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

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.

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

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Acknowledgements

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

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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.

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Correspondence to Alexandre Ingels.

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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.

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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.

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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

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