Radiotherapeutic Option Radiotherapeutic Option in Management of in Management of Hepatocellular CarcinomaHepatocellular Carcinoma

Dr. CK Tang, Tuen Mun HospitalDr. CK Tang, Tuen Mun Hospital

OverviewOverview

External beam External beam radiotherapyradiotherapy

Transarterial Transarterial radioembolisationradioembolisation

Aim :Aim : Overview Overview of clinical of clinical use of external beam use of external beam radiotherapy in HCC radiotherapy in HCC patientspatients

BackgroundBackground

Hepatocellular carcinomaHepatocellular carcinoma HCCHCC

5th5th most common most common cancer in the worldcancer in the world

3rd 3rd ranked cause of ranked cause of global cancer mortalityglobal cancer mortality

Worldwide Incidence of HCC

BackgroundBackground

MultidisciplinaryMultidisciplinary management of HCCmanagement of HCC

AggressiveAggressive treatment treatment

Increasing interest in Increasing interest in radiotherapy as an option radiotherapy as an option of management for HCCof management for HCC

BackgroundBackground

Traditionally, radiotherapy Traditionally, radiotherapy is regarded as of is regarded as of limitedlimited useuse

Radiation-induced liver Radiation-induced liver disease RILDdisease RILD

Low dose radiationLow dose radiation Relatively diffuse fieldRelatively diffuse field ““Radio-resistant”Radio-resistant”

BackgroundBackground

New technologies :New technologies :

Advanced imaging to improve Advanced imaging to improve tumour definitiontumour definition

3D conformal treatment 3D conformal treatment planningplanning

Computer-assisted organ Computer-assisted organ trackingtracking

Intensity modulated RTIntensity modulated RT Improved knowledge of Improved knowledge of

partial volume tolerance of partial volume tolerance of liverliver

BackgroundBackground

Greater conformalityGreater conformality of of the radiation dose cloud the radiation dose cloud around liver tumorsaround liver tumors

Less radiation delivered Less radiation delivered to surrounding “normal to surrounding “normal liver”liver”

Higher radiation dosage Higher radiation dosage could be delivered to could be delivered to tumour up to 70 Gytumour up to 70 Gy

Stereotactic body Stereotactic body radiotherapy SBRTradiotherapy SBRT

Clinical Questions

Is it useful ?

Which patient group are we going to offer to ?

What are the outcomes ?

Is it useful ?

EvidenceEvidence

Radiotherapy for hepatocellular carcinoma: Systematic review of radiobiology and modeling projections indicate reconsideration of its use

Wigg et al 2010

Level I evidence that HCC is radiosensitive

Early results came from experience in palliative care

EvidenceEvidence

EvidenceEvidence Bujold et alBujold et al.. Phase II prospective seriesPhase II prospective series including including 102 102 patientspatients High riskHigh risk

Extrahepatic diseaseExtrahepatic disease Large size HCC up to 7cmLarge size HCC up to 7cm Main portal vein thrombosisMain portal vein thrombosis

EvidenceEvidence Bujold et alBujold et al..

Overall local control at 1 year was Overall local control at 1 year was 87%.87%. Median overall survival was Median overall survival was 17.0 months17.0 months 1-year survival rate1-year survival rate compared favorably with best supportive care and with compared favorably with best supportive care and with sorafenibsorafenib Conclusion : SBRT has Conclusion : SBRT has substantial local control activitysubstantial local control activity against HCC against HCC

EvidenceEvidence Feasibility and efficacy of high-dose three-dimensional-conformal

radiotherapy in cirrhotic patients with small-size hepatocellular carcinoma non-eligible for curative therapies – mature results of the French phase II RTF-a trial

Mornex et al 2006

Stereotactic body radiotherapy for primary hepatocellular carcinomaAndolino et al. 2011

85-95% response rate

Which patient group are we going to offer radiotherapy to?

We don’t know. No RCT No guideline Expert opinion

Preserved liver functionPreserved liver function Huge tumourHuge tumour Main portal vein thrombusMain portal vein thrombus

EvidenceEvidence

Synergistic effect of TACE with RTSynergistic effect of TACE with RT Direct tumour necrosisDirect tumour necrosis Veno-occlusive effect of RT to surrounding liver tissueVeno-occlusive effect of RT to surrounding liver tissue

Preserved liver functionPreserved liver function Huge tumourHuge tumour Main portal vein thrombusMain portal vein thrombus

What are the outcomes ?

