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Surgery Followed by Chemotherapy in Treating Young Patients With Soft Tissue Sarcoma

Primary Purpose

Childhood Malignant Fibrous Histiocytoma of Bone, Sarcoma

Status
Completed
Phase
Phase 3
Locations
United Kingdom
Study Type
Interventional
Intervention
dactinomycin
carboplatin
cyclophosphamide
epirubicin hydrochloride
etoposide
ifosfamide
vincristine sulfate
adjuvant therapy
conventional surgery
neoadjuvant therapy
brachytherapy
radiation therapy
Sponsored by
Societe Internationale d'Oncologie Pediatrique
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Childhood Malignant Fibrous Histiocytoma of Bone focused on measuring embryonal childhood rhabdomyosarcoma, alveolar childhood rhabdomyosarcoma, pleomorphic childhood rhabdomyosarcoma, mixed childhood rhabdomyosarcoma, embryonal-botryoid childhood rhabdomyosarcoma, nonmetastatic childhood soft tissue sarcoma, childhood fibrosarcoma, childhood synovial sarcoma, childhood malignant hemangiopericytoma, childhood liposarcoma, childhood alveolar soft-part sarcoma, childhood leiomyosarcoma, childhood neurofibrosarcoma, childhood angiosarcoma, childhood epithelioid sarcoma, childhood malignant fibrous histiocytoma of bone, childhood malignant mesenchymoma, previously untreated childhood rhabdomyosarcoma, childhood desmoplastic small round cell tumor, localized Ewing sarcoma/peripheral primitive neuroectodermal tumor

Eligibility Criteria

undefined - 17 Years (Child)All SexesDoes not accept healthy volunteers

DISEASE CHARACTERISTICS: Histologically confirmed primary soft tissue sarcoma: Rhabdomyosarcoma Non-rhabdomyosarcoma Soft tissue primitive neuroectodermal tumor (PNET) Extraosseous Ewing's sarcoma PATIENT CHARACTERISTICS: Age: Under 18 Performance status: Not specified Life expectancy: Not specified Hematopoietic: Not specified Hepatic: Not specified Renal: Not specified PRIOR CONCURRENT THERAPY: Biologic: Not specified Chemotherapy: Not specified Endocrine: Not specified Radiotherapy: Not specified Surgery: Prior primary surgery allowed Other: No other prior therapy

Sites / Locations

  • Institute of Child Health

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

First Posted
November 1, 1999
Last Updated
December 3, 2013
Sponsor
Societe Internationale d'Oncologie Pediatrique
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1. Study Identification

Unique Protocol Identification Number
NCT00002898
Brief Title
Surgery Followed by Chemotherapy in Treating Young Patients With Soft Tissue Sarcoma
Official Title
MMT 95 Study For Rhabdomyosarcoma and Other Malignant Soft Tissue Tumors of Childhood
Study Type
Interventional

2. Study Status

Record Verification Date
May 1999
Overall Recruitment Status
Completed
Study Start Date
January 1995 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
December 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Societe Internationale d'Oncologie Pediatrique

