Submitted - October 18, 2022 | Revised December 4, 2022 Accepted - December 7, 2022 | | ePublished - December 31, 2022
https://doi.org/10.52733/KCJ21n1-r1
ABSTRACT
Renal Cell Carcinoma (RCC) is among the most frequently diag-nosed cancers in the United States. One-third of patients present
with metastatic disease, and up to another half may progress to
metastasis following surgical treatment. Survival rates for metastatic
RCC have risen over the past 20 years, an improvement partially attri-butable to the increased availability of immune checkpoint inhibitors
(ICI). However, mRCC remains a fatal genitourinary cancer, with pa-tients often demonstrating both primary and secondary resistance to
available immunotherapies. Sarcopenia, inflammation and nutrition
have emerged as important prognostic factors in RCC. Recent studies
have demonstrated their impact in predicting efficacy and tolerability
of ICIs for RCC and other advanced solid malignancies. In this review,
we aim to highlight the major milestones in ICI therapy for RCC, and
associated mechanisms of action. We also examine how sarcopenia,
inflammation and nutrition affect outcomes in RCC, particularly with
consideration of the impact on immunotherapy efficacy and toxicity.
INTRODUCTION
Renal Cell Carcinoma (RCC) is
among the top 10 cancer diagnoses in
the United States, with an estimated
79,000 new cases and 14,000 deaths
in 2022.1
The incidence has doubled
over the past half-century, likely
attributed to improved and more
frequent imaging.2 Nevertheless,
one-third of patients present with
distant metastatic disease and 20-
50% progress to metastasis despite
surgical resection.3 Over the past
decade, the 5-year survival rate for
metastatic RCC (mRCC) has risen
from 12% to 15.3%,1,3 an improvement
at least partially attributed to the
increased availability of systemic
treatment options. Primary systemic
therapy options for RCC include
vascular endothelial growth factor
(VEGF)-targeted tyrosine kinase
inhibitors (TKI) and the more recent
introduction of immune checkpoint
inhibitors (ICI) such as nivolumab,
ipilimumab, pembrolizumab and
avelumab. The development of
immune checkpoint blockade with
antibodies against programmed cell
death protein 1 (PD-1), programmed
cell death ligand 1 (PD-L1), and
cytotoxic T-lymphocyte-associated
antigen 4 (CTLA-4) has resulted in
significant and durable responses
in RCC with acceptable safety.4–10
Multiple phase III randomized
clinical trials comparing ICI
monotherapy and combination
therapies against targeted therapies
for RCC have demonstrated higher
median overall survival (OS) and
progression-free survival (PFS)
with improved objective response
rates (ORR).4–8,11 This has resulted
in a major shift towards ICI-based
combination therapies as preferred,
first-line options for the management
of advanced RCC.12
However, ICI efficacy and tolerance
may be impacted by other factors,
such as sarcopenia, inflammation,
and nutritional status, which
influence survival outcomes in
patients with cancer. Sarcopenia
is a progressive and generalized
skeletal muscle disorder with
accelerated loss of muscle mass and
function associated with increased
risk of falls, frailty, and mortality.13
Although observed in the context of
aging, sarcopenia additionally occurs
concurrently or independently in
the setting of cancer,14,15 where
there is malignancy-related weight
loss and muscle wasting known as
cancer cachexia.16 Sarcopenia and
its association with worse survival
has been widely reported in patients
with RCC, especially in patients
with advanced or metastatic
disease.14,17–24 Similarly, markers
of malnutrition and inflammation,
such as C-reactive protein (CRP),
low body mass index (BMI),
hypoalbuminemia and neutrophil,
lymphocyte, and platelet counts, have
also been associated with survival in
RCC and other malignancies.25–29
In addition to influencing
survival in RCC, studies have
documented the impact of these
factors on the efficacy and tolerability
of ICI treatment. Here, we briefly
review the major milestones in
ICI therapy for advanced RCC and
associated mechanisms of action. We
focused on data from clear cell RCC
as the most commonly encountered
histology, recognizing that much of
our management of non-clear cell
subtypes are extrapolated from this
body of work. Then, we examine
sarcopenia, inflammation, and
malnutrition in RCC and consider
its impact on immunotherapy
efficacy and tolerance and discuss
future considerations for guiding
management.
