EUROPEAN UROLOGY 82 (2022) 613–622

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Platinum Priority – Review – Kidney Cancer – Editor’s Choice

Editorial by Diana E. Magee, Jessica Karen Wong, Andres F. Correa on pp. 623–624 of this issue

The Role of Stereotactic Ablative Body Radiotherapy in Renal Cell

Carcinoma

Muhammad Ali a,b,*, Jennifer Mooi c, Nathan Lawrentschuk d,e,f, Rana R. McKay g,
Raquibul Hannan h, Simon S. Lo i, William A. Hall j, Shankar Siva a,b
a
Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; b Sir Peter MacCallum Department of Oncology,
The University of Melbourne, Melbourne, Victoria, Australia; c Department of Medical Oncology, Northern Health, Melbourne, Victoria, Australia; d Department
of Urology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; e Department of Surgery, Peter MacCallum cancer Centre, Melbourne, Victoria, Australia;
f
Department of Surgery, The University of Melbourne, Melbourne, Victoria, Australia; g University of California, San Diego, CA, USA; h Department of Radiation
Oncology, UT Southwestern Medical Centre, Dallas, TX, USA; i Department of Radiation Oncology, University of Washington, Seattle, WA, USA; j Department of
Radiation Oncology, Medical College of Wisconsin, WI, USA

Article info Abstract

Article history: Context: Stereotactic ablative body radiotherapy (SABR) is an emerging treatment
Accepted June 21, 2022 modality for primary and metastatic renal cell carcinoma (RCC).
Objective: To review and summarise the evidence on the use of SABR in RCC in a narra-
Associate Editor: tive review.
Sarah P. Psutka Evidence acquisition: We performed an online search of the PubMed database from
January 2000 through December 2021. Studies of SABR/stereotactic radiosurgery (SRS)
Keywords: targeting primary, extracranial, or intracranial metastatic RCC were included.
Stereotactic ablative Evidence synthesis: Two meta-analyses (including 54 studies), and 13 prospective and
radiotherapy 20 retrospective studies were included in this review. In aggregate, SABR for 589 primary
Stereotactic ablative body RCCs in 575 patients resulted in a local control rate of above 90% with grade 3–4 toxicity
radiotherapy of 0–9%. Similarly, the local control rate ranged between 90% and 97% with SRS in 1225
Renal cell carcinoma patients with intracranial metastatic RCC. SABR was able to delay systemic therapy for at
least 1 yr in 70–90% of oligometastatic RCC patients with grade 3–4 toxicity of <10%. As
per the early data, the combination of SABR with systemic therapy for metastatic RCC,
such as targeted therapy or immunotherapy, appears safe, feasible, and tolerable.
Conclusions: We outlined data supporting SABR in the key clinical scenarios of primary
Please visit www.eu-acme.org/europeanurology and metastatic, including oligometastatic, RCC in lieu of systemic therapy, in combina-
to answer questions on-line. The EU-ACME cred-
tion with systemic therapy, and palliation of brain and spinal metastases.
its will then be attributed automatically.
Patient summary: Stereotactic ablative body radiotherapy (SABR) is a relatively new
treatment option in kidney cancer. Here, we review the published literature on the expe-
rience of using SABR in kidney cancer. The accumulated evidence demonstrates that
SABR can be used safely and effectively to treat selected cases of primary or secondary
kidney cancer.
Ó 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. 305 Grattan Street, Melbourne, Victoria 3000, Australia. Tel. +6138 5597
749.
E-mail address: muhammad.ali@petermac.org (M. Ali).

