Hepatocellular Carcinoma

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Hepatocellular Carcinoma

GI Practice Guideline

Michael Sanatani,

MD, FRCPC (Medical Oncologist)

Walter Kocha,

MD, FRCPC (Medical Oncologist)

Approval Date:

October 2006

This guideline is a statement of consensus of the GI Disease Site Team regarding their views of currently accepted approaches to treatment. It is not intended to replace the independent medical judgement of the physician in the context of individual clinical circumstances to determine any patient’s care or treatment.

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Hepatocellular Carcinoma - GI Practice Guideline Approved October 2006

Hepatocellular Carcinoma

GI Practice Guideline

Background

• Most common in subsahara Africa, Orient.

• Risk factors:

• Infection

− Hep B, C esp. genotype 1b

• Cirrhosis

• Environmental

- Androgenss - aflatoxins - EtOH

- tobacco - N-nitrosylated compounds - algae toxins

- Thorotrast contrast medium - pyrrolizidine alkaloids - ?betel nuts?

• Presentation

- abdominal pain - anorexia - bone pain

- intraperitoneal bleed - paraneoplastic hypoglycemia/erythrocytosis

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TNM Staging

Fibrosis score 5-6 (severe fibrosis or cirrhosis) F1

Fibrosis score 0-4 (none to moderate fibrosis) F0 Fibrosis Score (F) Distant metastasis M1 No distant metastasis M0

Distant metastasis cannot be assessed M X

Distant metastasis (M)

Regi onal lymph node metastasis N1

No regional lymph node metastasis N0

Regi onal lymph nodes cannot be assessed NX

Regional lymph nodes (N)

Tumors with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum T4

Multiple tumors more than 5 cm or tumor invol ving a major branch of the portal or hepatic vein(s)

T3

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

T2

Solitary tumor without vascular invasion T1

No evidence of primary tumor T0

Primary tumor cannot be assessed TX

Primary Tumor (T)

Fibrosis score 5-6 (severe fibrosis or cirrhosis) F1

Fibrosis score 0-4 (none to moderate fibrosis) F0 Fibrosis Score (F) Distant metastasis M1 No distant metastasis M0

Distant metastasis cannot be assessed M X

Distant metastasis (M)

Regi onal lymph node metastasis N1

No regional lymph node metastasis N0

Regi onal lymph nodes cannot be assessed NX

Regional lymph nodes (N)

Tumors with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum T4

Multiple tumors more than 5 cm or tumor invol ving a major branch of the portal or hepatic vein(s)

T3

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

T2

Solitary tumor without vascular invasion T1

No evidence of primary tumor T0

Primary tumor cannot be assessed TX Primary Tumor (T) M1 M0 M0 M0 M0 M0 Any N N1 N0 N0 N0 N0 Any T Stage IV Any T Stage IIIC T4 Stage IIIB T3 Stage IIIA T2 Stage II T1 Stage I Stage grouping M1 M0 M0 M0 M0 M0 Any N N1 N0 N0 N0 N0 Any T Stage IV Any T Stage IIIC T4 Stage IIIB T3 Stage IIIA T2 Stage II T1 Stage I Stage grouping <3 mg/dl >3mg/dl Bilirubin >3 mg/dl <3 mg/dl Albumin Clinically absent Clinically detectable Ascites <50 percent >50 percent Tumor size* Negative Positive Criteria <3 mg/dl >3mg/dl Bilirubin >3 mg/dl <3 mg/dl Albumin Clinically absent Clinically detectable Ascites <50 percent >50 percent Tumor size* Negative Positive Criteria

* Largest cross-sectional area of tumor to largest cross-sectional area of the liver

Three of four positives III

One or two positives II

No positive I

Stage

* Largest cross-sectional area of tumor to largest cross-sectional area of the liver

Three of four positives III

One or two positives II

No positive I

Stage

Okuda Staging System for Hepatocellular Carcinoma – The okuda system is commonly

used for staging hepatocellular carcinoma. Survival correlates with the Okuda stage in untreated patients (8.3, 2.0 and 0.7 for stages I, II, and III, respectively). Adapted from Okuda, K. Ohtuiki, T, Obata, H, et al., Cancer 1985; 56:918

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Overall Pathway – Hepatocellular Carcinoma

Presentation

Required Work-up

Surgical Assessment

LRCP Referral

MO + RO

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Investigations – Required Work-up

• CNCCN guidelines

- H&P - Hepatitis panel - Bilirubin - transaminases

- alkaline phosphatase - LDH, PT or INR - albumin - protein

- BUN - creatinine - CBC - platelets

- Hepatitis B surface antigen - CT/MRI - Chest x-ray - AFP

- Hepatitis C antibodies

• Biopsy if AFP < 400 ng/ml (HepB SAg-) / < 4000 ng/ml (HepB SAg+)

• American Association for the Study of Liver Diseases (AASLD)

• See next page.