IMMUNE CHECKPOINT
INHIBITORS IN ADVANCED
RENAL CELL CARCINOMA
Numerous immunotherapies have
been studied and received approval
for treatment of RCC since 2015. A
representative summary of these
randomized controlled trials are
summarized in Table 1. A summary
of the mechanism of immune
checkpoint inhibition is also
represented in Figure 1.
History of Immune Checkpoint
Inhibitors
The FDA approved the first ICI,
ipilimumab (CTLA-4 checkpoint
inhibitor), in 2011 for metastatic
melanoma.30,31Then, in 2014,
the FDA approved the first PD-1
checkpoint inhibitor, nivolumab.30,31
The phase 3 CheckMate 025 trial,
published in 2015, compared
nivolumab versus everolimus in
mRCC following prior treatment,
which demonstrated longer median
OS (25.0 months [95% confidence
interval, 21.8 to not estimable] vs
19.6 months [95% CI, 17.6-23.1])
with less grade 3-4 treatment
related adverse events (TRAE), but
no difference in progression free
survival (PFS, 4.6 [95% CI, 3.7-5.4]
vs 4.4 months [95% CI, 3.7-5.5]).4
Nivolumab for the treatment of
mRCC after treatment with standard
antiangiogenic therapy was then
approved. Combination therapy of
nivolumab plus ipilimumab versus
sunitinib in previously untreated
mRCC was studied in the phase III
Checkmate 214 trial. This showed
significantly longer OS (median OS
not reached [95% CI, 28.2 months to
not estimable] versus 26.0 months
[95% CI, 22.1 to not estimable]),
higher objective response rate (ORR,
42% [95% CI, 37-47] vs 27% [95%
CI, 22-31], p<0.0001) and complete
response rate (CRR, 9% vs 1%),
which led to FDA approval as first-line treatment for intermediate to
poor-risk advanced RCC in April
2018.5,31 In the long-term analysis
with minimum 42-month follow-up, duration of response was
longer, and more patients achieved
complete response with nivolumab
plus ipilimumab regardless of
International mRCC Database
Consortium (IMDC) risk group.32
Pembrolizumab, another PD-1
checkpoint inhibitor, was first
approved in 2014 for advanced
melanoma, and showed antitumor
activity in untreated mRCC.33 The
KEYNOTE-426 trial comparing
pembrolizumab plus axitinib, an
anti-VEGF TKI, versus sunitinib for
treatment-naive advanced ccRCC
showed a 12-month OS benefit
(89.9% [95% CI, 86.4-92.4] vs
78.3% [95% CI, 73.8-82.1]) with a
longer PFS (15.1 [95% CI, 12.6-17.7]
vs 11.1 months [95% CI, 8.7-12.5])
and improved ORR (59.3% [95%
CI, 54.5-63.9] vs 35.7% [95% CI,
31.1-40.4], p<0.001). These results
were observed across all IMDC
risk groups regardless of PD-L1
expression.11 FDA approval followed
soon after in April 2019 as first-line
combination immunotherapy for all-risk advanced RCC.