https://doi.org/10.1016/j.eururo.2022.06.017
0302-2838/Ó 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.
614 EUROPEAN UROLOGY 82 (2022) 613–622
1. Introduction
Renal cell carcinoma (RCC) was historically considered one
of the most radioresistant tumours when treated with con-
ventional fractionation (<5 Gy per fraction). The basis of this
historic radioresistant description of RCC is unclear. How-
ever, in vitro cell culture studies revealed that ablative
doses of radiation could eradicate RCC cells when higher
doses per fraction are used [1]. Biological mechanisms
underlying this dichotomy are not clearly understood but
may be related to translocation of acid sphingomyelinase
and production of proapoptotic ceramide, resulting in rapid
endothelial cell death within 1 h of radiotherapy [2,3].
Furthermore, there is evidence that radiotherapy also
has immunomodulatory effects, orchestrating a spectrum
of cellular and molecular alterations culminating in the
potentiation of systemic immune response. Chow et al. [4]
analysed samples of patients treated with 15 Gy stereotac-
tic ablative body radiotherapy (SABR) for primary RCC fol-
lowed 4 wk later by nephrectomy. The authors found
broad transcriptional immune activation and increased
clonality of immune cells within the tumour microenviron-
ment. An analysis of peripheral blood samples revealed a
dynamic reshaping of the peripheral T-cell repertoire within
the first 2 wk following radiation.
With the advent of SABR also known as stereotactic body
radiotherapy (SBRT), high local control (LC) rates have been
reported for primary and metastatic RCC (mRCC), contrary
to the historical belief that RCC is radioresistant [5,6]. The
changing perception brought on by the demonstrated effi-
cacy with an excellent safety profile in clinical practice
has resulted in the increased use of SABR for patients with
RCC [7]. The review aims to summarise the key contempo-
rary evidence of SABR in localised RCC and mRCC.
We present the following article as per the Narrative
Review reporting checklist (Supplementary Table 1).
1.1. SABR in RCC: current guidelines
Current European Association of Urology and European
Society of Medical Oncology guidelines consider SABR as
an alternative treatment for patients with localised RCC in
whom surgery cannot be carried out due to poor perfor-
mance status or unsuitable clinical condition, and other
local therapies such as thermal ablation (TA) are not consid-
ered appropriate [8,9]. The 2022 National Comprehensive
Cancer Network version 1.0 kidney cancer guidelines state
that ‘‘SABR may be considered for medically inoperable
patients with stage I kidney cancer (category 2B) and stage
II/III kidney cancer (category 3)’’ [10]. These guidelines also
recommend SABR as a treatment option for metastatic sites
including the lung, bone, and brain for selected patients
with oligometastatic (OM) RCC or oligoprogression, or in
cases treated with immunotherapy (IO) or targeted therapy
(TT) [8–10].
2. Evidence acquisition
PubMed was used to conduct literature search from January
2000 to December 31, 2021. Keywords used to search titles
and abstracts included renal cell carcinoma, RCC, kidney
cancer, advanced RCC, metastatic RCC, radiotherapy, SBRT,
SABR, and stereotactic radiosurgery (SRS). After consensus,
two meta-analyses (including 54 studies), and 13 prospec-
tive and 20 retrospective studies published in English lan-
guage were included for this narrative review.
3. Evidence synthesis
Clinical outcomes, safety, and key indications of SABR in
RCC are summarised in Fig. 1.
3.1. SABR for primary RCC
SABR is emerging as an alternative noninvasive treatment
option in the paradigm of localised RCC management. In
2019, Correa et al. [5] reported a systematic review and
meta-analysis of 26 studies involving 372 patients with
383 primary tumours (included studies are summarised in
Supplementary Table 2). The LC and grade 3–4 toxicity were
97.2% and 1.5%, respectively. The estimated glomerular fil-
tration rate (eGFR) mean difference before and after SABR
was –7.7 ml/min. Dialysis was required in six patients, all
of whom had pre-existing renal dysfunction. None of the
35 solitary kidney patients required dialysis.
Multiple prospective and retrospective studies have
reported the outcomes for SABR in localised RCC, sum-
marised in Table 1 and discussed in subsequent sections.
3.2. SABR for large renal masses (T1b)
Nephron-sparing partial nephrectomy, if technically feasi-
ble, is recommended for T1b tumours [8–10]. The evidence
for partial nephrectomy in T2 tumours is contradictory and
of low quality [8,9]. The treatment options are limited for
patients with T1b disease who are not surgical candidates.
TA is not suitable for patients with T1b RCC due to an
increased risk of local recurrence and complications [11].
In this subset of patients, SABR can be an attractive
approach.
In a retrospective report from the International Radio-
surgery Oncology Consortium for Kidney (IROCK), Siva
et al. [12] reported outcomes for 95 patients with T1b pri-
mary RCC receiving SABR. The median age was 76 yr and
tumour diameter 4.9 cm. One-third of the cohort had a
baseline eGFR of <45 ml/min. At a median follow-up of
2.7 yr, local failure rate was 2.9%. Cancer-specific survival
(CSS), overall survival (OS), and progression-free survival
(PFS) were, respectively, 91.4%, 69.2%, and 64.9% at 4 yr.
After treatment, the mean eGFR decreased by 7.9 ml/min.
No grade 3–5 toxicities were reported. Similarly, another
retrospective review of 36 patients treated with stereotactic
magnetic resonance guided radiotherapy reported 1-yr LC
of 95.2% [13]. This study included patients with a median
tumour size of 5.6 cm, with 31 patients having T1b or T2
disease.
3.3. SABR for elderly or comorbid patients with primary RCC
In contrast to surgical approaches or TA, SABR is noninva-
sive and does not require anaesthesia or sedation.
 EUROPEAN UROLOGY 82 (2022) 613–622 615

Fig. 1 – Safety and efficacy of SABR in renal cell carcinoma. FFST = freedom from systemic therapy; G-3/4 = grade 3 and 4; IO = immunotherapy; IVC = inferior
vena cava; LC = local control; NSS = nephron-sparing surgery; RCC = renal cell carcinoma; SABR = stereotactic ablative body radiotherapy; TA = thermal
ablation.

