CHILDHOOD LIVER CANCER-paedhpb.org/2017/Sunday/Childhood Liver Cancer.pdf · Marked elevation in...
Transcript of CHILDHOOD LIVER CANCER-paedhpb.org/2017/Sunday/Childhood Liver Cancer.pdf · Marked elevation in...
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