








































This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited.  
© 2022 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

Key Words Competing Interests Article Information

Renal cell carcinoma, treatment-related 
adverse events, vascular endothelial growth 
factor receptor tyrosine kinase inhibitors, 
mTOR inhibitors, immune checkpoint inhibitors

None declared. Received on August 1, 2022 
Accepted on September 21, 2022 
This article has been peer reviewed.

Soc Int Urol J. 2022;3(6):485–499

DOI: 10.48083/SYAB9165

2022 WUOF/SIU International Consultation on 
Urological Diseases: Management of Toxicity and Side  
Effects of Systemic Therapy for Renal Cell Carcinoma

Kate Young,1 Andreas M. Schmitt,1,2 Deborah Mukherji,3 Lavinia Spain,4 Manuela Schmidinger,5 
Lisa M. Pickering1

1 Renal and Skin Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom 2 Department of Clinical Research, University Hospital Basel, Basel, Switzerland. 
3 Department of Medical Oncology, American University of Beirut, Lebanon; Department of Medical Oncology, Clemenceau Medical Center Dubai, United Arab Emirates 
4 Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; Department of Medical Oncology, Eastern Health, Melbourne, Australia; 
Eastern Health Clinical School, Monash University, Melbourne, Australia 5 Department of Urology, Medical University of Vienna, Vienna, Austria

Abstract

Standard approved systemic treatment options for the management of renal cancer have entirely transformed in the 
last 15 years and now comprise molecularly targeted therapies against the vascular endothelial growth factor receptor 
(VEGFR) and the mammalian target of rapamycin (mTOR) as well as immune checkpoint inhibitors. These agents 
may be used alone as monotherapies but increasingly are used in various combinations. The associated important 
improvements in cancer control and survival have therefore been accompanied by a range of new toxicities. Good 
management of these toxicities is important for patient safety and quality of life, and also to optimize patients’ 
opportunity to continue with and therefore benefit from these therapies. The most common toxicities associated 
with VEGFR tyrosine kinase inhibitors are fatigue, skin rashes, gastrointestinal, stomatitis, hypertension and other 
cardiovascular toxicities, and hematological and endocrine dysfunction. Common side effects of mTOR inhibitors 
include asthenia, stomatitis, skin rashes, pneumonitis, metabolic changes and infections. Checkpoint inhibitors 
can lead to toxicities of any organ system with those seen most frequently including dermatologic, gastrointestinal 
and hepatic, endocrine, musculoskeletal, and pulmonary, whilst renal, hematological, ophthalmic, cardiac and 
neurological toxicities are seen less often. In general terms, toxicity management should start preemptively with 
patient education and may also include a combination of supportive approaches, dose reduction, schedule alteration, 
treatment interruption and occasionally treatment cessation. Treatment of individual toxicities is dependent on the 
likely causative agent and is guided by its grade or severity. Specific recommendations for management are discussed 
in this chapter.

Introduction

Since the mid-2000s, the introduction of new systemic therapies has transformed the management of renal cell 
carcinoma (RCC). Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs), 
mammalian target of rapamycin (mTOR) inhibitors (mTORIs), and most recently immune checkpoint inhibitors 
(CPIs) have led to dramatically improved outcomes in advanced disease. In the past 5 years, several studies have 
demonstrated improved survival for the combination of CPIs and TKIs or the combination of the 2 CPI agents 
nivolumab and ipilimumab compared to first-line therapy with single-agent TKIs, and these combinations are now 
established as standard of care[1–4]. The CPI pembrolizumab is also now approved as adjuvant therapy following 

484SIUJ.ORG SIUJ  •  Volume 3, Number 6  •  November 2022

2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES

https://orcid.org/0000-0002-9500-2046
https://orcid.org/0000-0002-9568-8164
https://orcid.org/0000-0002-0192-5828
https://orcid.org/0000-0002-2567-2749
https://orcid.org/0000-0002-7579-340X
http://SIUJ.org


resection of high-risk localized disease, or following 
nephrectomy and full resection of all metastatic 
lesions[5]. However, alongside their beneficial effects, 
these agents can cause a range of toxicities. Optimal 
management of such side effects is required to ensure 
safe treatment, manageable quality of life, and optimal 
drug delivery.

General Principles of RCC Toxicity 
Management
Prior to initiating systemic therapy for RCC, the patient’s 
current fitness, medical history and comorbidities, 
and concurrent medications should be considered. 
This allows for identification of patients at greater risk 
for toxicity and can trigger targeted pretreatment 
investigations, such as evaluation of cardiac, endocrine, 
gastrointestinal, or respiratory status. It may also 
highlight use of cy tochrome P450 3A4 (CYP3A4) 
enzyme inducers or inhibitors that will interact with the 
planned RCC treatment[6].

When toxicities arise, they should be graded accord-
ing to the Common Terminology Criteria for Adverse 
Events (CTCAE)[7] in conjunction with guidelines for 
immune-related adverse events (irAEs) to help select 
optimal management strategies. These include treat-
ment interruption, dose or schedule modification, or 
occasionally treatment cessation, each of which has a 
role to play according to the severity or “grade” of the 
toxicity. Early recognition and intervention aids opti-
mal management of treatment-related adverse events 
(TRAEs). Support and education for patients, general 
physicians, and oncologists therefore minimizes the 
risks associated with these treatments. This is particu-
larly important in the first few months after treatment 
initiation, but ongoing vigilance is required throughout, 
especially for CPI-induced toxicities, which can emerge 
late into, or even after, treatment.

Toxicity of VEGFR TKIs
VEGFR TK Is including a x it inib, caboza nt inib, 
lenvatinib, pazopanib, sorafenib, sunitinib, and 
tivozanib are highly effective treatments for advanced 
RCC, with approvals by the United States Food and 
Drug Administration (FDA) both as single agents and in 
combination with CPIs or mTOR inhibitors. Collectively, 
these agents have led to a marked improvement in 
sur vival compared with the “pre-TKI” era[8–14]. 
VEGFR TKIs have varying potency and selectivity for 
VEGFRs and other tyrosine kinase receptors including 
platelet-derived growth factor receptor (PDGF), MET, 
and c-KIT, which contributes to differences in their 
toxicity and clinical profiles. Most patients experience 
some side effects, with TRAE rates for all-grade toxicity 
> 98% in the registration clinical trials and grade ≥3 
toxicity in 10% to 15% of patients. Dose interruptions 
were reported in 19% to 40% of patients, dose reductions 
in 14% to 46%, and treatment discontinuation in 4% to 
21%. The most common TRAEs reported in registration 
trials are skin, gastrointestinal, stomatitis, hypertension, 
hematological abnormalities, fatigue, and endocrine 
dysfunction (Table 1). 

Management of VEGFR TKI–Associated 
Toxicities
General principles of managing VEGFR TKI–induced 
toxicities involve supportive interventions, treatment 
interruption, dose reduction and, particularly with 
sunitinib, schedule modification, with occasional 
treatment discontinuation. Grade 1 and 2 toxicities can 
often be managed with supportive approaches in the 
first instance but may benefit from temporary treatment 
interruption. For treatment-related toxicities grade ≥ 3, 
treatment interruption is usually required, other than 
for some laboratory abnormalities. Subsequent dose 
reduction or schedule modification may be needed.

Most VEGFR TKIs are administered on a continu-
ous dosing schedule. Sunitinib, however, is routinely 
administered on a dosing schedule that incorporates 
treatment-free periods: its approved starting dose 
and schedule is 50 mg daily for 4 weeks followed by a 
2-week treatment break (4/2). Several nonrandomized 
studies[15–17] and the prospective SURF study[18] have 
shown that the alternate schedule of 2 weeks continu-
ous dosing followed by a 1-week treatment break (2/1) 
reduces toxicity with no apparent compromise to effi-
cacy. This schedule is not recommended at initiation 
of sunitinib but can be a useful switch option for ther-
apy management. In selected cases in clinical practice, 
similar dosing regimens or "drug holidays” can be used 
for the management of toxicity associated with other 
VEGFR TKIs[19,20].