Therefore, it may be a more suitable option for frail patients,
those on long-term anticoagulation, or those with multiple
competing comorbidities that render them high risk from
anaesthesia, surgery, or TA.
In one study, Grelier et al. [14] reported outcomes for 23
frail patients with SABR for primary RCC. The median age
was 81 yr. All the patients were medically unfit for surgery
due to multiple comorbidities and older age. They were
poor candidates for TA due to tumour size of >4 cm or a
close approximation to renal pelvic structures. After a med-
ian follow-up of 22 mo, local recurrence-free survival, CSS,
and OS were 96%, 96%, and 83%, respectively. There were
616 EUROPEAN UROLOGY 82 (2022) 613–622

Table 1 – SABR for primary RCC (inclusive of, and since the Correa et al. [5] meta-analyses)

Author (year) Study Patients Tumour Follow-up Dose (Gy)/ Toxicity LC (%)
type (n) sizea (mo) fraction (grade 3/4)
Grelier et al. (2021) [14] R 23 4.0 cm 22 35/5–7 0 96
Grubb et al. (2021) [17] P 11 3.7 cm 34.3 48/3 9.1% 90
54/3
60/3
Swaminath et al. (2021) [16] P 28 13 patients with 4 cm NA 30–42/3–5 NA NA
and 19 with >4 cm
Margulis et al. (2021) [21]b P 6 NA 24 40/5 0 NA
Tetar et al. (2020) [13] R 36 5.6 cm 16.4 40/5 0 95.2
Siva et al. (2020) [12] R 95 4.9 cm 32.4 – 0 97.1
Senger et al. (2019) [15] R 10 7 patients with T1a disease 27 24–25/1 0 92.3
(size range 1.0–3.9 cm) 36/3
and 3 patients with T3a disease
(size range 0.9–7.0 cm)
Correa et al. (2019) [5] MA 372 4.6 cm 28 26/1 1.5% 97.2
30-40/3-5
IVC-TT = tumour thrombus in the renal vein that can invade the inferior vena cava; LC = local control; MA = meta-analyses; NA = not available; P = prospective;
R = retrospective; SABR = stereotactic ablative body radiotherapy.
a
Median or mean.
b
Neoadjuvant SABR for patients with IVC-TT (tumour thrombus).

no grade 3–4 side effects. The authors concluded that SABR 3.5. Response evaluation after SABR for primary RCC
appeared to be a promising alternative to treat primary RCC
LC after SABR is measured using the Response Evaluation Cri-
in frail patients. Another study investigated ten RCC
teria in Solid Tumors (RECIST). However, this assessment tool
patients with moderate to severe chronic kidney disease
has some limitations as it does not explicitly reflect the treat-
and reported LC of 92.3% with no grade 3 or 4 toxicity [15].
ment modality. Owing to the different mechanisms involved
In one prospective cohort study of 28 patients, of whom
in cell kill, a complete response following SABR is a rare event,
the majority were over 80 yr of age, treated with 30–42 Gy
as there typically is a tumour carcass that remains after treat-
SABR in three to five fractions [16], the authors reported
ment. Persistent post-SABR stable masses are common find-
minimal impact on quality of life (QOL) after SABR. Using
ings immediately after treatment. Furthermore, RCC is a
the minimal clinically important difference, the global
slow-growing tumour, and it can be expected to show a slow
QOL score reached a 10-point reduction at 1 wk but
radiographic response. Currently, arrest of radiological
reverted to baseline at subsequent follow-up.
growth and subsequent slow regression on size criteria is con-
sidered a successful response to treatment [5,19].
3.4. Optimal SABR dose fractionation for localised RCC Future research should focus on novel imaging modali-
ties, including multiparametric magnetic resonance imag-
A variety of dose-fractionation schedules were used in stud-
ing (MRI) and positron emission tomography, for a better
ies included in the systematic review and meta-analyses
response assessment after SABR. Functional MRI sequences
reported by Correa et al. [5]. The most common schedules
show promise in detecting early response to therapy. The
were 26 Gy in a single fraction and 30–45 Gy in three to five
early changes in diffusion and perfusion following renal
fractions. Reported local failures tended to occur in low-
SABR appear to be an early imaging biomarker that corre-
dose groups or where the tumour was underdosed to min-
lates with subsequent computed tomography–based
imise toxicity due to nearby structures. Grubb et al. [17]
tumour response [5].
reported a prospective study of dose escalation for SABR
Postprocedure biopsy is utilised to assess the success of
in 11 patients with localised RCC. Groups of four, four, and
TA for primary RCC. However, post-SABR biopsy is not rec-
three patients received, respectively, 48, 54, and 60 Gy in
ommended in routine clinical practice and should be con-
three fractions. There was no dose-limiting toxicity. One
sidered experimental [5]. In the study reported by Grubb
patient in the 60 Gy cohort had local progression of the dis-
et al. [17], five patients consented to undergo biopsy after
ease. The TransTasman Radiation Oncology Group (TROG)
6 mo of SABR. Interestingly, all five biopsy results were pos-
15.03 FASTRACK II is evaluating 26 Gy in one fraction for
itive for residual tumour cells. However, there was no radio-
tumours 4 cm and 42 Gy in three fractions for tumours
graphic evidence of local or distant disease progression in
>4 cm in size [18].
the three patients where follow-up scans were available
A dose-response relationship may exist in RCC, but there
after biopsy. Furthermore, Ki-67 staining was negative in
are no data to guide the maximum safe dose level to opti-
the postbiopsy samples, confirming that presence of cells
mise LC rates while minimising toxicity. In clinical practice
does not necessarily indicate tumour viability.
outside of clinical trials, optimal dose fractionation depends
on the tumour size and its proximity to the adjacent normal
3.6. SABR for locally advanced RCC: novel applications and
tissues. Until longer follow-up and more prospective stud-
future perspectives
ies, we recommend following the IROCK consensus state-
ment, which suggested 25–26, 35–45, and 40–50 Gy in RCC forms tumour thrombus in the renal vein that can
single, three, and five fractions, respectively [19]. invade the inferior vena cava (IVC-TT) in approximately
 EUROPEAN UROLOGY 82 (2022) 613–622 617

