Treatment of Liver Tumours-Current Trends

Dr.Venugopal B

Dept .of HPB & Liver Transplant

KIMS, Thiruvananthapuram.

Liver Tumours

• Benign

• Malignant

-PrimaryHepatocellular ca

Cholangio Ca

-Secondary

Colorectal

Neuroendocrine

Non colorectal non neuroendocrine

Hepatocellular carcinoma

• 5th most common malignancy

• 3rd most common cause of cancer death

• 70% occur in Cirrhotic livers

• Incidence is increasing

Treatment options

• Surgical resection

• Liver transplantation

• Radiofrequency ablation

• TACE, TARE

• Radiotherapy

• Targeted therapy

Treatment selection

• Applicability

• Safety

• Efficacy

BCLC staging

Surgical resection

• Cirrhotics with HCC (<5%)

• HCC without cirrhosis

• Criteria

-Child-Pugh class A

-Normal bilirubin

-Absence of portal hypertension

- <5cm in diameter

Postoperative Liver Failure is the commonest cause of mortality

Risk factors for Liver Resection

• Advanced age

• Comorbidities

• Chronic Liver Disease

• Cholestatic liver

• Post chemotherapy liver

• Extent and complexity of the resection

Cause of Postoperative Liver Failure

• Impaired functional reserve

• Inadequate residual volume

Risk assessment

• Clinical

• Biochemical

• Volumetric

• Functional

Portal hypertension

• Previous variceal haemorrhage or ascites

• Presence of oesophageal varices

• Platelet count <100000

• Radiologically visible portosystemic shunt

Indocyanine green clearance test

< 14% 14-20%

>20%

Major hepatic resection

contraindicated

&

Adequate liver remnant CT

Major hepatectomy

Child- Pugh score

• Child A - major liver resection

• Child B - segmental/subsegmental

resection

• Child C - Absolute contraindication

Contrast CT scan

• Site , Size

• Relation to blood vessels

• Residual liver volume(FLRV)

TUMOR VOLUME

Safe remnant liver volume

Residual liver volume

• FLRV = Total liver volume - Tumor volume

• >30% - Normal liver

• > 40% - Cirrhotic

Strategies to deal with impaired functional reserve

• Parenchyma sparing resection

• Resection after PVE

• Resection in combination with RFA

• Two stage resection

• Resection after chemotherapy

• Resection after TACE

Augmentation FLRV

• PVE

• PV ligation

• Repeat CT after 3 weeks

• FLRV increases by 20-46%

• Resectability 70 to 100 %

• Can be used as a dynamic test for liver regeneration

not randomized but alternatively assigned28 pts with PVE27 pts without PVE

Portal Vein Embolization Before Right Hepatectomy

Farges O, Belghiti J et al, Ann Surg 2003;237:208-17

future liver remnant volume after PVE4419% in normal liver3528% in chronic liver disease

the postoperative course and complications similar between PVE(+) and (-) in normal liver significantly decreased in PVE(+) with chronic liver diseases, but no difference in surgical mortality

Portal vein embolisation

Portal vein embolisation

Safe Liver Resection

Adequate Biliary

drainage

Adequate functioning Parenchyma

Adequate outflow

Adequate Inflow

Surgical resection -Result

• 5 yr survival: 60-70%

• Tumour recurrence: 50% at 3 yrs

Liver transplantation for HCC

• Ideal treatment for small HCC in Cirrhotics

-Widest possible surgical margin!

-Cure of underlying liver disease

(denovo tumorogenesis)

Early Results

Survival(%) Recurrence (%)

Center 1 yr 2 yr 3 yr

Cincinnati 45 30 20 39

UCLA 40 22 – 67

Cambridge 45 38 – 65

Pittsburgh 64 47 48 43

Liver Transplantation for Hepatocellular Carcinoma

Liver Transplantation for HCC

• Early experience in 1980s- disappointing

• Paul Brousse > 50% DFS 3yrs

Single <3cm, < 3tumour

Bismuth etal. Ann Surg 1993

• Milan group 4yr OS 75% DFS 83%

Single <5cm, <3 tumours <3cm

Mazaffero etal. NEJM 1996

UCSF Criteria

• Lesion <6.5cm• 2-3 lesions

-Largest <4.5cm-total dia <8cm

• No vascular invasion• No extrahepatic metastases• One yr survival 90%• Five yr survival 75%

Yao FY etal.Hepatology2001;33: 1394-403

Radiofrequency Ablation

• Local application of thermal energy generated by high frequency electric current

• Complete ablation in tumours up to 4cm

Radiofrequency Ablation

• 148 pts, single, small (< 4cm)

