Hepatocellular Carcinoma (HCC) Treatment Algorithm Author Robert G.

Gish MD

HCC treatment algorithm 1. BCLC (Barcelona Clinic Liver Cancer) Staging

To best assess the prognosis of HCC patients, it is recommended that the staging system take into account tumor stage, liver function and physical status. The impact of treatment should also be considered when estimating life expectancy. Currently, the BCLC system is the only staging system that accomplishes these aims (level II). [1, 2]

Hepatocellular Carcinoma (HCC) Treatment Algorithm Author Robert G. Gish MD

a. Resection

i.

Patients with a single lesion can be offered surgical resection if they are non-cirrhotic or have cirrhosis but still have well preserved liver function, normal bilirubin, no varices, platelet count over 100 000 and hepatic vein pressure gradient <10mmHg (level II)

b. Liver Transplantation

i.

Milan Criteria 1 lesion smaller than 5cm or with up to 3 lesions smaller than 3cm Expected 5 year survival >70% Downstage (UCSF criteria) No vascular invasion on imaging 1 lesion: >5 but 8 cm 2 or 3 lesions: a. None >5 cm AND b. Total diameter of all lesions 8 cm 4 or 5 lesions a. None >3 cm A resection or biopsy specimen with micro- or macrovascular invasion disqualifies a candidate for liver transplantation. Candidates undergo imaging 1 month (+/- 1 week) after downstaging (TACE, ablation, resection) to assess completeness of the procedure Repeat imaging at three months after downstaging and every 3 months thereafter. Transplant cannot occur until 3 months after downstaging procedure and imaging studies must demonstrate that tumor burden is stable and within Milan (UNOS) criteria. Ablation sites without evidence of viable tumor are not considered to contain tumor. Candidates who decompensate acutely secondary to any downstaging procedure are not candidates for transplantation unless they meet above criteria. Chest CT scan should be negative at the time of petitioning for HCC exception status. Bone Scan if symptoms.

ii.

Hepatocellular Carcinoma (HCC) Treatment Algorithm Author Robert G. Gish MD

c. RFA/MWA/PEI

i.

Local ablation is safe and effective therapy for those with early stage HCC (BCLC stage 0, A) who are not candidate or liver transplantation and should be consider to be closely equivalent to resection. Radiofrequency ablation (RFA) and microwave ablation (MWA) provide more necrotic effect with less treatment sessions compared to ethanol injection (PEI). PEI is used for small selected tumors (i.e. near bowel, gallbladder) when complication due to thermal ablation to the surrounding organ is of concern.

ii.

d. TACE/TABE

i. ii.

TABE (transarterial drug eluting bead embolization) should be standard treatment for those intermediate/ advanced stage HCC (BCLC stage B and C). TABE is safe and effective in the treatment of HCC. First large RCT comparing conventional TACE (transarterial chemoembolization) and TABE (TACE with doxorubicin eluting bead) showed TABE had higher rates of complete response and disease control with improved tolerability and with less serious liver toxicity compared to cTACE. [3] TAE, bland embolization for selected patients IA infusion of chemotherapy for selected patients

iii. iv.

e. TARE

i.

TARE (transarterialradioembolization) with Yttrium 90 microspheres has been shown to be safe and effective to treat unresectable hepatocellular carcinoma [4, 5]. Especially for patients with main portal venous thrombus, which is generally considered a contraindication of TACE, TARE has been shown safely done and effective, thus is considered a good indication. Please see TARE section for details. Consider for radiation segmentectomy

Hepatocellular Carcinoma (HCC) Treatment Algorithm Author Robert G. Gish MD

f. Sorafenib

i.

Sorafenib (Nexavar) is a multi-kinase inhibitor of serine/threonine, is approved to treat unresectable HCC and is a standard treatment. Large RCT, SHARP trial [6]showed significantly longer overall survival (10.7 vs 7.9 months (P < .001), 1-year survival: 44% vs 33%, (P = .0009). Asia Pacific trial [7] also showed significantly longer overall survival (6.5 months vs 4.2 months (P < .005). Details in Sorafenib section.

g. Clinical Trial

i.

BCLC stage C patients who have failed above treatment should be enrolled in clinical trials if eligible.

h. Palliative Care

i.

BCLC stage D patients should be offered palliative, supportive care.

