A Phase 3 multi-institutional study for treatment of children with newly diagnosed hepatoblastoma using a modified Paediatric Hepatic International Tumour Trial (PHITT) strategy incorporating a randomized assessment of sodium thiosulfate as auditory protection for children with localized disease, and response adapted therapy for patients with metastatic disease
Primary aims: 1. Localized Disease: Groups B and C: To evaluate and validate the efficacy of sodium thiosulfate (STS) to reduce the hearing impairment caused by a cisplatin monotherapy in non-metastatic patients without adverse features (localized PRETEXT I-III tumors without positive VPEFR annotation factors) (Group B - treated with cisplatin mono-therapy) or with adverse features (localized PRETEXT I-III tumors with positive VPEFR annotation factors) (Group C - treated with regimen C5VD) 2. Metastatic Disease: Group D: To determine the 3-year Event-free survival (EFS) in patients with metastatic disease treated with International Society of Paediatric Oncology (SIOPEL 4) induction therapy followed by response adapted consolidation therapy. 3. To determine the 3-year EFS in patients with HB whose tumor is completely resected at diagnosis (Group A) and either receive no adjuvant chemotherapy (Group A1, completely resected well differentiated fetal (WDF) histology HB) or 2 cycles of standard dose cisplatin monotherapy (Group A2, completely resected non-well differentiated fetal histology HB) Secondary aims: 1. To determine any impact of STS on chemotherapy response and survival in children with localized hepatoblastoma 2. To assess the feasibility of complete resection after 2 cycles of interval compressed lower dose cisplatin monotherapy (80 mg/m2/cycle) in non-metastatic patients and without adverse features 3. To assess the feasibility of complete resection after 2 cycles of C5VD in non-metastatic patients with adverse features.5. To determine the adherence to PRETEXT and Post-treatment extent of disease (POSTTEXT) based surgical guidelines 4. To determine the prognostic relevance in HB of a "small cell undifferentiated", tumor component, percentage of tumor necrosis in post chemotherapy specimens, and the relevance of a positive microscopic margin in resected HB specimens. 5. To determine the concordance between institutional, regional expert panel (prospective) and international expert panel (retrospective) review assessment of PRETEXT and POSTTEXT stage, and correlate with outcome variables. 6. To prospectively collect patient HB tumor, peripheral blood and urine specimens, for translational biology studies.
Study Type
INTERVENTIONAL
Weight ≥ 10 kg: 20 g/m2/dose STS or Weight 5-10 kg: 15 g/m2/dose STS or Weight \< 5 kg: 10 g/m2/dose STS will be administered by IV over 2 hours beginning 6 hours after the completion of each cisplatin infusion.
Resection of the primary tumor up-front
Cisplatin 100 mg/m2/dose Day 1 . All non-WDF patients (A2) will receive 2 cycles of mono cisplatin (100 mg/m2/dose) chemotherapy. Each cycle lasts 3 weeks (21 days).
Shanghai Children's Medical Center
Shanghai, Shanghai Municipality, China
RECRUITINGAudiogram
The grade (from 0 to 4, higher scores mean a worse outcome) of audiograms evaluated by Boston Grading Scale for Ototoxicity.To evaluate and validate the efficacy of sodium thiosulfate (STS) to reduce the hearing impairment caused by a cisplatin monotherapy in non- metastatic patients without adverse features (localized PRETEXT I-III tumors without positive VPEFR annotation factors) (Group B - treated with cisplatin mono-therapy) or with adverse features (localized PRETEXT I-III tumors with positive VPEFR annotation factors) (Group C - treated with regimen C5VD).
Time frame: From diagnosis through study completion, an average of 1 year
3 -year Event-free survival (EFS)
Calculated from the time of randomisation to the first of the following events: progression, relapse, secondary malignancy or death.
Time frame: UP to 3years
Treatment-related adverse events
Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0
Time frame: UP to 3years
Response to chemotherapy
Complete response (CR): no evidence of disease and normal serum AFP value (for age). Partial response (PR): any tumour volume shrinkage associated with a decreasing serum AFP value, \> 1 log below the original measurement. Stable disease (SD): no tumour volume change and no change, or \< 1 log fall of the serum AFP concentration. Progressive disease (PD): unequivocal increase in 1 or more dimensions and/or any unequivocal increase of the serum AFP concentration (three successive 1-2 weekly determinations) even without clinical (physical and/or radiological) evidence of tumour re-growth.
Time frame: UP to 3years
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Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
330
All the patients in Group C (2 arms) will receive 6 cycles chemotherapy in total. Cisplatin 100 mg/m2/dose Day 1; 5-Fluorouracil 600 mg/m2/dose Day 1; Vincristine 1.5 mg/m2/dose Day 1,8 and 15; Doxorubicin 30 mg/m2/dose Day 1 and 2; (Dexrazoxane : 300 mg/m2/dose Day 1 and 2, where is available)
Tumors are deemed unresectable at diagnosis.
Ideal timing to resect of the primary tumors or transplant if if excellent response achieved at 1st or 2nd evaluation timepoint. But surgery timing is not mandated. Irrespective of the timing of surgery, patients should complete all planned protocol cycles of chemotherapy (including post transplantation). If surgical resection of the primary tumor is delayed until the end of therapy, no further post-operative chemotherapy should be given.
Resection of pulmonary nodules should be considered in Group D2, patients at any cycle if continuing to respond to consolidation therapy.
Cisplatin 80 mg/m2/dose Day 1. All patients in Group B (2 arms) will receive 6 cycles of mono cisplatin chemotherapy. Each cycle lasts 2 weeks (14 days).
Block 1 and 2: Cisplatin 70 mg/m2/dose Day1, 8 and 15; Doxorubicin 30 mg/m2/dose, Day 8 and 9; (Dexrazoxane: 300 mg/m2/dose Day 1 and 2, where is available); Block 3: Cisplatin 70 mg/m2/dose Day1and 8; Doxorubicin 30 mg/m2/dose Day 8 and 9; (Dexrazoxane BSA ≥ 0.6 m2/dose: 300 mg/m2/dose Day 8 and 9, where is available) All patients in Group D will receive 3 blocks in induction, followed by consolidation therapy. Block 1 and 2 last 28 days. Block 3 is 21 cycles.
Following Block 1-3 of induction therapy, Group D1 patients will receive 3 cycles of Carboplatin + Doxorubicin consolidation therapy. Each cycle lasts 3 weeks (21 days). Carboplatin 500 mg/m2/dose Day 1; Doxorubicin 20 mg/m2/dose Day 1 and 2; (Dexrazoxane: 200 mg/m2/dose Day 1 and 2, where is available).
Following Block 1-3 of induction therapy, patients in Group D2, will receive 6 cycles of consolidation chemotherapy with Carboplatin + Doxorubicin in Cycles 1, 3, and 5 alternating with Vincristine + irinotecan in Cycles 2, 4, and 6. One cycle of therapy lasts 3 weeks (21 days). Cycle 1, 3 and 5: Carboplatin 500 mg/m2/dose Day 1; Doxorubicin 20 mg/m2/dose Day 1 and 2; (Dexrazoxane: 200 mg/m2/dose Day 1 and 2, where is available). Cycle 2, 4 and 6: Vincristine 1.5 mg/m2/dose, Day 1 and 8; Irinotecan 50 mg/m2/dose, Day 1 to 5;