Neoplasms

All Conditions

Digestive System Diseases

Symptoms and General Pathology

Rare Diseases

Carcinoma

Carcinoma, Hepatocellular

Recurrence

Liver Neoplasms

Hepatoblastoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Neoplasms by Histologic Type

Childhood Hepatocellular Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Anti-Infective Agents

Carboplatin

Doxorubicin

Liposomal doxorubicin

Cisplatin

Liver Extracts

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

carboplatin

cisplatin

doxorubicin hydrochloride

conventional surgery

Giorgio Perilongo, MD

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known which chemotherapy regimen is more effective in treating children with liver cancer.

PURPOSE: Randomized phase III trial to study the effectiveness of cisplatin with or without doxorubicin and the effectiveness of combining cisplatin, carboplatin, and doxorubicin in treating children who have liver cancer.

OBJECTIVES:

* Compare the efficacy of cisplatin with or without doxorubicin in terms of tumor response, complete resection rate, overall survival, and event free survival in children with standard risk hepatoblastoma.
* Compare the toxicity of cisplatin with or without doxorubicin in this patient population.
* Evaluate whether an intensive multiagent regimen including carboplatin, cisplatin, and doxorubicin improves the response rate to chemotherapy and subsequent resection rate of children with high risk hepatoblastoma or hepatocellular carcinoma.

OUTLINE: This is a randomized, multicenter study. All hepatoblastoma patients are intended to be treated with primary chemotherapy. Hepatoblastoma patients are stratified by risk (standard vs high).

Patients receive cisplatin IV over 24 hours on day 1, beginning within 15 days of diagnosis. Standard risk patients are then randomized to one of two treatment arms. High risk hepatoblastoma patients and hepatocellular carcinoma patients receive a separate multiagent regimen.

* Arm I: Patients receive cisplatin IV over 24 hours and doxorubicin IV over 48 hours beginning on day 15. Treatment repeats every 21 days for a maximum of 5 courses. Tumor response is evaluated prior to the second course. Patients with responsive disease receive the remaining 2 courses of the preoperative phase, then undergo delayed primary surgery if their tumors are deemed resectable, prior to receiving 2 additional courses of chemotherapy. Patients whose tumors are still unresectable after 3 courses receive 2 more courses of chemotherapy, then undergo surgery if feasible. Patients with stable disease are considered for radical surgery or salvage chemotherapy. Patients with unresectable tumors after 5 courses may be considered for liver transplant or salvage chemotherapy.
* Arm II: Patients receive cisplatin IV over 24 hours every 15 days for a maximum of 5 additional courses. Tumor response is evaluated after the second course. Patients with responsive disease receive another 2 courses of cisplatin. Patients with resectable tumors after 4 courses undergo delayed primary surgery, then receive 2 more courses of cisplatin. Patients whose tumors are still unresectable after 4 courses receive 2 more courses of cisplatin, then undergo surgery if their tumors are resectable. Patients with stable disease may be moved to the high risk regimen or considered for radical surgery. Patients with unresectable tumors after 6 courses may be considered for liver transplant or salvage chemotherapy.

Patients with high risk hepatoblastoma or unresectable hepatocellular carcinoma receive cisplatin IV over 24 hours on days 29, 57, and 85, and carboplatin IV over 1 hour followed by doxorubicin IV over 48 hours on days 15, 43, and 71. Patients with responsive resectable disease undergo surgery either after day 43 or within 3 weeks of day 85 of preoperative chemotherapy, then receive another 2 courses of carboplatin and doxorubicin on days 1 and 29 post surgery, and one more course of cisplatin on day 15 post surgery, for a total of 5 courses each. Patients with responsive but unresectable disease after day 85 also receive 2 more courses of carboplatin and doxorubicin alternating with 1 course of cisplatin. Definitive surgery will be re-considered after these further courses of chemotherapy. Patients with stable disease at day 43 or a tumor that remains unresectable after completion of chemotherapy may be considered for liver transplant.

Patients with a resectable hepatocellular carcinoma have primary surgery followed by alternating courses of cisplatin, and carboplatin and doxorubicin for a total of 4 courses of cisplatin and 3 courses of carboplatin and doxorubicin.

