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Current Surgical Resection for Primary
Liver Malignancies
Vatche G. Agopian, MD, FACSAssociate Professor of Surgery
Director – Dumont-UCLA Liver Cancer Center
Liver Transplantation and Hepatobiliary Surgery
David Geffen School of Medicine at UCLA
Disclosures
All faculty, staff, and reviewers involved in the planning, review, or presentation of
continuing education activities sponsored/provided by Rehoboth McKinley Christian
Health Care Services (RMCHCS) are required to disclose to the audience any relevant
commercial financial affiliations related to the content of the presentation or enduring
material.
Full disclosure of all commercial relationships must be made in writing to the audience
prior to the activity. All additional planning committee members, staff, and reviewers of
the Chronic Liver Disease Foundation (CLDF) and Rehoboth McKinley Christian Health
Care Services (RMCHCS) have no relationships to disclose.
Faculty:
• Vatche G. Agopian, MD, FACS
– No relevant financial relationships with any commercial interests to disclose.
Overview
• Evaluation of patients for resection
– Defining surgical procedures
– Evaluation of candidacy
• Surgical Resection of HCC
– Current guidelines
– Outcomes (comparison to LT)
– Expanding Indications/Future Directions
Hepatic Resection: Early Results
“…20% of patients died in the operating room because of exsanguinating hemorrhage… Another 14% died postoperatively as a direct consequence of enormous blood loss during operation. 15% died of liver failure caused by technical factors other than hemostasis, including three bile duct injuries…”
Foster, Major Problems in Clin Surgery 1977
“Brave new world” of Liver Surgery
• Hospital mortality now < 5%
• Advances have come because of:
– a better understanding of the basic principles of liver surgery
“Brave new world” of Liver Surgery
• Hospital mortality now < 5%
• Advances have come because of:
– a better understanding of the basic principles of liver surgery
– Innovative techniques and energy devices
“Brave new world” of Liver Surgery
• Hospital mortality now < 5%
• Advances have come because of:
– a better understanding of the basic principles of liver surgery
– Innovative techniques and energy devices
– Improved systemic/medical therapy
Operations
• Wedge
• Segmentectomy
• Lobectomy
• Extended hepatectomy
• Mesohepatectomy
Wedge Resections
Left Lateral Sectorectomy
Left Hepatic Lobectomy
Right Hepatic Lobectomy
Mesohepatectomy
Mesohepatectomy
Considerations for Resection
• Anatomically feasible
• Medically fit
• Minimal underlying liver dz
• nl bili, plt > 100K, no ascites
• NASH
• CASH (chemo-assoc SH)
• Future Liver Remnant
Future Liver Remnant (FLR)
• FLR – ratio of volume of liver remnant to total liver volume
• Needs interpretation in context of underlying liver function
• FLR < 20% ↑ risk of death/liver failure
• No guidelines on FLR for specific populations (NASH/CASH/cirrhosis)
• FLR > 30-40% if underlying liver disease
Kishi, Ann Surg 2009
Ferrero, WJS 2007
How do we assess the FLR??
and
What can we do about it??
CT/MR Volumetrics
• Volumetric CT is most commonly used
• Thin slice contrast-enhanced CT
• Manually outline liver margins on multiple slices
• Software integrates between slices and calculates volume
• Volumes of interest
• Total liver volume (TLV)
• Corrected TLV by subtracting tumor volume
• Standardized TLV by using body surface area
• Future liver remnant (FLR)
• Tumor
Pulitano, J Surg Onc 2014
Portal Vein Embolization
Liver resection is often limited due to inadequate
volume of the future liver remnant
– Normal patients can survive if 20% of liver volume remains
– Post-chemotherapy patients need 30% of liver
– Patients with fibrosis/early cirrhosis need 40% of liver
• Portal vein embolization can pre-operatively enlarge
the future liver remnant
– Redirection of nutrient-rich portal vein blood enlarges the
FLR
– May enable resection in patients who would otherwise not
be candidates
De Baere, Tech Vasc Interv Radiol 2007
Portal Vein Embolization
Hepatocellular Carcinoma (HCC)
Worldwide Burden of HCC
Mittal S, El Serag HB; J Clin Gastro 2013
Growing Burden of HCC in US
White DL, El Serag et al ; Gastroenterology 2017
HCC- Fastest Rising Cause of Cancer-Related
Death in the US
Ryerson et al ; 2016
Risk Factors for HCC
Populations at Risk
Hepatitis B
Hepatitis C
Alcohol
Hemochromatosis
NASH!!!
