To Be or “Node” to Be: Nodal Disease and the Role of Lymphadenectomy in the Treatment of Renal Cell Carcinoma
Main Article Content
Abstract
Lymph node involvement in renal cell carcinoma (RCC) correlates with poor oncologic outcomes. However, current RCC staging guidelines may not fully reflect the survival impact of lymph node positive disease. Recent data demonstrates that nodal disease has significant impact on survival and modifications to current staging guidelines have been proposed. Lymph node dissection (LND) at the time of surgical intervention for RCC remains controversial. While clinical trial data have demonstrated conflicting evidence for LND, some institutional studies suggests that carefully selected patients at high-risk for recurrence may benefit from LND. Prospectively, clinical trials are examining treating nodal disease and disease at high-risk of recurrence in the neoadjuvant and/or adjuvant setting at the time of nephrectomy. These promising trials are poised, if successful, to influence the treatment paradigm for localized RCC.
Keywords:
renal cell carcinoma, lymph node dissection, immunotherapy
Article Details
How to Cite
PATEL, Hiren V.; SRIVASTAVA, Arnav; SINGER, Eric A..
To Be or “Node” to Be: Nodal Disease and the Role of Lymphadenectomy in the Treatment of Renal Cell Carcinoma.
Medical Research Archives, [S.l.], v. 8, n. 5, may 2020.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2091>. Date accessed: 17 nov. 2024.
doi: https://doi.org/10.18103/mra.v8i5.2091.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
2. Kroeger N, Pantuck AJ, Wells JC, Lawrence N, Broom R, Kim JJ, et al. Characterizing the impact of lymph node metastases on the survival outcome for metastatic renal cell carcinoma patients treated with targeted therapies. Eur Urol. 2015;68(3):506-15.
3. Yu KJ, Keskin SK, Meissner MA, Petros FG, Wang X, Borregales LD, et al. Renal cell carcinoma and pathologic nodal disease: implications for american joint committee on cancer staging. cancer. 2018;124(20):4023-31.
4. Rodriguez-Covarrubias F, Castillejos-Molina R, Sotomayor M, Mendez-Probst CE, Gomez-Alvarado MO, Uribe-Uribe N, et al. Impact of lymph node invasion and sarcomatoid differentiation on the survival of patients with locally advanced renal cell carcinoma. Urol Int. 2010;85(1):23-9.
5. Whitson JM, Harris CR, Reese AC, Meng MV. Lymphadenectomy improves survival of patients with renal cell carcinoma and nodal metastases. J Urol. 2011;185(5):1615-20.
6. Blute ML, Leibovich BC, Cheville JC, Lohse CM, Zincke H. A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma. J Urol. 2004;172(2):465-9.
7. Capitanio U, Jeldres C, Patard JJ, Perrotte P, Zini L, de La Taille A, et al. Stage-specific effect of nodal metastases on survival in patients with non-metastatic renal cell carcinoma. BJU Int. 2009;103(1):33-7.
8. Campbell S, Uzzo RG, Allaf ME, Bass EB, Cadeddu JA, Chang A, et al. Renal mass and localized renal cancer: AUA Guideline2017. Available from: https://www.auanet.org/guidelines/renal-cancer-renal-mass-and-localized-renal-cancer-guideline.
9. Blom JH, van Poppel H, Marechal JM, Jacqmin D, Schroder FH, de Prijck L, et al. Radical nephrectomy with and without lymph-node dissection: final results of European Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol. 2009;55(1):28-34.
10. Crispen PL, Breau RH, Allmer C, Lohse CM, Cheville JC, Leibovich BC, et al. Lymph node dissection at the time of radical nephrectomy for high-risk clear cell renal cell carcinoma: indications and recommendations for surgical templates. Eur Urol. 2011;59(1):18-23.
11. Hadley DA, Stephenson RA, Samlowski WE, Dechet CB. Patterns of enlarged lymph nodes in patients with metastatic renal cell carcinoma. Urol Oncol. 2011;29(6):751-5.
12. Parker AE. Studies on the main posterior lymph channels of the abdomen and their connections with the lymphatics of the genito-urinary system. American Journal of Anatomy. 1935;56(3):409-43.
