The Results of neo-adjuvant intra-arterial [131I]lipiodol in liver resection and transplantation for

HCC B. Launois, J.L. Raoul, L.A. Veilhan, B. Meunier,

K. Boudjema, M. S. Metcalfe,

G.J. Maddern

Departments of Surgery

University of Rennes (France)

University of Adelaide (Australia)

Bucharest (Romania) 9-11 April, 2003

Surgery for HCC

• Recurrences– After resection 80-100% at 5 years– After OLT 40-50% if >5cm, 10% if <3cm

• Adjuvant treatments– To improve results, decreasing recurrence rate– Chemoembolisation, chemotherapy– Retinoids– [131I] lipiodol

Injection of [131I]Lipiodol

• 131I Lipiodol concentrates in the tumour– Injection of 60 mCu [131I] lipiodol– Without embolisation

• Biodistribution– Phase I: well tolerated

• Radiology 1988 168: 541-5

– Phase II: well tolerated with objective tumour response

• Cancer 1992 69: 346-52

IA injection of [131I] lipiodol

• Phase III: HCC with portal vein thrombosis– [131I] lipiodol vs medical support– Higher survival in treatment group

• J Nucl Med 1994; 35: 1782-7

• Phase III: unresectable HCC– [131I] lipiodol vs chemoembolisation– Equal efficacy, but [131I] lipiodol better tolerated

• Hepatology 1997; 26: 1156-61

Pre-operative [131I] lipiodol

• Well tolerated

• Preserve liver vasculature

• Aim:– To decrease recurrence rate

• Induce tumour necrosis

• Treatment during the waiting period

• Reduce micrometastases related to manipulation

• I – Liver resection versus transplantation with [131I] lipiodol

• II – Liver transplantation with and without [131I] lipiodol

• I – Liver resection versus Liver transplantation with [131I] lipiodol

Study design

• Open study• Inclusion criteria

– HCC: proven/highly suspected– Resection or transplantation candidate– Informed consent

• Treatment– IA injection of [131I] lipiodol at M0 and M2

– Isolation room 6 days– Surgery M3

Patients

• 26 male: 2 female• Age 57.6 +/-9.4 years• Cirrhosis: 24/28• Child A (21), B (5), C (2)• Etiology:

– Alcohol (15)– Post-hepatitis (4)– Haemochromatosis (6)– Multiple (2)– Normal liver (1)

Tumours

• Number– One (18)

– Two (6)

– Three (1)

– Four (3)

• Tumour size 5.7+/-4.2cm– <3cm (10)

– 3-5cm (8)

– 5-10cm (5)

– >10cm (5)

• Tumour to liver volume ratio:

– <25% (23)

– 25-50% (3)

– >50% (2)

Surgery

• Resections 16– Tumour resection 11– Hepatectomy 5

• Liver transplants 11

• Laparotomy 1

Results: efficacy• Tumour response: pathology size/CT size

– Progression >25% (2)– Stabilisation +/-25% (6)– Minor response 25-50% (12)– Objective response >50%(4)

• Pathological examination: % necrosis– 100% (5)– >90% (4)– 50-90% (4)– <50% (12)

Tolerance

• IA injection of [131I] lipiodol – Acute mesenteric infarction – 1 case

• Surgery– Post-operative deaths (<4 weeks): 2/28 (7%),

• Resection 1/16, transplantation 1/11

– Severe side effects• Liver failure – 1 death (4 months)

• Septic complications – 1 death (2 months)

• II - Liver transplantation with and without [131I] lipiodol

Patients1 January 1987- 1 August 1999

• 52 patients (17.3%)– HCC in cirrhotic liver (49)– HCC in diseased liver (3)

• Mean age: 52 years (27-66)– 51 males, 1 female– Indication: HCC 39 cases (75%), incidental in

13 cirrhosis cases (25%)

Etiology of Cirrhosis

• Alcoholic 31 (60%)• Haemochromatosis 10 (19%)• Post-hepatitis C 16 (31%)• Post-hepatitis B 4 (8%)• Multiple 8 (17%)• SEVERITY:

– Child A (23) B (15) C (14)

– Mean Child Pugh Score: 7 (+/-2)

Three groups• A One or 2 injections of [131I] lipiodol

22 cases

• B No injection of [131I] lipiodol19 cases

• C Incidental HCC13 cases

Group CharacteristicsHCC+ [131I]L: HCC, no [131I]:Incidental P

No. 20 19 13 NS

Age (yrs) mean(sd) 51(5) 51.1(8.5) 54.9(5.3) NS

Etiology:

Alcoholic 11 (55%) 6 (32%) 6(46%) NS

+Haemochromatosis 2 (20%) 1 (5%)

