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#B2BGUCancerTriad

Kidney Cancer

Proceedings from the  
SIU B2B Uro-Oncology:  
GU Cancers Triad  
Virtual Meeting 
May 21–22, 2021

https://www.siu-urology.org
https://twitter.com/search?q=%23B2BGUCancerTriad


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PROCEEDINGS FROM THE SIU B2B URO-ONCOLOGY: GU CANCERS TRIAD • MAY 21–22, 2021 – SIUJ VOLUME 2, SUPPLEMENT 1, JULY 2021

Simon Tanguay,a,* E. Jason Abel,b Laurence Albigès,c Toni Choueiri,d Axel Bex,e

Umberto Capitanio,f Maxine Tran,e Alessandro Volpe,g Peter C. Blackh,†

aDivision of Urology, McGill University, Montreal, Canada bDepartments of Urology and Radiology, University of Wisconsin School 
of Medicine and Public Health, Madison, United States cGustave Roussy Institute, Villejuif, France dDana-Farber Cancer Institute, 
Harvard Medical School, Boston, United States eDivision of Surgery and Interventional Science, University College London, London, 
United Kingdom fSan Raffaele Scientific Institute, Milan, Italy gDepartment of Urology, University of Eastern Piedmont, Novara, 
Italy hDepartment of Urologic Sciences, University of British Columbia, Vancouver, Canada *Co-Chair of the Scientific Programme 
Committee (RCC) †Chair of the Scientific Programme Committee

The Bench-to-Bedside Uro-Oncology GU Cancer Triad Meeting was organized by the Société 
Internationale d’Urologie and was held online on May 21st and 22nd, 2021. The session on 
kidney cancer took place on the morning of Friday, May 21st, and was chaired by Dr. Simon 
Tanguay (Canada). This session covered practice-changing advances on the horizon for renal 
cell carcinoma (RCC), optimal sequencing of systemic therapy, HIF-α inhibition as a novel 
therapy for RCC, the use of local therapy for metastatic disease, as well as the multimodal 
management of localized RCC.

The first presentation was led by Dr. Jason Abel 
(United States). He discussed five practice-changing 
advances on the horizon for differing RCC settings, 
including recent developments for small, sarcoma-
toid, and papillary tumours, as well as early-stage Von 
Hippel-Lindau syndrome (VHL) and high-risk, non-
metastatic RCC. First, Dr. Abel focused on strategies 
for improving risk stratification for active surveillance 
of small RCC, which represents the majority of initially 
diagnosed kidney cancers[1]. Most patients diag-
nosed with small RCC will not progress to metastatic 
disease or die from kidney cancer, as pointed out by 
Dr. Abel. Active surveillance is an established man-
agement approach for small RCC, as indicated in sev-
eral guidelines[2,3]. However, as more natural history 
data become available, improved risk stratification 
strategies may help to select patients and determine 
follow-up for active surveillance. 

While active surveillance is usually recommended 
for elderly patients with limited life expectancy, new 
data are providing additional insights for managing 
younger patients with small RCC. In the DISSRM regis-
try, which evaluated 224 patients aged 60 or younger, 
30% of whom were managed with active surveillance, 
no patient developed metastatic disease or had dis-
ease recurrence following delayed intervention[4]. This 
study suggests that active surveillance is a safe initial 

strategy for selected younger patients and potentially 
avoiding some interventions. However, longer follow-up 
is necessary given the long natural history of the dis-
ease. Improved risk stratification based on genetic 
alterations may further help to select patients for 
active surveillance. In a study by the National Cancer 
Institute (NCI), patients with pathologic germline alter-
ations and RCC were shown to have differing tumour 
growth rates[5]. While it may be difficult to extrapo-
late the results to the general RCC population, these 
findings are encouraging given the paucity of genetic 
characterization of kidney cancers in the context of 
active surveillance. Dr. Abel emphasized that, as the 
understanding of small RCC biology improves, active 
surveillance will become more personalized.