Hepatocellular Carcinoma (HCC) Treatment Algorithm Author Robert G. Gish MD

Appendix: Sorafenib
Sorafenib (Nexavar) is a multi-kinase inhibitor of serine/threonine, is approved to treat unresectable HCC. Training for hepatologists to use sorafenib include: 1) To understand of HCC staging (BCLC staging) and treatment algorithm. Prescribing provider needs to be able to determine the proper indication for the use of sorafenib a. The use of sorafenib should be discussed at the weekly multidisciplinary liver tumor board (liver cancer group meeting, AKA LCG), and the recommendation will be documented in EPIC b. BCLC stage C patients (Advanced stage (C) with Portal invasion,N1, M1, PST 1-2 are good candidate for sorafenib c. Downstaging for liver transplantation (UCSF criteria) or combination with TACE (transarterial chemoembolization), TABE (transarterial drug eluded beads embolization), or TARE (transarterialradioembolization) needs further study d. Child-Pugh A patients are good candidates for sorafenib in general. Child-Pugh B patients can be candidates for sorafenib, but needs to be carefully evaluated for indication. Child-Pugh C patients should not receive sorafenib. e. Patients with active bleeding should be stabilized for bleed prior to initiation of sorafenib. EGD for screening EV/GV should be done within 6 months prior to sorafenib initiation. 2) To understand the mechanism of sorafenib. The provider should be familiar with the results of SHARP trial, and Asian Pacific trial. a. SHARP trial: Sorafenib treatment associated with significantly longer overall survival and time to radiologic progression vs placebo, 10.7 vs 7.9 months, respectively (P < .001), 1-year survival: 44% vs 33%, respectively (P = .0009). Time to symptomatic progression not significantly different between sorafenib and placebo groups, 4.1 vs 4.9 months, respectively (P = .77). Time to radiologic progression significantly longer with sorafenib vs placebo, 5.5 vs 2.8 months, respectively (P < .001). Disease-control rate significantly greater with sorafenib vs placebo, 43% vs 32%, respectively (P = .002).

Hepatocellular Carcinoma (HCC) Treatment Algorithm Author Robert G. Gish MD

3) To understand the possible side effects (SE), and frequency. How to prevent and manage SEs. a. Hand-foot syndrome i. Creams and lotions ii. Avoid tight footwear iii. May require dose reduction b. Diarrhea i. Antidiarrheal agents if severe c. Fatigue i. Consider modafinil or methylphenidateif severe ii. Check for hypophosphatemia d. Hypertension i. Start or adjust antihypertensives 4) To determine when to stop treatment a. Severe SEs not manageable with above b. Progressive disease

Hepatocellular Carcinoma (HCC) Treatment Algorithm Author Robert G. Gish MD

Indications for transarterialradioembolization (TARE) for hepatocellular carcinoma (HCC)

ECOG 0-2 Unresectable HCC with portal venous thrombosis (PVT) /Child A: safe, and effective[4] Unresectable HCC without PVT /Child A and selected Child B: safe, and effective[4] Relative contraindications for TACE/TABE: o o o tumor in main PV TIPS or surgical portosystemic shunts hepatofugal PV flow

Large Tumors not amenable to TABE or TACE Patients with T3 disease to downstage to T2 for OLT candidacy [8] (retrospective series from Northwestern that shows T3 --> T2 conversion about double for Y90 compared to TACE) Patients with unifocal disease (regardless of tumor size) in whom a radiation segmentectomy or lobectomy is planned

Indication for TARE: further discussion

Use of Y90 to bridge to transplant o If we elect to use Y90 RE for patients who are on the OLT list, we need to address the issue of taking these patients off the list for a period of time (eg, 1 week or <10 half lives). At issue is radiation exposure to the operating team, and potential radioactive contamination of the OR, pathology, etc. which should be a non issue due to the 2mm penetration of the radiation in tissues

TACE/TABE candidate, benefit of using TARE o Retrospective data from NW indicates that both TACE and Y90 RE about equally effective for tumor control and survival, but Y90 is associated with better quality of life (much less post embolization syndrome). Financial impact to UCSD could be considerable, so administration will need to weigh in.

Hepatocellular Carcinoma (HCC) Treatment Algorithm Author Robert G. Gish MD

Contraindications to ablative therapy:

Pre treatment laboratory findings within 15 days of treatment demonstrating liver dysfunction o o AST or ALT >5 times UNL Serum total bilirubin >2.0mg /dL or direct bilirubin >1.2mg/dL (unless segmental infusion is planned)

Any contraindications to angiography and hepatic artery catheterization such as o o o History of severe allergy or intolerance to any contrast media, narcotics, sedatives or atropine that cannot be corrected or premedicated Bleeding diathesis, not correctable by usual forms of therapy Severe peripheral vascular disease that would preclude catheterization

