Role of Surgery

Role of Surgery in HCC

March 2014Dubai-UAE

Mohammed Al Sebayel MD,FRCS,MPHProfessor and Chairman

Dept. of Liver Transplantation & Hepatobiliary-Pancreatic SurgeryKing Faisal Specialist Hospital &RC, Riyadh, SAUDI ARABIA

Themes ……..Themes ……..

• Introduction• Anatomy and technical aspects.• Diagnosis and Staging.• Where does resection and OLTx stands with

other modalities.• Selection aspects.• Outcome.• Neo-adjuvant and Down staging• Future direction

HEPATOCELLULAR CARCINOMA

• Most common Liver Tumor in adult.• Account for as many as 1 million death

per year.• The 5th most common cancer in the world.• The 3rd most common cause of cancer-

related death in the world.• Incidence as high as 50/100,000/year

Liver Cancer: Sixth Most Common Cancer Worldwide1

196,298

226,787230,555

200,774

314,256330,963

529,283559,094

711,128782,647

1,066,5431,167,020

1,301,8671,549,121

0 200,000 400,000 600,000 800,000 1,000,000 1,200,000 1,400,000 1,600,000 1,800,000

Non-Hodgkin's Lymphoma

Corpus UteriOvary

Oral Cavity

BladderLeukemia

EsophagusCervix Uteri

LiverProstateStomach

Colon/RectalBreast

Lung

• Liver cancer is the third most common cause of cancer-related death2

• HCC is the most common primary liver malignancy in adults2

• HCC is the most common primary liver malignancy in adults21. Garcia M, et al. American Cancer Society, 2007. www.cancer.org. Accessed March 20, 2008.

2. http://www.who.int/mediacentre/factsheets/fs297/en/index.html. Accessed June, 2008.3. Perz JF, et al. J Hepatol. 2006;45:529-538.

http://www.who.int/mediacentre/factsheets/fs297/en/index.html

ChinaMiddle AfricaJapanEastern AfricaSoutheastern AfricaMelanesiaWestern AfricaSouthern EuropeMicro/PolynesiaCaribbeanSouthern AfricaWestern EuropeEastern EuropeNorthern AmericaCentral AmericaWestern AsiaNorthern AfricaAustralia/New ZealandSouth AmericaNorthern Europe

0 10 20 30 40 501020304050

Liver Cancer: Global Incidence

Age Standardized Incidence per 100,000

Parkin D, et al. CA Cancer J Clin. 2005;55;74-108.

Worldwide HCC IncidenceWorldwide HCC Incidence

Incidence per 100,000

Worldwide- 100 million cases

- 1.2 million case/yr

-1 million deaths/yr

-3rd leading cause of

cancer-related death

Hepatocellular Carcinoma

Liver Cirrhosis (HBV – HCV)

Extent of Resection

Incision

Liver Mobilization

Hilar DissectionBlumgart, 2000

Blumgart, 2000

Mobilization of R. lobe

Blumgart, 2000

Transection of R. Hepatic Vein

Parenchymal

Transection

Blumgart, 2000

Technique of Parenchymal Transection

• Finger fracture.• Ultrasonic transection • Water Jet.• Control of Bleeding:

– Diathermy.– Suture ligature and clips.– Ligature– RFA……..etc

SVIII HV

MHV

SIVb HVRHV

Mortality and Morbidity for Benign and Malignant liver lesions

• Benign lesions and colo-rectal tumors.• Mortality was 0.• Morbidity 31% (16% were major)• Multivariate analysis/

– Prolonged surgical procedure.– Co-morbid conditions– Surgical irradicality

Erdagon et al Liver International (2009); 175-180

HCCCT FINDINGS

HCCMRI

Prognosis-Staging Systems for HCC

SystemTumor

FeaturesVasc.

