Ifosfamide and Doxorubicin, Radiation Therapy, and/or Surgery in Treating Young Patients With Localized Soft Tissue Sarcoma

Localized Non-Rhabdomyosarcoma Soft Tissue Sarcomas

RATIONALE: Drugs used in chemotherapy, such as ifosfamide 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. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy with or without radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving radiation therapy after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This phase III trial is studying how well giving ifosfamide and doxorubicin, radiation therapy, and/or surgery works in treating young patients with localized soft tissue sarcoma.

Study Overview

• Status: Unknown
• Conditions: Sarcoma; Childhood Malignant Fibrous Histiocytoma of Bone
• Intervention / Treatment: Radiation: radiation therapy; Procedure: adjuvant therapy; Procedure: neoadjuvant therapy; Drug: doxorubicin hydrochloride; Procedure: conventional surgery; Drug: ifosfamide

Detailed Description

OBJECTIVES:

Primary

• Determine survival rates (event-free survival and overall survival [OS]) and the pattern of treatment failure in patients with synovial sarcoma or adult-type soft tissue sarcoma treated with ifosfamide and doxorubicin hydrochloride, radiotherapy, and/or surgery.
• Determine the role of ifosfamide and doxorubicin hydrochloride in improving the response rate in patients with unresectable synovial sarcoma or adult-type soft tissue sarcoma.

Secondary

• Evaluate clinical/pathological prognostic factors, particularly tumor grade and radiological and pathological response to neoadjuvant treatment.
• Determine the impact of omitting adjuvant chemotherapy in patients with low-risk synovial sarcoma (tumor < 5 cm).
• Determine the role of adjuvant chemotherapy in improving the metastases-free survival and OS in patients with adult-type soft tissue sarcoma (Intergroup Rhabdomyosarcoma Study [IRS] postsurgical grouping system I-II, tumor grade 3, tumor size > 5 cm).

OUTLINE: This is a nonrandomized, prospective, historically controlled, multicenter study. Patients with synovial sarcoma are stratified according to the Intergroup Rhabdomyosarcoma Study (IRS) postsurgical grouping system (I vs II vs III) and tumor size ( ≤ 5 cm vs > 5 cm). Patients with adult-type soft tissue sarcoma are stratified according to the IRS postsurgical grouping system (I vs II vs III), tumor size ( ≤ 5 cm vs > 5 cm), and tumor grade (G1 vs G2 vs G3). Patients are assigned to 1 of 9 treatment groups according to disease and stratification.

Synovial sarcoma

• Group 1 (IRS group I, tumor ≤ 5 cm): Patients undergo surgical resection of tumor.
• Group 2 (IRS group I, tumor > 5 cm): Patients receive ifosfamide IV over 3 hours on days 1-3 and doxorubicin hydrochloride IV over 4-6 hours on days 1 and 2 (IFO-DOX). Treatment repeats every 21 days for 4 courses.
• Group 3 (IRS group II, tumor ≤ 5 cm): Patients receive 3 courses of IFO-DOX. After the completion of chemotherapy, patients undergo radiotherapy 5 days a week for 5-6 weeks.
• Group 4 (IRS group II, tumor > 5 cm): Patients receive 3 courses of IFO-DOX. Patients then receive ifosfamide alone IV over 3 hours on days 1-3. Treatment with ifosfamide repeats every 21 days for 2 courses. Patients also receive concurrent radiotherapy (concurrently with ifosfamide) 5 days a week for 5-6 weeks. After completion of radiotherapy, patients receive 1 additional course of IFO-DOX.

• Group 5 (IRS group III, N1): Patients receive 3 courses of IFO-DOX. Patients with no response to chemotherapy receive 1 of the following local therapies:

  • Delayed complete resection*
  • Radiotherapy (as in group 3) followed by surgery*
  • Delayed complete resection* followed by radiotherapy** (as in group 3)
  • Delayed incomplete resection* followed by radiotherapy** (as in group 3)
  • Radiotherapy (as in group 3) Patients with major or minor response to chemotherapy receive 2 courses of ifosfamide with concurrent radiotherapy followed by 1 additional course of IFO-DOX (as in group 4, above).

NOTE: * Patients undergo surgery 5 weeks after completion of chemotherapy and/or radiotherapy.

NOTE: **Patients undergo radiotherapy beginning < 21 days after surgery.

Adult-type soft tissue sarcoma

• Group 1 (IRS group I, tumor ≤ 5 cm): Patients undergo surgical resection of tumor.

• Group 2 (IRS group I, tumor > 5 cm): Patients receive therapy according to tumor grade:

  • G1 disease: Patients undergo surgical resection.
  • G2 disease: Patients undergo radiotherapy 5 days a week for 5-6 weeks.
  • G3 disease: Patients receive the following sequential treatment: 3 courses of IFO-DOX followed by 2 courses of ifosfamide with concurrent radiotherapy followed by 1 course of IFO-DOX.

