Radiotherapeutic Option in Management of Hepatocellular Carcinoma Dr. CK Tang, Tuen Mun Hospital

Overview External beam radiotherapy Transarterial radioembolisation Aim : Overview of clinical use of external beam radiotherapy in HCC patients

Background Hepatocellular carcinoma HCC 5th most common cancer in the world 3rd ranked cause of global cancer mortality Worldwide Incidence of HCC

Background Multidisciplinary management of HCC Aggressive treatment Increasing interest in radiotherapy as an option of management for HCC

Background Traditionally, radiotherapy is regarded as of limited use Radiation-induced liver disease RILD Low dose radiation Relatively diffuse field “Radio-resistant”

Background New technologies : Advanced imaging to improve tumour definition 3D conformal treatment planning Computer-assisted organ tracking Intensity modulated RT Improved knowledge of partial volume tolerance of liver Advanced imaging to improve tumour definition 3D confromal treatment planning Computer-assisted organ tracking Image modulated RT Improved knowledge of partial volume tolerance of liver

Background Greater conformality of the radiation dose cloud around liver tumors Less radiation delivered to surrounding “normal liver” Higher radiation dosage could be delivered to tumour up to 70 Gy Stereotactic body radiotherapy SBRT

Clinical Questions Is it useful ? Which patient group are we going to offer to ? What are the outcomes ?

Is it useful ?

Evidence 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

Evidence Early results came from experience in palliative care

Evidence Bujold et al. Phase II prospective series including 102 patients High risk Extrahepatic disease Large size HCC up to 7cm Main portal vein thrombosis

Evidence Bujold et al. Overall local control at 1 year was 87%. Median overall survival was 17.0 months 1-year survival rate compared favorably with best supportive care and with sorafenib Conclusion : SBRT has substantial local control activity against HCC

Evidence 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 carcinoma Andolino 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 function Huge tumour Main portal vein thrombus

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

Preserved liver function Huge tumour Main portal vein thrombus

What are the outcomes ? Local control activity against HCC And apart from that…

Case 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 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 1 Before After

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

Case presentation 1

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

Case 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 2 Right hepatectomy 6 months after initial diagnosis of HCC Before After

Combination of Radiotherapy with 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 with other modalities Hung KC et al. 2011

Combination of Radiotherapy with other modalities Hung KC et al. 2011

Summary Is it useful ? Level I evidence to support radio-sensitivity of HCC Prospective studies to support local control activity in HCC Whom to select ? No RCT, no guideline Expert opinion Huge tumour, MPV thrombus, Preserved liver function

Summary What are the clinical outcomes ? Prospective studies support the clinical use of radiotherapy for local control A few case reports and small case series to support combination of radiotherapy and TACE with surgical resection

Summary But still lacking RCTs to provide comparison with other treatment modalities, in terms of survival benefit Relatively new approach with scanty clinical data meanwhile Controversy

Future perspective ? Overall survival ? Disease-free survival Evidence limited to prospective studies, case reports and case studies Evidence concentrated in Asia No RCT Data are emerging China Japan Korea

As a Surgeon… Overview only Share our experience of managing patients with radiotherapy As a Surgeon… Multidisciplinary approach in management of HCC Operation is only a part of it Explore combination of radiotherapy with resection / ablative surgery / liver transplantation Ongoing research should be promoted

Adverse reactions

Limitations Evidence limited to prospective studies, case reports and case studies Evidence concentrated at Asia No RCT conducted Limited to a selected group of patient No generalised selection criteria No homogeneous treatment protoccol

Radiation-induced liver disease Radiation hepatitis Fatigue, RUQ pain, ascites, jaundice, elevated liver enzymes Develops usually 1-2 months after RT (range 2 weeks - 8 months) Treatment: supportive; most patients recover, but can lead to liver failure and death

Radiation-induced liver disease Dawson report in 2002 The mean liver dose is directly proportional to risk of RILD 5% risk of RILD for whole liver RT is at 32 Gy Small liver volumes (<25%) can tolerate doses >100 Gy Difference between normal liver tolerance and HCC liver tolerance