hcc

1. Management of Hepatocellular
carcinoma (HCC)
Dr Sneha George

2. Introduction
• Primary malignant neoplasms of the hepatocytes
are termed HCC.
• 5th most common cancer in the world
• 3rd most common cause of cancer related deaths
• M:F = 4:1
• Etiology – Cirrhosis, Hep B, Hep C, Aflatoxins,
Alcohol, smoking, NASH , p53 mutation
• MC histology – Adenocarcinoma

3. DIAGNOSIS
• Complete history and physical examination
• Symptoms
- Pain
- Abdominal distension
- Jaundice
- Vomiting
- Loss of weight
- Pruritus
• Signs - Icterus, Ascites, Hepatosplenomegaly,
Spider naevi

4. INVESTIGATIONS
Laboratory
• LFT
• AFP
Radiological
• USG
• CT
• MRI
• Hepatic , celiac and
superior mesenteric
angiography
• Radionuclide scans
- Gallium scan

5. STAGING

6. BCLC staging classification

7. Child Pugh Scoring
Score Operative risk
• 5-6 Good
• 7-9 Moderate
• 10-15 Poor

8. PROGNOSTIC FACTORS
• Number, size and location of liver lesions
• Vein involvment
• Extent and type of resection
• Hepatic reserve

9. Treatment modalities
• Surgery
• Chemotherapy
• Radiotherapy
• Targeted Therapy

11. SURGERY
• INDICATIONS :
- No major vascular invasion
- Well compensated liver function
- Solitary lesion < 5 cm
- Multiple lesions < 3 cm
• TYPES
- Partial hepatectomy
- Total hepatectomy  Liver transplantation

12. Liver transplantation
• Patient criteria:
- Child-Pugh B and C patients
- MELD score is measured and has been adopted by UNOS
to stratifypatients on the transplant list according to their
risk of death within 3 months
• Tumour criteria:
- UNOS/Milan criteria: single lesion ≤5 cm, or 1–3 lesions all
≤3 cm
- UCSF criteria: solitary lesion ≤6.5 cm or up to 3 lesions
with the largest <4.5 cm and total tumor diameter <8 cm
- No evidence of extrahepatic disease or macrovascular
involvement

13. • TYPES
- Cadaveric liver transplantation
- Living donor liver transplantation
• 5 year OS rates – 70%
• Recurrence – <15%

14. RFA – Radiofrequency ablation
• Achieved by exposing the tumor to heat
• The candidate must have a tumor located away from
major intrahepatic vessels which could absorb some
of the heat, thus limiting effective delivery
• Tumor should be <3 cm
• Laparoscopic, open, or percutaneous route
• Complete necrosis has been observed in ~60% of
tumors
• <3 cm in diameter treated with RFA
• Can be combined with embolisation for better
results

15. TACE- Transarterial chemo-embolisation
• In intermediate stage HCC
• Trans – arterial injection of various
chemotherapy agents such as lipiodol
resulting in reduction of blood flow to the
tumour (tumour necrosis)
• Improved median survival as compared to
supportive care – Llovet et al

16. • Indications
- Till Child Pugh B
- Solitary nodule < 5cm
- Multifocal HCC
- No evidence of vascular
invasion or extrahepatic
spread.
• Contraindications
- Portal vein occlusion
- Child-Pugh class C
- Total bilirubin > 3mg/ml

17. CHEMOTHERAPY
• Limited role
• No significant difference in median survival
• High intrinsic and acquired drug resistance of
this tumour
• Agents used : Single agent Doxorubicin
Single agent Gemcitabine
PIAF (Cisplatin, Interferon,
Doxorubicin and Fluorouracil)
• Toxicity – Neutropenia , Thrombocytopenia,
Hypokalemia

18. TARGETED THERAPY
• Tyrosine kinase inhibitors are used
• MOA: Inhibits multiple signal transduction
pathways (VEGF, EGF, IGF, MAPK)
• Eg: Sorafenib, Sunitinib,Linifanib, Brivanib,
Everolimus