The first PD-L1 checkpoint inhibitor
that received approval for mRCC was
avelumab with combination axitinib
in May 2019. This was supported by
the phase III JAVELIN Renal 101
trial of avelumab plus axitinib as
compared with sunitinib in patients
with previously untreated advanced
RCC. Primary endpoints focused
on PFS and OS among patients
with PD-L1 positive tumors. The
median PFS among this cohort was
significantly longer for patients that
received avelumab plus axitinib
(13.8 [95% CI, 11.1 to not estimable]
vs 7.2 months [95% CI, 5.7-9.7]), and
in the overall population, PFS was
also longer (13.8 [95% CI,
11.1 to non estimable] vs 8.4 months
[95% CI, 6.9-11.1]).6
In 2021, the FDA granted approval
to the two remaining frontline
combination immunotherapies
for advanced RCC treatment:
cabozantinib (TKI) plus nivolumab,
and lenvatinib (TKI) plus
pembrolizumab. The phase III
CheckMate 9ER trial comparing
nivolumab plus cabozantinib versus
sunitinib for advanced RCC showed
benefits in median PFS (16.6 [95%
CI, 12.5-24.9] vs 8.3 months [95%
CI, 7.0-9.7]) and ORR (55.7% [95%
CI, 50.1-61.2] vs 27.1% [95% CI, 22.4-
32.3], p<0.001). Grade 3 or higher
TRAEs were similar, with patients
also reporting better health-related
quality of life with the combination
regiment, demonstrating its
acceptable safety profile.7 In the
CLEAR trial comparing lenvatinib
plus pembrolizumab or everolimus
versus sunitinib for advanced RCC,
significant benefits were observed
with the immunotherapy-containing
regimen in terms of PFS (23.9 [95%
CI, 20.8-27.7] vs 9.2 months [95% CI
6.0-11.0]), OS at 24 months (79.2% vs
70.4%; hazard ratio [HR] for death,
0.66 [95% CI, 0.49-0.88]; p=0.005),
and ORR (71.0% vs 36.1%; relative
risk [RR], 1.97 [95% CI, 1.69-2.29])
versus sunitinib.
These immunotherapy regimens
represent the approved, first-line and preferred options for the
treatment of RCC, with many other
immune-checkpoint inhibitor-based
combinations or monotherapies
currently under investigation or
awaiting approval12,34–38.
Interplay between ICIs and RCC
The tumorigenesis and development
of RCC is well documented. Clear
cell RCC frequently contains
multiple loss-of-function mutations
in the tumor suppressor gene Von
Hippel-Lindau (VHL). This results
in the induction of hypoxia inducible
factors (HIF), which promotes cells
to express VEGF and other factors
that increase tumor angiogenesis
and growth.39 These findings were
the basis for anti-angiogenic agents
becoming the standard of care
for advanced RCC. These drugs
demonstrated improvements in OS
and PFS, but without significant
complete or durable response rates
as monotherapies.40
It has become better documented
how multiple subtypes of RCC share
alterations of specific pathways
involving metabolism, hypoxia,
and immune checkpoints.41, 42 RCC
is notably associated with a highly
inflammatory microenvironment
with increased frequency of tumor
infiltrating lymphocytes.43 Despite
prominent levels of T-cells within
tumors, RCC often escapes via
immunosuppressive mediators from
the microenvironment or tumor cell
overexpression of CTLA-4 and PD-L1 which block T-cell responses.43
This infiltrate is partially composed
of regulatory T cells (Treg),
which can prevent cancer antigen
recognition, and reduce the
antitumor activity of lymphocytes
present.44 Markers associated with
T-cell exhaustion along with the
promotion of Th2 induction have
been identified, which can allow
for unchecked tumor growth in a
state of chronic inflammation.41, 45
These findings support the use and
improved benefits associated with
immunotherapy in the treatment
of RCC. However, many patients
may not respond to immunotherapy
and durable responses remain an
exception, which can reflect the
presence of primary and secondary
resistance to ICIs.
