Chapter 15: Hepatocellular Carcinoma

Tim Greten; Nadine Abi-Jaoudeh

INTRODUCTION

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Epidemiology

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Epidemiology

Incidence^✫:

16 cases per 100,000 population worldwide: 626,000 cases per year

Stage at presentation

Stage A:

35%

Deaths (worldwide):

598,000 per year

Stage B:

25%

Median age^✫ (Asia and Western Europe):

50–60 years

Stage C:

10%

Male to female ratio:

~2.4:1

Stage D:

30%

^✫The incidence and age of hepatocellular carcinoma vary widely according to geographic location. The distribution also differs among ethnic groups and regions within the same country

Forner et al. Lancet 2012;379:1245–1255

Llovet JM et al. J Natl Cancer Inst 2008;100:698–711

Parkin DM et al. CA Cancer J Clin 2005;55:74–108

Work-up

Alpha-fetoprotein (AFP)
Liver function test (see Child-Pugh classification)
Ultrasound and abdominal/chest spiral CT and/or dynamic liver MRI
Specific clinical scenarios such as selection for liver transplantation may also require bone scintigraphy to exclude bone metastases, but there are no robust data supporting the cost-efficiency of this policy

Diagnostic Criteria for HCC: Non-invasive criteria (Restricted to cirrhotic patients)

Radiological criteria: (arterial hypervascularization/washout in portal phase)

Two coincident imaging techniques, nodule <2 cm

One imaging technique, nodule >2 cm
Combined criteria: one imaging technique associated with AFP

Focal lesion >2 cm with arterial hypervascularization

Bruix J, Sherman M. Hepatology 2005;42:1208–1236

Forner A et al. Hepatology 2008;47:97–104

Pathology

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Pathology

Hepatocellular carcinoma

99%

Fibrolamellar hepatocellular carcinoma

<1%

Nakashima T, Kojiro M. Hepatocellular Carcinoma. Tokyo, Japan: Springer Verlag, 1987

Staging

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Staging

Primary Tumor (T)

Primary tumor cannot be assessed

No evidence of primary tumor

Solitary tumor without vascular invasion

Solitary tumor with vascular invasion or multiple tumors none more than 5 cm

T3a

Multiple tumors more than 5 cm

T3b

Single tumor or multiple tumors of any size involving a major branch of the portal vein or hepatic vein

Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum

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Staging

Regional Lymph Nodes (N)

Regional lymph nodes cannot be assessed

No regional lymph node metastasis

Regional lymph node metastasis

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Staging

Distant Metastasis (M)

No distant metastasis (no pathologic M0; use clinical M to complete stage group)

Distant metastasis

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Staging

Staging

IIIA

T3a

IIIB

T3b

IIIC

IVA

any T

IVB

any T

any N

Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010

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Staging

Child-Pugh Classification

Measure

Score^✫

1 Point

2 Points

3 Points

Ascites

Absent

Slight

Moderate

Serum bilirubin

<2.0 mg/dL (<34.2 mmol/L)

2.0–3.0 mg/dL (34.2–51.3 mmol/L)

>3.0 mg/dL (>51.3 mmol/L)

Serum albumin

>3.5 g/dL

2.8–3.5 g/dL

<2.8 g/dL

Prothrombin time (seconds prolonged)

4–6

Encephalopathy grade

None

1–2

3–4

^✫Child-Pugh A: 5 or 6 points; Child-Pugh B: 7–9 points; Child-Pugh C: >9 points

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Staging

Barcelona Clinic Liver Cancer (BCLC) Classification

Tumor Status

Child-Pugh Classification

Performance Status

Stage 0

Very Early Stage

Single HCC <2 cm;

Carcinoma in situ

Stage A

Early Stage

Single HCC or 3 nodules <3 cm

A–B

Stage B

Intermediate Stage

Large/multinodular. Without vascular invasion or extrahepatic spread

A–B

Stage C

Advanced Stage

Any size with vascular invasion or extrahepatic spread. [N1M1]

A–B

1–2

Stage D

Terminal Stage

Any size

3–4

Llovet Jm Et Al. J Natl Cancer Inst 2008;100:698–711

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Staging

Survival (BCLC Staging)

Stage

3-Year Survival

Stage 0-A

40–70%

Stage B

50%

Stage C

10%

Stage D

Llovet JM et al. J Natl Cancer Inst 2008;100:698–711

Llovet JM et al. Lancet 2003;362:1907–1917

Expert Opinion

TREATMENT ACCORDING TO STAGE

European Association for the Study of the Liver (EASL)/European Organization for Research and Treatment of Cancer (EORTC) Guidelines J. Hepatol 2012;56:908–943

Stage 0–A

Patients diagnosed at an early stage (BCLC A) should be considered for one of the options that can achieve complete response: resection, liver transplantation from cadaveric or live donor, and percutaneous ablation by ethanol injection or radiofrequency
Stage B

Chemoembolization
Stage C

Sorafenib
Stage D

Symptomatic treatment

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Hepatocellular Carcinoma—BCLC Staging and Treatment Strategy

Adapted from Forner et al, Lancet 2012;379:1245–1255

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Therapeutic Strategies/Options

Adapted from Forner A et al. Lancet 2012;379:1245–1255

Procedure/Treatment

Benefit

Level of Evidence

Comment

Surgical Treatments

Surgical resection

Increased survival

3ii A

Treatment of choice in 5–10% without cirrhosis and one tumor. High rate of CRs; potential for cure
5-year survival: ~70% without portal hypertension and normal bilirubin; 50% with portal hypertension; <50% if bilirubin increased

Adjuvant treatments

Controversial

1 A–D

Tumor recurrence 70% at 5 y. Includes early (true) recurrence, usually in first 2 years > resection, and late (de novo) tumors
No effective neo-adjuvant or adjuvant treatments

Liver transplantation

Increased survival

3ii A

Most effective option to prevent intrahepatic recurrence; recurrence rate <25%. One tumor ≤5 cm or ≤3 cm without vascular invasion or extra-hepatic spread ~75% 4-year survival; <15% recurrence rates
Can offer to patients treated with resection but with a high risk of recurrence according to pathologic analysis

Adjuvant treatments

Treatment response

3 Diii

If transplant donors wait >6 months, trans-arterial chemoembolization and ablation are done, even though effectiveness is unproven

Loco-Regional Treatments—Image-Guided Tumor Ablation

Percutaneous treatment [injection of chemicals (ethanol, acetic acid) or temperature modification (radiofrequency (RFA), microwave, laser)]

Increased survival

3ii A

First-line technique now radiofrequency ablation (RFA)
Both ethanol and RFA highly effective in HCC <2 cm, but effectiveness of ethanol falls in 2–5 cm tumors
Effectiveness limited by (1) tumor size—ablation not recommended for tumors >5 cm; and (2) tumor location—with RFA avoid tumors located in subcapsular region, vicinity of major blood vessels or biliary tree, near to bowel or heart
Side-effects more frequent after RFA
Better disease control with RFA than ethanol could translate into better outcomes

Radiofrequency ablation (RFA)

Increased survival

1ii A

Other modalities

Treatment response

2 D

Combined modalities

3ii D

Loco-Regional Treatments—Image-Guided Transcatheter Tumor Treatment

Chemoembolization

Increased survival

1ii A

Best candidates patients with compensated Child-Pugh A with asymptomatic multifocal or large hepatocellular tumors not amenable to resection (BCLC stage B)
>50% of patients have objective response that translates into improved in survival
Portal vein thrombosis, even if segmental, predicts poor tolerability and worse outcome

Radioembolization [Internal radiotherapy, ¹³¹I, ⁹⁰Y]

Treatment response

3ii Diii

Anti-tumor activity but survival benefit not proven
Role not yet defined

Systemic Treatments

Sorafenib

↑ survival

1i A

Non-curative treatment that improves survival

Hormonal compounds [Tamoxifen, Octreotide, Antiandrogen, Seocalcitiol]