The presence of sarcomatoid features in RCC is 
associated with aggressive tumour biology and early 
mortality[6]. Although sarcomatoid dedifferentiation 
occurs in only ~5% of tumours overall, these patients 
have some of the worst outcomes: they frequently 
present with metastatic disease and have poor survival 
despite aggressive treatment[6]. While management 
of this patient population remains challenging, recent 
efforts have improved the molecular characterization 
of sarcomatoid tumours and identified the basis of 
response to immune checkpoint inhibitor (ICI) ther-
apy[7]. In parallel, a post hoc subgroup analysis of 

DOI: 10.48083/SCPM5983



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PROCEEDINGS FROM THE SIU B2B URO-ONCOLOGY: GU CANCERS TRIAD • MAY 21–22, 2021 – SIUJ VOLUME 2, SUPPLEMENT 1, JULY 2021

139 patients with sarcomatoid RCC enrolled in the 
CheckMate 214 trial demonstrated positive outcomes 
in response to dual ICI therapy with nivolumab + ipil-
imumab[8]. Compared to treatment with sunitinib, 
treatment with nivolumab + ipilimumab resulted in 
significantly improved median overall survival (OS) (not 
reached vs. 14.2 months; HR=0.45 [95% CI 0.3–0.7]; 
P=0.0004) and higher confirmed objective response 
rate (ORR). Dr. Abel also highlighted the high propor-
tion of patients achieving complete response (CR) with 
nivolumab + ipilimumab, which was almost double that 
observed in RCC without sarcomatoid dedifferentia-
tion. These advances in tumour characterization and 
ICI combination therapy development may significantly 
improve outcomes for patients with sarcomatoid RCC.

Historically, most research in systemic therapies for 
metastatic RCC has targeted the most prevalent clear 
cell subtype. By contrast, very few clinical trial data are 
available for papillary RCC, the second most common 
subtype[9]. Papillary RCC is generally characterized by 
alterations in the MET pathway, which can be further 
classified into type 1 and type 2 tumours. However, the 
pathologic heterogeneity of this RCC subtype may be 
challenging. A recent trial with cabozantinib, a tyrosine 
kinase inhibitor (TKI) targeting vascular endothelial 
growth factor (VEGF) receptors and the MET pathway, 
has shown promising results for patients with papillary 
RCC. In this open-label, randomized, phase 2 trial, 
treatment with cabozantinib significantly improved 
median progression-free survival (PFS) compared to 
sunitinib in patients with metastatic papillary RCC 
(9.0 vs. 5.6 months; HR=0.60 [95% CI 0.37–0.97]; one-
sided P=0.019)[10]. While data for systemic therapy 
in papillary RCC may be difficult to evaluate given the 
low frequency and complex pathology of this disease 
subtype, the promising results of combined MET and 
VEGFR2 inhibition with cabozantinib may lead to 
improved outcomes in this patient population in the 
future. Additionally, improved molecular characteri-
zation of the disease may help inform the selection of 
novel agents for treating papillary RCC.

Dr. Abel also discussed the recent potentially 
practice-changing use of HIF-2α inhibitors for the 
treatment of VHL disease, a syndrome caused by 
germline inactivation of the VHL gene[11]. Patients with 

VHL disease may develop clear cell RCC (ccRCC), as 
well as hemangioma, pheochromocytoma, and other 
tumours in the pancreas, retina, and other sites. The 
treatment of patients with VHL is challenging. Many 
of these patients undergo multiple partial nephrecto-
mies for ccRCC over their lifetime and can progress to 
metastatic disease. In addition, repeated treatment 
can also lead to renal dysfunction. In an open-label, 
phase 2 trial, the efficacy of belzutifan (MK-6482) was 
evaluated in patients with VHL disease and nonmet-
astatic RCC[12]. Belzutifan is an inhibitor of HIF-2α, a 
transcription factor that becomes constitutively active 
and drives tumour growth due to VHL gene inactiva-
tion. In the trial, the ORR was 36% for VHL-associated 
ccRCC per RECIST v1.1 by independent review com-
mittee (IRC). Tumour response was also observed for 
non-RCC tumours, including ORR of 64% for pancreatic 
lesions, 30% for hemangioblastomas, and 69% for ret-
inal lesions. Only one patient discontinued treatment 
due to a treatment-related adverse event (TRAE) and 
no grade 4 or 5 TRAEs were observed. These early 
results are encouraging and show the potentially 
practice-changing application of systemic therapy 
with HIF-2α inhibitors for treatment of RCC tumours 
associated with VHL disease.

