22

CENTER OF GENERAL SURGERY AND LIVER TRANSPLANTATION – FUNDENI CLINICAL INSTITUTE – BUCHAREST

International Association of Surgeons and
Gastroenterologists
Romanian Society of Surgery
Romtransplant

The V-th Symposium and
Postgraduate Course of IASG
ostgraduate
- honoring Th. E. Starzl -
Bucharest 9-11 April 2003

MULTIMODAL TREATMENT
MULTIMODAL TREATMENT
OF HEPATOCELLULAR
OF HEPATOCELLULAR
CARCINOMA
CARCINOMA

IRINEL POPESCU

Center of General Surgery and
Liver Transplantation
Fundeni Clinical Institute
Bucharest


 In the Western and Asian experience 70%
of hepatocellular carcinoma (HCC) occurs in
patients with cirrhosis, as the most severe
complication of this disease (especially
macronodular – regenerative)
 There are series in which the proportion is
inversed on behalf of HCC occurring in
normal livers
 The treatment is not standardized
 HCC is one of the most treatment-resistant
tumors
 For the majority of the patients the chances
of cure are still limited


AVAILABLE THERAPEUTICAL
METHODS
 surgical resection
 transplantation
 TAE – transarterial embolization
 systemic chemotherapy
 chemoembolization
 immunochemotherapy
 various forms of in situ ablation
 PEIT – percutaneous ethanol injection therapy
 cryosurgery
 radiofrequency
 microwaves
 laser
 various methods of radiotherapy


1. SURGICAL RESECTION
1. SURGICAL RESECTION
 the preferred method of treatment in non-
cirrhotic patients
 Surgery for hepatocellular carcinoma has
improved dramatically during the last two
decades1
 development of intraoperative ultrasound-
guided operative procedures such as
Makuuchi's segmentectomy
 establishment of the precise criteria for
indications of various hepatectomy procedures
 use of preoperative portal vein embolization

1 Makuuchi M et al. – Oncology 2002, 62 Suppl 1, 74


RESECTION
IN NON-CIRRHOTIC PATIENTS
 Anatomical resections are indicated
 In selected patients with large tumors (more than
5-10 cm diameter) resection may also be
performed ab initio1,2 or following embolization /
ligature of a portal venous branch (this allows
hypertrofy of the contralateral lobe and prevents
postoperative liver failure)3,4
 Yamamoto et al.5: the use of a remnant tumor
index in palliative reduction surgery for advanced
hepatocellular carcinoma

1 Usatoff V et al. – Hepatogastroenterology 2001, 48, 46 4 Popescu I et al. – Chirurgia 2002, 97, 459
2 Hanazaki K et al. – Hepatogastroenterology 2002, 49, 518 5 Yamamoto K et al. – Arch Surg 1994, 132, 120
3 Makuuchi M – Hepatogastroenterology 2002, 49, 36


 Postoperative mortality

 around 2-3% in Western studies1,2

 approaching 0% in Asian series3

1 Bismuth H et al. - World J Surg 1995, 19, 35
2 Belghiti J et al. – Hepato-Gastroenterology 2002, 49, 41
3 Makuuchi M - Hepatogastroenterology 2002, 49, 36


Debulking
In selected cases (i.e. non-cirrhotic
patients with large tumors and
bilateral metastases)

resection of the tumor („debulking”) and
association of other treatment methods
for the remaining nodules1,2

1 Lau WY – J R Coll Surg Edinb 2002, 47, 389
2 Shimamura Y et al. - Hepatogastroenterology 1993, 40, 10


RESECTION IN CIRRHOTIC
PATIENTS

Postoperative mortality
 in chronic liver disease (CLD)

patients – mortality of 4-7%

Belghiti J et al. – Hepato-Gastroenterology 2002, 49, 41


Preoperative assessment of
surgical risk
 evaluation of
 liver function
 volume and quality of the remaining parenchyma
 age of the patient
 biological status

 resection is recommended in Child A cirrhotic
patients, but:
 even in these patients the risk of postoperative liver
failure still exists
 the relatively frequent recurrences don’t seem to justify
the resection


Assessing the risk for resection
in CLD patients
 prediction scores for postoperative
mortality according to Child-Pugh
classification
 indocyanine-green test at 15 minutes
(ICG-15’)1,2
 mandatory histological examination of
the remaining parenchyma before
taking a surgical decision3
1 Makuuchi M – Hepatogastroenterology 2002, 49, 36
2 Hemming AW et al. – Am.J.Surg. 1992, 163, 515
3 Takenaka K et al. – World J Surg. 1990, 14, 123