No survival benefit

1i A

Completely ineffective

Systemic chemotherapy

1i A

Marginal activity; frequently toxic

Immunotherapy

1ii A

Evidence-based classification adapted from the National Cancer Institute

1 = Randomized controlled trial or meta-analysis [1i = Double-blinded, 1ii = Non-blinded]; 2 = Non-randomized controlled trial; 3 = Case series [3i = Population-based, 3ii = Non-population-based, consecutive, 3iii = Non-population-based, non-consecutive]. A = Survival endpoint. B = Cause-specific mortality. C = Quality of life. D = Indirect surrogates [Di = Disease-free survival, Dii = Progression-free survival, Diii = Tumor response]

Surgical Resection

Best candidates patients with small solitary tumors and well-preserved liver function
Tumor recurrence 70% at 5 years. Includes true recurrence, usually within the first 2 years after resection, and de novo tumors
“Early” (true) recurrence: Microvascular invasion, poor histological differentiation, satellites, and multifocal disease predict early recurrence
Late (de novo) recurrence: Depends mainly on carcinogenic effect of underlying chronic liver disease. Estimated by liver function variables related to inflammatoryactivity, evolutionary stage, or both
No effective neo-adjuvantor adjuvant treatment options to reduce risk of recurrenceare available

Bruix and Sherman. Hepatology 2011;53:1020–1022

Imamura et al. J Hepatol 2003;38:2000–2007

Llovet et al. Semin Liver Dis 2005;25:181–200

Sala et al. Liver Transpl 2004;10:1294–1300

Liver Transplantation

Most beneficial for patients deemed poor candidates for resection, especially those within Milano criteria (solitary tumor ≤5 cm and up to three nodules ≤3 cm)
Donor shortage limits applicability
Excellent results achieved in era with prompt availability of organs. Shortage of donors has imposed delay before transplantation, and tumor can progress and impede transplantation. Delays impair effectiveness of transplantation when considered according to intention
When waiting >6 months, ablation and trans-arterial chemoembolization are done, even though effectiveness is unproven
No role for systemic chemotherapy prior to transplantation

Bismuth et al. Ann Surg 1993;218:145–151

Clavien et al. Lancet Oncol 2011;2045:70175–70179

Freeman et al. Am J Transplant 2006;6:1416–1421

Jonas et al. Hepatology 2001;33:1080–1086

Mazzaferro et al. N Engl J Med 1996;334:693–699

Percutaneous Ablation

Induces tumor necrosis by injection of chemicals (eg, ethanol, acetic acid) or temperature modification (ablation by radio frequency (RFA), microwave, or laser)

Note: Cryoablation resulted in shock and hepatic failure, and laser is not yet approved by the FDA
Most ablation procedures done percutaneously, but can also done intraoperatively
First-line technique is now radiofrequency ablation (RFA). Both ethanol injection and RFA highly effective in HCC <2 cm, but effectiveness of ethanol falls in 2–5 cm tumors
Effectiveness limited by
1. Tumor size: All ablation not recommended for tumors >5 cm
2. Tumor location: With RFA avoid some tumors located in subcapsular region, vicinity of major blood vessels or biliary tree, near to bowel or heart
Better disease control with RFA than ethanol could translate into better outcomes
Side-effects more frequent after RFA
Survival ≤ ablation in Child-Pugh A patients is 50–75% at 5 years, paralleling surgical resection. Has challenged resection as the first-line treatment in patients with small solitary HCCs. Ablation nearly 100% effective in HCCs <2 cm and survival almost identical after resection or ablation
RFA is associated with less treatment-associated morbidity than resection

Chen et al. Ann Surg 2006;243:321–328

Cho et al. Hepatology 2009;49:453–459

Germani et al. J Hepatol 2010;52:380–388

Huang et al. Ann Surg 2005;242:36–42

Huang et al. Ann Surg 2010;252:903–912

Lencioni. Hepatology 2010;52:762–773

Orlando et al. Am J Gastroenterol 2009;104:514–524

Tateishi et al. Cancer 2005;103:1201–1209

Image-Guided Transcatheter Tumor treatment—Chemoembolization

Best candidates for trans-arterial chemoembolization are patients with compensated Child-Pugh A with asymptomatic multifocal or large hepatocellular carcinomas not amenable to resection (ie, BCLC stage B)
>50% of patients have an objective response, and this translates into improvement in survival
After initial success with transarterial chemoembolization, treated tumors re-vascularize and can be re-treated. However, in the long term, control is lost
Median survival in old series almost 2 years but with better selection and optimum treatment, median survival >3 years
Portal vein thrombosis, even if segmental, is a predictor of poor tolerability and impaired outcome
No standard regimen established
Extra systemic therapy between/following TACE procedures failed to improve outcome and is not recommended

Lammer et al. Cardiovasc Intervent Radiol 2010;33:41–52

Lin et al. Gastroenterology 1988;94:453–456

Llovet et al. Lancet 2002;359:1734–1739

Pelletier et al. J Hepatol 1990;11:181–184

Image-Guided Transcatheter Tumor Treatment—Radioembolization

Radioembolization with yttrium-90 (Yt⁹⁰)-labeled spheres has anti-tumor activity. There are no randomized controlled trials comparing this option with any other established treatment. A retrospective comparison to chemoembolization (TACE) found that radioembolization and chemoembolization had similar survival rates; however, radioembolization had longer time to progression and less toxicity than chemoembolization [Salem R et al. Gastroenterology 2011;140:497–507]

Hilgard et al. Hepatology 2010;52:1741–1749

Salem et al. Gastroenterology 2010;138:52–64

Sangro et al. Hepatology 2011;54:868–878

Systemic Treatment—Sorafenib

602 patients in a multicenter, randomized, double-blind placebo-controlled trial
Median OS in sorafenib group 10.7 months (95% CI 9.4–13.3) versus 7.9 months (6.8–9.1) in placebo group (hazard ratio 0.69, 95% CI 0.55–0.87; p = 0.0001)
Median PFS 5.5 months for sorafenib versus 2.8 months for placebo (0.58, 0.45–0.74; p <0.001)
No difference in median time to symptomatic progression (4.1 months vs 4.9 months; p = 0.77)
Overall incidence of treatment-related adverse events (predominantly grade 1 or 2 in severity) 80% in sorafenib group and 52% in placebo group
Findings have been replicated by a randomized controlled trial in Asia
These results have established sorafenib as the standard of care for advanced HCC

Cheng et al. Lancet Oncol 2009;10:25–34

Llovet et al. N Engl J Med 2008;359:378–390

EXTRAHEPATIC COLLATERAL VESSELS SUPPLYING HEPATOCELLULAR CARCINOMAS

Kim HC et al. Radiographics 2005;25(Suppl 1):S25–S39

Extra-hepatic collateral arteries commonly supply hepatocellular carcinomas especially if the tumors are large or peripherally located
Development of these vessels can interfere with effective tumor control with transcatheter arterial chemoembolization (TACE)
When both the hepatic artery and extra-hepatic collateral vessels supply a tumor, additional extra-hepatic collateral vessel chemoembolization should be attempted to increase the therapeutic efficacy of TACE
Extrahepatic collateral vessels originated from thirteen different sources (see Table): Considering the broad contact between the liver and the diaphragm, it is not surprising that diaphragmatic blood supplies, including the inferior phrenic, internal mammary, and intercostal arteries, are major sources of collateral circulation. Exophytic growth and extra-capsular HCC infiltration can cause omental adhesion. Direct contact or invasion into other organs, including the stomach, colon, adrenal gland, and kidney, may create blood supply to the tumor from these organs
Extrahepatic collateral vessels suspected when:
1. A tumor grows exophytically or invades adjacent organs
2. A tumor is in contact with the ligaments and bare area of the liver
3. A hypertrophied extrahepatic collateral vessel is observed on a computed tomographic (CT) scan
4. A peripheral defect of iodized oil retention within a tumor is seen during chemoembolization or on a follow-up CT scan
5. A local recurrence develops at the peripheral portion of the treated tumor during follow-up
6. A sustained elevation in serum α-fetoprotein level is noted despite adequate embolization of the hepatic artery
Outcomes:
1. 2104 such vessels observed in 1622 sessions in 860 (27%) patients
2. TACE performed via 1556 extrahepatic collateral vessels (74%) in 732 patients in 1281 sessions
3. Multiple extrahepatic collateral vessels embolized in 221 patients (two vessels in 186 patients, three vessels in 27, four vessels in six, and five vessels in two)

