Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Complementary roles of surgery and systemic treatment in clear cell renal cell carcinoma

Nature Reviews Urology volume 19, pages 391–418 (2022)Cite this article

Subjects

Abstract

Standard-of-care management of renal cell carcinoma (RCC) indisputably relies on surgery for low-risk localized tumours and systemic treatment for poor-prognosis metastatic disease, but a grey area remains, encompassing high-risk localized tumours and patients with metastatic disease with a good-to-intermediate prognosis. Over the past few years, results of major practice-changing trials for the management of metastatic RCC have completely transformed the therapeutic options for this disease. Treatments targeting vascular endothelial growth factor (VEGF) have been the mainstay of therapy for metastatic RCC in the past decade, but the advent of immune checkpoint inhibitors has revolutionized the therapeutic landscape in the metastatic setting. Results from several pivotal trials have shown a substantial benefit from the combination of VEGF-directed therapy and immune checkpoint inhibition, raising new hopes for the treatment of high-risk localized RCC. The potential of these therapeutics to facilitate the surgical extirpation of the tumour in the neoadjuvant setting or to improve disease-free survival in the adjuvant setting has been investigated. The role of surgery for metastatic RCC has been redefined, with results of large trials bringing into question the paradigm of upfront cytoreductive nephrectomy, inherited from the era of cytokine therapy, when initial extirpation of the primary tumour did show clinical benefits. The potential benefits and risks of deferred surgery for residual primary tumours or metastases after partial response to checkpoint inhibitor treatment are also gaining interest, considering the long-lasting effects of these new drugs, which encourages the complete removal of residual masses.

Key points

  • Peri-operative targeted therapy for high-risk localized renal cell carcinoma (RCC) has not shown real benefits in terms of overall survival and is not recommended in current clinical practice.

  • Neoadjuvant treatments have been reported to result in tumour downstaging, but never became a standard of care owing to a lack of evidence of cancer-specific and overall survival improvement, and a small number of patients. Results from trials in which the efficacy and safety of neoadjuvant immunotherapies and combined treatments will be assessed in patients with RCC are awaited.

  • Peri-operative immunotherapies in locally advanced RCC are gaining interest. Promising outcomes with adjuvant pembrolizumab were reported in 2021 and results from other trials are awaited.

  • Upfront cytoreductive nephrectomy is not considered the standard of care any longer, but might remain beneficial for a subset of patients with favourable disease characteristics (good performance status, single-site tumour, oligometastatic disease and only one International Metastatic RCC Database Consortium criterion).

  • Deferred surgery might be an option in selected patients who show an objective response to systemic treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mechanisms of action of systemic treatments in renal cell carcinoma.

Similar content being viewed by others

References

  1. Capitanio, U. et al. Epidemiology of renal cell carcinoma. Eur. Urol. 75, 74–84 (2019).

    Article  PubMed  Google Scholar 

  2. Bukowski, R. M. Natural history and therapy of metastatic renal cell carcinoma: the role of interleukin-2. Cancer 80, 1198–1220 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 353, 14–17 (1999).

  4. Rosenberg, S. A. et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N. Engl. J. Med. 316, 889–897 (1987).

    Article  CAS  PubMed  Google Scholar 

  5. Atzpodien, J., Körfer, A., Franks, C. R., Poliwoda, H. & Kirchner, H. Home therapy with recombinant interleukin-2 and interferon-alpha 2b in advanced human malignancies. Lancet 335, 1509–1512 (1990).

    Article  CAS  PubMed  Google Scholar 

  6. West, W. H. et al. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N. Engl. J. Med. 316, 898–905 (1987).

    Article  CAS  PubMed  Google Scholar 

  7. Ljungberg, B. et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update. Eur. Urol. 75, 799–810 (2019).

    Article  PubMed  Google Scholar 

  8. NCI. Cancer of the Kidney and Renal Pelvis — Cancer Stat Facts. NIH https://seer.cancer.gov/statfacts/html/kidrp.html (2022).

  9. Patard, J.-J. et al. Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study. J. Clin. Oncol. 22, 3316–3322 (2004).

    Article  PubMed  Google Scholar 

  10. Mickisch, G. H., Garin, A., van Poppel, H., de Prijck, L. & Sylvester, R. European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 358, 966–970 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Flanigan, R. C. et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N. Engl. J. Med. 345, 1655–1659 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Flanigan, R. C. Debulking nephrectomy in metastatic renal cancer. Clin. Cancer Res. 10, 6335S–6341SS (2004).

    Article  PubMed  Google Scholar 

  13. Turajlic, S. et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx renal. Cell 173, 581–594.e12 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Motzer, R. J. et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115–124 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. ESMO. eUpdate — renal cell carcinoma treatment recommendations. ESMO https://www.esmo.org/guidelines/genitourinary-cancers/renal-cell-carcinoma/eupdate-renal-cell-carcinoma-treatment-recommendations-3 (2020).

  18. Méjean, A. et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N. Engl. J. Med. 379, 417–427 (2018).

    Article  PubMed  Google Scholar 

  19. Escudier, B. et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann. Oncol. 30, 706–720 (2019).

    Article  CAS  PubMed  Google Scholar 

  20. Baldewijns, M. M. L., van Vlodrop, I. J. H. & Schouten, L. J. Soetekouw PMMB, de Bruïne AP, van Engeland M. Genetics and epigenetics of renal cell cancer. Biochim. Biophys. Acta 1785, 133–155 (2008).

