes a genomic test that could potentially replace or serve as an adjunct to PSA kinetics, imaging, and validated instruments such as the Stephenson nomogram [1] and CAPRA-S score [2] to guide the use of post-RP RT. However, use of this test as suggested by the authors may not be where it could have the greatest value. A primary endpoint of metastasis at 5 yr may be inadequate as a basis for management decisions considering that the median actuarial time from a rising PSA after RP to metastasis is 8 yr [3]. Perhaps GC scores may hold greater promise in selecting patients for whom RT alone might be inadequate. A high GC score may suggest that such patients require ADT in addition to post-RP RT. This notion is supported by a recent decision impact study in which the biggest change in treatment recommendations for radiation oncologists occurred when they were faced with