Primary liver tumor Hepatoblastoma - PowerPoint Presentation

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Primary liver tumor Hepatoblastoma 

M. tashvighiPediatric Hematology oncologistMAHAK Pediatric Cancer Treatment and Research Center2018

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Primary Hepatic tumor is Rare - only 1-2% of all childhood cancers

Hepatoblastoma & hepatocellular carcinoma are the two most common malignancies that arise de novo in the liverHepatic tumors have a wide geographic variation in incidence: They are seen more frequently in Asian and African childre They are the third most common abdominal cancer in Japan.

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The geographic variation is thought to reflect the etiologic role of environmental conditionsWhite males /

females 1.4/0.5 per million African American males/females 0.9/ 0.0 per million

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BenignHemangioendotheliomaMesenchymal

HamartomaMesenchymal (mixed) AdenomaAngiomyolipomaEmbryonal sarcoma HamartomaMalignantHepatoblastoma

Hepatocellular carcinoma

Rhabdomyosarcoma

Undifferentiated

Angiosarcoma

Biliary cyst

Sarcoma

Teratoma

Rhabdoid tumor Myofibroblastic tumorYolk sac tumorLeiomyosarcomaLangerhans Cell HistocytosisAML-M7

Different

Diagnosis

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Hepatoblastoma is Approximately two-thirds of liver tumors in childrenMedian age 1 year Male : female ratio

1.7:1.0

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EtiologyUnknownCongenital anomalies which have been reported with

hepatoblastoma & HCC

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Disorders Associated with Increased Risk of HepatoblastomaLow-birth-weight infantCongenital

cystathioninuria and hemihyperplasiaMaternal use of hormonal therapyExposure to metals such as in welding and soldering fumesBeckwith -Wiedemann syndromeHemihypertrophy syndromes Li.Fraumeni syndromeVon Gierke diseaseFAB

Trisomy 18

Fetal alcohol syndrome

Gardner

syndromea

Type I glycogen storage disease(Von

Gierke

)

Prader

Willi – syndromewilm’s tumor (WT1)Meckel’s diverticulumCongenital absence of adrenal gland

Congenital absence of kidney

Umbilical hernia

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Conditions associated with a high risk for HCC development are ;Antitrypsin deficiency

Wilson’s diseaseHemochromatosisHereditary tyrosinemiaFanconi’s anemiaFamilial adenomatous polyposis Gardener’s syndrome

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Familial Adenomatous PolyposisFAPAD

Mean age 16 yr.Mutation in APC gene (5q21)Other manifestation;Congenital hypertrophy of retinal epithelium(CHRPE)Supernumerary teethSkull & jaw osteomasEpidermoid cysts,fibromas, lipomas, skin, hyperpigmentation,keloids

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Neoplasia in FAPColon carcinomaAdrenal carcinoma

Thyroid papillary carcinomaPeriampullary carcinomaFibrosarcomaGastric adenocarcinomaMedulloblastomaHepatoblastomaAstrocytomaETC

GENETIC TEST FOR

FAB

Protein

Truncation test(PTT)

80-90% of FAB families

100% accurate if know

Direct

sequenceing

Difficult due to large gene100% accurate if know

1/3 new mutation

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Most common sign of primary liver malignancy;

Upper abdominal mass May have abd. Pain ,wt. loss ,anorexia ,N/V50-70% Unresectable mass at diagnosisGeneralized abdominal enlargementAbdominal distention Pallor Jaundice Fever Diarrhea Constipation

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Children with a ruptured tumor usually present with;VomitingS

ymptoms of peritoneal irritationSevere anemiaRare cases manifest precocious puberty/virilization due to β-human chorionic gonadotropin (hCG) secretion by the tumorPediatric hepatoblastoma: diagnosis and treatmentTransl Pediatr 2014;3(4):293-29

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DIAGNOSTIC EVALUATIONHistoryPhysical examination

Diagnostic test:Complete blood count Anemia Moderate leukocytosis is common Thrombocytosis >500,000/mm3 UrinalysisLiver profile and electrolytes

(

Bilirubin and liver enzymes are usually

normal )

Fibrinogen

,

PT & PTT

HBsAg

,

HBcAg and core antibody(positive hepatitis B e Ag., higher HBV-DNA level, HBV genotype C infection, core promoter mutation are associated with a higher risk of HCC)AFP (Low AFP levels are associated with anaplastic histology and poor outcome )

β-

hCG

CEAg

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High AFPHepatoblastomaHepatocellular Carcinoma

Germ cell tumorsTerato CarcinomaViral Hepatitis & other Active liver diseaseCirrhosisInflammatory Bowel DiseaseYolk Sac tumors

Pregnancy

Gastrointestinal

tumors

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90% of children with hepatoblastomas 50% -70%

of children with HCC have elevated AFP some variants of both HBL ,HCC that have low or normal AFP levelsRhabdoid tumor, have low AFP levels and worse prognosis

half-life

of AFP is

4-9 days

levels fall to within reference range within

4-6 weeks

following resection

Reference range AFP levels are high

at birth

and higher in premature infantsPediatric hepatoblastoma: diagnosis and treatmentTransl Pediatr 2014;3(4):293-29

