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Management of Hepatocellular
carcinoma (HCC)
Dr Sneha George
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
DIAGNOSIS
• Complete history and physical examination
• Symptoms
- Pain
- Abdominal distension
- Jaundice
- Vomiting
- Loss of weight
- Pruritus
• Signs - Icterus, Ascites, Hepatosplenomegaly,
Spider naevi
INVESTIGATIONS
Laboratory
• LFT
• AFP
Radiological
• USG
• CT
• MRI
• Hepatic , celiac and
superior mesenteric
angiography
• Radionuclide scans
- Gallium scan
STAGING
BCLC staging classification
Child Pugh Scoring
Score Operative risk
• 5-6 Good
• 7-9 Moderate
• 10-15 Poor
PROGNOSTIC FACTORS
• Number, size and location of liver lesions
• Vein involvment
• Extent and type of resection
• Hepatic reserve
Treatment modalities
• Surgery
• Chemotherapy
• Radiotherapy
• Targeted Therapy
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
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
• TYPES
- Cadaveric liver transplantation
- Living donor liver transplantation
• 5 year OS rates – 70%
• Recurrence – <15%
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
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
• 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
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
TARGETED THERAPY
• Tyrosine kinase inhibitors are used
• MOA: Inhibits multiple signal transduction
pathways (VEGF, EGF, IGF, MAPK)
• Eg: Sorafenib, Sunitinib,Linifanib, Brivanib,
Everolimus
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
Phase III clinical trials of targeted
agents
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
METHODS OF RADIATION:
Conventional radiation
3-D Conformal Radiation /IMRT
Stereotactic body radiotherapy
Protons & heavy ion therapy
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
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
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
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
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
SBRT dose regimes
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
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%
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)
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
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
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
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
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
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%
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%
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
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
Follow up
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.
Grading of RILD
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
Management of hcc sneha

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Management of hcc sneha

  • 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
  • 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
  • 10.
  • 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
  • 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
  • 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.
  • 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

Editor's Notes

  1. Radiographic response, Reduction in AFP, palliative improvement LN ,Bone mets, brain mets, soft tissue mets
  2. 29mth median FU in field control was seen in 78% . 92% had a tumor response rate & 80% had CR.Child Pugh A 3pts developed gr3 toxicity.No gr4 toxicity was seen. In CP – B 3pts developed gr4 toxicity but all had gr 3 toxicity before the start of RT
  3. Phase 1 dose escalation study started at 36Gy in 3# in 5-10 days. CP A were successfully escalated to 48Gy in 3# CP B developed toxicity& dose was modified to 40 Gy in 5# ( 800 cGy /# 1-2 # /week) Patients with CP score > 8 are at a higher risk of developingsevere toxicity unless they undergo liver transplant
  4. BED=Biologically equivqlent dose; EUD+=Equivqlent uniform dose; TCP=tumor control probability