Breaking the Paradox: Expanding Options and New Questions in HCC Management—Mapping the Pathways to Better Patient Outcomes

Richard S. Finn, MD, Anthony El-Khoueiry, MD, and Josep M. Llovet, MD, PhD, prepared useful practice aids pertaining to hepatocellular carcinoma for this CME activity titled "Breaking the Paradox: Expanding Options and New Questions in HCC Management: Mapping the Pathways to Better Patient Outcomes." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2HU6L5K. CME credit will be available until February 14, 2020.

1. Systemic Therapy in Advanced HCC
A Guide to Status and Treatment Principles
PRACTICE AID TKIs / Targeted Agents
Sorafenib
1,2
First-line treatment of
unresectable HCC
Approved; NCCN Category 1 (Child-Pugh A)
and 2A (B7)
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
Lenvatinib
2,3

First-line treatment of
unresectable HCC
Approved; NCCN Category 2A (Child–Pugh A)
Regorafenib
2,4
Second-line setting following
treatment with sorafenib
Approved; NCCN Category 1 (Child–Pugh A)
Cabozantinib
2,5,6
Second-line setting following
treatment with sorafenib
Approved; NCCN Category 1 (Child–Pugh A)
Ramucirumab
2,7

Evidence in second-line setting
following treatment with sorafenib
in patients with AFP ≥400 ng/mL
Phase 3; NCCN Category 1 (Child–Pugh A)
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 (Y90, SBRT,

TACE, or others)
8
• Combinations with immune
checkpoint inhibitors
9
• Other next-generation TKIs
10
• Biomarker-driven treatments
11
The approval of TKI therapy in
HCC has fueled additional research
into the use of targeted agents
in combination strategies and in
early stages of HCC; several
examples are provided below.
Access the activity, "Breaking the Paradox: Expanding Options and New Questions in HCC Management—Mapping the Pathways to Better Patient Outcomes," at www.peerview.com/EJX40.

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.
AFP: ≥-fetoprotein; HCC: hepatocellular carcinoma; NCCN: National Comprehensive Cancer Network; 1; SBRT: stereotactic body radiation therapy; TACE: transarterial chemoembolization; TKI: tyrosine kinase inhibitor; VEGF: vascular endothelial growth factor; Y90: yttrium90.
1. Nexavar (sorafenib) Prescribing Information. http://labeling.bayerhealthcare.com/html/products/pi/Nexavar_PI.pdf. December 26, 2018. 2. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers. v1.2019. https://www.nccn.
org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed January 11, 2019. 3. Lenvima (lenvatinib) Prescribing Information. http://www.lenvima.com/pdfs/prescribing-information.pdf. Accessed December 26, 2018. 4. Stivarga (regorafenib) Prescribing Information. https://www.
accessdata.fda.gov/drugsatfda_docs/label/2012/203085lbl.pdf. Accessed December 26, 2018. 5. Abou-Alfa GK et al. ASCO Gastrointestinal Cancers Symposium 2018 (ASCO GI 2018). Abstract 207. 6. Abou-Alfa GK et al. N Engl J Med . 2018;379:54-63. 7. Zhu AX et al. J Clin Oncol . 2018;36(suppl).
Abstract 4003. 8. https://clinicaltrials.gov/ct2/show/NCT00846131. Accessed December 26, 2018. 9. https://clinicaltrials.gov/ct2/show/NCT03006926. Accessed December 26, 2018. 10. https://clinicaltrials.gov/ct2/show/NCT02421185. Accessed December 26, 2018. 11. Harris WP et al. Semin
Oncol. 2018;45:116-123. 12. Opdivo (nivolumab) Prescribing Information. https://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed December 26, 2018. 13. Zhu AX et al. ASCO GI 2018. Abstract 209. 14. Keytruda (pembrolizumab) Prescribing Information. https://www.merck.com/product/
usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed December 26, 2018. 15. Wainberg ZA et al. ASCO 2017. Abstract 4071. 16. https://clinicaltrials.gov/ct2/show/NCT02519348. Accessed December 26, 2018. 17. Stein S et al. J Clin Oncol . 2018;36(suppl). Abstract 4074.
PRACTICE AID
Access the activity, "Breaking the Paradox: Expanding Options and New Questions in HCC Management?Mapping the Pathways to Better Patient Outcomes," at www.peerview.com/EJX40. Nivolumab
2 ,12
Second-line setting following
treatment with sorafenib
Approved
Phase 3 testing (CheckMate -459;
NCT02576509) as first-line treatment;
NCCN Category 2A (Child–Pugh A and B7)
240 mg every 2 wk or
480 mg every 4 wk
Pembrolizumab
2 ,13,14
Second-line setting following
treatment with sorafenib
Approved; NCCN Category 1 (Child–Pugh A)
Durvalumab
15
HCC (Child–Pugh class A)
Phase 3 (also being studied in combination
with tremelimumab in the phase 3
HIMALAYA study
16
)
Atezolizumab + bevacizumab
17
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
8,16,17
• Combinations with TKIs, VEGF
inhibitors, other checkpoint inhibitors,
and locoregional therapies
• Use in first-line and earlier
treatment settings
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
Minimal or no symptoms; diagnostic changes only
Immune checkpoint inhibitors are associated with important clinical benefts, 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, in≤iximab may be o ered
  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 o ered; 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 Patients Treated 
With Immune Checkpoint Inhibitor Therapy:  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 insufciency
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 Inhibitors
1, 2
Access the activity, "Breaking the Paradox: Expanding Options and New Questions in HCC Management— Mapping the Pathways to Better Patient Outcomes," at www.peerview.com/EJX40.