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Radiographic evaluation of intrahepatic disease;• Sonogram• Abdominal

CT-scan• Abdominal -MRI• MRI angiogram• MRI cholangiogramRadiographic evaluation of extrahepatic disease;CXR-AP, latChest CT-scanBrain CT-scanBone

scan

Bone

marrow

aspirate/biopsy

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Abdominal ultrasonography ;large mass in liver, sometimes with satellite lesions &

areas of hemorrhage within the tumorUltrasound,may not be as sensitive in the evaluation of the postoperative bed due to the presence of either omental flap or gas-filled loops of bowelPercutaneous biopsy, either ultrasound or CT guidance can be used

Pediatric

hepatoblastoma

: diagnosis and treatment

Transl

Pediatr

2014;3(4):293-29

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The most useful diagnostic modality is multiphase CT or MRI;Focal / Multifocal solid tumor

Hypervascular lesions in the liver with delayed contrast excretion are highly suggestive of a malignant liver tumorStippled or chunky calcifications detect in 40%-50% of patients, is significantly higher than in patients with benign lesions such as hemangiomas and

hemangioendotheliomas

MRI

is more sensitive than

CT

in discriminating between;

Disease

recurrence

Postoperative abnormalities(fibrosis and post-treatment necrosis in the liver Angelina Cistaro Editor Atlas of PET/CT in Pediatric Patients

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Positron emission tomography (PET) scanning: Studies support a potential role for PET scanning at diagnosis &

follow-up in hepatoblastomaSeveral articles on the impact of PET/CT in adult HCC published, but there are no reports on the use of this imaging technique in pediatric patients Uptake of the 18F -FDG tracer reflect the ability of HB cells to store large amounts of glycogen granules in their cytoplasm

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lung metastases by 18 F-FDG– PET/CT was

lower than that obtained with CT & for lesions below 1 cm, because of the limited resolution18 F-FDG– PET/CT was significantly superior to bone scan in patients with bone metastasesFDG–PET/CT in the assessment of tumor response and tumor viability after interventional therapy

(

transcatheter

arterial chemoembolization & radiofrequency ablation

)

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Conventional arteriographyNewer modalities for extent of hepatic involvement by tumor and its

proximity to the portal vein Transarterial chemoembolization is a therapeutic consideration. Ultrasound in conjunction with color Doppler, a noninvasive modality, is especially useful in young infants

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hepatoblastoma usually affects one or more contiguous liver segments. Occasionally, the tumor can be multifocal.

This presents a surgical challenge & liver transplantation may be required.  

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MetastasesHepatoblastoma, Right lobe of the liver is more commonly

involved than LeftTumor involves both lobes in 30% of patientsMetastases at diagnoses occur in 10%-20% of patients lung being the predominant site 10-20% of patients with hepatic tumors have pulmonary metastases

D

istant

metastases, including

brain

and

bone

, are

rare

Higher incidence of nonpulmonary metastases in congenital hepatoblastoma Childhood Cancers: Hepatoblastoma-The Oncologist 2000;5:445-453

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StagingStage I Complete resection of tumor by wedge resection lobectomy

or by extended lobectomy as initial treatmentStage II GTR with microscopic residual Stage III A. Gross residual tumor involving both lobes of liver B. Regional lymph node involvement

Stage IV

Metastatic disease

with complete or incomplete resection

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In Europe, the Childhood Liver Tumor Study Group of the International Society of Pediatric Oncology (SIOPEL) has developed the preoperative evaluation of the tumor extent (PRETEXT) staging system

Segmental assessment of the extent of the tumor main hepatic vessels Pediatric hepatoblastoma: diagnosis and treatmentTransl Pediatr 2014;3(4):293-29

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Hepatic segmental anatomy according to Couinaud. This method of hepatic segmentation is based on portal venous supply &

hepatic venous drainage

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PRETEXT SIOP(based on presurgical findings) Staging for Hepatoblastoma

Stage 1 Tumor involves one quadrant Three adjoining quadrants are free of diseaseStage 2 Tumor involves two adjoining quadrants with remaining two free of diseaseStage 3 Tumor involves three adjoining quadrants or two nonadjoining quadrants.One quadrant or two

nonadjoining

quadrants are free of disease

Stage

4

Tumor involves

all four

quadrants

Slide29

The pathologic classifications for hepatoblastoma and HCC are :

Hepatoblastoma Epithelial type (56%) Pure fetal pattern Embryonal pattern -Macrotrabecular type CholangioblasticSmall cell undifferentiated type or anaplastic

Mixed

epithelial and mesenchymal

type (

44%)

HCC

Fibrolamellar

HCC

(

Histologic variant of HCC - most frequent &is commonly observed in children & adolescents- has a similar prognosis when adjusted for stage)

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Some histological types are associated with prognosis so;Pre-chemotherapy specimens for the initial diagnoses and tumor classification.

tissue banking for biological studiesWell differentiated fetal histology composed only of cells resembling fetal hepatocytes with minimal mitotic activity (COG);pure fetal histologyand low mitotic activity may be treated exclusively with surgery, and

no chemotherapy

is

necessary

7%

of the total number of

patients & showed

100%

(

EFS)Most HBs are extremely heterogeneous, often with closely intermixed histological components, and only rarely composed of a single histological type

