Systemic therapies such as targeted agents (TKIs) and immune checkpoint inhibitors are increasingly used to treat advanced hepatocellular carcinoma (HCC). These therapies can cause adverse events that require careful management. TKIs commonly cause hand-foot skin reactions, which are graded based on severity from 1-3. Management involves prophylaxis like moisturizing and avoiding friction, along with topical steroids and potentially dose reductions. Immune checkpoint inhibitors can cause immune-related adverse events affecting many organ systems from 1-4 based on severity. Most grade 1-2 events are managed with corticosteroids and holding immunotherapy, while higher grades often require high-dose steroids, other immunosuppression, and potentially discontin

1. Systemic Therapy in Advanced HCC
A Guide to Status and Treatment Principles
PRACTICE AID
TKIs / Targeted Agents
Sorafenib1
First-line treatment of
unresectable HCC
Approved
400 mg 2x/d w/o food; treatment
interruption and/or dose reduction
for possible AEs: 400 mg 1x/d or
400 mg every other d
Lenvatinib2
First-line treatment of
unresectable HCC
Approved
Regorafenib3
Second-line setting following
treatment with sorafenib
Approved
Cabozantinib4,5
Efficacy evidence in advanced HCC
after progression with ≤1 prior
therapy, including sorafenib
Phase 3
Ramucirumab6
Evidence in second-line setting
following treatment with sorafenib
for advanced HCC
Phase 3
12 mg 1x/d for patients ≥60 kg
or 8 mg 1x/d for patients ≤60 kg; dose
modification may be needed for patients
with renal or hepatic impairment
160 mg orally;
3 wk on, 1 wk off (4-wk cycle)
60 mg/d (dose studied
in phase 2 and 3 trials)
8 mg/kg IV every other wk
(dose studied in phase 3 trial)
Agent
Indication/Status
Dosage Future Directions
• Multiple combination strategies with
locoregional therapy (Y-90, SBRT,
TACE, or others)7
• Combinations with immune
checkpoint inhibitors8
• Other next-generation TKIs are also
being explored9
The approval of TKI therapy in
HCC has fueled additional research
into the use of targeted agents
in combination strategies or in
settings other than advanced
HCC; several examples are
provided below.

2. Systemic Therapy in Advanced HCC
A Guide to Status and Treatment Principles
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
CTLA-4: cytotoxic T-lymphocyte–associated antigen-4; HCC: hepatocellular carcinoma; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; SBRT: stereotactic body radiation therapy; TACE: transarterial chemoembolization; TKI: tyrosine kinase inhibitor;
Y-90: yttrium-90.
1. Nexavar (sorafenib) Prescribing Information. https://www.nexavar-us.com/. Accessed October 8, 2018. 2. Lenvima (lenvatinib) Prescribing Information. http://www.lenvima.com/pdfs/prescribing-information.pdf. Accessed October 8, 2018. 3. Stivarga (regorafenib) Prescribing
Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203085lbl.pdf. Accessed October 8, 2018. 4. Abou-Alfa GK et al. ASCO Gastrointestinal Cancers Symposium 2018 (ASCO GI 2018). Abstract 207. 5. Abou-Alfa GK et al. N Engl J Med. 2018;379:54-63.
6. Zhu AX et al. J Clin Oncol. 2018;36(suppl). Abstract 4003. 7. https://clinicaltrials.gov/ct2/show/NCT00846131. Accessed October 19, 2018. 8. https://clinicaltrials.gov/ct2/show/NCT03006926. Accessed October 19, 2018. 9. https://clinicaltrials.gov/ct2/show/NCT02421185.
Accessed October 19, 2018. 10. Opdivo (nivolumab) Prescribing Information. https://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed October 8, 2018. 11. Zhu AX et al. ASCO GI 2018. Abstract 209. 12. Wainberg ZA et al. ASCO 2017. Abstract 4071.
13. Stein S et al. J Clin Oncol. 2018;36(suppl). Abstract 4074. 14. https://clinicaltrials.gov/ct2/show/NCT02519348. Accessed October 19, 2018. 15. https://clinicaltrials.gov/ct2/show/NCT03006926. Accessed October 19, 2018.