There are multiple theories that
explain resistance including
certain patient-intrinsic,
tumor cell-intrinsic, and tumor
microenvironment factors.46 One
explanation is the tumor cell-induced
release of VEGF which promotes
abnormal neovascularization, Treg
proliferation, and reduces CD8+
T-cell proliferation and penetration
into the tumor. This supports
the rationale for combining ICIs
and anti-VEGFR TKIs as dual
therapy for mRCC to target both
antitumor processes.40, 47Other
explanations for potential ICI
resistance include Wnt/ß-catenin
pathway overexpression leading to
T-cell exclusion and resistance to
anti-PD(L1) and CTLA-4 antibodies
along with MAP Kinase alterations
that inhibit T-cell recruitment and
function.46 For patients that do
respond to ICIs there is often a
robust activation of CD8+ T-cells
within the microenvironment, along
with increased interferon-gamma
signaling that promotes acute
inflammation.48 However, over time,
evidence suggests an adaptation
to increased T-cell checkpoint
molecule expression that can lead
to immunotherapy resistance.48
Patient-specific factors, including
sarcopenia, systemic inflammation
and markers of nutritional status,
remain an important barrier to
immunotherapy efficacy and can
be identified and addressed for
improved management of advanced
RCC.
SARCOPENIA, INFLAMMATION,
AND MALNUTRITION IN
ADVANCED RENAL CELL
CARCINOMA
Definitions, Epidemiology,
Relationships, and
Pathophysiology
Sarcopenia is a generalized skeletal
muscle disorder defined by 3
main criteria: low levels of muscle
strength, muscle quantity and/
or quality, and decreased physical
performance which can indicate
severity.13,49 Cross-sectional imaging
with computed tomography (CT) or
magnetic resonance imaging (MRI)
is widely prevalent during RCC
screening, staging, and follow-up and
can additionally be used to evaluate
for sarcopenia at the third lumbar
vertebra (L3), which correlates well
with total skeletal muscle mass.50-53 Commonly, the skeletal muscle
index (SMI, cm2/m2) is calculated
by dividing cross-sectional area of
skeletal muscle at L3 by the patient’s
height in meters squared.54 Then,
SMI thresholds are used to define
sarcopenia vs. nonsarcopenia;
however, it should be noted that
there is wide variation in SMI
thresholds used to define sarcopenia,
which is an important consideration
for future incorporation and study
interpretation.55
There has been further investigation
since sarcopenia was first defined to
clarify specific categories including
primary and secondary forms, acute
and chronic sarcopenia, sarcopenic
obesity, and malnutrition-associated
sarcopenia.49 Primary sarcopenia
refers to age-related changes,
where, in addition to hormonal,
physical activity, and nutritional
changes, a state of chronic low-grade
inflammation can contribute to the
loss of muscle over time.49,56 Based
on established thresholds for muscle
mass, up to 20% of those aged 70-79
and 30% of the population 80 or older
meets this criterion for sarcopenia.57
In addition, studies have
demonstrated a high prevalence of
weak muscle strength and decreased
physical performance in populations
aged 65 or older, affecting up to half
of all individuals.57
Normal aging is associated with
elevated levels of pro-inflammatory
markers, including tumor necrosis
factor-α (TNF-α), interleukin-6
(IL-6), and C-reactive protein
(CRP), often associated with
long-standing mitochondrial and
immune dysfunction, cellular
injury, and increased adiposity.58
Multiple studies have demonstrated
that higher levels of circulating
cytokines, including TNF-α and
IL-6, are associated with loss of
skeletal muscle mass and strength,
with an overall increased risk of
sarcopenia.59–61 In a separate meta-analysis, CRP is suggested to be a
potential parameter for detecting
sarcopenia given its association with
higher serum levels in sarcopenic
patients.62 Alterations in pro-inflammatory markers can, directly
and indirectly, affect skeletal muscle