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Small cell undifferentiated (SCU, component intermixed with other histologies ,associated with

low serum AFP levels, and poor response to chemotherapysome, but not all, of these tumors may represent INI1 negative neoplasms within the spectrum of primary rhabdoid tumorsshould be submitted for molecular testing, and patients and family members referred to a genetics counselor to possible be screened for germline mutations

significance of small cell component when ad

mixed with other epithelial types

, and whether th

ese

small foci are sometimes

INI1expressing

Hepatoblastoma

State of the Art ;Pathology, Genetics, Risk Stratification, and Chemotherapy

Piotr Czauderna, Dolores Lopez

Terrada

 

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The most common mesenchymal elements are osteoid and cartilage The presence of

mesenchymal elements associated with improved prognosis in patients with advanced disease

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Cytogenetic AbnormalitiesGain of chromosome 20 ,most common

,Gain of chromosome 2 or 8Associated with FAP and trisomy 20 is a common finding in colon adenomas Chromosomal aberration, der(4)t(1q;4q) t(1;4)(q12;q34) Gain

of material on

1q

Studies of DNA content have shown that

diploid tumors with low proliferation index

have a

better

prognosis than aneuploid tumors & high proliferative index

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Changes in the expression of H19 and IGF2 have also been implicated in the etiology of hepatoblastoma

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Prognostic factorGood prognostic factor

(COG) ;Complete resection(stage I) completely resected tumors pure fetal histologyRate of fall alpha- fetoproteinLarge early response (>2 log decline in AFP)strongest dependent predictor of outcome ( P<0001)Poor prognostic factor (SIOPEL and the COG) ;

AFP<100

ng/ml or

>

1/000/000

ng/ml at

diagnosis

and

/ or with small cell undifferentiated (SCUD) histology Regardless of the PRETEXT staging

systemVascular invasionPediatric hepatoblastoma: diagnosis and treatmentTransl Pediatr 2014;3(4):293-29

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Potential Prognostic Factors in Hepatoblastoma

PRE- TREATMENTRESPONSE TO TREATMENTPRETEXT StagePositive Surgical MarginsMetastasis at diagnosisSurgical ResectabilityUnresectable

Vessel involvement

Tumor Relapse

Extrahepatic tumor extension

Response to

Chemotherapy

Lymph Nodes

Tumor Rupture at diagnosis

AFP level (<100,100-1000, >1 million)

Pathologic subtype (Pure Fetal

, Small Cell Undifferentiated)

Age (<1 year - >6 year)

Birth weight

Platelet Count

Co-Morbidity

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TREATMENTOveral survival IN stage 3 & 4 is 20-30%

Surgery; complete resection can be chance of cure Initial surgical resection-most prognostic factorDelayed surgical resection after chemotherapyOrthotopic liver transplantationChemotherapy ;

plays

an important role, not only in

eradicating subclinical

metastases

in

completely resected disease

,

but

also may allow unresectable disease to become resectableTranscatheter arterial chemoembolization

Slide39

Timing of surgeryIn the United States;

Initial surgical resection in appropriate patients is preferred The European approach is different; Patients are staged by PRETEXT and neoadjuvant chemotherapy is administered prior to surgery to all patients except PRETEXT stage 1Surgery is recommended

for

limited metastatic disease

(especially in

lung

)

This surgery is often done at time of liver

tumor resection

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Classic reasons for unresectable ;Extremely large tumor that may lead to excessive

bleeding Involvement of both the right and left lobesInvolvement of major hepatic veins or the inferior vena cava (IVC) Diffuse multifocal diseaseOnly 30% have been

considered

resectable

at

diagnosis

In the

unresectable

patient

Biopsy should be performed

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Surgical BiopsyDiagnostic surgical biopsy is strongly recommended ;

Children <6 months ,Wide range of possible tumours presenting at this age Possible confounding effect of a physiologically elevated AFP level Children older > 3 years of age, to distinguish hepatoblastoma from hepatocellular carcinomaAll patients with a normal serum AFP

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BiopsyBiopsy may not be necessary for young children (6 months to 3 years) with a very high AFP level

Avoiding a biopsy theoretically reduces the risks of tumor seeding or disseminationThe Japanese Study Group for Pediatric Liver Tumors (JPLT) strongly recommends that liver tumors of children should be treated after definitive diagnosis of a biopsy specimen, except in urgent life threatening circumstances such as tumor invasion of the right atrium or tumor rupture Pediatric hepatoblastoma: diagnosis and treatmentTransl

Pediatr

2014;3(4):293-29

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Most common intraoperative complication ;Hemorrhage

The risk of bleeding is increased ;Extended hepatectomy Tumor proximity to the IVC or hepatic vessels Air embolus

D

amage

to

the portal vein

,

hepatic artery

, or

hepatic

duct

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Postoperative complications;Sub phrenic abscessBile leak

Postoperative bleedingSmall bowel obstruction

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Radical hepatic resection results in many potential postoperative complications:• Hypovolemia• Hypoglycemia• Hypo albuminemia

