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  • Review Article
  • Published:

Radiotherapy for renal cell carcinoma: renaissance of an overlooked approach

Key Points

  • Conventional radiotherapy has a limited role in the treatment of renal cell carcinoma (RCC), and is largely limited to the palliation of symptoms of metastatic disease

  • Evolving technology has facilitated the safe delivery of ablative doses of radiotherapy, in fewer fractions, and has been increasingly adopted in the clinical management of patients

  • Preclinical and clinical evidence demonstrates that RCC is sensitive to ablative doses of radiation (typically ≥8 Gy per fraction), with tumour control rates of approximately 90%

  • High-dose radiation seems to have an immunogenic effect in patients with RCC, and might explain the abscopal effects sometimes observed with this approach

  • Combinations of ablative radiotherapy with systemic targeted therapies or immunotherapies are promising approaches that might improve outcomes

Abstract

Conventional radiotherapy previously had a limited role in the definitive treatment of renal cell carcinoma (RCC), owing to the disappointing outcomes of several trials and the perceived radioresistance of this type of cancer. In this context, radiotherapy has been relegated largely to the palliation of symptoms in patients with metastatic disease, with variable rates of response. Following the availability of newer technologies that enable safe delivery of high-dose radiotherapy, stereotactic ablative radiotherapy (SABR) has become increasingly used in patients with RCC. Preclinical evidence demonstrates that RCC cells are sensitive to ablative doses of radiotherapy (≥8–10 Gy). Trials in the setting of intracranial and extracranial oligometastases, as well as primary RCC, have demonstrated excellent tumour control using this approach. Additionally, an awareness of the capacity of high-dose radiation to stimulate antitumour immunity has resulted in novel combinations of SABR with immunotherapies. Here we describe the historical application of conventional radiotherapy, the current biological understanding of the effects of radiation, and the clinical evidence supporting the use of ablative radiotherapy in RCC. We also explore emerging opportunities to combine systemic targeted agents or immunotherapies with radiation. Radiotherapy, although once an overlooked approach, is moving towards the forefront of RCC treatment.

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Figure 1: Timeline of advances in radiotherapy for the management of RCC.
Figure 2: Models of microvascular endothelial engagement in tumour responses to radiotherapy.

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Correspondence to Shankar Siva.

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PowerPoint slides

Glossary

SABR

Stereotactic ablative radiotherapy, refers to high-dose per fraction, conformal radiotherapy, typically delivered in one or a few sessions.

Gy

Gray, the unit of radiation, used in the International System of Units, defined in joules per kilogram.

α-subunit of hypoxia inducible factor

(HIF-1α). A subunit of the transcription factor hypoxia inducible factor-1, which has a critical role in the management of the cellular response to hypoxia, and can stimulate transcription of a number of genes that are responsible for various functions, including angiogenesis, cell proliferation and survival.

von Hippel Lindau (VHL) tumour suppressor gene

A regulator of tumorigenesis located on chromosome 3, which is subject to dominant inheritance and associated with cancer growth when lost or mutated.

E3 ubiquitin ligase

A protein that is involved in the regulation of cell trafficking, DNA repair, and signalling, as well as cell-cycle control.

Gap 2 (G2) phase

G2 phase is a phase of the cell cycle that directly precedes mitosis, during which the cell undergoes rapid growth and protein synthesis. The checkpoint between G2 and mitosis results in cell-cycle arrest during the G2 phase in response to stressors such as oxidative stress or radiation.

α/β ratio

A measure of a tissue or tumour response to a specific radiation dose.

Caki-1

A human clear cell RCC cell line derived from a patient of white ethnicity. This cell line has an epithelial morphology and provides a useful model for the study of kidney cancer.

A498

A commonly used renal cell carcinoma cell line typically used to model the behaviour of clear cell RCC.

SMPD1

Sphingomyelin phosphodiesterase 1, an enzyme that is found in lysosomes and has a role in the conversion of sphingomyelin to ceramide, and in maintaining the normal structure and function of the cell.

SRS

Stereotactic radiosurgery, describes a high, single-fraction, ablative dose of radiotherapy, delivered in a very conformal, precise manner.

SBRT

Stereotactic body radiotherapy, high dose-per-fraction ablative and highly conformal radiotherapy typically delivered as a single, or small number of fractions to an extracranial site. Often used interchangeably with SABR.

CKD

Chronic kidney disease, usually a progressive irreversible decline in kidney function, typically over a period of months to years

High mobility group protein B1

A chromatin protein that is secreted by immune cells and acts as a mediator of inflammation

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Siva, S., Kothari, G., Muacevic, A. et al. Radiotherapy for renal cell carcinoma: renaissance of an overlooked approach. Nat Rev Urol 14, 549–563 (2017). https://doi.org/10.1038/nrurol.2017.87

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