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Bone Cancer: Treatment Outcome Based on Tumor Response

Official Title: Osteosarcoma: Outcome of Therapy Based on Histologic Response: A Collaborative Effort of the POB/NCI, Texas Children's Hospital and University of Oklahoma

Purpose

This study will evaluate the safety and effectiveness of chemotherapy using the drugs doxorubicin, cisplatin, and methotrexate along with surgery to treat patients with bone cancer. Patients undergo chemotherapy followed by surgery to remove the tumor and then receive another course of chemotherapy.

Patients < 25 years old and diagnosed with osteosarcoma may be eligible for this study. Candidates are screened with a medical history and physical examination, blood and urine tests, MUGA (nuclear medicine test of heart function) or echocardiogram, computed tomography (CT) magnetic resonance imaging (MRI), bone scans, chest x-ray, and a hearing test.

Participants have a catheter (plastic tube) placed in a vein through which they receive treatment with chemotherapy, other medicines, intravenous fluids, and blood, if needed. Blood samples can be withdrawn through the catheter. Chemotherapy consists of doxorubicin, cisplatin and methotrexate given over 9 weeks. In addition, patients receive a drug called dexrazoxane before each dose of doxorubicin to protect the heart from possible injury due to doxorubicin, and they receive leucovorin after methotrexate to protect healthy cells from potential side effects of that drug.

When first screened and after 9 weeks of chemotherapy, patients have a type of MRI called dynamic enhanced magnetic resonance imaging (DEMRI). In addition to showing the bone and muscle, DEMRI provides information on blood flow in the area affected by the tumor. MRI takes about 35 minutes to complete, and the DEMRI portion of the imaging may take an additional 15 to 60 minutes. DEMRI may be done in conjunction with or separately from conventional MRI.

After the first 10 weeks of chemotherapy, patients are referred for surgery to remove the primary tumor and any other tumor tissue that may have spread to other sites. Portions of the tumor may be used for research tests.

The removed tumor is examined to determine the amount of tumor that has survived, and patients then receive more courses of doxorubicin with dexrazoxane, cisplatin and methotrexate.

Patients with non-metastatic osteosarcoma of the extremity have a 60-70% long-term survival with current therapy which includes neoadjuvant chemotherapy, surgical resection, and adjuvant combination chemotherapy. Response to neoadjuvant chemotherapy as measured histologically (% tumor necrosis) at the time of resection is a strong predictor of long-term outcome. Neoadjuvant regimens have typically included 2 or more of the following: doxorubicin, cisplatin, high-dose methotrexate and ifosfamide. In this collaborative pilot study between Texas Children's Hospital, the Pediatric Oncology Branch/NCI and University of Oklahoma Health Sciences Center, we propose to administer cisplatin, methotrexate, and doxorubicin with dexrazoxane for cardioprotection in the neoadjuvant setting. Patients will then receive additional courses of cisplatin, methotrexate and doxorubicin in the post surgical setting. Currently, three groups of patients with poor outcome can be identified:

1. metastatic disease at diagnosis
2. unresectable disease
3. non-metastatic disease with poor response to neoadjuvant chemotherapy (less than 90% tumor necrosis).

Biologic studies including cDNA microarray analysis of tumor gene expression patterns and orthotopic implantation of tumor into SCID-Beige mice are planned in order to improve our understanding of the biology of osteosarcoma. Finally, Dynamic Magnetic Resonance Imaging (DEMRI) is proposed as a potential modality to be used in evaluating response to therapy.

Eligibility

Genders Eligible for Study: Both

Criteria

Inclusion Criteria:

• Patients with histologically proven newly diagnosed osteosarcoma (patients with biopsy obtained at institutions other than NIH are eligible)
• Non-metastatic malignant high-grade osteosarcoma of bone.
• Patients with metastatic disease and/or unresectable primary disease are eligible. Metastatic disease should be biopsy-proven. It is recommended that any lung lesion seen on chest CT greater than 0.5 cm should be biopsied before designating it as metastatic disease. Thoracotomies are recommended for assessment.
• Age less than or equal to 25 years.
• Adequate bone marrow function with an ANC greater than or equal to 1000/mm(3), platelet count greater than or equal to 100,000 mm(3) and hemoglobin greater than or equal to 8.0 g/dl.
• Adequate renal function with serum creatinine less than or equal to 1.5 times normal and creatinine clearance or radioisotope GFR greater than 70 ml/min/1.73 m(2).
• Adequate cardiac function as determined by ECHO or MUGA (SF greater than or equal to 27% or EF greater than or equal to 45%).
• Adequate liver function (Total bilirubin less than or equal to 2.0 mg/dl; ALT less than 5 times normal).
• Informed Consent: All patients or their legal guardians (if the patient is less than 18 years of age) must sign a document of informed consent indicating their awareness of the investigational nature and the risks of the study. When appropriate the patient will be included in all discussions in order to obtain verbal assent. Consent for research imaging will be obtained for those patients who agree to research imaging.

Exclusion Criteria:

• Pregnancy.
• Low-grade osteosarcoma, parosteal or periosteal osteosarcoma.
• Patients who are currently receiving chemotherapy on other protocols or treatment plans with no evidence of progressive disease are not eligible for any part of this protocol.

Location and Contact Information

Maryland

National Cancer Institute (NCI), 9000 Rockville Pike, Bethesda, Maryland, 20892, United States; Recruiting
Clinical Studies Support Center/NCI 1-888-624-1937. E-mail