metabolism by increasing catabolic
pathways for muscle breakdown,
and preventing appropriate use of
proteins for muscle synthesis.56
Systemic inflammation is also
associated with solid malignancies
and can exacerbate typical age-related skeletal muscle mass loss and
contribute to worse outcomes. In a
meta-analysis of over 80,000 patients
with malignant tumors, sarcopenia
was identified in 35.3%, and varied
between 35-50% in RCC.15 Cancer
and its treatments can increase the
risk of developing sarcopenia via
the promotion of anorexia, physical
inactivity, and pro-inflammatory
states, along with treatment related
damage to muscle tissue.63 The
development of sarcopenia can also
co-occur as a component of cancer
cachexia, defined as a progressive,
multifactorial syndrome with
continuous loss of skeletal muscle
mass resulting in functional
impairment that cannot be fully
reversed.16 Cancer cachexia arises
from a combination of systemic
inflammation and negative energy
balance and affects ~30% of all
cancer patients and close to 80%
of patients with metastatic disease
to the brain.64 The diagnosis
requires certain changes in overall
weight, BMI, and sarcopenic
criteria.16 Furthermore, advanced
cancer patients are often affected
by nutritional impact symptoms,
including anorexia, nausea,
vomiting, taste, and smell changes,
as a result of chemotherapy,
radiotherapy, and even systemic
inflammation that can alter hunger/
satiety signaling thus preventing
compensation for the ongoing
negative energy balance.64
General Impact of Sarcopenia,
Inflammation and Malnutrition
on Survival in RCC
Sarcopenia is associated with poor
OS and CSS across a wide variety of
non-hematological solid tumors.65
In a systematic review examining
treatment-related outcomes for
patients undergoing nephrectomy
for localized and mRCC, sarcopenia
was an independent predictor of
mortality, especially following
systemic treatment.66 In patients
with non-mRCC treated with
radical nephrectomy, Psutka et
al found sarcopenia as inferior
5-year CSS (79% vs 85%, p=0.05)
as well as inferior 5-year OS (65%
vs 74%, p=0.005).19 In a study of
mRCC patients, sarcopenia was
associated with a 2.5x higher risk of
all-cause mortality. and improved
the prognostic ability of the
MSKCC risk model when included
with or substituted for Karnofsky
performance status.21 Similar
results have been found in other
cohorts of patients with metastatic
and nonmetastatic RCC.18, 67
Increasingly, sarcopenia with
other markers of inflammation and
nutrition are being considered and
have demonstrated an association
with increased mortality.17,18,20,68
Higher modified Glasgow prognostic
scores (mGPS), which features
CRP and albumin as measures of
inflammation and nutrition, have
been associated with worse OS, CSS,
RFS, and PFS, and have an even
greater association when combined
with sarcopenia.18,29,69 Other
studies have analyzed the predictive
impact of the prognostic nutritional
index (PNI) in patients undergoing
nephrectomy, as calculated by
albumin and lymphocyte levels.26
Increases in PNI scores have shown
a decreased risk of death from
RCC.25 PNI also demonstrated
greater prognostic ability for both
OS and PFS when compared to other
inflammatory measures, such as
Neutrophil-to-Lymphocyte (NLR),
Platelet-to-Lymphocyte (PLR), and
Lymphocyte-to-Monocyte (LMR)
ratios.25,26 On univariate analysis,
these indices were associated with
shorter OS and PFS, but only PNI
was significant on multivariable
analysis.26 Multiple methods
of evaluating for sarcopenia,
inflammation, and nutritional status
exist and demonstrate prognostic
utility in localized and advanced
RCC.
IMPACT OF SARCOPENIA,
MALNUTRITION, AND
INFLAMMATION ON IMMUNE
CHECKPOINT EFFICACY
Examination of ICI efficacy and
toxicity in relation to sarcopenia
and other markers of nutrition and
inflammation has emerged over
the past decade. A representative
summary of studies examining
these interactions is summarized in
Table 2.