• More emphasis on imaging characteristics and size (>1 cm)

• AFP cutoff for biopsy <200 ng/ml

Biopsy risks controversial

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AASLD (2005) Diagnostic Approach

Mass on surveillance ultrasound in a cirrhotic liver

Two dynamic imaging studies

Repeat US at 3-4 month intervals

< 1 cm 1-2 cm >2 cm

One dynamic imaging technique

Coincidental typical vascular pattern on dynamic imaging

Typical vascular pattern with one technique

Atypical vascular pattern with both techniques Stable over 18-24 months Return to standard surveillance protocol (6-12 months) _Proceed according to lesion size Atypical vascular pattern Typical vascular pattern on dynamic imaging or AFP > 200 Biopsy

Treat as hepatocellular carcinoma

Enlarging

Diagnostic of HCC Non diagnostic Other diagnosis

Repeat imaging and/or biopsy Change in size/profile Repeat biopsy or imaging follow-up Positive Negative

Fig. 1 A suggested algorithm for investigation of a nodule found on ultrasound duri ng screening or surveillance. Note that nodules smaller than 1 cm initially which enl arge over time shoul d be investigated using one of the other two algorithms shown depending on the size of the nodule. The typical vascular pattern referred to means that the lesion is hypervascular in the arteri al phase, and washes out in the portal/ venous phase. All other patterns are considered atypical.

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Investigations – Surgical Assessment

• Needed in regards to resectability (tumor and patient characteristics)

• Will be to some extent determined by individual surgeon

• For example: Barcelona Clinic Liver Cancer approach/AASLD guideline) – see next

page

Alternative:

Class A: 5 – 6 points; Good operative risk Class B: 7 – 9 points; Moderate operative risk Class C: 10 – 15 points; Poor operative risk

Class A: Good operative risk Class B: Moderate operative risk Class C: Poor operative risk

Original

Class A= 5 – 6 points; Class B = 7 – 9 points; Class C= 10 – 15 points.

> 3 > 10 2 – 3 4 –10 1 – 2 1 – 4 Bilirubin (mg/dL)

–For primary biliary cirrhosis

> 6 4 – 6

1 – 4 Prothrombin time prolonged (sec)

< 2.8 2.8 – 3.5 > 3.5 Albumin (g/dL) Moderate Slight None Ascites 3-4 1-2 None Encephalopathy (grade) 3 2 1

Scores (Points) for Increasing Abnormality Chemical and Biochemical Parameters

Child-Pugh Score

Alternative:

Class A: 5 – 6 points; Good operative risk Class B: 7 – 9 points; Moderate operative risk Class C: 10 – 15 points; Poor operative risk

Class A: Good operative risk Class B: Moderate operative risk Class C: Poor operative risk

Original

Class A= 5 – 6 points; Class B = 7 – 9 points; Class C= 10 – 15 points.

> 3 > 10 2 – 3 4 –10 1 – 2 1 – 4 Bilirubin (mg/dL)

–For primary biliary cirrhosis

> 6 4 – 6

1 – 4 Prothrombin time prolonged (sec)

< 2.8 2.8 – 3.5 > 3.5 Albumin (g/dL) Moderate Slight None Ascites 3-4 1-2 None Encephalopathy (grade) 3 2 1

Scores (Points) for Increasing Abnormality Chemical and Biochemical Parameters

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Barcelona / AASLD Approach to Surgical Assessment

HCC

PST 0, Child-Pugh A PST 0-2, Child-Pugh A-B PST >2, Child-Pugh C

Very early stage Single < 2cm Early stage Single or 3 nodules <3cm, PS 0 Intermediate stage Multinodular, PS 0 Advanced stage Portal invasion, N1, M1, PS 1-2 Terminal stage 3 nodules <3cm Single

Portal pressure/ bilirubin

Associated diseases

Normal

Increased

No Yes No Yes

Portal invasion, N1, M1

Resection Liver Transplantation (CLT / LDLT

PEI/R F

Chemoembolization New Agents

Curative Treatments Randomized controlled trials Symptomatic

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Prognosis in US. Population by Surgical/Interventional

Treatment Received

N.B. Not always deemed appropriate for stage, by external review. J. Hepat 1/2006, p. 158

“Curative”