13. Brouwer OR, Noe A, Olmos RA, Bex A. Lymphatic drainage from renal cell carcinoma along the thoracic duct visualized with SPECT/CT. Lymphat Res Biol. 2013;11(4):233-8.
14. Karmali RJ, Suami H, Wood CG, Karam JA. Lymphatic drainage in renal cell carcinoma: back to the basics. BJU Int. 2014;114(6):806-17.
15. Robson CJ, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell carcinoma. J Urol. 1969;101(3):297-301.
16. Capitanio U, Suardi N, Matloob R, Roscigno M, Abdollah F, Di Trapani E, et al. Extent of lymph node dissection at nephrectomy affects cancer-specific survival and metastatic progression in specific sub-categories of patients with renal cell carcinoma (RCC). BJU Int. 2014;114(2):210-5.
17. Delacroix SE, Jr., Chapin BF, Chen JJ, Nogueras-Gonzalez GM, Tamboli P, Matin SF, et al. Can a durable disease-free survival be achieved with surgical resection in patients with pathological node positive renal cell carcinoma? J Urol. 2011;186(4):1236-41.
18. Kwon T, Song C, Hong JH, Kim CS, Ahn H. Reassessment of renal cell carcinoma lymph node staging: analysis of patterns of progression. Urology. 2011;77(2):373-8.
19. Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, et al. Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol. 2003;169(6):2076-83.
20. Farber NJ, Rivera-Nunez Z, Kim S, Shinder B, Radadia K, Sterling J, et al. Trends and outcomes of lymphadenectomy for nonmetastatic renal cell carcinoma: A propensity score-weighted analysis of the National Cancer Database. Urol Oncol. 2019;37(1):26-32.
21. Radadia KD, Rivera-Nunez Z, Kim S, Farber NJ, Sterling J, Falkiewicz M, et al. Accuracy of clinical nodal staging and factors associated with receipt of lymph node dissection at the time of surgery for nonmetastatic renal cell carcinoma. Urol Oncol. 2019;37(9):577 e17- e25.
22. Capitanio U, Becker F, Blute ML, Mulders P, Patard JJ, Russo P, et al. Lymph node dissection in renal cell carcinoma. Eur Urol. 2011;60(6):1212-20.
23. Bazzi WM, Sjoberg DD, Feuerstein MA, Maschino A, Verma S, Bernstein M, et al. Long-term survival rates after resection for locally advanced kidney cancer: Memorial Sloan Kettering Cancer Center 1989 to 2012 experience. J Urol. 2015;193(6):1911-6.
24. Canfield SE, Kamat AM, Sanchez-Ortiz RF, Detry M, Swanson DA, Wood CG. Renal cell carcinoma with nodal metastases in the absence of distant metastatic disease (clinical stage TxN1-2M0): the impact of aggressive surgical resection on patient outcome. J Urol. 2006;175(3 Pt 1):864-9.
25. Gershman B, Moreira DM, Thompson RH, Boorjian SA, Lohse CM, Costello BA, et al. Renal cell carcinoma with isolated lymph node involvement: long-term natural history and predictors of oncologic outcomes following surgical resection. Eur Urol. 2017;72(2):300-6.
26. Trinh QD, Schmitges J, Bianchi M, Sun M, Shariat SF, Sammon J, et al. Node-positive renal cell carcinoma in the absence of distant metastases: predictors of cancer-specific mortality in a population-based cohort. BJU Int. 2012;110(2 Pt 2):E21-7.
27. Sun M, Bianchi M, Hansen J, Abdollah F, Trinh QD, Lughezzani G, et al. Nodal involvement at nephrectomy is associated with worse survival: a stage-for-stage and grade-for-grade analysis. Int J Urol. 2013;20(4):372-80.
28. Shao N, Wang HK, Zhu Y, Ye DW. Modification of American Joint Committee on cancer prognostic groups for renal cell carcinoma. Cancer Med. 2018;7(11):5431-8.
29. Srivastava A, Rivera-Nunez Z, Kim S, Sterling J, Farber NJ, Radadia KD, et al. Impact of pathologic node positive renal cell carcinoma on survival in patients without metastasis: Evidence in support of expanding the definition of Stage IV kidney cancer. Cancer. 2020:In Press.