4–10% of patients and sometimes reach the right atrium
[20]. IVC-TT can lead to multiple serious complications such
as pulmonary embolism or Budd-Chiari syndrome. The only
effective treatment option for IVC-TT is nephrectomy,
which is associated with significant operative morbidity
and mortality, and a high risk of tumour recurrence [20].
Neoadjuvant SABR has been tested with the goal of
improved disease control for patients with RCC IVC-TT.
Margulis et al. [21] reported initial results on six patients
in the safety lead-in phase of a phase II trial
(NCT02473536), which is on-going. All patients underwent
SABR (40 Gy in five fractions) to the IVC-TT, followed by sur-
gery. In total, 81 adverse events were reported within 90 d
of surgery: 4% were grade 3 with no grade 4 or 5 events.
Based on the immunomodulatory effects of RCC SABR, it
may be hypothesised that immunomodulation with IO and
SABR in the neoadjuvant setting before nephrectomy might
elicit a more potent antitumour immune response due to
the presentation of a large repertoire of tumour-associated
antigens prior to the removal of the antigen depot. One trial
(NCT05024318) is assessing this approach in patients with
T1B-T3, N0 or N1, or M0 or low-volume M1 RCC before
nephrectomy.
3.7. SABR for stage IV RCC
Approximately one-third of patients with RCC present with
metastatic disease, and up to 30% treated for localised dis-
ease develop metachronous metastases [22]. RCC can
metastasise to almost all soft tissues in the body, but most
commonly to the lung followed by bone, liver, and brain.
While systemic treatment with TT and IO alone or in com-
bination is the standard of care for stage IV RCC, there is a
key role for metastasis-directed therapy (MDT) with sur-
gery, TA, or SABR in selected patients with mRCC [8–10].
As SABR is noninvasive, this approach is increasingly used
in the management paradigm for mRCC [7].
In a meta- analysis (SABR ORCA) of 28 studies including
1602 patients, Zaorsky et al. [6] evaluated the use of SABR/
SRS in mRCC (included studies are summarised in Supple-
mentary Table 3). The 1-yr LC was 89.1% for extracranial
and 90.1% for intracranial disease. The incidence of any
grade 3–4 toxicity was 0.7% for extracranial disease and
1.1% for intracranial disease. Multiple other studies have
reported the safety and efficacy of SABR in mRCC (Fig. 1).
3.8. Stereotactic radiotherapy for brain and spinal metastatic
disease
Brain metastases (BMs) occur in approximately 3–20% of
patients with RCC [23–26]. Although patients with active
RCC BMs were excluded from clinical trials using TT and
IO, the recently reported results of the NIVOREN study
have shown overall intracranial response rate of 12% with
nivolumab [27]. Another study has reported considerable
intracranial activity (response rate 55%) with cabozantinib
[28]. However, local treatment in the form of surgery, SRS,
and/or whole-brain radiotherapy (WBRT) remains the
mainstay of treatment. Recently, SRS has been preferred
to WBRT for patients with limited BMs due to minimal
toxicity and improved LC without compromising survival.
Published literature on patients receiving SRS for RCC
BM is mainly limited to retrospective studies (Table 2)
[23–26,29].
Klausner et al. [23] reported the largest series involving
120 patients with 362 BMs from RCC. The median number
(range) and volume (range) of BMs were 2 (1–35) and 13
mm (1–50), respectively. The median (range) prescription
doses were 18 Gy (14–22) and 16 Gy (10–26) by gamma-
knife and LINAC, respectively. The authors reported 94%
and 92% LC at 1 and 3 yr, respectively. In multivariate anal-
yses, a minimum dose of >17 Gy and concomitant use of TT
were associated with higher rates of LC. Seventeen patients
had grade 3 or 4 adverse effects. As outlined in Table 2, the
results of other retrospective series also showed good LC
rates with SRS [24–26,29].
The spine is the most common bone site to be involved
by mRCC [30]. Local treatment modalities (surgical resec-
tion, spinal fixation, radiotherapy, or a combination of
these) play an integral part in the management of spinal
mRCC [30]. SABR showed LC rates of 70–90% with good pain
control and acceptable toxicity [30]. A recent randomised
phase III trial confirmed superiority of SABR over conven-
tional radiotherapy for complete pain response and
included patients with RCC [31]. The control rates after
spinal SABR are relatively lower than those for SABR to
other bone sites, which can be explained by dose limitations
near the spinal cord to avoid myelopathy. There is increas-
ing interest in a hybrid approach of separation surgery with
adjuvant radiotherapy in cases with epidural disease
extension.