    CAS  PubMed  Google Scholar 

  21. Motzer, R. J., Bander, N. H. & Nanus, D. M. Renal-cell carcinoma. N. Engl. J. Med. 335, 865–875 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Buti, S. et al. Chemotherapy in metastatic renal cell carcinoma today? A systematic review. Anticancer Drugs 24, 535–554 (2013).

    Article  CAS  PubMed  Google Scholar 

  23. Escudier, B. et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370, 2103–2111 (2007).

    Article  PubMed  Google Scholar 

  24. Motzer, R. J. et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 27, 3584–3590 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 20, 1370–1385 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Motzer, R. et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N. Engl. J. Med. 384, 1289–1300 (2021).

    Article  CAS  PubMed  Google Scholar 

  29. Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).

    Article  CAS  PubMed  Google Scholar 

  30. Motzer, R. J. et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1103–1115 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Choueiri, T. K. et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 384, 829–841 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Akhtar, M., Al-Bozom, I. A., Al & Hussain, T. Molecular and metabolic basis of clear cell carcinoma of the kidney. Adv. Anat. Pathol. 25, 189–196 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. NCBI. VHL von Hippel-Lindau tumor suppressor [Homo sapiens (human)] — Genev — NCBI. NIH https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=7428 (2022).

  34. Kaelin, W. G. The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin. Cancer Res. 13, 680s–684ss (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Los, M., Roodhart, J. M. L. & Voest, E. E. Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. Oncologist 12, 443–450 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zwick, E., Bange, J. & Ullrich, A. Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr. Relat. Cancer 8, 161–173 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Robinson, C. J. & Stringer, S. E. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J. Cell Sci. 114, 853–865 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Porter, A. C. & Vaillancourt, R. R. Tyrosine kinase receptor-activated signal transduction pathways which lead to oncogenesis. Oncogene 17, 1343–1352 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Escudier, B. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125–134 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Sternberg, C. N. et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J. Clin. Oncol. 28, 1061–1068 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Rini, B. I. et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378, 1931–1939 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Motzer, R. J. et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 16, 1473–1482 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Rini, B. I. et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 21, 95–104 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03680521 (2021).

  46. Cohen, R. B. & Oudard, S. Antiangiogenic therapy for advanced renal cell carcinoma: management of treatment-related toxicities. Invest. N. Drugs 30, 2066–2079 (2012).

    Article  CAS  Google Scholar 

  47. Kollmannsberger, C. Sunitinib side effects as surrogate biomarkers of efficacy. Can. Urol. Assoc. J. 10, S245–S247 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes. Dev. 18, 1926–1945 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Yin, Y. et al. mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR. Cell Res. 26, 46–65 (2016).

    Article  CAS  PubMed  Google Scholar 

  50. Faes, S., Demartines, N. & Dormond, O. Mechanistic target of rapamycin inhibitors in renal cell carcinoma: potential, limitations, and perspectives. Front. Cell Dev. Biol. 9, 636037 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Loewith, R. et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Albiges, L. et al. Incidence and management of mTOR inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma. Ann. Oncol. 23, 1943–1953 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. Rodriguez-Pascual, J., Cheng, E., Maroto, P. & Duran, I. Emergent toxicities associated with the use of mTOR inhibitors in patients with advanced renal carcinoma. Anticancer Drugs 21, 478–486 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Penttilä, P. et al. Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma. Eur. J. Cancer 81, 9–16 (2017).

    Article  PubMed  CAS  Google Scholar 

  55. Braun, D. A. et al. Progressive immune dysfunction with advancing disease stage in renal cell carcinoma. Cancer Cell 39, 632–648.e8 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhang, Y. & Zheng, J. Functions of immune checkpoint molecules beyond immune evasion. Adv. Exp. Med. Biol. 1248, 201–226 (2020).

    Article  CAS  PubMed  Google Scholar 

  58. Iwai, Y., Hamanishi, J., Chamoto, K. & Honjo, T. Cancer immunotherapies targeting the PD-1 signaling pathway. J. Biomed. Sci. 24, 26 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Walunas, T. L. et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1, 405–413 (1994).

    Article  CAS  PubMed  Google Scholar 

  60. Qureshi, O. S. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600–603 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Carlo, M. I., Voss, M. H. & Motzer, R. J. Checkpoint inhibitors and other novel immunotherapies for advanced renal cell carcinoma. Nat. Rev. Urol. 13, 420–431 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Boussiotis, V. A. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N. Engl. J. Med. 375, 1767–1778 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Agata, Y. et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765–772 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Okazaki, T. & Honjo, T. PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 19, 813–824 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Comin-Anduix, B., Escuin-Ordinas, H. & Ibarrondo, F. J. Tremelimumab: research and clinical development. Onco Targets Ther. 9, 1767–1776 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Massard, C. et al. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J. Clin. Oncol. 34, 3119–3125 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03288532 (2020).

  70. Drugs.com. Pembrolizumab monograph for professionals. Drugs.com https://www.drugs.com/monograph/pembrolizumab.html (2021).