• Hypo fibrinogenemia and deficiency of coagulation proteins• Hyper bilirubinemia persists for 24 weeks after resectionHepatic regeneration is complete by 13 months post surgery

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Transcatheter arterial chemoembolization Hepatic arterial chemoembolization involves giving chemotherapy and

vascular occlusive agents via catheter into the artery supplying the tumorCryoablation, and more recently radiofrequency ablation, have also been used in the treatment of liver tumors in adults with little experience in children

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ABLATION THERAPY Tumors are destroyed using

;Heat (Radiofrequency ablation)Cold (Cryoablation) Chemical agents (Percutaneous ethanol instillation)Ablative therapy is for tumors involving the liver,

kidney

,

lung

and

painful tumors of

bone

The

goal of ablative therapy is

complete tumor destructionAblative therapy is an alternative to surgical resection and appropriate primarily for patients with four or fewer tumors limited to the liver

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RADIOFREQUENCY ABLATIONGeneration of heat to destroy the

tumorExposure of both normal and cancer cells to heat above 122 F° - 9 up to 14 min. )causes the cells to die, resulting in cellular destructionSound waves to interact with molecules in the tumor, causing them to vibrate and generate heatEnergy is delivered through a

needle

G

uidance

provided by

ultrasound

,

CT

or

MRI

Slide49

Slide50

ADVERSE REACTIONnot uncommon ;Fatigue

Muscle ache Low grade fever Rarely Liver injury in the form of bleeding leakage of liver fluid (bile) Heat damage to surrounding organs ,the gall bladder or bowelLung surrounds the liver may be lung injury or collapse

Slide51

Success is influenced ;Tumor size, as larger tumors are more difficult to completely eradicate than smaller

onesTumor location adjacent to flowing blood initial treatment did not destroy all of the tumor, the procedure may be repeatedDestroys very little normal liver Radiofrequency ablation

does not interfere

with

future surgical

procedures or

other types of

therapy

Continued

monitoring

with CT or MRI at 3 mo.- 6 mo.

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CRYOABLATIONIce ball with subzero temperatures is created by circulating liquid nitrogen in a probe that is directly inserted into the tumor

Tumor in ,liver, kidney, prostate, lung , bone

Slide53

PERCUTANEOUS ETHANOL INSTILLATIONAlcohol destroys cells on contact through destruction of their lining membranes

More treatment sessions Slightly less effectiveoften employed in conjunction with radiofrequency ablation to enhance the success of the procedure. Vascular Interventional Radiology of the Robert Wood Johnson University Hospital and the UMDNJ- Robert Wood Johnson Medical School

Slide54

Combination chemotherapy plays several roles in the management:Adjuvant therapy for patients who have undergone complete resection, its use

improves disease-free survivalPreoperative therapy for patients who have initially unresectable disease to shrink the primary tumor Palliative therapy for patients with metastatic disease at diagnosisThe outcome of high risk hepatoblastomas with multi focally disseminating growth in the liver, invasion of large vessels, extrahepatic extension and metastases is still poor,

especially since these tumors often rapidly develop resistance against cytotoxic

drugs

Chemotherapy

Slide55

Patients are assigned to the following risk groups(COG):

Very low-risk:Grossly resected tumors (stage I) with PFH & an elevated AFP level > 100 ng/mL Low-risk: Grossly resected tumors (stage I-II) & lacking any unfavorable biologic feature ( any SCU elements or a low diagnostic AFP level < 100 ng/mL)

Intermediate-risk;

G

ross

residual disease/

unresectable

disease OR grossly resected disease with any SCU elements but no metastatic disease and no low diagnostic AFP level < 100 ng/mL

High-risk:

M

etastatic disease OR low diagnostic AFP level < 100 ng/mL regardless of stage

COG AHEP0731: Phase III Study of Combination Chemotherapy in Pediatric Patients With Newly Diagnosed

Hepatoblastoma

Slide56

Slide57

Children’s Hepatic Tumors International Collaboration (CHIC)Hepatoblastoma Risk Stratification;

PRETEXT Standard risk High risk (HR) Very high risk (VHR)Low risk

(primary resection at diagnosis)

Intermediate risk

Any M+

–

–

–

M+

I M–

VPERF—(any AFP, any age) –

VPERF + AND age <8 years (any AFP)

VPERF + AND age ≥8 years

II M–

VPERF—AND Age <3 AND AFP >1,000 ng/mL

VPERF—AND Age <3 AND AFP 100-1,000 ng/mL

Age 3-7 AND/OR VPERF +

AFP <100 ng/mL, AND/OR age ≥8 year

III M–

–

VPERF—AND Age<3 AND AFP >1,000 ng/mL

Age 3-7 AND/OR VPERF + AND/OR AFP 100-1,000 ng/mL

AFP <100 ng/mL, AND/OR age ≥8 year

IV M–

–

–

AFP >100 ng/mL

AFP <100 ng/mL, AND/OR age ≥8 years

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Multicenter groups in CHIC are JPLT, SIOPEL, GPOH and COG;Standard low-risk patients;