PRACTICE AID
Access the activity,“Surveying the View From the Driver’s Seat in Hepatocellular Carcinoma: Bringing Into Focus Hepatology’s Key Role in Guiding
HCC Care Down the Path to Improved Outcomes,”at www.peerview.com/WDR40.
Nivolumab10
Second-line setting following
treatment with sorafenib
Approved
Phase 3 testing (CheckMate-459;
NCT02576509) as first-line treatment
240 mg every 2 wk or
480 mg every 4 wk
Pembrolizumab11
Second-line setting following
treatment with sorafenib
Priority review
Durvalumab12
HCC (Child-Pugh class A)
Phase 3
Atezolizumab + bevacizumab13
First-line treatment of advanced
or metastatic HCC
Breakthrough therapy designation
200 mg every 3 wk
(dose studied in phase 2 trial)
10 mg/kg IV every other wk
(dose studied in phase 1/2 trial)
Atezo 1,200 mg IV every 3 wk or
840 mg every 2 wk and bev 15 mg/kg IV
every 3 wk or 10 mg/kg every 2 wk
(dose studied in phase 1 trial)
Agent
Indication/Status
Dosage Future Directions
• Dual checkpoint blockade
(anti–PD-1/L1 + anti–CTLA-4)14
• Combinations with TKIs and with
locoregional therapy15
As in other cancer settings,
multiple explorations of
checkpoint inhibitors in HCC,
including immune combinations
or as treatments, are underway:
Immune Checkpoint Inhibitors

3. Managing Adverse Events Associated
With Systemic Therapies Used in Patients
With Hepatocellular Carcinoma
PRACTICE AID
• In general, checkpoint inhibitor therapy should be continued with close monitoring, with the
exception of some neurologic, hematologic, and cardiac toxicities
Minimalornosymptoms;diagnosticchangesonly
Immune checkpoint inhibitors are associated with important clinical benefits, but general immunologic
enhancement can also lead to a unique spectrum of irAEs
Grade 1
What is the spectrum of potential irAEs?Why do irAEs occur?
General recommendations and management principles include the following:
irAEs are often diagnosed by
exclusion; other causes should be ruled
out (including AEs of other therapies
used), but immunotherapy-related
toxicity should always be included
in the differential
There should be a high level of
suspicion that new symptoms are
treatment-related; early recognition,
evaluation, and treatment of irAEs
plus patient education are essential
for best outcome
Depending on severity of irAEs,
management may require corticosteroid
or other immunosuppressive treatment
and interruption or discontinuation
of therapy
If appropriate immunosuppressive
treatment is used, patients generally
recover from irAEs
Use of immunosuppressive therapy
to manage irAEs does not affect
response to immunotherapy
How should irAEs be diagnosed and managed?
• Hold checkpoint inhibitor therapy for most grade 2 toxicities
• Consider resuming immunotherapy when symptoms and/or laboratory values revert to grade 1 or lower
• Corticosteroids (initial dose of 0.5-1 mg/kg/d of prednisone or equivalent) may be administered
Grade 3 toxicities:
• Hold checkpoint inhibitor therapy
• Initiate high-dose corticosteroids (prednisone 1-2 mg/kg/d or methylprednisolone IV 1-2 mg/kg/d)
• If symptoms do not improve with 48-72 hours of high-dose corticosteroids, infliximab may be offered
for some toxicities
• Taper corticosteroids over the course of at least 4-6 weeks
• When symptoms and/or laboratory values revert to grade 1 or lower, rechallenging with
immunotherapy may be offered; however, caution is advised, especially in those patients with
early-onset irAEs. Dose adjustments are not recommended
Grade 4 toxicities:
• In general, permanent discontinuation of checkpoint inhibitor therapy is warranted, with the exception
of endocrinopathies that have been controlled by hormone replacement
Brahmer JR et al. Management of Immune-Related Adverse Events in PatientsTreated
With Immune Checkpoint InhibitorTherapy: American Society of Clinical Oncology
Clinical Practice Guideline. J Clin Oncol. 2018;36:1714-1768.