  71. Choueiri, T. K. et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N. Engl. J. Med. 385, 683–694 (2021).

    Article  CAS  PubMed  Google Scholar 

  72. AdisInsight. Toripalimab — Shanghai Junshi Biosciences — AdisInsight. AdisInsight https://adisinsight.springer.com/drugs/800046697 (2022).

  73. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04385654 (2020).

  74. Rini, B. I. 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 393, 2404–2415 (2019).

    Article  PubMed  Google Scholar 

  75. Drugs.com. Avelumab monograph for professionals. Drugs.com https://www.drugs.com/monograph/avelumab.html (2022).

  76. Weber, J. S., Yang, J. C., Atkins, M. B. & Disis, M. L. Toxicities of immunotherapy for the practitioner. J. Clin. Oncol. 33, 2092–2099 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhou, X. et al. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis. BMC Med. 18, 87 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Postow, M. A., Callahan, M. K. & Wolchok, J. D. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33, 1974–1982 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. EAU. EAU Guidelines: renal cell carcinoma. Uroweb https://uroweb.org/guideline/renal-cell-carcinoma/#note_472 (2022).

  80. Heng, D. Y. C. et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 14, 141–148 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Heng, D. Y. C. et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J. Clin. Oncol. 27, 5794–5799 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Ljungberg, B. et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur. Urol. 58, 398–406 (2010).

    Article  PubMed  Google Scholar 

  83. Albiges, L. et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 5, e001079 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Tannir, N. M. et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clin. Cancer Res. 27, 78–86 (2021).

    Article  CAS  PubMed  Google Scholar 

  85. Shuch, B. et al. Impact of pathological tumour characteristics in patients with sarcomatoid renal cell carcinoma. BJU Int. 109, 1600–1606 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Cella, D. et al. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol. 20, 297–310 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Powles, T. et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 21, 1563–1573 (2020).

    Article  CAS  PubMed  Google Scholar 

  88. Atkins, M. B. et al. Patient-reported outcomes from the phase III randomized IMmotion151 trial: atezolizumab + bevacizumab versus sunitinib in treatment-naïve metastatic renal cell carcinoma. Clin. Cancer Res. 26, 2506–2514 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Klaassen, Z. ASCO 2021: health-related quality-of-life analysis from the phase 3 CLEAR trial of lenvatinib + pembrolizumab or everolimus versus sunitinib for patients with advanced RCC. Uro Today https://www.urotoday.com/conference-highlights/asco-2021/asco-2021-kidney-cancer/130132-asco-2021-health-related-quality-of-life-analysis-from-the-phase-3-clear-trial-of-lenvatinib-pembrolizumab-or-everolimus-versus-sunitinib-for-patients-with-advanced-rcc.amp.html (2021).

  90. Bedke, J. et al. The 2021 updated European Association of Urology Guidelines on renal cell carcinoma: immune checkpoint inhibitor-based combination therapies for treatment-naive metastatic clear-cell renal cell carcinoma are standard of care. Eur. Urol. 80, 393–397 (2021).

    Article  PubMed  Google Scholar 

  91. Law, T. M. et al. Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer 76, 824–832 (1995).

    Article  CAS  PubMed  Google Scholar 

  92. O’Neill, L. A. J., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Bhindi, B. et al. Systematic review of the role of cytoreductive nephrectomy in the targeted therapy era and beyond: an individualized approach to metastatic renal cell carcinoma. Eur. Urol. 75, 111–128 (2019).

    Article  PubMed  Google Scholar 

  94. Posadas, E. M. & Figlin, R. A. Kidney cancer: progress and controversies in neoadjuvant therapy. Nat. Rev. Urol. 11, 254–255 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Rini, B. I. et al. A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma. J. Urol. 194, 297–303 (2015).

    Article  CAS  PubMed  Google Scholar 

  96. Cai, W. et al. Comparison of efficacy and safety among axitinib, sunitinib, and sorafenib as neoadjuvant therapy for renal cell carcinoma: a retrospective study. Cancer Commun. 39, 56 (2019).

    Article  Google Scholar 

  97. Hatiboglu, G. et al. Effective downsizing but enhanced intratumoral heterogeneity following neoadjuvant sorafenib in patients with non-metastatic renal cell carcinoma. Langenbecks Arch. Surg. 402, 637–644 (2017).

    Article  PubMed  Google Scholar 

  98. Lebacle, C. et al. Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study. BJU Int. 123, 804–810 (2019).

    Article  CAS  PubMed  Google Scholar 

  99. Silberstein, J. L. et al. Feasibility and efficacy of neoadjuvant sunitinib before nephron-sparing surgery. BJU Int. 106, 1270–1276 (2010).

    Article  PubMed  Google Scholar 

  100. Roy, A. M., Briggler, A., Tippit, D., Dawson, K. & Verma, R. Neoadjuvant cabozantinib in renal-cell carcinoma: a brief review. Clin. Genitourin. Cancer 18, e688–e691 (2020).

    Article  PubMed  Google Scholar 

  101. Cowey, C. L. et al. Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma. J. Clin. Oncol. 28, 1502–1507 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Field, C. A. et al. Neoadjuvant sunitinib decreases inferior vena caval thrombus size and is associated with improved oncologic outcomes: a multicenter comparative analysis. Clin. Genitourin. Cancer 17, e505–e512 (2019).