Patients are followed every 2-3 months for 2 years, every 6 months for 1 year, then annually thereafter.

PROJECTED ACCRUAL: A total of 170-260 patients (85-130 patients per treatment arm) will be accrued for this study over 5.5 years.

Chemotherapy in Treating Children With Liver Cancer

Liver Tumour Studies - Hepatoblastoma and Hepatocellular Carcinoma

Societe Internationale d'Oncologie Pediatrique

Neoplasms, Glandular and Epithelial

Fibrolamellar Carcinoma

Dermatologic Agents

Etoposide

Gemcitabine

Irinotecan

Fluorouracil

Vincristine

Daunorubicin

Oxaliplatin

Etoposide phosphate

Podophyllotoxin

Sorafenib

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Topoisomerase I Inhibitors

Tubulin Modulators

Antimitotic Agents

Protein Kinase Inhibitors

Keratolytic Agents

Patients receive cisplatin IV over 6 hours on day 1 following surgery. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for 4 cycles (2 pre-surgery, 2 post-surgery) in the absence of disease progression or unacceptable toxicity.

Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for 6 cycles (2 pre-surgery, 4 post-surgery) in the absence of disease progression or unacceptable toxicity.

Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles (4 pre-surgery, 2 post-surgery). After cycle 4, patients undergo surgery, then continue with 2 additional cycles of cisplatin.

Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles.

Patients receive cisplatin IV over 6 hours on day 1, 5-fluorouracil IV over 1-15 minutes, vincristine sulfate IV over 1 minute on days 1, 8, and 15 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4.

Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4.

SIOPEL-4 INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9 during cycles 1 and 2 and days 1 and 2 during cycle 3. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients with lung complete remission (either with chemotherapy and/or surgery) receive carboplatin IV over 1 hour on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

SIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

Patients receive carboplatin IV over 1 hour on days 1 and 2, doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5, and carboplatin over 1 hour and etoposide IV over 2 hours on day 1 and 2 of cycles 2, 4 and 6. Treatments repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

SIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

Patients receive carboplatin IV over 1 hour on days 1 and 2 and doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan IV over 90 minutes QD on days 1 to 5 of cycles 2, 4 and 6. Treatments repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Patients receive cisplatin IV over 6 hours on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2 following surgery. Treatments repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib PO BID on days 3-21. Treatments repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may undergo surgery, if tumors are resectable, or receive an additional 3 cycles of the treatment.

Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib PO BID on days 3-14 of cycles 1 and 3. Patients also receive gemcitabine IV over 90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 and sorafenib PO on days 1-14 of cycles 2 and 4. Patients may undergo surgery, if tumors are resectable, or receive an additional 4 cycles of the treatment.

Laboratory Biomarker Analysis

Patient Observation

Resection

Vincristine Sulfate

Gregory M Tiao

This partially randomized phase II/III trial studies how well, in combination with surgery, cisplatin and combination chemotherapy works in treating children and young adults with hepatoblastoma or hepatocellular carcinoma. Drugs used in chemotherapy, such as cisplatin, doxorubicin, fluorouracil, vincristine sulfate, carboplatin, etoposide, irinotecan, sorafenib, gemcitabine and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving combination chemotherapy may kill more tumor cells than one type of chemotherapy alone.

PRIMARY OBJECTIVES:

I. To reduce therapy associated toxicity for patients with non-metastatic hepatoblastoma (HB) and hepatocellular carcinoma (HCC) without adversely affecting long term outcomes.