Cirrhosis (any cause)
Associated Factors
Diabetes
Obesity
NAFLD
Cigarette smoking
Oral contraceptives
Aflatoxin exposure
80-90% with underlying cirrhosis
Diagnosis of HCC Primarily
by Imaging
Contrast CT/MR
Arterial enhancement
Portal Venous washout
Biopsy if imaging non-dx
Factors to Consider
Extent of Tumor Involvement
Nodal disease
Extrahepatic mets
Assessment of Liver Reserve
Child’s Pugh Score
ECOG
Portal hypertension
BCLC
Clinical Management of HCC
Surgical Management of HCC – Case 1
• 54 M w obesity, known HCV, underwent screening U/S
• AFP elevated 20
• MRI: 2cm arterially enhancing mass in segment 3/4B
• Labs: Plt 149, T bili 0.8, INR 1.1
NOT A SINGLE RANDOMIZED CONTROLLED TRIAL
Guidelines for Surgical Management
Manzini et al; BMJ Gastro 2017
Guidelines for Surgery – Healthy Liver
Manzini et al; BMJ Gastro 2017
Guidelines for Surgery – CP A Cirrhosis
Surgical Resection in Cirrhotic HCC
• Compensated Liver Disease
Child’s A
MELD < 10
Normal Serum Bilirubin
• No prohibitive portal hypertension
HVWP < 10 mm Hg
Plt > 100
No Ascites
• Single lesion or within Milan criteria
Case 1 – Laparoscopic Resection
Case 1 – Laparoscopic Resection
Case 1 – Laparoscopic Resection
Case 1 – Laparoscopic Resection
Case 1 – Laparoscopic Resection
Laparoscopic Liver Resection
Goh, Int J Surg 2018
Advantages of Liver Transplantation
• Best oncologic
resection
• Replaces diseased
liver
• Restores normal
hepatic function
Outcomes: Resection vs Transplantation
Merchant N, Int J Hep 2011
Arguments for Considering Liver Resection
as Primary Treatment Modality
• Accessibility (organ availability, wait times, dropout)
• Safety (perioperative, long-term)
• Efficacy
• Options after Failure
Accessibility
Access to Organs Vary Significantly
Donation Rates Vary
Significantly by DSA
Transplant Rates Vary
Significantly by DSA
Kim, 2015 Annual Liver Report, AJT 2017
Wait Time Variability
Short Medium Long
53 275152
Wait Times Vary
Significantly by
UNOS Region
Kim, 2015 Annual Liver Report, AJT 2017
Wait List Dropout –
Tumor Progression/Death
Short Medium Long
Dropout Rates
Vary Significantly
by
UNOS Region
6.8 28.717.0
Kim, 2015 Annual Liver Report, AJT 2017
Must Examine Intent-to-Treat Analyses
51
69
Resection, n=77 Transplantation, n=87
Llovet, Hepatology 1999
Intent-to-Treat Analyses
Resection, n=77 Transplantation, n=87
Llovet, Hepatology 1999
Intent-to-Treat Meta-Analyses (9 studies)
Menahem et al, Liv Tx 2017
ITT Meta-Analyses - Recurrence
Menahem et al, Liv Tx 2017
ITT Meta-Analyses – 5yr Overall Survival
Menahem et al, Liv Tx 2017
Intent-to-Treat UNOS Analysis
61%
32%
3-yr dropout 20%
Pelletier et al, Liv Tx 2009
Safety
Safety of Liver Resection:
Morbidity/Mortality
Morbidity similar
Mortality 60% less
Cunningham, Ann Surg Onc 2009
Post-LT Impact of IS: Renal Failure
Ojo, NEJM 2003
Post-LT Impact of IS:
De Novo Malignancy
Engels, JAMA 2011
Efficacy
Efficacy of Liver Resection in LT
Eligible HCC
5-y OS 69%
5-y RFS 48%
Cha, Ann Surg 2003
Liver Resection can Achieve Cure
Pinna AD, Ann Surg 2018
3286 HCC
HR=2068
LT=1218
Options after Failure/Recurrence
Strategy of Salvage Liver Transplantation
Similar Characteristics Similar Periop Complications Similar Survival
Belghiti, Ann Surg 2003
Strategy of Salvage LT: Intent-to-Treat
De Haas, Hepatology 2017
Strategy of Salvage LT: Intent-to-Treat
De Haas, Hepatology 2017
Success of ITT SLT Strategy= 55%
Failed SLT:
Liver failure or
Recurrence w/o
LT
Successful SLT:
No recurrence
LT if recurred
Salvage LT: ITT compared to Primary LT
Bhangui, Ann Surg 2016
Comparison of ITT
SLT to primary LT
Salvage LT: ITT compared to Primary LT
Bhangui, Ann Surg 2016
Primary LT
Salvage LT
Salvage LT: ITT compared to Primary LT
Bhangui, Ann Surg 2016
Rsx → SLT actually had
best outcomes at 5 years
Achilles Heel of SLT:
What predicts success?