Recognized guidelines for VEGFR TKI–driven toxic-
ities should be followed where available. However, unlike 

Abbreviations 
CPI immune checkpoint inhibitor
CTCAE Common Terminology Criteria for Adverse Event
CTLA-4cytotoxic T-lymphocyte antigen 4
irAE immune-related adverse event
mRCC metastatic renal cell carcinoma
mTOR mammalian target of rapamycin
mTORI mammalian target of rapamycin inhibitor
PD-1 programmed cell death 1 receptor
RCC renal cell carcinoma
TRAE treatment-related adverse event
VEGFR vascular endothelial growth factor receptor

485 SIUJ  •  Volume 3, Number 6  •  November 2022 SIUJ.ORG

2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES

http://SIUJ.org


TABLE 1. 

Safety outcomes reported in pivotal clinical trials of vascular endothelial growth factor receptor tyrosine kinase 
inhibitors in metastatic renal cell carcinoma 

Sunitinib
first line 

 
NCT00083889 

n = 375 
17215529[13]

Pazopanib
first or 

second line, 
NCT00334282 

n = 290 
20100962[11]

Tivozanib
first or  

second line 
NCT01030783 

n = 260 
24019545[12]

Cabozantinib
first line 

 
NCT01835158  

n = 78 
28199818[10]

Axitinib
first line 

 
NCT00835978  

n = 192 
NCT00920816[19]

Lenvatinib
second line 

 
NCT01136733 

n = 52 
26482279[9]

TRAE leading to 
discontinuation in %

8 NR 4 21 4

Death due to TRAE 
— n (%)

NR 4 (1) NR 3 (4) None

Adverse event in % All
Grade 

3/4
All

Grade 
3/4

All
Grade 

3/4
All

Grade 
3/4

All
Grade 

3/4
All

Grade  
3/4

Diarrhea 53 5 52 4 23 2 72 10 50 9 71 12

Fatigue 51 7 19 2 19 5 86 6 33 5 50 8

Nausea 44 3 26 < 1 12 < 1 32 3 20 1 62 8

Stomatitis 25 1 – – 11 < 1 36 5 – – 25 2

Hypertension 24 8 40 4 44 27 81 28 49 13 48 17

Vomiting 24 4 21 2 – – – – – – 38 4

Hand-foot syndrome 20 5 – – 14 2 42 8 26 7 15 0

Anorexia – – 22 2 18 3 47 5 – – 48 6

Back pain – – – – 14 3 – – 21 0

Decreased appetite – – – – 10 < 1 – – 29 2 58 4

Lower respiratory tract 
infection

– – – – – – – – – – 8 8

Laboratory abnormality

Neutropenia 72 11 34 1 11 2 15 0 – – – –

Thrombocytopenia 65 8 32 1 18 < 1 40 1 – – – –

Lymphopenia 60 12 31 4 – – – – – – – –

Leukopenia 60 5 0 0 – – 12 0 – – – –

AST increase 52 2 53 8 37 2 62 3 – – – –

Increased lipase 52 13 – – 46 11 – – – – – –

ALT increase 46 3 53 12 28 1 55 5 – – – –

Hyponatremia – – 31 5 – – – – – – –

Proteinuria 3 – – – 72 3 – – – – 31 19

Hypothyroidism – – – – – – – – – – 37 2

All adverse events grade 3 or worse that occurred in at least 5% of patients in one of the trials are reported. 
ALT: alanine transaminase; AST: aspartate transaminase; NR: not reported in cited publication; TRAE: treatment-related adverse event. 

486SIUJ.ORG SIUJ  •  Volume 3, Number 6  •  November 2022

Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma

http://SIUJ.org


for toxicities associated with immune CPIs, there are 
no regularly updated consensus guidelines, and recom-
mendations are primarily derived from clinical exper-
tise. Practical recommendations for common VEGFR 
TKI–associated toxicities are summarized in Table 2.  
A related and important point concerns hypertension 
as a potential biomarker for efficacy, best demonstrated 
with axitinib. It has been shown that blood pressure rise 
is somewhat correlated with axitinib serum concentra-
tion and that correct axitinib dose titration, including 

dose increase according to its approval, is associated 
with improved response to treatment[19].

Toxicity of mTOR Inhibitors 
The mTORIs temsirolimus and everolimus are usually 
well tolerated, with low rates of grade 3 and 4 adverse 
events[21–24]. Common side effects include asthenia, 
stomatitis, skin rashes, pulmonary toxicity, metabolic 
changes particularly hyperglycemia and hyperlipidemia, 

TABLE 2. 

Management recommendations for key toxicities associated with VEGFR tyrosine kinase inhibitors 

Toxicity Management recommendations

Hypertension

Almost all patients commencing these medications experience a dose-dependent elevation in blood pressure. 
Pretreatment evaluation and treatment of blood pressure and cardiovascular risk essential as treatment-related 
reduction in LVEF correlates with baseline risk. 
Blood pressure should be monitored regularly with initiation of antihypertensive therapy ≥140/90 mmHg  
according to clinical practice guidelines. Nondihydropyridine calcium-channel blockers that inhibit CPY3A4 
(verapamil, diltiazem) should be avoided[25].

Fatigue

Fatigue is common and often multifactorial. Monitoring for and treatment of anemia, hypothyroidism, cardiac 
dysfunction, diarrhea, hypophosphatemia, and low testosterone levels in males can be of help. Dose reduction  
may be required if fatigue persists despite correcting these factors. Aerobic exercise reduces fatigue in fit 
patients. 

Diarrhea
Dietary adjustment (BRAT diet: bananas rice, applesauce, toast) and increase in fluid intake. 
Loperamide or pancreatic enzyme supplementation can also be considered in specific cases.

Diarrhea / Emerging data

Probiotics have been shown to reduce the severity of chemotherapy-induced diarrhea; however; have not 
specifically been evaluated in TKI-induced diarrhea[25]. 
Fecal microbiota transplantation has recently shown promising results for the treatment of TKI-induced 
diarrhea[27].

Hand-foot syndrome

Preventative advice includes avoiding unnecessary friction/removing hyperkeratosis prior to treatment and 
avoiding excessively hot water. 
For erythema (grade 1), recommend self-care plus moisturizing creams and 20% to 40% urea creams. 
Pain (grade 2) requires dose interruption/modification with addition of clobetasol 0.05% ointment/topical or 
systemic analgesia as required[28]. Other dermatologic effects including skin and hair color changes are  
relatively common, thus patients should be counseled accordingly.

Stomatitis Stomatitis may result in a significant reduction in food intake and QOL.

Good oral hygiene.
Oral rinses (saline, sodium bicarbonate, or nonalcoholic mouthwash) can be used for mucosal erythema (grade 1). 
For grade ≥ 2 mucositis requiring dose interruption/modification; topical anesthetics, mucosal coating agents,  
and/or benzydamine HCl may be administered as needed for pain[29]

Hypothyroidism
TSH should be measured at baseline and monitored during treatment at least every 3 cycles. Replacement with 
thyroxine should be considered for patients with TSH above 10 IU/mL[30] 

LVEF: left ventricular ejection fraction; QOL: quality of life; TSH: thyroxine stimulating hormone; VEGFR: vascular endothelial growth factor receptor.

487 SIUJ  •  Volume 3, Number 6  •  November 2022 SIUJ.ORG

2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES

http://SIUJ.org


and infections[31]. As for VEGFR TKI–related toxicities, 
the general principles of managing the side effects from 
mTORIs are to consider treatment interruption, dose 
reduction, and use of supportive therapies, as well as 
treatment cessation for grade 3 and 4 toxicities[32].  
Key recommendations are summarized in Table 3.

Toxicity of Immune Checkpoint Inhibitors
Immune CPIs are a well-established component of 
treatment for advanced renal cell carcinoma and now 
are also approved in the adjuvant setting[2,5,33,34]. 
While CPIs are well tolerated by many patients, immune 
checkpoint blockade is associated with a unique 
collection of irAEs. These irAEs behave differently 
than the more predictable toxicities oncologists are 

accustomed to managing with chemotherapy or targeted 
therapies, occurring any time between initiation of 
treatment to many months after treatment cessation.