Lastly, Dr. Abel presented recent advances for the 
treatment of high-risk nonmetastatic RCC. Generally, 
this patient population is treated with nephrectomy 
and surveillance. However, patients with pathologic 
T3 disease are more likely to develop metastasis after 
surgery compared to patients with T1 or T2 tumour 
stage. Two hypotheses may explain metastatic pro-
gression in this patient population: failure to detect 
micrometastasis by conventional imaging at the time 
of surgery or failure of the patient’s immune system to 
prevent any tumour cells from implanting and growing 
at different sites. The latter could be improved with 
the use of ICIs as adjuvant therapy. Adjuvant therapy 
with pembrolizumab for high-risk nonmetastatic RCC 
is under investigation in the randomized phase 3 
KEYNOTE-564 trial. In a recent press release, it was 
announced that the trial had met its primary endpoint 
of improved disease-free survival (DFS) compared to 



B2B: Kidney Cancer Summary

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placebo[13]. These data are positive and have impor-
tant future implications for managing patients with 
high-risk nonmetastatic RCC.

During the Q&A, Dr. Abel discussed whether early 
biopsy may help identify patients with a sarcomatoid 
subtype who could benefit from neoadjuvant ther-
apy for locally advanced RCC. Although this is a rare 
subtype and biopsies are typically performed pre-op-
eratively in patients with metastatic disease only, in 
the context of a clinical trial, Dr. Abel believes this 
is a logical approach that bears investigation in the 
future. Next, Dr. Abel addressed the utility of genetic 
profiling in patients with small RCC. He believes this 
will provide better insights on management options, 
particularly in patients who are neither very young or 
elderly and correspond to the majority of small RCC 
diagnoses. Lastly, Dr. Abel provided his perspective 
on the recently positive results of adjuvant ICI therapy 
in RCC. He believes that if ongoing clinical trials in 
this setting are able to demonstrate OS benefit, it will 
lead to important changes that would change clinical 
practice.

Next, Dr. Laurence Albigès (France) presented the 
optimal sequencing strategies in metastatic RCC. Over 
the past decades, advances in understanding the RCC 
pathophysiology have led to the identification of two 
major therapeutic targets: first, the role of the HIFα-
VEGF axis in tumour angiogenesis[14] and, second, the 
development of ICIs as drivers of immune response to 
tumours[15]. In addition, management of metastatic 
RCC is also influenced by the IMDC risk assessment, 
not only to evaluate patient prognosis but also to guide 
treatment decisions[16]. 

The new guidelines of the European Society 
for Medical Oncology (ESMO) outline two main 
approaches for standard systemic first-line treatment 
of intermediate and poor risk ccRCC (adapted from 
[17]). The first approach uses dual ICI combination 
therapy with nivolumab + ipilimumab, which has 
demonstrated long-term benefits in OS and PFS[18]. 
The second approach combines VEGFR TKI with ICI. 
Multiple studies over the past 3 years have reported 
positive results for different TKI + ICI combinations in 
the treatment of metastatic RCC[19–21]. These studies 

have demonstrated that TKI + ICI combination may 
result in modulation of immune response by targeting 
VEGF inhibition, which may underlie the OS benefit 
with TKI + ICI versus standard of care observed in the 
trials. Most notably, TKI + ICI has been shown to result 
in high tumour response rate and sustained response 
over time, as well as clinical benefit across IMDC 
patient risk groups[19–21]. At the moment, both the 
dual ICI and TKI + ICI combination have demonstrated 
clinical benefits and there is no evidence to support 
one approach over the other. As highlighted by Dr. 
Albigès, clinical trials comparing dual ICI versus TKI 
+ ICI would help guide treatment decisions between 
the two approaches. 