InvasionHistol.Grade

Liver FunctionMet. AFP

CancerSymptoms

TNM1

Okuda2

JIS3

CLIP4

BCLC5

CUPI6

GRETCH7

Vasc. = vascular; Histol. = histologic; AP = alkaline phosphatase; Met. = metastases;

Child-Pugh Bilirubin AP Ascites

1. AJCC Cancer Staging Manual. 6th ed. 2002; 2. Schafer DF, et al. Lancet. 1999;353:1253-1257; 3. Liver Cancer Study Group of Japan. 4th edn. Tokyo: Kanehara, 2000. 4. CLIP. Hepatology. 1998;28:751-755; 5. Llovet JM, et al. Semin Liver Dis. 1999;19:329-338; 6. Leung T, et al. Cancer. 2002;94:1760-69;

7. Chevret S, et al. J Hepatol. 1999;31:133-141.

Child-Pugh Scoring System

Points

1 2 3

Encephalopathy (grade) None 1-2 3-4

Ascites None Slight Moderate

Albumin (g/dL) >3.5 2.8-3.5 <2.8

Prothrombin time prolonged (sec) 1-4 4-6 >6

Bilirubin (mg/dL) 1-2 2-3 >3

For primary biliary cirrhosis 1-4 4-10 >10

Class A = 5-6 points; Class B = 7-9 points; Class C = 10-15 points.

Pugh RN, et al. Br J Surg. 1973;60:646-649.

HCC Staging is Multifaceted

ECOGPS

TNMChild-Pugh

Liver Tumor

BCLC4

GRETCH5

Okuda6

CUPI7CLIP8

JIS9

Patient Staging is used for prognosis and to guide

treatment1

Staging HCC1

– Most patients have underlying liver disease

– Key prognostic indicators are not clearly defined

– Prognostic indicators vary during the course of disease

Factors affecting staging systems2,3

– Tumor stage– Liver function– Health status

– Impact of treatment

Barcelona Clinic Liver Cancer staging and treatment strategy

Stage A–C Okuda 1–2; Child–Pugh A–B; PST 0–2

Stage D Okuda 3; Child–Pugh C; PST >2

Liver transplantation Chemoembolisation SorafenibResection PEI/RFSymptomatic treatment (30%)

1-year survival: 10% Curative treatments (30%)5-years survival: 50–70%

Randomised controlled trials (30%)

3-years survival: 20–40%

Extrahepatic disease

YesNoAssociated diseases

YesNo

3 nodules ≤3cm

Increased

Normal

Portal pressure/bilirubin

HCC

Very early stage (0)

Single HCC <2cmCarcinoma in situ

Early Stage (A) Single HCC or

3 nodules <3cmPST 0

Intermediate stage (B)

Multinodular; PST 0

Advanced stage (C)Portal invasion N1, M1,

PST 1–2Terminalstage (D)

Stage 0Child–Pugh A; PST 0

Single HCC

Llovet JM, et al, Lancet 2003;362:1907–17PST=Performance status

Surgery Remains the

Gold Standard

Liver Resection

Resection in cirrhotics

• Best in a single lesion• Asymptomatic• Preserved liver function

– Absent clinically relevant portal hypertension ( hepatic venous pressure gradient less than 10, platelets less than 100,000 and no varices or splenomegally)

– Normal bilirubin• 70% survival at 5 years• Only 5-10% meet these criteria

Llovet et al, Resection Vs Tx, hepatology 1999

OUTCOMES OF HCC PATIENTS TREATED WITH CURATIVE INTENTION SURGICAL RESECTION

TREATMENT & SELECTION CRITERIA

N ACTUAL SURVIVAL1 year 5 years

Fong et al, Ann Surg 1999Child A-B, median 6 cm

100 77% 37%

Llovet et al,Hepatology 1999 Single, no portal HT, normal bilirubinPortal HT, normal bilirubinPortal HT, abnormal bilirubin

351527

91%93%74%

74%50%25%

Arii et al, Hepatology 2000 Stage I: HCC < 2 cm HCC 2-5 cmStage II: HCC < 2 cm HCC 2-5 cm