Mechanism, Spectrum, and Frequency  
of CPI-Associated Toxicities
Mechanisms of Immune-Related Adverse Events
The exact mechanisms responsible for the development 
of irAEs are not fully understood. The immune 
checkpoint proteins cytotoxic T-lymphocyte antigen 4 
(CTLA-4) and programmed cell death 1 receptor (PD-1) 
play important roles in immune homeostasis and self-
tolerance, acting to suppress T-cell function. CTLA-4 
signaling reduces T-cell proliferation early in the 
immune response, and PD-1 signaling inhibits activated 

TABLE 3. 

Management recommendations for key toxicities of mTOR inhibitors 

Toxicity Management recommendations

Stomatitis

One of the most common TRAEs, presenting with an aphthous stomatitis different from cytotoxic induced 
mucositis[35,36]. 
Grade 1: Modified diet and alcohol-free mouthwash may alleviate symptoms. 
Grade ≥ 2: Treatment should be interrupted and can be restarted at full (grade 2) or reduced (grade 3) dose. 
Grade 4: Treatment should be discontinued permanently in most cases. 
Investigation to rule out herpes and fungal infection may be helpful[37].

Skin rash

Usually papulopustular/maculopapular, can be pruritic. Avoid heavy sun exposure. 
Grade 1 (covering < 10% BSA) and grade 2 (covering > 10% to < 30% BSA) toxicity can be managed with topical 
moisturizers and steroids. 
Grade 3 toxicity (covering > 30% BSA) may require dose interruption and treatment with low-dose systemic 
steroids (eg, 10–20 mg prednisolone).

Noninfectious pneumonitis

Characterized by noninfectious, nonmalignant pulmonary inflammatory infiltrates[21,38]. If preexisting pulmonal 
morbidity, consider baseline LuFT. 
Grade 1 (radiological findings only): Clinical follow-up sufficient. 
Grade 2 (cough, SOB, no oxygen requirement): Workup for other causes of symptoms including chest imaging. 
Grade 3 (interference with ADL or oxygen requirement): Interrupt treatment and start steroids (prednisolone 
0.75–1 mg/kg). Treatment can be restarted with a reduced dose. 
Grade 4 (life-threatening pneumonitis): Start treatment with intravenous steroids  
(eg, methylprednisolone 2–5 mg/kg). Discontinue treatment permanently. Workup including BAL is recommended.

Endocrine: Hyperglycemia

Hyperlipidemia

Hypophosphatemia

Common, educate patients regarding symptoms of hyperglycemia, measure and correct according to standard 
guidelines[39–41]. 
Grade 2 and 3 hyperglycemia (glucose > 8.9 mmol/L): Treat according to guidelines, focus on avoiding symptomatic 
hyper- and hypoglycemia.

Infections
Increased risk (candidiasis, pneumonia, invasive fungal infections, and infection reactivation). If high risk, hepatitis 
and HIV serology and prior TB exposure should be checked and active infection treated.

ADLs: activities of daily living; BAL: bronchoalveolar lavage; BSA: body surface area; LuFT: lung function test; mTOR: mammalian target of rapamycin; 
SOB: shortness of breath; TRAEs: treatment-related adverse events.

488SIUJ.ORG SIUJ  •  Volume 3, Number 6  •  November 2022

Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma

http://SIUJ.org


T cells in peripheral tissues[42]. While inhibiting these 
pathways enables the immune system to recognize 
and attack the patient’s cancer, inf lammation of 
normal tissues through the production of cytokines, 
autoreactive T cells, and autoantibodies may occur, 
resulting in irAEs[43,44].

Range of Immune-Related Adverse Events
The spectrum of irAEs experienced depends on whether 
the CPI is used in combination or alone and according 
to the malignancy being treated, alongside yet poorly 
understood host factors such as an individual’s genetics, 
epigenetics, and microbiome. Overall, dermatological, 
gastrointestinal, endocrinological, musculoskeletal, 
and pu lmonar y irAEs are more common, w it h 
renal, hematological, ophthalmological, cardiac, and 
neurological irAEs seen more rarely[45,46]. IrAEs have 
a variable and wide range of onset, although typically 
dermatitis and colitis present early, followed by hepatitis 
and endocrinopathies, with pneumonitis and nephritis 
presenting later[47,48]. Fatal irAEs are fortunately rare, 
with reported rates ranging from 0.36% with anti–PD-1 
antibodies to 1.23% in combination with CTLA4[49]. 
Given the increasing use of CPIs in the treatment of solid 
cancers in general, and in renal cancer in particular, an 
absolute increase in irAEs and also the occurrence of 
rare irAEs are to be expected in these patients[50]. The 
frequency and severity of irAEs do not appear to be 
dose-dependent and there is no role for dose reduction 
following CPI toxicity.

Immune-Related Adverse Events in RCC
Landmark clinical trials demonstrate that small 
percentages of patients experience grade 3 or 4 toxicities, 
with overall benefits for health-related quality of 
life[51-53] (Table 4). Check Mate 025 investigated 
nivolumab versus everolimus as second- or subsequent-
line treatment in patients with advanced RCC[33], 
Check Mate 214 investigated the combination of 
nivolumab and ipilimumab versus sunitinib in the first-
line treatment of patients with advanced RCC[2], and 
KEYNOTE-564 investigated adjuvant pembrolizumab 
versus placebo following nephrectomy[2]. TR AEs 
leading to discontinuation of CPI occurred in between 
8% to 22% of patients in these trials, as outlined in 
Table 4.

Management of CPI-Associated Toxicities
General Principles for Management of Immune-
Related Adverse Events
The management of irAEs in patients with RCC is the 
same as in other solid tumors, and detailed guidelines 
are available from European Society for Medical 
Oncolog y (ESMO), American Society of Clinical 
Oncology (ASCO), Society for Immunotherapy of 

Cancer (SITC), and the National Comprehensive Cancer 
Network (NCCN)[46,54-56]. The guidelines have been 
developed based on consensus opinion from specialist 
physicians and oncologists, are regularly updated, 
and are strongly recommended to guide management 
of specific toxicities. The overarching principle of 
management is to control the inflammation that has 
precipitated the irAE. Management is directed by 
the severity of the irAE and typically involves prompt 
immunosuppression with corticosteroids, treatment 
interruption, with hospita lization and specia list 
management in more serious cases.

Corticosteroids and Corticosteroid-Sparing Agents 
in Immune-Related Adverse Events
In general, for CTCAE grade 1 irAEs, corticosteroids are 
not required, and immunotherapy may be continued[46]. 
For grade 2 irAEs, oral prednisone (or equivalent) may 
be considered, starting at 0.5–1 mg/kg daily, increasing 
to 2 mg/kg daily if required. For grade ≥3 irAEs, oral 
prednisone at 1–2 mg/kg daily, or equivalent intravenous 
methylprednisolone, is commenced. Immunotherapy is 
paused until the irAE has resolved to grade 1 or less and 
steroids have been weaned, usually over 4 to 6 weeks. 
In severe or refractory cases, or where steroid sparing 
is desirable, other immunomodulatory agents may be 
considered. These agents may have specific immune 
targets such as TNFα (infliximab), IL-6 (tocilizumab), 
or α4 integrin (vedolizumab), or be nonselective, such as 
mycophenolate mofetil[57]. In such cases, liaising with 
specialist physicians is of paramount importance.

Restarting immunotherapy treatment may be consid-
ered on a case-by-case basis after a grade 3 irAE, but 
immunotherapy is discontinued after grade 4 irAEs. 
Most irAEs are reversible with steroid treatment, but 
endocrinopathies, especially hypothyroidism and diabe-
tes, may require lifelong hormone replacement, although 
these rarely require steroid treatment[58,59].

