CHILDHOOD LIVER CANCER- AN ONCOLOGIST’S

PERSPECTIVE PROFESSOR JANET POOLE

PAEDIATRIC HAEMATOLOGY/ONCOLOGY, CMJAH, & FACULTY OF HEATH SCIENCES, UNIVERSITY OF THE WITWATERSRAND,

JOHANNESBURG

INTRODUCTION TO LIVER TUMOURS

• > 1+ % of all paediatric malignancies 100 – 150 new cases in U.S. annually

• Hepatoblastoma accounts for 2/3 of liver tumours in kids

• Other liver malignancies: Hepatocellular carcinoma, sarcomas, germ cell tumors, & rhabdoid tumors

• Benign tumours: Vascular tumours, hamartomas, adenomas

EVALUATION OF A LIVER MASS

Verify exact location of palpable abdominal mass Abdominal ultrasound Definitive characterization with abdominal CT or MRI scan Chest CT to evaluate lung parenchyma for distant metastasis

Laboratory Evaluation FBC

Normocytic, normochromic anemia Thrombocytosis

Serum Tumour Markers AFP, β‐HCG

CMP Family History Detail to any history of colon cancer /polyps, liver tumour

Evaluation of a Liver Mass: Serum Tumour Markers

• AFP α‐fetoprotein Marked elevation in >90% hepatoblastoma cases May also be elevated in hepatocellular carcinoma Elevated in malignant germ cell tumors

Returns to normal levels with effective therapy Half‐life approximately 7 days (range 4‐9) Not always a marker of tumor Normal term infants can have AFP levels > 100,000 ng/ml Normalizes to <10 ng/ml over first few months of life

• β‐HCG Hormone commonly expressed by liver tumors May result in precocious puberty

HEPATOBLASTOMA

• Most common malignant tumour of the liver in kids • Peak incidence in very young children • Median age at diagnosis = 18 months • Only 5% are diagnosed in children > 4 years of age • Males > Females • Most commonly presents in right lobe • Histological Subtypes

– Epithelial (mixture of embryonal & fetal cell types) – Mixed epithelial / mesenchymal – Pure fetal – Small cell undifferentiated*

HEPATOCELLULAR CARCINOMA

• 2nd most common liver malignancy in kids Most cases diagnosed after 10 years of age Most common hepatic malignancy in adolescents

• Often associated with known hepatic viral infection (Hepatitis B, C) or cirrhosis Arises from well differentiated hepatocytes Incidence in SE Asia > Western countries High hepatitis carrier rates Association with Tyrosinemia, Alagille Syndrome

• 3 year OS < 25% Chemo-resistant, advanced disease at diagnosis

Miscellaneous Malignancies of the Liver

• Undifferentiated Embryonal Sarcoma 3rd most common hepatic malignancy Children ages 5 – 10 years of age Mesenchymal in appearance

• Angiosarcoma of the Liver Aggressive subtype with poor prognosis

• Embryonal Rhabdomyosarcoma Children < 5 y/o Arise from biliary ducts – children often present with obstructive jaundice Treatment similar to rhabdomyosarcoma of other sites

BENIGN LIVER TUMOURS

• 30% of all liver tumors in children (40‐50 cases/year) • Hemangioendotheliomas

Most common benign tumor of the liver 1o diagnosed within 1st 6 months of life

More common in whites, females Characterized by period of rapid growth then involution

Benign pathology, potential to metastasize

Morbidity and Mortality Triad of hepatomegaly, CHF, anemia Consumptive Coagulopathy & bleeding

Kasabach‐Merrit Syndrome • Mesenchymal Hamartoma • AV malformations

History

1898, Misick OS. A case of Teratoma Hepatis. J Pathol Bacteriol 5:128-137

• ‘tumor contai ning cysts, carti lagenous and bony deposits, and venous tumour infi ltration’

1962, Willis introduced the term Hepatoblastoma 1967, Ishak and Glunz defined morphologic criteria for HB and HCC

AAP surg section survey – 1974 data on liver tumors operated on for the past

10 years, 110 replies

• 129 HB – Multifocal 15% – OS 35% – Complete resection – survival 60% – Incomplete resection (2/3) –survival 0% – –/+ chemo (n=53) – – /+ irradiation (n=15) – 3 unresectable tumors became resectable (lobectomy) after

vincristine, actinomycin D, cyclophosphamide; these patients were long term survivors