19. SORAFENIB (Nexavar)
• FDA approved for the treatment of
unresectable HCC or advanced HCC
• Inhibits multiple receptor tyrosine kinases and
intracellular kinases
• Inhibits VEGF-R2 and R3 and PDGFR
• Dose : 400 mg BD
• Side effects: Skin rash, Hand foot
syndrome(30%), Hypertension, Epistaxis,
Diarrrhoea, Nausea

20. Phase III clinical trials of targeted
agents

21. RADIOTHERAPY
• Radiosensitive tumour but in a radiosensitive organ –
risk of RILD (radiation induced liver disease)
• INDICATIONS
Large unresectable HCC
Symptomatic portal vein thrombosis
Symptomatic jaundice
Part of combined modality treatment
Metastatic disease

22. METHODS OF RADIATION:
Conventional radiation
3-D Conformal Radiation /IMRT
Stereotactic body radiotherapy
Protons & heavy ion therapy

23. Palliative Use:
Metastatic disease
 8Gy/1# ; 50Gy/25#
Pain relief in 73-83% patients
 Whole liver radiation
Borgelt (IJROBP, 1983)
– Whole liver RT can relieve symptoms
– Ascites, anorexia, pain, nausea, vomiting, fever, etc.
Russell (IJROBP, 1993)
– 21 Gy standard dose
– Dose escalation 27Gy →30Gy →33Gy
– No injury at 27Gy and 30Gy → toxicities started developing at
33 Gy
RT – Historical Perspective

24. From Palliation to Cure
Improved knowledge of partial organ
tolerance of the liver to radiation
Advanced imaging
3D conformal treatment planning
Image guided radiotherapy
Tumor immobilisation & organ tracking
Increased availability of stereotactic
radiotherapy & charged-particle therapy

25. RT techniques
• Simulation and target volume delineation
- Position : Supine with arms overhead
- Immobilisation : Body cradle
Full body mould – SBRT
Half body mould – 3DCRT
- A triphasic contrast enhanced 4DCT scan is done
- CT portals : from apex of lung till iliac crest
- Percutaneously implanted fiducials are used if
IGRT technique or cone beam CT
- If respiratory gating used, CT in exhale phase only

26. Treatment Planning
• Target : GTV ( enhancing lesion as seen on CT)
No elective nodal irradiation
• Margins: If elective target (CTV) : GTV + 0.8 cm
In SBRT , direct target expansion of GTV to PTV
based on individual organ motion
• Commonly used breathing control techniques:
- Abdominal compression
- Active breathing control
- Respiratory gating

27. Treatment planning
• Dose :
- Conventional : 66Gy at 1.8-2 Gy/F
- If 3DCRT , better results when combined with TACE
(Lipiodol/Doxorubicin foll by 3DCRT – 44Gy at 1.8Gy/F
- Whole liver : 21Gy/7# ; 28Gy/14#; 31Gy1.5Gy/#BD
- Partial liver : determined individually
Prescribe dose that gives 10% risk of RILD based on
NTCP model
Limit isocenter dose to 90 Gy even if risk of RILD is <
10%
1.5 Gy bd with at least 6hrs between fractions

28. SBRT dose regimes

29. Dose constraints of OAR’s in SBRT
• Spinal Cord : Max dose – 18 Gy
• Kidney: V15<35% (bilateral)
• Small bowel:Max dose 30Gy
• Stomach: Max dose 30 Gy

30. Liver:
• Whole Liver : > 33Gy – risk of RILD
• Partial Liver: Univ of Michigan trial – 1/3rd of
liver – 72.6 Gy
• Atleast 700 ml of liver should get only <15%

31. RT – 3D Conformal
 French RTF1 prospective phase II trial (IJROBP, 2006)
Investigated high-dose RT for unresectable
cirrhotic patients
Methods
25 Pts, Child-Pugh A/B, small HCC
Ineligible for curative therapies
66 Gy in 2 Gy Fx
Results
1 yr Local Control: 78% (92% tumor
response)
Grade 4 toxicities in 3pts(22%) of Child-Pugh
B pts only, (already had Grade 3)