Table 2 – Single fraction radiosurgery for intracranial metastatic RCC (inclusive of, and since the Zaorsky et al. [6] meta-analyses)

Author (year) Study Patients Total lesions Median size/ Median radiation % On systemic Toxicity (grade LC
type (n) (n) volume dose treatment 3/4) (%)
Stenman et al. (2021) R 43 194 0.1 cm3 22 Gy 88 7 97
[24]
Uezono et al. (2021) R 48 372 0.6 cm 20 Gy 92 5 89.6
[25]
Kroeze et al. (2021) R 53 77 0.84 ml 20 Gy 100 3 NR
[29]
Klausner et al. (2019) R 120 362 1.3 cm 18 Gy (GK) 31 17 94
[23] 16 Gy (LINAC)
Wardak et al. (2019) R 38 243 0.6 cm 18 Gy 100 2 91.8
[26]
3
Zaorsky et al. (2019) MA 923 2733 2.3 cm – NR 1.1% 90.1
[6]
GK = gamma knife; LC = local control; MA = meta-analyses; NR = not reported; R = retrospective; RCC = renal cell carcinoma.
618 EUROPEAN UROLOGY 82 (2022) 613–622

Hussain et al. [32] reported outcomes for 90 RCC patients
with high-grade epidural spinal cord compression who
underwent separation surgery with adjuvant SABR. The
authors reported a 2-yr LC rate of 92%. Only seven patients
experienced local progression requiring repeated treatment.
The 2-yr incidence of significant complications was 7.7% for
hardware failure, 3.3% for wound infection, and 1.1% for
oesophageal perforation. These findings suggest the need
for a multimodality approach in managing spinal mRCC.
3.9. SABR for OM RCC and deferral of systemic therapy
OM disease is described as an intermediate condition in
which the number of metastatic lesions is limited (one to
five lesions), involving either single or multiple organs
[33]. The clinical behaviour of OM RCC varies from rapidly
progressive to indolent, with some patients experiencing
long-term survival with local therapies alone [33]. In care-
fully selected OM RCC patients, MDT may delay the need
for systemic treatment without compromising survival
and maintaining QOL. At least three prospective and two
retrospective studies have reported favourable outcomes
with SABR in this setting (summarised in Table 3) [33–36].
In a prospective phase II clinical trial, Tang et al. [35]
evaluated the feasibility and efficacy of definitive intent
radiotherapy in 30 mRCC patients with fewer than six
lesions. Feasibility was defined as completion of SABR with
<7 day of unplanned break. Patients received SABR for all
lesions and were maintained off systemic therapy.
At median follow-up of 17.5 mo, the trial demonstrated
impressive 1-yr PFS and systemic therapy–free survival of
64% and 82%, respectively, with two grade 3 and one grade
4 (hyperglycaemia) adverse events.
Similarly, in another phase II clinical trial, Hannan et al.
[34] reported outcomes of 57 metastatic sites in 23 patients
with SABR in mRCC (three or fewer extracranial disease).
The primary objective was to delay the start of systemic
therapy by >1 yr in >60% of patients. The study met its pri-
mary endpoint of 1-yr freedom from systemic therapy in
91.3%. When compared with baseline, there was no signifi-
cant decline in QOL. In a multicentre prospective registry
trial of various primary tumour types, Chalkidou et al.
[37] reported the OS outcomes of 145 OM RCC patients to
be 94% at 1 yr and 85% at 2 yr, which is consistent with
the reported 1-yr OS rates of 100% and 95.5% in the studies
of Tang et al. [35] and Hannan et al. [34], respectively.
These results suggest that SABR might facilitate deferral
of systemic treatment in carefully selected OM RCC patients
without compromising OS and maintaining QOL. Before
implementing this approach outside clinical trials, clini-
cians need to acknowledge the limitations of short follow-
up, single-arm noncomparative design, and relatively novel
nature of freedom from systemic treatment as an endpoint.
Future areas of investigation should focus on long-term
safety/outcomes of this approach, appropriate clinical/
biomarkers for better selection of patients, and dose frac-
tionation schedules for SABR.
3.10. SABR in combination with systemic treatment for
extracranial metastatic disease
Systemic treatment (TT and IO) has improved outcomes for
patients with mRCC and is considered the frontline treat-
ment [8–10]. New combinations of systemic therapies
(TT + IO and IO + IO) have further improved outcomes in
patients with high-risk disease based on the International
Metastatic Renal Cell Carcinoma Database Consortium
(IMDC) risk criteria [8]. However, complete response (CR)
rates remains low (<10%), and at present, resistance to sys-
temic treatment is inevitable [38]. In a multidisciplinary
approach to mRCC treatment, combining SABR with sys-
temic treatment may exploit potential additive or synergis-
tic interactions between the modalities to increase
responses [39].