4. Oversight

5. Study Description

Brief Summary
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one chemotherapy drug with surgery and/or radiation therapy may kill more tumor cells. PURPOSE: This randomized phase III trial is studying surgery followed by different regimens of combination chemotherapy given together with radiation therapy and/or additional surgery to compare how well they work in treating patients with soft tissue sarcoma.
Detailed Description
OBJECTIVES: Assess whether good survival rates can be maintained for patients with stage I (pathologic T1) soft tissue sarcomas (STS) treated with limited chemotherapy after complete surgical resection, and whether disease-free survival can be improved by improving the precision of pretreatment staging and the assessment of the completeness of the resection. Compare the survival of patients with high-risk nonmetastatic STS treated with alternating regimens of carboplatin, epirubicin, and vincristine (CEV) and ifosfamide, vincristine, and etoposide (IVE) vs continuation of ifosfamide, vincristine, and dactinomycin (IVA) after initial therapy with IVA. Assess whether the improved outcome seen for patients with stage III (node positive) STS in an earlier protocol (SIOP-MMT-89) can be maintained with 3 courses of alternating CEV/IVE without altering local therapy. Compare outcome of patients with nonmetastatic STS to those with stage IV STS who are registered on this protocol but referred to treatment on the European Intergroup Stage IV Study. Assess survival and the risk of late sequelae in patients with non-rhabdomyosarcoma malignant mesenchymal tumors treated on this protocol. Evaluate the role of neoadjuvant chemotherapy, new prognostic factors (e.g., ploidy, histologic grading), and recommendations for the management of fibrosarcoma in infants and of fibromatoses. Assess ifosfamide nephrotoxicity based on total dose administered and the long-term toxicity based on the potential predictive value of early evidence of nephrotoxicity. OUTLINE: This is a randomized study for patients with high-risk, nonmetastatic sarcoma, except those with the following characteristics: age less than 6 months, stage I/II non-alveolar orbital tumor, stage III disease, or age less than 3 years with parameningeal disease. Patients are stratified according to disease type (rhabdomyosarcoma (RMS) vs non-RMS disease), parameningeal site of disease, and participating center. Patients with RMS are further randomized by alveolar histology. Randomization occurs after the first course of chemotherapy. All patients, regardless of disease stage, are registered to this study and outcome is followed, although patients with metastatic RMS or non-RMS malignant mesenchymal tumors are referred for treatment on the SIOP-MMT-98 study. Patients diagnosed more than 8 weeks prior to entry or who are unavailable for follow-up are not treated on study. Doses are modified for patients under 1 year of age or under 10 kg of body weight. All other patients are assigned therapy based on risk group. After surgery, patients with complete resection and with proven or possible chemosensitive histologies proceed to chemotherapy on the low-risk regimen. Patients with questionable completeness of resection proceed to chemotherapy for standard-risk or high-risk tumors, as appropriate. Regardless of resection results, patients who underwent scrotal surgery for paratesticular tumors proceed to chemotherapy for standard-risk tumors. Alveolar RMS is considered high risk. LOW-RISK TUMORS (T1 N0 M0): Strategy 951 Tumors must be resectable without extensive, mutilating surgery, and resection margins must be microscopically negative at all sites. Patients with positive margins may undergo re-excision. Vincristine is administered weekly for 4 weeks with dactinomycin given on the same day as the first and fourth doses of vincristine. The course is repeated once after a 3-week rest. STANDARD-RISK TUMORS (T1-2 N0 M0): Strategy 952 After resection as above, patients with incompletely resected T1 tumors, completely resected T1 tumors that extended beyond the tissue or organ of origin, or completely or incompletely resected T2 tumors at favorable sites (vagina, uterus, or paratesticular region) receive chemotherapy on this regimen. Ifosfamide, vincristine, and dactinomycin (IVA) is started within 8 weeks of surgery and administered every 3 weeks for 3 courses; during this course only, vincristine is administered weekly throughout the 6 weeks. Response is assessed at week 8. Patients with at least a 50% response at week 8 receive 3 more courses of IVA and are reassessed at week 17; those with a complete response (CR) discontinue treatment, while those with less than a CR begin local therapy (described below) on week 18 concurrently with 3 more courses of IVA (unless no further response was seen after week 8). Patients with less than a 50% response at week 8 receive carboplatin, epirubicin, and vincristine (CEV) on weeks 9, 15, and 21 and ifosfamide, vincristine, and etoposide (IVE) on weeks 12, 18, and 24. Patients with less than a CR at week 17 receive concurrent local therapy beginning at week 18. HIGH-RISK TUMORS: Strategy 953 Patients with high-risk tumors after surgery are randomized to IVA as in strategy 952 (Arm I) or to 3 weeks of IVA (1 course) as in Strategy 952 followed by CEV and IVE as in Strategy 952 (Arm II). Response is assessed at week 8. Patients with parameningeal disease who are at least 3 years of age proceed to radiotherapy at week 9, regardless of response. Patients on Arm I with at least a 50% response at week 8 receive 3 more courses of IVA and are reassessed at week 17; those who continue to respond between weeks 8 and 17 receive 3 additional courses of IVA. Patients with no further response receive 4 alternating courses of CEV and IVE. All patients with less than a CR at week 17 begin local therapy on week 18 concurrently with the additional chemotherapy. Patients on Arm I with less than a 50% response at week 8 receive alternating CEV and IVE as in Strategy 952. Patients with less than a CR at week 17 begin concurrent local therapy at week 18. Patients on Arm II who have at least a 50% response at week 8 continue treatment with 2 courses of sequential IVA, CEV, and IVE. Local therapy is concurrently administered, beginning on week 18, to patients who have not achieved a CR by week 17. Patients on Arm II who have less than a 50% response at week 8 proceed immediately to local therapy with additional chemotherapy at the investigator's discretion. Patients with less than a CR after local therapy are considered for treatment on a phase II protocol. LOCAL THERAPY Local therapy consists of conservative resection of residual disease (unless more debilitating surgery is appropriate). Patients with residual disease after surgery undergo external-beam radiotherapy 5 days per week for 6-7 weeks or brachytherapy; hyperfractionation is specifically excluded. For patients receiving radiotherapy, the dactinomycin dose in the IVA regimen is omitted from the middle course of chemotherapy and possibly the last course of chemotherapy during concurrent administration. Patients receiving alternating CEV and IVE have the courses reversed during concurrent radiotherapy, with possible omission of epirubicin for the third course. Radical surgery is considered for any patient who has residual disease at week 27. TREATMENT FOR RELAPSE Patients treated with Strategy 951 proceed to therapy with at least 6 alternating courses of IVE and CEV, with local therapy initiated after the second course. Other patients receive at least 6 alternating courses of CEV and vincristine, carboplatin, and etoposide (modified Vincaepi), with local therapy initiated after the second course. Patients who have already received either regimen may be re-treated with carboplatin and etoposide and vincristine and cyclophosphamide if relapse occurs more than 6 months after treatment, while those who relapse in less than 6 months are considered for phase II chemotherapy trials. Patients with metastatic relapse are evaluated for bone marrow or peripheral blood stem cell transplantation. Patients are followed every 2 months until 2 years after diagnosis, every 3 months for 1 year, every 6 months for 2 years, and then annually until 10 years after diagnosis. PROJECTED ACCRUAL: A total of 400 patients with high-risk nonmetastatic disease will be accrued for this study within approximately 4 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Childhood Malignant Fibrous Histiocytoma of Bone, Sarcoma
Keywords
embryonal childhood rhabdomyosarcoma, alveolar childhood rhabdomyosarcoma, pleomorphic childhood rhabdomyosarcoma, mixed childhood rhabdomyosarcoma, embryonal-botryoid childhood rhabdomyosarcoma, nonmetastatic childhood soft tissue sarcoma, childhood fibrosarcoma, childhood synovial sarcoma, childhood malignant hemangiopericytoma, childhood liposarcoma, childhood alveolar soft-part sarcoma, childhood leiomyosarcoma, childhood neurofibrosarcoma, childhood angiosarcoma, childhood epithelioid sarcoma, childhood malignant fibrous histiocytoma of bone, childhood malignant mesenchymoma, previously untreated childhood rhabdomyosarcoma, childhood desmoplastic small round cell tumor, localized Ewing sarcoma/peripheral primitive neuroectodermal tumor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Allocation
Randomized
Enrollment
400 (Anticipated)