Type of resection for HCC in
cirrhotic patients
 major hepatectomies and wedge
resections were abandoned
 anatomical segmental resections are
preferred:
 conserve liver parenchyma (thus preventing
postoperative liver failure)
 similar results as major resections1,2; this
conservative approach was not accompanied
by an increase in positive resection margins3

1 Billingsley KG et al. – J Am Coll Surg 1998, 187, 471
2 Regimbeau JM et al - Surgery 2002, 131, 311
3 Fan ST et al. – Ann Surg 1999, 229, 322


Recurrence of HCC after
surgical resection
 66% at 5 years1
 factors influencing recurrence2:
 tumor size
 multiple tumors
 vascular invasion
 high preoperative AFP levels correlated
 histological Edmonson classification3
 resection margin4
 perioperative blood transfusion5
 delineation: the type of recurrence
 multicentric metachronous hepatocarcinogenesis (less than 3
nodules – surgically respectable)
 multinodular recurrences by metastatic dissemination through
portal system, with no possibility of surgical treatment and
with a dismal prognois6

1Sherman M - The Gastroenterologist, 1995, 3, 55 4 Lee CS et al. – Br J Surg 1996, 93, 330
2 Fong Y et al. – Ann Surg 1999, 229, 790 5 Yamamoto J, Makuuchi M et al. Surgery 1994, 115, 303
3 Liver Cancer Study Group of Japan – 1994 6 Adachi E et al. - Surgery 2002, 131, S148


Repeat resections for recurrent
HCC
 may be successfully performed in selected cases1-4
 more difficult than the primary resection due, first
of all, to the modified vascular anatomy
 intraoperative US permits localization of
intrahepatic recurrences
 alternative in cirrhotic patients: destruction by
interstitial ablation
 aggressive treatment of recurrent HCC may
prolong survival

1 Popescu I et al - Chirurgia (Buc ) 1998, 93, 87 3 Poon RT et al. - J Am Coll Surg 2002, 195, 311
2 Hu R-H et al. - Surgery 1996, 120, 23 4 Lo CM et al. - Br J Surg 1994, 81, 1019


Five year survival following
resection of HCC
 steady increase during the last 4 decades
 3% in the ’60
 12% in the ’70
 40-50% after the ’80, following increased
 limited resection for small HCC
 resection for early detected recurrences
 cytoreductive or sequential resections in tumors prior
considered non-resectable1
 limiting resection to patients with Child A cirrhosis (5
year survival in Child B – only 10%)2

1 Tang ZY et al. - Sem Surg Oncol 1993, 9, 293
2 Shirabe K et al. – Cancer 1998, 83, 2312


2. LIVER TRANSPLANTATION
2. LIVER TRANSPLANTATION

 still under debate
 LTx from cadaver donors is practically
prohibited by the organ shortage
 solutions: DOMINO LTx / LIVING DONOR LTx
 risk of a high rate of recurrence
(immunosuppression)


 H Bismuth1:
 liver transplantation offers a disease-free
survival that is better than after liver
resection, and similar to the survival of
liver transplantation for benign liver
disease
 patients with contraindications to
transplantation, patients in whom a long
waiting- time before transplantation is
anticipated, and patients in countries with
limited access to transplantation can be
treated with a palliative intent (because of
de novo tumors) by liver resection

1 Bismuth H – Zentralbl Chir 2000, 125, 647


Selection criteria
 the selection criteria differ between
various centers but the mostly used are
the Milan Criteria
 LTx is indicated in a subgroup of patients
with compensated cirrhosis and HCC
 small tumors (up to 3.0 cm, or 5 cm if solitary)
 no more than 3 nodules
 absence of portal vein tumor thrombus
 in some cases with tumors greater than 5
cm, transplantation was possible following
reduction of the tumor size after
chemoembolization1-4
1 Schwartz ME et al. – J Am Coll Surg 1995, 180, 596 3 Olthoff KM et al. – Arch Surg 1990, 125,1261
2 Van Thiel DH et al. – J Surg Oncol 1993, 3, 78 4 Moreno Gonzalez E et al. – Am J Surg 1992, 163, 395


 in the opinion of some centers with
experience LTx is indicated also in
non-cirrhotic patients
 non-resectable bilobar tumors
 limited recurrences following resection
(there is a slow progression of this
subtype of HCC)