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Extra-Hepatic Collateral Vessels Supplying HCC in 3179 Patients

Collateral Vessel

Observed Vessels

Embolized Vessels^✫

Right inferior phrenic artery

1026

864 (84)

Omental branch

306

176 (58)

Adrenal artery

188

152 (81)

Intercostal and subcostal artery

128

83 (65)

Cystic artery

82 (92)

Left inferior phrenic artery

58 (74)

Right internal mammary artery

59 (78)

Renal or renal capsular artery

29 (41)

Branch of superior mesenteric artery

20 (42)

Left gastric artery

12 (26)

Right gastric artery

5 (22)

Left internal mammary artery

14 (67)

Lumbar artery

2 (40)

Total

2104

1556

^✫Percentages in parentheses

REGIMEN: CHEMOEMBOLIZATION WITH DOXORUBICIN

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Regimen: Chemoembolization with Doxorubicin

Llovet JM et al. Lancet 2002;359:1734–1739

Doxorubicin dose adjusted to serum bilirubin concentration (see table below) prepared as an emulsion with 10 mL of ethiodized oil injection administered intra-arterially followed by mechanical obstruction achieved by intra-arterial injection of gelatin sponge fragments suspended in radiologic contrast media until flow stagnation occurred. Chemoembolization was performed at baseline, repeated 2 months and 6 months later, and then every 6 months until disease progression observed

Notes:

Doxorubicin dosage was based on serum total bilirubin concentration as per the table below:

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Total Bilirubin

Doxorubicin Dosage

(μmol/L)

(mg/dL)

<25.6

<1.5

75 mg/m²

25.6–51.3

1.5–3

50 mg/m²

51.3–85.5

3–5

25 mg/m²

Extra-hepatic arterial supply of HCC is important. See section on Extrahepatic collateral vessels supplying hepatocellular carcinomas [Kim HC, Chung JW, Lee W, Jae HJ, Park JH, Radiographics 2005;25(Suppl 1):S25–S39]
The mean numbers of treatment sessions were 3.08 (95% CI 2.4–3.5; range 0–7) for embolization and 2.8 (2.3–3.2; 1–8) for chemoembolization (p = 0.5)

GENERAL GUIDELINES

Prior to embolization:

Hydration
- Start intravenous hydration with 0.9% sodium chloride injection (0.9% NS)
- Continuous 0.9% NS 100 mL/h beginning a minimum of 6 hours prior to procedure
Antibiotic prophylaxis not always required but may be considered with the first doses given before embolization:
- Metronidazole 500 mg; administer intravenously prior to procedure followed by 500 mg every 12 hours × 3 doses, plus
- Cefazolin 1000 mg; administer intravenously prior to procedure followed by Cefazolin 500 mg; administer intravenously every 8 hours × 5 doses
Antiemetic primary prophylaxis

Give a serotonin receptor (5HT₃) antagonist plus a high-potency glucocorticoid
- Ondansetron 16 mg; administer intravenously or 24 mg orally, plus
- Dexamethasone 10–12 mg; administer intravenously or orally 30–60 minutes before the procedure

Post-embolization syndrome:

The triad of abdominal pain, vomiting, and fever that frequently occurs 24–72 hours after chemoembolization is commonly referred to as post-embolization syndrome
Post-embolization syndrome uniformly responds to supportive care including analgesics and antiemetics
Use care administering acetaminophen (paracetamol) and non-steroidal anti-inflammatory drugs in patients with liver cirrhosis

After embolization:

Continue intravenous hydration with 0.9% NS or another clinically appropriate fluid until patient resumes adequate oral fluid intake
Provide analgesic support with parenterally administered opioid medications (morphine, hydromorphone, fentanyl) after chemoembolization until patient is able to continue analgesic treatment with oral products
Continue antiemetic prophylaxis with a 5HT₃ antagonist plus a high-potency glucocorticoid:
- Ondansetron 8 mg; administer intravenously or orally every 8 hours, plus
- Dexamethasone 8 mg; administer intravenously or orally every 8 hours for 2–3 days
Filgrastim (G-CSF) 5 mcg/kg per day; administer by subcutaneous injection
- May be used for patients who develop an ANC <500/mm³, neutropenia and fever, or documented infections during neutropenia
- Discontinue filgrastim at least 24 hours before a chemoembolization procedure

Patient Population Studied

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A total of 903 patients were screened and 791 excluded due to early HCC, advanced liver disease, vascular invasion, extra-hepatic spread, and end-stage cancer. 112 patients with intermediate BCLC stage (stage B or C) randomized to conservative treatment (n = 35), embolization (n = 37), or chemoembolization (n = 40)

Patient Characteristics

Embolization (n = 37)

Chemoembolization (n = 40)

Control (n = 35)

Demography

Age, years^✫

64 (62–67)

63 (61–66)

66 (64–68)

M/F

30/17 [81%/19%]

32/8 [80%/20%]

23/12 [66%/34%]

Cause of cirrhosis

Hepatitis C virus

30 (81%)

33 (82%)

32 (91%)

Hepatitis B virus

2 (5%)

4 (10%)

1 (3%)

Alcohol

4 (11%)

3 (8%)

1 (3%)

Other

1 (3%)

—

1 (3%)

Tumor-related symptoms

Ascites

9 (24%)

6 (15%)

11 (31%)

Abdominal pain

7 (19%)

3 (8%)

3 (9%)

Constitutional syndrome

1 (3%)

1 (2%)

4 (11%)

Biochemistry

Serum bilirubin (mmol/L)^✫

22.2 (18.8–27.4)

20.5 (18.8–23.9)

25.6 (22.2–29.1)

Prothrombin activity (%)^✫

81 (75–87)

82 (77–87)

77 (71–83)

Serum albumin (g/L)^✫

35 (33–37)

γ-glutamyltranspeptidase^✫,‡

113 (70–156)

112 (85–139)

101 (66–137)

Alkaline phosphatase^✫,‡

233 (203–263)

220 (182–258)

257 (202–311)

Distribution of α-fetoprotein concentrations

<10 mg/L

10–100 mg/L

>100 mg/L

Tumor stage

Solitary (66%)^†

9 (24%)

13 (32%)

8 (23%)

Multinodular

27 (73%)

26 (65%)

27 (77%)

Two nodules

More than two nodules

Diffuse

1 (3%)

—

Disease Characteristics

Diameter main nodule (mm)^✫

52 (46–60)

49 (40–58)

44 (39–49)

Bilobar disease

18 (49%)

19 (47%)

18 (51%)

Child-Pugh class A/B

27/10

31/9

21/14

Okuda Stage I/II

24/13

27/13

22/13

BCLC Stage B/C

28/9

35/5

27/8

Performance Status

Data are numbers of patients unless otherwise indicated

^✫Mean (95% CI)

^†Solitary tumors with or without satellites

^‡(IU/L)

Treatment Modifications

Doxorubicin dosage modifications were based on serum total bilirubin concentrations before treatment

Efficacy

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Efficacy

1. Chemoembolization induced objective responses sustained for at least 6 months in 35% (14) of cases, and was associated with a significantly lower rate of portal vein invasion than conservative treatment

2. Probability of portal vein invasion reduced from 58% in control to 17% in patients with chemoembolization

3. Survival probabilities at 1 year and 2 years were 75% and 50% for embolization, and 82% and 63% for chemoembolization

4. Patients who achieved objective responses sustained for at least 6 months had probabilities of survival at 1, 2, and 3 years of 96%, 77%, and 47%, respectively (p = 0.002 compared with patients with treatment failure, and p = 0.006 vs control group)

5. Treatment allocation was the sole baseline variable independently related to survival (odds ratio 0.45 [95% CI 0.25–0.81], p = 0.02) in the Cox's regression model. Inclusion of treatment response identified this variable as an independent predictor (odds ratio 0.59 [0.44–0.81], p = 0.0007) together with constitutional syndrome (0.46 [0.25–0.86], p = 0.04)

6. There were no differences in intention-to-treat survival between non-responders and the control group (1-year survival 65% vs 63%; 2-year survival 41% vs 26%, p = 0.3)

