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

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.

Study Overview

• Status: Unknown
• Conditions: Liver Cancer
• Intervention / Treatment: Drug: cyclophosphamide; Procedure: adjuvant therapy; Procedure: neoadjuvant therapy; Drug: cisplatin; Drug: doxorubicin hydrochloride; Procedure: conventional surgery; Drug: thalidomide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• Ireland
  • Dublin, Ireland, 12
    • Our Lady's Hospital for Sick Children Crumlin
• United Kingdom
  • England
    • Birmingham, England, United Kingdom, B4 6NH
      • Birmingham Children's Hospital
    • Bristol, England, United Kingdom, BS2 8AE
      • Institute of Child Health at University of Bristol
    • Cambridge, England, United Kingdom, CB2 2QQ
      • Addenbrooke's Hospital
    • Leeds, England, United Kingdom, LS9 7TF
      • Leeds Cancer Centre at St. James's University Hospital
    • Leicester, England, United Kingdom, LE1 5WW
      • Leicester Royal Infirmary
    • Liverpool, England, United Kingdom, L12 2AP
      • Royal Liverpool Children's Hospital, Alder Hey
    • London, England, United Kingdom, E1 1BB
      • Royal London Hospital
    • London, England, United Kingdom, WC1N 3JH
      • Great Ormond Street Hospital for Children
    • Manchester, England, United Kingdom, M27 4HA
      • Royal Manchester Children's Hospital
    • Newcastle-Upon-Tyne, England, United Kingdom, NE1 4LP
      • Sir James Spence Institute of Child Health at Royal Victoria Infirmary
    • Nottingham, England, United Kingdom, NG7 2UH
      • Queen's Medical Centre
    • Oxford, England, United Kingdom, 0X3 9DU
      • Oxford Radcliffe Hospital
    • Sheffield, England, United Kingdom, S10 2TH
      • Children's Hospital - Sheffield
    • Southampton, England, United Kingdom, SO16 6YD
      • Southampton General Hospital
    • Sutton, England, United Kingdom, SM2 5PT
      • Royal Marsden - Surrey
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT12 6BE
      • Royal Belfast Hospital for Sick Children
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZG
      • Royal Aberdeen Children's Hospital
    • Edinburgh, Scotland, United Kingdom, EH9 1LF
      • Royal Hospital for Sick Children
    • Glasgow, Scotland, United Kingdom, G3 8SJ
      • Royal Hospital for Sick Children
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 4XW
      • Childrens Hospital for Wales

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 29 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed hepatocellular carcinoma (HCC) family of tumors by percutaneous needle biopsy (unless primary tumor resection is attempted)

  • Newly diagnosed disease
  • No recurrent disease
  • Fibrolamellar and transitional variants

  • Noncirrhotic disease

    • If suspicious of liver cirrhosis (e.g., abnormal liver function tests and/or positive viral serology and/or radiological evidence) at diagnosis, patient must undergo biopsy of normal liver to exclude liver cirrhosis

PATIENT CHARACTERISTICS:

• Able to follow the protocol
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Life expectancy at least 3 months
• Glomerular filtration rate ≥ 75-50% of the lower limit of normal for age (≥ 60 mL/min for patients ≥ 2 years old)
• Cardiac ejection fraction ≥ 29% at baseline ECHO

PRIOR CONCURRENT THERAPY:

• No prior treatment for HCC

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Event-free and overall survival following tumor resection

Secondary Outcome Measures

Outcome Measure
Efficacy and tolerability following course 2 and 4 of pre-operative chemotherapy

Collaborators and Investigators

• Sponsor: Children's Cancer and Leukaemia Group
• Investigators: Study Chair: Bruce Morland, MD, Birmingham Children's Hospital

Study record dates

Study Major Dates

• Study Start: June 1, 2005
• Primary Completion (Anticipated): April 1, 2009

Study Registration Dates

• First Submitted: January 12, 2006
• First Submitted That Met QC Criteria: January 12, 2006
• First Posted (Estimate): January 13, 2006

Study Record Updates

• Last Update Posted (Estimate): September 17, 2013
• Last Update Submitted That Met QC Criteria: September 16, 2013
• Last Verified: June 1, 2009

More Information

Terms related to this study

• Keywords: advanced adult primary liver cancer; localized unresectable adult primary liver cancer; localized resectable adult primary liver cancer; adult primary hepatocellular carcinoma; stage IV childhood liver cancer; childhood hepatocellular carcinoma; stage I childhood liver cancer; stage II childhood liver cancer; stage III childhood liver cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Antibiotics, Antineoplastic; Cyclophosphamide; Thalidomide; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: CDR0000454579; CCLG-LT-2005-05; CCLG-SIOPEL-HCC; CCLG-SIOPEL-5; EU-20590; EUDRACT-2005-000427-42