30. Han J, Li Q, Li P, Wang S, Zhang R, Qiao Y, et al. Reassessment of american joint committee on cancer staging for stage iii renal cell carcinoma with nodal involvement: propensity score matched analyses of a large population-based study. Frontiers in Oncology. 2020;10.
31. Patel HV, Srivastava A, Shinder B, Sadimin E, Singer EA. Strengthening the foundation of kidney cancer treatment and research: revising the AJCC staging system. Ann Transl Med. 2019;7(Suppl 1):S33.
32. Chin AI, Lam JS, Figlin RA, Belldegrun AS. Surveillance strategies for renal cell carcinoma patients following nephrectomy. Rev Urol. 2006;8(1):1-7.
33. The Nobel Prize in Physiology or Medicine 2019 [press release]. Nobel Media AB 20202020.
34. Harshman LC, Xie W, Moreira RB, Bosse D, Ruiz Ares GJ, Sweeney CJ, et al. Evaluation of disease-free survival as an intermediate metric of overall survival in patients with localized renal cell carcinoma: A trial-level meta-analysis. Cancer. 2018;124(5):925-33.
35. Motzer RJ, Ravaud A, Patard JJ, Pandha HS, George DJ, Patel A, et al. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur Urol. 2018;73(1):62-8.
36. Patel HV, Shinder B, Srinivasan R, Singer EA. Challenges and opportunities in the management of metastatic renal cell carcinoma: combination therapy and the role of cytoreductive surgery. Curr Opin Oncol. 2020;32(3):240-9.
37. Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal cell carcinoma. Nat Rev Dis Primers. 2017;3:17009.
38. The Nobel Prize in Physiology or Medicine 2018 [press release]. Nobel Media AB 20202020.
39. Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-90.
40. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-15.
41. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New England Journal of Medicine. 2019.
42. Patel HD, Puligandla M, Shuch BM, Leibovich BC, Kapoor A, Master VA, et al. The future of perioperative therapy in advanced renal cell carcinoma: how can we PROSPER? Future Oncol. 2019;15(15):1683-95.
43. Motzer RJ, editor JAVELIN Renal 101: a randomized, phase 3 study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). European Society for Medical Oncology (ESMO) 2018 Congress; 2018 10/21/2018; Munich, Germany: ESMO.
44. Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019;393(10189):2404-15.
45. Edge SB, American Joint Committee on Cancer., American Cancer Society. AJCC cancer staging handbook : from the AJCC cancer staging manual. 7th ed. New York: Springer; 2010. xix, 718 p. p.
46. Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, 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(10032):2008-16.
47. Motzer RJ, Haas NB, Donskov F, Gross-Goupil M, Varlamov S, Kopyltsov E, et al. Randomized phase iii trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol. 2017;35(35):3916-23.
48. Gross-Goupil M, Kwon TG, Eto M, Ye D, Miyake H, Seo SI, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol. 2018;29(12):2371-8.
2. Kroeger N, Pantuck AJ, Wells JC, Lawrence N, Broom R, Kim JJ, et al. Characterizing the impact of lymph node metastases on the survival outcome for metastatic renal cell carcinoma patients treated with targeted therapies. Eur Urol. 2015;68(3):506-15.
3. Yu KJ, Keskin SK, Meissner MA, Petros FG, Wang X, Borregales LD, et al. Renal cell carcinoma and pathologic nodal disease: implications for american joint committee on cancer staging. cancer. 2018;124(20):4023-31.
4. Rodriguez-Covarrubias F, Castillejos-Molina R, Sotomayor M, Mendez-Probst CE, Gomez-Alvarado MO, Uribe-Uribe N, et al. Impact of lymph node invasion and sarcomatoid differentiation on the survival of patients with locally advanced renal cell carcinoma. Urol Int. 2010;85(1):23-9.
5. Whitson JM, Harris CR, Reese AC, Meng MV. Lymphadenectomy improves survival of patients with renal cell carcinoma and nodal metastases. J Urol. 2011;185(5):1615-20.
6. Blute ML, Leibovich BC, Cheville JC, Lohse CM, Zincke H. A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma. J Urol. 2004;172(2):465-9.
7. Capitanio U, Jeldres C, Patard JJ, Perrotte P, Zini L, de La Taille A, et al. Stage-specific effect of nodal metastases on survival in patients with non-metastatic renal cell carcinoma. BJU Int. 2009;103(1):33-7.