PRETEXT I, II, and III tumorsno extrahepatic features [hepatic vein/cava involvement (V), portal vein involvement (P), contiguous extrahepatic tumor (E), rupture at diagnosis (R), and multifocality (F)] or distant metastasis (M)JPLT and COG -primary hepatectomy for PRETEXT I and II tumorsSIOPEL -preoperative chemotherapy for every patient followed by tumor resectionor

liver transplantation

and a short course of postoperative chemotherapy for most

cases

CIHC

; initial

resection

for

PRETEXT I or II tumors if the tumor is located at least 1 cm from the middle hepatic vein &bifurcation of the portal veinPreoperative chemotherapy performed for other situationsCisplatin monotherapy recently achieved similar rates of complete resection and survival among children with resectable tumors

Slide59

High-risk (HR) patients Unresectable tumor at diagnosis and/or associated with so-called “combi

factors” without distant metastasisCombi factor is a combination of the cross sectional imaging componentsMacrovascular involvement retrohepatic vena cava or all three hepatic veins (V)Macrovascular involvement portal bifurcation or both right and left portal veins (P)Contiguous extrahepatic tumor (E)M

ultifocal

disease (

F)

S

pontaneous

rupture (R) at

diagnosis

Pediatric

hepatoblastoma: diagnosis and treatmentTransl Pediatr 2014;3(4):293-29

Slide60

High-risk (HR) patients CHIC ;these patients were included as

high-risk patients, even if their tumor was resectable Conventional preoperative chemotherapy used in the PLADO,and C5V trials for patients with PRETEXT IV unresectable tumors resulted in tumors that could be resected by hepatectomy in some patients; but the outcome of patients with unresectable tumors at diagnosis remained unsatisfactory. Pediatric hepatoblastoma: diagnosis and treatmentTransl Pediatr 2014;3(4):293-29

Slide61

Regimen 1-CCG823F (every 3-4 weeks)-(six cycles of chemotherapy)

Doxorubicin (25 mg/m2/day×3 days - > 10 kg 0.83 mg/kg/day - continuous infusion by central line)Cisplatin( 20 mg/m2/day- ×5 days - > 10 kg ,0.66 mg/kg/day - continuous infusion)Regimen 2- (C5V)(every 3-4 weeks)

Cisplatin

(100 mg/m2 IV infused over 6 h

,

>1 yr. 3.3 mg/kg

- day

1)

Vincristine

(1.5 mg/m2 IV (max 2 mg), >1 yr. 0.05 mg/kg - day 3, 10, 17)Fluorouracil (600 mg/m2 IV - day 3)

Slide62

Regimen 3 (every 3-4 weeks)Cisplatin

(90 mg/m2 - >1 yr. - 3 mg/kg - IV infused over 6 h ), day 0Doxorubicin( 20 mg/m2/day - >1 yr. 0.66 mg/kg - continuous infusion × 4 days, days 0-3)Toxicity of this regimen

was more

severe

All

patients will receive

G-CSF

and

bactrim

to reduce toxicity

After four cycles, surgical resection followed by four additional courses of chemotherapy

Slide63

Treatments for HBLCOG and JPLT studies have approved

primary resection for children with resectable tumors, especially PRETEXT I or II Patients with stage I PFH treated with surgery alone. Stage I

hepatoblastoma

(non-pure fetal histology [PFH])

,

non-small cell undifferentiated [SCU])

and

Stage II

(non-SCU)

is a highly curable disease with 2 cycles of adjuvant cisplatin, 5-fluorouracil, and vincristine (C5V) SIOPEL studies have not permitted the used of primary resectionPediatric hepatoblastoma: diagnosis and treatmentTransl Pediatr 2014;3(4):293-29

COG AHEP0731: Phase III Study of Combination Chemotherapy in Pediatric Patients With Newly Diagnosed

Hepatoblastoma

Slide64

Intermediate-risk group : Receive C5VD chemotherapy comprising;

Cisplatin (100 mg/m2 IV infused over 6 h, >1 yr. 3.3 mg/kg- over 6 hours on day 1)Fluorouracil (600 mg/m2 IV - on day 2)Vincristine (1.5 mg/m2 IV (max 2 mg), >1 yr. 0.05 mg/kg - IV on days 2, 9, and 16) Doxorubicin

(

20 mg/m2/day - >1 yr. 0.66 mg/kg

-

IV over 15 minutes on days 1-2)

Repeats

every 21 days for 6 courses in the absence of disease progression or unacceptable

toxicity

Surgical

resection after course 2 OR surgical resection or liver transplantation after course 4 of C5VD COG AHEP0731: Phase III Study of Combination Chemotherapy in Pediatric Patients With Newly Diagnosed

Hepatoblastoma

Slide65

Vincristine/irinotecan upfront window treatment of high-risk hepatoblastoma:

Vincristine (1.5 mg/m2/day -IV on days 1 & 8) Irinotecan (50 mg/m2/day -IV over 90 minutes on days 1-5) Repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicityResponders ;

30

% decrease in tumor burden according to RECIST criteria

90

% (> 1 log

10

) decline in the AFP

level

Reevaluation every

2 cycle/Until second surgerySignificant antitumor activity & acceptable toxicity in relapse hepatoblastomapediatr hematol oncol 2015 feb;32

