Management of Management of hepatocellular carcinoma: a hepatocellular carcinoma: a

case reportcase report

Giovanni BrandiGiovanni Brandi

Institute of Hematology end Medical Oncology “L e A Seràgnoli”

Bologna University

The patientMale, 61 year-old

Smoker

Alcohol abuse

In 1999 first ascitic failure

Diagnosis of chronic C hepatitis

The patient

In 2000 refractory ascitis

Transjugular Intrahepatic

Portosystemic Shunt(TIPSS)

Right atrium

TIPSS

Portal Vein

Hepatic veins

Abdomen ultrasound scan: nodular lesion in the VI hepatic segment.

March 2002March 2002

CT scan:negative

?

Abdomen ultrasound scan: multiple hepatic

nodular formations.

June 2004June 2004

CT scan:negative

?

CEUS: HCC nodule in the VI hepatic segment.

MRI: HCC nodule in the VII hepatic segment.

August 2004August 2004

CT scan:HCC nodule inthe VIII hepatic segment

December 2004December 2004

Abdomen ultrasound scan: multiple nodular

lesion, the largest in the VI hepatic segment.

April 2005April 2005

CT scan:Nodular HCC betweenV and VI hepatic segment,a second lesion in the II segmentand a third in the VII segment

May 2005May 2005

July 2005: chemoembolization of the largest nodule (3,4 cm). CEUS “complete response in the lesion treated; 2 residual lesions in the remaining parenchyma. Multiple rigenerative nodules”.

FP always within the normal range

Select between

Liver transplant Surgical resection

Termoablation Yttrium

Which is the best treatment for this

patient?

15 $1 MILLION14 $500.00013 $250.00012 $100.00011 $50.00010 $25.0009 $16.0009 $16.0008 $8.0007 $4.0006 $2.0005 $1.0004 $5003 $3002 $2001 $100

Treatment options: Barcellona criteria

Liver trasplant: indications

Solitary nodule with less than 5 cm of diameter or

Less than 3 nodules with each less than 3 cm of diameter and

No gross vascular invasion andNo ilum’s nodes involvement

Milano’s criteria

Mazzaferro V. et al. NEJM 1996

Predictors of Long-Term Survival After Predictors of Long-Term Survival After LiverLiver

Transplantation for Hepatocellular Transplantation for Hepatocellular Carcinoma.Carcinoma.

Zavaglia et al. Am. J. G. 2005

Survival bygrade

Predictors of Long-Term Survival After Predictors of Long-Term Survival After LiverLiver

Transplantation for Hepatocellular Transplantation for Hepatocellular Carcinoma.Carcinoma.

Zavaglia et al. Am. J. G. 2005

Beyond Milano’s Beyond Milano’s criteria ? criteria ?

From june 2006 to april 2007, 1556 patients transplanted, 1112 exceeding Milano’s criteria:

Median size of largest nodule: 40 mmMedian numbers of nodule: 441% of microvascular invasion(*)5-years OS 53% vs 73% in patient meet

criteria

Mazzaferro V. et al. Lancet 2009

*worst prognostic factor

The patient

A first nodule of 2 cm

A second nodule of 1 cm

No invasion of main

hepatic vessels

Liver TransplantLiver Transplant

Anastomosis between celiac tripode of the graft andaccessory left hepatic artery of the receiver

February 2006

Pathologist exam of the Pathologist exam of the explanted liverexplanted liver

Solitary HCC nodule, almost necrotic (the one treated by chemoembolization)

Multiple rigenerative nodulesDiffuse, microscopic vascular

invasion

HCC G2-G3 by Edmodson degrees

Immunosoppression and Immunosoppression and other therapiesother therapies

Daclizumab

(Zenapax®)

+ Tacrolimus

NorvascLansoxTiklidBactrim

forteDeursilZyloricEskimTorvastAranesp

Immunosoppression protocol

Adverse event within the Adverse event within the immunosoppression/tacrolimimmunosoppression/tacrolim

ususInfectionsDecrease of renal functionCNS impairment (headache, trembling,

depression..)CytopeniaHirsutismDiabetes mellitusIncrease incidence of lymphoma…..

Follow-upFollow-up

Progressive increase of creatinine+

Emerging albuminuria

Dose reduction of Tacrolimus then switch to Sirolimus

Nephrologic evaluationNephrologic evaluation

Ecodoppler: no thrombosis or

stenosis in the main renal vessels

Renal biopsy

Nephropaty with mesangial deposition of IgA

October 2006

Abdomen ultrasound scan

Suspect for hepatic lesion

CT: December CT: December 20062006

Pet-CT: January Pet-CT: January 20072007

Multiple microscopichepatic lesions.One macroscopic nodule.