RCC Outcomes in Patients Who Experience 
Immune-Related Adverse Events
Although the development of irAEs is not required 
to benefit from CPI, there are some data, including in 
RCC, to suggest that patients who experience irAEs have 
better outcomes, particularly with anti–PD-1 and anti–
PD-L1 treatment[60-65]. High-dose steroid treatment 
is not thought to impact outcomes negatively, although 
there are conf licting reports in the literature, and 
patients receiving high-dose corticosteroids at baseline 
do appear to experience inferior outcomes[43,61] 
Immunosuppression with steroids may be associated 
with side effects including hyperglycemia, weight 
gain, hypertension, edema, gastritis, anxiety, adrenal 
insufficiency, osteoporosis, glaucoma, proximal muscle 
weakness, and opportunistic infections[43]. Supportive 

489 SIUJ  •  Volume 3, Number 6  •  November 2022 SIUJ.ORG

2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES

http://SIUJ.org


TABLE 4. 

Safety outcomes reported in pivotal registration clinical trials of immune checkpoint inhibitors in renal cell carcinoma 

Nivolumab mRCC, 
second or later line,  

CheckMate 025, 
NCT01668784 

n = 406[33]

Nivolumab & ipilimumab 
mRCC, first line, 
CheckMate 214, 
NCT02231749, 
n = 547[2,52]

Pembrolizumab 
adjuvant setting, 
KEYNOTE-564, 
NCT03142334 

n = 488[5]

TRAE leading to 
discontinuation in %

8 22 21

Death due to TRAE— 
n (%)

None 8 (1) 2 (< 1)

Toxicity in % All Grade 3/4 All Grade 3/4 All Grade 3/4

Any 79 19 93 46 79 19

Fatigue 33 2 37 4 30 1

Pruritis 14 0 28 < 1 23 < 1

Nausea 14 < 1 20 1 16 < 1

Diarrhea 12 1 27 4 25 2

Reduced appetite 12 < 1 14 1 - -

Rash 10 < 1 22 1 20 1

Cough 9 0  –* – 16 0

Dyspnea 7 1 –  –* – –

Pneumonitis 4 1 –  –* – –

Hypothyroidism – – 16 < 1 21 < 1

Asthenia – – 13 1 10 < 1

Vomiting – – 11 < 1 – –

Arthralgia – – – – 22 < 1

Headache – – – – 14 0

Hyperthyroidism – – – – 12 < 1

Increased creatinine – – – – 10 < 1

*While cough, dyspnea, and pneumonitis were not reported, in the combination arm of the CheckMate 214 study, 1 patient died from pneumonitis,  
1 with pneumonia, 1 with immune-mediated bronchitis, and 1 with lung infection. 
mRCC: metastatic renal cell carcinoma; NR: not reported in paper; TRAE: treatment-related adverse event.

490SIUJ.ORG SIUJ  •  Volume 3, Number 6  •  November 2022

Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma

http://SIUJ.org


therapies must therefore be considered for all patients 
on steroids, including gastric protection, calcium and 
vitamin D, and pneumocystis pneumonia prophylaxis, 
particularly for patients requiring a longer course.

Toxicities of Combination VEGFR TKI/CPI 
Regimens
Regimens that combine a VEGFR TKI with a CPI 
have become a standard of care in first-line therapy 
of advanced RCC due to improved cancer outcomes 
c omp a re d  w it h  T K I  monot her apy[1,4 , 6 6 , 6 8]. 
Collectively, these regimens are regarded as having 
acceptable safety profiles with manageable toxicity. 
Given the impressive cancer control conferred by these 
regimens, patients are often on treatment for many 
months or years, thus good toxicity management is of 
great importance for durable good quality of life.

Spectrum and Frequency of Toxicities with 
TKI/CPI Combination Regimens
T he reg ist r at ion t r ia ls of approved T K I /CPI 
combinations have repor ted a variet y of safet y 
endpoints and toxicities, each compared with sunitinib 
monotherapy. Although there are differences across 
both the trial populations and the toxicity measures 
reported, the data illustrate the acceptable tolerability of 
each of the regimens in trial populations (Table 5).

The rate of of grade ≥3 TRAEs reported with the TKI/
CPI combinations in registration studies was 57% to 72% 
(compared with 51% to 59% for the comparator suni-
tinib in these trials). Across all trials, the most frequently 
occurring TRAEs were consistently hypertension, raised 
transaminases, and diarrhea. Discontinuation of at least 
one of the agents due to TRAEs occurred in 15% to 37% 
of patients and discontinuation of both in 3% to 13%.

Management of Toxicities Associated with 
TKI/CPI Combination Regimens
Optimal management of the toxicities from TKI/CPI 
combination regimens requires appreciation of the 
expected range of side effects of each agent. However, 
there is additional complexity because some toxicities 
may be caused by both TKIs and CPIs. This requires an 
approach for identifying the more likely cause.

The common and serious toxicities resulting from 
VEGFR TKIs and CPIs are described above. Toxicity 
caused by VEGFR TKIs most commonly manifests 
in the first few weeks following treatment initiation, 
whereas toxicities caused by immune CPIs can start 
acutely or many months into treatment. However, there 
is considerable variation at the individual patient level, 
and the toxicity profiles do overlap considerably, there-
fore despite best efforts, reliable attribution can be chal-
lenging. Points to consider include:

1. VEGFR TKIs have considerably shorter half-lives 
than CPIs. Axitinib has the shortest half-life at 2.5–6 
hours, those of lenvatinib and cabozantinib are 28 
hours and 100–120 hours, respectively. The half-lives 
of both pembrolizumab and nivolumab are around 
26 days. Thus, VEGFR TKI–driven toxicity, espe-
cially from axitinib, typically starts to improve within 
a few days of treatment interruption, including when 
used in an axitinib plus CPI combination[69].

2. In some cases, directed investigation may help to 
differentiate the cause, assess impact and sever-
ity, and guide management such as sigmoidoscopy 
and biopsy for evaluation of colitis; assessment of 
the pituitary fossa by magnetic resonance imaging 
(MRI) for hypophysitis; and cardiac MRI to identify 
immune-mediated myocarditis.

Toxicities should be managed in accordance with the 
strategies described earlier in this article, including 
treatment interruption, dose reduction (for TKIs but not 
CPIs), and treatment discontinuation when indicated. 
As a general principle, grade 1 and 2 toxicities may not 
require any intervention other than supportive therapies 
and monitoring. Grade 3 and higher toxicities usually 
require at least temporary treatment interruption. When 
treatment interruption of a TKI/CPI regimen is required 
and there is uncertainty about the cause, the following 
pragmatic approach is suggested:

• First stop the TKI. Improvement in toxicity should be 
seen within a few days if the toxicity is TKI related.

• If there is no improvement after 5 to 7 days, or less 
for axitinib, interruption of the CPI and initiation of 
steroids should be considered following a recognized 
irAE guideline.

• Consider immediate interruption of both agents for 
severe, clinically significant toxicities.

• Continue to use appropriate supportive measures 
according to the toxicity.

• Ongoing regular assessment is required until improve-
ment or resolution with vigilance for reemergence 
during steroid wean or following further treatment.

Toxicities of Novel Therapeutic 
Approaches
Ongoing clinical trials are investigating new agents 
and combinations that will require attention to their 
tolerability and emergent toxicities. COSMIC-313 
(NCT03937219) is a fully recruited, randomized trial 
assessing the triplet combination of cabozantinib 
plus ipilimumab and nivolumab in 840 patients with 
intermediate- and poor-risk advanced RCC[70]. While 
there should be scrutiny of the tolerability of this 
triplet regimen, it has been successfully delivered in 

491 SIUJ  •  Volume 3, Number 6  •  November 2022 SIUJ.ORG

2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES

http://SIUJ.org


a pan-genitourinary phase 1B trial with acceptable 
tolerability[71].