• RFA: 55 pts, Resection: 93 pts

• Recurrence:RFA: 58.2%---- 40% remote, 18.2% local

Resection: 45.2%---- 43% remote, 2.2% local

• Survival:RFA: 100%, 72.7% at 1 & 3 yrs

Resection: 97.9%, 83.9% at 1 & 3 yrs

SN Hong et al. J Clin Gastroenterol 2005;39:247 Samsung Medical Center, Seoul, Korea

Hepatocellular Carcinoma

Resection vs RFA

BEFORE RF AFTER RF

Resection vs RF ablation

• Similar results for tumours < 3cm

• Comparable for 3 to 5 cm

• Resection better for >5cm

Transarterial chemoembolisation-Contrindications

• Serum bilirubin >2mg/dl

• LDH >425 U/L

• AST >100 U/L

• Tumour burden >50% of the Liver

• Cardiac or renal insufficiency

• Ascites,recent variceal bleed or significant thrombocytopenia

Transarterial Chemoembolization

Meta-analysis of 7 randomized controlled trials

• 2 yr survival: 41% (19-63%)

• Treatment response: 35% (16-61%)

• Average no. of sessions: 1-4.5

• Risks:

– Infection

– Tumor lysis syndrome

– Hepatic failure

• Llovel J He aloI2003"37:429

Radioembolization

• Similar to TACE

• Use radiation particles eg Yttrium, Rhenium

• Results slightly better than TACE

Targeted therapy

• Sorafenib

-increases survival

-Disease progression delayed

Colorectal Liver Metastases

Introduction

Liver is the most common site for hematogenous metastasis from colorectal carcinomas.

~ 25% synchronous.Bengmark S. Cancer 23: 198- 202

~ 50% metachronousBozzetti F. Ann Surg 205:264- 270

In patients with isolated liver metastasis, the extent of liver disease is the prime determinant of survival.

Natural History of CRM

Stangl R et al –Lancet 1994

Prospective study 1980-1990

484 consecutive untreated patients

Avg survival(yr) 31%-1 ,7.9%-2, 2.6%-3,

0.9%-4 (Median survival 7.5 months)

The prosnosis is most closely related to the extent of liver replacement by tumor.

Natural History of CRM

• Wagner JS Ann Surg 1984

Study comparing outcome in potentially operable but not resected metastases with those who underwent surgery

5- year survival 25% in the operated group compared to 2%in the nonoperated group.

Colorectal liver met-treatment options

• Resection

• Ablation

• Liver directed therapy

• Chemotherapy

Rationale for treatment

• Spread to liver is via portal circulation before systemic spread.

• Stepwise spread provides an opportunity to prevent dissemination of tumor to other sites by treatment of hepatic metastasis.

• This way hepatic colorectal metastasis differ from other metastasis.

• Regenerative capacity of liver has allowed major resections to be possible with increasing frequency

• Hepatic resection has become standard treatment after Foster et al showed survival after hepatic resection to be consistently above 20% as compared to 0% with no treatment.

• With improvement in surgery, resection of hepatic metastatic tumors have been increasingly undertaken

• 5 year survival after margin negative hepatic resection have been 24-58%(40%) with 10 year survival of 15-20%.

Prognostic scoring

• Fong et al Ann Surg 1999Data base of 1001 consecutive patients

undergoing hepatic resection for CR metstases5 preoperative clinical criteria for clinical risk score

• Disease free survival <12 months• Number of mets >1• Preoperative CEA level>200U/ml• Size of largest lesion >5cm• Lymphnode positive primary tumor

Clinical risk score

• Presence of any one characteristic was associated with 5 year survival of 24-34%

• Score of 2 or less –good prognosis (ideal for resection)

• 3-4 outcome less favorable so aggressive trial of adjuvant therapy required

• 5- long term survivors are rare so adjuvant treatment trials are required

Patient selection -Imaging

• CECT

• MRI

• PET Scan

Effect of PET Before Liver Resection on Surgical

Management

for Colorectal Adenocarcinoma Metastases

A Randomized Clinical TrialCarol-Anne Moulton, MB, BS; Chu-Shu Gu, MSc; Calvin H. Law, MD; Ved R. Tandan, MD; Richard Hart, MD; Douglas

Quan, MD;

Robert J. Fairfull Smith, MB; DiederickW. Jalink, MD; Mohamed Husien, MD; Pablo E. Serrano, MD; Aaron L. Hendler,

MD; Masoom A. Haider, MD;

Leyo Ruo, MD; Karen Y. Gulenchyn, MD; Terri Finch, BA; Jim A. Julian, MMath; Mark N. Levine, MD; Steven

Gallinger,MD

CONCLUSIONS AND RELEVANCE Among patients with potentially

resectable hepatic

metastases of colorectal adenocarcinoma, the use of PET-CT

compared with CT alone did not

result in frequent change in surgical management. These findings

raise questions about the

value of PET-CT scans in this setting.