In the second-line setting, there are well-defined 
treatment recommendations for patients who received 
single-agent first-line therapy[3]. However, the new 
combination therapy options available as first line may 
impact treatment decisions in the second-line setting. 
While ongoing clinical trials may help to identify the 
optimal second-line approach, several critical consid-
erations are still unanswered. Dr. Albigès summarized 
those as the following questions: 1) Is there a role for 
salvage ipilimumab, if not used in the first line, for 
patients who progressed after programmed cell death 
protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) 
therapy? 2) Is there a role for combination therapy as 
second-line or subsequent treatment? 3) Is there a 
role for sustained PD-1 inhibition in the second-line 
therapy? 4) Are there any new targets that should be 
considered in this setting? For salvage ipilimumab, 
several studies have shown only a small benefit of 
combining ipilimumab to nivolumab in patients who 
did not respond to anti-PD-1/PD-L1 as first-line mon-
otherapy[22–24]. While dual ICI combination therapy 
following first-line ICI has shown ORR around ~10%–
15% across studies[22,23], the VEGFR-ICI combination 
with lenvatinib + pembrolizumab reached 50%[25]. Dr. 
Albigès believes more data are necessary to elucidate 
the role of sustained PD-1 inhibition. This is currently 
under investigation in the phase 3 CONTACT-03 trial, 
which randomized patients to receive either atezoli-
zumab + cabozantinib or cabozantinib following pro-
gression with ICI therapy[26].



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Among non-ccRCC subtypes, distinct response 
to ICI is observed depending on the tumour type. In 
papillary RCC, the encouraging results observed in the 
SWOG trial may result in the adoption of cabozantinib 
as the new standard to treat patients with this RCC 
subtype[10]. Ongoing studies are aiming to provide 
insights into molecular MET screening for papillary 
RCC, which may reveal new therapeutic targets. Other 
trials may also help to guide the choice of combina-
tion therapy in patients with non-ccRCC subtypes. 
Lastly, Dr. Albigès highlighted the critical implications 
of adjuvant ICI therapy on subsequent first-line meta-
static treatment options, given the positive results of 
the KEYNOTE-564 trial, which may lead to important 
practice changes in advanced RCC.

In the Q&A period, Dr. Albigès was asked whether 
patients who progress while on treatment with 
nivolumab + ipilimumab could be rechallenged with 
ipilimumab. She indicated that there are no data sup-
porting ipilimumab rechallenge and very limited infor-
mation on ipilimumab activity at later stages. Instead 
of a rechallenge, she would recommend patient 
inclusion in a clinical trial with different agents. Next,  
Dr. Albigès detailed her approach for stopping treat-
ment in patients who achieved CR or prolonged stable 
disease (SD). She emphasized that this is a discussion 
to be had with the tumour board as well as the patient. 
Generally, Dr. Albigès will only recommend discontin-
uation with at least 1 year of treatment if the patient 
has an overall good safety profile and has achieved CR. 
Otherwise, these discussions may occur between 1 to 
2 years following the beginning of treatment. Lastly,  
Dr. Albigès discussed her perspective on new strate-
gies for improving patient response to systemic ther-
apy. She believes that a triple ICI-TKI combination may 
be a way to intensify treatment and potentially improve 
outcomes. She also emphasized that this approach 
may have an increased toxicity profile and that early 
identification of patients who could benefit from triple 
agent combination is critical.

The following presentation was made by Dr. Toni 
Choueiri (United States), who discussed the role of 
HIF-2α inhibitors as a novel therapeutic class for 
RCC treatment. HIF-α activity is intrinsically asso-
ciated with oxygen concentration and VHL gene 

alterations. During hypoxia or when there are muta-
tions in VHL, such as in VHL syndrome and ccRCC,  
HIF-α becomes intrinsically active, leading to down-
stream transcriptional effects[27]. HIF-2α is one of the 
three subunits of HIF-α and regulates multiple onco-
genic pathways, making it an important therapeutic 
target for ccRCC[28]. 