The hy poxia-inducible factor (HIF)-2α inhibitor 
belzutifan was approved by the FDA in 2021 for the 
treatment of von Hippel-Lindau (VHL)-associated 
metastatic renal cell carcinoma (mRCC)[72], and its 
role in sporadic mRCC is being evaluated in a phase 3 
trial after promising initial results (NCT04195750)[73]. 
Belzutifan is relatively well tolerated, although grade ≥ 3 
AEs were reported in 25% of patients and included grade 
≥ 3 anemia (related to inhibition of the erythropoietin 
gene) a nd hy pox ia , t hu s mon itor i ng for a nd 
management of these toxicities is essential[72] including 
blood transfusion and/or the use of erythropoietin-
stimulating agents[74].

Patient Selection and Toxicity Prediction
Good patient selection is an important tool in ensuring 
the optima l ba lance of eff icacy with acceptable 
toxicity and quality of life. The toxicities associated 
with treatment of RCC are not insignificant, leading 
to discontinuation of VEGFR TKI therapy in 12% to 
24%[75,76], combination nivolumab plus ipilimumab 
in 22%[2,52], and TKI/CPI combinations in 6% 
to11%[1,4,66,68]. Therefore, understanding predictors 
of toxicity is an important focus of research. Most 
research in this field to date has evaluated clinical and 
genomic predictors of toxicity to VEGFR TKI therapy 
with low body surface area, older age, and female 
gender identified as possible clinical predictors[77]. 
Several studies have focused on the role of single-
nucleotide polymorphisms (SNPs) in genes related to 
pharmacodynamic properties of VEGFR TKIs[78–80]. 
While research has not yet yielded practice-influencing 
results, it is hoped that large collaborative projects such 
as the EuroTARGET cohort[81], incorporating analysis 
of genomic, transcriptomic, and clinical parameters, 
will produce clinically useful information.

Currently, there are no defined biomarkers that 
predict toxicity to immune CPIs, although it is appar-
ent that some patients are at greater risk of experienc-
ing irAEs[45,49]. Historically, patients thought to be 
at higher risk for irAEs have been excluded from clini-
cal trials, so data are lacking, but as real-world experi-
ence grows, multidisciplinary strategies for managing 
such patients are evolving. Patients with chronic viral 

infections such as hepatitis and HIV, mild-to-moderate 
organ dysfunction, autoimmune disease, and even trans-
plant recipients have been successfully treated with CPIs 
in some circumstances, although a personalized discus-
sion regarding potential risks and benefits is import-
ant[60]. There is growing interest in the role of the gut 
microbiome in modulating both the efficacy and toxic-
ity of CPI therapy. In patients with advanced melanoma 
who received ipilimumab plus nivolumab, enrichment 
with Bacteroides intestinalis and Intestinibacter bartlet-
tii was seen in patients who developed grade ≥3 adverse 
events versus those who did not[82]. Investigation of this 
field continues, including in mRCC.

In the future, as doublet, and potentially triplet, 
combination regimens are increasingly used, effective 
strategies to manage toxicity will be needed to transfer 
clinical trial regimens to more diverse real-world patient 
populations. Genomic approaches may offer the possi-
bility of refining treatment selection for patients accord-
ing to expected toxicity profiles. However, at present, 
there are no robust or validated genomic predictors, 
therefore selection is reliant on traditional measures of 
performance status and comorbidities.

Summary
Toxicity management is an essential component 
of effective cancer control. In the past 15 years, 
considerable experience has been gained in the 
management of the side effects of molecularly targeted 
therapies, with strategies including dose modification, 
schedule modification, switching between agents, 
and use of supportive therapies. Immune checkpoint 
inhibitors are also now used widely in treatment of 
mRCC. This advance has necessitated RCC oncologists 
to develop an understanding of a new range of toxicities 
and become familiar with new strategies and algorithms 
that have evolved to manage irAEs, including use of 
corticosteroids and steroid-sparing agents, as well as 
increasing involvement of other organ- or system-
specific specialists. Combination regimens of CPIs and 
VEGFR TKIs are now increasingly used, but careful 
management can balance treatment delivery with 
tolerable side effects. It is hoped that ongoing research 
will identify robust means of prospectively identifying 
those at increased risk for treatment-related toxicities 
to allow for improved therapy selection at an individual 
level.

492SIUJ.ORG SIUJ  •  Volume 3, Number 6  •  November 2022

Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma

http://SIUJ.org


TABLE 5. 

Safety outcomes reported in pivotal clinical trials for the combinations of tyrosine kinase inhibitors and immune 
checkpoint inhibitors in first line metastatic renal cell carcinoma and occurred in at least 15% of patients who  
received the VEGFR TKI / CPI combination 

Axitinib + 
pembrolizumab 

First line, KEYNOTE-426, 
NCT02853331, 

n = 429[4]

Axitinib + 
avelumab 

First line, JAVELIN 
Renal-101, NCT02684006, 

n = 442[67]

Cabozantinib + 
nivolumab 

First line, CheckMate 9ER, 
NCT03141177 

n = 322[1]

Lenvatinib + 
pembrolizumab 

First line, 
CLEAR, NCT02811861 

n = 355[3]

Treatment discontinuation  
for TRAE in % 
 Both drugs 
 Either

 
 
8 

26

 
 
8 

NR

 
 
3 
15

 
 

13 
37

Treatment-related 
deaths— n (%)

4 (< 1) 3 (< 1) 1 (< 1) 4 (1)

Toxicity in % All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4

Any 96 63 100 71 100 61 100 82

Diarrhea 54 9 62 7 64 7 61 10

Hypertension 45 22 50 26 35 13 55 30

Fatigue 39 3 42 4 32 3 40 4

Hypothyroidism 35 < 1 25 < 1 34 < 1 47 1

Decreased appetite 30 3 26 2 28 2 40 4

Hand–foot syndrome 28 5 33 6 40 8 29 4

Nausea 29 1 34 1 27 1 36 3

ALT increased 27 13 17 6 28 5 12 4

AST increased 26 7 15 4 25 3 11 3

Dysphonia 25 < 1 31 1 17 < 1 30 0

Cough 21 < 1 23 < 1 17 0 20 0

Constipation 20 0 18 0 12 1 25 1

Arthralgia 18 1 20 1 18 < 1 28 1

Weight decreased 18 3 20 3 11 1 30 8

Proteinuria 18 3 – – 10 3 30 8

Dyspnea 16 2 20 3 – – 15 3

Table 5 shows the safety outcomes that were reported in the referenced pivotal trials and occurred in at least 15% of patients who received the VEGFR 
TKI / CPI combination. ALT: alanine transaminase; AST: aspartate transaminase; CPI: immune checkpoint inhibitor; TRAE: treatment-related adverse 
event; VEGFR TKI: vascular endothelial growth factor receptor tyrosine kinase inhibitor.

continued on page 494

493 SIUJ  •  Volume 3, Number 6  •  November 2022 SIUJ.ORG

2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES

http://SIUJ.org


TABLE 5. 

Safety outcomes reported in pivotal clinical trials for the combinations of tyrosine kinase inhibitors and immune 
checkpoint inhibitors in first line metastatic renal cell carcinoma and occurred in at least 15% of patients who  
received the VEGFR TKI / CPI combination 

Axitinib + 
pembrolizumab 

First line, KEYNOTE-426, 
NCT02853331, 

n = 429[4]

Axitinib + 
avelumab 

First line, JAVELIN 
Renal-101, NCT02684006, 

n = 442[67]

Cabozantinib + 
nivolumab 

First line, CheckMate 9ER, 
NCT03141177 

n = 322[1]

Lenvatinib + 
pembrolizumab 

First line, 
CLEAR, NCT02811861 

n = 355[3]

Treatment discontinuation  
for TRAE in % 
 Both drugs 
 Either

 
 
8 

26

 
 
8 

NR

 
 
3 
15

 
 

13 
37

Treatment-related 
deaths— n (%)

4 (< 1) 3 (< 1) 1 (< 1) 4 (1)

Toxicity in % All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4

Stomatitis 16 1 24 2 17 3 35 2

Headache 16 1 21 < 1 16 0 23 1

Vomiting 15 < 1 18 1 17 2 26 3

Asthenia 15 3 15 3 22 < 1 22 5

Pruritis 15 < 1 14 0 19 < 1 17 < 1

Rash 14 < 1 14 1 22 2 27 4

Back pain 13 1 18 1 18 2 17 1

Mucosal inflammation 13 1 14 1 21 1 – –

Pyrexia 13 0 13 0 12 1 15 1

Abdominal pain 11 1 14 1 16 2 2 2

Dysgeusia 11 < 1 13 0 24 0 12 < 1

Increased lipase – – – – 17 6 18 13

Hyponatremia – – – – 16 9 – –

Increased amylase – – – – 15 3 18 9

Table 5 shows the safety outcomes that were reported in the referenced pivotal trials and occurred in at least 15% of patients who received the VEGFR 
TKI / CPI combination. ALT: alanine transaminase; AST: aspartate transaminase; CPI: immune checkpoint inhibitor; TRAE: treatment-related adverse 
event; VEGFR TKI: vascular endothelial growth factor receptor tyrosine kinase inhibitor.