• Group 3 (IRS group II, N0): Patients receive therapy according to tumor grade:

  • G1 disease: Patients undergo surgical resection.
  • G2-3 disease (≤ 5 cm) and G2 disease (> 5 cm): Patients undergo radiotherapy 5 days a week for 5-6 weeks.
  • G3 disease (> 5 cm): Patients undergo sequential treatment (as in group 2, adult-type soft tissue sarcoma).
• Group 4 (IRS group III, N1): Patients receive 3 courses of IFO-DOX. Patients with no response to chemotherapy receive local therapy (as in group 5 synovial sarcoma). Patients with major or minor response to chemotherapy receive 2 courses of ifosfamide with concurrent radiotherapy followed by 2 additional courses of IFO-DOX (as in group 4, synovial sarcoma).

After completion of study therapy, patients are followed periodically for up to 10 years.

PROJECTED ACCRUAL: A total of 250 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Anticipated): 250
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, A-1090
    • Recruiting
    • St. Anna Children's Hospital
• Belgium
  • Montegnee, Belgium, 4420
    • Recruiting
    • Clinique de l'Esperance
    • Contact: Nadine Francotte, MD; Phone Number: 32-4-224-9111; Email: nadine.francotte@chc.be
• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Rigshospitalet - Copenhagen University Hospital
    • Contact: Catherine Rechnitzer, MD, PhD; Phone Number: 45-3545-1368; Email: rechnitzer@rh.dk
• France
  • Paris, France, 75248
    • Recruiting
    • Institut Curie Hopital
    • Contact: Daniel Orbach, MD; Phone Number: 33-14-432-4550
• Ireland
  • Dublin, Ireland, 12
    • Recruiting
    • Our Lady's Hospital for Sick Children Crumlin
    • Contact: Anne O'Meara, MD; Phone Number: 353-409-6659
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Vall d'Hebron University Hospital
    • Contact: Soledad Gallego, MD, PhD; Phone Number: 34-93-489-3090; Email: sgallego@vhebron.net
• Sweden
  • Uppsala, Sweden, SE-75185
    • Recruiting
    • Uppsala University Hospital
    • Contact: Gustaf Ljungman, MD; Phone Number: 46-18-611-5586
• Switzerland
  • Zurich, Switzerland, CH-8032
    • Recruiting
    • University Children's Hospital
    • Contact: Felix Niggli, MD; Phone Number: 41-44-266-7823
• United Kingdom
  • England
    • Birmingham, England, United Kingdom, B16 8ET
      • Recruiting
      • Birmingham Children's Hospital
      • Contact: David Hobin, MD; Phone Number: 44-121-454-4851
    • Bristol, England, United Kingdom, BS2 8AE
      • Recruiting
      • Institute of Child Health at University of Bristol
      • Contact: M. C. G. Stevens, MD; Phone Number: 44-117-342-0205; Email: m.stevens@bristol.ac.uk
    • Cambridge, England, United Kingdom, CB2 2QQ
      • Recruiting
      • Addenbrooke's Hospital
      • Contact: Denise Williams, MD; Phone Number: 44-1223-256-298
    • Leeds, England, United Kingdom, LS9 7TF
      • Recruiting
      • Leeds Cancer Centre at St. James's University Hospital
    • Leicester, England, United Kingdom, LE1 5WW
      • Recruiting
      • Leicester Royal Infirmary
    • Liverpool, England, United Kingdom, L12 2AP
      • Recruiting
      • Royal Liverpool Children's Hospital, Alder Hey
    • London, England, United Kingdom, WC1N 3JH
      • Recruiting
      • Great Ormond Street Hospital for Children
      • Contact: Julia Chisholm, MD; Phone Number: 44-20-7829-7924
    • London, England, United Kingdom, W1T 3AA
      • Recruiting
      • Middlesex Hospital
    • Manchester, England, United Kingdom, M27 4HA
      • Recruiting
      • Royal Manchester Children's Hospital
    • Newcastle-Upon-Tyne, England, United Kingdom, NE1 4LP
      • Recruiting
      • Sir James Spence Institute of Child Health at Royal Victoria Infirmary
    • Nottingham, England, United Kingdom, NG7 2UH
      • Recruiting
      • Queen's Medical Centre
      • Contact: Martin Hewitt, MD, BSc, FRCP, FRCPCH; Phone Number: 44-115-924-9924 ext. 63394; Email: martin.hewitt@nuh.nhs.uk
    • Oxford, England, United Kingdom, 0X3 9DU
      • Recruiting
      • Oxford Radcliffe Hospital
    • Sheffield, England, United Kingdom, S10 2TH
      • Recruiting
      • Children's Hospital - Sheffield
    • Southampton, England, United Kingdom, SO16 6YD
      • Recruiting
      • Southampton General Hospital
    • Sutton, England, United Kingdom, SM2 5PT
      • Recruiting
      • Royal Marsden - Surrey
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT12 6BE
      • Recruiting
      • Royal Belfast Hospital for Sick Children
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZG
      • Recruiting
      • Royal Aberdeen Children's Hospital
      • Contact: Derek King, MD; Phone Number: 44-1224-681-818
    • Edinburgh, Scotland, United Kingdom, EH9 1LF
      • Recruiting
      • Royal Hospital for Sick Children
    • Glasgow, Scotland, United Kingdom, G3 8SJ
      • Recruiting
      • Royal Hospital for Sick Children
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 4XW
      • Recruiting
      • Childrens Hospital for Wales