    Article  PubMed  Google Scholar 

  103. Bex, A. et al. Neoadjuvant sunitinib for surgically complex advanced renal cell cancer of doubtful resectability: initial experience with downsizing to reconsider cytoreductive surgery. World J. Urol. 27, 533–539 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Bigot, P. et al. Neoadjuvant targeted molecular therapies in patients undergoing nephrectomy and inferior vena cava thrombectomy: is it useful? World J. Urol. 32, 109–114 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. Karam, J. A. et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. Eur. Urol. 66, 874–880 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hellenthal, N. J. et al. Prospective clinical trial of preoperative sunitinib in patients with renal cell carcinoma. J. Urol. 184, 859–864 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Thomas, A. A. et al. Response of the primary tumor to neoadjuvant sunitinib in patients with advanced renal cell carcinoma. J. Urol. 181, 518–523 (2009). discussion 523.

    Article  CAS  PubMed  Google Scholar 

  108. Zhang, Y. et al. Sorafenib neoadjuvant therapy in the treatment of high risk renal cell carcinoma. PLoS One 10, e0115896 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Rini, B. I. et al. The effect of sunitinib on primary renal cell carcinoma and facilitation of subsequent surgery. J. Urol. 187, 1548–1554 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Cost, N. G. et al. The impact of targeted molecular therapies on the level of renal cell carcinoma vena caval tumor thrombus. Eur. Urol. 59, 912–918 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. van der Veldt, A. A. M. et al. Sunitinib for treatment of advanced renal cell cancer: primary tumor response. Clin. Cancer Res. 14, 2431–2436 (2008).

    Article  PubMed  Google Scholar 

  112. Hutson, T. E., Thoreson, G. R., Figlin, R. A. & Rini, B. I. The evolution of systemic therapy in metastatic renal cell carcinoma. Am. Soc. Clin. Oncol. Educ. Book. 35, 113–117 (2016).

    Article  PubMed  Google Scholar 

  113. Choueiri, T. K. et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1814–1823 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Therasse, P. et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Inst. 92, 205–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. AUA. Renal Cancer: renal mass & localized renal cancer guideline. AUA https://www.auanet.org/guidelines/guidelines/renal-cancer-renal-mass-and-localized-renal-cancer-guideline (2017).

  116. Russo, P. Oncological and renal medical importance of kidney-sparing surgery. Nat. Rev. Urol. 10, 292–299 (2013).

    Article  PubMed  Google Scholar 

  117. Van Poppel, H. et al. A prospective, randomised 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. 59, 543–552 (2011).

    Article  PubMed  Google Scholar 

  118. Lane, B. R. et al. Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma. Urol. Oncol. 33, 112.e15–21 (2015).

    Article  CAS  Google Scholar 

  119. Kutikov, A. & Uzzo, R. G. The R.E.N.A.L. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. J. Urol. 182, 844–853 (2009).

    Article  PubMed  Google Scholar 

  120. Pfizer. SUTENT prescribing information. Pfizer http://labeling.pfizer.com/showlabeling.aspx?id=607 (2006).

  121. Minami, H. et al. Phase I and pharmacokinetic study of sorafenib, an oral multikinase inhibitor, in Japanese patients with advanced refractory solid tumors. Cancer Sci. 99, 1492–1498 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Mootha, R. K., Butler, R., Laucirica, R., Scardino, P. T. & Lerner, S. P. Renal cell carcinoma with an infrarenal vena caval tumor thrombus. Urology 54, 561 (1999).

    Article  CAS  PubMed  Google Scholar 

  123. Neves, R. J. & Zincke, H. Surgical treatment of renal cancer with vena cava extension. Br. J. Urol. 59, 390–395 (1987).

    Article  CAS  PubMed  Google Scholar 

  124. Karnes, R. J. & Blute, M. L. Surgery insight: management of renal cell carcinoma with associated inferior vena cava thrombus. Nat. Clin. Pract. Urol. 5, 329–339 (2008).

    Article  PubMed  Google Scholar 

  125. Labbate, C. et al. Complete response of renal cell carcinoma vena cava tumor thrombus to neoadjuvant immunotherapy. J. Immunother. Cancer 7, 66 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Singla, N. et al. Pathologic response and surgical outcomes in patients undergoing nephrectomy following receipt of immune checkpoint inhibitors for renal cell carcinoma. Urol. Oncol. 37, 924–931 (2019).

    Article  CAS  PubMed  Google Scholar 

  127. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02212730 (2020).

  128. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02575222 (2020).

  129. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02595918 (2020).

  130. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02762006 (2020).

  131. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03055013 (2022).

  132. Dall’Olio, F. G. et al. Immortal time bias in the association between toxicity and response for immune checkpoint inhibitors: a meta-analysis. Immunotherapy 13, 257–270 (2021).

    Article  PubMed  CAS  Google Scholar 

  133. Bex, A. et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx). J. Clin. Oncol. 40, 289–289 (2022).

    Article  Google Scholar 

  134. Pizzocaro, G. et al. Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a multicentric randomized study. J. Clin. Oncol. 19, 425–431 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Messing, E. M. et al. Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. J. Clin. Oncol. 21, 1214–1222 (2003).