, Cont'd 

494SIUJ.ORG SIUJ  •  Volume 3, Number 6  •  November 2022

Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma

http://SIUJ.org


References

3. Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski 
B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced 
renal-cell carcinoma. N Engl J Med.2021 Mar 4;384(9):829–841.

4. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar 
B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus sunitinib 
in advanced renal-cell carcinoma. N Engl J Med.2018 Apr 
5;378(14):1277–1290.

5. Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. 
Lenvatinib plus pembrolizumab or everolimus for advanced renal cell 
carcinoma. N Engl J Med.2021 Apr 8;384(14):1289–1300.

6. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. 
Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell 
carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116–1127.

7. Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, et 
al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. 
N Engl J Med.2021;385(8):683–694. doi: 10.1056/NEJMoa2106391

8. Shao J, Markowitz JS, Bei D, An G. Enzyme- and transporter-mediated 
drug interactions with small molecule tyrosine kinase inhibitors. J 
Pharm Sci.2014 Dec;103(12):3810–3833.

9. Cancer Institute N. Common terminology criteria for adverse events 
(CTCAE) v5.0. 2017. Available at: https://www.meddra.org/. Accessed 
February 24, 2022.

10. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, 
et al. Comparative effectiveness of axitinib versus sorafenib 
in advanced renal cell carcinoma (A XIS): a randomised phase 
3 t r ial. Lan cet . 2 011; 3 7 8 (9 8 0 7) :19 31–19 3 9. doi: 10.1016 /
S0140-6736(11)61613-9

11. Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, 
et al. Lenvatinib, everolimus, and the combination in patients with 
metastatic renal cell carcinoma: a randomised, phase 2, open-label, 
multicentre trial. Lancet Oncol.2015;16(15):1473–1482. doi: 10.1016/
S1470-2045(15)00290-9

12. Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh 
MK, et al. Cabozantinib versus sunitinib as initial targeted therapy for 
patients with metastatic renal cell carcinoma of poor or intermediate 
risk: the alliance A031203 CABOSUN trial. J Clin Oncol.2017 Feb 
20;35(6):591–597.

13. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et 
al. Pazopanib in locally advanced or metastatic renal cell carcinoma: 
results of a randomized phase III trial. J Clin Oncol. 2010 Feb 
20;28(6):1061–1068.

14. Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, et al. 
Tivozanib versus sorafenib as initial targeted therapy for patients with 
metastatic renal cell carcinoma: results from a phase III trial. J Clin 
Oncol.2013 Oct 20;31(30):3791–3799. doi: 10.1200/JCO.2012.47.4940

15. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, 
Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell 
carcinoma. N Engl J Med.2007 Jan 11;356(2):115–124. doi: 10.1056/
NEJMoa065044.

16. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et 
al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J 
Med.2007 Jan 11;356(2):125-34. doi: 10.1056/NEJMoa060655

17. Lee JL, Kim MK, Park I, Ahn JH, Lee DH, Ryoo HM, et al. RandomizEd 
phase II trial of Sunitinib four weeks on and two weeks off versus Two 
weeks on and One week off in metastatic clear-cell type REnal cell 
carcinoma: RESTORE trial. Ann Oncol.2015;26(11):2300-2305. doi: 
10.1093/annonc/mdv357

18. Chen C, Fang H, Jiao Y, Zhou Y, Guo Q, Lv Z. Clinical efficacy and 
complication rate of sunitinib 2/1 versus 4/2 schedule for the 
treatment of metastatic renal cell cancer: a systematic review and 
meta-analysis. Clin Genitourin Cancer.2019 Oct;17(5):319-331. doi: 
10.1016/j.clgc.2019.06.002

19. Deng H, Li M, Wu Q, Wang L, Hong Z, Yi F, et al. A 2/1 sunitinib dosing 
schedule provides superior antitumor effectiveness and less toxicity 
than a 4/2 schedule for metastatic renal cell carcinoma: a systematic 
review and meta-analysis. Front Oncol.2020;10:313. doi: 10.3389/
fonc.2020.00313. eCollection 2020.

20. Thiery-Vuillemin A, Gravis G, Schlürmann F, Bompas E, Rolland 
F, Gross-Goupil M, et al. Randomized phase II study to assess 
the efficacy and tolerability of sunitinib by dose administration 
regimen in anti-angiogenic naïve patients with metastatic renal cell 
carcinoma (mRCC): Final analysis of SURF study. J Clin Oncol.2022 Feb 
20;40(6_suppl):344–344.

21. Rini BI, Melichar B, Ueda T, Grünwald V, Fishman MN, Arranz JA, et al. 
Axitinib with or without dose titration for first-line metastatic renal-cell 
carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol.2013 
Nov ;14(12):1233–1242. doi: 10.1016/S1470-2045(13)70464-9

22. Sternberg CN, Motzer RJ, Hutson TE, Choueiri TK, Kollmannsberger 
C, Bjarnason GA, et al. COMPARZ post hoc analysis: characterizing 
pazopanib responders with advanced renal cell carcinoma. Clin 
Genitourin Cancer.2019 Dec 1;17(6):425-435.e4.

23. Rodriguez-Pascual J, Cheng E, Maroto P, Duran I. Emergent toxicities 
associated with the use of mTOR inhibitors in patients with advanced 
renal carcinoma. Anticancer Drugs.2010 Jun;21(5):478-86. doi: 
10.1097/cad.0b013e32833760bf

24. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et 
al. Temsirolimus, interferon alfa, or both for advanced renal-cell 
carcinoma. N Engl J Med.2007;356(22):2271-2281. doi: 10.1056/
NEJMoa066838

25. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, 
et al. Efficacy of everolimus in advanced renal cell carcinoma: 
a double-blind, randomised, placebo-controlled phase III trial. 
Lancet.2008;372(9637):449-456.doi: 10.1016/S0140-6736(08)61039-9

26. Paluri RK, Sonpavde G, Morgan C, Rojymon J, Mar AH, Gangaraju 
R. Renal toxicity with mammalian target of rapamycin inhibitors: A 
meta-analysis of randomized clinical trials. Oncol Rev.2019;13(2):455. 
doi: 10.4081/oncol.2019.455

495 SIUJ  •  Volume 3, Number 6  •  November 2022 SIUJ.ORG

2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES

http://SIUJ.org


27. Rini BI, Melichar B, Fishman MN, Oya M, Pithavala YK, Chen Y, et 
al. Axitinib dose titration: analyses of exposure, blood pressure and 
clinical response from a randomized phase II study in metastatic 
renal cell carcinoma. Ann Oncol.2015;26(7):1372-1377. doi:10.1093/
ANNONC/MDV103

28. Schmidinger M. Understanding and managing toxicities of vascular 
endothelial growth factor (VEGF) inhibitors. EJC Suppl.2013.11(2):172-
191. doi:10.1016/j.ejcsup.2013.07.016