8. Campbell S, Uzzo RG, Allaf ME, Bass EB, Cadeddu JA, Chang A, et al. Renal mass and localized renal cancer: AUA Guideline2017. Available from: https://www.auanet.org/guidelines/renal-cancer-renal-mass-and-localized-renal-cancer-guideline.
9. Blom JH, van Poppel H, Marechal JM, Jacqmin D, Schroder FH, de Prijck L, et al. Radical nephrectomy with and without lymph-node dissection: final results of European Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol. 2009;55(1):28-34.
10. Crispen PL, Breau RH, Allmer C, Lohse CM, Cheville JC, Leibovich BC, et al. Lymph node dissection at the time of radical nephrectomy for high-risk clear cell renal cell carcinoma: indications and recommendations for surgical templates. Eur Urol. 2011;59(1):18-23.
11. Hadley DA, Stephenson RA, Samlowski WE, Dechet CB. Patterns of enlarged lymph nodes in patients with metastatic renal cell carcinoma. Urol Oncol. 2011;29(6):751-5.
12. Parker AE. Studies on the main posterior lymph channels of the abdomen and their connections with the lymphatics of the genito-urinary system. American Journal of Anatomy. 1935;56(3):409-43.
13. Brouwer OR, Noe A, Olmos RA, Bex A. Lymphatic drainage from renal cell carcinoma along the thoracic duct visualized with SPECT/CT. Lymphat Res Biol. 2013;11(4):233-8.
14. Karmali RJ, Suami H, Wood CG, Karam JA. Lymphatic drainage in renal cell carcinoma: back to the basics. BJU Int. 2014;114(6):806-17.
15. Robson CJ, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell carcinoma. J Urol. 1969;101(3):297-301.
16. Capitanio U, Suardi N, Matloob R, Roscigno M, Abdollah F, Di Trapani E, et al. Extent of lymph node dissection at nephrectomy affects cancer-specific survival and metastatic progression in specific sub-categories of patients with renal cell carcinoma (RCC). BJU Int. 2014;114(2):210-5.
17. Delacroix SE, Jr., Chapin BF, Chen JJ, Nogueras-Gonzalez GM, Tamboli P, Matin SF, et al. Can a durable disease-free survival be achieved with surgical resection in patients with pathological node positive renal cell carcinoma? J Urol. 2011;186(4):1236-41.
18. Kwon T, Song C, Hong JH, Kim CS, Ahn H. Reassessment of renal cell carcinoma lymph node staging: analysis of patterns of progression. Urology. 2011;77(2):373-8.
19. Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, et al. Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol. 2003;169(6):2076-83.
20. Farber NJ, Rivera-Nunez Z, Kim S, Shinder B, Radadia K, Sterling J, et al. Trends and outcomes of lymphadenectomy for nonmetastatic renal cell carcinoma: A propensity score-weighted analysis of the National Cancer Database. Urol Oncol. 2019;37(1):26-32.
21. Radadia KD, Rivera-Nunez Z, Kim S, Farber NJ, Sterling J, Falkiewicz M, et al. Accuracy of clinical nodal staging and factors associated with receipt of lymph node dissection at the time of surgery for nonmetastatic renal cell carcinoma. Urol Oncol. 2019;37(9):577 e17- e25.
22. Capitanio U, Becker F, Blute ML, Mulders P, Patard JJ, Russo P, et al. Lymph node dissection in renal cell carcinoma. Eur Urol. 2011;60(6):1212-20.
23. Bazzi WM, Sjoberg DD, Feuerstein MA, Maschino A, Verma S, Bernstein M, et al. Long-term survival rates after resection for locally advanced kidney cancer: Memorial Sloan Kettering Cancer Center 1989 to 2012 experience. J Urol. 2015;193(6):1911-6.
24. Canfield SE, Kamat AM, Sanchez-Ortiz RF, Detry M, Swanson DA, Wood CG. Renal cell carcinoma with nodal metastases in the absence of distant metastatic disease (clinical stage TxN1-2M0): the impact of aggressive surgical resection on patient outcome. J Urol. 2006;175(3 Pt 1):864-9.