32. 3DCRT/IMRT
Advantages
• Improved conformality
• Non invasive
• Several lesions can be
treated together
• Deeper lesions
• Larger tumours close to the
biliary tree and diaphragm
Disadvantages
• No published data on
efficacy about IMRT
• Dose to the organs at risk

33. RT - SBRT
SBRT, is demonstrated safe & similarly
effective and having equivalent results
as surgery but is non invasive and can
be done on an OPD basis without
anaesthesia

34. RT – SBRT
Dawson (IJROBP, 2007)
Phase 1 study of SBRT for unresectable HCC
No RILD observed, minimal toxicity incidence
Concluded SBRT safe treatment
Methods
31 Pts, Child-Pugh A
25-57 Gy in 6 Fractions
Utilized NTCP model for dose prescription
Results
9 month local control: 78%
Median Survival: 11 months

35. RT – SBRT
Cardenes (IJROBP, 2008)
Dose escalation for primary HCC
Concurred SBRT safe treatment
2 pts developed Grade 3 toxicity with high doses
>>scores of C-P > 8
No significant toxicities with dose adjustments
Methods
16 Pts, Child-Pugh A,B
48 Gy (3 Fx) for class A
40 Gy (5 Fx) for C-P >8

36. RT – SBRT
Studies for Liver Metastases
Wulf 2001 – 24 Lesions
18 month Local Control: 61%
Herfarth, Debus 2005 – 70 pts, (22 Gy, single Fx)
 18 month Local Control: 66%
University of Colorado – 2006, 28 Lesions (60 Gy, 3 Fx)
18 month Local Control: 93%
Ongoing study

37. RT – Charged Particles
Japan trials with protons (Chiba, Clinical Cancer
Research, 2005)
Retrospective review over 15 years
Methods
162 pts, mostly Child-Pugh A/B
With/without TACE, PEI
72 Gy in 16 Fx
Results
5 yr local control: 87%
5 yr OS: 23.5%
New HCC lesion: 85%

38. RT – Charged Particles
Loma Linda Phase II trial (Bush, 2004)
Preliminary results of proton treatments
Methods
34 Pts, Child-Pugh A/B
63 Gy in 15 Fx
Results
2 yr Local Control: 75%
2 yr OS: 55%
New HCC lesion: 35%

39. Challenges
 More specialized training of physicians and physicists
rather than specialized equipment – more demanding
 L.A. should be equipped with image guidance
 Robust body immobilisation devices
 Labour - intensive treatment planning & delivery
 Individualised QA measures for each plan
 Treatment typically takes more than 45 mins

40. Challenges
 Highly Conformal Radiation Therapy
 Risk of complications may increase as even a small
error can result in dosimetric uncertainities with
overdose of the adjacent OAR
 Relative lack of knowledge about the tolerance of
normal tissues with high dose hypofractionated
Radiotherapy
 Cost is generally 3-4 times more than conventional
radiation

41. Follow up

42. Radiation Induced Liver Disease
• RILD is a clinical syndrome with anicteric
hepatomegaly, ascites and elevated liver enzymes
occurring from 2 weeks to 4 months after
radiation therapy
• Mean dose of 31 Gy is considered as safe except
for those with deranged LFT’s
• 2 types
1) Classical - Fatigue, abdominal pain, anicteric
hepatomegaly, ascites, isolated elevation of ALP
2) Non classical - Jaundice , Markedly elevated
serum transaminase.

43. Grading of RILD

44. Radiation Induced Liver Disease
• Diagnosis of exclusion
• CT – Sharp demarcation line between the
normal enhancing lesion and the hypo-
attenuation along the trajectory of the
radiation beam ( ‘straight-border sign)
• Treatment – Steroids, Diuretics,
Anticoagulants, Paracentesis of ascitic fluid