Combination Chemotherapy With or Without Amifostine in Treating Young Patients With Liver Cancer

Intergroup Protocol for Treatment of Children With Hepatoblastoma

Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. Chemoprotective drugs such as amifostine may protect normal cells from the side effects of chemotherapy. It is not yet known which chemotherapy regimen is most effective for children and young adults with liver cancer. This randomized phase III trial is studying giving combination chemotherapy together with amifostine to see how well it works compared to combination chemotherapy alone in treating patients with liver cancer.

Study Overview

• Status: Completed
• Conditions: Recurrent Childhood Liver Cancer; Childhood Hepatoblastoma; Stage I Childhood Liver Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: vincristine sulfate; Drug: cisplatin; Drug: carboplatin; Procedure: therapeutic conventional surgery; Drug: amifostine trihydrate

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the response and efficacy of amifostine (amifostine trihydrate) in reducing the toxicity associated with platinum agents.

II. To test whether there is any effect of amifostine on event-free survival by comparing outcome of those treated with amifostine to those treated without on this study and with historic controls.

SECONDARY OBJECTIVES:

I. To estimate the event-free survival of patients with stage I pure fetal histology treated with surgery alone.

II. To estimate the efficacy of amifostine in reducing the toxicity associated with cisplatinum in children with resected tumors receiving treatment 01 by randomizing to receive or not receive amifostine.

III. To collect tumor tissue in all patients for cytogenetic and genetic analysis in order to prospectively analyze biologic features and prognosis of patients with detailed treatment history, and to provide a resource for future biologic studies in hepatoblastoma.

IV. To assess the prognostic significance with respect to event-free survival of hepatoblastoma pathologic variants in patients with stage I tumors treated with surgery and chemotherapy (cisplatin + 5FU + vincristine).

OUTLINE: This is a randomized study. Patients are stratified according to disease stage (stage I pure fetal histology vs stage I other histology or stage II [stage II closed to accrual as of 11-25-03] vs stage III or IV [stages III and IV closed to accrual as of 11-25-03]). Patients are randomized to one of four treatment arms. (Arms III and IV closed to accrual as of 4-5-02) (Arm II closed to accrual as of 11-25-03)

All patients undergo surgical resection or attempted resection of tumor. Patients with pure fetal histology achieving complete tumor resection receive no further treatment. All other patients receive postoperative chemotherapy.

Arm I: Patients receive cisplatin IV over 4 hours on day 1, vincristine IV on days 3, 10, and 17, and fluorouracil on day 3.

Arm II (closed to accrual as of 11-25-03): Patients receive treatment as in arm I with the addition of amifostine IV over 15 minutes prior to cisplatin on day 1.

Arm III (closed to accrual as of 4-5-02): Patients receive carboplatin IV over 1 hour on day 1 and cisplatin IV over 4 hours on day 15.

Arm IV (closed to accrual as of 4-5-02): Patients receive treatment as in arm III with the addition of amifostine IV over 15 minutes prior to carboplatin on day 1.

Treatment repeats every 3 weeks for 4 courses in arms I and II (arm II closed to accrual as of 11-25-03) and every 4 weeks for 4 courses in arms III and IV (arms III and IV closed to accrual as of 4-5-02) in the absence of disease progression or unacceptable toxicity. Patients with stage III or IV disease (stages III and IV closed to accrual as of 11-25-03) undergo second look surgery and receive 2 additional courses of chemotherapy if achieving complete response after surgery.

Patients are followed monthly for 6 months, every 2 months for 2 years, every 3 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 356 patients will be accrued for this study within 5.5 years.

• Study Type: Interventional
• Enrollment (Actual): 277
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Arcadia, California, United States, 91006-3776
      • Children's Oncology Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically proven hepatoblastoma

  • Any stage allowed(stages II-IV closed to accrual as of 11-25-03)

• Stratum 1 (stage I):

  • Pure fetal histology
  • Complete surgical resection of tumor

• Stratum 2 (stages I or II) (stage II closed to accrual as of 11-25-03), meeting 1 of the following criteria:

  • Complete resection of tumor with histology other than pure fetal
  • Gross resection of tumor, including resected tumors with preoperative/intraoperative rupture

• Stratum 3 (stages III or IV) (stages III and IV closed to accrual as of 11-25-03), meeting 1 of the following criteria:

  • Unresectable tumors

    • Partial resection of tumor with measurable residual disease OR lymph node involvement
  • Measurable metastatic disease to lungs or other organs
• No hepatocellular carcinoma
• Creatinine normal for age
• Glomerular filtration rate normal for age
• Not pregnant or nursing
• Fertile patients must use effective contraception
• No prior biologic therapy
• No prior chemotherapy
• No prior endocrine therapy
• No prior radiotherapy
• See Disease Characteristics
• No prior therapy except tumor resection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (cisplatin, vincristine sulfate, fluorouracil); Patients receive therapeutic conventional surgery (tumor resection). Patients receive cisplatin IV over 4 hours on day 1, vincristine sulfate IV on days 3, 10, and 17, and fluorouracil on day 3.	Drug: fluorouracil; Given IV; Other Names: 5-FU; 5-fluorouracil; 5-Fluracil; Drug: vincristine sulfate; Given IV; Other Names: VCR; leurocristine sulfate; Vincasar PFS; Drug: cisplatin; Given IV; Other Names: CDDP; DDP; CACP; CPDD; Procedure: therapeutic conventional surgery; Undergo surgical resection
Experimental: Arm II (cisplatin, vincristine, fluorouracil, amifostine); Patients receive therapeutic conventional surgery (tumor resection). Patients receive treatment as in arm I with the addition of amifostine trihydrate IV over 15 minutes prior to cisplatin on day 1.	Drug: fluorouracil; Given IV; Other Names: 5-FU; 5-fluorouracil; 5-Fluracil; Drug: vincristine sulfate; Given IV; Other Names: VCR; leurocristine sulfate; Vincasar PFS; Drug: cisplatin; Given IV; Other Names: CDDP; DDP; CACP; CPDD; Procedure: therapeutic conventional surgery; Undergo surgical resection; Drug: amifostine trihydrate; Given IV; Other Names: Ethyol; WR-2721; ethiofos; gammaphos
Experimental: Arm III (carboplatin, cisplatin); Patients receive therapeutic conventional surgery (tumor resection). Patients receive carboplatin IV over 1 hour on day 1 and cisplatin IV over 4 hours on day 15.	Drug: cisplatin; Given IV; Other Names: CDDP; DDP; CACP; CPDD; Drug: carboplatin; Given IV; Other Names: Carboplat; CBDCA; JM-8; Paraplatin; Paraplat; Procedure: therapeutic conventional surgery; Undergo surgical resection
Experimental: Arm IV (carboplain, cisplatin, amifostine); Patients receive therapeutic conventional surgery (tumor resection). Patients receive treatment as in arm III with the addition of amifostine trihydrate IV over 15 minutes prior to carboplatin on day 1.	Drug: cisplatin; Given IV; Other Names: CDDP; DDP; CACP; CPDD; Drug: carboplatin; Given IV; Other Names: Carboplat; CBDCA; JM-8; Paraplatin; Paraplat; Procedure: therapeutic conventional surgery; Undergo surgical resection; Drug: amifostine trihydrate; Given IV; Other Names: Ethyol; WR-2721; ethiofos; gammaphos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival (EFS) rates	EFS rates will be estimated using the method of Kaplan and Meier. Survival curves will be compared using stratified logrank tests.	Up to 8 years
Toxicity rates assessed using National Cancer Institute (NCI) Common Toxicity Criteria (CTC)	For comparing the toxicity rates in the +/- amifostine arms, stratified binomial test for proportions (Mantel-Haenszel) will be used assuming no qualitative interaction between the two chemotherapy regimens and amifostine trihydrate.	Up to 8 years

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Howard Katzenstein, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start: March 1, 1999
• Primary Completion (Actual): October 1, 2007

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): June 14, 2013
• Last Update Submitted That Met QC Criteria: June 13, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Neoplasms, Complex and Mixed; Liver Neoplasms; Hepatoblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Phytogenic; Radiation-Protective Agents; Carboplatin; Cisplatin; Fluorouracil; Vincristine; Amifostine
• Other Study ID Numbers: P9645; U10CA098543 (U.S. NIH Grant/Contract); NCI-2012-02306 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); COG-P9645 (Other Identifier: Children's Oncology Group); CCG-P9645 (Other Identifier: Children's Cancer Group); POG-9645 (Other Identifier: Pediatric Oncology Group); CDR0000067200 (Other Identifier: Clinical Trials.gov)