• Reported rates of eligibility of SLT following resection
range from 20% to 75-80%
• This is mainly based on the recurrence remaining within
Milan criteria
Achilles Heel of SLT: What predicts
recurrence within Milan?
Lee, HPB 2014
Development of a
Clinical Risk
Score
For Recurrence
Beyond Milan
Achilles Heel of SLT: What predicts
recurrence within Milan?
Zheng, Ann Surg 2017
Validation of the
Clinical Risk
Score
For Recurrence
Beyond Milan
Within Milan
patient with
1 tumor →
CRS = 0 or 1
Resection as a Selection Tool for OLT
Cho, JACS 2008
Agopian, JACS 2014
Recurrence of HCC following
Liver Resection
1. 46% didn’t develop recurrence
2. 65% liver only recurrence
3. Multiple treatment options
Tabrizian, Ann Surg 2015
Recurrence following LT more Virulent
Median Survival following recurrence was
21months in resection vs 10.6 months in LT
Median Time to recurrence was 22 months in
resection vs 16 months in LT
Agopian, JACS 2014, Tabrizian Ann Surg 2017
Expand(ing) Indications for Resection
• Increasing number of systemic (and LRT) treatments which are highly active in HCC
• Better the systemic treatment, more the role of surgery
• Revisit role of surgical resection in BCLC B/C HCC
Dong et al, Hepatology International 2020
Case 2- BCLC B HCC
• 72 F w with past h/o obesity and GERD; s/p NissenFundoplication
• USOH until she developed significant RUQ pain
• CT: Large 16cm mass in right lobe, liver enlarged. Biopsy revealed “cirrhosis”
• Labs: Plt 279, T bili 1.1, Cr 0.6, INR 1.1; AFP 31,442!
Case 2 – Arterial Phase MRI
Case 2 – Portal Venous Phase MRI
Case 2 - Volumetrics
FLR 28.9%
LL 1104 cc
Case 2 – Open Hepatic Resection
Case 2 – Open Hepatic Resection
16.1 cm
G2 Moderately
Differentiated
Margins negative
+MVI
0/2 LNs
High risk of recurrence – role for adjuvant
therapy?
1114 HCC
HR=900
TA=214
Bruix J Lancet Onc 2015
Current Adjuvant StudiesCheckmate 9DX1 EMERALD-22 IMbrave0503 KEYNOTE-9374
Phase 3 3 3 3
Patient
population
N=530
• Patients with HCC who have undergone
curative resection or ablation
• ECOG PS 0 or 1
• Child-Pugh score 5 or 6
N=888
• HCC and completed curative
therapy (resection or
ablation)
• ECOG PS 0 or 1
• Child-Pugh score 5 or 6
N=662
• Patients with HCC who
have undergone curative
resection or ablation
(RFA or MWA only)
• ECOG PS 0 or 1
• Child-Pugh A
N=950
• HCC who have
• Complete radiological
response after surgical
resection or local
ablation
• ECOG PS 0
• Child-Pugh A
• AFP <400 ng/mL
Treatment Nivolumab Durvalumab 1120 mg q3w ±
bevacizumab 15 mg/kg q3w
Atezolizumab 1200 mg q3w
+ bevacizumab 15 mg/kg
q3w
Pembrolizumab 200 mg
q3w
Comparator Placebo Placebo Active surveillance Placebo
Primary
endpoint(s)
RFS RFS (for durvalumab
monotherapy vs placebo)
RFS (IRF) RFS (BICR), OS
Secondary
endpoint(s)
OS, TTR RFS (for durvalumab +
bevacizumab vs placebo), OS,
TTR, RFS2/PFS2
OS, RFS (INV), TTR, time
to EHS or MVI, RFS in PD-
L1-high subgroup, safety,
serum concentration, ADAs
Safety, PROs
Estimated
primary
completion
April 2022 June 2022 March 2023 June 2025
Neoadjuvant vs Adjuvant Immunotherapy
Pinato DJ et al. Hepatol. 2020 Dec 28. doi: 10.1002/hep.31697.
