Primary liver tumor Hepatoblastoma M. tashvighi Pediatric Hematology oncologist MAHAK Pediatric Cancer Treatment and Research Center 2018

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 liver Hepatic 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.

The geographic variation is thought to reflect the etiologic role of environmental conditions White males / females 1.4/0.5 per million African American males/females 0.9/ 0.0 per million

Different Diagnosis Benign Malignant Hemangioendothelioma Mesenchymal Hamartoma Mesenchymal (mixed) Adenoma Angiomyolipoma Embryonal sarcoma Hamartoma Hepatoblastoma Hepatocellular carcinoma Rhabdomyosarcoma Undifferentiated Angiosarcoma Biliary cyst Sarcoma Teratoma Rhabdoid tumor Myofibroblastic tumor Yolk sac tumor Leiomyosarcoma Langerhans Cell Histocytosis AML-M7

Hepatoblastoma is Approximately two-thirds of liver tumors in children Median age 1 year Male : female ratio 1.7:1.0

Etiology Unknown Congenital anomalies which have been reported with hepatoblastoma & HCC Patients with BeckwithWiedemann syndrome and isolated hemihyperplasia should be screened every 3 months for hepatoblastoma with measurements of α-fetoprotein (AFP) tumor markers and abdominal ultrasounds until age 7 years familial adenomatous polyposis (FAP), hepatoblastoma occurs in less than 1% of members of families with FAP. Screening in these families is controversial, but in children with APC gene (adenomatous polyposis coli) mutations it may be warranted

Disorders Associated with Increased Risk of Hepatoblastoma Low-birth-weight infant Congenital cystathioninuria and hemihyperplasia Maternal use of hormonal therapy Exposure to metals such as in welding and soldering fumes Beckwith -Wiedemann syndrome Hemihypertrophy syndromes Li.Fraumeni syndrome Von Gierke disease FAB Trisomy 18 Fetal alcohol syndrome Gardner syndromea Type I glycogen storage disease(Von Gierke) Prader Willi – syndrome wilm’s tumor (WT1) Meckel’s diverticulum Congenital absence of adrenal gland Congenital absence of kidney Umbilical hernia

Conditions associated with a high risk for HCC development are ; Antitrypsin deficiency Wilson’s disease Hemochromatosis Hereditary tyrosinemia Fanconi’s anemia Familial adenomatous polyposis Gardener’s syndrome

Familial Adenomatous Polyposis FAP Mean age 16 yr. Mutation in APC gene (5q21) Other manifestation; Congenital hypertrophy of retinal epithelium(CHRPE) Supernumerary teeth Skull & jaw osteomas Epidermoid cysts,fibromas, lipomas, skin, hyperpigmentation,keloids

Neoplasia in FAP Colon carcinoma Adrenal carcinoma GENETIC TEST FOR FAB Protein Truncation test(PTT) 80-90% of FAB families 100% accurate if know Direct sequenceing Difficult due to large gene 1/3 new mutation Colon carcinoma Adrenal carcinoma Thyroid papillary carcinoma Periampullary carcinoma Fibrosarcoma Gastric adenocarcinoma Medulloblastoma Hepatoblastoma Astrocytoma ETC

Most common sign of primary liver malignancy; Upper abdominal mass May have abd. Pain ,wt. loss ,anorexia ,N/V 50-70% Unresectable mass at diagnosis Generalized abdominal enlargement Abdominal distention Pallor Jaundice Fever Diarrhea Constipation

Children with a ruptured tumor usually present with; Vomiting Symptoms of peritoneal irritation Severe anemia Rare cases manifest precocious puberty/virilization due to β-human chorionic gonadotropin (hCG) secretion by the tumor Pediatric hepatoblastoma: diagnosis and treatment Transl Pediatr 2014;3(4):293-29