4. Managing Adverse Events Associated
With Systemic Therapies Used in Patients
With Hepatocellular Carcinoma
PRACTICE AID Guidelines for Hepatic irAE Management by Grade
2
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 wkIf 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
Symptoms
Prophylaxis
3-6
Hand-Foot-Skin Reaction
qqErythema with or without blisters; hyperkeratotic
lesions on palms and soles
qqCommonly accompanied by dysesthesia (burning,
pain, tingling)
qqTypically within 45 d of therapy initiation
qqPerform full-body skin examination, focusing on
deformities and hyperkeratotic areas on palms and
soles, before treatment initiation
qqExamine patients' feet during each visit
qqRecommend podiatrist and orthotist evaluations

and use of orthotic devices in patients with
abnormal weight bearing
qqDuring early therapy (2-4 wk), encourage rest and
avoidance of vigorous exercise and activity
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
REPORT APPLY
RAAR
6
Management of AEs Associated With TKIs
Access the activity, "Breaking the Paradox: Expanding Options and New Questions in HCC Management— Mapping the Pathways to Better Patient Outcomes," at www.peerview.com/EJX40.

5. 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 December 26, 2018.
Access the activity, "Breaking the Paradox: Expanding Options and New Questions in HCC Management? Mapping the Pathways to Better Patient Outcomes," at www.peerview.com/EJX40. Management of AEs Associated With TKIs (Cont'd)
Grade
7,a
Characteristic
4
Management
3-6
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 afecting 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
General Management Patient Education
Medical Intervention
Diarrhea
5,6
Fatigue
5,7
qqMonitor bowel habits, and report increased activity
qqAvoid spicy or fatty foods; plain, simple foods are best
qqAvoid fruit and caffeine
qqMaintain adequate fluid intake
qqMonitor/manage electrolytes
qqStay as active as possible to help regulate sleep
qqMaintain a normal work and social schedule
qqTake breaks as needed
qqTell your medical team if activity is intolerable
or fatigue worsens
qqLoperamide is usually effective
qqIf loperamide is ineffective, consider diphenoxylate/atropine

6. Liver Cancer Resources:
Tools to Facilitate
Professional-Patient Conversations
PRACTICE AID
Access the activity, "Breaking the Paradox: Expanding Options and New Questions in HCC Management— Mapping the Pathways to Better Patient Outcomes," at www.peerview.com/EJX40. Conversations about liver cancer can be difficult for patients.
This resource can help guide discussions about this important topic.
What are the risk factors for and causes of liver cancer?
1-3
Long-term HBV or HCV
Excessive alcohol use
Obesity and diabetes (both closely associated with
nonalcoholic fatty liver disease, which may increase the
risk of liver cancer, especially in those who drink heavily
or have viral hepatitis)


Certain inherited metabolic diseases
Environmental exposure to aflatoxins
Many other liver diseases that can lead to
cirrhosis, including autoimmune diseases
a
and other rare diseases
b
What are the symptoms of liver cancer?
1,3
Fatigue, bloating, pain on the right side of the upper abdomen or back and shoulder, nausea, loss of appetite, feelings of fullness, weight loss, weakness, fever, and jaundice (yellowing of the eyes and skin)
How is liver cancer diagnosed?
1-3
A physical examination or imaging tests may suggest liver cancer; blood tests, ultrasound tests, CT scans, MRI, and angiograms may confirm the diagnosis
A liver biopsy (removal of a small piece of liver tissue) may also be performed

7. Liver Cancer Resources:
Tools to Facilitate
Professional-Patient Conversations
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
Primary biliary cholangitis.
b
Tyrosinemia, alpha1-antitrypsin deficiency, porphyria cutanea tarda, glycogen storage disease, and Wilson disease.
1. https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/liver-cancer/#information-for-the-newly-diagnosed. Accessed January 11, 2019. 2. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Hepatobiliary Cancers. V.1.2019. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed January 11, 2019. 3. https://www.bluefaery.org/clinical-trials/. Accessed January 11, 2019.
Access the activity, "Breaking the Paradox: Expanding Options and New Questions in HCC Management— Mapping the Pathways to Better Patient Outcomes," at www.peerview.com/EJX40. Treatment depends on the liver’s condition; size,
location, and number of tumors; whether the cancer
has spread outside the liver; and the patient’s age
and overall health. For cancer that has not spread
outside of the liver:
Liver transplant
Surgery to remove the tumor (partial hepatectomy)
Radiofrequency ablation: a special probe is used to destroy cancer cells with heat
Cryosurgery: a metal probe is used to freeze and destroy cancer cells
Embolization: procedures used to block the blood supply to the tumor; some use anticancer drugs (chemoembolization), while others do not (bland embolization)
Radiation therapy: high-energy x-rays are used to destroy cancer cells
How is liver disease treated?
1-3
The American Liver Foundation
(liverfoundation.org) has many other
resources available for patients
For cancer that has spread outside of the liver (hepatocellular carcinoma is the most common type):
Oral and intravenous medications such as targeted therapies and immunotherapies
Clinical trials
Additional Patient Resources: Blue Faery Clinical Trial Tool
3
Clinical trials are studies of investigational treatments or methods and are conducted in volunteers; enrollment in a clinical trial can be a useful option to consider
Discuss the advantages, disadvantages, and side effects of treatment options with your doctor
Ask your doctor about the possibility of using experimental therapies and eligibility to participate in clinical trials; if you want to participate in a clinical trial, ask about the phase of the trial
Consider seeking a second opinion if your health insurance allows you to do so
Blue Faery Clinical Trial Tool
(https://www.bluefaery.org/clinical-trials)
Many other patient resources are available
at www.bluefaery.org, including listings
of ongoing trials open for patients