Durand F & Belghiti J - Hepatogastroenterology 2002, 49, 47


PreTx tumor biopsy: strongly indicated
by some authors for the selection of the
patients
high grading predictors of vascular invasion –
important element affecting the survival
size > 4 cm

Esnaola NF et al. – J Gastrointest Surg 2002, 6, 224


Survival following Tx for
cirrhotic patients with HCC
 at 3 years it nears survival of non-HCC
patients transplanted for cirrhosis (70-
80%)1
 at 5 years - 44%
 in practice: good prognosis especially for
those patients with incidentally discovered
tumors at the time of transplantation (in
which the indication for LTx was
determined by the evolution of cirrhosis,
not by the tumor)

1 Durand F & Belghiti J - Hepatogastroenterology, 2002, 49, 47


3. ARTERIAL EMBOLIZATION
3. ARTERIAL EMBOLIZATION

 recommended because of the well-
known arterial hypervascularization
of the HCC
 its efficiency is still under debate

Berger DH – J Surg Oncol 1995, 60, 116


4. CHEMOTHERAPY
4. CHEMOTHERAPY

a) SYSTEMIC

 Efficient-considered drugs:
adriamycin, cysplatinum, mytomycin C


b. LOCO-REGIONAL
 premise: locally administered cytostatic drugs are
more efficient than systemic administration1
 repeatedly delivered by selective catheterization
through the femoral artery or through a catheter in
the gastroduodenal artery (connected to a simple
reservoir or a pump)
 same cytostatic drugs as in systemic chemotherapy
 indications:
 non-resectable HCC
 postresection recurrences
 HCC with indication for transplantation2

1 Clavien PA et al. – Surgery 2002, 131, 433
2 Poon RT – Ann Surg 2002, 235, 466


c) CHEMOEMBOLIZATION
(TACE, TAOCE)
 combination of
 embolization + chemotherapy + Lipiodol / Lipiodol
& Urografin (elective fixation in liver tumors,
“carriers” for the cytostatic drugs)
 some authors contest the carrier role of
Lipiodol and Urografin: these drugs don’t link
covalent bonds with the cytostatic drugs, but
rather they form an emulsion1
 CLD – contraindication for chemoembolization
(it may decompensate the disease)
 evaluation of the quality of the liver parenchyma
before starting the treatment

1 Sherman M - The Gastroenterologist 1995, 3, 55


 despite the fact that theoretically the loco-
regional methods of chemotherapy seem
attractive, there isn’t yet an unanimous positive
opinion over their role in the treatment of HCC
 the excellent results published by some authors
could not be reproduced by others
 one-year survival following chemoembolization is
reported between 30-60%, higher than after
systemic chemotherapy
 none of the various methods of chemotherapy
(neoadjuvant or adjuvant), administered through
different methods, significantly improve global or
„disease-free” survival1

1 Schwartz JD et al. - Lancet Oncol 2002, 3, 593


c) IMMUNOCHEMOTHERAPY
 In the last two decades: promising results
offered by immunochemotherapy1
 Lymphokine-activated killer (LAK) cells and
recombinant interleukin 2 (rIL-2) are infused
via a catheter in the splenic / gastroduodenal
artery, together with a cytostatic drug
(Doxorubicin) in emulsion of Lipiodol-
Urografin (substances preferentially retained
in hypervascularized liver tumors)
1 Okuno K et al. Cancer 1986, 58, 1001
2 Lygidakis NJ et al. Hepatogastroenterology 2001, 48, 1685
3 Kountouras J et al. Hepatogastroenterology 2002, 49, 1109


5. METHODS OF LOCAL
5. METHODS OF LOCAL
ABLATIVE THERAPY
ABLATIVE THERAPY


a) Percutaneous ethanol
injection therapy
 depending on liver function, percutaneous
ethanol injection therapy (PEIT) can be
effective for small HCC
 advantage of repeated applications
 indicated in the case of small tumors (less
than 3 cm diameter) and of recurrences1
 the complete resolution of the tumors was
noted in some studies2,3
 recurrence rate 60%
 5-year survival rate 60%4
1 Poon RT – Ann Surg 2002, 235, 466 3 Livraghi T – World J Surg 1995, 164, 215
2 Lee MJ et al. – Am J Roentgenol 1995, 82, 122 4 Shiina S – Am J Roentgenol 1990, 154, 947


