Clinical trial NCT00334854: Ifosfamide and Doxorubicin, Radiation Therapy, and/or Surgery in Treating Young Patients With Localized Soft Tissue Sarcoma
Official title: Localized Non-Rhabdomyosarcoma Soft Tissue Sarcomas
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Childhood Malignant Fibrous Histiocytoma of Bone
Sarcoma
Keywords: childhood synovial sarcoma
nonmetastatic childhood soft tissue sarcoma
childhood alveolar soft-part sarcoma
childhood angiosarcoma
childhood epithelioid sarcoma
childhood fibrosarcoma
childhood leiomyosarcoma
childhood liposarcoma
childhood neurofibrosarcoma
localized childhood malignant fibrous histiocytoma of bone
childhood malignant hemangiopericytoma
dermatofibrosarcoma protuberans
chondrosarcoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: Italian Association for Pediatric Hematology Oncology
name: Cooperative Weichteilsarkom Studie
name: Children's Cancer and Leukaemia Group
name: Dutch Childhood Oncology Group
First posted: 2006-06-08
Enrollment: 250
Sex: ALL
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Event-free survival
measure: Local relapse-free survival
measure: Metastases-free survival
measure: Overall survival
measure: Response rate (complete response, very good partial response [PR], PR, minor PR, and stable disease)
Secondary outcomes:
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: St. Anna Children's Hospital
city: Montegnee
country: Belgium
facility: Clinique de l'Esperance
city: Copenhagen
country: Denmark
facility: Rigshospitalet - Copenhagen University Hospital
city: Paris
country: France
facility: Institut Curie Hopital
city: Dublin
country: Ireland
facility: Our Lady's Hospital for Sick Children Crumlin
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Zurich
country: Switzerland
facility: University Children's Hospital
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: 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: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
name: Andrea Ferrari, MD
role: STUDY_CHAIR
affiliation: Azienda Ospedaliera di Padova
name: Modesto Carli, MD
role: STUDY_CHAIR
affiliation: Olgahospital
name: Joern Treuner, MD
role: STUDY_CHAIR
affiliation: Royal Manchester Children's Hospital
name: Bernadette Brennan, MD
role: STUDY_CHAIR
affiliation: Erasmus MC-Sophia Children's Hospital
name: Max Van Noesel, MD, PhD
role: STUDY_CHAIR
References: