EURURO-7529; No. of Pages 3 E U R O P E A N U R O L O G Y X X X ( 2 0 17 ) X X X – X X X
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Opinion
New Insights into Adjuvant Renal Cell Carcinoma Treatment with Vascular Endothelial Growth Factor Inhibitors: What Have We Learned So Far? Bernard Escudier a,*, Michael Staehler b a
Gustave Roussy Cancer Institute, Villejuif Cedex, France; b Department of Urology, University of Munich, Klinikum Grosshadern, Munich, Germany
The incidence of renal cell carcinoma (RCC) has increased worldwide by >30% during 1990–2013 [1] and continues to contribute to the global burden of cancer. Owing to improvements in imaging and subsequent diagnosis, this rise in RCC incidence has largely been due to the increased diagnosis of locoregional disease. Locoregional disease is typically treated with surgery, followed by observation. Overall, 27.6% of patients undergoing curative surgery for nonmetastatic RCC will have tumour recurrence within 5 yr [2]. Surveillance protocols are variable, and there has been intensive research to better differentiate between patients with low-risk tumours that will have a largely indolent course and those with tumours that are more aggressive and more likely to recur. Accordingly, several risk scores based on clinical features such as tumour stage and Fuhrman grade have been identified and clinically validated, including the Mayo clinic stage, size, grade, necrosis (SSIGN) and University of California Los Angeles Integrated Staging System (UISS) scores [2,3]. More recently, molecular scores, such as those based on gene expression, have also been developed and validated [4]. The commonly used UISS score, based on tumour, node, metastasis stage, Fuhrman grade, and Eastern Cooperative Oncology Group performance status, has shown vast discrepancy in the 5-yr recurrence rate between low-risk tumours (at 9.6%) and high-risk tumours (at 58.1%) [2]. Awareness of this variability in recurrence between high-, intermediate- and low-risk patients has prompted research into adjuvant treatments that could prevent recurrence by abolishing oligometastatic disease. This is especially important in high-risk patients and currently represents an unmet therapeutic need. Following the
success of translating effective treatments in the metastatic setting to the adjuvant setting in tumour types such as breast cancer and gastrointestinal stromal tumours [5], this approach has been investigated in RCC. However, despite the established efficacy and availability of several treatments in the metastatic setting, trials with agents of the prevascular endothelial growth factor (pre-VEGF) era in the RCC adjuvant setting failed to meet their primary endpoint [6]. Subsequently, despite the success of paradigm-changing VEGF inhibitors in metastatic RCC, anticipation of the results of trials with these agents in the adjuvant setting was tempered by the failure of antiangiogenic treatments in other diseases, such as breast and colon cancer [7]. In this context, the S-TRAC trial of sunitinib versus placebo in highrisk patients with clear cell renal cell carcinoma met its primary endpoint of improving disease-free survival (DFS) in sunitinib versus placebo-treated patients (Table 1) [8]. Together with the ASSURE trial (which did not meet its primary endpoint) and the recently presented PROTECT trial, these results have reignited the debate around efficacy of VEGF inhibitor adjuvant treatment in RCC [9,10]. On the surface, ASSURE, S-TRAC, and PROTECT may seem similar: all enrolled patients with RCC and treated patients with VEGF inhibitors. On closer inspection, however, there are numerous distinctions between these trials, including study design and conduct. Three of the key differences are patient characteristics (including tumour histology and recurrence risk), assessment of progression (blind independent review vs investigator review), and dosing (Table 2). With respect to patient inclusion criteria, ASSURE enrolled patients with any histological subtype of RCC, whereas PROTECT and S-TRAC limited inclusion to clear cell histology only (Table 2). Clear cell RCC comprises 90% of all
* Corresponding author. Department of Oncology, Gustave Roussy, 114 rue Edouard Vaillant, Villejuif, France. Tel. +331 4211 5410. E-mail address: [email protected] (B. Escudier). http://dx.doi.org/10.1016/j.eururo.2017.08.020 0302-2838/© 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Escudier B, Staehler M. New Insights into Adjuvant Renal Cell Carcinoma Treatment with Vascular Endothelial Growth Factor Inhibitors: What Have We Learned So Far? Eur Urol (2017), http://dx.doi.org/10.1016/j. eururo.2017.08.020
EURURO-7529; No. of Pages 3 2
E U R O P E A N U R O L O G Y X X X ( 2 0 17 ) X X X – X X X
Table 1 – Basic trial characteristics and outcomes of ASSURE, S-TRAC, and PROTECT ASSURE
S-TRAC
PROTECT
Patients enrolled (n)
1943
615
Primary endpoint Population analysed Treatment groups (n)
DFS ITT Sunitinib (647) Sorafenib (649) Placebo (647)
DFS ITT Sunitinib (309) Placebo (306)
No significant difference 5.8 yr (IQR 1.6–8.2) in the sunitinib group and 6.6 yr (IQR 1.5–NE) in the placebo group (HR 102, 975% CI 085–123, p = 08038)
Significant difference 6.8 yr (95% CI 5.8–NR) in the sunitinib group and 5.6 yr (95% CI 3.8–6.6) in the placebo group (HR 0.76, 95% CI 0.59–0.98, p = 0.03)
Primary endpoint outcome Median disease-free survival
b
1135 (600 mg) 403 (800 mg) DFS a ITT a ITT (600 mg) Pazopanib (571) Placebo (564) ITT (800 mg) Pazopanib (198) Placebo (205) No significant difference Not yet reached
CI = confidence interval; DFS = disease-free survival; HR = hazard ratio; IQR = interquartile range; ITT = intention to treat; NE = not estimable; NR = not reached. Patients were originally planned to be analysed by ITT; however, a protocol amendment changed the starting dose of pazopanib from 800 to 600 mg and the primary endpoint from disease-free survival in the ITT population to disease-free survival in all patients treated with 600 mg pazopanib (modified ITT). b Median disease-free survivals in ASSURE are shown only for the sunitinib and placebo groups. a
Table 2 – Key differences between the ASSURE, S-TRAC, and PROTECT trials ASSURE Assessment of recurrence (investigator vs central review) Patient inclusion criteria Clear cell histology Performance status: ECOG 0 Performance status: KPS 100% Primary (AJCC) tumour stage I–II Dose of active agent administered Starting dose levels Standard dose as starting dose Minimum dose permitted 1 yr completion rate
S-TRAC
PROTECT
Investigator
Central
Investigator
79.1% 81.8%
99.0% 73.8%
33.4%
0%
100% Not reported 67% (600 mg) 66% (800 mg) 16% (600 mg) 15% (800 mg)
2a (50 mg/37.5 mg) 69.6% 25 mg 49%
1 (50 mg) 100% 37.5 mg 56%
2 (600 mg/800 mg) 26% 400 mg 48%
AJCC = American Joint Committee on Cancer; ECOG = Eastern Cooperative Oncology Group; KPS = Karnofsky performance status. Refers to dose of sunitinib only.
a
RCC [6]. Previous data have shown that non–clear cell tumour subtypes represent a very diverse group of malignancies that usually have less robust responses to VEGF inhibitors compared with clear cell tumours [6]. Therefore, inclusion of patients with non–clear cell tumours in the ASSURE trial may have skewed data towards a null result [9]. The second aspect of patient inclusion criteria is risk of recurrence, and again the trials differ markedly: ASSURE and, to a lesser extent, PROTECT both included a broader risk profile in their enrolment criteria than S-TRAC [8–10]. ASSURE included patients with T1b tumours and higher, and PROTECT included patients with T2b tumours and higher; conversely, S-TRAC was exclusively limited to patients with T3 and higher-stage tumours [8–10]. In terms of the assessment of recurrence, S-TRAC analysed progression by independent central review, whereas both PROTECT and ASSURE relied on investigator assessment alone, an inherently biased approach [8–10]. Importantly, all three trials demonstrated how crucial appropriate dosing is in this setting: the starting dose
of sunitinib in S-TRAC was 50 mg/d and reductions to 37.5 mg/d were permitted, whereas a trial amendment in ASSURE changed the starting dose of sunitinib to 37.5 mg/d and allowed reductions to 25 mg/d [8,9]. Similarly, an amendment in PROTECT changed the starting dose of pazopanib from 800 mg/d to 600 mg/d [10]. Encouragingly, analysis of PROTECT in the population that received the full effective dose of 800 mg/d (n = 403) showed a significant difference in DFS in the pazopanib-treated patients relative to the placebo-treated patients (hazard ratio 0.69, 95% confidence interval 0.51–0.94; p = 0.02) [10]. Together, these data strongly indicate that maintaining the dose at effective levels might be required to realise clinical benefit in this setting. The safety profile of sunitinib and pazopanib in these adjuvant therapy trials was consistent with that previously observed in the metastatic setting, and all toxicities were manageable [8–10]. Interestingly, compared with patients treated with VEGF inhibitors, patients treated with placebo had a similar cumulative incidence of adverse effects that were likely associated with treatment-related anxiety.
Please cite this article in press as: Escudier B, Staehler M. New Insights into Adjuvant Renal Cell Carcinoma Treatment with Vascular Endothelial Growth Factor Inhibitors: What Have We Learned So Far? Eur Urol (2017), http://dx.doi.org/10.1016/j. eururo.2017.08.020
EURURO-7529; No. of Pages 3 E U R O P E A N U R O L O G Y X X X ( 2 0 17 ) X X X – X X X
3
However, treatment with any of these agents in these trials necessitated dose reduction and modification in some patients; thus, the risk versus benefits of treatment must be communicated clearly to patients [8–10]. Collectively, the efficacy of VEGF inhibitors in the adjuvant RCC setting has been shown in principle, and the current data strongly suggest that patient selection is crucial: patients with high-risk clear cell tumours, who can tolerate the full effective dose, are more likely to benefit. Considering the increased risk of recurrence in these highrisk patients, treatment that provides a meaningful improvement in DFS is a clear clinical benefit and must be discussed as an option for patients in this setting.
[2] Lam JS, Shvarts O, Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS.
Conflicts of interest: Bernard Escudier has received honorarium for
trials. J Urol. In press. http://dx.doi.org/10.1016/j.juro.2017.04.092.
consultancy from Pfizer, Novartis, BMS, Ipsen, Roche, and Exilixis.
[6] Ljungberg B, Albiges L, Bensalah K, et al. EAU guidelines on renal cell
Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. J Urol 2005; 174:466–72. [3] Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with renal cell carcinoma of clear cell type treated by radical nephrectomy based on tumor stage, size, grade, and necrosis: the SSIGN score. J Urol 2002;168: 2395–400. [4] Rini B, Goddard A, Knezevic D, et al. A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies. Lancet Oncol 2015;16:676–85. [5] Lenis A, Donin NM, Johnson DC, et al. Adjuvant therapy for high-risk localized kidney cancer– emerging evidence and future clinical
Michael Staehler has received consulting fees from Pfizer, GlaxoSmithK-
carcinoma. http://uroweb.org/guideline/renal-cell-carcinoma.
line, Novartis, Bayer, Roche, Aveo, EUSAPharm, Astellas, Ipsen, Exelixis,
[7] Vasudev N, Reynolds AR. Anti-angiogenic therapy for cancer: cur-
Pelloton, and EISAI; honoraria from Pfizer, GlaxoSmithKline, AVEO,
rent progress, unresolved questions and future directions. Angio-
Novartis, Bayer, EUSAPharm, Astellas, Ipsen, Exelixis, Pelloton, and EISAI;
genesis 2014;17:471–94.
and research funding from Pfizer, GlaxoSmithKline, AVEO, Novartis, Bayer, Roche/Genentech, Immatics, Wilex, Ipsen, Exelixis, and EISAI. Funding support: This work was funded by Pfizer. Acknowledgements: Medical writing assistance was provided by Synergy Medical Communications Ltd.
References
[8] Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. NEJM 2016;375:2246–54. [9] Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805):a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016;387:2008–16. [10] Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients
[1] Global Burden of Disease Cancer Collaboration. The global burden of cancer 2013. JAMA Oncol 2015;1:505–27.
with locally advanced renal cell carcinoma (RCC) (PROTECT). J Clin Oncol 2017;35(Suppl), abstr 4507.
Please cite this article in press as: Escudier B, Staehler M. New Insights into Adjuvant Renal Cell Carcinoma Treatment with Vascular Endothelial Growth Factor Inhibitors: What Have We Learned So Far? Eur Urol (2017), http://dx.doi.org/10.1016/j. eururo.2017.08.020
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Opinion
New Insights into Adjuvant Renal Cell Carcinoma Treatment with Vascular Endothelial Growth Factor Inhibitors: What Have We Learned So Far? Bernard Escudier a,*, Michael Staehler b a
Gustave Roussy Cancer Institute, Villejuif Cedex, France; b Department of Urology, University of Munich, Klinikum Grosshadern, Munich, Germany
The incidence of renal cell carcinoma (RCC) has increased worldwide by >30% during 1990–2013 [1] and continues to contribute to the global burden of cancer. Owing to improvements in imaging and subsequent diagnosis, this rise in RCC incidence has largely been due to the increased diagnosis of locoregional disease. Locoregional disease is typically treated with surgery, followed by observation. Overall, 27.6% of patients undergoing curative surgery for nonmetastatic RCC will have tumour recurrence within 5 yr [2]. Surveillance protocols are variable, and there has been intensive research to better differentiate between patients with low-risk tumours that will have a largely indolent course and those with tumours that are more aggressive and more likely to recur. Accordingly, several risk scores based on clinical features such as tumour stage and Fuhrman grade have been identified and clinically validated, including the Mayo clinic stage, size, grade, necrosis (SSIGN) and University of California Los Angeles Integrated Staging System (UISS) scores [2,3]. More recently, molecular scores, such as those based on gene expression, have also been developed and validated [4]. The commonly used UISS score, based on tumour, node, metastasis stage, Fuhrman grade, and Eastern Cooperative Oncology Group performance status, has shown vast discrepancy in the 5-yr recurrence rate between low-risk tumours (at 9.6%) and high-risk tumours (at 58.1%) [2]. Awareness of this variability in recurrence between high-, intermediate- and low-risk patients has prompted research into adjuvant treatments that could prevent recurrence by abolishing oligometastatic disease. This is especially important in high-risk patients and currently represents an unmet therapeutic need. Following the
success of translating effective treatments in the metastatic setting to the adjuvant setting in tumour types such as breast cancer and gastrointestinal stromal tumours [5], this approach has been investigated in RCC. However, despite the established efficacy and availability of several treatments in the metastatic setting, trials with agents of the prevascular endothelial growth factor (pre-VEGF) era in the RCC adjuvant setting failed to meet their primary endpoint [6]. Subsequently, despite the success of paradigm-changing VEGF inhibitors in metastatic RCC, anticipation of the results of trials with these agents in the adjuvant setting was tempered by the failure of antiangiogenic treatments in other diseases, such as breast and colon cancer [7]. In this context, the S-TRAC trial of sunitinib versus placebo in highrisk patients with clear cell renal cell carcinoma met its primary endpoint of improving disease-free survival (DFS) in sunitinib versus placebo-treated patients (Table 1) [8]. Together with the ASSURE trial (which did not meet its primary endpoint) and the recently presented PROTECT trial, these results have reignited the debate around efficacy of VEGF inhibitor adjuvant treatment in RCC [9,10]. On the surface, ASSURE, S-TRAC, and PROTECT may seem similar: all enrolled patients with RCC and treated patients with VEGF inhibitors. On closer inspection, however, there are numerous distinctions between these trials, including study design and conduct. Three of the key differences are patient characteristics (including tumour histology and recurrence risk), assessment of progression (blind independent review vs investigator review), and dosing (Table 2). With respect to patient inclusion criteria, ASSURE enrolled patients with any histological subtype of RCC, whereas PROTECT and S-TRAC limited inclusion to clear cell histology only (Table 2). Clear cell RCC comprises 90% of all
* Corresponding author. Department of Oncology, Gustave Roussy, 114 rue Edouard Vaillant, Villejuif, France. Tel. +331 4211 5410. E-mail address: [email protected] (B. Escudier). http://dx.doi.org/10.1016/j.eururo.2017.08.020 0302-2838/© 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Escudier B, Staehler M. New Insights into Adjuvant Renal Cell Carcinoma Treatment with Vascular Endothelial Growth Factor Inhibitors: What Have We Learned So Far? Eur Urol (2017), http://dx.doi.org/10.1016/j. eururo.2017.08.020
EURURO-7529; No. of Pages 3 2
E U R O P E A N U R O L O G Y X X X ( 2 0 17 ) X X X – X X X
Table 1 – Basic trial characteristics and outcomes of ASSURE, S-TRAC, and PROTECT ASSURE
S-TRAC
PROTECT
Patients enrolled (n)
1943
615
Primary endpoint Population analysed Treatment groups (n)
DFS ITT Sunitinib (647) Sorafenib (649) Placebo (647)
DFS ITT Sunitinib (309) Placebo (306)
No significant difference 5.8 yr (IQR 1.6–8.2) in the sunitinib group and 6.6 yr (IQR 1.5–NE) in the placebo group (HR 102, 975% CI 085–123, p = 08038)
Significant difference 6.8 yr (95% CI 5.8–NR) in the sunitinib group and 5.6 yr (95% CI 3.8–6.6) in the placebo group (HR 0.76, 95% CI 0.59–0.98, p = 0.03)
Primary endpoint outcome Median disease-free survival
b
1135 (600 mg) 403 (800 mg) DFS a ITT a ITT (600 mg) Pazopanib (571) Placebo (564) ITT (800 mg) Pazopanib (198) Placebo (205) No significant difference Not yet reached
CI = confidence interval; DFS = disease-free survival; HR = hazard ratio; IQR = interquartile range; ITT = intention to treat; NE = not estimable; NR = not reached. Patients were originally planned to be analysed by ITT; however, a protocol amendment changed the starting dose of pazopanib from 800 to 600 mg and the primary endpoint from disease-free survival in the ITT population to disease-free survival in all patients treated with 600 mg pazopanib (modified ITT). b Median disease-free survivals in ASSURE are shown only for the sunitinib and placebo groups. a
Table 2 – Key differences between the ASSURE, S-TRAC, and PROTECT trials ASSURE Assessment of recurrence (investigator vs central review) Patient inclusion criteria Clear cell histology Performance status: ECOG 0 Performance status: KPS 100% Primary (AJCC) tumour stage I–II Dose of active agent administered Starting dose levels Standard dose as starting dose Minimum dose permitted 1 yr completion rate
S-TRAC
PROTECT
Investigator
Central
Investigator
79.1% 81.8%
99.0% 73.8%
33.4%
0%
100% Not reported 67% (600 mg) 66% (800 mg) 16% (600 mg) 15% (800 mg)
2a (50 mg/37.5 mg) 69.6% 25 mg 49%
1 (50 mg) 100% 37.5 mg 56%
2 (600 mg/800 mg) 26% 400 mg 48%
AJCC = American Joint Committee on Cancer; ECOG = Eastern Cooperative Oncology Group; KPS = Karnofsky performance status. Refers to dose of sunitinib only.
a
RCC [6]. Previous data have shown that non–clear cell tumour subtypes represent a very diverse group of malignancies that usually have less robust responses to VEGF inhibitors compared with clear cell tumours [6]. Therefore, inclusion of patients with non–clear cell tumours in the ASSURE trial may have skewed data towards a null result [9]. The second aspect of patient inclusion criteria is risk of recurrence, and again the trials differ markedly: ASSURE and, to a lesser extent, PROTECT both included a broader risk profile in their enrolment criteria than S-TRAC [8–10]. ASSURE included patients with T1b tumours and higher, and PROTECT included patients with T2b tumours and higher; conversely, S-TRAC was exclusively limited to patients with T3 and higher-stage tumours [8–10]. In terms of the assessment of recurrence, S-TRAC analysed progression by independent central review, whereas both PROTECT and ASSURE relied on investigator assessment alone, an inherently biased approach [8–10]. Importantly, all three trials demonstrated how crucial appropriate dosing is in this setting: the starting dose
of sunitinib in S-TRAC was 50 mg/d and reductions to 37.5 mg/d were permitted, whereas a trial amendment in ASSURE changed the starting dose of sunitinib to 37.5 mg/d and allowed reductions to 25 mg/d [8,9]. Similarly, an amendment in PROTECT changed the starting dose of pazopanib from 800 mg/d to 600 mg/d [10]. Encouragingly, analysis of PROTECT in the population that received the full effective dose of 800 mg/d (n = 403) showed a significant difference in DFS in the pazopanib-treated patients relative to the placebo-treated patients (hazard ratio 0.69, 95% confidence interval 0.51–0.94; p = 0.02) [10]. Together, these data strongly indicate that maintaining the dose at effective levels might be required to realise clinical benefit in this setting. The safety profile of sunitinib and pazopanib in these adjuvant therapy trials was consistent with that previously observed in the metastatic setting, and all toxicities were manageable [8–10]. Interestingly, compared with patients treated with VEGF inhibitors, patients treated with placebo had a similar cumulative incidence of adverse effects that were likely associated with treatment-related anxiety.
Please cite this article in press as: Escudier B, Staehler M. New Insights into Adjuvant Renal Cell Carcinoma Treatment with Vascular Endothelial Growth Factor Inhibitors: What Have We Learned So Far? Eur Urol (2017), http://dx.doi.org/10.1016/j. eururo.2017.08.020
EURURO-7529; No. of Pages 3 E U R O P E A N U R O L O G Y X X X ( 2 0 17 ) X X X – X X X
3
However, treatment with any of these agents in these trials necessitated dose reduction and modification in some patients; thus, the risk versus benefits of treatment must be communicated clearly to patients [8–10]. Collectively, the efficacy of VEGF inhibitors in the adjuvant RCC setting has been shown in principle, and the current data strongly suggest that patient selection is crucial: patients with high-risk clear cell tumours, who can tolerate the full effective dose, are more likely to benefit. Considering the increased risk of recurrence in these highrisk patients, treatment that provides a meaningful improvement in DFS is a clear clinical benefit and must be discussed as an option for patients in this setting.
[2] Lam JS, Shvarts O, Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS.
Conflicts of interest: Bernard Escudier has received honorarium for
trials. J Urol. In press. http://dx.doi.org/10.1016/j.juro.2017.04.092.
consultancy from Pfizer, Novartis, BMS, Ipsen, Roche, and Exilixis.
[6] Ljungberg B, Albiges L, Bensalah K, et al. EAU guidelines on renal cell
Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. J Urol 2005; 174:466–72. [3] Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with renal cell carcinoma of clear cell type treated by radical nephrectomy based on tumor stage, size, grade, and necrosis: the SSIGN score. J Urol 2002;168: 2395–400. [4] Rini B, Goddard A, Knezevic D, et al. A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies. Lancet Oncol 2015;16:676–85. [5] Lenis A, Donin NM, Johnson DC, et al. Adjuvant therapy for high-risk localized kidney cancer– emerging evidence and future clinical
Michael Staehler has received consulting fees from Pfizer, GlaxoSmithK-
carcinoma. http://uroweb.org/guideline/renal-cell-carcinoma.
line, Novartis, Bayer, Roche, Aveo, EUSAPharm, Astellas, Ipsen, Exelixis,
[7] Vasudev N, Reynolds AR. Anti-angiogenic therapy for cancer: cur-
Pelloton, and EISAI; honoraria from Pfizer, GlaxoSmithKline, AVEO,
rent progress, unresolved questions and future directions. Angio-
Novartis, Bayer, EUSAPharm, Astellas, Ipsen, Exelixis, Pelloton, and EISAI;
genesis 2014;17:471–94.
and research funding from Pfizer, GlaxoSmithKline, AVEO, Novartis, Bayer, Roche/Genentech, Immatics, Wilex, Ipsen, Exelixis, and EISAI. Funding support: This work was funded by Pfizer. Acknowledgements: Medical writing assistance was provided by Synergy Medical Communications Ltd.
References
[8] Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. NEJM 2016;375:2246–54. [9] Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805):a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016;387:2008–16. [10] Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients
[1] Global Burden of Disease Cancer Collaboration. The global burden of cancer 2013. JAMA Oncol 2015;1:505–27.
with locally advanced renal cell carcinoma (RCC) (PROTECT). J Clin Oncol 2017;35(Suppl), abstr 4507.
Please cite this article in press as: Escudier B, Staehler M. New Insights into Adjuvant Renal Cell Carcinoma Treatment with Vascular Endothelial Growth Factor Inhibitors: What Have We Learned So Far? Eur Urol (2017), http://dx.doi.org/10.1016/j. eururo.2017.08.020