Evidence of potential delivery of greater than 16.5mCi (30 Gy absorbed doses) of radiation to the lungs in a single treatment or hepatopulmonary shunt > 20%. Evidence of any detectable Tc-99m MAA flow to the stomach or duodenum after application of established angiographic technique to stop or mitigate such flow. (NOTE: Free Tc may be secreted by normal gastric mucosa thus flow assessments to stomach and duodenum will be determined using this factor. Therefore, gastric Tc activity may not necessarily represent a contraindication if activity is also detected in the salivary glands, thyroid, kidneys, and bladder -all sites of Tc excretion, secretion, or accumulation) Active systemic uncontrolled infection Pregnancy

Warnings/Precautions
High Risk Factors for nonresponse to Y90 or liver decompensation after TARE o o o o o o Infiltrative tumor type Bulk disease (tumor volume >70% of the target liver volume, or tumor nodules too numerous to count) AST or ALT > 5 times ULN Total bilirubin >2mg/dL or direct bilirubin >1.2mg/dL Tumor volume >50% combined with an albumin <3g/dL Advanced portal hypertension. Y90 TARE is associated with hepatic fibrosis, hepatic atrophy, and splenomegaly.

Hepatocellular Carcinoma (HCC) Treatment Algorithm Author Robert G. Gish MD

Notes o Shunt: in some patients, anhepatopulmonary shunt (HPS) is a contra indication esp for TARE. For hepatopulmonary shunt 10-20%, dose reduction is in order. For HPS >20%, Y90 TARE should not be performed. Imaging follow up At 30 days, then q3 months, prefers MRI 4 phase with DWI o Realize that full impact of tare is hard to determine on imaging, and full effect may not be seen for up to 6 months Lab F/U: LFTs, AFP, CBC

Complications gall bladder injury (very rarely) and GI ulceration(1-2%) have been reported Radioembolization induced liver disease probably occurs approximately 5%, infrequently fatal: advanced Child and MELD scores: high risk of radiation induced liver disease(RILD), radioembolization induced liver disease (REILD) o All patients should be on PPI for 30 days due to risk of GI ulceration medrol dose pak for 5 days, prophylactic antibiotics for 5 days, IV flagyl and oral cipro preferred until DC, then oral dual abx for total of 5 days

Radiation exposure to others: Y90 emits Beta rays which have the mass of an electron, and beta radiation has a mean penetration of 2.5 mm in soft tissue. It is permanently embedded within the liver. Exposure to others is minimal. Current recommendations: 1) Sleep in separate bed 3 nights 2) avoid direct contact with small children and pregnant women for 3 days 3) double flush the toilet after use for 3 days

Hepatocellular Carcinoma (HCC) Treatment Algorithm Author Robert G. Gish MD

Hepatocellular Carcinoma (HCC) Treatment Algorithm Author Robert G. Gish MD

Definition of the Okuda Staging System for Hepatocellular Carcinoma

Points 0 1

Tumor size Ascites Albumin (g/dl) Bilirubin (mg/dl)

<50% of liver >50% of liver No 3 <3 Yes <3 3

Okuda stage I, 0 points; Okuda stage II, 1 or 2 points; Okuda stage III, 3 or 4 points.

Definition of the Cancer of the Liver Italian Program (CLIP) Scoring System For Hepatocellular Carcinoma

Points 0 1 2

ChildPugh stage Tumor morphology

A Uninodular and extension 50% 400 No

B Multinodular and extension 50% 400 Yes

C Massive or extension 50%

AFP (ng/ml) Portal vein thrombosis

Early stage, 0 points; Intermediate stage, 13 points; Advanced stage, 46 points; AFP, -fetoprotein.

Hepatocellular Carcinoma (HCC) Treatment Algorithm Author Robert G. Gish MD

References:
1. 2. 3. Bruix, J. and M. Sherman, Management of hepatocellular carcinoma. Hepatology, 2005. 42(5): p. 1208-36. Bruix, J. and M. Sherman, Management of Hepatocellular Carcinom: An Update. Hepatology, 2010(July): p. 1-35. Lammer, J., et al., Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 33(1): p. 41-52. Kulik, L.M., et al., Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology, 2008. 47(1): p. 71-81. Salem, R., et al., Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology. 138(1): p. 52-64. Llovet, J.M., et al., Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008. 359(4): p. 378-90. Cheng, A.L., et al., 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(1): p. 25-34. Lewandowski, R.J., et al., A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant, 2009. 9(8): p. 1920-8.

4. 5. 6. 7.

8.

Credits to Yuko Kono and Claude Sirlin at UCSD