    Article  CAS  PubMed  Google Scholar 

  136. Clark, J. I. et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J. Clin. Oncol. 21, 3133–3140 (2003).

    Article  CAS  PubMed  Google Scholar 

  137. Passalacqua, R. et al. Adjuvant low-dose interleukin-2 (IL-2) plus interferon-α (IFN-α) in operable renal cell carcinoma (RCC): a phase III, randomized, multicentre trial of the Italian Oncology Group for Clinical Research (GOIRC). J. Immunother. 37, 440–447 (2014).

    Article  CAS  PubMed  Google Scholar 

  138. Jocham, D. et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet 363, 594–599 (2004).

    Article  CAS  PubMed  Google Scholar 

  139. Janowitz, T., Welsh, S. J., Zaki, K., Mulders, P. & Eisen, T. Adjuvant therapy in renal cell carcinoma-past, present, and future. Semin. Oncol. 40, 482–491 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Janzen, N. K., Kim, H. L., Figlin, R. A. & Belldegrun, A. S. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol. Clin. North. Am. 30, 843–852 (2003).

    Article  PubMed  Google Scholar 

  141. Porta, C. et al. The adjuvant treatment of kidney cancer: a multidisciplinary outlook. Nat. Rev. Nephrol. 15, 423–433 (2019).

    Article  PubMed  Google Scholar 

  142. Haas N. B., Uzzo R. G. Perioperative therapy in renal cell carcinoma: what do we know, what have we learned, what’s next? J. Clin. Oncol. 36, 3608–3614 (2018).

    Article  CAS  Google Scholar 

  143. Figlin, R. A., Leibovich, B. C., Stewart, G. D. & Negrier, S. Adjuvant therapy in renal cell carcinoma: does higher risk for recurrence improve the chance for success? Ann. Oncol. 29, 324–331 (2018).

    Article  CAS  PubMed  Google Scholar 

  144. Frank, I. et al. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J. Urol. 168, 2395–2400 (2002).

    Article  PubMed  Google Scholar 

  145. Leibovich, B. C. et al. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 97, 1663–1671 (2003).

    Article  PubMed  Google Scholar 

  146. Zisman, A. et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J. Clin. Oncol. 19, 1649–1657 (2001).

    Article  CAS  PubMed  Google Scholar 

  147. Cortellini, A. et al. Predictive ability for disease-free survival of the GRade, Age, Nodes, and Tumor (GRANT) score in patients with resected renal cell carcinoma. Curr. Urol. 14, 98–104 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Brooks, S. A. et al. ClearCode34: a prognostic risk predictor for localized clear cell renal cell carcinoma. Eur. Urol. 66, 77–84 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Rini, B. et al. A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies. Lancet Oncol. 16, 676–685 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. Ingels A., et al. Vimentin over-expression and carbonic anhydrase IX under-expression are independent predictors of recurrence, specific and overall survival in non-metastatic clear-cell renal carcinoma: a validation study. World J. Urol. 35, 81–87 (2016)

    Article  PubMed  CAS  Google Scholar 

  151. Haas, N. B. et al. Adjuvant treatment for high-risk clear cell renal cancer: updated results of a high-risk subset of the ASSURE randomized trial. JAMA Oncol. 3, 1249–1252 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Motzer, R. J. 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. 35, 3916–3923 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Gross-Goupil M., et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann. Oncol. 29, 2371–2378 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Ravaud, A. et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N. Engl. J. Med. 375, 2246–2254 (2016).

    Article  CAS  PubMed  Google Scholar 

  155. Motzer, R. J. et al. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur. Urol. 73, 62–68 (2018).

    Article  CAS  PubMed  Google Scholar 

  156. Larroquette, M. et al. Adjuvant therapy in renal cell carcinoma: current knowledges and future perspectives. Cancer Treat. Rev. 97, 102207 (2021).

    Article  CAS  PubMed  Google Scholar 

  157. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/record/NCT01120249 (2021).

  158. Sun, M. et al. Adjuvant vascular endothelial growth factor-targeted therapy in renal cell carcinoma: a systematic review and pooled analysis. Eur. Urol. 74, 611–620 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Escudier, B. et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 25, iii49–iii56 (2014).

    Article  PubMed  Google Scholar 

  160. Rini, B. I. et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC). J. Immunother. Cancer 7, 354 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Palumbo, C. et al. A plea for optimizing selection in current adjuvant immunotherapy trials for high-risk nonmetastatic renal cell carcinoma according to expected cancer-specific mortality. Clin. Genitourin. Cancer 18, 314–321.e1 (2020).

    Article  PubMed  Google Scholar 

  162. Eggermont, A. M. M. et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 16, 522–530 (2015).

    Article  CAS  PubMed  Google Scholar 

  163. Weber, J. et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med. 377, 1824–1835 (2017).

    Article  CAS  PubMed  Google Scholar 

  164. Bajorin, D. F. et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N. Engl. J. Med. 384, 2102–2114 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03024996 (2022).

  166. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03138512 (2022).

  167. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03142334 (2021).

  168. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03055013 (2022).

  169. Harshman, L. C. 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 124, 925–933 (2018).

    Article  PubMed  Google Scholar 

  170. FDA. Renal cell carcinoma: developing drugs and biologics for adjuvant treatment. FDA https://www.fda.gov/regulatory-information/search-fda-guidance-documents/renal-cell-carcinoma-developing-drugs-and-biologics-adjuvant-treatment (2020).