II. To determine the event-free survival (EFS) in patients with HB whose tumor is completely resected at diagnosis and either receive no adjuvant chemotherapy (completely resected well differentiated fetal \[WDF\] histology HB) or 2 cycles of standard dose cisplatin monotherapy (completely resected non-well differentiated fetal histology HB - 100 mg/m\^2/cycle given 3 weeks apart). (Group A) III. To demonstrate that 4 to 6 cycles of interval compressed lower dose cisplatin monotherapy (80 mg/m\^2/cycle; 320-480 mg/m\^2 total) is adequate for low risk HB. (Group B) IIIa. In patients who are resected after 2 cycles of cisplatin monotherapy, to compare EFS following a randomized comparison of 2 versus 4 post-operative cycles of cisplatin monotherapy. (Group B) IIIb. In patients whose tumors are deemed unresectable after 2 cycles of cisplatin monotherapy, to determine the proportion of tumors rendered completely resectable by an additional 2 or 4 cycles of chemotherapy. (Group B) IV. To compare in a randomized fashion, EFS in patients with intermediate risk HB treated with 6 cycles of cisplatin/5-fluorouracil/vincristine/doxorubicin (C5VD) chemotherapy versus 6 cycles of interval compressed cisplatin monotherapy (100 mg/m\^2/dose). (Group C) V. To determine the EFS in patients with HCC whose tumor is completely resected at diagnosis who receive no adjuvant chemotherapy (completely resected HCC arising in the context of underlying liver disease) or 4 cycles of cisplatin/doxorubicin (PLADO) (completely resected de novo HCC). (Group E) VI. To improve the EFS of patients with high risk HB by treating them with interval compressed cisplatin and doxorubicin based induction regimen followed by response-adapted consolidation therapy. (Group D) VIa. In patients whose metastatic disease resolves with the administration of Societe Internationale d'Oncologie Pediatrique (SIOPEL) 4 Induction therapy, to determine if the promising pilot results observed in SIOPEL 4 can be validated in a large international study. (Group D1) VIb. In patients whose metastatic disease does not resolve with the administration of SIOPEL 4 Induction therapy, to determine in a randomized comparison which post induction treatment (irinotecan and vincristine sulfate \[vincristine\] alternating with carboplatin and doxorubicin or carboplatin and etoposide alternating with carboplatin and doxorubicin) results in superior outcomes. (Group D Arm CE \& Arm VI) VII. In patients with unresectable/metastatic HCC at diagnosis, to determine whether the addition of gemcitabine and oxaliplatin (GEMOX + sorafenib) to a cisplatin, doxorubicin and sorafenib backbone improves chemotherapy response, resectability and survival. (Group F)

EXPLORATORY OBJECTIVES:

I. To determine if the Childhood Hepatic tumor International Consortium (CHIC) hepatoblastoma risk stratification analysis of very low risk (Group A), low risk (Group B), intermediate risk (Group C) and high risk (Group D) groups stratifies patients allowing appropriate utilization of varying intensity chemotherapy regimens and surgical resection strategies.

II. To define the prognostic relevance of a positive microscopic margin in Group A-D resected HB specimens.

III. To define the frequency of histologically detectable multifocal lesions in liver explants and resected specimens in which multifocal disease was detected at diagnosis and disappeared on cross sectional imaging following treatment with chemotherapy.

IV. To define the prognostic relevance in HB of a 'small cell undifferentiated' tumor component and percentage of tumor necrosis in post chemotherapy specimens.

V. To determine the prognostic impact on EFS and overall survival (OS) of biopsy technique in liver tumors unresectable at diagnosis.

VI. To determine the 3-year EFS and OS of HB patients who undergo liver transplantation vs extreme resection in Group C and D patients.

VII. To determine the 3-year EFS and OS of Group D patients who undergo pulmonary metastasectomy.

VIII. To determine the 3-year EFS and OS of patients who undergo liver transplantation for HCC.

IX. To determine the frequency of relapse in non-metastatic HCC in children treated by liver transplantation versus conventional resection.

X. To determine the concordance of Pretreatment Extent of Disease (PRETEXT) and Post-treatment Extent of disease (POSTTEXT) based surgical guidelines and the surgical intervention performed.

XI. To collect for future analysis, HB and HCC tumor specimens that can be molecularly characterized to validate newly identified molecular and immunohistochemical biomarkers correlating with known clinical prognostic factors and outcome.

XII. To evaluate the hepatoblastoma molecular risk-predictive model (HB-MRP) to risk stratify hepatoblastoma patients in the context of the current AHEP1531 trial.

