Current Surgical Resection for Primary Liver Malignancies

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





– Innovative techniques and energy devices





– 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





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


Wait List Dropout –

Tumor Progression/Death

Short Medium Long

Dropout Rates

Vary Significantly

by

UNOS Region

6.8 28.717.0


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


ITT Meta-Analyses – 5yr Overall Survival


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



Primary LT

Salvage LT



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!

Documents

Current Surgical Resection for Primary Liver Malignancies