  171. Bedke, J. et al. 2021 Updated European Association of Urology guidelines on the use of adjuvant pembrolizumab for renal cell carcinoma. Eur. Urol. 82, 134–137 (2021).

    Google Scholar 

  172. Martinez Chanza, N., Tripathi, A. & Harshman, L. C. Adjuvant therapy options in renal cell carcinoma: where do we stand? Curr. Treat. Options Oncol. 20, 44 (2019).

    Article  PubMed  Google Scholar 

  173. Mazzaschi, G., Quaini, F., Bersanelli, M. & Buti, S. Cytoreductive nephrectomy in the era of targeted- and immuno-therapy for metastatic renal cell carcinoma: an elusive issue? A systematic review of the literature. Crit. Rev. Oncol. Hematol. 160, 103293 (2021).

    Article  PubMed  Google Scholar 

  174. Culp, S. H. et al. Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy? Cancer 116, 3378–3388 (2010).

    Article  PubMed  Google Scholar 

  175. Rini, B. I., Campbell, S. C. & Escudier, B. Renal cell carcinoma. Lancet 373, 1119–1132 (2009).

    Article  CAS  PubMed  Google Scholar 

  176. Bex, A. et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial. JAMA Oncol. 5, 164–170 (2019).

    Article  PubMed  Google Scholar 

  177. Roussel, E. et al. Rates and predictors of perioperative complications in cytoreductive nephrectomy: analysis of the registry for metastatic renal cell carcinoma. Eur. Urol. Oncol. 3, 523–529 (2020).

    Article  PubMed  Google Scholar 

  178. Choueiri, T. K. et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J. Urol. 185, 60–66 (2011).

    Article  PubMed  Google Scholar 

  179. Motzer, R. J. et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J. Clin. Oncol. 17, 2530–2540 (1999).

    Article  CAS  PubMed  Google Scholar 

  180. De Bruijn, R. E. et al. Surgical safety of cytoreductive nephrectomy following sunitinib: results from the multicentre, randomised controlled trial of immediate versus deferred nephrectomy (SURTIME). Eur. Urol. 76, 437–440 (2019).

    Article  PubMed  CAS  Google Scholar 

  181. Méjean, A. et al. Sunitinib alone or after nephrectomy for patients with metastatic renal cell carcinoma: is there still a role for cytoreductive nephrectomy? Eur. Urol. 80, 417–424 (2021).

    Article  PubMed  CAS  Google Scholar 

  182. Rini, B. I. et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol. 17, 1317–1324 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Roussel E., et al. Too good for CARMENA: criteria associated with long systemic therapy free intervals post cytoreductive nephrectomy for metastatic clear cell renal cell carcinoma. Scand. J. Urol. 54, 493-499 (2020).

  184. Mason, R. J. et al. Kidney Cancer Research Network of Canada (KCRNC) consensus statement on the role of cytoreductive nephrectomy for patients with metastatic renal cell carcinoma. Can. Urol. Assoc. J. 13, 166–174 (2019).

    PubMed  Google Scholar 

  185. Bex, A. et al. Updated European Association of Urology guidelines for cytoreductive nephrectomy in patients with synchronous metastatic clear-cell renal cell carcinoma. Eur. Urol. 74, 805–809 (2018).

    Article  PubMed  Google Scholar 

  186. Motzer, R. J. et al. NCCN guidelines insights: kidney cancer, version 1.2021. J. Natl Compr. Cancer Netw. 18, 1160–1170 (2020).

    Article  Google Scholar 

  187. Motzer, R. J. & Russo, P. Cytoreductive nephrectomy — patient selection is key. N. Engl. J. Med. 379, 481–482 (2018).

    Article  PubMed  Google Scholar 

  188. Larcher, A. et al. Cytoreductive nephrectomy in metastatic patients with signs or symptoms: implications for renal cell carcinoma guidelines. Eur. Urol. 78, 321–326 (2020).

    Article  PubMed  Google Scholar 

  189. Larcher, A. et al. Individualised indications for cytoreductive nephrectomy: which criteria define the optimal candidates? Eur. Urol. Oncol. 2, 365–378 (2019).

    Article  PubMed  Google Scholar 

  190. Mejean, A. et al. Cytoreductive nephrectomy (CN) in metastatic renal cancer (mRCC): update on Carmena trial with focus on intermediate IMDC-risk population. J. Clin. Oncol. 37, 4508–4508 (2019).

    Article  Google Scholar 

  191. Bhindi, B. et al. Deferred cytoreductive nephrectomy in patients with newly diagnosed metastatic renal cell carcinoma. Eur. Urol. 78, 615–623 (2020).

    Article  CAS  PubMed  Google Scholar 

  192. Méjean, A. Primum non nocere: when nephrectomy becomes a selective approach in metastatic renal cell carcinoma. Eur. Urol. Oncol. 3, 174–175 (2020).

    Article  PubMed  Google Scholar 

  193. Albiges, L. et al. Updated European Association of Urology guidelines on renal cell carcinoma: immune checkpoint inhibition is the new backbone in first-line treatment of metastatic clear-cell renal cell carcinoma. Eur. Urol. 76, 151–156 (2019).

    Article  PubMed  Google Scholar 

  194. Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016).