13182722

5021548

96%95%

92%95%

72%58%

55%58%

Yamamoto et al, Hepatology 2001 </= 3 cm, Child A-B

58 96% 61%

Sakamoto et al, Jpn J Clin Oncol Single HCC < 2 cm early tumors

53 100% 89%

LIVER TRANSPLANTATION



Mazzaferro et al, N Engl J Med 1996 Single </= 5 cm, 3 nodules </= 3 cm

48 84% 74%

Llovet et al,Hepatology 1998 [28] Single </=5 cm

58 84% 74%

Bismuth et al, Semin Liver Dis 1999 3 nodules </= 3 cm

45 82% 74%

Llovet et al, Hepatology 1999 Single </= 5 cm Intention-to-treat analysis

7987

86%84%

75%69%

Jonas et al, Hepatology 2001 Well-differentiated HCC Moderately-differentiated HCC Poorly-differentiated HCC

406020

90%90%75%

84%73%41%\

PERCUTANEOUS THERAPIES



Livraghi et al, Radiology 1995 [35] Child A, HCC </= 5 cm Child B, HCC </= 5 cm

293149

98%93%

47%29%

Arii et al, Hepatology 2000 [18]Stage I: HCC < 2 cm HCC 2-5 cmStage II: HCC < 2 cm HCC 2-5 cm

767587

426483

96%95%

92%87%

54%38%

33%28%

Rossi et al, Am J Roentgenol 1996 [36] HCC </= 3 cm 39 94% 40%

• Curative Strategies in one third of all patients

• Resection…….compensated• Ablation……non surgical candidate ???

Curative• Liver Transplantation……….Best Survival

with up to 70% at 5 yearsNo comparative studies in

compensated patients

Surgery for Hepatocellular Carcinoma

• Resection

• Limitations are:• Anatomy

• Cirrhosis

• Resection Vs Transplantation

• Donor Issue

Criteria for Selection

• Anatomical:– Imaging– Simulation

• Functional:– Clinical.– Biochemical.– Functional test: ICG

How Much Can be Resected?

• Child Classification:A Formal ResectionB 25%C Never or 15%

• Tumor is non functioning, Look for Hypertrophy

MELD as a predictor of Mortality/Morbidity after Resection

MELD below 9 MELD 9-10 Meld Above 10Na above 140

Major resectionUp to 4 segments

Segmentectmy or limited resection

Risk of irreversible liver failure more than 15% in all type of resection

Na below 140Segmentectmy or bisegmentectomy

Cecon et al: ARCH SURG/VOL 144 (NO. 1), JAN 2009

5 years Survival after Resection

Function Single Multiple

PHT** No PHT PHT No PHT

Child-Pugh A 68% 71% 58% 56%

Child-Pugh B Over all 5 year survival 19%

Resection after recurrence*

79% 81% 73% 73%

*3 year survival**PHT defined as varices and or platelets less than 100000

Ishizawa T, Gastroenterology. 2008;134:1908–16.

Best candidate and second to best candidate

• Portal hypertension• Functional capacity• Multiple tumors• Vascular invasion• Comorbid conditions

Safety, Accuracy and outcome

– Surgical techniques – Perioperative care.– Patient selection

Outcome

• offers a 5-year overall survival rate of more than 50%.

• operative mortality as low as 0.8% in Japan.• Operative mortality of 0–6.4% at major

hepatobiliary centers in other countries.

Ikai et al: Hepatol Res. 2007;37:676–91.Fan ST et al: Ann Surg. 1999;229:322–30.Fong Y et al. Ann Surg.1999;229:790–9.

