Treatment of liver tumours current trends

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

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


Workup

• CT

• MRI

• Octeriotide scan

• Dota PET scan


Treatment modalities

• Liver resection and debulking (90% debulking)

• Ablation

• Liver directed therapy; chemoembolization, radioembolization

• Chemotherapy or hormonal therapy

• PRRT


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


Hepatic Transplantation

• Offers potential for cure or best palliation

•Prerequisites – complete excision of primary & regional disease

• 5 yr survival- 36- 89%


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


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


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

Thank you

Treatment of liver tumours current trends

Health & Medicine

Transcript of Treatment of liver tumours current trends