    Article  CAS  PubMed  Google Scholar 

  195. Kinsey, E. N. & George, D. Can I get a multidisciplinary consult, please? Systemic immunotherapy and the timing of cytoreductive nephrectomy. Eur. Urol. Focus 6, 9–10 (2020).

    Article  PubMed  Google Scholar 

  196. Bakouny, Z. et al. Cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI) or targeted therapy (TT): a propensity score-based analysis. J. Clin. Oncol. 38, 608 (2020).

    Article  Google Scholar 

  197. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03977571 (2020).

  198. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04510597 (2021).

  199. Jonasch, E. et al. Phase II presurgical feasibility study of bevacizumab in untreated patients with metastatic renal cell carcinoma. J. Clin. Oncol. 27, 4076–4081 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Powles, T. et al. The outcome of patients treated with sunitinib prior to planned nephrectomy in metastatic clear cell renal cancer. Eur. Urol. 60, 448–454 (2011).

    Article  CAS  PubMed  Google Scholar 

  201. Bex, A. et al. A phase II, single-arm trial of neoadjuvant axitinib plus avelumab in patients with localized renal cell carcinoma who are at high risk of relapse after nephrectomy (NEOAVAX). Future Oncol. 15, 2203–2209 (2019).

    Article  CAS  PubMed  Google Scholar 

  202. Reimers, M. A. et al. Elective cytoreductive nephrectomy after checkpoint inhibitor immunotherapy in patients with initially unresectable metastatic clear cell renal cell carcinoma. Clin. Genitourin. Cancer 18, 361–366 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Pignot, G. et al. Nephrectomy after complete response to immune checkpoint inhibitors for metastatic renal cell carcinoma: a new surgical challenge? Eur. Urol. 77, 761–763 (2020).

    Article  PubMed  Google Scholar 

  204. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02210117(2020).

  205. Epaillard, N. et al. BIONIKK: a phase 2 biomarker driven trial with nivolumab and ipilimumab or VEGFR tyrosine kinase inhibitor (TKI) in naïve metastatic kidney cancer. Bull. Cancer 107, eS22–eS27 (2020).

    Article  PubMed  Google Scholar 

  206. Beuselinck, B. et al. Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting. Clin. Cancer Res. 21, 1329–1339 (2015).

    Article  CAS  PubMed  Google Scholar 

  207. Roussel, E. et al. Molecular subtypes and gene expression signatures as prognostic features in fully resected clear cell renal cell carcinoma: a tailored approach to adjuvant trials. Clin. Genitourin. Cancer 19, e382–e394 (2021).

  208. McDermott, D. F. et al. Publisher correction: clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med. 24, 1941 (2018).

    Article  CAS  PubMed  Google Scholar 

  209. Najjar, Y. G. et al. Myeloid-derived suppressor cell subset accumulation in renal cell carcinoma parenchyma is associated with intratumoral expression of IL1β, IL8, CXCL5, and Mip-1α. Clin. Cancer Res. 23, 2346–2355 (2017).

    Article  CAS  PubMed  Google Scholar 

  210. Osada, T. et al. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol. Immunother. 57, 1115–1124 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Hannan, R. et al. Phase II trial of stereotactic ablative radiation (SAbR) for oligometastatic kidney cancer. J. Clin. Oncol. 39, 311–311 (2021).

    Article  Google Scholar 

  212. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04090710 (2022).

  213. Jadvar, H., Chen, X., Cai, W. & Mahmood, U. Radiotheranostics in cancer diagnosis and management. Radiology. 286, 388–400 (2018).

    Article  PubMed  Google Scholar 

  214. Courcier, J. et al. Carbonic anhydrase IX in renal cell carcinoma, implications for disease management. Int. J. Mol. Sci. 21, E7146 (2020).

    Article  PubMed  CAS  Google Scholar 

  215. Muselaers, C. H. J. et al. Phase 2 study of lutetium 177-labeled anti-carbonic anhydrase IX monoclonal antibody girentuximab in patients with advanced renal cell carcinoma. Eur. Urol. 69, 767–770 (2016).

    Article  CAS  PubMed  Google Scholar 

  216. Filetti, S. et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann. Oncol. 30, 1856–1883 (2019).

    Article  CAS  PubMed  Google Scholar 

  217. Hofman, M. S. et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet 397, 797–804 (2021).

    Article  CAS  PubMed  Google Scholar 

  218. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04118855 (2019).

  219. Motzer, R. J., Bacik, J., Murphy, B. A., Russo, P. & Mazumdar, M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J. Clin. Oncol. 20, 289–296 (2002).

    Article  CAS  PubMed  Google Scholar 

  220. de Velasco, G. et al. A case series of advanced renal cell carcinoma patients treated with neoadjuvant cabozantinib prior to cytoreductive nephrectomy within the phase 2 CABOPRE trial. Oncotarget. 11, 4457–4462 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  221. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04393350 (2022).

Download references

Acknowledgements

This work was carried out on behalf of the YAU working group.