XIII. To collect for future analysis samples to assess the pharmacogenomics (PG) related to cisplatin therapy in pediatric and adolescent liver tumor patients and correlate PG with Boston Grading Scale for ototoxicity.

XIV. To collect for future analysis samples such that novel biomarkers of renal toxicity (urine neutrophil gelatinase-associated lipocalin \[NGAL\], cystatin C and Kim1) from cisplatin therapy can be correlated with pharmacogenomics, other associated toxicities, and outcomes.

XV. To determine which system (Children's Oncology Group \[COG\] PRETEXT, SIOPEL PRETEXT, or a new hybrid definition of PRETEXT) of the annotation factors for V, P, E, F and R provides the best prognostic information for determining response to chemotherapy, guiding risk based therapy, predicting surgical resectability, and EFS.

XVI. To determine the concordance between institutional and expert panel review assessment of PRETEXT and POSTTEXT stage in an international cooperative group setting.

OUTLINE:

GROUP A (VERY LOW RISK HB): Patients are assigned to 1 of 2 groups.

GROUP A1 (WDF): Patients undergo observation.

GROUP A2 (NON-WDF): Patients receive cisplatin (CDDP) intravenously (IV) over 6 hours on day 1 following surgery. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

GROUP B (LOW RISK HB): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients are then assigned to 1 of 2 groups.

GROUP B1 (RESECTABLE): Patients receive 2 cycles of cisplatin, undergo surgery, then are randomized to 1 of 2 arms (2 vs 4 additional cycles of cisplatin).

GROUP B1 ARM 4-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 4 total cycles (2 pre-surgery, 2 post-surgery) in the absence of disease progression or unacceptable toxicity.

GROUP B1 ARM 6-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles (2 pre-surgery, 4 post-surgery) in the absence of disease progression or unacceptable toxicity.

GROUP B2 (UNRESECTABLE): Patients receive 2 cycles of cisplatin, then are assigned to 1 of 2 arms (resectable vs unresectable).

GROUP B2 ARM I (RESECTABLE): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles (4 pre-surgery, 2 post-surgery). After cycle 4, patients undergo surgery, then continue with 2 additional cycles of cisplatin.

GROUP B2 ARM II (UNRESECTABLE): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles.

GROUP C (INTERMEDIATE RISK HB): Patients are randomized to 1 of 2 arms.

GROUP C ARM CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4.

GROUP C ARM C5VD: Patients receive cisplatin IV over 6 hours on day 1, 5-fluorouracil IV over 1-15 minutes, vincristine sulfate IV over 1 minute on days 1, 8, and 15 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4.

GROUP D (HIGH RISK HB): SIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9 (for cycles 1 and 2) and days 1 and 2 (for cycle 3). Cycles 1 and 2 are 28 days; cycle 3 is 21 days. Patients are then assigned to 1 of 2 arms.

GROUP D1: CONSOLIDATION THERAPY: Patients with lung complete remission (either with chemotherapy and/or surgery) receive carboplatin IV over 1 hour on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

GROUP D2: Patients with residual metastatic disease are randomized to 1 of 2 arms.

GROUP D2 ARM CE: Patients receive carboplatin IV over 1 hour on days 1 and 2, doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5, and carboplatin IV over 1 hour and etoposide IV over 2 hours on day 1 and 2 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

GROUP D2 ARM VI: Patients receive carboplatin IV over 1 hour on days 1 and 2 and doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan IV over 60-90 minutes once daily (QD) on days 1 to 5 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

GROUP E (RESECTED HCC): Patients are assigned to 1 of 2 groups.

GROUP E1: Patients with HCC secondary to underlying hepatic disease undergo observation only.

GROUP E2 (PLADO): Patients with de novo HCC receive cisplatin IV over 6 hours on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2 following surgery. Treatments repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

GROUP F (UNRESECTED AND/OR METASTATIC HCC): Patients are randomized to 1 of 2 arms.

GROUP F ARM 1 (PLADO): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib orally (PO) twice daily (BID) on days 3-21. Treatments repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may undergo surgery, if tumors are resectable, or receive an additional 3 cycles of the treatment.