For organ-specific assessment and management of irAEs, please see the ASCO guidelines:
Additional resources available on the ASCO website:
https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/supportive-care-and-treatment-related-issues#/29866
Grade 2
Mild to moderate symptoms
Severe or life-threatening symptoms
Grades 3/4
Any organ system can be affected; commonly occurring are pulmonary
(pneumonitis), dermatologic (rash, pruritus, blisters, ulcers, vitiligo),
gastrointestinal (diarrhea, enterocolitis, transaminitis, hepatitis, pancreatitis),
and endocrine (thyroiditis, hypophysitis, adrenal insufficiency) irAEs
The precise pathophysiology is unknown, but translational studies have
shown that T-cell, antibody, and cytokine responses may be involved
Q
Q
Q
A
A
A
Pancreatitis,
autoimmune diabetes
Colitis
Enteritis
Encephalitis, aseptic meningitis
Thyroiditis, hypothyroidism,
hyperthyroidism
Dry mouth, mucositis
Hypophysitis
Uveitis
Pneumonitis
Thrombocytopenia,
anemia
Hepatitis
Adrenal insufficiency
Nephritis
Vasculitis
Arthralgia
Neuropathy
Rash, vitiligo
Myocarditis
Increasing T-cell
activity against
antigens that
are present in
tumors and
healthy tissue
Activated T cell
Antithyroid
antibodies
Increasing
levels of
inflammatory
cytokines
Increasing levels
of pre-existing
autoantibodies
Enhancing
complement-mediated
inflammation due to
direct binding of an
anti–CTLA-4 antibody
with CTLA-4
expressed on
normal tissue
Activated T cell
Anti–CTLA-4 antibody
CTLA-4 on pituitary Complement-
mediated
inflammation
Cytokines
Tumor with antigen
and activated T cells
Immune-Related Adverse Events (irAEs) Associated
With Immune Checkpoint Inhibitors1, 2

4. Managing Adverse Events Associated
With Systemic Therapies Used in Patients
With Hepatocellular Carcinoma
PRACTICE AID
Guidelines for Hepatic irAE Management by Grade2
General Management
q Monitor AST, ALT, and bilirubin prior to each infusion
q Counsel patients
q Rule out other causes
Grade ICPi Therapy Monitor Corticosteroid Other
1
Asymptomatic (AST or
ALT > ULN to 3.0 × ULN
and/or total bilirubin
> ULN to 1.5 × ULN)
Continue Weekly or more No —
2
Asymptomatic (AST or
ALT >3 to ≤5 × ULN
and/or total bilirubin
>1.5 to ≤3 × ULN)
Hold Every 3 d 0.5-1 mg/kg/d
Consider
resuming ICPi
when grade 1
or lower
3
Symptomatic liver
dysfunction, fibrosis by
biopsy, compensated
cirrhosis, reactivation of
chronic hepatitis (AST or
ALT 5-20 × ULN and/or total
bilirubin 3-10 × ULN)
Discontinue
permanently
Every 1-2 d
1-2 mg/kg/d
Taper at 4-6 wk If no
improvement
in 3 d, consider
mycophenolate
mofetil
(infliximab not
recommended)
4
Decompensated
liver function (eg,
ascites, coagulopathy,
encephalopathy, coma; AST
or ALT >20 × ULN and/or
total bilirubin >10 × ULN)
Discontinue
permanently
Daily; consider
impatient
2 mg/kg/d
Taper at 4-6 wk

5. Managing Adverse Events Associated
With Systemic Therapies Used in Patients
With Hepatocellular Carcinoma
PRACTICE AID
Management of AEs Associated With TKIs
Symptoms
Prophylaxis3-6
Onset
Hand-Foot-Skin Reaction
qq Erythema with or without blisters;
hyperkeratotic lesions on palms and soles
qq Commonly accompanied by dysesthesia
(burning, pain, tingling)
qq Perform full-body skin examination, focusing
on deformities and hyperkeratotic areas on
palms and soles, before treatment initiation
qq Have patients remove their shoes and examine
their feet during each visit
qq Recommend podiatrist evaluation (can help with
removal of calluses and hyperkeratotic regions)
and orthotist evaluation and use of orthotic
devices in patients with abnormal weight bearing
qq During early therapy (2-4 wk), encourage rest
and avoidance of vigorous exercise and traumatic
activity
qq Typically within 45 d of therapy initiation