8. Arms, Groups, and Interventions

Intervention Type
Biological
Intervention Name(s)
dactinomycin
Intervention Type
Drug
Intervention Name(s)
carboplatin
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Intervention Type
Drug
Intervention Name(s)
epirubicin hydrochloride
Intervention Type
Drug
Intervention Name(s)
etoposide
Intervention Type
Drug
Intervention Name(s)
ifosfamide
Intervention Type
Drug
Intervention Name(s)
vincristine sulfate
Intervention Type
Procedure
Intervention Name(s)
adjuvant therapy
Intervention Type
Procedure
Intervention Name(s)
conventional surgery
Intervention Type
Procedure
Intervention Name(s)
neoadjuvant therapy
Intervention Type
Radiation
Intervention Name(s)
brachytherapy
Intervention Type
Radiation
Intervention Name(s)
radiation therapy

10. Eligibility

Sex
All
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS: Histologically confirmed primary soft tissue sarcoma: Rhabdomyosarcoma Non-rhabdomyosarcoma Soft tissue primitive neuroectodermal tumor (PNET) Extraosseous Ewing's sarcoma PATIENT CHARACTERISTICS: Age: Under 18 Performance status: Not specified Life expectancy: Not specified Hematopoietic: Not specified Hepatic: Not specified Renal: Not specified PRIOR CONCURRENT THERAPY: Biologic: Not specified Chemotherapy: Not specified Endocrine: Not specified Radiotherapy: Not specified Surgery: Prior primary surgery allowed Other: No other prior therapy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
M. C. G. Stevens, MD
Organizational Affiliation
Institute of Child Health at University of Bristol
Official's Role
Study Chair
Facility Information:
Facility Name
Institute of Child Health
City
Bristol
State/Province
England
ZIP/Postal Code
BS2 8AE
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
21357778
Citation
Chisholm JC, Marandet J, Rey A, Scopinaro M, de Toledo JS, Merks JH, O'Meara A, Stevens MC, Oberlin O. Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy. J Clin Oncol. 2011 Apr 1;29(10):1319-25. doi: 10.1200/JCO.2010.32.1984. Epub 2011 Feb 28.
Results Reference
background
PubMed Identifier
21495161
Citation
Orbach D, Mc Dowell H, Rey A, Bouvet N, Kelsey A, Stevens MC. Sparing strategy does not compromise prognosis in pediatric localized synovial sarcoma: experience of the International Society of Pediatric Oncology, Malignant Mesenchymal Tumors (SIOP-MMT) Working Group. Pediatr Blood Cancer. 2011 Dec 15;57(7):1130-6. doi: 10.1002/pbc.23138. Epub 2011 Apr 14.
Results Reference
background
PubMed Identifier
19204197
Citation
Defachelles AS, Rey A, Oberlin O, Spooner D, Stevens MC. Treatment of nonmetastatic cranial parameningeal rhabdomyosarcoma in children younger than 3 years old: results from international society of pediatric oncology studies MMT 89 and 95. J Clin Oncol. 2009 Mar 10;27(8):1310-5. doi: 10.1200/JCO.2008.19.5701. Epub 2009 Feb 9.
Results Reference
background
PubMed Identifier
22665534
Citation
Oberlin O, Rey A, Sanchez de Toledo J, Martelli H, Jenney ME, Scopinaro M, Bergeron C, Merks JH, Bouvet N, Ellershaw C, Kelsey A, Spooner D, Stevens MC. Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study. J Clin Oncol. 2012 Jul 10;30(20):2457-65. doi: 10.1200/JCO.2011.40.3287. Epub 2012 Jun 4.
Results Reference
result

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Surgery Followed by Chemotherapy in Treating Young Patients With Soft Tissue Sarcoma

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