DIAGNOSTIC EVALUATION History Physical examination Diagnostic test: Complete blood count Anemia Moderate leukocytosis is common Thrombocytosis >500,000/mm3 Urinalysis Liver 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 elevated β-hCG level is found in the occasional patient with HCC who has associated precocious puberty. However, β-hCG levels do not necessarily reflect the clinical course of the tumor None of the patients with hepatoblastoma were hepatitis B surface antigen positive, in contrast to 64% of the hepatocellular carcinoma group. liver is a source of thrombopoietin production and increased thrombopoietin has been reported in hepatoblasoma

High AFP Hepatoblastoma Hepatocellular Carcinoma Germ cell tumors Terato Carcinoma Viral Hepatitis & other Active liver disease Cirrhosis Inflammatory Bowel Disease Yolk Sac tumors Pregnancy Gastrointestinal tumors

some variants of both HBL ,HCC that have low or normal AFP levels 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 levels Rhabdoid 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 infants Pediatric hepatoblastoma: diagnosis and treatment Transl Pediatr 2014;3(4):293-29

Radiographic evaluation of intrahepatic disease; • Sonogram • Abdominal CT-scan • Abdominal -MRI • MRI angiogram • MRI cholangiogram Radiographic evaluation of extrahepatic disease; CXR-AP, lat Chest CT-scan Brain CT-scan Bone scan Bone marrow aspirate/biopsy anatomic details are much better presented by CT [ 3] , which is currently the gold standard for the diagnosis, preoperative evaluation, and follow-up of pediatric liver tumors

Abdominal ultrasonography ; large mass in liver, sometimes with satellite lesions & areas of hemorrhage within the tumor Ultrasound,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 bowel Percutaneous biopsy, either ultrasound or CT guidance can be used Pediatric hepatoblastoma: diagnosis and treatment Transl Pediatr 2014;3(4):293-29

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 tumor Stippled 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

Positron emission tomography (PET) scanning: Studies support a potential role for PET scanning at diagnosis & follow-up in hepatoblastoma Several 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

lung metastases by 18 F-FDG– PET/CT was lower than that obtained with CT & for lesions below 1 cm, because of the limited resolution 18 F-FDG– PET/CT was significantly superior to bone scan in patients with bone metastases FDG–PET/CT in the assessment of tumor response and tumor viability after interventional therapy (transcatheter arterial chemoembolization & radiofrequency ablation)

PET/CT ( c , e ) fusion images show the FDG-avid peritoneal lesions

Conventional arteriography Newer 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

hepatoblastoma usually affects one or more contiguous liver segments 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.  

Metastases Hepatoblastoma, Right lobe of the liver is more commonly involved than Left Tumor involves both lobes in 30% of patients Metastases at diagnoses occur in 10%-20% of patients lung being the predominant site 10-20% of patients with hepatic tumors have pulmonary metastases Distant metastases, including brain and bone, are rare Higher incidence of nonpulmonary metastases in congenital hepatoblastoma Childhood Cancers: Hepatoblastoma-The Oncologist 2000;5:445-453

Staging Stage I Stage II Stage III Stage IV Complete resection of tumor by wedge resection lobectomy or by extended lobectomy as initial treatment Stage 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

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 treatment Transl Pediatr 2014;3(4):293-29

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

PRETEXT SIOP(based on presurgical findings) Staging for Hepatoblastoma Stage 1 Tumor involves one quadrant Three adjoining quadrants are free of disease Stage 2 Tumor involves two adjoining quadrants with remaining two free of disease Stage 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

The pathologic classifications for hepatoblastoma and HCC are : Epithelial type (56%) Pure fetal pattern Embryonal pattern -Macrotrabecular type Cholangioblastic Small 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) Hepatocellular carcinoma and the fibrolamellar variant have an unfavorable prognosis. Studies of DNA content have shown that diploid tumors with low proliferation index have a better prognosis than aneuploid tumors and high proliferative index.