Author information

Authors and Affiliations

  1. Department of Urology, University Hospital Henri Mondor, APHP, UPEC, Créteil, France

    Alexandre Ingels & Alexandre de la Taille

  2. Young Academic Urologists (YAU) Renal Cancer Working Group, Arnhem, Netherlands

    Alexandre Ingels, Riccardo Campi, Umberto Capitanio, Daniele Amparore, Riccardo Bertolo, Umberto Carbonara, Selcuk Erdem, Önder Kara, Tobias Klatte, Maximilian C. Kriegmair, Michele Marchioni, Maria C. Mir, Idir Ouzaïd, Nicola Pavan, Angela Pecoraro & Eduard Roussel

  3. Department of Urological Robotic Surgery and Renal Transplantation, University of Florence, Careggi Hospital, Florence, Italy

    Riccardo Campi

  4. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

    Riccardo Campi

  5. Unit of Urology, IRCCS Ospedale San Raffaele, Milan, Italy

    Umberto Capitanio

  6. Division of Experimental Oncology, Urological Research Institute (URI), IRCCS Ospedale San Raffaele, Milan, Italy

    Umberto Capitanio

  7. Department of Urology, San Luigi Hospital, University of Turin, Turin, Italy

    Daniele Amparore & Angela Pecoraro

  8. Department of Urology, San Carlo di Nancy Hospital, Rome, Italy

    Riccardo Bertolo

  9. Department of Urology, University of Bari, Bari, Italy

    Umberto Carbonara

  10. Department of Urology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey

    Selcuk Erdem

  11. Department of Urology, Kocaeli University School of Medicine, Kocaeli, Turkey

    Önder Kara

  12. Department of Urology, Royal Bournemouth Hospital, University Hospitals Dorset NHS Foundation Trust, Bournemouth, UK

    Tobias Klatte

  13. Department of Surgery, University of Cambridge, Cambridge, UK

    Tobias Klatte

  14. Department of Urology, University Medical Centre Mannheim, Mannheim, Germany

    Maximilian C. Kriegmair

  15. Unit of Urology, SS. Annunziata Hospital, G. D’Annunzio University, Chieti, Italy

    Michele Marchioni

  16. Department of Urology, Fundacion Instituto Valenciano Oncologia, Valencia, Spain

    Maria C. Mir

  17. Department of Urology, Bichat Claude Bernard Hospital, Paris, France

    Idir Ouzaïd

  18. Urology Clinic, Department of Medical, Surgical and Health Science, University of Trieste, Trieste, Italy

    Nicola Pavan

  19. Department of Urology, University Hospitals Leuven, Leuven, Belgium

    Eduard Roussel

Authors
  1. Alexandre Ingels
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Riccardo Campi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Umberto Capitanio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniele Amparore
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Riccardo Bertolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Umberto Carbonara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Selcuk Erdem
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Önder Kara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tobias Klatte
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maximilian C. Kriegmair
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michele Marchioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Maria C. Mir
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Idir Ouzaïd
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nicola Pavan
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Angela Pecoraro
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Eduard Roussel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Alexandre de la Taille
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.I., D.A., R.B., R.C., U. Carbonara, S.E., Ö.K., T.K., M.C.K., M.M., M.C.M., I.O., A.P. and E.R. researched data for the article. A.I., R.B., R.C., U. Capitanio, S.E., Ö.K., T.K., M.C.K., M.C.M., I.O., N.P. and E.R. made substantial contributions to the discussion of content. A.I., D.A., R.B., R.C., U. Carbonara, S.E., Ö.K., T.K., M.C.K., M.M., M.C.M., I.O. and E.R. wrote the article. A.I., D.A., R.B., R.C., U. Capitanio, S.E., Ö.K., U. Carbonara, T.K., M.C.K., M.M., M.C.M., N.P., A.P., E.R. and A.D.L.T. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Alexandre Ingels.

Ethics declarations

Competing interests

A.I. declares competing interests with Intuitive Surgical, Ipsen, Bristol-Myers Squibb, Pfizer and Elypta. D.A. declares competing interests with Elypta. R.C. declares competing interests with Elypta, Janssen and Merck. E.R. declares competing interests with Pfizer and Ipsen. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Urology thanks E. Jonasch, S. Buti, M. Staehler and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

FKSI-19

A validated 19-item instrument that measures tumour-specific patient-reported outcomes (PROs) in patients with kidney cancer and contains several domains (disease-related symptoms, disease-related symptoms physical, disease-related symptoms emotional, treatment side effects, and functional well-being); patients rate their symptoms on a five-point scale with responses ranging from “not at all” to “very much”. The FKSI-19 total score is based on all 19 items and ranges from 0 to 76, with a high score indicating few symptoms; a change ≥3 points has been established as a clinically important difference.

EQ-5D-3L

A validated, standardized instrument for measuring general health status that includes five domains: mobility; self-care; usual activities; pain and discomfort; and depression and anxiety. Patients self-rate their health state on a visual 100-point analogue rating scale, with zero being the worst health imaginable and 100 the best health imaginable. An EQ-5D-3L health-state utility index score ranging from 0 to 1 is calculated for each of the health states described by the instrument on the basis of values provided in large general population studies.

Simon’s two-stage design

Simon’s two-stage design is a type of phase II clinical trial. It is one of the most common multi-stage designs used in phase IIa clinical trials. Simon’s two-stage design is an exact design, which enables flexibility regarding the null and alternative hypotheses, also enabling stopping for futility.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ingels, A., Campi, R., Capitanio, U. et al. Complementary roles of surgery and systemic treatment in clear cell renal cell carcinoma. Nat Rev Urol 19, 391–418 (2022). https://doi.org/10.1038/s41585-022-00592-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41585-022-00592-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer