Hepatocellular Carcinoma HCC Updated: April 2018 by Dr. Michael Herman (Medical Oncology Fellow, University of Toronto) April 2017 by Dr. Jenny Ko (Medical Oncologist, Abbotsford Centre, BC Cancer Agency) November 2015 by Dr. Mohammed Alghamdi (Medical Oncology Fellow, University of Calgary) Staff Reviewers: Dr. Yoo-Joung Ko (Medical Oncologist, Sunnybrook Odette Cancer Centre, University of Toronto), Dr. Vincent Tam (Medical Oncologist, Tom Baker Cancer Centre, University of Calgary), Dr. Jennifer Knox (Medical Oncologist, Princess Margaret Cancer Centre, University of Toronto) DISCLAIMER: The following are study notes compiled by the above medical oncology fellow and reviewed by staff medical oncologists. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH

EPIDEMIOLOGY - Incidence: 18th most common cancer in Canadians (12th among men, 18th among

women) (Canadian Cancer Statistics 2017) o 6.1 cases per 100,000 Canadians o 6th

most common cancer worldwide (5th in men, 9th

in women) o Highest-incidence regions: Sub-Saharan Africa, China, Hong Kong, Taiwan o Rising incidence in North America due to increasing rates of HCV infection and NASH

leading to higher incidence of liver cirrhosis - Mortality: 17th most common cause of cancer death in Canadians (12th among men, 18th

among women) (Canadian Cancer Statistics 2017) o 2nd

most common cause of cancer death worldwide

RISK FACTORS - Liver cirrhosis - Infections: chronic hepatitis B virus, chronic hepatitis C virus - Alcoholic liver disease (Most common cause in North America) - Metabolic liver disease (i.e. non-alcoholic steatohepatitis, hemochromatosis, Wilson’s

disease, alpha1-antitrypsin deficiency) - Autoimmune disease (i.e. autoimmune hepatitis, primary biliary cirrhosis, primary

sclerosing cholangitis) - Environmental toxins (i.e. aflatoxin, blue-green algae toxin, Betel nut chewing)

SCREENING - Guidelines recommend screening for HCC with ultrasounds every 6 months in:

o Cirrhotic patients o HBV carriers:

o Asian male >40 or Asian female >50 o Family history of HCC o African age >20

- Role of AFP in screening is controversial, but generally not recommended as a screening test

B) PRESENTATION & DIAGNOSIS

SYMPTOMS & SIGNS - Most of the patients with HCC have underlying liver cirrhosis and hepatomas are identified

on routine ultrasound screening of asymptomatic patients

- Symptoms depend on the location of the tumor, size and distant metastasis - Symptoms can include: right upper quadrant abdominal pain, right shoulder pain,

fatigue, anorexia, weight loss and unexplained fever are the most common symptoms. INVESTIGATIONS - Laboratory: (CBC, Chemistry, liver enzymes, bilirubin INR, albumin) - Tumor marker: AFP - Microbiology: serology for HBV and HCV - Diagnostic Imaging:

o Multi-phase liver CT (triphasic or quadraphasic) showing hypervascularity in the arterial phase and venous washout

o MRI abdomen o Contrast-enhanced ultrasound o CT chest and abdomen to rule out metastases o Bone scan to rule out bone metastases

- Common sites of Metastases: lung, intra-abdominal lymph nodes, bone - Diagnostic Procedures:

o clinical diagnosis can be made (i.e. biopsy not necessary) in patients with liver cirrhosis if there is a nodule ≥1cm + imaging shows hypervascularity in arterial phase with venous washout (American Association for the Study of Liver Disease Algorithm (AASLD), see below)

o biopsy should be considered if a clinical diagnosis of HCC cannot be made or if required for clinical trial participation

o large solitary lesions may be excised by hepatobiliary surgeon without need for biopsy o risk of seeding the needle tract estimated at 3%

AASLD Approach to Diagnosis of HCC in a Cirrhotic Liver

PATHOLOGY & MOLECULAR BIOLOGY - Common Histology:

o Hepatocellular carcinoma is the most common pathology o Fibrolamellar carcinoma is a variant of HCC which occurs more in young people,

not associated with elevation of AFP and has a favorable prognosis

STAGING - TNM

- Barcelona Liver Clinic (BCLC) Staging System

- Child- Pugh Classification

C) TREATMENT Algorithm for the Management of HCC According to the Updated AHS Clinical Practice Guidelines (from the Alberta Health Services Clinical Practice Guideline: Hepatocellular Carcinoma)

LOCALIZED / ADJUVANT - Bottom Line General Approach: Ideally managed by a multi-disciplinary team including

hepatobiliary surgeons, hepatologists, radiologists and radiation oncologists since the treatment options include: surgical resection, liver transplant, RFA, TARE, TACE as per above figure

Surgery - Indications:

o BCLC stage 0 o BCLC stage A with a single lesion or up to 3 lesions that are in close proximity

- Requires all to be met: o Adequate liver function (Child-Pugh A with mild or moderate hypertension) o Absence of major vascular invasion o Adequate future liver remnant (at least 20% without cirrhosis and at least 30%- 40% with Child-

Pugh A cirrhosis, adequate vascular and biliary inflow/outflow) § Absence of Indicators of poor functional reserve: portal hypertension (hepatic vein

pressure gradient >10mmHg, splenomegaly, platelets <100, varices), elevated bilirubin, altered indocyanine green clearance

- Neoadjuvant or adjuvant therapy has no proven benefit Liver Transplant - Indications:

o BCLC stage 0 with features of portal hypertension or liver dysfunction o BCLC stage A o May be considered in BCLC stage B with Child-Pugh score C

- Requires all to be met: o Milan criteria: 1 lesion <5cm or 3 lesions <3cm 5yr OS 70-80%. (Patients who do not meet Milan

criteria can be accepted but will have higher recurrence rates). UCSF criteria (1 tumor <6.5cm or 3 lesions <4.5cm)

- Contraindications (determined by Transplant team): o Vascular invasion o Extrahepatic spread o Tumor volume >115mm^3 o AFP >400 ng/ml o Extensive comorbidities o Age >70 o BMI >45 o Uncontrolled HIV o Another cancer within the last 2-5 years o Unstable psychiatric disorder o EtOH/drug misuse within the last 6 months o Unwillingness to follow advice of health team, social support/compliance issues prohibiting

adherence to post-operative medications - While patient is on waiting list for transplant can be bridged with TACE or RFA - Patients with more advanced liver failure (Child-Pugh B-C) should have liver transplant favored

over resection. Radiofrequency Ablation - Indications

o Less than or equal to 3 lesions that are <4cm who are not candidates for resection (for example due to portal HTN or CP-B) or transplantation. Ideal candidate for RFA is <2.5cm, single lesion. If 3-5cm in size TACE may be favored.

- Contraindications: o Lesion next to vessel due to heat-sink effect o Lesion on edge of liver o CP C

TACE (Transarterial chemoembolization): - 80% of blood supply to tumors provided by hepatic artery, only supplies 25% of blood to liver - Ligation or embolization of the hepatic artery can result in tumor responses Potentially even more efficacious when embolization combined with chemotherapy (e.g. doxorubicin,

cisplatin, epirubicin) - Mainly used for large unresectable HCCs or multifocal HCCs not amenable to local treatments - Contraindicated in patients with: portal vein thrombosis/obstruction, encephalopathy, biliary

obstruction, Childs-Pugh C liver cirrhosis, ECOG 2 or more - Toxicities: acute liver failure, acute renal failure, encephalopathy, UGIB, hepatic abscess. Death in

2.4% - Meta-analysis #1 (Llovet JM & Bruix JSO, Hepatology. 2003;37(2):429) compared arterial

embolization with control (conservative management or suboptimal therapy) and showed a statistically significant improvement in 2-year survival with arterial embolization (OR = 0.53, 95% CI 0.32-0.89) but only for TACE and not bland embolization alone

- Meta-analysis #2 (Cardiovasc Intervent Radiol. 2007;30(1):6.) showed: o Significant survival benefit with TACE vs no treatment (OR for death = 0.705, 95% CI 0.50-0.99) o No survival advantage to TACE vs bland embolization (TAE) o No clearly superior chemotherapy agent o RR = 40% o Median survival = 18 months

- Meta-analysis #3 (2012 Cochrane meta-analysis) failed to find a survival benefit from either TACE or bland embolization (hazard ratio [HR] for death 0.81, 95% CI 0.64-1.02) overall, but after excluding 4 trials of arterial embolization undergoing resection of localized HCC (i.e. limiting the analysis to TACE for advanced HCC), there was a trend toward better survival, but it was not statistically significant (HR for death = 0.65, 95% CI 0.40-1.05)

- Adjuvant Sorafenib: Not recommended. STORM Trial compared adjuvant sorafenib to placebo after surgical resection or local ablation and found no recurrence-free survival benefit (Bruix J et al, Lancet Oncol. 2015;16(13):1344-54). Other negative trials include TACE 2 (Meyer et al, Lancet Oncology. 2017). TACTICS trial (Kudo et al, JCO. 2018) showed improvement in PFS but not in OS

