role of surgery
TRANSCRIPT
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
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.
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)
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
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
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
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
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
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
TREATMENT & SELECTION CRITERIA
N ACTUAL SURVIVAL1 year 5 years
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
TREATMENT & SELECTION CRITERIA
N ACTUAL SURVIVAL1 year 5 years
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
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
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
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
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
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
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
6 Bridging Superselective 221 None 5 6 None 231 LDLT
7 Down staging Selective 146 None 5 6 None 394 LDLT
8 Bridging Superselective 148 None 6 6 None 126 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
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
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