Slide66

Responders were VI , receive 2 additional cycles of VI intermixed with 6 cycles of

cisplatin/doxorubicin/5-fluorouracil/vincristine (C5VD)- VI in between each 2-course (C5VD)Patients undergo tumor resection or liver transplantation after course 4 of C5VD followed by 2 courses of adjuvant C5VD. Referral for orthotopic liver transplant (OTL) is as potentially unresectable following central surgical review and staging according to the PRE TEXT (Pretreatment Extent of Disease) grouping system

(COG) AHEP0731

Upfront VI treatment of high risk

hepatoblastoma

(COG) AHEP0731- CANCER 2017 JUN15

Slide67

' High risk' HB SIOPEL group;

Intensive multi-agent regimen including CARBO, CDDP and DOXO, preceded by a single dose of CDDP Pre-operative phase alternating administration ;Cisplatin at days 1, 29, 57 & 85 80 mg/m2 over 24 hours as a continuous i.v- ( >5kg-1.7 mg/kg: if well tolerated increase to 2.6 mg/Kg )Administered regardless of the blood cell count

CARBO

/DOXO at

days 15, 43 &71

CARBO

-

500

mg/m2 as an

i.v.

infusion from hours 0-1 (>5kg -11.5 mg/kg: if well tolerated increase 16.6 mg/Kg)DOXO- 60 mg/m2 /48 hours continuous - starting soon after the end of the CARBO (>5kg -1.34 mg/Kg in 48 hours continuous infusion: if well tolerated increase to 2.0 mg/Kg/48 hours)Tumour response evaluate before days 29, 57 and 85, and just before surgery

Childhoodliver

tumor

stratege

group-HR

HB Guidelines 11.01.2010

Slide68

Slide69

German Society for Pediatric Oncology two courses- (IPA) ;

Ifosfamide (3 g/m2/ over 72 h (days 1-3)Cisplatin ( 20 mg/m2/d for 5 days (days 4-9)Doxorubicin ( 60 mg/m2 /over 48 h (days 9-10) two

courses of IPA, followed by a tumor resection and a 4th course of IPA

2003 May-Jun;215(3):159-65.

[Differentiated treatment protocols for high- and standard-risk

hepatoblastoma

--an interim report of the German Liver Tumor Study HB99].

' High risk' HB

Slide70

German group has given carboplatin and etoposide to patients who have failed IPA ;Carboplatin

(800 mg/m2) Etoposide (400 mg/m2) In case of tumor response, they received one or two courses of HD-chemotherapy with carboplatin (2000 mg/m2) and etoposide (2000 mg/m2) after sampling of peripheral stem cells, followed by resection of the primary tumor and metastases, whenever possible.2003 May-Jun;215(3):159-65.

[Differentiated treatment protocols for high- and standard-risk

hepatoblastoma

--an interim report of the German Liver Tumor Study HB99].

Slide71

Topotecan may prove useful in preparative regimens for autologous stem cell transplant in the treatment of hepatoblastoma. Stem

cell transplant following; thiotepa, melphalan and busulfan has been used in the treatment of microscopic residual disease with good results ifosfamide, carboplatin, and etoposide and achieved a very good partial response prior to liver transplant.

Slide72

Orthotropic liver transplantation has improved the outcome for some patients with unresectable tumors (PRETEXT IV tumors or tumors with portal or hepatic vein involvement)

Pediatric hepatoblastoma: diagnosis and treatmentTransl Pediatr 2014;3(4):293-29

Slide73

Very high-risk patients (metastatic HBL)with lung metastases have a poor prognosisOlder patients (≥8 years old at diagnosis)

Patients with low AFP levels (<100 ng/mL) have unfavorable outcomes Pediatric hepatoblastoma: diagnosis and treatmentTransl Pediatr 2014;3(4):293-29

Slide74

Very high-risk patients (metastatic HBL)Resection of lung metastases has been effective for some patients with metastatic tumorsCISPLAIN intensification therapy such as that used in the SIOPEL-4 protocol seems to be effective

new molecular targeting therapy using vincristine and irinotecan will be investigated by COGliver transplantationTransarterial embolization (TAE) is used to control peritoneal hemorrhage in patients with ruptured tumorsPediatric hepatoblastoma: diagnosis and treatmentTransl Pediatr 2014;3(4):293-29

Slide75

Very high-risk patients (metastatic HBL)Malignant liver tumors, including HBL, are mainly fed by the hepatic arteryTrans arterial

chemoembolization (TACE) Cisplatin & Anthracycline are used for embolization Effect of TACE equivalent to systemic chemotherapy less toxic in comparison with systemic chemotherapyAdministering TACE to children is somewhat difficult and requires general

anesthesia

Pediatric

hepatoblastoma

: diagnosis and treatment

Transl

Pediatr

2014;3(4):293-29

Slide76

SIOPEL-1 ; four triweekly preoperative ,two postoperative cycles

Cisplatin Doxorubicin JPLT ; four preoperative & two postoperative cycles Cisplatin Pirarubicin