Embolization (n = 37)

Chemoembolization (n = 40)^✫

Control (n = 35)^✫

Mean follow-up, month

21.7

21.2

14.5

Mean follow-up, 95% CI

17.5–26.0

17.3–25.1

10.6–18.4

Probability of survival at 1 year

75%

82%

63%

Probability of survival at 2 years

50%

63%

27%

Probability of survival at 3 years

29%

17%

Mean survival, months

25.3

28.7

17.9

Mean survival, 95% CI

20.3–30.2

23.6–33.7

13.1–22.7

Assessment of response in 102 Patients Who Survived for at Least 5 Months

Objective responses

16^†

14^†

Probability of portal-vein invasion at 2 years

—

17%

58%

p = 0.005

^✫Survival was significantly better in the chemoembolization group than in the control group (p = 0.009)

^†Embolization vs control, p = 0.001; chemoembolization vs control, p = 0.004

Causes of Death

Embolization (n = 37)

Chemoembolization (n = 40)

Control (n = 35)

Total (n = 112)

Deaths

25 (67%)

21 (52%)

25 (71%)

71 (63%)

Cause of Death

Tumor progression

Hepatic failure with SD^✫

Other

1^†

2^‡

^✫SD, stable disease

^†Neoplasm of lung

^‡Neoplasm of tongue and treatment-related death (septic shock)

Reasons for Treatment Discontinuation Among Patients Who Received Embolization^✫

Embolization (n = 37)

Chemoembolization (n = 40)

Both Groups (n = 77)

Reason

Tumor progression (portal thrombosis, extra-hepatic spread, or performance status >2)

Liver failure without tumor progression

Technical problems (arterial hepatic obstruction, collateral or hepatofugal blood flow, low ejection fraction)

Adverse events (leucopenia, ischemic biliary stricture, transient ischemic attack, allergic dermatitis)

Patient's decision

Death on treatment

Other (lung cancer, percutaneous ethanol injection)

Treatment discontinuation

29 (78%)

31 (77%)

60 (78%)

Active treatment at end of follow-up

8 (22%)

9 (23%)

17 (22%)

^✫There were no significant differences between groups

Toxicity (N = 40)

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Toxicity (N = 40)

Adverse Event

Number of Patients

Cholecystitis

Leukopenia

Ischemic biliary stricture

Hepatic infarction

Spontaneous bacterial peritonitis

Bacteremia

Septic shock

Allergic dermatitis

Severe alopecia

Other complications associated with TACE procedures in general:

Hepatic artery occlusion: 4%
Damage to the hepatic artery: pseudoaneurysm (rare), occlusion, and dissection
Treatment was discontinued in 60 (78%) patients

Therapy Monitoring

Days 7 and 14 after TACE and then monthly: CBC and LFTs
Response assessment using computed tomography (CT) every 3 months

REGIMEN: CHEMOEMBOLIZATION WITH CISPLATIN

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Regimen: Chemoembolization with Cisplatin

Lo C-M et al. Hepatology 2002;35:1164–1171

Chemoembolization: Cisplatin (1 mg/mL) emulsified with ethiodized oil injection in equivalent volumes (1:1)

Administer cisplatin intra-arterially via the left or right hepatic artery as appropriate for tumor vascularization. If selective catheterization is not possible, the cisplatin emulsion is injected into the hepatic artery, distal to the gastroduodenal artery
The emulsion is injected slowly under fluoroscopic monitoring to a maximum volume of 60 mL (≤30 mg cisplatin) at a controlled rate to prevent retrograde flow, followed by mechanical obstruction achieved by intra-arterial injection of gelatin sponge pellets 1 mm in diameter mixed with gentamicin 40 mg
Chemoembolization is repeated every 2–3 months until comorbid pathologies, adverse events, or disease progression are observed

Notes:

Extra-hepatic arterial supply of HCC is important. See section on Extrahepatic collateral vessels supplying hepatocellular carcinomas [Kim HC, Chung JW, Lee W, Jae HJ, Park JH. Radiographics 2005;25(Suppl 1):S25–S39]
Forty patients assigned to the chemoembolization group received a total of 192 courses of chemoembolization, with each patient receiving a median of 4.5 courses (range, 1–15). Ninety-four courses (49%) of the chemoembolization were performed by selective injection into the right or left hepatic artery. The median volume of cisplatin-ethiodized oil emulsion injected in 1 course was 20 mL (range, 2–60), and the dosage was significantly related to the tumor size (r = 0.70; P <0.001)

Two patients were scheduled for continuation of chemoembolization as of the date of the latest follow-up. The remaining 38 patients had treatment stopped because of progressive disease (12 patients), death (7 patients), poor liver function (6 patients), adverse effects (6 patients), patient refusal (3 patients), arteriovenous shunting (2 patients), and hepatic artery thrombosis (2 patients)

The most common clinical adverse effect was a self-limiting syndrome consisting of fever, abdominal pain, and vomiting. The median hospital stay for each course of treatment was 2 days (range, 1–21)

GENERAL GUIDELINES

Prior to embolization:

Hydration
- Start intravenous hydration with 0.9% sodium chloride injection (0.9% NS)
- Continuous 0.9% NS 100 mL/h beginning a minimum of 6 hours prior to procedure
Antibiotic prophylaxis not always required but may be considered with the first doses given before embolization:
- Metronidazole 500 mg; administer intravenously prior to procedure followed by Metronidazole 500 mg; administer intravenously every 12 hours × 3 doses, plus
- Cefazolin 1000 mg; administer intravenously prior to procedure followed by Cefazolin 500 mg; administer intravenously every 8 hours × 5 doses
Antiemetic primary prophylaxis

Give a serotonin receptor (5HT₃) antagonist plus a high-potency glucocorticoid
- Ondansetron 16 mg; administer intravenously or 24 mg orally, plus
- Dexamethasone 10–12 mg; administer intravenously or orally 30–60 minutes before the procedure

Post-embolization syndrome:

The triad of abdominal pain, vomiting, and fever that frequently occurs 24–72 hours after chemoembolization is commonly referred to as post-embolization syndrome
Post-embolization syndrome uniformly responds to supportive care including analgesics and antiemetics
Use care administering acetaminophen (paracetamol) and non-steroidal anti-inflammatory drugs in patients with liver cirrhosis

After embolization:

Continue intravenous hydration with 0.9% NS or another clinically appropriate fluid until patient resumes adequate oral fluid intake
Provide analgesic support with parenterally administered opioid medications (morphine, hydromorphone, fentanyl) after chemoembolization until patient is able to continue analgesic treatment with oral products
Continue antiemetic prophylaxis with a 5HT₃ antagonist plus a high-potency glucocorticoid:
- Ondansetron 8 mg; administer intravenously or orally every 8 hours, plus
- Dexamethasone 8 mg; administer intravenously or orally every 8 hours for 2–3 days
Filgrastim (G-CSF) 5 mcg/kg per day; administer by subcutaneous injection
- May be used for patients who develop an ANC <500/mm³, neutropenia and fever, or documented infections during neutropenia
- Discontinue filgrastim at least 24 hours before a chemoembolization procedure

Treatment Modifications

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Treatment Modifications

Withhold or discontinue chemoembolization for:

Hepatic artery thrombosis
Main portal vein thrombosis
Arteriovenous shunting
Hepatic encephalopathy
Ascites not controlled by diuretics
Variceal bleeding within the last 3 months
Serum total bilirubin >50 μmol/L (>2.9 mg/dL)
Serum albumin <28 g/L (<2.8 g/dL)
Prothrombin time 4 seconds > control

Patient Population Studied

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Patient Population Studied

A study of 80 patients with Okuda Stages I–II HCC and no contraindications for chemoembolization; 40 assigned to chemoembolization and 39 assigned to control

Baseline Characteristics of the Study Patients According to the Treatment Group

Chemoembolization (N = 40)

Control (N = 39)

Age (y)^✫

62 (53–69)

63 (53–70)

Sex (men/women)

36/4

34/5

Serum hepatitis B surface antigen (positive/negative)