25. Gershman B, Moreira DM, Thompson RH, Boorjian SA, Lohse CM, Costello BA, et al. Renal cell carcinoma with isolated lymph node involvement: long-term natural history and predictors of oncologic outcomes following surgical resection. Eur Urol. 2017;72(2):300-6.
26. Trinh QD, Schmitges J, Bianchi M, Sun M, Shariat SF, Sammon J, et al. Node-positive renal cell carcinoma in the absence of distant metastases: predictors of cancer-specific mortality in a population-based cohort. BJU Int. 2012;110(2 Pt 2):E21-7.
27. Sun M, Bianchi M, Hansen J, Abdollah F, Trinh QD, Lughezzani G, et al. Nodal involvement at nephrectomy is associated with worse survival: a stage-for-stage and grade-for-grade analysis. Int J Urol. 2013;20(4):372-80.
28. Shao N, Wang HK, Zhu Y, Ye DW. Modification of American Joint Committee on cancer prognostic groups for renal cell carcinoma. Cancer Med. 2018;7(11):5431-8.
29. Srivastava A, Rivera-Nunez Z, Kim S, Sterling J, Farber NJ, Radadia KD, et al. Impact of pathologic node positive renal cell carcinoma on survival in patients without metastasis: Evidence in support of expanding the definition of Stage IV kidney cancer. Cancer. 2020:In Press.
30. Han J, Li Q, Li P, Wang S, Zhang R, Qiao Y, et al. Reassessment of american joint committee on cancer staging for stage iii renal cell carcinoma with nodal involvement: propensity score matched analyses of a large population-based study. Frontiers in Oncology. 2020;10.
31. Patel HV, Srivastava A, Shinder B, Sadimin E, Singer EA. Strengthening the foundation of kidney cancer treatment and research: revising the AJCC staging system. Ann Transl Med. 2019;7(Suppl 1):S33.
32. Chin AI, Lam JS, Figlin RA, Belldegrun AS. Surveillance strategies for renal cell carcinoma patients following nephrectomy. Rev Urol. 2006;8(1):1-7.
33. The Nobel Prize in Physiology or Medicine 2019 [press release]. Nobel Media AB 20202020.
34. Harshman LC, Xie W, Moreira RB, Bosse D, Ruiz Ares GJ, Sweeney CJ, et al. Evaluation of disease-free survival as an intermediate metric of overall survival in patients with localized renal cell carcinoma: A trial-level meta-analysis. Cancer. 2018;124(5):925-33.
35. Motzer RJ, Ravaud A, Patard JJ, Pandha HS, George DJ, Patel A, et al. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur Urol. 2018;73(1):62-8.
36. Patel HV, Shinder B, Srinivasan R, Singer EA. Challenges and opportunities in the management of metastatic renal cell carcinoma: combination therapy and the role of cytoreductive surgery. Curr Opin Oncol. 2020;32(3):240-9.
37. Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal cell carcinoma. Nat Rev Dis Primers. 2017;3:17009.
38. The Nobel Prize in Physiology or Medicine 2018 [press release]. Nobel Media AB 20202020.
39. Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-90.
40. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-15.
41. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New England Journal of Medicine. 2019.
42. Patel HD, Puligandla M, Shuch BM, Leibovich BC, Kapoor A, Master VA, et al. The future of perioperative therapy in advanced renal cell carcinoma: how can we PROSPER? Future Oncol. 2019;15(15):1683-95.
43. Motzer RJ, editor JAVELIN Renal 101: a randomized, phase 3 study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). European Society for Medical Oncology (ESMO) 2018 Congress; 2018 10/21/2018; Munich, Germany: ESMO.
44. Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019;393(10189):2404-15.
45. Edge SB, American Joint Committee on Cancer., American Cancer Society. AJCC cancer staging handbook : from the AJCC cancer staging manual. 7th ed. New York: Springer; 2010. xix, 718 p. p.
46. Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, 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(10032):2008-16.
47. Motzer RJ, Haas NB, Donskov F, Gross-Goupil M, Varlamov S, Kopyltsov E, et al. Randomized phase iii trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol. 2017;35(35):3916-23.
48. Gross-Goupil M, Kwon TG, Eto M, Ye D, Miyake H, Seo SI, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol. 2018;29(12):2371-8.