ADVANCED / METASTATIC Bottom Line General Approach:

First-line treatment: - Sorafenib:

o Indications: BCLC stage C, CP-A (Safe to use in CP-B7 however evidence of benefit is lacking). BCLC stage B if failed TACE or are not candidates for TACE

o Contraindications: CP-C, PS 3 or higher, unstable coronary disease o Pharmacology: TKI or VEGF, PDGF, RAF-1, BRAF, CRAF o Dose: Usual dose 400mg po BID. Reduce to 200 BID in CP B or bilirubin >1.5X ULN, consider

reduction if >age 75 o HCV+ patients likely have improved prognosis with sorafenib (HR 0.65) o Adverse effects: HTN, MI, fatigue, hand foot syndrome, diarrhea, rare perforation, rare

hemorrhage, impaired wound healing - Lenvatinib is another option if funding can be obtained Second-line treatments: - Regorafenib - Cabozantinib when available and funded - Ramucirumab (AFP ≥400) if funding can be obtained - PDL-1 inhibitor: Nivolumab or Pembrolizumab if funding can be obtained

o Checkmate-040: Phase 2 trial of Nivolumab 3mg/kg q 2 weeks after either first line or on progression of Sorafenib. Patients were Child-pugh score 7 or less. 68% received prior Sorafenib. ORR was 20%. At 9 months PFS is 28%, OS is 74%

o Keynote-224: Phase 2 trial of pembrolizumab 200mg q 3 weeks after progression of Sorafenib. Patients were Child-pugh class A. ORR was 16%, median PFS is 4.8 months with a 6-month overall survival of 78%.

Negative trials:

o REACH: phase 3 trial with ramucirumab vs. placebo 2nd line (CP stage C or stage B with disease not amenable to locoregional therapy) – no OS benefit

o CALGB 80802: phase 3 trial with doxorubicin + sorafenib vs sorafenib: higher toxicity and did not improve PFS or OS

Important Phase III Clinical Trials: SHARP Trial Sorafenib in Advanced Hepatocellular Carcinoma N Engl J Med 2008;359:378-90.

Regimen • Sorafenib 400mg po BID vs. placebo Mechanism of Small molecule that inhibits tumour cell proliferation, tumour angiogenesis and Action of increases the rate of apoptosis by inhibiting multiple tyrosine kinase including Raf- Experimental Drug 1, B-Raf, VEGFRs 1,2,3 and PDGFR-B.

Primary Endpoint Overall survival and the time to symptomatic progression.

Inclusion/Exclusion • Advanced stage HCC, no prior systemic therapy, ECOG 2 or less, Child-Pugh Criteria liver function class A

• Size (N) • 602 patients Results Median Survival = 10.7 months vs. 7.9 months, P<0.001

Time to Symptomatic Progression = 4.1 months vs. 4.9 months, P=0.77 Time to Radiologic Progression = 5.5 months 2.8 months (P<0.001) Response Rate: 2% vs. 1%

Toxicity Diarrhea, weight loss and hand–foot skin reaction were more frequent in the sorafenib group.

Conclusion In patients with advanced hepatocellular carcinoma, median survival and time to radiologic progression were approximately 3 months longer for patients treated with sorafenib compared to placebo

Asia-Pacific Trial Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular

carcinoma: a phase III randomised, double-blind, placebo-controlled trial Lancet Oncol 2009; 10: 25–34.

Regimen • Sorafenib 400mg po BID vs. placebo Mechanism of Small molecule that inhibits tumour cell proliferation, tumour angiogenesis and Action of increases the rate of apoptosis by inhibiting multiple tyrosine kinase including Raf- Experimental Drug 1, B-Raf, VEGFRs 1,2,3 and PDGFR-B.

Primary Endpoint No predefined primary endpoint; OS, TTP, time to symptomatic progression,

disease control rate, and safety were assessed Inclusion/Exclusion • Advanced stage HCC, no prior systemic therapy, ECOG 2 or less, Child-Pugh

Criteria liver function class A, 18 years or older

Size (N) • 271 patients Results Median Survival = 6.2 months vs. 4.2 months, P<0.014)

Time to Progression = 2.8 months vs. 1.4 months, P=0.0005 Time to Symptomatic Progression = 3.5 months vs. 3.4 months, P=0.50 Response Rate = 3.3 vs. 1.3%

Toxicity Diarrhea, hand–foot skin reaction, HTN more frequent with sorafenib Conclusion HCC patients randomized to treatment with sorafenib had significantly longer

overall survival than did those who received placebo

Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment

(RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 7;389(10064):56-66.

Regimen • Best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle.

Primary Endpoint OS Inclusion/Exclusion Adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of Criteria treatment), progressed on sorafenib, and had Child-Pugh A liver function Size (N) • N=573 Results Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-

0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) for placebo.

Toxicity Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand-foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group.

Conclusion Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. REFLECT

Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma

JCO May 2017 Regimen Lenvatinib: Body weight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day Mechanism of Action of Small molecule that inhibits tumour cell proliferation, tumour angiogenesis and

increases the rate of apoptosis by inhibiting multiple tyrosine kinase including VEGF 1-3, PDGFRa, RET, KIT

Experimental Drug

Primary Endpoint OS

Inclusion/Exclusion Unresectable HCC, No prior systemic therapy, 1 or more measurable lesion, BCLC

Criteria stage B or C, Child-Pugh class A, ECOG 1 or less

Size (N) N=954 Results Lenvatinib was non-inferior to sorafenib with respect to OS (median OS 13.6 vs 12.3

months. HR=0.92 CI 0.79-1.06). Median PFS was improved with lenvatinib (7.4 vs 3.7 months. HR 0.66 CI 0.57-0.77)

Toxicity Most common adverse effects were hypertension (42%), diarrhea (39%), decreased appetite (34%), decreased weight (31%), and fatigue (30%)

Conclusion LEN is noninferior in OS, and achieves statistically significant and clinically meaningful improvements in PFS, TTP, and ORR, as first line therapy for uHCC. TEAEs were consistent with the known LEN safety profile.

CELESTIAL Phase III Trial of Cabozantinib vs Placebo in patients with advanced HCC after progression on Sorafenib

2018GastrointestinalCancersSymposium/ASCOAnnualMeeting

Regimen Cabozantinib 60mg once daily or placebo

Mechanism of Small molecule tyrosine kinase inhibitor of c-MetandVEGFR2,AXLandRET.

Action of Experimental Drug

Primary Endpoint OS

Inclusion/Exclusion

Adults with advanced HCC and progression on up to two prior lines of systemic therapy, one of which must have been Sorafenib. Child-pugh A cirrhosis, and good performance status

Criteria

Size (N) N= 707

Results Cabozantinib improved median overall survival to 10.2 months versus 8.0 months in placebo with a HR of 0.76

Improvement in PFS (median 5.2 vs 1.9 months, HR 0.44) ORR 4% vs. 0.4%

In patients who had previous treatment with sorafenib alone median OS was 11.3 vs 7.2 months

Toxicity

The most common grade 3/4 adverse events seen more frequently in the cabozantinib group included hand-foot syndrome (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase levels (12% vs 7%), fatigue (10% vs 4%), diarrhea (10% vs 2%), asthenia (7% vs 2%), and decreased appetite (6% vs < 1%).

Conclusion Cabozantinib given in the second or third line, after prior Sorafenib improves overall survival over placebo in patients with advanced HCC

REACH-2 A randomized, double-blind, placebo-controlled phase 3

study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular

carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib

2018ASCOAnnualMeeting

Regimen Cabozantinib 60mg once daily or placebo

Mechanism of VEGF inhibitor

Action of Experimental Drug

Primary Endpoint OS

Inclusion/Exclusion Adults with advanced HCC and progression on sorafenib. AFP≥400 ng/mL, ECOG 0-1, Child-pugh A cirrhosis.

Criteria

Size (N) N= 292

Results Ramucirumab improved median overall survival to 8.5 months versus 7.3 months in placebo with a HR of 0.71

Improvement in PFS (median 2.8 vs 1.6 months, HR 0.45) ORR 4.6% vs. 1.1%

Toxicity

The most common grade 3/4 adverse events seen more frequently in the ramucirumab group included hypertension (13% vs 5%), bleeding/hemorrhage (5% vs 3%) which was 3.6% GI hemorrhage and 0.5% epistaxis

Conclusion

REACH-2 met its primary endpoint showing a significant survival benefit of ramucirumab treatment in patients with HCC and AFP >=400 who progressed on or were intolerant of sorafenib. Ramucirumab was well tolerated, safety profile consistent with trials of monotherapy in other cancer sites.

- Prognosis: Median survival without treatment about 4-8 months, with sorafenib treatment 6-11 months

D) REFERENCES

- Alberta Health Services cancer guide line. - Canadian cancer statistic 2015 - UpToDate 2015 - AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc. - AASLD Practice Guideline, Management of Hepatocellular Carcinoma: An Update. Bruix,

J, Sherman, M. - Multidisciplinary Canadian consensus recommendations for the management and

treatment of hepatocellular carcinoma