Local controlLocal control activity against activity against HCCHCC

And apart from that…And apart from that…

Case presentation 1Case presentation 1 55 year-old gentleman Attended TMH Non-Hep B, non-Hep C HCC AFP 1085 Child’s A CT : 10.4cm HCC at right lobe BCLC stage C

Case presentation 1Case presentation 1 TACE to RHA, then stereotactic radiotherapy 4 Gy x 9 Follow-up CT : Interval decrease in size of HCC to

6.2cm, with hypertrophy of left lateral section CT volumetry : 57%

Case presentation 1Case presentation 1

BeforeBefore AfterAfter

Case presentation 1Case presentation 1 Right tri-sectionectomy 6 months after initial diagnosis of

HCC

Case presentation 1Case presentation 1

Case presentation 2Case presentation 2 Child’s A Presented to us for RUQ pain CT : Huge HCC occupying the right lobe, contained

rupture

Case presentation 2Case presentation 2 TACE, then stereotactic radiotherapy 4 Gy x 8 Follow-up CT : Interval decrease in size of HCC from

13.4cm to 9cm Hypertrophy of left lateral section

Case presentation 2Case presentation 2

BeforeBefore AfterAfter

Right hepatectomy 6 months after initial diagnosis of HCC

Combination of Radiotherapy Combination of Radiotherapy with other modalitieswith other modalities

Choi SB et al. 2009 Case series 16 patients with HCC greater than 5 cm in size TACE and radiation therapy, then resection Median survival 13.3 months 5 patients had survived more than 2 yr and 2 patients who had survived more

than 5 yr

Combination of Radiotherapy Combination of Radiotherapy with other modalitieswith other modalities

Hung KC et al. 2011

Combination of Radiotherapy Combination of Radiotherapy with other modalitieswith other modalities

Hung KC et al. 2011

SummarySummary

Is it useful ?Is it useful ? Level I evidenceLevel I evidence to support to support radio-sensitivityradio-sensitivity of HCC of HCC Prospective studies Prospective studies to support local control activity in to support local control activity in

HCCHCC

Whom to select ?Whom to select ? No RCT, no guidelineNo RCT, no guideline Expert opinionExpert opinion

Huge tumour, MPV thrombus, Preserved liver functionHuge tumour, MPV thrombus, Preserved liver function

SummarySummary

What are the clinical outcomes ?What are the clinical outcomes ? Prospective studiesProspective studies support the clinical use of support the clinical use of

radiotherapy for radiotherapy for local controllocal control A few A few case reportscase reports and and small case seriessmall case series to support to support

combination of radiotherapy and TACE with surgical combination of radiotherapy and TACE with surgical resectionresection

SummarySummary

But still But still lacking RCTslacking RCTs to provide comparison with other to provide comparison with other treatment modalities, in terms of treatment modalities, in terms of survivalsurvival benefit benefit

Relatively new approach with Relatively new approach with scanty clinical data scanty clinical data meanwhilemeanwhile

ControversyControversy

Future perspectiveFuture perspective ? Overall survival? Overall survival ? Disease-free survival ? Disease-free survival

Evidence limited to Evidence limited to prospective studies, case prospective studies, case reports and case studiesreports and case studies

Evidence concentrated in Evidence concentrated in AsiaAsia

No RCTNo RCT

Data are emergingData are emerging

ChinaChinaJapanJapan

KoreaKorea

As a Surgeon…As a Surgeon…

Overview onlyOverview only Share our experience of managing patientsShare our experience of managing patients with with

radiotherapyradiotherapy

As a Surgeon…As a Surgeon…

MultidisciplinaryMultidisciplinary approach in management of HCC approach in management of HCC Operation is only a part of itOperation is only a part of it Explore Explore combinationcombination of radiotherapy with resection / of radiotherapy with resection /

ablative surgery / liver transplantationablative surgery / liver transplantation Ongoing research should be promotedOngoing research should be promoted

Adverse reactionsAdverse reactions

LimitationsLimitations

Evidence limited to prospective studies, case reports Evidence limited to prospective studies, case reports and case studiesand case studies

Evidence concentrated at AsiaEvidence concentrated at Asia No RCT conductedNo RCT conducted

Limited to a selected group of patientLimited to a selected group of patient No generalised selection criteriaNo generalised selection criteria No homogeneous treatment protoccolNo homogeneous treatment protoccol

Radiation-induced liver diseaseRadiation-induced liver disease

Radiation hepatitisRadiation hepatitis Fatigue, RUQ pain, ascites, jaundice, elevated liver Fatigue, RUQ pain, ascites, jaundice, elevated liver

enzymesenzymes Develops usually 1-2 months after RT (range 2 weeks Develops usually 1-2 months after RT (range 2 weeks

- 8 months) - 8 months) Treatment: supportive; most patients recover, but can Treatment: supportive; most patients recover, but can

lead to liver failure and death lead to liver failure and death

Radiation-induced liver diseaseRadiation-induced liver disease

Dawson report in 2002 Dawson report in 2002 The mean liver dose is directly proportional to risk of The mean liver dose is directly proportional to risk of

RILDRILD 5% risk of RILD for whole liver RT is at 32 Gy 5% risk of RILD for whole liver RT is at 32 Gy Small liver volumes (<25%) can tolerate doses >100 Small liver volumes (<25%) can tolerate doses >100

Gy Gy Difference between normal liver tolerance and HCC Difference between normal liver tolerance and HCC

liver toleranceliver tolerance