PT2385 was the first generation of HIF-2α inhib-
itors. It was validated for the treatment of heavily  
pretreated patients with metastatic ccRCC in a phase  1 
trial, resulting in an ORR of 13%[29]. Modifications 
of PT2385 led to the development of belzutifan a 
second generation of HIF-2α inhibitor with greater 
efficacy, increased bioavailability, and less protein 
binding[30]. In a recently published phase 1 trial of 
patients with metastatic ccRCC who had previously 
received systemic therapy, belzutifan resulted in an 
ORR of 25%, with a median PFS of 14.5 months[31]. This 
second-generation HIF-2α has also been investigated 
in VHL syndrome-associated RCC, which typically pre-
sents as localized ccRCC. In the preliminary analysis of 
a phase 2 trial, treatment with belzutifan resulted in an 
ORR of 28%, with ~87% of patients exhibiting tumour 
shrinkage[32]. In an updated analysis of this trial, dis-
cussed earlier by Dr. Abel, the ORR was improved to 
36% for VHL-associated ccRCC[12].

In terms of safety profile, HIF-2α inhibitors have dif-
ferent toxicity compared to VEGF inhibitors. In a phase 
1 trial, 15% of patients with metastatic ccRCC who 
received belzutifan developed grade 3 hypoxia[31]. 
This was seen without any concomitant cardiac or 
pulmonary complications. HIF-2α has an important 
role in the pulmonary vasculature and carotid body 
physiology. While the underlying mechanism is not 
fully understood, blocking HIF-2α might exacerbate 
ventilation-perfusion mismatch and ventilatory sensi-
tivity to hypoxia. This is an important consideration for 
patients with chronic pulmonary diseases or those at 
high altitude, who may be relying on enhanced sen-
sitivity to hypoxia to maintain adequate ventilation.

Combination therapy with HIF-2α inhibitor and 
ICI/TKI is also under investigation. In the phase 1 trial, 
patients with advanced RCC treated with PT2385 
+ nivolumab combination had an ORR of 22% and 
median PFS of 10 months, for those who were exposed 



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to therapeutic doses of PT2385[33]. In a phase 2 
trial, preliminary analysis of patients with up to two 
prior systemic therapies, including ICI (Cohort 2), 
demonstrated tumour shrinkage in 88% of patients 
and a median PFS of 16.8 months following treatment 
with belzutifan + cabozantinib[34]. Phase 3 studies are  
underway to evaluate the efficacy and safety of belzutifan 
either in combination with lenvatinib[35] or as monother-
apy[36] for the treatment of advanced RCC.

Dr. Choueiri emphasized the importance of exam-
ining the potential mechanisms of resistance as part 
of the development of a new therapeutic agent. For 
HIF-2α inhibition, pre-clinical and translational models 
suggest that mutations in HIF-2α and HIF-1β may 
preclude binding of HIF-2α inhibitors and lead to 
increased affinity between the two subunits, resulting 
in activation of the HIF pathway (summarized in [28]). 
RNA interference (RNAi) may provide an alternative 
to small-molecule HIF-2α inhibition by targeting and 
silencing HIF-2α expression. This approach is under 
investigation in a phase 1 trial evaluating the efficacy 
of a proprietary targeted RNAi molecule delivery plat-
form (ARO-HIF2) for the treatment of ccRCC[37] and 
has shown encouraging results in pre-clinical mod-
els[38]. With positive results from several trials and 
ongoing development, HIF-2α represents a novel 
therapeutic target whose implications may expand 
beyond VHL syndrome and RCC.

The presentation was followed by a Q&A session 
during which Dr. Choueiri discussed his perspective 
on how different VHL mutations may affect treatment 
response to HIF-2α inhibition in patients with RCC. 
He believes that most RCC patients likely have some 
form of VHL mutation that may be difficult to detect. 
He pointed out that, under these circumstances, 
downstream alterations may help identify other RCC 
syndromes that could be targeted with HIF-2α inhib-
itors. Next, Dr. Choueiri discussed the potential role 
of HIF-2α inhibitors in triple-agent combination ther-
apy for RCC. He explained that the latest advances in 
HIF-2α inhibition are promising and may lead to the 
development of improved molecules that could be 
combined with other agents. However, he advised 
caution in regards to the cost and potentially increased 
toxicities of combination approaches.