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

Small cell undifferentiated (SCU, component intermixed with other histologies ,associated with low serum AFP levels, and poor response to chemotherapy some, but not all, of these tumors may represent INI1 negative neoplasms within the spectrum of primary rhabdoid tumors should 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 these small foci are sometimes INI1expressing Hepatoblastoma State of the Art ;Pathology, Genetics, Risk Stratification, and Chemotherapy Piotr Czauderna, Dolores Lopez Terrada  

The most common mesenchymal elements are osteoid and cartilage The presence of mesenchymal elements associated with improved prognosis in patients with advanced disease osteoid made up a small component of 36% of untreated hepatoblastoma, but was increased in treated hepatoblastoma to 82% and composed up to 90% of the tumor area

Cytogenetic Abnormalities Gain of chromosome 20 ,most common, Gain of chromosome 2 or 8 Associated 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

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

Prognostic factor Good prognostic factor (COG) ; Complete resection(stage I) completely resected tumors pure fetal histology Rate of fall alpha- fetoprotein Large 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 system Vascular invasion Pediatric hepatoblastoma: diagnosis and treatment Transl Pediatr 2014;3(4):293-29

Potential Prognostic Factors in Hepatoblastoma PRE- TREATMENT RESPONSE TO TREATMENT PRETEXT Stage Positive Surgical Margins Metastasis at diagnosis Surgical Resectability Unresectable 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

TREATMENT Overal survival IN stage 3 & 4 is 20-30% Surgery; complete resection can be chance of cure Initial surgical resection-most prognostic factor Delayed surgical resection after chemotherapy Orthotopic liver transplantation Chemotherapy ; plays an important role, not only in eradicating subclinical metastases in completely resected disease, but also may allow unresectable disease to become resectable Transcatheter arterial chemoembolization Tumor-free survival from hepatoblastoma could be improved to 75 % of all patients by combining surgery with chemotherapy. This figure reaches 90 % for potentially resectable (SR, standard risk) tumors

The European approach is different; Timing of surgery In 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 1 Surgery is recommended for limited metastatic disease (especially in lung) This surgery is often done at time of liver tumor resection

Classic reasons for unresectable ; Extremely large tumor that may lead to excessive bleeding Involvement of both the right and left lobes Involvement of major hepatic veins or the inferior vena cava (IVC) Diffuse multifocal disease Only 30% have been considered resectable at diagnosis In the unresectable patient Biopsy should be performed

Surgical Biopsy Diagnostic 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 carcinoma All patients with a normal serum AFP

Biopsy Biopsy 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 dissemination The 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 treatment Transl Pediatr 2014;3(4):293-29

Most common intraoperative complication ; Hemorrhage The risk of bleeding is increased ; Extended hepatectomy Tumor proximity to the IVC or hepatic vessels Air embolus Damage to the portal vein, hepatic artery, or hepatic duct

Postoperative complications; Sub phrenic abscess Bile leak Postoperative bleeding Small bowel obstruction

Hepatic regeneration is complete by 13 months post surgery 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 resection Hepatic regeneration is complete by 13 months post surgery

Transcatheter arterial chemoembolization Hepatic arterial chemoembolization involves giving chemotherapy and vascular occlusive agents via catheter into the artery supplying the tumor Cryoablation, and more recently radiofrequency ablation, have also been used in the treatment of liver tumors in adults with little experience in children

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

RADIOFREQUENCY ABLATION Generation of heat to destroy the tumor Exposure of both normal and cancer cells to heat above 122 F° - 9 up to 14 min. )causes the cells to die, resulting in cellular destruction Sound waves to interact with molecules in the tumor, causing them to vibrate and generate heat Energy is delivered through a needle Guidance provided by ultrasound, CT or MRI

The needle used for radiofrequency ablation is seen in the photograph on the left. On the right the needle is deployed in a tumor with a margin of liver which will also be ablated to assure destruction of the entire tumor

ADVERSE REACTION not 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 bowel Lung surrounds the liver may be lung injury or collapse

Success is influenced ; Tumor size, as larger tumors are more difficult to completely eradicate than smaller ones Tumor location adjacent to flowing blood initial treatment did not destroy all of the tumor, the procedure may be repeated Destroys 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.