Other forms of treatment currently are being
under evaluation
 hyperthermic destruction
 microwave
 radio-frequency
 laser
 cryo-therapy
 they offer advantages similar to PEIT,
some of them without the need for
multiple sessions
 all these forms of chemical or physical
ablation therapies may be associated with
different forms of chemotherapy, with
increased efficiency1

1 Livraghi T et al. – Hepatogastroenterology 2002, 49, 62


b) Cryoablation

 destruction by freezing at very low
temperatures of non-resectable
lesions:
 local invasion
 multiplicity
 some preliminary results were
promising
 limited by a significant morbidity1,2
1 Que FG et al. – Br J Surg 1994, 81, 255
2 Hemming AW – Br J Surg 1994, 81, 1553


c) Radiofrequency ablation
 encouraging results1
 the best results are achieved when performed
intraoperatively2, with
 direct control on the liver and iop US
 Pringle maneuver (diminishes the amount of heat
“stolen” by the high blood stream through the tumor)
 RF may also be applied percutaneously
 less side effects
 less effective
 promising strategy for the treatment of larger
tumors: association of RF tumor destruction and
transarterial embolization3
1 Curley SA et al. – Minerva Chir 2002, 57, 165
2 Mahvi DM et al. – Ann Surg 1999, 230, 9
3 Poon RT – Ann Surg 2002, 235, 466


Other forms of therapy

 irradiation with I-131 lipiodol
 irradiation with yttrium marked glass
pellets
 irradiation with I-131 tagged
antiferritin antibodies1

1 Sitzman JV et al. – Dig Surg 1995, 12, 73


6. MINIMALLY INVASIVE
6. MINIMALLY INVASIVE
SURGERY
SURGERY
 becomes more often used in
 pretherapeutic assessment (preresection, preTx)
 treatment of CHC
 laparoscopic US allows
 detection of lesions that have not been identified
preoperatively
 tumor biopsy
 guidance for interstitial ablative therapies
 resection of small HCCs, located in
laparoscopic accessible liver segments, is also
feasible
1 Tait IS et al. – Br J Surg 2002, 89, 1613
2 Teramoto K et al. – Surg Endosc 2002, 16, 1363
3 Montorsi M et al. – Hepatogastroenterology 2002, 49, 56


Further progress
Further progress

 wider use of screening to detect a
larger proportion of treatable lesions
 strategies to prevent carcinogenesis
in the cirrhotic liver
 gene therapy to alter the tumor
biology


CENTER OF GENERAL SURGERY AND
LIVER TRANSPLANTATION
- Fundeni Clinical Institute –
Bucharest

January 1, 1995 – March 15, 2003
556 liver resections
88 PATIENTS WITH HCC
with normal liver 52 cases (60%)
with cirrhosis 36 cases (40%)


RESECTIONS IN NON-CIRRHOTIC
PATIENTS
52 PATIENTS

 Right hepatectomy 17
 Extended right hepatectomy 7
 One case following ligation of the right portal branch
 Right lateral sectoriectomy 3
 Left hepatectomy 5
 Extended left hepatectomy 2
 Left lateral sectoriectomy 3
 Segmentectomy VIII 1
 Non – anatomical resection 14


Two-staged
resection for HCC

December 2000

January 2001


1/2/2001 – Ligation of RPB

16 days following ligation


8 weeks following ligation
Volumetric assessment
 2/02/2001 segm I-III 493 cm3, segm IV-VIII 1885 cm3
 5/04/2001 segm I-III 515 cm3, segm IV-VIII 1055 cm3


Extended right hepatectomy specimen (+ segment IV),
8 weeks following ligature of the
right portal branch


1 Year postoperatively
(april 2002)

Still alive, free of disease, in March 2003 (normal US)


Associated surgical procedures

 resection of the diaphragm 6
 partial resection of the inferior vena cava /
cavorrhaphy 2
 resection of thrombus from the portal vein
1


DEBULKING


ABDOMINAL CT
ABDOMINAL CT

 a large, multinodular, dense,
slightly iodophyllic, imprecisely
delimited liver tumor localized
in segments V+VI
 other disseminated
micronodular lesions in both
liver lobes – metastases ?