Next, Dr. Axel Bex (United Kingdom) discussed why 
and when local therapy should be used to manage 
metastatic kidney cancer. First, Dr. Bex focused on 
the why. In general, patients who undergo resection 
of multiple metastases over time may have 5-year OS 
that are comparable to those who underwent single 
metastasectomy[39]. If achievable, complete resection 
of metastases may lead to cure, potential improvement 
of DFS, PFS, and OS (although not yet evaluated in 
a randomized clinical trial setting), as well as delay 
or discontinuation of targeted therapies. However,  
Dr. Bex questioned whether metastasectomy is indeed 
required to achieve these objectives. For instance, 
active surveillance may be a viable, safe option for 
patients with oligometastasis to manage the disease 
prior to starting systemic therapy[40]. In addition, cure 
is generally not achievable in high-risk patients treated 
for recurrence[41]. Finally, while a systematic review 
favours metastasectomy based on the hazard ratio for 
OS, this may be biased because of the distinct patient 
populations evaluated in retrospective studies[42]. 

RCC has different pathways of metastatic evolution 
and management approaches. In patients who pres-
ent with the primary tumour and single metastasis, 
treatment involves nephrectomy and resection of the 
metastatic lesion, which may result in several years of 
survival without the disease. These patients generally 
present with a linear evolution driven by VHL mutation 
or an attenuated progression, as a result of PBRM1 
mutations. On the other end of the spectrum, there 
are patients who present with multiple metastatic 
sites and follow a punctuated evolution with rapid 
progression, mainly driven by BAP1 alterations[43].  
By contrast, translational data in prostate cancer 
suggest that metastasis-to-metastasis spread can 
occur[44]. The time to transformation into a more 
aggressive subtype may also be unpredictable and 
lead to a metastatic shower[45], which would further 
support the role of metastasectomy in patient man-
agement. Nevertheless, these treatment decisions 
remain challenging in the absence of prospective 
randomized studies to evaluate the true impact of 
metastasectomy on survival.

Dr. Bex then discussed the timing for performing 
metastasectomy. Although early presentation of 



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PROCEEDINGS FROM THE SIU B2B URO-ONCOLOGY: GU CANCERS TRIAD • MAY 21–22, 2021 – SIUJ VOLUME 2, SUPPLEMENT 1, JULY 2021

recurrence is a strong indicator of poor prognosis[46], 
it is impossible to predict the momentum of meta-
static progression. General predictors associated with 
positive outcomes after metastasectomy include: the 
presence of solitary or oligometastatic lesions, a com-
plete resection, disease-free interval of over 2 years, 
single-organ site, no sarcomatoid features or high-
grade tumour, absence of nodal metastases, good 
performance status, and a favourable-to-intermediate 
risk IMDC[47]. Dr. Bex emphasized the importance 
of keeping these factors in mind when deciding the 
management approach for metastases, given the high 
complication rates of metastasectomies[48].

There are ongoing phase 3 trials evaluating the 
role of adjuvant ICI therapy in RCC that have included 
patients who also underwent complete metastasec-
tomy, namely KEYNOTE-564 (pembrolizumab vs. 
placebo) and IMmotion 010 (atezolizumab vs. pla-
cebo). If these trials demonstrate DFS or OS benefit, 
metastasectomy followed by ICI may become the new 
standard based on prospective randomized data.

During the Q&A, Dr. Bex discussed whether some 
sites should not undergo metastasectomy due to poor 
associated outcomes. He advised that the site as well 
as the complexity of the surgical procedure should be 
considered. In general, metastases in the liver, pan-
creas, and brain may require a different management 
approach. Next, Dr. Bex provided his insights on the 
advances of stereotactic body radiation therapy (SBRT) 
to manage multiple metastatic lesions. He believes 
that SBRT may provide an alternative, and even pref-
erable, approach to metastasectomy, although data 
comparing both strategies are needed. Lastly, Dr. 
Bex discussed his management approach for patients 
who achieve partial response to ICI and have one or 
two metastatic sites. If the lesions are small and sta-
ble, he does not see a benefit for metastasectomy. 
By contrast, if the lesions grow during treatment, he 
recommends controlling the metastatic growth with 
a focal therapy (e.g., SBRT) rather than switching to a 
different line of systemic therapy.