CRYOABLATION Ice 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

PERCUTANEOUS ETHANOL INSTILLATION Alcohol destroys cells on contact through destruction of their lining membranes More treatment sessions Slightly less effective often 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

Chemotherapy Combination chemotherapy plays several roles in the management: Adjuvant therapy for patients who have undergone complete resection, its use improves disease-free survival Preoperative therapy for patients who have initially unresectable disease to shrink the primary tumor Palliative therapy for patients with metastatic disease at diagnosis The 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

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; Gross 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: Metastatic 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

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 IV M– AFP >100 ng/mL AFP <100 ng/mL, AND/OR age ≥8 years M+, distant metastases; VEPRF+, one or more of the following criteria; V, hepatic vein/cava involvement; P, portal vein involvement; E, contiguous extrahepatic tumor; R, rupture at diagnosis; F, multifocality; AFP, α-fetoprotein (ng/mL); PRETEXT, pretreatment extent of disease

Multicenter groups in CHIC are JPLT, SIOPEL, GPOH and COG; Standard low-risk patients; PRETEXT I, II, and III tumors no 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 tumors SIOPEL -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 vein Preoperative chemotherapy performed for other situations Cisplatin monotherapy recently achieved similar rates of complete resection and survival among children with resectable tumors Children’s Hepatic Tumors International Collaboration (CHIC) regimen in European (SIOPEL) and Japanese (JPLT GPOH (German Paediatric Oncology and Haematology Society Children’s Oncology Group (COG)

High-risk (HR) patients Unresectable tumor at diagnosis and/or associated with so-called “combi factors” without distant metastasis Combi factor is a combination of the cross sectional imaging components Macrovascular 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) Multifocal disease (F) Spontaneous rupture (R) at diagnosis . V, P, E, F and R where a patient is categorized as positive when at least 1 of the components is present in HR Pediatric hepatoblastoma: diagnosis and treatment Transl Pediatr 2014;3(4):293-29

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 treatment Transl Pediatr 2014;3(4):293-29

Regimen 2- (C5V)(every 3-4 weeks) 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)

Regimen 3 (every 3-4 weeks) Cisplatin (90 mg/m2 - >1 yr. - 3 mg/kg - IV infused over 6 h ), day 0 Doxorubicin( 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 A cure rate of over 90% can be reached by conventional cisplatin and doxorubicin containing chemotherapy and radical surgery in SR-hepatoblastoma. International Society of Paediatric Oncology intensified cisplatin (every 2 weeks) in patients with high-risk disease

Treatments for HBL COG 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 resection COG AHEP0731: Phase III Study of Combination Chemotherapy in Pediatric Patients With Newly Diagnosed Hepatoblastoma Pediatric hepatoblastoma: diagnosis and treatment Transl Pediatr 2014;3(4):293-29

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

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 toxicity Responders ; 30% decrease in tumor burden according to RECIST criteria 90% (> 1 log10 ) decline in the AFP level Reevaluation every 2 cycle/Until second surgery Significant antitumor activity & acceptable toxicity in relapse hepatoblastoma pediatr hematol oncol 2015 feb;32

(COG) AHEP0731 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 Upfront VI treatment of high risk hepatoblastoma (COG) AHEP0731- CANCER 2017 JUN15

' 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 Delayed surgery - Delayed surgery should be performed within three weeks of day 85 of the preoperative chemotherapy. However, if feasible, definitive surgery could be considered also after the second administration of the combination CARBO/DOXO (after day 43). If surgery, is not feasible after the 85th day of the pre-operative phase, but the tumour is responding to chemotherapy, the patient should be treated with, at the most, another 2 doses of CARBO/DOXO alternating with one dose of CDDP. Definitive surgery should be re-considered at the end of these further courses of chemotherapy. All patients should receive at the most 5 courses of CARBO/DOXO and 5 of CDDP alone if the tumour continues to respond to chemotherapy). Childhoodliver tumor stratege group-HR HB Guidelines 11.01.2010

' High risk' HB Cisplatin ( 20 mg/m2/d for 5 days (days 4-9) 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 The outcome of high risk (HR) hepatoblastomas with multifocally 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. 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].

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].

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.

Orthotropic liver transplantation has improved the outcome for some patients with unresectable tumors (PRETEXT IV tumors or tumors with portal or hepatic vein involvement) timing of liver transplantation and the role of rescue transplantation therapy remain controversial, consultation for liver transplantation should be performed for high-risk patients during the early stages of preoperative chemotherapy Pediatric hepatoblastoma: diagnosis and treatment Transl Pediatr 2014;3(4):293-29

Very high-risk patients (metastatic HBL) with lung metastases have a poor prognosis Older patients (≥8 years old at diagnosis) Patients with low AFP levels (<100 ng/mL) have unfavorable outcomes Pediatric hepatoblastoma: diagnosis and treatment Transl Pediatr 2014;3(4):293-29

Very high-risk patients (metastatic HBL) Resection of lung metastases has been effective for some patients with metastatic tumors CISPLAIN 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 COG liver transplantation Transarterial embolization (TAE) is used to control peritoneal hemorrhage in patients with ruptured tumors Pediatric hepatoblastoma: diagnosis and treatment Transl Pediatr 2014;3(4):293-29

Very high-risk patients (metastatic HBL) Malignant liver tumors, including HBL, are mainly fed by the hepatic artery Trans arterial chemoembolization (TACE) Cisplatin & Anthracycline are used for embolization Effect of TACE equivalent to systemic chemotherapy less toxic in comparison with systemic chemotherapy Administering TACE to children is somewhat difficult and requires general anesthesia normal liver receives blood from two sources, the hepatic artery and portal vein. Pediatric hepatoblastoma: diagnosis and treatment Transl Pediatr 2014;3(4):293-29

SIOPEL-1 ; four triweekly preoperative ,two postoperative cycles Cisplatin Doxorubicin JPLT ; four preoperative & two postoperative cycles Pirarubicin resulted in almost similar survival rates Pediatric hepatoblastoma: diagnosis and treatment Transl Pediatr 2014;3(4):293-29

Radiotherapy is not curative useful in shrinking unresectable disease or microscopic residual disease Radiation dosages 1200 to 2000 cGy Occasionally, higher doses to localized areas of tumor Radiotherapy immediately after hepatic resection will limit hepatic regeneration

Criteria for judging tumor response Complete Response ; 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

< 40 dB at all frequencies 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 withdrawn BILATERAL HEARING LOSS GRADE Designation < 40 dB at all frequencies 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

Renal toxicity Glomerular toxicity Tubular toxicity Nephrotoxicity of CDDP in children (as in adults) is dose-related and Plasma creatinine measurements and creatinine clearances are not reliable in children Careful measurement of GFR by isotope clearance is essential for accurate monitoring of renal status Tubular toxicity Renal loss of Magnesium and consequent Hypomagnesemia Renal tubulopathy (careful monitoring of electrolytes) Hypomagnesemia may persist years after stopping therapy

Bone marrow toxicity; ANC >1000/mm3 platelet count >100.000/mm3 are necessary before starting chemotherapy with Carboplatin and Doxorubicin It is better to delay slightly the institution of chemotherapy until these criteria are met, rather than decreasing the dose If 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%

Echocardiogram should be performed when the patient is; Cardiotoxicity; Echocardiogram should be performed when the patient is; normothermic normal haemoglobin is not being hyperhydrated prior to administration of DOXO

50% reduction of DOXO dosage if Total Bili. > 3 mg/100 ml, 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. SIOEPL (Childhood liver tumors strategy group)

Imaging-tumor marker(AFP) Diagnosis and treatment algorithm for hepatoblastoma Abdominal tumor TAE/TACE TUMOR RUPTURE Imaging-tumor marker(AFP) M(+):VHR M(-) IR or HR LR BIOPSY BIOPSY Primary resection Pre –op CX Pre –op CX Post –op CX Resection Metastectomy Resection/LTX transarterial embolization (TAE) or transarterial chemoembolization (TACE) postoperative chemotherapy (Post-op CX). Post –op CX CXs CXs Metastectomy Resection/LTX Recurrence / Progression CXs Rescue CXs

Hepatoblastoma report at MPCTRC

sex frequency Percent Female 10 43.5% Male 13 56.5% total 23 100%

Age & Sex Female Male Age 3 1 <1Y 9 1-3Y 2 3-5Y 5-10Y 10(43.5%) 13(56.5%) Total

Nationality Frequency Iranian 10 Tehran 2 Alborz 1 Markazi Gilan Kerman Fars kashan Golestan Bandar Abbas 21 Total Frequency 21 Iranian 2 Afghan 23 Total

Consanguinity Frequency Consanguinity 13 No 9 Yes 1 Missing(child adopt) 23 Total

Family History Of Cancer One 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

Signs & symptom

Staging Percent Frequency Staging 17.4% 4 Stage1 Stage2 46.8% 12 Stage2 46.8% 12 Stage3 34.8% 7 Stage4 100% 23 Total 1 child in Stage1 after relapse was in stage 4

Metastasis relapse Frequency Metastasis 3 16 No - 7 Yes 23 Total

Total Uni Focal Multi Focal 16 4 12 Rt. Lobe 1 Lt. Lobe 6 Both Lobes 23 5 18

Lab Data After Chemotherapy Before Chemotherapy Max Min 19.8 1 21.7 5.2 WBC 36.4 6.7 16.4 8.1 Hb 94 73 91. 7 54.9 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 17 HBsAg 249 810 .6 HBsAb .1 49 HCVAb

AFP Minimum =12 Maximum =120000 Mean=17464 Frequency Percent <100 9 39.0% 100-1000 6 26.3% >1000 8 34.7% Minimum =12 Maximum =120000 Mean=17464

First Chemotherapy

Second Chemotherapy

Off treatment/Follow up/alive status Frequency Percent Under treatment 3 13.1% Off treatment/Follow up/alive 9 39.1% death 11 47.8%

Relapse percent Frequency Relapse 74% 17 No 26% 6 Yes 100% 23 Total One pa. has two relapse

Pathology Type Type 14 4 5 23 Epithelial Mixed Epithelial& Mesenchymal Unknown type 23 Total

Stage 1 Stage 3 biopsy <1 + - 100-1000 Cis/VCR Alive 3-5 ? >1000 Consanguinity History 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 Doxo/Cis <100 hepatoblastoma C5V IPA lung DC relapse 3-5 ? >1000 _ Stage 3 Mixed Epithelial& Mesenchymal +/IVF Chemo +/Leukemia pneumonia Liver/ peritoneum adopt 5-10 Electrolyte imbalance

biopsy stage4 Heart lung Lung Brain age History of cancer in family Consanguinity History 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 ? +/ leukemia <100 Mixed Epithelial& Mesenchymal Alive stage4 1-3 +/GI IVC /mass in Rt.A >1000 DOX/CIS Lung/ adenopathy Relapse DIC CIS/carbo. Heart hepatoblastoma lung Respiratory insuf. 3-5 rinotecan Lung Brain Adenopathy L.Transplant +/brain Sepsis/ Electrolyte imbalance

Global 5-year survival rates for hepatoblastoma are : Stage I/II 90 60 Stage IV 20

1 year EFS=25%±.2

A Boy<1year,Pathology: Mixed Epithelial& Mesenchymal, Stage 4,In Left Liver Lobe, Left Lobectomy With bone marrow involve AFP 8 Courses Chemo Out of Mahak,protocol (5FU,VCR,Carbo) Had Autolog Transplantation In Mahak Four Years Ago In 19 Months Old , Living Now Transplantation Protocol; Carboplatin(3 days) Etoposide(3 days) Melfalan(1 day)

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