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Treatment – Curative Intent

• Treatment in addition to surgery – curative intent

• Neoadjuvant

− 131-I – Lipiodol intra-arterial treatment

• case series 19/34 pts objective response

• Intra-arterial chemotherapy

– conflicting series. Most show reduction in size but no large survival difference – One controlled trial of resectable tumours demonstrated worse survival in Rx

group, presumably because of delay to surgery (Br J Surg 1995 Jan;82(1):122-6) – Not recommended by AASLD guidelines

– Should be reserved for tumours of borderline resectability only

• Adjuvant

− Adjuvant therapy: most positive study is Lau et al (Lancet 1999) with I-131

Lipiodol 85 vs 46% 3YS. Current (Oct 2006) Phase III trial at NCI ongoing and open to accrual (NCT00027768)

− Bland or chemoembolization data less positive (Izumi et al., Hepatology 1994

Aug;20(2):295-301).

− Polyprenoic acid may reduce new HCC's (Muto et al, N Engl J Med 1996;

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Treatment – Palliative-intent therapy (localized)

• Radiofrequency ablation / Percutaneous ethanol ablation

• neither of these has directly been compared to BSC alone, however, survivals and

local control rates are generally better than what would be expected; > 75-80 % at 2 years. Some consider this “curative”. Studies limited by short f/u (2-5 years)

− External beam radiation research protocol

− Transarterial embolisation with 131Iodine lipiodol

• One randomized trial with benefit in pts with portal vein thrombosis.

− 6 month survival 48% vs 0% (27 pts total), 9 month survival 7% vs 0%. (Nucl

Med 1994 Nov;35(11):1782-7)

− Transarterial chemotherapy/embolisation (‘HACE’ or ‘TACE’)

• Benefit very dependent on patient selection. Recommended by AASLD

− A prognostic index of the survival of patients with unresectable hepatocellular

carcinoma after transcatheter arterial chemoembolization, Cancer 2000 Jan 1;88(1):50-7

− Transarterial chemotherapy/embolisation + lipiodol (‘HALCE’)

• Two randomized trials with survival benefit e.g. Hepatology 2002

May;35(5):1164-71, HR 0.49.

− Transarterial chemotherapy/embolisation + 131I- lipiodol

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Treatment – Palliative-intent therapy (systemic)

• Tamoxifen – negative RCTs

• Octreotide – negative RCTs however follow-up too short. Ongoing HECTOR trial in

Europe pending final analysis

• Chemotherapy

• Doxorubicin vs. BSC 10.6 vs 7.5 weeks OS (Lai et al, Cancer 1988;62(3):479-83)

• Resp rate around 20%, higher than 5FU or etoposide, but no OS difference

• Gemcitabine, Capecitabine [11% RR] also in series only

• Combination therapy: cisplatin/5FU, cisplatin/doxorubicin, gemcitabine/cisplatin etc.

RR around 10-45% in series

− ECF: 15% RR in 21 pts (1/21 pCR)

Boucher et al Cancer Chemother Pharmacol 2002 Oct;50(4):305-8

• Little if any QOL data

• Adding interferon – inc RR? but not survival

− A randomized phase III study of doxorubicin versus cisplatin/interferon

alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 2005 Oct 19;97(20):1532-8

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Overall pathway – Hepatocellular Carcinoma (summary)

Presentation

Liver mass suspicious for helatocellular carcinoma (HCC) or histologically confirmed HCC

• Assess liver status Child-Pugh A/B vs C

• Biopsy?

• Partial hepatectomy 2 feasible?

• solitary HCC in liver, no inv of hepatic artery, no severe portal HTN, etc.

• Transplant candidate?

• unresectable HCC <5cm, or up to 3 lesions < 3 cm, no gross vascular inv, no nodal metastases, etc.

• Borderline resectability? Surgical Assessment LRCP referral MO + RO Required Work-up • H&P • Hepatitis panel

• Hepatitis B surface antigen

• Hepatitis C antibodies

• Bilirubin, transaminases, alkaline phosphoatase, LDH

• PT or INR, albumin, protein, BUN, creatinine

• CBC, platelets • AFP • CT/MRIb • Chest x-ray Potentially Curative Rx • Partial hepatectomy • Transplant • Assessment at LRCP regarding

• ?Neoadjuvant embolisation with 131l-lipiodol4

• ?Adjuvant embolisation with 131l-lipiodol3

Palliative Rx • Localized therapy

• External beam radiation (experimental protocol/Dr. M. Lock - ?concurrent 5FU)

• Radiofrequency ablation/ Percutaneous ethanol ablation

• Transarterial embolisation with 131I lipiodol/ cisplatin/ doxorubicin.5

• Systemic therapy:

• Clinical trial or best supportive care

• Selected patients : consider chemotherapy (doxorubicin or ECF [ECF = Epirubicin 60 mg/m2 + Cisplatin 50 mg/m2 q21d; 5FU daily 200mg/m2 infusion] or PIAF [PIAF = Cisplatin 20mg/m2 day 1-4, doxorubicin 40mg/m2 day 5, 5FU 400mg/m2 day 1-4,

∝

-IFN 5MU/ m2, SC days 1-4, all q21 days] ); survival advantage not clearly demonstrated.