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed synovial sarcoma or adult-type soft-tissue sarcoma

  • Adult-type soft tissue sarcoma includes any of the following:

    • Fibrosarcoma (adult-type)

      • No infantile fibrosarcoma

    • Malignant peripheral nerve sheath tumor

      • Malignant schwannoma
      • Neurofibrosarcoma
    • Epithelioid sarcoma
    • Leiomyosarcoma
    • Clear cell sarcoma
    • Liposarcoma
    • Alveolar soft-part sarcoma
    • Malignant fibrous histiocytoma
    • Hemangiopericytoma
    • Angiosarcoma
    • Dermatofibrosarcoma protuberans
    • Mesenchymal chondrosarcoma
• No borderline tumors (e.g., hemangioendothelioma)
• No small round cell tumors (e.g., extraosseous Ewing's sarcoma/primitive neuroectodermal tumor or desmoplastic small round cell tumor)
• Post-irradiation soft-part sarcomas allowed
• Diagnostic surgery performed within the past 8 weeks (for patients who require adjuvant chemotherapy)

• No evidence of metastatic disease

  • Involved locoregional lymph nodes are allowed

PATIENT CHARACTERISTICS:

• No prior malignancy
• No pre-existing illness precluding study treatment*
• Normal renal function (nephrotoxicity grade 0-1)*
• No history of cardiac disease*
• Normal shortening fraction (> 28%)*
• Ejection fraction > 47%* NOTE: * For patients who require adjuvant chemotherapy

PRIOR CONCURRENT THERAPY:

• No prior cancer treatment except primary surgery

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Overall survival
Event-free survival
Local relapse-free survival
Metastases-free survival
Response rate (complete response, very good partial response [PR], PR, minor PR, and stable disease)

Collaborators and Investigators

• Sponsor: European Paediatric Soft Tissue Sarcoma Study Group
• Collaborators: Children's Cancer and Leukaemia Group; Dutch Childhood Oncology Group; Italian Association for Pediatric Hematology Oncology; Cooperative Weichteilsarkom Studie
• Investigators: Study Chair: Andrea Ferrari, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; Study Chair: Modesto Carli, MD, Azienda Ospedaliera di Padova; Study Chair: Joern Treuner, MD, Olgahospital; Study Chair: Bernadette Brennan, MD, Royal Manchester Children's Hospital; Study Chair: Max Van Noesel, MD, PhD, Erasmus MC - Sophia Children's Hospital

Study record dates

Study Major Dates

• Study Start: March 1, 2006
• Primary Completion (Anticipated): May 1, 2010

Study Registration Dates

• First Submitted: June 7, 2006
• First Submitted That Met QC Criteria: June 7, 2006
• First Posted (Estimate): June 8, 2006

Study Record Updates

• Last Update Posted (Estimate): August 12, 2013
• Last Update Submitted That Met QC Criteria: August 9, 2013
• Last Verified: July 1, 2009

More Information

Terms related to this study

• Keywords: chondrosarcoma; nonmetastatic childhood soft tissue sarcoma; childhood fibrosarcoma; childhood synovial sarcoma; childhood neurofibrosarcoma; childhood alveolar soft-part sarcoma; childhood angiosarcoma; childhood epithelioid sarcoma; childhood leiomyosarcoma; childhood liposarcoma; localized childhood malignant fibrous histiocytoma of bone; childhood malignant hemangiopericytoma; dermatofibrosarcoma protuberans
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Neoplasms, Fibrous Tissue; Sarcoma; Histiocytoma, Malignant Fibrous; Histiocytoma; Histiocytoma, Benign Fibrous; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Ifosfamide; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: CCLG-EPSSG-NRSTS-2005; CDR0000482277 (Registry Identifier: PDQ (Physician Data Query)); EU-20620; EUDRACT-2005-001139-31; UKCCSG-CTA-21275/0215/001/0001; CCLG-EpSSG-STS-2006-03