Sarcopenia
A retrospective analysis of patients
with advanced cancer receiving
ICIs found sarcopenic patients
experienced worse ORR (15.9%
vs 30.5%, p=0.095) although this
was statistically insignificant.70
However, 1-year PFS (10.8% vs 32%;
RR, 1.31; p<0.001) and OS (43%
vs 66%; RR 1.71; p<0.001) were
significantly lower for the sarcopenic
patients.70 In another group of
patients with advanced solid tumors
that received ICI monotherapy,
sarcopenia prevalence was nearly
50% and a significant predictor
of worse OS, PFS, and ORR and
not dependent on the type of ICI
received.71
In addition to baseline muscle
measurements, longitudinal
change during ICI therapy has
additionally exhibited prognostic
ability. In one prospective study, 88
patients received either nivolumab
(55.7%), pembrolizumab (28.4%),
or nivolumab plus ipilimumab
(9.1%) for various solid organ
malignancies.72Although no
difference in baseline SMI between
responders vs. non-responders was
observed, patients that responded
to ICI therapy at the 3-month mark
experienced an increase in SMI (+1.73
vs -3.20 mm2/cm, p=0.002) and
median muscle attenuation (+0.89
vs -1.0 HU, p=0.090), an indicator
of muscular fat deposition.72
Furthermore, OS was significantly
lower (127 vs 547 days, p<0.001)
in patients that experienced a
strong decline in SMI (<-6.18 mm2/
cm) or muscle attenuation (<-0.4
HU) compared to patients with
stable or mild decreases.72 The
progressive loss of muscle mass with
increased myosteatosis might reflect
increased malignancy-associated
inflammation which may negatively
influence the antitumor effects of
ICIs.73
Alternative Body Composition
Parameters
In addition to quantified muscle
composition, other parameters such
as BMI, adipose distribution, and
muscle quality may be informative.
In an analysis of 79 patients treated
with ICI for mRCC, Martini et al
measured density (as measured via
HU) of skeletal muscle, subcutaneous
fat, intramuscular fat, and visceral
fat in addition to SMI. Patients were
stratified into poor, intermediate, or
favorable risk groups based on these
measurements, with the poor risk
groups experiencing significantly
shorter OS, PFS, and lower chance
of radiographic response at 6
months compared to the favorable
risk group.74 Furthermore, a lower
total fat index was also associated
with shorter OS, PFS, and a lower
chance of radiographic response.74
These findings suggest that, in
addition to muscle quantification,
markers of adiposity and muscle
quality (i.e. intramuscular fat)
may be informative and predict
outcomes for patients with RCC
receiving ICI therapy. This aligns
with prior studies demonstrating
that increased BMI, weight gain,
increased subcutaneous fat index,
and decreased intermuscular fat
index during ICI treatment are
associated with prolonged survival
or treatment response in patients
with cancer,75 including mRCC.76,77
Inflammation
Relationships between
inflammation and body composition
in patients receiving ICI have also
been considered. In 90 patients
enrolled in immunotherapy-based
phase 1 clinical trials, Bilen et al.
risk-stratified patients based on
sarcopenia measurements and
baseline inflammatory markers (i.e.
NLR, MLR, and PLR). A negative
correlation was observed between
SMI and PLR, and very high-risk (PLR ≥242 and sarcopenic)
or intermediate (PLR <242 and
sarcopenic) risk groups experienced
significantly shorter OS and PFS
compared with low-risk patients
(PLR <242 and non-sarcopenic).78 In
a separate study of 38 mRCC patients
treated with nivolumab, Bilen et al
demonstrated that low NLR values
were associated with longer median
PFS (not estimable vs 2.6 months;
HR 0.20 [95% CI, 0.07-0.64;
p=0.006]) and OS (not estimable
vs 2.7 months; HR 0.06 [95%
CI, 0.01-0.55; p=0.012]).79 These
findings were echoed by Zahoor et
al, where a higher baseline NLR was
associated with an increased risk
of progression in mRCC patients
treated with nivolumab.80 It is well
documented how both inflammation
and sarcopenia contribute to worse
outcomes in malignancy and can
limit treatment efficacy, but the
inclusion of multiple markers for
risk stratification may better account
for multiple underlying prognostic
factors.
Nutritional Status
Advanced RCC patients are often
susceptible to malnutrition and
resulting cancer cachexia, which
can affect ICI efficacy. As previously
discussed, higher PNI is associated
with better survival. In a series of
studies from Asian countries looking
at PNI and survival outcomes in
advanced cancer patients treated
with ICIs, higher PNI was associated
with greater ORR and longer OS and
PFS.81 The cachexia index is another
combined score of sarcopenic and
inflammatory markers used as a
prognostic model in cancer patients.