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References

Re: biopsy Percutaneous fine-needle aspiration cytology in the diagnosis and

management of liver tumours. Br J Surg 2002 Jun;89(6):757-62 (3% seeding rate); Assessment of the benefits and risks of percutaneous biopsy before surgical resection of hepatocellular carcinoma. J Hepatol 2001 Aug;35(2):254-8 (1.6%); Comparison of liver biopsy and noninvasive methods for diagnosis of hepatocellular carcinoma. Clin

Gastroenterol Hepatol. 2006 Mar;4(3):361-8 (0%)

1. AFP (a – fetoprotein) sensitivity 41-65%, spec 80-94%; +’ve likelihood ratio 3.1-6.8; -’ve LR 0.4-0.6 using cutoffs of 16-100 µ g/L

2. Partial hepatectomy: 5YS 30-90%. Requires Child-Pugh A or B with good PS. Consider preoperative portal vein embolization to induce hypertrophy.

3. Adjuvant therapy: most positive study is Lau et al (Lancet 1999) with I-131 Lipiodol 85 vs 46% 3YS. Bland or chemoembolization data less positive (Izumi et al.,

Hepatology 1994 Aug;20(2):295-301). Polyprenoic acid may reduce new HCC's (Muto et al, N Engl J Med 1996; 334:1561-1568).

4. Neoadjuvant I-131 Lipiodol in development Br J Surg. 2003 Nov;90(11):1379-83. Case series, 25/34 pts objective response or histological necrosis, 19/34 obj. resp. 5. 50-60% RR. Need KPS>60-70, no severe weight loss. HALCE contraindications:

PV thrombus, encephalopathy, biliary manipulation Hx/obstr; relative: bili>35, AST>100, >50% of liver replaced by tumour, CHF/CRF, ascites, variceal bleed, low plts. I-131 lipiodol/chemoembolisation at LRCP; other centres use only one

modality/no radiolabelled oil – evidence controversial for that (e.g. lipiodol alone insuff.: N Engl J Med 1995;332:1256-61.)

6. Evidence controversial. Hepatology 2002(3):687 negative but OS only 2 mos each arm and 60% no Rx or only 1 dose. HECTOR study ongoing. Kuroumalis et al. 1998; Gut 62 : positive but retrospective.

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Authors, Contact Information

Michael Sanatani, MD, FRCPC (Medical Oncologist)

London Regional Cancer Program London Health Sciences Centre 790 Commissioners Road East London, Ontario, Canada N6A 4L6 Telephone: 519.685.8600 Ext. 58640

Barbara Fisher, MD, FRCPC (Radiation Oncologist)

London Regional Cancer Program London Health Sciences Centre 790 Commissioners Road East London, Ontario, Canada N6A 4L6 Telephone: 519.685.8600 Ext. 58650

This guideline is a statement of consensus of the GI Disease Site Team regarding their views of currently accepted approaches to treatment. It is not intended to replace the independent medical judgement of the physician in the context of individual clinical circumstances to determine any patient’s care or treatment.

Hepatocellular Carcinoma

Hepatocellular Carcinoma

GI Practice Guideline

Michael Sanatani,

MD, FRCPC (Medical Oncologist)

Walter Kocha,

MD, FRCPC (Medical Oncologist)

October 2006

Table of Contents

Hepatocellular Carcinoma

GI Practice Guideline

Background

TNM Staging

Overall Pathway – Hepatocellular Carcinoma

Presentation

Required Work-up

Surgical Assessment

LRCP Referral

MO + RO

Investigations – Required Work-up

AASLD (2005) Diagnostic Approach

Investigations – Surgical Assessment

Barcelona / AASLD Approach to Surgical Assessment

HCC

Prognosis in US. Population by Surgical/Interventional

Treatment Received

Treatment – Curative Intent

Treatment – Palliative-intent therapy (localized)

Treatment – Palliative-intent therapy (systemic)

Overall pathway – Hepatocellular Carcinoma (summary)

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References

Authors, Contact Information