Combination Chemotherapy in Treating Patients Undergoing Surgery for Newly Diagnosed High-Grade Osteosarcoma

Treatment of Newly Diagnosed Untreated Osteosarcoma: A Pilot Study of a New Chemotherapeutic Regimen Including Ifosfamide

RATIONALE: Drugs used in chemotherapy, such as ifosfamide, methotrexate, cisplatin, 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 chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving it after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This clinical trial is studying how well combination chemotherapy works in treating patients undergoing surgery for newly diagnosed high-grade osteosarcoma.

Study Overview

• Status: Completed
• Conditions: Sarcoma
• Intervention / Treatment: Procedure: therapeutic conventional surgery; Drug: methotrexate; Procedure: adjuvant therapy; Procedure: neoadjuvant therapy; Drug: cisplatin; Drug: doxorubicin hydrochloride; Drug: ifosfamide

Detailed Description

OBJECTIVES:

• To evaluate the efficacy of a new induction regimen comprising ifosfamide in combination with high-dose methotrexate, cisplatin, and doxorubicin hydrochloride, in terms of clinical response and pathological response of the tumor, in patients with newly diagnosed high-grade osteosarcoma.
• To determine the overall survival and disease-free survival of these patients.
• To evaluate the toxicity of this regimen.
• To correlate MRI imaging of the primary tumor with histopathologic grading after treatment with this regimen.

OUTLINE: This is a multicenter study.

• Neoadjuvant chemotherapy (weeks 1-15): Patients receive ifosfamide IV over 1 hour on days 1-5 and 36-40; doxorubicin hydrochloride IV over 18 hours on days 1-3 and 36-38 and IV over 72 hours on days 71-73; high-dose methotrexate IV over 4 hours on days 22, 29, 57, 64, 92, and 99; and cisplatin IV over 4 hours on day 71.
• Surgery (week 16): Patients undergo resection of the tumor on day 106. Patients found to have unresectable disease are treated on an alternative protocol unless they have clear clinical and pathologic response to treatment.
• Adjuvant chemotherapy (weeks 18-43): Beginning 2 weeks after surgery, patients receive ifosfamide IV over 1 hour on days 120-124, 155-159, 225-229, and 260-264; doxorubicin hydrochloride IV over 18 hours on days 120-122 and 155-157 and IV over 72 hours on days 190-192; high-dose methotrexate IV over 4 hours on days 141, 148, 176, 183, 211, 218, 246, 253, 281, and 288; and cisplatin IV over 4 hours on days 190 and 289.

After completion of study therapy, patients are followed every 2 months for 1 year, every 4 months for 2 years, every 6 months for 2 years, and then annually thereafter.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed osteosarcoma of the extremity

  • High-grade (grade III or IV) disease

    • No low-grade disease (e.g., parosteal or periosteal osteosarcoma)
• No secondary osteosarcoma (i.e., tumor occurring in a radiotherapy field designed for a prior tumor)
• No Paget's disease
• No known metastases

PATIENT CHARACTERISTICS:

• Total bilirubin < 2 times normal
• AST < 2 times normal
• Alkaline phosphatase < 2 times normal
• Creatinine ≤ 1.5 mg/dL OR creatinine clearance > 60 mL/min
• LVEF ≥ 45%
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

• No other prior malignancy except retinoblastoma

  • Patients with familial retinoblastoma syndrome who develop osteosarcoma unrelated to radiotherapy (e.g., in a primary site in the extremities) are eligible

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy or radiotherapy

  • Patients with retinoblastoma may have received radiotherapy to the orbits
• At least 28 days since prior initial amputation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Toxicity
Overall survival
Disease-free survival
Clinical response rate
Histopathologic response rate

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Gerald S. Gilchrist, MD, Mayo Clinic; Principal Investigator: Tom R Fitch, M.D., Mayo Clinic; Principal Investigator: Gerardo Colon-Otero, M.D., Mayo Clinic

Study record dates

Study Major Dates

• Study Start: November 1, 1990
• Primary Completion (Actual): January 1, 1995
• Study Completion (Actual): January 1, 2008

Study Registration Dates

• First Submitted: March 26, 2008
• First Submitted That Met QC Criteria: March 26, 2008
• First Posted (Estimate): March 27, 2008

Study Record Updates

• Last Update Posted (Estimate): May 16, 2011
• Last Update Submitted That Met QC Criteria: May 13, 2011
• Last Verified: May 1, 2011

More Information

Terms related to this study

• Keywords: localized osteosarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Osteosarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Ifosfamide; Doxorubicin; Liposomal doxorubicin; Methotrexate
• Other Study ID Numbers: CDR0000582263; P30CA015083 (U.S. NIH Grant/Contract); 909101 (Other Identifier: Mayo Clinic Cancer Center); 549-90 (Other Identifier: Mayo Clinic IRB)