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

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ClinicalTrials.gov Identifier: NCT00003052

Recruitment Status : Completed

First Posted : January 27, 2003

Last Update Posted : September 17, 2013

Sponsor:

Collaborator:

The European Society for Hyperthermic Oncology

Information provided by:

National Cancer Institute (NCI)

Study Description

Brief Summary:

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Hyperthermia therapy kills tumor cells by heating them to several degrees above body temperature. It is not known whether receiving chemotherapy plus hyperthermia is more effective than receiving chemotherapy alone in treating patients with soft tissue sarcoma.

PURPOSE: This randomized phase III trial is studying combination chemotherapy alone to see how well it works compared to combination chemotherapy and hyperthermia therapy in treating patients with soft tissue sarcoma.

Condition or disease	Intervention/treatment	Phase
Sarcoma	Drug: doxorubicin hydrochloride Drug: etoposide Drug: ifosfamide Procedure: conventional surgery Procedure: hyperthermia treatment Radiation: radiation therapy	Phase 3

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	340 participants
Allocation:	Randomized
Primary Purpose:	Treatment
Official Title:	Randomized Study Comparing Neoadjuvant Chemotherapy Etoposide + Ifosfamide + Adriamycin (EIA) Combined With Regional Hyperthermia (RHT) Versus Neoadjuvant Chemotherapy Alone in the Treatment of High-Risk Soft Tissue Sarcomas in Adults
Study Start Date :	July 1997
Actual Study Completion Date :	June 2010

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fever Soft Tissue Sarcoma

Genetic and Rare Diseases Information Center resources: Soft Tissue Sarcoma Undifferentiated Pleomorphic Sarcoma Osteosarcoma Leiomyosarcoma Liposarcoma Synovial Sarcoma Malignant Peripheral Nerve Sheath Tumor Neurofibrosarcoma Fibrosarcoma

U.S. FDA Resources

Arms and Interventions

Outcome Measures

Primary Outcome Measures :

Local progression-free survival

Secondary Outcome Measures :

Response as assessed by WHO criteria
Overall survival
Relapse-free survival
Acute and late complications as assessed by CTC v 1.0

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years to 70 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00003052

Locations

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Germany
Robert Roessle Comprehensive Cancer Center at University of Berlin - Charite Campus Buch
Berlin, Germany, D-13122
Universitaetsklinikum Essen
Essen, Germany, D-45122
Universitaetsklinikum Hamburg-Eppendorf
Hamburg, Germany, D-20246
Klinikum der Universitaet Muenchen - Grosshadern Campus
Munich, Germany, D-81377

Sponsors and Collaborators

European Organisation for Research and Treatment of Cancer - EORTC

The European Society for Hyperthermic Oncology

Investigators

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OverallOfficial:	Rolf D. Issels, MD, PhD	Klinikum der Universitaet Muenchen - Grosshadern Campus
Study Chair:	Rolf D. Issels, MD, PhD	Klinikum der Universitaet Muenchen - Grosshadern Campus

More Information

Publications of Results:

Issels RD, Lindner LH, Verweij J, Wust P, Reichardt P, Schem BC, Abdel-Rahman S, Daugaard S, Salat C, Wendtner CM, Vujaskovic Z, Wessalowski R, Jauch KW, Dürr HR, Ploner F, Baur-Melnyk A, Mansmann U, Hiddemann W, Blay JY, Hohenberger P; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG); European Society for Hyperthermic Oncology (ESHO). Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 2010 Jun;11(6):561-70. doi: 10.1016/S1470-2045(10)70071-1. Epub 2010 Apr 29.

Issels RD, Lindner LH, Wust P, et al.: Regional hyperthermia (RHT) improves response and survival when combined with systemic chemotherapy in the management of locally advanced, high grade soft tissue sarcomas (STS) of the extremities, the body wall and the abdomen: a phase III randomised pros. [Abstract] J Clin Oncol 25 (Suppl 18): A-10009, 547s, 2007.

Lindner LH, Schlemmer M, Hohenberger P, et al.: Risk assessment of early progression among 213 pts with high-risk soft tissue sarcomas (HR-STS) treated with neoadjuvant chemotherapy regional hyperthermia: EORTC 62961/ESHO-RHT 95 intergroup phase III study. [Abstract] J Clin Oncol 23 (Suppl 16): A-9020, 821s, 2005.

Other Publications:

Stahl R, Wang T, Lindner LH, Abdel-Rahman S, Santl M, Reiser MF, Issels RD. Comparison of radiological and pathohistological response to neoadjuvant chemotherapy combined with regional hyperthermia (RHT) and study of response dependence on the applied thermal parameters in patients with soft tissue sarcomas (STS). Int J Hyperthermia. 2009 Jun;25(4):289-98. doi: 10.1080/02656730902873616.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Issels RD, Noessner E, Lindner LH, Schmidt M, Albertsmeier M, Blay JY, Stutz E, Xu Y, Buecklein V, Altendorf-Hofmann A, Abdel-Rahman S, Mansmann U, von Bergwelt-Baildon M, Knoesel T. Immune infiltrates in patients with localised high-risk soft tissue sarcoma treated with neoadjuvant chemotherapy without or with regional hyperthermia: A translational research program of the EORTC 62961-ESHO 95 randomised clinical trial. Eur J Cancer. 2021 Oct 16;158:123-132. doi: 10.1016/j.ejca.2021.09.015. [Epub ahead of print]

Issels RD, Lindner LH, Verweij J, Wessalowski R, Reichardt P, Wust P, Ghadjar P, Hohenberger P, Angele M, Salat C, Vujaskovic Z, Daugaard S, Mella O, Mansmann U, Dürr HR, Knösel T, Abdel-Rahman S, Schmidt M, Hiddemann W, Jauch KW, Belka C, Gronchi A; European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group and the European Society for Hyperthermic Oncology. Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial. JAMA Oncol. 2018 Apr 1;4(4):483-492. doi: 10.1001/jamaoncol.2017.4996. Erratum in: JAMA Oncol. 2018 Apr 1;4(4):590.

Knösel T, Altendorf-Hofmann A, Lindner L, Issels R, Hermeking H, Schuebbe G, Gibis S, Siemens H, Kampmann E, Kirchner T. Loss of p16(INK4a) is associated with reduced patient survival in soft tissue tumours, and indicates a senescence barrier. J Clin Pathol. 2014 Jul;67(7):592-8. doi: 10.1136/jclinpath-2013-202106. Epub 2014 Apr 19.

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ClinicalTrials.gov Identifier:	NCT00003052
Other Study ID Numbers:	CDR0000065699 EORTC-62961
First Posted:	January 27, 2003 Key Record Dates
Last Update Posted:	September 17, 2013
Last Verified:	November 2006

Keywords provided by National Cancer Institute (NCI):


adult angiosarcoma adult fibrosarcoma adult leiomyosarcoma adult liposarcoma adult neurofibrosarcoma adult synovial sarcoma stage III adult soft tissue sarcoma	recurrent adult soft tissue sarcoma adult extraskeletal osteosarcoma adult malignant fibrous histiocytoma adult rhabdomyosarcoma stage I adult soft tissue sarcoma stage II adult soft tissue sarcoma

Additional relevant MeSH terms:

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Sarcoma Hyperthermia Neoplasms, Connective and Soft Tissue Neoplasms by Histologic Type Neoplasms Body Temperature Changes Heat Stress Disorders Wounds and Injuries Doxorubicin Liposomal doxorubicin Etoposide	Ifosfamide Antibiotics, Antineoplastic Antineoplastic Agents Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Phytogenic Antineoplastic Agents, Alkylating Alkylating Agents

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