34/6

29/10

Serum creatinine, μmol/L^✫

92 (82–102)

87 (78–98)

Serum total bilirubin, μmol/L^✫

14 (10–21)

13 (11–23)

Serum albumin, g/L^✫

38 (32–42)

37 (33–40)

Serum alanine aminotransferase, U/L^✫

51 (38–83)

53 (35–88)

Prothrombin time, s^✫

11.5 (10.9–12.4)

11.5 (10.8–12.5)

Serum α-fetoprotein, ng/mL^✫

505 (55–5, 874)

500 (58–24, 458)

Serum α-fetoprotein (ng/mL; <20/20–500/>500)

6/14/20

8/12/19

Indocyanine green retention at 15 minutes (%)^✫

24 (6–33)

18 (6–38)

ECOG performance status rating (0/1/2/3)

20/16/3/1

14/19/4/2

Presenting symptom (asymptomatic/ symptomatic)

12/28

10/29

Diameter of largest tumor mass, cm^✫

7 (4–14)

7 (5–11)

Number of tumors (solitary/multinodular)

17/23

15/24

Portal vein obstruction (right/left/main)^†

6/3/0

7/5/0

Okuda stage (I/II)

19/21

18/21

Note: P >0.05 for all variables when the 2 groups are compared

^✫Values are medians, with interquartile ranges shown in parentheses

^†Assessed by computed tomography

Efficacy

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Efficacy

Patients with Measurable Disease^✫

Chemoembolization (N = 28)

Control (N = 18)

Objective response

39%

P = 0.014

Complete response

(0)

Major responses

11/28 (39.3)

1 (5.55%)

Minor response

6/28 (21.4%)

2 (11.1%)

Stabilization

7/28 (25%)

6 (33.3%)

Progression

4/28 (14.3%)

9 (50%)

Patients with Measurable AFP^†

Chemoembolization (N = 29)

Control (N = 21)

Objective response in α-FP

21/29 (72.4%)

2/21 (9.5%)

P <0.001

Complete response in α-FP

9/29 (31%)

0/21 (0)

Major responses α-FP

12/29 (41.4%)

2/21 (9.5%)

Minor response in α-FP

0/29 (0)

0/21 (0)

Stabilization of α-FP

1/29 (3.4%)

1/21 (4.8%)

Progression of α-FP

7/29 (24.1%)

18/21 (85.7%)

All Patients

Chemoembolization

Control

1-Year survival

57%^‡

32%^‡

2-Year survival

31%^‡

11%^‡

3-Year survival

26%^✫^,‡

3%^‡

^✫Patients who survived more than 3 months and had a measurable tumor on computed tomographic scan

^†Patients with a baseline serum α-fetoprotein level >20 ng/mL who survived more than 3 months

^‡Relative risk of death in the chemoembolization group was 0.50; 95% CI, 0.31–0.81; p <005

Univariate Analysis of Prognostic Variables for Survival

Characteristics

Number of Patients

Probability of Survival (%)

12 Months

24 Months

36 Months

Study treatment

Chemoembolization

0.002

Control

Sex

Men

NS (0.720)

Women

Age (y)

≤60

NS (0.274)

>60

ECOG performance status rating

NS (0.384)

1–3

Presenting symptom

Asymptomatic

0.004

Symptomatic

Tumor size (cm)

≤5

0.019

Tumor number

Single

NS (0.225)

Multiple

Unilobar portal vein obstruction

Negative

<0.001

Positive

Okuda stage

0.003

Serum albumin (g/L)

≤37

NS (0.341)

>37

Serum bilirubin (μmol/L)

≤14

NS (0.967)

>14

% Indocyanine green retention at 15 minutes

≤20

NS (0.635)

>20

α-Fetoprotein (ng/mL)

≤500

NS (0.059)

>500

Comparison of Survival Between the Chemoembolization and Control Groups Stratified by Baseline Prognostic Variables^✫

Chemoembolization

Control

Presenting symptom

Asymptomatic

25.4 (17.5)

16.6 (2.5)

0.039

Symptomatic

11.2 (2.6)

5.2 (1.4)

0.019

Unilobar portal vein obstruction

Negative

18.0 (3.5)

9.2 (5.6)

0.008

Positive

5.1 (2.2)

2.6 (2.3)

NS (0.406)

Tumor size (cm)

≤5

29.8 (12.2)

11.5 (3.0)

0.003

11.2 (1.8)

5.3 (1.4)

NS (0.115)

Okuda stage

25.4 (9.1)

11.5 (5.8)

0.016

9.2 (4.1)

5.2 (1.5)

0.040

^✫Values are median survival times in months with standard errors in parentheses

Comparison of Liver Function as Assessed by the Serum Bilirubin Level, Serum Albumin Level, and Indocyanine Green Retention Rate at 15 Minutes

Chemoembolization Group

Control Group

Number of Patients

Median (Interquartile Range)

Number of Patients

Median (Interquartile Range)

Bilirubin (μmol/L)

3 Months

15 (10–31)

21 (14–42)

0.038

6 Months

14 (11–24)

17 (10–28)

0.987

9 Months

16 (10–20)

18 (12–32)

0.385

12 Months

13 (9–23)

15 (11–30)

0.517

Albumin (g/L)

3 Months

36 (31–40)

32 (26–37)

0.073

6 Months

35 (31–39)

35 (28–38)

0.425

9 Months

35 (31–37)

33 (28–36)

0.223

12 Months

33 (31–39)

34 (27–39)

0.499

Indocyanine green retention at 15 minutes (%)

3 Months

25 (14–43)

36 (20–52)

0.169

6 Months

25 (18–38)

26 (17–51)

0.433

9 Months

25 (20–34)

28 (15–48)

0.405

12 Months

26 (13–34)

32 (22–47)

0.146

Toxicity

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Toxicity

(N = 40 Patients/192 Courses)

Number (%) Cycles

Fevers ≥38°C (≥100.4°F)^✫

63 (32.8)

Abdominal pain^✫

50 (26%)

Vomiting^✫

32 (16.7%)

Ascites

10 (5.2%)

Gastrointestinal bleeding

8 (4.2%)

Bleeding at femoral puncture

3 (1.6%)

Encephalopathy

3 (1.6%)

Ruptured tumor

2 (1%)

Pleural effusion

2 (1%)

Liver abscess

1 (0.5%)

Hematuria

1 (0.5%)

Hypotension

1 (0.5%)

Bradycardia

1 (0.5%)

^✫The most common clinical adverse effect was a self-limiting syndrome consisting of fever, abdominal pain, and vomiting. The median hospital stay for each course of treatment was 2 days (range, 1–21)

Therapy Monitoring

Days 7 and 14 after TACE and then monthly: CBC and LFTs
Response assessment using computed tomography (CT) every 3 months

REGIMEN: DEB-TACE: TRANSARTERIAL CHEMOEMBOLIZATION (TACE) USING DRUG-ELUTING BEADS (DEB)

Listen

Regimen: DEB-TACE: Transarterial Chemoembolization (TACE) Using Drug-Eluting Beads (DEB)

Lammer J et al. Cardiovasc Intervent Radiol 2010;33:41–52

Transarterial chemoembolization using drug-eluting beads (DEB), an embolizing device that slowly releases chemotherapy to decrease systemic toxicity

Pretreatment approach:

A baseline angiography of the celiac trunk, superior mesenteric artery, and hepatic artery is performed using a peripheral arterial approach
Antibiotic prophylaxis is not required but may be considered

Note: Extra-hepatic arterial supply of HCC is important. See section on Extrahepatic collateral vessels supplying hepatocellular carcinomas [Kim HC, Chung JW, Lee W, Jae HJ, Park JH. Radiographics 2005;25(Suppl 1):S25–S39]

Drug-eluting beads (DEB) [BioCompatibles Ltd., UK] with a diameter ranging between 300 and 700 micrometers are loaded with doxorubicin and mixed with an equal volume of contrast media. Additional unloaded spheres are used to complete the embolization procedure

Doxorubicin 150 mg (bilirubin <1.5 mg/dL; <25.7 μmol/L)

Loading process to obtain a final loading dose of 150 mg doxorubicin per two 2-mL vials of beads:

Begin about 2 hours before the TACE is planned
Reconstitute a vial containing doxorubicin 50 mg with 2 mL of sterile water for injection. Mix well to obtain a clear red doxorubicin solution with concentration = 25 mg/mL
Remove as much of the solution as possible from a vial of beads using a syringe with a small-gauge needle
Using a syringe and needle, add 2 mL of reconstituted doxorubicin solution directly to the vial of beads
Agitate the beads in the doxorubicin solution occasionally to encourage mixing. The dark red color of the suspension should become slightly pink and the beads, which are initially blue, should become red, indicating that doxorubicin has been loaded into the beads

Note: Although the solution retains a red color, the doxorubicin will be loaded. Loading will take a minimum of 20 minutes for the smallest beads and up to 120 minutes for the largest beads
Prior to use, transfer the beads loaded with doxorubicin to a syringe and add an equal volume of non-ionic contrast media. Invert the syringe gently to obtain an even suspension of beads

Note: Beads should only be loaded with doxorubicin HCl; liposomal formulations of doxorubicin are not suitable for loading into beads. A dose of up to 37.5 mg doxorubicin per mL of beads can be loaded. The maximum recommended total dose of doxorubicin per procedure is 150 mg. Beads loaded with doxorubicin may be stored for up to 24 hours at 2°–8°C (35.6°–46.4°F) in the presence or absence of non-ionic contrast media. Two hours of dwell time for 500–700 μmol DEB has been reported to allow for loading of more than 90% of 100 mg doxorubicin in the beads (Lewis AL et al. J Vasc Interv Radiol 2006;17:1335–1343)

TACE Procedure:

The vascular network associated with the lesion is carefully evaluated using high-resolution imaging prior to beginning the embolization procedure
Highly selective catheterization is performed with a 3-French microcatheter in order to obtain complete obstruction of the nourishing arteries and avoid damage to non-tumoral liver
Beads are available in a range of sizes and care should be taken to choose the appropriate size of the bead that best matches the pathology (ie, vascular target/vessel size) and provides the desired clinical outcome
A delivery catheter is chosen based on the size of the target vessel. Beads can tolerate temporary compression of 20–30% in order to facilitate passage through a delivery catheter
The delivery catheter is introduced into the target vessel according to standard techniques. The catheter tip is positioned as close as possible to the treatment site to avoid inadvertent occlusion of normal vessels
Because the beads are not radiopaque, monitoring the embolization under fluoroscopic visualization necessitates adding contrast medium to the DEB suspension
Care should be taken to ensure proper suspension of the beads in the contrast medium to enhance distribution during injection
Beads are drawn into a syringe and slowly injected
After completion of the treatment, the catheter is removed while maintaining gentle suction so as not to dislodge beads still within the catheter lumen
The embolization end point will be to achieve complete occlusion of the neovascularity, avoiding, however, complete stasis in the afferent artery, which could lead to endothelial damage and subsequent thrombosis precluding future treatments

Note: Treatment is given at 2-monthly intervals, with a maximum of three chemoembolization (at baseline, 2 months, and 4 months) with a 6-month follow-up

GENERAL GUIDELINES

Prior to embolization:

Hydration
- Start intravenous hydration with 0.9% sodium chloride injection (0.9% NS)
- Continuous 0.9% NS 100 mL/h beginning a minimum of 6 hours prior to procedure
Antibiotic prophylaxis not always required but may be considered with the first doses given before embolization:
- Metronidazole 500 mg; administer intravenously prior to the procedure followed by Metronidazole500 mg; administer intravenously every 12 hours × 3 doses, plus
- Cefazolin 1000 mg; administer intravenously prior to the procedure followed by Cefazolin500 mg; administer intravenously every 8 hours × 5 doses
Antiemetic primary prophylaxis

Give a serotonin receptor (5HT₃) antagonist plus a high-potency glucocorticoid
- Ondansetron 16 mg; administer intravenously or 24 mg orally, plus
- Dexamethasone 10–12 mg; administer intravenously or orally 30–60 minutes before the procedure

Post-embolization syndrome:

The triad of abdominal pain, vomiting, and fever that frequently occurs 24–72 hours after chemoembolization is commonly referred to as post-embolization syndrome
Post-embolization syndrome uniformly responds to supportive care including analgesics and antiemetics
Use care administering acetaminophen (paracetamol) and non-steroidal anti-inflammatory drugs in patients with liver cirrhosis

After embolization:

Continue intravenous hydration with 0.9% NS or another clinically appropriate fluid until patient resumes adequate oral fluid intake
Provide analgesic support with parenterally administered opioid medications (morphine, hydromorphone, fentanyl) after chemoembolization until the patient is able to continue analgesic treatment with oral products
Continue antiemetic prophylaxis with a 5HT₃ antagonist plus a high-potency glucocorticoid:
- Ondansetron 8 mg; administer intravenously or orally every 8 hours, plus
- Dexamethasone 8 mg; administer intravenously or orally every 8 hours for 2–3 days
Filgrastim (G-CSF) 5 mcg/kg per day; administer by subcutaneous injection
- May be used for patients who develop an ANC <500/mm³, neutropenia and fever, or documented infections during neutropenia
- Discontinue filgrastim at least 24 hours before a chemoembolization procedure

Patient Population Studied

A trial in which 212 patients with Child-Pugh A/B cirrhosis (76% male, 59% HCV) with HCC unsuitable for resection without portal invasion or extra-hepatic spread and less than 50% liver involvement received chemoembolization with doxorubicin loaded DEB at doses adjusted for bilirubin and body surface (range: 47–150 mg). Patients were excluded if they had another primary tumor, advanced liver disease (bilirubin levels >3 mg/dL, AST or ALT >5 × upper limit of normal or >250 U/L), advanced tumoral disease (vascular invasion or extrahepatic spread, or diffuse HCC, defined as >50% liver involvement), or contraindications for doxorubicin administration. In this international, multicenter, prospective, randomized single-blind, phase II study patients were randomized to receive doxorubicin with DC Bead or conventional TACE defined as 50–75 mg/m² doxorubicin emulsified in ethiodized oil followed by particle embolization with an embolic agent of choice

Therapy Monitoring

Days 7 and 14 after TACE and then monthly: CBC and LFTs
Response assessment using computed tomography (CT) every 3 months

Efficacy

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Efficacy

Response Rates

Tumor Response Rate at 6 Months

DC Bead (N = 93)^✫

cTACE (N = 108)^✫

Objective response

48/93 (51.6%)

47/108 (43.5%)

one-sided P = 0.11^†

Complete response

25/93 (26.9%)

24/108 (22.2%)

Partial response

23/93 (24.7%)

23/108 (21.3%)

Stable disease

11/93 (11.8%)

9/108 (8.3%)

Disease control rate

59/93 (63.4%)

56/108 (51.9%)

two-sided P = 0.11

Progressive disease

30/93 (32.3%)

44/108 (40.7%)

Advanced disease patients^‡

Objective response, advanced disease^‡

32/61 (52.4%)

25/72 (34.7)

Chi-square P = 0.038

Complete response, advanced disease^‡

15/61 (24.5%)

10/72 (13.9%)

Chi-square P = 0.091

Disease control rate, advanced disease^‡

38/61 (63.5%)

32/72 (44.4%)

Chi-square P = 0.026

Disease control rate, Child-Pugh B

21/33 (63%)

13/41 (32%)

Disease control rate, ECOG 1

19/30 (63%)

21/66 (32%)

Disease control rate, bilobar

51/86 (59%)

46/94 (49%)

Disease control rate, recurrent disease

17/23 (73%)

13/24 (54%)

^✫4 DC Bead patients and 8 cTACE patients withdrew prior to the first MRI scan. Reasons for these withdrawals were AEs (four DC Bead and four cTACE), withdrawn consent (two cTACE), and post consent ineligibility (two cTACE)

^†The hypothesis of superiority was not met. The difference between groups in favor of DC Bead was 8.1% (two-sided 95% repeated confidence interval (RCI), −4.8 to 22.6%)

^‡Advanced disease = 67% of patients with Child-Pugh B, ECOG 1, bilobar or recurrent disease