Neoadjuvant Checkpoint Inhibitor Therapy
CA209-956/
NCT032220761
AURORA/
NCT033378412 NCT035108713 PRIME-HCC/
NCT036822764 NCT041233795 NCT039166276
SponsorMD Anderson Cancer
Center/NCI
Kindai University
(Japan)
National Health Research
Institutes (Taiwan)Imperial College London
Icahn School of Medicine at
Mount Sinai
Regeneron Pharmaceuticals
Phase 2 2 2 1/2 2 2
Patient population
N=45
• Prior therapy allowed,
including prior
surgery, RT, LRT, and
systemic therapy
(sorafenib or
chemotherapy)
• ECOG PS ≤1
N=50
• Child-Pugh A
• ECOG PS 0
N=40
• HCC with potential for
curative surgical resection
• Prior local therapy is allowed
• ECOG PS 0 or 1
• Child-Pugh A
N=32
• HCC, ineligible for
liver transplant
• ECOG PS 0 or 1
• Child-Pugh A
N=50
• ECOG PS 0 or 1
N=94
• ECOG PS 0 or 1
Treatment
Nivolumab q2w ±
ipilimumab q2w x3 doses
→ liver surgery →
nivolumab q4w ±
ipilimumab q6w
Pembrolizumab 200
mg x1 dose →
resection or RFA →
pembrolizumab 200
mg q3w
Nivolumab + ipilimumab →
curative surgery, if eligible
Ipilimumab 1 mg/kg x1
dose + nivolumab 3
mg/kg q3w x2 doses
Nivolumab q4w x2 doses ±
(BMS-813160 bid x28 days or
BMS-986253 2400 mg x1 dose)
→ surgery -> nivolumab q4w x3
doses
Cemiplimab
Primary endpoint(s) Safety 1-year RFS Tumor shrinkage Delay to surgery, safetyMajor pathologic response,
significant tumor necrosis
Significant tumor
necrosis
Secondary endpoint(s)ORR, TTP, PFS,
conversion rate to surgery
RFS, OS, ORR after
neoadjuvant phase,
tumor markers, safety
and tolerability
--ORR, pathologic
response rate
Time to surgery, safety,
radiographic response, PFS, OS
Delay to surgery,
DFS, ORR, OS,
safety
Estimated primary
completionSeptember 2022 October 2019 December 2022 December 2020 October 2020 June 2022
1. Clinicaltrials.gov. NCT03222076. Accessed March 30, 2020. 2. Clinicaltrials.gov. NCT03337841. Accessed March 30, 2020. 3. Clinicaltrials.gov. NCT03510871. Accessed March 30, 2020.
4. Clinicaltrials.gov. NCT03682276. Accessed March 30, 2020. 5. Clinicaltrials.gov. NCT04123379. Accessed March 30, 2020. 6. Clinicaltrials.gov. NCT03916627. Accessed March 30, 2020.
HCC Surgical Resection Summary
• Ideal for healthy liver and cirrhotics with single lesions without portal hypertension, low MELD, and adequate FLR
• While post-resection recurrence is higher than with LT, comparable intent-to-treat survival and numerous options following recurrence
• Improvement in LRT/systemic therapies will expand indications, with active studies utilizing neoadjuvant/adjuvant therapy
Thank You!
Thank you!
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