Result of resection with bad prognostic factors

• With clinically relevant portal hypertension, 5 year survival is 50%

• With CRPH and Jaundice survival at 5 years is only 25%

Recurrence after resection

• Micro vascular invasion• Differentiation• Satellite nodules

High recurrence rate with more than 70% at 5 years

RESECTION in Non CirrhoticsApplies to only 5% of patients

Philosophy of Liver Resection in Compensated Cirrhotics

“Why Not Transplantation?”

• Immunosuppressive therapy may accelerate the growth rate of recurrent HCC

• Mean tumour doubling times (TDT) after transplantation is 40 days after resection is 275 days

(Yokoyama et al, 1991)• Sever organ shortage• Doubtful Diagnosis (regenerating nodules)

Liver Transplantation

• The most effective treatment in cirrhotics• Classical selection criteria leads to 70%

survival at 5 years and recurrence rate of 15%

• Drop out rate while waiting 20-50% if waiting is more than 1 year

• MELD score and adjuvant therapy• LDLT

Liver Transplantation for HCC“Patient Selection”

Milan’s Criteria (Mazzaferro et al, 1994)

Single tumor Single tumor ≤ 5≤ 5 cmcm

or ≤≤ 3 lesions, each lesion 3 lesions, each lesion ≤ 3 ≤ 3 cmcm

NoNo Macro-Vascular Invasion and Macro-Vascular Invasion and NoNo Extra-hepatic Extra-hepatic SpreadSpread

Management While on the Waiting List

24 12 39 6 (Months)

5 mm 10 15 2030 40

Tumor Doubling Time (TDT)

(From J Fung with permission)

2 yrs 9 months

LT for HCC at KFSH&RC: Patients Selection

HCCWithin Milan Outside

Milan

Multiple ≥2 cm

RejectDDLT +/-Neo-adjuvant

AcceptLDLT

Solitary ≤2 cm

Within UCSF

Outside UCSF

RFA

Down Staging



other modalities.• Selection aspects.• Outcome.• Neo-adjuvant and Down staging.• Future direction

Neo-adjuvant and Down-staging prior to resection

• Not recommend if tumor is resectable:– Delay (tumor progression or liver failure in 10%).– Technically more difficult.– May be associated with more morbidity.

• Not resectable for anatomical reasons ….6-28% become respectable.– Recurrence: 40-85%– Survival: 5 years…..25 to 60%

• These strategies are well established and accepted for resection.

Neo-adjuvant and Down-staging prior to Transplantation

• More complex than in resection.• Is the patient within transplant criteria?

Neo-adjuvant Vs down-staging• Waiting list priority.• Living Vs. Cadaveric• Community Vs. Individual.

Neo-adjuvant for transplant candidate within the criteria

Currently one third to half receive neo-adjvant while on the waiting list. (TACE followed by RFA).

It decreases drop out from waiting list. Better post transplant survival (UNOS data). Full response to TACE better survival than partial. Best palliation for patients who eventually will drop

out. Recommendation: Neo-adjuvant if this does not

delay transplant LDLT Vs Cadaveric

Down-Staging Which tumors to be down-staged? Inclusion

criteria. What to use? What are the criteria of success? When to do the transplant? What kind of survival outcome is accepted? What is the price we pay?

• Community Vs individual……• Living donor……..

Inclusion Criteria• Entry Criteria:

– Size and number or total volume.– Biological, molecular or pathological

characteristics.• Definition success of down staging:

– Size (radiological)– Necrosis (radiological)– AFP (biological)

• Defining the time between down staging and listing

Down staging to Resection, RFA and Bridge to transplantation;

• 90Y for 35 patients with T3 unresectable HCC.• Down-Staging in 19 (56%) to T2.• 8 patient were transplanted.• Survival 84 and 27% at one and 3 years

Kulik et al (2006) Journal of surgical oncology; 94:572-586

• 90Y for 21 patient with T3 Unresectable HCC.• Down staging in 21.• 2 transplanted, 3 resected and one RF and resection• Median survival 44 month Vs 22 months.