SURGERY
SURGERY
September 1999:
September 1999:
V+VI BISEGMENTECTOMY
V+VI BISEGMENTECTOMY

CITOREDUCTION
OF THE
PRIMITIVE TUMOR
Multiple disseminated tumors in the remaining RL and
in the LL, of different dimensions


Liver angiography
Liver angiography

Multiple hypervascularised Permeability of the
zones portal vein


November 1999:
November 1999:
TRANSARTERIAL OILY
TRANSARTERIAL OILY
CHEMOEMBOLIZATION (TAOCE)
CHEMOEMBOLIZATION (TAOCE)
doxorubicin 50 mg
dissolved in
urografin 5 ml
mixed with
lipiodol 5 ml
Injected in both liver
lobes through a catheter
in the common hepatic
artery
(Seldinger technique)


 US-guided biopsy:
HCC, G2
 PERCUTANEOUS
ETHANOL
INJECTION


CT at 24 hours –
complete tumoral
necrosis

CT at 1 month

CT at 8 months (June 2002)


July 2002
July 2002

αFP – 350 IU
CT – suspected
recurrence


September 2002
September 2002
Non-anatomical
resection of 2nd
recurrent tumor


 Currently: alive and well, with no
signs of recurrence at 43 months
after the initial operation


RESECTION OF RECURRENCES

 resection of hepatic recurrence 3
 resection of extrahepatic recurrence 1


RE-RESECTION FOR RECURRENT HCC
II, m, 23
February 1996: right hepatectomy
+ phrenectomy
+ lymphadenectomy
April 1997: atypical hepatectomy


MORBIDITY AND MORTALITY IN
PATIENTS WITH HCC ON NORMAL LIVER
Postoperative
complications Deaths
 hepato – renal failure 1 1
 biliary fistula 3
 pleuresy 2
 hemoperitoneum 3 2
 subphrenic abscess 1
 deep venous thrombophlebitis 1
 pulmonary abscess 1 1
 subphrenic hematoma 1
 bronchopneumonia 1 1
 acute heart failure 1 1
 subhepatic abscess 2
 partial necrosis of parenchyma 1
40% 11%
All deaths – before 1999


RESECTIONS IN CIRRHOTIC
PATIENTS

36 patients
 Left lateral sectoriectomy 8
 Left hepatectomy 2
 Right hepatectomy 4
 Extended right hepatectomy 1
 Right lateral sectoriectomy 2
 Non – anatomical resections 19


MORBIDITY AND MORTALITY IN
PATIENTS WITH HCC ON CIRRHOSIS
Postoperative
complications Deaths
 choleperitoneum 1 1
 haemoperitoneum 3 2
 bilateral pleuresy 1
 liver failure 1(4) 1(4)
 interhepatodiaphragmatic
hematoma and necrosis
of the transection edge 1 1
19% 14%
All deaths – before 1999


Survival of patients with HCC

HCC without cirrhosis HCC and cirrhosis

Patients still alive (%)
Patients still alive (%)

Time survival (months) Time survival (months)

30 months survival: > 60% 24 months survival: 30%


LIVER TRANSPLANTATION
 2 CASES
 1 – recipient of a domino LTx from a
familial hypercholestoremia patient
 alive and well at 18 months
 1 – HCC on VHC cirrhosis - recipient of the
right side of a split LTx
 alive at 5 months; recurrent VHC hepatitis
 both patients were submitted to
chemoembolisation prior to LTx


RESECTED SPECIMEN IN PATIENT 1

RESECTED SPECIMEN IN PATIENT 2


LOCAL INTERSTITIAL
THERAPIES
June 1, 2001 – March 15, 2003

13 PATIENTS

 IM 10
 PM 9
 IRF 4 IM – intraoperative MW
PM – percutaneous MW
IRF – intraoperative RF
 PRF 2 PRF – percutaneous RF


CONCLUSIONS
 Treatment of HCC is at present time
multimodal
 In non-cirrhotic patients resection is the
preferred treatment
 In cirrhotic patients liver transplantation
seems to be the best treatment option
 If LTx is unavailable, other alternative
tumor ablative treatments (MW, RF, PEIT)
should be used

END

22

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to 22

Similar to 22 (20)

More from fundeni

More from fundeni (20)

Recently uploaded

Recently uploaded (20)

22