GROUP F ARM 2 (P/GEMOX): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib PO BID on days 3-14 of cycles 1 and 3. Patients also receive gemcitabine IV over 90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 and sorafenib PO on days 1-14 of cycles 2 and 4. Patients may undergo surgery, if tumors are resectable, or receive an additional 4 cycles of the treatment.

After completion of study treatment, patients are followed up for a minimum of 2 years.

Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery

Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT)

Failure free survival is defined as the time from randomization (or registration into the trial for non-randomized patients) to first failure event. Failure events are: progression of existing disease or occurrence of disease at new sites, death from any cause prior to disease progression, diagnosis of a second malignant neoplasm, or failure to go to resection.

Overall survival is defined as the time from randomization (or registration for non-randomized patients) to death from any cause.

The percentage of patients experiencing grade 3 or higher toxicity will be reported, where adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Hearing loss will be measured according to the SIOP Boston Scale for ototoxicity.

Response in hepatocellular carcinoma (HCC) will be defined as complete (CR) or partial (PR) response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Response in HB will be defined as CR or PR based on radiological response (RECIST v1.1) and AFP decline.

Surgical resectability is defined as complete resection, partial resection or transplant following randomization (or enrollment for non-randomized patients).

Adherence to surgical guidelines is defined as the local clinician's surgical decision to resect or not compared to the current SIOPEL surgical guidelines.

EFS is defined as the time from randomization (or registration into the trial for non-randomized patients) to the first failure event where the failure events are defined as: progression of existing disease or occurrence of disease at new sites, death from any cause prior to disease progression, or diagnosis of a second malignant neoplasm. Patients who have not had an event will be censored at their last follow-up date. EFS for group A, group B1, group C, group D1, group D2 and E will be presented.

Group B patients who are unresectable after cycles 1 \& 2 of cisplatin treatment will be assigned to Group B2. These patients will receive cycles 3-6 of cisplatin treatment.

Response is defined as complete (CR) or partial (PR) response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Patients who are not assessable for response - e.g. because of early stopping of treatment or death - will be classified as non-responders.

National Cancer Institute (NCI)

Children's Oncology Group

Primary Liver Cancer

Antirheumatic Agents

Thalidomide

Cyclophosphamide

Antineoplastic Agents, Alkylating

Alkylating Agents

Angiogenesis Inhibitors

Growth Inhibitors

cyclophosphamide

thalidomide

adjuvant therapy

neoadjuvant therapy

Bruce Morland, MD

RATIONALE: Drugs used in chemotherapy, such as cisplatin and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Thalidomide may stop the growth of liver cancer by blocking blood flow to the tumor. Chemoembolization kills tumor cells by blocking the blood flow to the tumor and keeping chemotherapy drugs near the tumor. Giving combination chemotherapy, thalidomide, and chemoembolization before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving thalidomide together with chemotherapy after surgery may kill any remaining tumor cells and prevent the tumor from coming back.

PURPOSE: This phase II trial is studying how well giving combination chemotherapy and thalidomide together with chemoembolization works in treating younger patients undergoing surgery for newly diagnosed liver cancer.

OBJECTIVES:

Primary

* Determine the event-free and overall survival of younger patients undergoing surgery for newly diagnosed, noncirrhotic hepatocellular carcinoma (HCC) treated with neoadjuvant cisplatin, doxorubicin hydrochloride, and thalidomide (PLADOTH) followed by transarterial hepatic arterial chemoembolization comprising cisplatin and doxorubicin hydrochloride and adjuvant cyclophosphamide and thalidomide.
* Determine the efficacy and tolerability of PLADOTH in patients with initially unresectable noncirrhotic HCC treated with this regimen.
* Determine the rate of complete surgical resection by encouragement of liver transplantation in the treatment strategy as a valid option for tumor removal when partial liver resection or other surgical options remain unfeasible for patients treated with this regimen.
* Determine the long-term remission and decreased relapse rates of patients treated with this regimen based on the postoperative regimen.

