Clinical trial NCT00077389: Intensive Neoadjuvant Chemotherapy in Treating Young Patients Undergoing Surgical Resection for High-Risk Hepatoblastoma
Official title: Intensified Pre-Operative Chemotherapy And Radical Surgery For High Risk Hepatoblastoma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Liver Cancer
Keywords: childhood hepatoblastoma
stage IV childhood liver cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2004-02-12
Enrollment: 57
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Giving chemotherapy drugs before surgery may shrink the tumor so that it can be removed.

PURPOSE: This phase II trial is studying how well neoadjuvant chemotherapy works in treating young patients who are undergoing surgical resection for high-risk hepatoblastoma.

Detailed description: OBJECTIVES:

Primary

* Determine the efficacy and short-term toxicity of intensified neoadjuvant chemotherapy in children with high-risk hepatoblastoma undergoing surgical resection.
* Increase the rate of complete surgical resection in these patients by fully implementing liver transplantation as a valid treatment option for tumor removal when partial liver resection or other surgical options remain unfeasible even after extensive preoperative chemotherapy.
* Determine, prospectively, the role of this regimen in rendering unresectable tumors resectable in these patients.
* Determine the accuracy of initial imaging in predicting the surgical options (after treatment with this regimen) for patients presenting with unresectable disease.

Secondary

* Determine the overall survival and event-free survival of patients treated with this regimen (with an acceptable overall toxicity).
* Determine the toxicity of this regimen in these patients.
* Determine the response rate in patients treated with this regimen.
* Determine whether response to this regimen, defined by the modified RECIST criteria, can be used for better monitoring of response in these patients.
* Determine whether a fall in alpha-fetoprotein during this neoadjuvant regimen can be used as a prognostic factor in these patients.
* Determine, prospectively, radiological, surgical, and pathological characteristics of the tumor that might identify possible novel factors that might influence treatment choice and outcome in these patients.

OUTLINE: This is an open-label, multicenter study.

* Intensified neoadjuvant chemotherapy: Patients receive cisplatin IV over 24 hours on days 1, 8, 15, 29, 36, 43, 57, and 64; and doxorubicin IV over 1 hour OR over 24 hours on days 8, 9, 36, 37, 57, and 58. Patients determined to have resectable disease proceed to surgery.

Patients determined to have unresectable disease after neoadjuvant chemotherapy receive additional neoadjuvant chemotherapy comprising carboplatin IV over 1 hour on days 1 and 22 and doxorubicin IV over 1 hour OR over 24 hours on days 1, 2, 3, 22, 23, and 24.

Treatment continues in the absence of unacceptable toxicity.

* Surgery: Patients determined to have resectable disease undergo complete resection and possibly liver transplantation.
* Adjuvant chemotherapy\*: Patients who undergo complete surgical resection receive carboplatin IV over 1 hour on day 1 and doxorubicin IV over 1 hour OR over 24 hours on days 1 and 2. Treatment repeats every 3 weeks for a total of 3 courses.

NOTE: \*Patients who received additional neoadjuvant chemotherapy for unresectable disease do not receive adjuvant chemotherapy.

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

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A total of 23-57 patients will be accrued for this study within 2 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed hepatoblastoma
* High-risk disease, meeting criteria for at least 1 of the following:

  * Tumor involving all 4 hepatic sections
  * Evidence of abdominal extrahepatic disease
  * Presence of metastases
  * Alpha-fetoprotein \< 100 ng/mL at diagnosis
* Must have had a prior diagnostic biopsy within the past 15 days
* No recurrent disease

PATIENT CHARACTERISTICS:

Age

* Under 18

Performance status

* Not specified

Life expectancy

* Not specified

Hematopoietic

* Not specified

Hepatic

* AST and/or ALT ≤ 3 times normal

Renal

* Glomerular filtration rate ≥ 60 mL/min

Cardiovascular

* Shortening fraction ≥ 29% OR
* Ejection fraction ≥ 40%

Other

* Not pregnant
* Negative pregnancy test
* No pre-existing clinically relevant bilateral hearing loss
* No other condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

* Not specified

Chemotherapy

* No prior chemotherapy

Endocrine therapy

* Not specified

Radiotherapy

* Not specified

Surgery

* Not specified

Other

* No prior therapy for hepatoblastoma

Primary outcomes:
measure: Rate of complete remission after completion of study therapy
Secondary outcomes:
measure: Complete resection rate
measure: Response rate to preoperative chemotherapy
measure: Rate of grade 2 cardiac and renal, grade 3 otological, and grade 4 nonhematological toxicity as assessed during and after completion of study therapy
measure: Overall survival
measure: Event-free survival
Other outcomes:
Locations:
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Dublin
country: Ireland
facility: Our Lady's Hospital for Sick Children Crumlin
city: Amsterdam
country: Netherlands
facility: Emma Kinderziekenhuis
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
state: England
city: Bristol
country: United Kingdom
facility: Institute of Child Health at University of Bristol
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: Leeds
country: United Kingdom
facility: Leeds Cancer Centre at St. James's University Hospital
state: England
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: England
city: Leicester
country: United Kingdom
facility: Children's Cancer and Leukaemia Group
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool Children's Hospital, Alder Hey
state: England
city: London
country: United Kingdom
facility: Middlesex Hospital
state: England
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
state: England
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
state: England
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: Sir James Spence Institute of Child Health at Royal Victoria Infirmary
state: England
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
state: England
city: Oxford
country: United Kingdom
facility: Oxford Radcliffe Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Children's Hospital - Sheffield
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Belfast
country: United Kingdom
facility: Royal Belfast Hospital for Sick Children
state: Northern Ireland
city: Aberdeen
country: United Kingdom
facility: Royal Aberdeen Children's Hospital
state: Scotland
city: Edinburgh
country: United Kingdom
facility: Royal Hospital for Sick Children
state: Scotland
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Sick Children
state: Scotland
city: Cardiff
country: United Kingdom
facility: Childrens Hospital for Wales
state: Wales
Study officials:
affiliation: Children's Cancer and Leukaemia Group
name: Margaret Childs
role: STUDY_CHAIR
References:
citation: Zsiros J, Brugieres L, Brock P, Roebuck D, Maibach R, Zimmermann A, Childs M, Pariente D, Laithier V, Otte JB, Branchereau S, Aronson D, Rangaswami A, Ronghe M, Casanova M, Sullivan M, Morland B, Czauderna P, Perilongo G; International Childhood Liver Tumours Strategy Group (SIOPEL). Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol. 2013 Aug;14(9):834-42. doi: 10.1016/S1470-2045(13)70272-9. Epub 2013 Jul 4.
citation: Weeda VB, Murawski M, McCabe AJ, Maibach R, Brugieres L, Roebuck D, Fabre M, Zimmermann A, Otte JB, Sullivan M, Perilongo G, Childs M, Brock P, Zsiros J, Plaschkes J, Czauderna P, Aronson DC. Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma--results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience. Eur J Cancer. 2013 Aug;49(12):2698-704. doi: 10.1016/j.ejca.2013.04.012. Epub 2013 May 15.