Pediatric

hepatoblastoma

: diagnosis and treatment

Transl

Pediatr

2014;3(4):293-29

Slide77

Radiotherapyis not curative

useful in shrinking unresectable disease or microscopic residual diseaseRadiation dosages 1200 to 2000 cGyOccasionally, higher doses to localized areas of tumor Radiotherapy immediately after hepatic resection

will limit hepatic

regeneration

Slide78

Criteria for judging tumor response Complete R

esponse ; no evidence of disease and normal serum AFP value (for age) Partial Response :Any tumor volume shrinkage associated with a decreasing serum AFP value, > 1 log below the original measurement Stable Disease ;no tumour volume change and no change, or <l log fall of the serum AFP concentration. Progressive Disease;

unequivocal

increase in 1 or more dimensions and/or any unequivocal increase of the serum AFP concentration

Childhoodliver

tumor

stratege

group-HR

HB Guidelines 11.01.2010

Slide79

toxicity Pure tone audiometry is the method of choice in children older than 3 years of age

If a child starts to show signs of high frequency hearing loss he/she should be followed carefully If grade 3 or 4 ototoxicity is documented, CDDP should be withdrawnBILATERAL HEARING LOSS GRADE Designation

< 40 dB at all frequencies

0

None

> 40 dB at 8,000 Hz only

1

Mild

> 40 dB at 4,000 Hz and above

2

Moderate > 40 dB at 2,000 Hz and above 3 Marked

> 40 dB at 1,000 Hz and above 4

Severe

a

possible increase of ototoxicity in patients treated with CARBO and

CDDP

Slide80

Renal toxicity Glomerular toxicity Nephrotoxicity of CDDP in children (as in adults) is

dose-related and Plasma creatinine measurements and creatinine clearances are not reliable in childrenCareful measurement of GFR by isotope clearance is essential for accurate monitoring of renal statusTubular toxicity Renal loss of Magnesium and consequent Hypomagnesemia Renal tubulopathy

(careful

monitoring of

electrolytes)

Hypomagnesemia

may

persist years

after stopping therapy

Slide81

Bone marrow toxicity; ANC >1000/mm3 platelet count

>100.000/mm3 are necessary before starting chemotherapy with Carboplatin and DoxorubicinIt is better to delay slightly the institution of chemotherapy until these criteria are met, rather than decreasing the doseIf a delay of one or more additional weeks is required, decrease dosage by 25% for the next course only, and use GCSF ANC <

500/mm3

associated with

fever and sepsis

or severe infection and/or severe thrombocytopenia

(< 10.000/mm3 lasting

more than 5 days) associated with bleeding, decrease dosage by 25%

Slide82

Cardiotoxicity; Echocardiogram should be performed when the patient is;n

ormothermicnormal haemoglobinis not being hyperhydratedprior to administration of DOXO

Slide83

Hepatic toxicity;No standardised criteria exist for the adjustment of DOXO dosage in the presence of hepatic dysfunction

50% reduction of DOXO dosage if Total Bili. > 3 mg/100 ml, +/-AST, ALT) are >5 times the normal value. Neither CARBO nor CDDP doses need to be modified.

Slide84

Abdominal tumorImaging-tumor marker(AFP)

TUMOR RUPTURETAE/TACEBIOPSYBIOPSY

Primary resection

Pre –op CX

Pre –op CX

Post

–op CX

Resection/LTX

R

esection

M

etastectomy

Post –op CX

CXs

CXs

Metastectomy

Resection/LTX

CXs

Recurrence /

Progression

Rescue CXs

Diagnosis and treatment algorithm for

hepatoblastoma

M(+):VHR

M(-)

IR or

HR

L

R

Slide85

Hepatoblastoma report

at MPCTRC

Slide86

sex

frequencyPercentFemale1043.5%Male1356.5%

total

23

100%

Slide87

Age & Sex

FemaleMaleAge31<1Y391-3Y

1

2

3-5Y

3

1

5-10Y

10(43.5%)

13(56.5%)

Total

Slide88

Nationality

Frequency21Iranian2Afghan23Total

Frequency

Iranian

10

Tehran

2

Alborz

1

Markazi

2

Gilan

2

Kerman

1

Fars

1

kashan

1

Golestan

1

Bandar Abbas

21

Total

Slide89

Consanguinity

FrequencyConsanguinity13No9Yes1Missing(child adopt)

23

Total

Slide90

Family History Of CancerOne pa. has 3 Family History Of Cancer(Liver-Skin-Uterus)

Five pa. have GI Family History Of Cancer(Pancreas-Intestine-Colon-GI)One pa. has Family History Of (brain Cancer)two pa. has Family History Of Leukemia

