Combination Chemotherapy in Treating Children With Metastatic Rhabdomyosarcoma or Other Malignant Mesenchymal Tumors

MMT 98 Study For Metastatic Disease Rhabdomyosarcoma And Other Malignant Soft Tissue Sarcoma Of Childhood

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy in treating children with metastatic rhabdomyosarcoma or other malignant mesenchymal tumors.

Study Overview

• Status: Completed
• Conditions: Sarcoma; Small Intestine Cancer; Ovarian Cancer
• Intervention / Treatment: Drug: carboplatin; Drug: cyclophosphamide; Radiation: radiation therapy; Drug: etoposide; Drug: vincristine sulfate; Drug: doxorubicin hydrochloride; Procedure: peripheral blood stem cell transplantation; Biological: filgrastim; Drug: epirubicin hydrochloride; Drug: ifosfamide; Biological: dactinomycin

Detailed Description

OBJECTIVES:

• Determine the overall survival of children with metastatic rhabdomyosarcoma or other malignant mesenchymal tumors treated with one of two different chemotherapy regimens based upon risk group.
• Determine the role of low-intensity maintenance chemotherapy after intensive conventional chemotherapy in standard-risk children.
• Determine the value of a therapeutic window in high-risk children.
• Determine the role of sequential high-dose chemotherapy with peripheral blood stem cell transplantation in achieving complete response in high-risk children.
• Determine the complete response, overall survival, and event-free survival in high-risk children.

OUTLINE: This is a multicenter study. Patients are stratified according to risk group (standard vs high).

Standard-risk patients:

• Initial chemotherapy: Patients receive vincristine IV on day 1 for weeks 1-7. Patients also receive dactinomycin IV on day 1 and ifosfamide IV over 1 hour on days 1-3 of week 1. Patients then receive carboplatin IV over 1 hour and epirubicin IV over 6 hours on day 1 of week 4. Patients then receive ifosfamide IV over 1 hour and etoposide IV over 4 hours on days 1-3 of week 7. Treatment repeats every 8 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. After the second course, patients with less than 50% partial response (PR) are removed from study.

Patients with parameningeal disease undergo radiotherapy 5 days a week for about 8 weeks beginning at week 9.

• Maintenance chemotherapy: Patients receive cyclophosphamide IV over 1 hour, vincristine IV, and dactinomycin IV on day 1. Treatment repeats every 3 weeks for 9 courses in the absence of disease progression or unacceptable toxicity.

Patients who remain in PR at week 17 undergo radiotherapy for about 9 weeks beginning at week 18.

High-risk patients:

• Initial chemotherapy: Patients receive window study drug carboplatin IV over 1 hour or doxorubicin on day 1. Treatment repeats every 3 weeks for 2 courses.

Patients receive high-dose cyclophosphamide IV over 1 hour on days 1-3 of week 7. Beginning on day 8, patients receive filgrastim (G-CSF) IV or subcutaneously (SC) daily until day 13. Patients may undergo peripheral blood stem cell (PBSC) collection.

Patients receive high-dose etoposide IV over 24 hours on days 15-17. Beginning on day 22, patients receive G-CSF IV or SC daily until day 27.

Patients receive high-dose cyclophosphamide IV over 1 hour on days 29-31. Beginning on day 36, patients receive G-CSF IV or SC daily until day 42. Patients may undergo PBSC collection if not previously performed. Patients who achieve complete response (CR) are removed from study.

Patients receive high-dose carboplatin IV over 1 hour on days 44-48. Patients undergo PBSC reinfusion on day 52. Beginning on day 55, patients receive G-CSF IV or SC daily until blood counts recover.

• Maintenance chemotherapy: Patients receive maintenance chemotherapy comprising cyclophosphamide, vincristine, and dactinomycin in the same manner as the standard-risk patients.

Patients with parameningeal disease and those not achieving CR undergo radiotherapy beginning at week 17. Patients achieving CR, unless metastatic disease is resected, undergo radiotherapy beginning on week 15.