Table 3 – SABR in lieu of systemic treatment for oligometastatic RCC (since the Zaorsky et al. [6] meta-analyses)

Author (year) Study Patients Site of Radiation dose Toxicity 1-yr 1-yr
type (n) disease (%) (grade 3/4) FFST (%) OS (%)
Tang et al. (2021) [35] P 30 Lung (57) Most common 50 Gy in 6%/3% 82 100
Bone (17) 4 fractions
Nodes (11)
Other (15)
Hannan et al, (2021) [34] P 23 Total 57 sites 25 Gy  1 fraction, 12 Gy  0 91.3 95
3 fractions, or 8 Gy 
5 fractions
Chalkidou et al. (2021) [37] P 143a Most common NR <5%b NR 95.3
site lung
Marvaso et al. (2021) [36] R 61 Bone (43) Median 25 Gy in 5–10 0 70 78
Lung (15) fractions
Liver (9)
Soft tissue (9)
Other (24)
Zhang et al. (2019) [33] R 47 Bone (34) 18–26 Gy/1 fraction 0 Median 15.2 mo 93.1
Lung (30) 36–42 Gy/3–5 fractions
Brain (12)
Nodes (8)
Other (16)
FFST = freedom from systemic therapy; NR = not reported; OS = overall survival; P = prospective; R = retrospective; RCC = renal cell carcinoma;
SABR = stereotactic ablative body radiotherapy.
a
A total of 143 renal cell carcinoma patients (total 1422 patients with different tumour histologies).
b
Toxicity for all 1422 patients.
 EUROPEAN UROLOGY 82 (2022) 613–622 619

In a prospective phase Ib trial, Dengina et al. [40] treated
17 patients on systemic treatment (single-agent TT or IO
with sunitinib was most common) with SABR for one lesion
while leaving other lesions within the same organ as an
internal control. The response in treated lesions was 76%,
with a CR of 29%. SABR-related toxicity was reported as
grade 1 in 12% of patients. The authors concluded that SABR
in patients with mRCC treated with systemic treatment is safe
and possibly efficacious. Multiple prospective and retrospec-
tive studies have reported the combination of SABR with TT
or IO in patients with mRCC (Table 4) [29,38,41–47].
The largest retrospective study included 190 mRCC
patients treated with front-line TT between December
2007 and June 2019 [38]. In this cohort, 85 (45%) patients
received SABR (most common dose 35–45 Gy in five frac-
tions). A total of 149 patients (78.4%) had IMDC
intermediate- or poor-risk disease. Sunitinib was the most
common (57.9%) TT. The median OS in the TT + SABR group
was significantly longer than that of TT alone (63.2 vs 29.8
mo, p < 0.001). Patients with OM disease and those with
IMDC favourable or intermediate risk had significantly
longer OS with combination treatment. SABR-related grade
3 toxicity was only 5.9%.
Considering radiation-induced dynamic changes to the
T-cell repertoire and immune system in RCC [4], there was
interest in combining SABR with IO to enhance antitumour
effects. In a single-arm multicentre phase II NIVES trial, 69
mRCC patients were treated with single-agent nivolumab
with SABR (30 Gy in three fractions) to a single lesion
[43]. The primary objective was to induce an objective
response rate (ORR) of 40%. However, the study could not
meet its primary objective (ORR of only 17%). Similarly,
another phase II study (30 patients) of interleukin-2 and
SABR by Hannan et al. [42] reported an ORR of 16%.
In contrast, RADVAX RCC, investigating the combination
of SABR to one to two metastatic sites with dual IO therapy
using nivolumab and ipilimumab, reported a more encour-
aging ORR of 56% [44]. However, the median PFS of 8.2 mo
was similar to the historic reported PFS of the combination
of IOs.
While the trials mentioned above tried to exploit the
abscopal effect of SABR by targeting some metastatic sites,
a more effective approach may be to target all disease sites
using SABR with IO. Recently, Siva et al. [46] reported the
RAPPORT single-arm phase I/II study of total metastatic
irradiation followed by eight cycles of pembrolizumab in
30 patients with one to five OM RCCs. The most common
site of metastatic disease was the lung (52%), and SABR
(20 Gy single fraction) was delivered in 77% of patients
(23% received 30 Gy in ten fractions with conformal radio-
therapy). After a median follow-up of 28 mo, 2-yr OS and
PFS were 74% and 45%, respectively. The freedom from local
progression at 2 yr was 92%, with an ORR of 63%. Four
patients (13%) experienced grade 3 toxicity.