Toxicity

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Toxicity

Incidence of Serious Adverse Events^✫ within 30 Days of a Procedure Analysis by Stratification (Safety Population)

Number of Patients/Total (%) Number of Events

DC Bead (N = 93)

cTACE (N = 108)

Treatment-related SAEs within 30 days of a procedure [primary safety endpoint]

19 (20.4%) 28 events

21 (19.4%) 24 events

P = 0.86

Number of Patients/Total (%)

Stratification factor

DC Bead (N = 93)

cTACE (N = 108)

All patients

22/93 (23.7)

32/108 (29.6)

Child-Pugh A

19/77 (24.7)

26/89 (29.2)

Child-Pugh B

3/16 (18.8)

6/19 (31.6)

ECOG 0

17/74 (23.0)

23/80 (28.8)

ECOG 1

5/19 (26.3)

9/28 (32.1)

Unilobar

12/52 (23.1)

18/63 (28.6)

Bilobar

10/41 (24.4)

14/45 (31.1)

No prior curative treatments

19/82 (23.2)

28/95 (29.5)

Recurrent disease

3/11 (27.3)

4/13 (30.8)

^✫Note: Serious adverse events were defined as events: (1) resulting in death; (2) that were immediately life-threatening; (3) resulting in permanent or significant disability/incapacity; (4) requiring or extending inpatient hospitalization; or (5) congenital anomaly/birth defects. Analysis of treatment groups overall: chi-square test P = 0.34; difference in incidence rates, −6.0%; 95% CI, −18.2 to 6.2

Effects of Systemic Doxorubicin

Events/SWOG Toxicity Grade

DC Bead (N = 93)

cTACE (N = 108)

Number of Events

Number of Patients

Number of Events

Number of Patients

All doxorubicin-related events

11 (11.8%)

28 (25.9%)

Incidence = −14.1%; 95% CI, −24.7% to −3.5%; P = 0.012

Alopecia

1 (1%)

22 (20.4%)

Grade 1

Grade 2

Marrow suppression

5 (5.4%)

6 (5.6%)

Grade 1

Grade 2

Grade 3

Grade 4

Mucositis

4 (4.3%)

6 (5.6%)

Grade 1

Grade 2

Grade 3

Skin discoloration

2 (2.2%)

2 (1.9%)

Grade 1

Grade 2

Post-embolization syndrome

23 (24.7%)

28 (25.9%)

REGIMEN: SORAFENIB

Listen

Regimen: Sorafenib

Llovet JM et al. N Engl J Med 2008;359:378–90

Cheng et al. Lancet Oncol 2009;10:25–34

Sorafenib 400 mg per dose; administer orally, twice daily, continually (total dose/week = 5600 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential: LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated, unless patient previously had an episode of HSV

See Chapter 47 for more information

Diarrhea management

Latent or delayed-onset diarrhea^✫:

Loperamide 4 mg orally initially after the first loose or liquid stool, then

Loperamide 2 mg orally every 2 hours during waking hours, plus

Loperamide 4 mg orally every 4 hours during hours of sleep

Continue for at least 12 hours after diarrhea resolves
Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode
Rehydrate orally with fluids and electrolytes during a diarrheal episode
If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

Alternatively, a trial of Diphenoxylate hydrochloride 2.5 mg with Atropine sulfate 0.025 mg (eg, Lomotil^®)

Initial adult dose is two tablets four times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as two tablets daily
Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Persistent diarrhea:

Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed-onset diarrhea:

A fluoroquinolone (eg, Ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm³ with or without accompanying fever in association with diarrhea

Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Patient Population Studied

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Patient Population Studied

Llovet JM et al. N Engl J Med 2008;359:378–390

Multicenter, phase 3, double-blind, placebo-controlled trial. Six hundred two patients with advanced hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned to receive either sorafenib (n = 299) or placebo (n = 303). The study population consisted of patients with advanced-stage hepatocellular carcinoma. Patients were classified as having advanced disease if they were not eligible or had disease progression after surgical or locoregional therapies. Eligibility criteria also included (a) Eastern Cooperative Oncology Group performance status score ≤2; (b) Child-Pugh liver function class A; (c) prothrombin time international normalized ratio ≤2.3 or prothrombin time ≤6 sec greater than control; (d) albumin, ≥2.8 g/dL; (e) total bilirubin ≤3 mg/dL (≤51.3 micromol/L); and (f ) alanine aminotransferase and aspartate aminotransferase ≤5 times the upper limit of the normal range

Cheng et al. Lancet Oncol 2009;10:25–34

Patients with advanced (unresectable or metastatic) hepatocellular carcinoma who had not received previous systemic therapy were eligible for this trial. Eligibility criteria also included ECOG PS of 0/1/2; Child-Pugh liver function class A; and a life expectancy ≥12 weeks; albumin concentration of at least 28 g/L; total bilirubin concentration of 51.3 μmol/L or less; alanine aminotransferase concentration of five times the upper limit of normal (ULN) or less. Patients who had received previous local therapy, such as surgery, radiotherapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous injection, or cryoablation, were eligible for enrolment in the study, provided that either the target lesion increased in size by 25% or more, or the target lesion had not been treated with local therapy. Furthermore, the local therapy must have been stopped at least 4 weeks before study entry. Patients with recurrent disease after previous resection were considered eligible for the study. Exclusion criteria included previous or concomitant systemic therapy (including new, molecularly targeted therapies)

Demographic and Baseline Characteristics of the Patients (Intention-to-Treat Population)^✫

Llovet JM et al. N Engl J Med 2008;359:378–390

Variable

Sorafenib (N = 299)

Placebo (N = 303)

Age, y

64.9 ± 11.2

66.3 ± 10.2

Sex, no. (%) Male/Female

260 (87)/39 (13)

264 (87)/39 (13)

Region, no. (%)

Europe and Australasia

263 (88)

263 (87)

North America

27 (9)

29 (10)

Central and South America

9 (3)

11 (4)

Cause of disease, no. (%)

Hepatitis C only

87 (29)

82 (27)

Alcohol only

79 (26)

80 (26)

Hepatitis B only

56 (19)

55 (18)

Unknown

49 (16)

56 (19)

Other

28 (9)

29 (10)

ECOG performance status, 0/1/2 no. (%)

161(54)/114(38)/24(8)

164(54)/117(39)/22(7)

BCLC stage, B (intermediate)/C (advanced) no. (%)

54(18)/244(82)^‡

51(17)/252(83)

Macroscopic vascular invasion, no. (%)

108 (36)

123 (41)

Extrahepatic spread, no. (%)

159 (53)

150 (50)

Lymph nodes, no. (%)

89 (30

65 (21)

Lung, no. (%)

67 (22)

58 (19)

Macroscopic vascular invasion, extra-hepatic spread, or both, Absent/Present, no. (%)

90 (30)/209 (70)

91 (30)/212 (70)

Child-Pugh class, A/B, no. (%)

284 (95)/14 (5)

297 (98)/6 (2)

Biochemical analysis

Albumin, g/dL, Median (Range)

3.9 (2.7–5.3)

4.0 (2.5–5.1)

Total bilirubin, mg/dL, Median (Range)^†

07. (0.1–16.4)

0.7 (0.2–6.1)

Alpha-fetoprotein, ng/mL—Median (Range)

44.3 (0–208 × 10⁴)

99.0 (0–5 × 10⁵)

Previous therapy, no. (%)^§

Surgical resection

57 (19)

62 (20)

Locoregional therapy

Transarterial chemoembolization

86 (29)

90 (30)

Percutaneous ethanol injection

28 (9)

20 (7)

Radiofrequency ablation

17 (6)

12 (4)

Radiotherapy

13 (4)

15 (5)

Systemic anticancer therapy

Hormonal therapy

7 (2)

8 (3)

Cytotoxic chemotherapy

1 (<1)

Concomitant systemic antiviral therapy, no. (%)

6 (2)

2 (1)

^✫Plus–minus values are means ± SD. None of the differences between the two study groups were significant (P ≥0.05)

^†To convert the values for bilirubin to micromoles per liter, multiply by 17.1. BCLC denotes

^‡One patient in the sorafenib group had a BCLC score of D and a Child-Pugh class of C