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

PROJECTED ACCRUAL: A total of 8-30 standard-risk patients will be accrued for this study within 4 years. A total of 15-75 high-risk patients will be accrued for this study within 4-5 years.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Lyon, France, 69373
    • Centre Léon Bérard
• Ireland
  • Crumlin, Ireland, 12
    • Our Lady's Hospital for Sick Children
• United Kingdom
  • England
    • Birmingham, England, United Kingdom, B4 6NH
      • Birmingham Children's Hospital
    • Bristol, England, United Kingdom, BS2 8BJ
      • Bristol Royal Hospital for Children
    • Cambridge, England, United Kingdom, CB2 2QQ
      • Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust
    • 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, WC1N 3JH
      • Great Ormond street Hospital for Children NHS Trust
    • London, England, United Kingdom, EC1A 7BE
      • Saint Bartholomew's Hospital
    • London, England, United Kingdom, WIT 3AA
      • Meyerstein Institute of Oncology at University College of London Hospitals
    • London, England, United Kingdom, W6 8RF
      • Leeds Cancer Centre at St. James's University Hospital
    • Manchester, England, United Kingdom, M27 4HA
      • Central Manchester and Manchester Children's University Hospitals NHS Trust
    • Newcastle-Upon-Tyne, England, United Kingdom, NE7 7DN
      • Newcastle Upon Tyne Hospitals NHS Trust
    • 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 NHS Foundation Trust - Surrey
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT12 6BE
      • Royal Belfast Hospital for Sick Children
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZN
      • Aberdeen Royal Infirmary
    • Edinburgh, Scotland, United Kingdom
      • Royal Hospital for Sick Children
    • Glasgow, Scotland, United Kingdom, G3 8SJ
      • Royal Hospital for Sick Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed metastatic rhabdomyosarcoma or other malignant mesenchymal tumors

  • Standard risk defined as:

    • Less than 10 years of age
    • No bone or bone marrow involvement

  • High risk defined as:

    • At least 10 years of age OR
    • Bone or bone marrow involvement
• Diagnosed less than 8 weeks ago
• Previously untreated disease except for initial surgery within the past 8 weeks

PATIENT CHARACTERISTICS:

Age:

• 6 months to under 18 years

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior biologic therapy

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• No prior endocrine therapy

Radiotherapy:

• Concurrent radiotherapy allowed

Surgery:

• See Disease Characteristics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

• Sponsor: Societe Internationale d'Oncologie Pediatrique
• Collaborators: Children's Cancer and Leukaemia Group; Societe Francaise Oncologie Pediatrique
• Investigators: Study Chair: Heather P. McDowell, MD, Royal Liverpool Children's Hospital, Alder Hey; Study Chair: Annabel B.M. Foot, Bristol Royal Hospital for Children; Study Chair: Christophe Bergeron, Centre Léon Bérard

Publications and helpful links

General Publications

• McDowell HP, Foot AB, Ellershaw C, Machin D, Giraud C, Bergeron C. Outcomes in paediatric metastatic rhabdomyosarcoma: results of The International Society of Paediatric Oncology (SIOP) study MMT-98. Eur J Cancer. 2010 Jun;46(9):1588-95. doi: 10.1016/j.ejca.2010.02.051. Epub 2010 Mar 24.

Study record dates

Study Major Dates

• Study Start: November 1, 1998
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: October 11, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): December 4, 2013
• Last Update Submitted That Met QC Criteria: December 3, 2013
• Last Verified: November 1, 2001

More Information

Terms related to this study

• Keywords: chondrosarcoma; small intestine leiomyosarcoma; stage IV uterine sarcoma; uterine leiomyosarcoma; ovarian sarcoma; metastatic childhood soft tissue sarcoma; alveolar childhood rhabdomyosarcoma; embryonal childhood rhabdomyosarcoma; embryonal-botryoid childhood rhabdomyosarcoma; mixed childhood rhabdomyosarcoma; pleomorphic childhood rhabdomyosarcoma; previously untreated childhood rhabdomyosarcoma; childhood desmoplastic small round cell tumor; childhood fibrosarcoma; childhood synovial sarcoma; childhood malignant mesenchymoma; childhood alveolar soft-part sarcoma; childhood angiosarcoma; childhood epithelioid sarcoma; childhood leiomyosarcoma; childhood liposarcoma; childhood malignant hemangiopericytoma; fibrosarcomatous osteosarcoma; extraosseous Ewing sarcoma/peripheral primitive neuroectodermal tumor
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Neoplasms, Muscle Tissue; Myosarcoma; Sarcoma; Intestinal Neoplasms; Rhabdomyosarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Carboplatin; Etoposide; Epirubicin; Ifosfamide; Doxorubicin; Liposomal doxorubicin; Vincristine; Dactinomycin
• Other Study ID Numbers: CDR0000068961; SIOP-MMT-98; SFOP-SIOP-MMT-98; CCLG-SIOP-MMT-98; EU-20126; STS-1998