29. 2Ianiro G, Rossi E, Thomas AM, Schnizari G, Masucci L, Quaranta G, 
et al. Faecal microbiota transplantation for the treatment of diarrhoea 
induced by tyrosine-kinase inhibitors in patients with metastatic 
renal cell carcinoma. Nat Commun.2020;11(1):4333. doi:10.1038/
s41467-020-18127-y

30. Anderson R, Jatoi A, Robert C, Wood LS, Keating KN, Lacouture 
ME. Search for evidence-based approaches for the prevention and 
palliation of hand–foot skin reaction (HFSR) caused by the multikinase 
inhibitors (MKIs). Oncologist.2009;14 (3):291-302. doi:10.1634/
theoncologist.2008-0237

31. Brown TJ, Gupta A. Management of cancer therapy-associated 
oral mucositis. JCO Oncol Pract.2020;16(3):103-109. doi:10.1200/
JOP.19.00652

32. Wolter P, Stefan C, Decallonne B, Dumez H, Bex M, Carmeliet P, et 
al. The clinical implications of sunitinib-induced hypothyroidism: a 
prospective evaluation. Br J Cancer.2008;99(3):448-454. doi:10.1038/
sj.bjc.6604497

33. Soefje SA, Karnad A, Brenner AJ. Common toxicities of mammalian 
target of rapamycin inhibitors. Target Oncol.2011. 6(2):125-9.doi: 
10.1007/s11523-011-0174-9

34. Porta C, Osanto S, Ravaud A, Climent MA, Vaishampayan U, White 
DA, et al. Management of adverse events associated with the use 
of everolimus in patients with advanced renal cell carcinoma. Eur J 
Cancer.2011 Jun;47(9):1287–1298.

35. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, 
Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell 
carcinoma. N Engl J Med.2015 Nov 5;373(19):1803–1813. doi: 10.1056/
NEJMoa1510665

36. Rini BI, Battle D, Figlin RA, George DJ, Hammers H, Hutson T, et al. 
The society for immunotherapy of cancer consensus statement on 
immunotherapy for the treatment of advanced renal cell carcinoma 
(RCC). J Immunother Cancer.2019 Dec 20;7(1):354. doi: 10.1186/
s40425-019-0813-8

37. Grünwald V, Weikert S, Pavel ME, Hörsch D, Lüftner D, Janni W, 
et al. Practical management of everolimus-related toxicities in 
patients with advanced solid tumors. Onkologie.2013;36(5):295-302. 
doi:10.1159/000350625

38. Boers-Doets CB, Epstein JB, Raber-Durlacher JE, Ouwerkerk 
J,Logan RM, Brakenhoff JA, et al. Oral adverse events associated 
with t yrosine kinase and mammalian target of rapamycin 
inhibitors in renal cell carcinoma: a structured literature review. 
Oncologist.2012;17(1):135-144. doi:10.1634/theoncologist.2011-0111

39. Peterson DE, Boers-Doets CB, Bensadoun RJ, Herrstedt J. 
Management of oral and gastrointestinal mucosal injury: ESMO 
Clinical Practice Guidelines for diagnosis, treatment, and follow-up. 
Ann Oncol.2015;26 Suppl 5:v139-151.doi:10.1093/annonc/mdv202

40. Albiges L, Chamming’s F, Duclos B, Stern M, Motzer RJ, Ravaud 
A, et al. Incidence and management of motor inhibitor-associated 
pneumonitis in patients with metastatic renal cell carcinoma. Ann 
Oncol.2012;23(8)1943-1953. doi:10.1093/annonc/mds115

41. American Diabetes Association. Improving care and promoting health 
in populations: standards of medical care in diabetes−2021. Diabetes 
Care. 2021;44(Suppl 1):S7-S14. doi:10.2337/dc21-s001

42. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon 
L, et al. 2019 ESC/ E AS Guidelines for the management of 
dyslipidaemias: ipid modification to reduce cardiovascular risk. Eur 
Heart J.2020;41(1):111-188. doi:10.1093/eurheartj/ehz455

43. Gaasbeek A, Meinders AE. Hypophosphatemia: an update on 
its etiology and treatment. Am J Med.2005;118(10):1094-1101. 
doi:10.1016/J.AMJMED.2005.02.014

44. Chen DS, Mellman I. Elements of cancer immunity and the cancer–
immune set point. Nature.2017 Jan 18;541(7637):321-330. doi: 
10.1038/nature21349

45. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events 
associated with immune checkpoint blockade. N Engl J Med.2018 Jan 
11;378(2):158–168. doi: 10.1056/NEJMra1703481

46. Khan S, Gerber DE. Autoimmunity, checkpoint inhibitor therapy 
and immune-related adverse events: a review. Semin Cancer 
Biol.2020;64:1044–1579. doi.org/10.1016/j.semcancer.2019.06.012

47. Teufel A, Zhan T, Härtel N, Bornschein J, Ebert MP, Schulte N. Mini-
review management of immune related adverse events induced by 
immune checkpoint inhibition. Cancer Lett.2019 Aug 1;456:80-87. doi: 
10.1016/j.canlet.2019.04.018

48. Puzanov I, Diab A, Abdallah K, Bingham CO, Brogdon C, Dadu R, et al. 
Managing toxicities associated with immune checkpoint inhibitors: 
consensus recommendations from the Society for Immunotherapy of 
Cancer (SITC) Toxicity Management Working Group. J Immunother 
Cancer.2017 Nov 21;5(1): doi: 10.1186/s40425-017-0300-z

49. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et 
al. Adverse effects of immune-checkpoint inhibitors: epidemiology, 
management and surveillance. Nat Rev Clin Oncol. 2019 Sep;16(9):563-
580. doi: 10.1038/s41571-019-0218-0 

50. Spain L, Diem S, Larkin J. Management of toxicities of immune 
checkpoint inhibitors. Cancer Treat Rev.2016 Mar 1;44:51–60.

51. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, 
et al. Fatal toxic effects associated with immune checkpoint 
inhibitors: a systematic review and meta-analysis. JAMA 
Oncol.2018;4(12):1721–1728.

52. Haslam A, Prasad V. Estimation of the percentage of US patients 
with cancer who are eligible for and respond to checkpoint inhibitor 
immunotherapy drugs. JAMA Netw Open. 2019;2(5):e192535.

496SIUJ.ORG SIUJ  •  Volume 3, Number 6  •  November 2022

Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma

http://SIUJ.org


53. Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, et al. Quality 
of life in patients with advanced renal cell carcinoma given nivolumab 
versus everolimus in CheckMate 025: a randomised, open-label, phase 
3 trial. Lancet Oncol.2016 Jul 1;17(7):994–1003.

54. Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, 
Barthélémy P, et al. Nivolumab plus ipilimumab versus sunitinib for 
first-line treatment of advanced renal cell carcinoma: Extended 4-year 
follow-up of the phase III CheckMate 214 trial. ESMO Open.2020 Nov 
27;5(6): e001079. doi: 10.1136/esmoopen-2020-001079.

55. Cella D, Grünwald V, Escudier B, Hammers HJ, George S, Nathan P, 
et al. Patient-reported outcomes of patients with advanced renal cell 
carcinoma treated with nivolumab plus ipilimumab versus sunitinib 
(CheckMate 214): a randomised, phase 3 trial. Lancet Oncol. 2019 Feb 
1;20(2):297–310. doi: 10.1016/S1470-2045(18)30778-2

56. Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et 
al. Management of toxicities from immunotherapy: ESMO Clinical 
Practice Guidelines for diagnosis, treatment and follow-up. Ann 
Oncol.2017;28:iv119–142.

57. Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins; Sherry, 
Anadkat M, et al. Management of immune-related adverse events 
in patients treated with immune checkpoint inhibitor therapy: ASCO 
Guideline Update. J Clin Oncol.2021;39(36):4073-4126. doi: 10.1200/
JCO.21.01440

58. Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand P, Bhatia 
S, et al. Management of Immunotherapy-Related Toxicities, Version 
1.2019. J Natl Compr Canc Netw.2019 Mar 1;17(3):255–289. doi: 
10.6004/jnccn.2019.0013

59. Martins F, Sykiotis GP, Maillard M, Fraga M, Ribi C, Kuntzer T, et 
al. New therapeutic perspectives to manage refractory immune 
checkpoint-related toxicities. Lancet Oncol.2019;20(1):e54-e64. doi: 
10.1016/S1470-2045(18)30828-3

60. Haanen J, Ernstoff M, Wang Y, Menzies A, Puzanov I, Grivas P, et al. 
Rechallenge patients with immune checkpoint inhibitors following 
severe immune-related adverse events: review of the literature 
and suggested prophylactic strategy. J Immunother Cancer.2020 
Jun;8(1):e000604. doi: 10.1136/jitc-2020-000604

61. Rzeniewicz K, Larkin J, Menzies AM, Turajlic S. Immunotherapy use 
outside clinical trial populations: never say never? Ann Oncol.2021 Jul 
1;32(7):866–880. doi: 10.1016/j.annonc.2021.03.199

62. Cortellini A, Buti S, Agostinelli V, Bersanelli M. A systematic review on 
the emerging association between the occurrence of immune-related 
adverse events and clinical outcomes with checkpoint inhibitors in 
advanced cancer patients. Semin Oncol. 2019;46:362–371. doi.
org/10.1053/j.seminoncol.2019.10.003

63. Das S, Johnson DB. Immune-related adverse events and anti-tumor 
efficacy of immune checkpoint inhibitors. J Immunother Cancer.2019 
Nov 15;7(1):306. doi: 10.1186/s40425-019-0805-8

64. Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, et 
al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic 
renal cell cancer associated with enteritis and hypophysitis. J 
Immunother.2007 Nov;30(8):825–830.

65. Ishihara H, Takagi T, Kondo T, Homma C, Tachibana H, Fukuda H, et al. 
Clinical-kidney cancer association between immune-related adverse 
events and prognosis in patients with metastatic renal cell carcinoma 
treated with nivolumab. Urol Oncol.2019;37:355.e21–355.e29. doi: 
10.1016/j.urolonc.2019.03.0032019

66. Verzoni E, Cartenì G, Cortesi E, Giannarelli D, de Giglio A, Sabbatini 
R, et al. Real-world efficacy and safety of nivolumab in previously-
treated metastatic renal cell carcinoma, and association between 
immune-related adverse events and survival: the Italian expanded 
access program. J Immunother Cancer.2019 Apr 3;7(1):99. doi: 10.1186/
s40425-019-0579-z

67. Martini DJ, Hamieh L, McKay RR, Harshman LC, Brandao R, Norton 
CK, et al. Durable clinical benefit in metastatic renal cell carcinoma 
patients who discontinue pd-1/pd-l1 therapy for immune-related 
adverse events. Cancer Immunol Res.2018 Apr 1;6(4):402–408. doi: 
10.1158/2326-6066.CIR-17-0220

68. Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. 
Lenvatinib plus pembrolizumab or everolimus for advanced renal cell 
carcinoma. N Engl J Med.2021 Apr 8;384(14):1289–1300.

69. Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results 
from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib 
versus sunitinib in patients with advanced renal cell carcinoma. Ann 
Oncol.2020;31(8):1030-1039. doi:10.1016/J.ANNONC.2020.04.010

70. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et 
al. Avelumab plus axitinib versus sunitinib for advanced renal-cell 
carcinoma. N Engl J Med.2019 Mar 21;380(12):1103–1115.

71. Rini BI, Atkins MB, Choueiri TK, Thomaidou D, Rosbrook B, Thakur 
M, et al. Time to resolution of axitinib-related adverse events after 
treatment interruption in patients with advanced renal cell carcinoma. 
Clin Genitourin Cancer.2021 Oct 1;19(5):e306–312.

72. Study of cabozantinib in combination with nivolumab and ipilimumab 
in patients with previously untreated advanced or metastatic renal 
cell carcinoma - full text view - ClinicalTrials.gov [Internet]. Available 
at: https://clinicaltrials.gov/ct2/show/NCT03937219

73. Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al. Phase 
I study of cabozantinib and nivolumab alone or with ipilimumab for 
advanced or metastatic urothelial carcinoma and other genitourinary 
tumors. J Clin Oncol. 2020;38:3672–3684. doi: 10.1200/JCO.20.01652

74. Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, 
Maughan BL, et al. Belzutifan for Renal Cell Carcinoma in von Hippel–
Lindau Disease. N Engl J Med.2021 Nov 25;385(22):2036–2046.

75. Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, 
McDermott DF, et al. Inhibition of hypoxia-inducible factor-2α in renal 
cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. 
Nat Med.2021 May 1;27(5):802–805.

76. Aapro M, Beguin Y, Bokemeyer C, Dicato M, Gascón P, Glaspy J, et 
al. Management of anaemia and iron deficiency in patients with 
cancer: ESMO Clinical Practice Guidelines. Ann Oncol.2018;29(Suppl 
4):iv96-iv110. doi: 10.1093/annonc/mdx758

497 SIUJ  •  Volume 3, Number 6  •  November 2022 SIUJ.ORG

2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES

http://SIUJ.org


77. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al.   
Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl 
J Med.2013 Aug 22;369(8):722–731.

78. Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, 
Hahn O, et al. Cabozantinib versus sunitinib as initial therapy for 
metastatic renal cell carcinoma of intermediate or poor risk (Alliance 
A031203 CABOSUN randomised trial): progression-free survival by 
independent review and overall survival update. Eur J Cancer.2018 
May 1;94:115–125.

79. van der Veldt AAM, Boven E, Helgason HH, van Wouwe M, Berkhof 
J, de Gast G, et al. Predictive factors for severe toxicity of sunitinib in 
unselected patients with advanced renal cell cancer. Br J Cancer.2008 
Jul 22;99(2):259–265.

80. Diekstra MHM, Swen JJ, Boven E, Castellano D, Gelderblom H, 
Mathijssen RHJ, et al. CYP3A5 and ABCB1 polymorphisms as 
predictors for sunitinib outcome in metastatic renal cell carcinoma. 
Eur Urol.2015 Oct 1;68(4):621–629.

81. de Velasco G, Gray KP, Hamieh L, Urun Y, Carol HA, Fay AP, et al. 
Pharmacogenomic markers of targeted therapy toxicity in patients 
with metastatic renal cell carcinoma. Eur Urol Focus.2016 Dec 
15;2(6):633–639.

82. Diekstra MH, Belaustegui A, Swen JJ, Boven E, Castellano D, 
Gelderblom H, et al. Sunitinib-induced hypertension in CYP3A4 
rs4646437 A-allele carriers with metastatic renal cell carcinoma. 
Pharmacogenomics.2017 Jan 1;17(1):42–46. doi: 10.1038/tpj.2015.100

83. van der Zanden LFM, Vermeulen SH, Oskarsdottir A, Maurits JSF, 
Diekstra MHM, Ambert V, et al. Description of the EuroTARGET cohort: 
A European collaborative project on TArgeted therapy in renal cell 
cancer—GEnetic- and tumor-related biomarkers for response and 
toxicity. Urol Oncol.2017 Aug 1;35(8):529.e9-529.e16.

84. Andrews MC, Duong CPM, Gopalakrishnan V, Iebba V, Chen WS, 
Derosa L, et al. Gut microbiota signatures are associated with 
toxicity to combined CTLA-4 and PD-1 blockade. Nat Med.2021 Aug 
1;27(8):1432–1441.

 ORCID iDs

Kate Young: 0000-0002-9500-2046, 
Andreas M. Schmitt: 0000-0002-9568-8164

Deborah Mukherji: 0000-0002-0192-5828
Manuela Schmidinger: 0000-0002-2567-2749

Lisa M. Pickering: 0000-0002-7579 -340X

498SIUJ.ORG SIUJ  •  Volume 3, Number 6  •  November 2022

Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma

https://orcid.org/0000-0002-9500-2046
http://SIUJ.org