Table 4 – SABR in combination with systemic treatment for extracranial metastatic RCC (since the Zaorsky et al. [6] meta-analyses)

Author (year) Study Patients Systemic treatment IMDC Toxicity (grade 3– Outcomes
type (n) risk, 4) %
%
Siva et al. (2022) [46] P 30 Pembrolizumab F 56 13 2-yr FFLP 92%
I 44 2-yr PFS 45%
2-yr OS 74%
Hannan et al. (2022) [42] P 30 IL-2 NA 73 ORR 16%
Median PFS 2 mo
Median OS 37 mo
Masini et al. (2022) [43] P 69 Nivolumab F 26 26 ORR 17%
I 65 Median PFS 5.6 mo
Po 09 Median OS 20 mo
Liu et al. (2021) [38] R 190 TKIs F 21 5.9 2-yr LC 92.8%
I 58 Median OS 63.2 mo (in TKI + SABR
Po 21 group)
Liu et al. (2021) [47] R 74 TKIs F 16 54.8 1-yr LC 98.2%
mTOR inhibitors I 66 Median PFS 13.2 mo
IO Po 18 Median OS 38.5 mo
Kroeze et al. (2021) [29] R 53 TKIs NA 0 1-yr LC 75%
mTOR inhibitors
IO
Hammers et al. (2020) [44] P 25 Nivolumab and F 08 0 ORR 56%
(abs) ipilimumab I 80
Po 12
He et al. (2020) [41] R 56 TKIs F 18 0 2-yr LC 94%
I 57 Median PFS 11.5 mo
Po 21
U 04
Buti et al. (2020) [45] R 48 NA F 38 0 1-yr LC 87.7%
I 54 Median PFS not reached
Po 08
Dengina et al. (2019) [40] P 17 TKIs NA 0 ORR in target lesions 76% with CR in
mTOR inhibitors 29%
IO

abs = abstract; CR = complete response; F = favourable; FFLP = freedom from local progression; I = intermediate; IL-2 = interleukin-2; IMDC = International
Metastatic RCC Database Consortium; IO = immunotherapy; LC = local control; NA = not available; ORR = overall response rate; OS = overall survival;
P = prospective; PFS = progression free survival; Po = poor; R = retrospective; RCC = renal cell carcinoma; SABR = stereotactic ablative body radiotherapy;
TKI = tyrosine kinase inhibitor; U = unknown.
620 EUROPEAN UROLOGY 82 (2022) 613–622

The evidence suggests that SABR in combination with
systemic treatment is safe. However, these studies have
inherent limitations of being single-arm prospective or ret-
rospective in nature, small sample size, and shorter follow-
up. Studies on the optimal dose have been limited, and
whether low or ablative doses should be utilised is not spec-
ified. We urge caution to clinicians considering the use of
this strategy off protocol. Before deployment in routine clin-
ical practice, further prospective randomised trials are
needed to elucidate the benefit and utility of this approach.
Moreover, combinatorial strategies would benefit from a
supportive mechanistic rationale.
3.11. SABR for oligoprogressive RCC
Oligoprogression is a term used to describe the clinical sit-
uation where a solitary or a few metastatic lesions progress,
while all other metastases are stable or responding to the
on-going systemic therapy. The standard approach for
oligoprogressive mRCC is to change systemic treatment
[8,10], but an alternative approach can be MDT to oligopro-
gressive site(s) while continuing the same systemic treat-
ment. Multiple prospective and retrospective studies have
shown that SABR for oligoprogressive disease can delay
the switching of systemic treatment in mRCC (Table 5)
[48–53].
In a prospective phase II trial, Cheung et al. [48] reported
outcomes for 37 mRCC patients (12 patients with IMDC
favourable and 25 with intermediate risk) with 57 oligopro-
gressive tumours while on TT. All oligoprogressive sites
were treated with SABR while continuing the same TT.
One-year LC rates of the irradiated tumours and OS were
93% and 92%, respectively. Post hoc exploratory analyses
showed that a cumulative incidence of changing systemic
therapy was 47% at 1 yr, with a median time to change in
systemic therapy of 12.6 mo. There was no reported
SABR-related grade 3 toxicity.
In another prospective phase II trial with the primary
objective to extend on-going systemic treatment by >6 mo
in >40% of patients, Hannan et al. [49] treated 37 oligopro-
gressive sites with SABR in 20 patients who progressed at
three or more sites while on systemic treatment. At a med-
ian follow-up of 10.4 mo, the study met its primary objec-
tive by extending systemic treatment by >6 mo in 70% of
patients. The median time to change in systemic treatment
after SABR was 11.1 mo. Owing to the previously mentioned
immunogenic properties of SABR, an improved benefit of
this strategy for patients on IO compared with TT has also
been reported in a retrospective study [53].
These studies highlight the role of SABR in extending on-
going systemic therapy in carefully selected oligoprogressive
mRCC patients and provide a strong rationale for evaluating
this paradigm in prospective randomised trials. Patients
who are tolerating systemic treatment well, with control of
most of the systemic disease and limited future treatment
options, may benefit from this approach. Further questions
that need to be evaluated in prospective trials include the
optimal number of lesions to be treated, radiation dose, and
timing of administration to achieve immunomodulation.
3.12. Future perspectives
In the era of newer systemic treatments with TT and IO,
cytoreductive nephrectomy (CN) is less commonly

