Combination Chemotherapy With or Without Hyperthermia Therapy in Treating Patients With Soft Tissue Sarcoma

OBJECTIVES:

• Determine local progression-free survival of patients with high-risk soft tissue sarcoma treated with neoadjuvant etoposide, ifosfamide, and doxorubicin with or without regional hyperthermia.
• Determine the tumor response rate, local disease control rate, and overall survival in patients treated with this regimen.

OUTLINE: This is a randomized study. Patients are stratified according to high-risk category (S1 vs S2 vs S3) and disease site (extremity vs nonextremity). Patients are randomized to one of two treatment arms.

• Arm I: Patients receive etoposide IV over 30 minutes on days 1 and 4, ifosfamide IV over 60 minutes on days 1-4, and doxorubicin IV over 30 minutes on day 1. Treatment continues every 21 days for a total of 4 courses. Patients also undergo regional hyperthermia.
• Arm II: Patients receive chemotherapy alone as in arm I. Patients in both arms undergo definitive surgery 4-6 weeks after chemotherapy. Patients also undergo radiotherapy beginning 4-6 weeks after surgery. After completion of surgery and radiotherapy, patients with non-resectable tumors showing no disease progression receive an additional 4 courses of chemotherapy with or without regional hyperthermia according to above treatment schedule.

Patients are followed every 3 months for 1 year, every 4 months for 2 years, and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 340 patients (170 patients per arm) will be accrued for this study within 3.5 years.

DISEASE CHARACTERISTICS:

• Histologically proven grade II or III soft tissue sarcoma of one of following high-risk groups:

• Grade II/III primary tumor with lesion size of at least 5 cm, deep, and extracompartmental (S1)
• Local recurrence of primary tumor (S2)
• Inadequate surgical excision of S1 or S2 (S3)
• Disease recurrence after prior surgery allowed
• The following histological types are eligible:

• Malignant fibrous histiocytoma
• Liposarcoma (round cell and pleomorphic)
• Leiomyosarcoma
• Fibrosarcoma
• Rhabdomyosarcoma
• Synovial sarcoma
• Malignant paraganglioma
• Neurofibrosarcoma (malignant schwannoma)
• Extraskeletal Ewing's sarcoma
• Extraskeletal osteosarcoma
• Malignant peripheral neuroectodermal tumors
• Mesenchymal chondrosarcoma
• Angiosarcoma
• Miscellaneous sarcoma
• Unclassified sarcoma
• No distant metastases

PATIENT CHARACTERISTICS:

Age:

• 18 to 70

Performance status:

• WHO 0-2 OR
• Karnofsky 60-100%

Life expectancy:

• Not specified

Hematopoietic:

• WBC at least 3,500/mm^3
• Platelet count at least 100,000/mm^3
• No bleeding disorder

Hepatic:

• Bilirubin less than 1.25 times upper limit of normal
• No severe hepatic dysfunction

Renal:

• Creatinine clearance greater than 60 mL/min
• No chronic renal failure

Cardiovascular:

• No documented existing cardiac failure
• No manifest heart failure (New York Heart Association class III or IV)
• Left ventricular ejection fraction no more than 10% below institutional normal

Other:

• No other prior or concurrent malignancy except adequately treated basal cell skin cancer or carcinoma in situ of the cervix
• No other severe disease
• No severe cerebrovascular disease
• No extremely obese patients
• No prior metallic implants relevant to the regional hyperthermia field
• Not pregnant or nursing

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy (except to disease recurrence outside study irradiation field)

Surgery:

• See Disease Characteristics
• No prior mutilative surgery