• 98 HCC – Multifocal 30% – OS 13%

CHEMOTHERAPY

1970’s – responses to combinations of

cyclophosphamide, vincristine, 5-FU and

actinomycin D

1980’s – introduction of cisplatin and

doxorubicin caused major breakthrough

THE SIOPEL STORY

Segmental Liver Architecture

PRETEXT PRE Treatment EXTent

THERAPEUTIC STATEGY OF SIOPEL

Neoadjuvant chemotherapy and delayed surgery –To make tumour smaller –Increase resection rate –To make tumor more solid and less prone to bleeding

–To treat (micro)metastasis in the lung without delay

Using PLADO (cisplatin, doxorubicin)

1990 start of SIOPEL-1 (SIOP Epithelial Liver tumor), the first full-scale prospective,

multinational study of hepatoblastoma ever performed

Before

After

SIOPEL STUDIES

SIOPEL 1: Cisplatin & Doxorubicin preoperatively Delayed Surgery Further chemotherapy 5 year EFS = 66%, OS = 75% Included SR/HR patients

SIOPEL 2: Pilot study of Cisplatin alone in SR hepatoblastoma 3 year OS = 91%** COG critique: 30% of patients received additional chemo (doxorubicin & carboplatin) EFS including these patients = 73% (± 11%)

SIOPEL 3

Prospective trial of Cisplatin vs. Cisplatin & Doxo in SR patients (pretext I‐III) Cisplatin (given every 14 days) •80 mg/m2 continuous over 24 hours Cisplatin / Doxorubicin (given every 21 days) •Cisplatin day 1 (80 mg/m2) •Doxorubicin (30 mg/m2) days 2 & 3

Assessment of Tumour Response: •4 cycles of Cisplatin or 1 cycle of Cisplatin plus 3 cycles of cisplatin / doxo*

•Surgical resection versus 2 additional cycles of chemotherapy

Results Doxorubicin can be safely omitted in treatment of standard‐risk hepatoblastoma 3 year EFS: 83% vs 85% OS 95% vs 93% Acute events (Grade 3 or 4) more frequent with combination therapy

Cannot compare rate of complete resection / OS / EFS to other trials because of differences in risk stratification

SIOPEL3-HR

• Multi‐agent chemotherapy & surgical regimen designed to improve cure rate of HR hepatoblastoma

High Risk ‐ Pretext‐IV, Vascular Invasion (P+, V+), Extrahepatic disease (E+), Metastatic Disease (M+)

AFP < 100 ng/ml at diagnosis Tumor rupture at presentation

• Treatment schema Alternating cycles of Cisplatin and Carboplatin plus Doxorubicin Total of 10 cycles of chemotherapy Evaluated for resectability after cycle 7 Patients ineligible at cycle 7, evaluated after cycle 10

Response evaluated by weekly AFP levels & imaging (after cycles 2, 4, 7)

• Zsiros J et al, JCO April

SIOPEL -3 scheme

SIOPEL‐3HR: PRETEXT‐IV

• Successful subgroup (no mets, no AFP <100)

• Initially unresectable tumor

50% responded sufficiently to chemo & underwent partial hepatectomy

Liver transplant curative in significant proportion of remaining patients

3‐year OS of all transplant patients = 75%

Microscopic residual disease after definitive surgery does not equal bad prognosis

3‐year OS = 82%

• Zsiros J et al, JCO

SIOPEL‐3HR: M Response

50% achieved total disappearance of lung lesions

Most Favorable: complete lung response + complete resection of primary tumor

(hepatectomy) 26 patients: Only 2 relapsed, no deaths

Unfavorable: complete lung response + liver transplant = high risk of relapse

4/5 patients died of pulmonary relapse

3/4 received postoperative chemo per protocol

Need further study to define role of liver transplant in metastatic patients

20% achieved partial response (n = 15)

Favorable: surgical resection of primary & metastatic lesions

3/3 patients with complete resection (liver & pulmonary) alive

4/9 patients liver, but no lung resection relapsed (3 deaths)

3/3 patients without resection of liver primary died

• Zsiros J et al, JCO

SIOPEL -4

SIOPEL HR outcomes

CHIC (Children’s Hepatic Tumour International Collaboration)

Risk Stratification

Prognostic Factors

Risk Group Analysis

Summary of Trials

Current Chemotherapy Recommendations

CURE = CO-OPERATION