Table 5 – SABR for oligoprogressive RCC (since the Zaorsky et al. [6] meta-analyses)

Author Study Patients Sites of Radiation dose Toxicity (grade 3–4), % Outcomes
(year) type (n) progression (%)
Hannan et al. P 20 Lung (27) Different schedules based on 5 1-yr LC 100%
(2022) Bone (30) treatment sites. Median BED10, Median time to change
[49] Liver (16) 72 Gy systemic treatment
Adrenal (8) 11.1 mo
Kidney (8)
Other (11)
Cheung et al. P 37 Lung (37) 25 Gy/1# 0 1-yr LC 93%
(2021) Bone (26) 36 Gy/3# Median time to change
[48] Nodes (12) 40 Gy/5# systemic treatment
Adrenal (7) 12.6 mo
Liver (7) 1-yr OS 92%
Other (11)
Franzese R 116 Most common site Variable, most common 48 Gy/ 0 1-yr LC 83%
et al. bone (32.7) 4# 25 Gy/5# Median time to change
(2021) systemic treatment
[51] 13.9 mo
Schoenhals R 36 Bone (46) Median None (1 patient died due to 1-yr LC 93%
et al. Lung (14) 36 Gy/3# haemoptysis? SABR related or Median PFS 9.2 mo
(2021) Liver (12) progressive disease) Median OS from SABR
[53] Soft tissue (12) 43.4 mo
Other (16)
De et al. R 72 Lung/mediastinum Median 50 Gy/4# 0 1-yr LC 96%
(2022) (49) 1-yr PFS 52%
[50] Bone (49) 1-yr OS 91%
Other (2)
Gebbia et al. R 28 Most common site Median 30 Gy/10# 0 Median PFS after
(2020) bone followed by radiotherapy 4.55 mo
[52] lung
LC = local control; OS = overall survival; P = prospective; PFS = progression-free survival; R = retrospective; RCC = renal cell carcinoma; SABR = stereotactic
ablative body radiotherapy; # = fractions.
 EUROPEAN UROLOGY 82 (2022) 613–622
performed, given the data from the CARMENA and SURTIME
trials. Nevertheless, CN is still considered in selective
patients with symptomatic disease or a high local disease
burden [8–10]. Given the local efficacy and immune-
modulatory effects of SABR, there is increased interest in
using cytoreductive SABR for the primary tumour in combi-
nation with systemic treatment. The on-going CYTOSHRINK
(NCT04090710) and upcoming NRG-GU012 SAMURAI trials
evaluate cytoreductive SABR for the primary tumour in
IMDC intermediate- and poor-risk mRCC patients receiving
first-line IO combination treatment [7].
4. Conclusions
SABR is associated with good oncological outcomes and a
favourable toxicity profile in patients with localised RCC.
Intriguing multimodality approaches, including SABR in
the operable setting, are emerging. In the context of mRCC,
SABR alone or in combination with systemic treatment has
shown promising clinical outcomes with minimal toxicity.
Other investigational applications of SABR, including
cytoreduction and neoadjuvant SABR, for primary RCC, OM
RCC in deferring systemic therapy, and oligoprogressive
RCC concurrent with systemic therapy are evolving and
should be tested in clinical trials.
Author contributions: Muhammad Ali had full access to all the data in
the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Ali.
Acquisition of data: Ali.
Analysis and interpretation of data: Ali.
Drafting of the manuscript: Ali.
Critical revision of the manuscript for important intellectual content: Mooi,
Lawrentschuk, McKay, Hannan, Lo, Hall, Siva.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Siva.
Other: None.
Financial disclosures: Muhammad Ali certifies that all conflicts of inter-
est, including specific financial interests and relationships and affiliations
relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: Muhammad Ali is a PhD candi-
date who is supported through an ‘‘Australian Government Research
Training Program (RTP) scholarship’’. Shankar Siva is funded by the Can-
cer Council Victoria Colebatch fellowship.
Funding/Support and role of the sponsor: None.
Peer Review Summary
Peer Review Summary and Supplementary data to this arti-
cle can be found online at https://doi.org/10.1016/j.eururo.
2022.06.017.
621
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