The session concluded with a case-based panel on 
multimodal management of localized RCC. This was led 
by Dr. Umberto Capitanio (Italy), with the discussion 
based on the input of Drs. Simon Tanguay (Canada), 

Maxine Tran (United Kingdom), and Alessandro Volpe 
(Italy). The case was a 51-year-old male with a high 
body mass index (BMI) of 42 kg/m2 who had a small 
renal mass incidentally detected during an abdominal 
ultrasound. Computed tomography (CT) revealed a 
35-mm renal tumour, which was >50% endophytic and 
lay in close proximity to the renal calices and sinus, 
representing intermediate complexity for surgery. 

The tumour was staged as cT1aN0M0, with a very 
low risk of metastasis, meaning that chest imaging and 
bone scan were not necessarily indicated according 
to published nomograms[49]. Other imaging options 
that may be considered for further evaluation include 
magnetic resonance imaging (MRI), if the patient 
had low estimated glomerular filtration rate (eGFR); 
sestamibi positron emission tomography (PET)/CT, 
to differentiate between RCC and oncocytoma; and 
contrast-enhanced ultrasound scan for equivocal 
lesions in patients with low eGFR. 

Biopsies are not performed routinely in this patient 
population. However, they may provide additional 
insights given that small renal masses are heteroge-
neous and may have differing patterns of growth and 
spread that can be predicted through diagnostic biop-
sies[50]. In addition, renal biopsies have high sensitivity 
and specificity to detect malignancies[51], with minimal 
complications associated with the procedure. In the 
patient case, biopsy revealed a grade 2 ccRCC.

In this clinical case, the patient underwent robot-
ic-assisted partial nephrectomy and final pathology 
indicated a grade 2 pT1a ccRCC with negative surgical 
margins. Surgery is the preferred management option 
for patients with small renal masses. Focal therapy and 
active surveillance may also be considered for some 
patients, such as the elderly and frail[2]. Focal thera-
pies (such as cryoablation, radiofrequency ablation, 
and microwave ablation) generally have low morbidity 
and may be performed in the outpatient setting but 
should be reserved to tumours ≤3 cm[2]. In addition, 
while these focal approaches show generally good 
outcomes in clinical practice, evidence supporting 
the preferred use of either focal therapies or surgery 
in managing small renal masses is currently lacking. 
Active surveillance may also be considered for patients 
with low-grade small RCC, although the tumour size 



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at diagnosis should also play a role in management 
selection[52]. Currently, the prospective EASE study 
is investigating the use of active surveillance in small 
RCC to determine standards for indication, follow-up, 
criteria for progression, and delayed intervention with 
this management approach[53].

Other approaches such as neoadjuvant treat-
ment, systemic therapy, and radiotherapy are only 
recommended in this disease setting through clin-
ical trial enrolment. Neoadjuvant therapy is usually 
implemented to reduce tumour size prior to sur-
gery and would unlikely benefit the patient in the 

case. By contrast, the recent positive experience with  
HIF-2α inhibitors in patients with VHL and RCC[12] 
might lead to important developments in this setting. 
SBRT allows the delivery of precise radiation doses to 
the target tumour, with the additional benefit of being 
performed in the outpatient setting. While this may 
be a compelling option for morbid and inoperable 
patients, particularly with metastatic disease, SBRT 
may have limited applicability in the localized setting, 
in which other treatment options are available.

Abbreviations Used in the Text
BMI body mass index
ccRCC clear cell renal cell carcinoma
CI confidence interval
CR complete response 
CT computed tomography
DFS disease-free survival
eGFR estimated glomerular filtration rate
ESMO European Society for Medical Oncology
HR hazard ratio
ICI immune checkpoint inhibitor
IMDC International Metastatic RCC Database 

Consortium
IRC independent review committee
MRI magnetic resonance imaging
NCI National Cancer Institute
ORR objective response rate

OS overall survival
PD-1 programmed cell death protein 1
PD-L1 programmed death-ligand 1
PET positron emission tomography
PFS progression-free survival
RCC renal cell carcinoma
RECIST Response Evaluation Criteria in Solid 

Tumours
RNAi RNA interference
SBRT stereotactic body radiation therapy
SD stable disease
TKI tyrosine kinase inhibitor
TRAE treatment-related adverse event
VEGF vascular endothelial growth factor
VHL Von Hippel-Lindau syndrome



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