JAMA. 2014;311(18):1863-1869. doi:10.1001/jama.2014.3740

Patient selection –Criteria for unresectability

• Nontreatable extrahepatic disease

• Unfitness for surgery

• Involvement of >70 % of liver or 6 segments

Resectability

• Currently, hepatic colorectal metastases should be defined as resectable when– Disease can be completely resected

– 2 adjacent liver segments can be spared

– Adequate vascular inflow and outflow and biliary drainage can be preserved

– Volume of the liver remaining after resection (i.e., the ‘‘future liver remnant’’) will be adequate (at least 20% of the total estimated liver volume).

• Instead of resectability being defined by what is removed, decisions regarding resectability should now focus on what will remain following resection.

Who cannot be operated

Resection for CRLM- Clinical situation

• Synchronous lesions

• Metachronous lesions

Timing of resection and synchronous lesion

• Best timing not yet defined

• Most investigators recommend staged approach 2-3 months after resection of primary

• Recently few series have shown equal results with simultaneous resections

• Staged or simultaneous resections can be considered depending on

– Complexity of resections

– Symptoms

– Comorbid disease

– Available surgical expertise

Extrahepatic disease

• No longer be considered an absolute C/I to hepatic resection

– If the patient is carefully selected

– Complete (margin-negative) resection of both intra- and extrahepatic disease is feasible.

• Survival rate was significantly higher in patients with

– fewer than five liver metastases

– Who received neoadjuvant chemotherapy

– In whom a complete resection could be achieved.

Residual liver volume

• 20% of residual liver volume is adequate for normal liver

• Most paitents with CRM have received chemotherapy and have CASH

• Exact extent of FRLV has not been defined.

• PVE helps in improving the resectability by hypertrophy of residual liver and providing adequate FRLV.

Indications of PVE

• FLRV ≤ 20% of TLV in patients with normal liver

• FLRV ≤ 30% of TLV in patients who have received extensive chemotherapy;

• FLRV ≤ 40% of TLV in patients with hepatic fibrosis or cirrhosis.

Margin status

• Negative resection margin decreases local recurrence rates and improves survival

• Cady et al recommended minimum margin of 1 cm

• Multicenter study 0f 557 pts.

• No difference in 5 yr OS or tumour recurrence rate for tumour free margin of 1-4mm,5-9mm or >10mm

Ann Surg 2005: 241:715

Radiological vs Pathological response

• Radiological complete response is rarely associated with complete pathological response

• Pathological response only in 4 to 9 %

• Mapping and timing of resection are critical.

• Resection should encompass segments involved based on pre-chemotherapy imaging.

Metachronous mets- Timing of sugery

Upfront Surgery

vs

Upfront Chemotherapy

Upfront surgery indications

• Low risk patients

-medically fit

-four or fewer lesions

• Potentially resectable

Upfront chemotherapy- Evidence

EORTC 40983- Perioperative FOLFOX vs. Surgery for resectable CRLM

• Eligibility:

• 1-4 Liver metastases that were technically resectable

• No extrahepatic (non-primary) disease

• No prior oxaliplatin

• Design:

• Experimental arm: 6 cycles (12 weeks) FOLFOX4 pre- and post surgery

Lancet. 2008 Mar 22;371(9617):1007-16

EORTC Trial

• Total no 364 Chemo 182 Resection 182

Resection rate 83% vs 84%

Nontherapeutic Lap 8/159(5%) vs 18/170(11%)

Postop complications 25% vs 16 %

Mortality 1 vs 2

EORTC Result

• Media follow-up 8.5 yrs

• 5 yr PFS 38% vs 30%( HR 0.81, p= 0.068)

• 5 yr OS 51% vs 48% (HR 0.88, 95% CI 0.68-1.14)

Aggressive surgical approach

• Repeat hepatectomy: 60-70% of operated cases develop recurrance. One third are liver only mets.

• Of these 10- 15% candidates for repeat resection.

• Periop mortality 1- 9%• Median survival 37 months.

Jarnagin. Ann Surg• Recurrence rate ~70%

Aggressive surgical approach

• En bloc vascular (IVC, hepatic vein) resection and Ex vivo surgery:

• For liver mets in central and posterior segments.

• Significant mortality and morbidity (~30%)

• Median survival 19 months.

Miyazaki M. Am j Surg

Aggressive Surgical approach

Conversion chemotherapy

• Preoperative chemotherapy permits complete resection in 12-33% of patients who were considered unresectable

• Survival in these patients is similar to those who have hepatic resection upfront ( 5yr SR 30 to 35%)

• Chemotherapy regimens based on (5-FU) rarely provided sufficient intrahepatic tumoricidal effect to convert hepatic metastases from unresectable to resectable (response rate < 20%).