Inarrairaegui, 2012 EJSO 38, 594-601

King Faisal Specialist Hospital Liver Transplant Program

Down-staging and bridging: KFSH Experience

• 9 patients: 5 female and 4 males• Their current age range is 40-72 years with a mean of

53.8± 9.5 years.• Follow up following liver transplantation ranged between

3.7 -60.1 months (mean of 15.8 ±17.7 moths).• TheraSphere and liver transplantation ranged between

14-707 days (mean of 194±226.2 days).• All living with excellent graft function and no disease

recurrence.

Patient #Number

of lesions

Size of lesion (in cms) Unilobar

diseaseAFP

(UI/mL)

Tumor volume BCLC Relation to the main transplantation criteria

V=(a*b2)/2 Stage1st 2nd 3rd UNOS Milan UCSF

1 2 6.2*4.7 1.7*1.3 - YES 217 69.9 (68.5+1.4) B T3 Beyond Within

2 1 3.7*3 - - YES 3 16.6 B T2 Within Within

3 2 4.7*4.6 2*2 - YES 7 53.7 (49.7+4) B T3/T4 Beyond Within*

4 1 7.3*6.3 - - YES 5 144.8 B T3 Beyond Beyond

5 1 3.5*2.4 - - YES 499 10.1 B T2 Within Within

6 1 5*4.4 - - YES 10 48.4 B T2 Within Within

7 1 8.7*7.6 - - YES 5 251.3 B T3 Beyond Beyond

8 1 2.1*1.3 - - YES 13 1.8 A T2 Within Within

9 3 1*1 2*1.2 1*1 YES 125 2.4 (0.5+1.4+0.5) A T2 Within Within

Patient #

TherasphereOther

locoregional modalities

Child Pugh score in relation to Therasphere

Complications

Interval to transplant Type of

transplantIndication Type Dose Following

Therasphere Before After (days)

1 Bridging Selective 140 None 5 6 None 32 DDLT

2 Bridging Superselective 146 None 6 6 None 14 DDLT

3 Down staging* Selective 156 None 6 7 None 40 DDLT

4 Down staging Selective 153 None 5 6 None 86 DDLT

5 Bridging Superselective 146 None 6 6 None 116 LDLT


7 Down staging Selective 146 None 5 6 None 394 LDLT


9 Bridging Selective 147 RFA/Alcohol 6 6 None 707 LDLT

Down staging and Bridging for advanced HCC

Patient Transplant date Relation to transplant criteriaUNOS Milan UCSF

1 June 2008 T3 Beyond Within

2 Oct. 2008 T2 Within Within

3 Oct. 2010 T3/T4 Beyond Within*

4 Feb. 2012 T3 Beyond Beyond

5 March 2012 T2 Within Within

6 March 2012 T2 Within Within

Case No: 4

Tumor Necrosis- Gross appearance

Normal Hepatocytes

Hepatocellular Carcinoma

Tumor Necrosis 1

Tumor Necrosis 2

Microsphere

Future Direction

• More technological advances in functional imaging.

• Better technology to facilitate resection.• Determination of where resection stay

within other options.• Down staging.• Diagnostics, genomics and Microarray.• Molecular targeted therapy.• Individualized treatment.

Preoperative Simulation of liver Resection using three dimensionalcomputed tomography

• Accurate assessment of the segmental liver volume

• vascular anatomy that is required to complete the anatomic resection.

• Estimation of venous occlusion.• Determination of the need for venous

reconstruction.– Remaining volume (non congested less than 40%)– ICG

Hepatectomy Simulation: Based on liver circulation

Saito S, Hepatology. 2005;41:1297–304.

Conclusion

• Surgical management of HCC is evolving.• Potential for cure is increasing.• Multidisciplinary Approach.• Technology.• Better techniques and perioperative care• Molecular biology.• Personalized medicine.

King Faisal Specialist Hospital & Research Center

Riyadh, KSA

Thank You

Role of Surgery

Health & Medicine

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