Grade7,a
Characteristic4
Management3-6
1 Tingling, numbness, accompanied
by minimal skin changes or dermatitis,
such as erythema, edema, or
hyperkeratosis of the hands and/or feet
without pain; does not disrupt ADLs
Avoid hot water, wear thick socks, wear cotton
gloves/socks at night, use moisturizing creams
and keratolytics (urea 20% to 40%;
salicylic acid 5% to 10%); no dose reduction needed;
follow up within 2 wk
2
Skin changes of the hands and/or feet,
may include peeling, blisters, bleeding,
edema, or hyperkeratosis with pain;
discomfort affecting ADLs
Employ grade 1 strategies, consider clobetasol
0.05% ointment 2x/d for erythematous areas,
use topical and systemic analgesics (if no
contraindications [eg, bleeding, kidney dysfunction]);
consider 50% dose reduction for 7-28 d until HFSR
is grade 1/0 → full dose
3 Severe skin changes of the hands
and/or feet; may include peeling, blisters,
bleeding, edema, or hyperkeratosis
with pain and/or severe discomfort
causing inability to work or perform ADLs
Employ grade 1/2 strategies; treatment interruption
for ≥7 d until HFSR is grade 1/0 → 50% of full dose
→ escalation, if possible; resume treatment at lower
dose as recommended in package insert; dose may
be escalated if reaction does not reoccur
Moisturizer (daily),
cold packs (indirectly)
for 20 min/d; wear
thick cotton gloves and
socks, gently pat hands/feet
dry after washing
Hot water, direct sunlight,
constrictive footwear,
excessive friction, vigorous
activity, and contact with
cleaning products with
strong chemicals
Signs and
symptoms
immediately
Calluses and
hyperkeratotic
regions
REMOVE AVOID
REPORTAPPLY
RAAR6

6. Managing Adverse Events Associated
With Systemic Therapies Used in Patients
With Hepatocellular Carcinoma
PRACTICE AID
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
a
Images courtesy of Elizabeth Manchen, RN, MS, OCN.
ADL: activities of daily living; ASCO: American Society of Clinical Oncology; CTLA-4: cytotoxic T-lymphocyte–associated protein 4; HFSR: hand-foot-skin reaction; ICPi: immune checkpoint inhibitor;
irAE: immune-related adverse event; RAAR: remove, avoid, apply, and report; TKI: tyrosine kinase inhibitor; ULN: upper limit of normal.
1. Postow MA et al. N Engl J Med. 2018;378:158-168. 2. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1768. 3. Lacouture ME et al. Oncologist. 2008;13:1001-1011. 4. McLellan B et al. Ann Oncol. 2015;26:2017-2026.
5. Brose MS et al. Semin Oncol. 2014;41(suppl 2):s1-s16. 6. Walko CM et al. Semin Oncol. 2014;41(suppl 2):s17-s28. 7. CTCAE version 5.0. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/
ctc.htm#ctc_50. Accessed October 11, 2018.
Access the activity,“Surveying the View From the Driver’s Seat in Hepatocellular Carcinoma: Bringing
Into Focus Hepatology’s Key Role in Guiding HCC Care Down the Path to Improved Outcomes,”at
www.peerview.com/WDR40.
General Management
Patient Education
Medical Intervention
Diarrhea5,6
Fatigue5,7
Patient should notify medical team of diarrhea
or abdominal distress!
Frequent, watery, bloody, or nocturnal stools
Educating your patients on managing fatigue is essential!
qq Monitor bowel habits, and report any increase
in activity above normal
qq Avoid spicy or fatty foods; plain, simple foods
are best
qq Avoid fruit and caffeine
qq Maintain adequate fluid intake to avoid
dehydration
qq Monitor/manage electrolytes
qq Staying as active as possible helps regulate sleep
qq Maintain a normal work and social schedule
qq Take breaks as needed
qq Tell your medical team if activity is intolerable or fatigue worsens
qq Loperamide is usually effective
qq If loperamide is ineffective, consider
diphenoxylate/atropine
Management of AEs Associated With TKIs