The Treatment of Metastatic Renal Cell Carcinoma

Abstract

Background: Approximately 15 000 people receive a diagnosis of renal cell carcinoma (RCC) in Germany each year; in 20-30% of cases, metastatic RCC (mRCC) is already present at the time of diagnosis. This disease in the metastatic stage is still mainly treated palliatively, yet the multimodal therapeutic landscape has changed markedly over the past 15 years, with the approval of many new treatments for patients with mRCC.

Methods: This review is based on prospective studies retrieved by a selective search in PubMed and the ASCO and ESMO databases and on the German and European oncological and urological guidelines for RCC.

Results: Drugs are the mainstay of treatment. mRCC can be treated with a combination of two immune checkpoint inhibitors (CPIs), a CPI and a tyrosine-kinase inhibitor (TKI) (evidence level IA), or a TKI as monotherapy (evidence level IIC-IC). With prognosis-based sequential drug treatment, a mean progressionfree survival of 12 to 24 months and an overall survival of approximately 50 months can be achieved from the time of initiation of first-line therapy. Aside from pharmacotherapy, the multidisciplinary tumor board should evaluate the indications for local treatments such as cytoreductive nephrectomy, metastasectomy, and radiotherapy, depending on the individual prognostic constellation and the patient's present condition.

Conclusion: Optimal individualized decisions require a high level of expertise and the collabo - ration of a multidisciplinary tumor board. Older prognostic parameters currently play a leading role in decision-making, while predictive parameters and molecular markers are not yet adequately validated.

Figure 1

Treatment algorithm for metastatic renal cell carcinoma, mRCC (modified from the Onkopedia guideline for renal-cell carcinoma) (2, 5, 37) *¹ In the Keynote 564 trial, patients who underwent metastasectomy with curative intent were given adjuvant pembrolizumab within one year (9, e4, 7). *² The specific aspects mentioned in the text are to be taken into account. *³ According to the current S3 guideline, a further alternative is bevacizumab + IFN-α, but this recommendation is no longer current according to the ESMO and EAU guidelines and is therefore not listed here. *⁴ The most recent long-term data do not show any inferiority with respect to overall survival for sunitinib monotherapy compared to CPI/TKI combination therapy (e18). *⁵ If CPI treatment is not possible. *⁶ Changes in systemic treatment should only be made after discussion in an interdisciplinary tumor board, only in case of clinically significant progession of disease and only after the exclusion of an oligometastatic state in which there may be good options for local treatment. CPI, checkpoint inhibitor; IFN, interferon; IMDC, International Metastatic Renal Cell-Carcinoma Database Consortium; mTOR, mammalian target of rapamycin; TKI, tyrosine kinase inhibitor. The dotted line (arrow) is meant to show that add-on therapy can only be used in certain specific cases and is not a general standard of treatment.

Figure 2

Relevant considerations for the selection of treatment, based on differentiating aspects of first-line therapy trials and effects on survival curves. The main objective of treatment must be considered in the individual case, i.e., either a high remission pressure (“early follow-up”) or tumor control for as long as possible (“long-term follow-up”) (e5, e18, e24). CPI, checkpoint inhibitor; HrQoL, health-related quality of life; TKI, tyrosine kinase inhibitor.

Figure 3

Substance-specific adverse drug reactions and overlapping toxicities (modified from McGregor et al) (38).