Secondary

* Determine the response rate of patients treated with this regimen after treatment with PLADOTH.
* Determine the short-term toxicity and feasibility of PLADOTH in patients treated with this regimen.
* Determine the efficacy and toxicity of the postoperative regimen in terms of maintenance and duration of complete remission (no more evidence of disease and normal alpha-fetoprotein, if initially elevated) in patients treated with this regimen.
* Determine whether response to PLADOTH by the RECIST criteria can be used for better monitoring of response of patients treated with this regimen.
* Determine whether the rate of fall of serum VEGF and bFGF levels during PLADOTH can be used as prognostic factors for short-term and long-term outcome in patients treated with this regimen.
* Determine the feasibility of chemoembolization in patients treated with this regimen who do not respond to PLADOTH.
* Determine which subset of tumors may benefit from an angiostatic treatment approach based on radiological, surgical, and pathological data collected from patients treated with this regimen.
* Identify possible novel factors that might influence treatment choice and disease outcome based on radiological, surgical, and pathological data collected from patients treated with this regimen.
* Determine guidelines for diagnostic, therapeutic, and follow-up management that would improve clinical care for patients treated with this regimen.

OUTLINE: This is a multicenter, nonrandomized, open-label study.

All patients undergo either tumor biopsy or resection. Patients with localized resectable tumors undergo resection. They then proceed directly to the postoperative treatment. Patients with initially unresectable tumors undergo biopsy then proceed to the pre-operative regimen.

* Pre-operative chemotherapy and thalidomide (PLADOTH): Patients receive PLADOTH comprising cisplatin IV continuously over 24 hours on day 1, doxorubicin hydrochloride IV over 1 hour on days 1 and 2 (or IV continuously over 24 hours on days 1 and 3), and oral thalidomide daily on days 1-21. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients whose tumors are deemed resectable proceed to surgery. Patients with responding disease but whose tumors remain unresectable proceed to chemoembolization or receive 2 additional courses of PLADOTH.
* Transarterial hepatic artery chemoembolization (TACE): Patients undergo TACE comprising cisplatin and doxorubicin hydrochloride administered through a catheter placed near the tumor. TACE may be repeated every 3-4 weeks for as long as disease continues to respond or until the tumor becomes resectable. Patients also receive oral thalidomide once daily during TACE. Once the tumor is deemed resectable, patients proceed to surgery.
* Surgery: Patients undergo surgical resection of the tumor. Patients undergo either partial or total hepatectomy followed by a liver transplant and lung surgery, if necessary. Patients then proceed to the postoperative treatment.
* Postoperative treatment: Beginning within 6 weeks after surgery, patients receive oral cyclophosphamide once every other day and oral thalidomide once daily for up to 1 year in the absence of disease progression or unacceptable toxicity.

Patients with metastatic disease who show disease progression at any time during treatment go off study and receive individual advice regarding further treatment based on the decision of the principal investigator.

After completion of study treatment, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 47 patients will be accrued for this study.

Combination Chemotherapy and Thalidomide in Treating Younger Patients Undergoing Surgery For Newly Diagnosed Liver Cancer

Hepatocellular Carcinoma Family of Tumours In Children / Adolescents and Young Adults

Children's Cancer and Leukaemia Group

Interferons

Interferon-alpha

Interferon alpha-2

Antiviral Agents

recombinant interferon alfa-2b

fluorouracil

oxaliplatin

diagnostic laboratory biomarker analysis

immunoenzyme technique

immunohistochemistry staining method

biopsy

therapeutic conventional surgery

Donald Poon, MD

Kian Fong Foo, MD

RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, doxorubicin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Interferon alfa may interfere with the growth of tumor cells. Giving combination chemotherapy together with interferon alfa may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with interferon alfa-2b works in treating patients with nonmetastatic liver cancer that cannot be removed by surgery.

OBJECTIVES:

Primary

* Determine the response rate in patients with unresectable, nonmetastatic hepatocellular carcinoma treated with neoadjuvant oxaliplatin, doxorubicin hydrochloride, fluorouracil, and recombinant interferon alfa-2b.

Secondary

* Determine the overall survival of patients treated with this regimen.
* Determine the progression-free survival of patients treated with this regimen.
* Determine the rate of conversion to resectability of tumor in patients treated with this regimen.
* Determine the toxicity profile of this regimen in these patients.
* Assess the quality of life of patients treated with this regimen.
* Correlate changes in serological markers of angiogenesis before and after treatment with clinical outcome in these patients.
* Correlate and validate the use of functional imaging before and after treatment with clinical outcome in these patients.

OUTLINE: Patients receive neoadjuvant OXAFI therapy comprising oxaliplatin IV and doxorubicin hydrochloride IV on days 1, 8 and 15; fluorouracil IV continuously on days 1-28; and recombinant interferon alfa-2b subcutaneously three times weekly in weeks 1-4. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients receive at least 2 courses of neoadjuvant therapy before undergoing evaluation for response. Patients whose disease becomes resectable after achieving a complete or partial response proceed to surgery. Patients whose disease remains unresectable are reevaluated until their disease either becomes resectable, they complete neoadjuvant therapy, or they meet discontinuation criteria.

At least 2 weeks after receiving neoadjuvant therapy, patients whose disease is resectable undergo surgery for potentially complete resection of their tumors with curative intent. Patients who achieve complete resection proceed to adjuvant therapy.

At least 4 weeks after surgery, patients may restart OXAFI as adjuvant therapy, provided they have fully recovered from surgery and have received fewer than 6 courses of neoadjuvant therapy. Adjuvant therapy repeats every 28 days for a total of 6 courses (including neoadjuvant OXAFI) in the absence of disease progression or unacceptable toxicity.

Patients undergo blood and tissue collection at baseline and periodically during study for evaluation of circulating and tissue biomarkers of angiogenesis. Serum from venous blood samples is analyzed for concentration of VEGF by ELISA. Tumor tissue obtained before and after treatment is examined for tumor VEGF expression, microvessel density, and cellular proliferation by IHC.

Patients complete quality of life questionnaires at baseline, monthly during study treatment, after course 6 of neoadjuvant chemotherapy, or upon discontinuation of study treatment.

Patients are followed periodically for up to 5 years after curative resection of their tumors.

PROJECTED ACCRUAL: A total of 54 patients will be accrued for this study.

Combination Chemotherapy and Interferon Alfa-2b in Treating Patients With Nonmetastatic Liver Cancer That Cannot Be Removed by Surgery

A Phase II Trial of Oxaliplatin/Adriamycin/5 Fluorouracil in Continuous Infusion / Interferon α-2b (OXAFI) Combination as Neoadjuvant Therapy in Unresectable Non-Metastatic Hepatocellular Carcinoma

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemotherapy in Treating Children With Liver Cancer	NCT00003912	Liver Cancer	carboplatin cisplatin doxorubicin hyd... conventional su...	- 16 Years	National Cancer Institute (NCI)
Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery	NCT03533582	Childhood Hepat... Childhood Malig... Fibrolamellar C... Hepatoblastoma Hepatocellular ...	Carboplatin Cisplatin Doxorubicin Etoposide Fluorouracil Gemcitabine Irinotecan Laboratory Biom... Oxaliplatin Patient Observa... Resection Sorafenib Vincristine Sul...	- 30 Years	Children's Oncology Group
Combination Chemotherapy and Thalidomide in Treating Younger Patients Undergoing Surgery For Newly Diagnosed Liver Cancer	NCT00276705	Liver Cancer	cisplatin cyclophosphamid... doxorubicin hyd... thalidomide adjuvant therap... conventional su... neoadjuvant the...	- 29 Years	National Cancer Institute (NCI)
Combination Chemotherapy and Interferon Alfa-2b in Treating Patients With Nonmetastatic Liver Cancer That Cannot Be Removed by Surgery	NCT00471484	Liver Cancer	recombinant int... doxorubicin hyd... fluorouracil oxaliplatin diagnostic labo... immunoenzyme te... immunohistochem... adjuvant therap... biopsy neoadjuvant the... therapeutic con...	16 Years - 75 Years	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for childhood hepatocellular carcinoma