Slide91

Signs & symptom

Slide92

Staging

PercentFrequencyStaging17.4%4 Stage10

0

Stage2

46.8%

12

Stage3

34.8%

7

Stage4

100%23Total

1 child in Stage1 after relapse was

in stage 4

Slide93

Metastasis

relapseFrequencyMetastasis316No-7Yes

-

23

Total

Slide94

Total

Uni FocalMulti Focal16412Rt. Lobe11

0

Lt. Lobe

6

0

6

Both Lobes

23

5

18Total

Slide95

After Chemotherapy

Before ChemotherapyMaxMinMaxMin19.81

21.7

5.2

WBC

36.4

6.7

16.4

8.1

Hb

947391. 754.9

MCV

529

26

998

71.2

Plt

8950

5

201

24

SGOT

1469

11

93

10

SGPT

2133

177

798

159

ALK

15.2

.2

1.5

.3

Bill

.5

.5

17

.3

HBsAg

249

1

810

.6

HBsAb

.1

.1

49

.1

HCVAb

Lab Data

Slide96

AFP

Minimum =12Maximum =120000Mean=17464

Frequency

Percent

<100

9

39.0%

100-1000

6

26.3%

>1000

8

34.7%

Slide97

First Chemotherapy

Slide98

Second Chemotherapy

Slide99

status

FrequencyPercentUnder treatment313.1%

Off treatment/Follow

up/alive

9

39.1%

death

11

47.8%

Slide100

Relapse

percentFrequencyRelapse74%17No26%

6

Yes

100%

23

Total

One pa. has two relapse

Slide101

Pathology Type

Type14Epithelial4Mixed Epithelial& Mesenchymal5Unknown type23

Total

Slide102

age

ConsanguinityHistory of cancer in family

AFP

biopsy

Second look surgery

Patology

First chemo

Second chemo.

RELAPSE.

status

Cause death

Stage 1

<1

+

-

100-1000

+

+

Epithelial

Cis/VCR

-

-

Alive

1-3

+

+/GI

100-1000

+

+

Epithelial

Doxo

/Cis

-

-

Alive

1-3

-

+/

GI

<100

+

-

hepatoblastoma

C5V

IPA

+

lung

DC

relapse

3-5

?

-

>1000

_

+

Epithelial

Doxo

/Cis

-

-

Alive

Stage 3

<1

?

+/GI

>1000

-

+

Mixed Epithelial& Mesenchymal

Doxo

/Cis

_

-

Alive

<1

+

/IVF

-

100-1000

+

-

hepatoblastoma

C5V

-

-

Chemo

<1

-

-

<100

+

hepatoblastoma

C5V

-

-

Alive

-

1-3

-

+/

Leukemia

>1000

+

-

hepatoblastoma

Doxo

/Cis

-

-

DC

pneumonia

1-3

+

-

>1000

-

+

Epithelial

Doxo

/Cis

-

-

Alive

1-3

+

-

100-1000

-

+

Epithelial

C5V

IPA

+

Liver/

peritoneum

Chemo

1-3

-

-

>1000

-

+

Epithelial

C5V

-

-

Chemo

1-3

+

-

>1000

+

+

Epithelial

Cis/VCR

C5V

-

-

Alive

1-3

adopt

?

>1000

+

+

Epithelial

Doxo

/Cis

_

-

Alive

5-10

-

-

100-1000

+

-

Mixed Epithelial& Mesenchymal

Doxo

/Cis

-

-

DC

Electrolyte imbalance

Slide103

age

ConsanguinityHistory of cancer in family

AFP

biopsy

Second look surgery

Patology

First chemo

Second chemo.

RELAPSE.

status

metastasis

Cause Death

stage3

5-10

-

-

100-1000

-

+

Epithelial

Cis/VCR

C5V

IPA

+/

liver

DC

-

DIC/ sepsis

5-10

?

+/

leukemia

<100

-

+

Mixed

Epithelial& Mesenchymal

C5V

-

-

Alive

-

-

stage4

1-3

+

+/GI

<100

-

+

Epithelial

C5V

-

-

DC

IVC /mass in

Rt.A

1-3

+

-

>1000

+

-

Epithelial

C5V

DOX/CIS

+

DC

Lung/

adenopathy

Relapse

DIC

1-3

-

-

<100

+

+

Mixed Epithelial& Mesenchymal

C5V

DOX/CIS

CIS/carbo.

+

DC

Heart

Relapse

1-3

-

+/liver

<100

+

-

hepatoblastoma

C5V

-

-

DC

lung

Respiratory

insuf

.

3-5

-

-

<100

+

-

Epithelial

C5V

-

-

DC

Lung/

adenopathy

Respiratory

insuf

.

3-5

-

+/GI

<100

+

+

Epithelial

DOX/CIS

C5V

rinotecan

+

DC

Lung

Brain

Adenopathy

L.Transplant

Relapse

DIC

5-10

+

+/brain

<100

+

-

Epithelial

C5V

-

-

DC

lung

Sepsis/

Electrolyte imbalance

Slide104

3&5

year survival=37.4%±.13Global 5-year survival rates for hepatoblastoma are :

Stage I/II

90

Stage III

60

Stage IV

20

Slide105

1 year EFS=25%±.2

Slide106

A Boy<1year,Pathology: Mixed Epithelial& Mesenchymal, Stage 4,In Left Liver Lobe, Left LobectomyWith bone marrow involveAFP

8 Courses Chemo Out of Mahak,protocol (5FU,VCR,Carbo)Had Autolog Transplantation In Mahak Four Years Ago In 19 Months Old , Living NowTransplantation Protocol; Carboplatin(3 days) Etoposide(3 days) Melfalan(1 day)

Slide107

THANKS FOR YOUR TIME & ATTENTION

Stay safe & have a great day!!!Her soul is happy

Slide108