^§Patients may have received more than one type of therapy. There was no significant difference between groups in the number of patients who had received previous palliative or curative therapy or previous adjuvant or neoadjuvant therapy (P ≥0.05)

Radiotherapy was applied to extrahepatic metastatic lesions in all patients except five in the sorafenib group and three in the placebo group

Dose Modifications

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Dose Modifications

Adverse Event

Dose Modification

G3/4 or persistent G2 drug-related adverse event

Decrease sorafenib to 400 mg daily^✫

G3/4 or persistent G2 drug-related adverse event on 400 mg daily

Decrease sorafenib to 400 mg every other day

G3/4 or persistent G2 drug-related adverse event on 400 mg every other day

Discontinue sorafenib

^✫A recent study in patients with thyroid cancer reduced doses initially from 400/400 daily to 400/200 each day before reducing the dose to 400 daily (Brose MS et al. Proc Am Soc Clin Oncol Annual Meeting 2013 [Abstract 4])

Efficacy

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Efficacy

Llovet JM et al. N Engl J Med 2008;359:378–390

Outcome

Sorafenib

Placebo

HR/p-value

Median overall survival, months [95% CI]

10.7 months [9.4–13.3]

7.9 months [6.8–9.1]

0.69 (0.55–0.87) <0.001

1-year survival rate

44%

33%

0.009

Time to symptomatic progression^✫, median [95% CI]

4.1 Months [3.5–4.8]

4.9 months [4.2–6.3]

1.08 (0.88–1.31) 0.77

Time to radiologic progression, median [95% CI]

5.5 months [4.1–6.9]

2.8 months [2.7–3.9]

0.58 (0.45–0.74) <0.001

Level of Response^†

Complete response

Partial response

0.05

Stable disease

71%

67%

0.17

Disease control rate^‡

43%

32%

^✫Symptomatic progression was defined as a decrease of 4 or more points from the baseline score on the Functional Assessment of Cancer Therapy–Hepatobiliary Symptom Index 8 (FHSI8), deterioration to a score of 4 in Eastern Cooperative Group performance status, or death, whichever occurred first

^†Response was measured according to RECIST

^‡Percentage of patients with CR/PR/SD according to RECIST maintained for 28 days

Cheng et al. Lancet Oncol 2009;10:25–34

Sorafenib Group (n = 150)

Placebo Group (n = 76)

Complete response

0 (0)

Partial response

5 (3.3)

1 (1.3)

Stable disease

81 (54.0)

21 (27.6)

Progressive disease

46 (30.7)

41 (54.0)

Not assessable

18 (12.0)

13 (17.1)

DCR^✫, n (%; 95% CI)

53 (35.3; 27.7–43.6)

12 (15.8; 8.4–26.0)

Median overall survival

6.5 mos (95% CI, 5.56–7.56)

4.2 mos (95% CI, 3.75–5.46)

HR 0.68 [95% CI, 0.50–0.93]; p = 0.014

6-month overall survival

53.3%

36.7%

Median time to progression

2.8 mos [95% CI, 2.63–3.58]

1.4 mos [95% CI, 1.35–1.55]

HR 0.57 [95% CI, 0.42–0.79]; p = 0.0005

TTSP as assessed by the FHSI-8^†

3.5 mos [95% CI, 2.80–4.24]

3.4 mos [95% CI, 2.40–4.08]

HR 0.90 [95% CI 0.67–1.22]; p = 0.50

^✫DCR (disease control rate) = proportion of patients who had the best response of complete response, partial response, or stable disease, maintained ≥4 weeks

^†Time To Symptomatic Progression was defined as deterioration to ECOG PS 4 status or a change from baseline score on the 8-item, symptom-focused Functional Assessment of Cancer Therapy–Hepatobiliary Symptom Index (FHSI-8) questionnaire, associated with a deterioration of symptoms

Toxicity

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Toxicity

Incidence of Drug-Related Adverse Events (Safety Population)^✫

Llovet JM et al. N Engl J Med 2008;359:378–390

Adverse Event

Sorafenib (N = 297)

Placebo (N = 302)

P Value

Any G

G3/4

Percent

Overall incidence

Constitutional symptoms

Fatigue

0.07

1.00

Weight loss

<0.001

0.03

Dermatologic events

Alopecia

<0.001

Dry skin

0.04

Hand–foot skin reaction

<0.001

Pruritus

0.65

1.0

Rash or desquamation

0.12

Other

<0.001

0.12

Gastrointestinal events

Anorexia

<0.001

1.00

Diarrhea

<0.001

Nausea

0.16

0.62

Vomiting

0.14

0.68

Voice changes

<0.001

Hypertension

0.05

0.28

Liver dysfunction

0.50

Abdominal pain not otherwise specified

0.007

0.17

Bleeding

0.07

1.00

Sorafenib (N = 297)

Placebo (N = 302)

Rate of discontinuation

38%

37%

Dose reductions due to adverse events^‡

26%

Dose interruptions due to adverse events

44%

30%

NA, denotes not applicable

^✫Listed are adverse events, as defined by the National Cancer Institute Common Terminology Criteria (version 3.0), that occurred in at least 5% of patients in either study group

^†The most frequent adverse events leading to discontinuation of sorafenib were gastrointestinal events (6%), fatigue (5%), and liver dysfunction (5%). Drug-related adverse events leading to permanent treatment discontinuation occurred in 34 patients in the sorafenib group (11%) and 15 patients in the placebo group (5%)

^‡The most frequent adverse events leading to dose reductions of sorafenib were diarrhea (8%), hand–foot skin reaction (5%), and rash or desquamation (3%)

Drug-related Adverse Events, Dose Reductions, and Discontinuations

Cheng et al. Lancet Oncol 2009;10:25–34

Sorafenib Group (n = 149)

Placebo Group (n = 75)

All

Grade 3/4

All

Grade 3/4

Drug-related, n (%)^✫

HFSR

67 (45.0)

16 (10.7)

2 (2.7)

0 (0)

Diarrhea

38 (25.5)

9 (6.0)

4 (5.3)

0 (0)

Alopecia

37 (24.8)

—

1 (1.3)

—

Fatigue

30 (20.1)

5 (3.4)

6 (8.0)

1 (1.3)

Rash/desquamation

30 (20.1)

1 (0.7)

5 (6.7)

0 (0)

Hypertension

28 (18.8)

3 (2.0)

1 (1.3)

0 (0)

Anorexia

19 (12.8)

0 (0)

2 (2.7)

0 (0)

Nausea

17 (11.4)

1 (0.7)

8 (10.7)

1 (1.3)

Dose reduction, n (%)^†

46 (30.9)

2 (2.7)

HFSR

17 (11.4)

—

0 (0)

—

Diarrhea

11 (7.4)

—

0 (0)

—

Discontinuation, n (%)^‡

29 (19.5)

10 (13.3)

Hemorrhage, upper GI

4 (2.7)

—

3 (4.0)

—

Ascites

4 (2.7)

—

2 (2.7)

—

Fatigue

4 (2.7)

—

0 (0)

—

Liver dysfunction

1 (0.7)

—

2 (2.7)

HFSR, hand-foot skin reaction; GI, gastrointestinal tract

^✫Drug-related adverse events in ≥10% of patients in any study group

^†Adverse events causing dose reduction ≥5% of patients in any study group

^‡Adverse events causing discontinuation ≥2.5% of patients in any study group

Therapy Monitoring

At screening and every 6 weeks: Tumor measurements by computed tomography or magnetic resonance imaging

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Chapter 15: Hepatocellular Carcinoma

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INTRODUCTION

Expert Opinion

TREATMENT ACCORDING TO STAGE

EXTRAHEPATIC COLLATERAL VESSELS SUPPLYING HEPATOCELLULAR CARCINOMAS

REGIMEN: CHEMOEMBOLIZATION WITH DOXORUBICIN

REGIMEN: CHEMOEMBOLIZATION WITH CISPLATIN

REGIMEN: DEB-TACE: TRANSARTERIAL CHEMOEMBOLIZATION (TACE) USING DRUG-ELUTING BEADS (DEB)

REGIMEN: SORAFENIB

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