This index, based on SMI, NLR,
and albumin levels, was used in a
retrospective review of 52 mRCC
patients who had received ICI as a
2nd-line or later treatment.82 Below
median cachexia index score was
found to significantly affect OS (7
vs 48 months; HR 4.5 [95% CI, 1.9-
11; p=0.001]) and PFS (4 months vs.
17 months; HR 2.6 [95% CI, 1.3-5.3;
p=0.007]) as opposed to the other
markers.82 One theory for why the
procatabolic and proinflammatory
state associated with cancer
cachexia may interfere with ICI
efficacy is increased clearance and
metabolism. A prospective cohort
study on the pharmacokinetics of
nivolumab used in advanced cancers,
including 14 patients (6.3%) with
mRCC, showed how increased body-surface area and decreased albumin
were associated with increased
clearance of the ICI.83 A clearance-response trend was observed in
mRCC where clearance was higher
in patients with progressive disease,
although this was non-significant.83
However, this trend was significant
in NSCLC (n=158; 71.5%), and given
the smaller percentage of patients
with mRCC, the study may have
been underpowered to demonstrate
statistical significance in this
subgroup.
IMMUNE CHECKPOINT
INHIBITOR TOLERANCE
In a series of 8 studies that featured
patients with advanced RCC and
other metastatic solid tumors, no
association between patients with
sarcopenia and adverse reactions of
any grade were identified.84 However,
in a separate review, an increased
risk of AEs with the use of ICIs
in sarcopenic cancer patients was
observed.85 In addition to standard
TRAEs from systemic therapy,
numerous immune-related adverse
events (irAE) associated with ICI
use that result from upregulation
of the host immune system.86 The
most commonly affected organs
include the gastrointestinal tract,
endocrine glands, skin, and liver.86
Intriguingly, in a review of 90
patients with ICI-treated RCC, there
was a 42% prevalence of irAEs, and
this cohort demonstrated improved
OS compared to patients without
irAEs (35.9 [95% CI, 24.3 to non-estimable] vs 26.5 months [95%
CI, 10.2-28.8]; p=0.002).87 Similar
studies have supported the findings
of longer OS and PFS in ICI-treated
RCC patients reporting greater
irAEs.88,89 In a meta-analysis of ,
patients with advanced solid tumors,
researchers analyzed sarcopenia in
relation to irAEs, but the findings
were mixed: two of the studies found
no significant association between
sarcopenia and irAEs, however, the
3rd study did identify a higher chance
of developing irAEs in the sarcopenic
group.85 An association between
sarcopenia and grade 3-4 irAEs may
explain the lack of survival benefit
in this cohort compared to other
studies assessing the prognostic
value of irAEs.90 Although certain
studies support sarcopenia as a
risk factor for ICI TRAEs, the topic
remains controversial and study-dependent. From a pharmacokinetic
perspective, susceptibility to
TRAEs in sarcopenic patients
makes sense; however, much of the
research is limited by sample size,
retrospective nature, and inclusion
of a wide diversity of tumor types.
New prospective studies should be
pursued to examine the impact that
muscle, inflammation, and nutrition
may have ICI-related toxicity in RCC.
CONCLUSION
There remains a high prevalence of
RCC cases that are either diagnosed
at or progress to an advanced stage.
ICI-based regimens including ICIs
have emerged as first-line treatments
for patients with advanced or
metastatic disease. Measurements
of sarcopenia, inflammation and
nutrition hold potential prognostic
value for the long-term outcomes
of localized and advanced RCC.
Strategies aimed for preventing
and managing sarcopenia may have
significant impact on improving
outcomes and quality of life in
patients with metastatic RCC
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* Corresponding Author: Rohan Garje, MD
Chief of Genitourinary Medical Oncology, Miami Cancer Institute, Baptist Health South Florida
8900 N. Kendall Drive | Miami, FL 33176 Email Id: rohan.garje@baptisthealth.net