Haemochromatosis 1 (5%) 4 (21%)

Alcohol+VHC 1 (5%) 1 (5%) 1 (8%) NS

VHC 3 (15%) 3 (16%) 6 (46%) NS

VHB+C 1 (5%)

VHB 3 (16%)

Child Pugh mean(sd) 7(2) 6(2) 10(2)

Characteristics of 38 liver transplants

[131I] lipiodol No [131I] lipiodol PNo. 19 19Diameter(mm)

Mean(sd) 36 (15) 61 (45) 0.036Median 33 40

Diameter2 (mm2)Mean(sd) 1027(43) 4293(5820) 0.027Median 729 1225

Protocol of IA injection of [131I] lipiodol

• No previous neo-adjuvant treatment• IA injection under general anaesthesia in

radiology department through catheter (Seldinger technique)

• 4 ml of lipiodol: mean activity 60millicuries (range 56-66)

• Safety measures– Containers– Lead-shielded Syringe– 6 days patient isolation

Morbidity post- [131I] lipiodol injection in 20 patients

Complication No. %

Decompensation 2 6

Fever 3 8

Abdominal pain 3 8

Temporary encephalopathy 2 6

Cough and dyspnoea 2 6

Arthralgia 2 6

Evaluation of response to [131I] lipiodol

• Tumour size

• Alpha fetoprotein

• Tumour necrosis

• Tolerance

• Recurrence

• Survival

Efficacy of [131I] lipiodol

CT before (14) CT after (14) PΣ diameter (mm)

Mean (sd) 49(28) 32(22) 0.004

Median (range) 39(20-110) 26(0-89)

Σ diameter2 (mm2)

mean (sd) 1307(896) 699(582) 0.003

median (range) 968(320-3000)462(0-1917)

Efficacy by alpha-fetoprotein

before [131I] lipiodol after [131I] lipiodol

No. 19 19

AFP

Mean(SD) 4798(16193) 2085(+/-8352) NS

Median (range) 30(1.4-70000) 8(1-36500)

Pathology of 51 liver transplants for HCC

lipiodol No lipiodol IncidentalP

No. patients 19 19 13

No. tumours:

Median(range)1(1-5) 1(1-5) 1(1-5) NS

Size of tumours:

Σ diameter (mm)

Mean (sd) 35(19) 53(37) 13(7)

Median (range) 34(0-70) 40(8-125) 11(5-30) 0.046

Pathology of 51 LT for HCC

Lipiodol No lipiodol Incidental

Tumoural necrosis

Total or >90% 4 (21%) 3 (16%)

Partial 11 (58%) 7 (37%)

Absent 2 (11%) 8 (42%) 13(100%)

Vascular involvement

Present 7 (37%) 2 (11%) 2 (15%)

Absent 11 (58%) 11 (58%) 11 (85%)

Unknown 1 (5%) 6 (32%)

Delay of Treatment

Lipoidol no lipoidol P

No. patients 20 19

Delay (days)

Mean (sd) 200(93) 140(133) NS

Median (range) 179(56-486) 106(11-500)

Post-operative course

lipiodol no lipiodol incidental PNo. 20 19 13Op. mortality 4(20%)6(32%)1(8%)Haemodynamic shock 1 1 1Septic shock 1 2Anaphylactic shock 1Acute rejection 2Acute respiratory fail. 2RC Packs 12(8) 15(10) 11(3) NSRe-Tx 2(10%)4(21%)2(15%)NS

Months

Overall survival of 52 liver transplant patients

months

Liver transplant survival by tumour diameter

<30mm

30-50mm

>50mm

Survival of liver transplants with and without vascular invasion

months

No vascular invasion

Vascular invasion

months

Survival of liver transplants by experimental groups

No lipiodol

incidental

lipiodol

Cumulative survival of 52 patients

lipiodol no lipiodol incidentaloverall

No. 20 19 13 52

1 year surv 77% 37% 92% 64%

3 year surv 77% 25% 92% 57%

5 year surv 77% 18% 48%

Characteristics of recurrences

• 4 recurrences (8%)– Mean time after LT: 16 months (7-38)– Location: Liver 3, Bone 1

• According to pre-operative treatment– [131I] lipiodol: 0/19 patients– No [131I] lipiodol: 3/19 patients (16%)– Incidental HCC: 1/13 patients (8%)

Conclusions

• [131I] lipiodol permits resection of HCC>3cm, 3yr survival is 42%

• Pre-operative [131I] lipiodol in liver transplantation for HCC of all sizes gives 5 year survival of 77%, compared to 18% without

• There has been no recurrence in the [131I] lipiodol group