• Actual conversion only 5 to 15%

Study Phase Regimen Number of patients

Response rate Resection rate R0 rate

First BEAT IV Chemotherapy+bevacizumab

1914704 (liver only)

225 (11.8%)107 (15.2%)

173 (9.0%)85 (12.1%)

NO16966 III FOLFOX/XELOX+bevacizumabFOLFOX/XELOX+placebo

699 211 (liver only)701 207 (liver only)

38%38%

44 (6.3%)24 (11.6%) 34 (4.9%)24 (11.6%)

CRYSTAL III FOLFIRI+cetuximabFOLFIRI

599599

57.3% (WT)39.7% (WT)

7%3.7%

4.8%1.7%

OPUS II FOLFOX+cetuximabFOLFOX

169168

57% (WT)34% (WT)

4.7%2.4%

CELIM II FOLFOX+cetuximabFOLFIRI+cetuximab

5655

68%57%

20 (38%)16 (30%)

Table 2. Conversion rates in unresectable colorectal cancer liver metastases patients treated with bevacizumab or cetuximab containing regimens.

WT, KRAS wild-type.

Intra arterial approaches

• Infusion

• Chemoembolization

• Radioembolization (SIRT)

• Given the effectiveness of systemic chemotherapy, regional chemotherapy should be used in conjunction with systemic chemotherapy.

• Too little data exist to determine an overall advantage of one form of regional therapy over another

RFA

• RFA is indicated in unresectable tumors due to– Size

– Location

– Number of lesions

– Co morbid conditions

• Mainly used as palliative therapy

• Can be used with resection in borderline resectable tumors

Metastatic Liver Tumors – Neuroendocrine Tumors

• Functional (carcinoid syndrome)

• Non functional

Metastatic Liver Tumors – Neuroendocrine Tumors

Workup

• CT

• MRI

• Octeriotide scan

• Dota PET scan

Metastatic Liver Tumors – Neuroendocrine Tumors

Treatment modalities

• Liver resection and debulking (90% debulking)

• Ablation

• Liver directed therapy; chemoembolization, radioembolization

• Chemotherapy or hormonal therapy

• PRRT

Metastatic Liver Tumors – Neuroendocrine Tumors

Hepatic resection

surgical resection is the first line treatment

Rationale

Slow growing tumor (ineffective to radiochemotherapy)

Biologically active tumors – mass dependent hormone production

5 yr survival- 85- 100%

R0 vs. R1 vs. R2: do not affect overall survival

Metastatic Liver Tumors – Neuroendocrine Tumors

Hepatic Transplantation

• Offers potential for cure or best palliation

•Prerequisites – complete excision of primary & regional disease

• 5 yr survival- 36- 89%

Metastatic Liver Tumors – Neuroendocrine Tumors

Hepatic Transplantation

•Factors increasing survival (Fernandez 2003)

– Age less than 50 years

–Limited hepatic metastases

– low Ki67 index

– regular E-cadherin staining

– R0 resection of the primary NET with no evidence of

Non colorectal Non neuroendocrine Metastasis (NCNN)

• Role of hepatectomy in (NCNN) tumors not well defined

• Increasing publications

• Overall 5 yr survival: 25- 36%

• Tumors of various pathological types resected

– Influences the outcome

Non colorectal Non neuroendocrine Metastasis (NCNN)

MSKCC series from 1981- 2002

Tumor pathology %age

Breast 20

Melanoma 12

Reproductive tract 28

Testicular 14

Gynecologic (ovarian, endometrial, cervical) 14

Adrenocortical 11

Renal 8

Gastrointestinal ( stomach, duodenum, periampullary, anal) 9

Others (lung, salivary gland, nasophyrangeal, thyroid, tonsil, sweat gland)

9

Unknown 3

Non colorectal Non neuroendocrine Metastasis (NCNN)

MSKCC series from 1981- 2002

Tumor pathology %age

Breast 20

Melanoma 12

Reproductive tract 28

Testicular 14

Gynecologic (ovarian, endometrial, cervical) 14

Adrenocortical 11

Renal 8

Gastrointestinal ( stomach, duodenum, periampullary, anal) 9

Others (lung, salivary gland, nasophyrangeal, thyroid, tonsil, sweat gland)

9

Unknown 3

Median follow-up: 35 months30 day mortality- 0 %3-year relapse-free survival rate was 30% 3-year cancer-specific survival rate was 57%

Liver Metastases: Gastric GIST with liver mets

• Most common indication among sarcomas

• Imatinib changed natural history of the disease

• 5-year overall survival rate: 30% in resected patients versus only 4% who do not underwent resection

MSKCC data

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