Only the largest was seen on FDG-TC-PET.

Colonoscopy was performed in order to exclude a large intestine primitive cancer

Negative

Hepatic biopsy :

Recurrence of HCC

Survival for recurrence HCC Survival for recurrence HCC after OLTafter OLT

Roayaie et al. Liver Trasplantation 2004

Survival from transplant

P < 0.0001

Survival for recurrence HCC Survival for recurrence HCC after OLTafter OLT

Roayaie et al. Liver Trasplantation 2004

Time from transplant to recurrence of hepatocellular carcinoma (P 0.0015)

Survival from time of recurrence

Survival for recurrence HCC Survival for recurrence HCC after OLTafter OLT

Roayaie et al. Liver Trasplantation 2004

Presence of bone metastases (P =0.002)

Survival from time of recurrence

Select between

Chemotherapy Surgical resection

Experimental treatment Termoablation

Which is the best treatment for this

patient, now?

15 $1 MILLION14 $500.00013 $250.00012 $100.00011 $50.00011 $50.00010 $25.0009 $16.0008 $8.0007 $4.0006 $2.0005 $1.0004 $5003 $3002 $2001 $100

Treatment options: Barcellona criteria

July 2008

Phase I/II trial of continuous hepatic arterial Phase I/II trial of continuous hepatic arterial infusion (HAI) infusion (HAI)

of Irinotecan in patients with hepatocellular of Irinotecan in patients with hepatocellular carcinoma (HCC). carcinoma (HCC).

• Efficacy of irinotecan on HCC cell lines • Low efficacy of intravenous irinotecan in HCC ( Boige V et al

2006)• HCC nodules are supplied only by arterial flow• Possibility to deliver a higher amount of drug into tumoral

vasculature• Higher conversion of CPT-11 in SN-38 during HAI vs IV

administration ( Van Riel JHM, 2002)• Lower systemic toxicity in HAI vs IV CHT administration

• Irinotecan is a phase specific drug: prolonged infusion increase fractional cell kill, produces lower peak-plasma drug concentration avoiding carboxylestease saturation and theoretically increasing glucoronation of SN-38 with reduced systemic toxicity (Gerrits CJ 1997)

Eligibility criteriaEligibility criteria

INCLUSION

• Pts with HCC on Child-Pugh A/B cirrhosis not eligible for curative treatment according to Barcelona consensus criteria

• Absent or incomplete portal vein thrombosis or present in only one branch

• Pts untreated with systemic CHT

or submitted to previous TAE, RF

with at least 1 measurable active lesion

• leuko/neutro >3000/1300• platelets> 75000 ; Hb> 10• Bilir up to 3.0; Pt >50%

EXCLUSION (main)

• HCC without cirrhosis• Child-Pugh C• Complete portal vein

thrombosis• Metastatic disease• History of differents neoplasias..• Recent AMI ; pregnancy.

• DLT

• One G4 haematological and/or• Two G3 non-haematological

toxicities (exepting nausea, vomiting, alopecia)

• Liver function impairment (Child C)

June 2007: First infusion of CPT-11 (20mg/m²).

July 2007: second infusionAugust 2007: third infusion then…

Hospitalization for worsening of chronic kidney failure…

Hepatic arteriographyHepatic arteriography

Disease progression

November 2007: we try to restart with HAI-therapy but..

Arteritis (CHT-induced)

Treatment interruption

Select between

Systemic chemotherapy Antiangiogenic therapy

Experimental treatment Yttrium

OK……and now?15 $1 MILLION14 $500.00013 $250.00013 $250.00012 $100.00011 $50.00010 $25.0009 $16.0008 $8.0007 $4.0006 $2.0005 $1.0004 $5003 $3002 $2001 $100

A phase II trial of A phase II trial of metronomic capecitabine in metronomic capecitabine in

HCCHCC

Diagnosis of HCC by histology or Barcellona’s criteria

Child-pugh cirrhosis A (or B)

Unfit for surgery or local treatment

Life expectancy > 3 months

Bilirubin serum level < 3 mg/dl

Child-pugh cirrhosis C Chronic heart failure Chronic kidney failure No bone marrow

impairment Hypersensitivity at 5-FU

Inclusion criteria Exclusion criteria

In december 2007 the patients starts with Xeloda® 1000 mg/daily

(500mg+500mg) without interruption

In march 2009 he completed the XIVth cicle of therapy…

This is the CT of revaluation…

ECOG<0ECOG<0