Osteosarcoma1999-A Study Of Intensive Chemotherapy for Osteosarcoma

• To compare the tumor response to chemotherapy with three drugs(ifosfamide, carboplatin, and doxorubicin)used before surgery in an earlier St.Jude Children's Research Hospital study.
• To study the accuracy of dynamic contrast-enhanced MR imaging in assessing the degree of response.

• To study the feasibility of administering therapy on an outpatient basis.
• To study whether a 3-cm surgical margin of normal bone (rather than the 5-cm standard margin)provides satisfactory
• resection of the primary tumor.
• To study biological markers including telomerase activity and DNA index.
• To learn what subjects and parents think about the of life during and after treatment

This trial (OS99) evaluates the use of ifosfamide, carboplatin, and doxorubicin in an up-front window before surgery for localized and resectable osteosarcoma. High-dose methotrexate, which may interfere with the dose-intensive delivery of other agents, is eliminated from the treatment of localized disease. The primary objective is to compare the response rate of pre-surgical chemotherapy comprised of ifosfamide, doxorubicin, and carboplatin to that obtained with ifosfamide and carboplatin in the St. Jude OS-91 trial for patients with non-metastatic resectable osteosarcoma. We hypothesize that the histologic response rate will be improved by the addition of one course of pre-operative chemotherapy on this trial compared to the previous OS-91 trial.

This study has multiple research objectives:

• To compare the response rate of pre-surgical chemotherapy comprised of ifosfamide, doxorubicin, and carboplatin to that obtained with ifosfamide and carboplatin in the St. Jude OS-91 trial for patients with non-metastatic resectable osteosarcoma
• To continue the evaluation of dynamic contrast-enhanced magnetic resonance imaging (DEMRI) in predicting tumor response and accurately assessing the degree of response (continued from OS-91).
• To determine the feasibility of delivering outpatient-based chemotherapy for osteosarcoma using ifosfamide-doxorubicin-carboplatin.
• To determine whether resection of the primary site may be satisfactorily performed with a 3 cm margin of normal bone (rather than 5 cm).
• To study biologic and biochemical characteristics of the tumor cells that may be of prognostic significance
• To study the patients' and parents' perspectives of the patients' quality of life during and after treatment.

Description of Treatment Plan:

This study employs the following treatment strategy: neoadjuvant chemotherapy followed by definitive surgery for local control and adjuvant chemotherapy after tumor resection.

Pre-operative chemotherapy phase (weeks 0-12): Three courses of ifosfamide/carboplatin given every 3 weeks followed by one 3-week course of doxorubicin.Disease evaluation is performed after 3 courses and after 4 courses of chemotherapy.

Weeks 0, 3, and 6 - Ifosfamide-Carboplatin Ifosfamide: 2.65 gm/m2 IV daily over 15-30 minutes x 3 (Days 1, 2, 3) with MESNA. Carboplatin: dose based on GFR and targeted to an AUC of 8 mg/mL/min, given IV over 1 hour (Day 1 only)

Week 9- Evaluation, followed by Doxorubicin Doxorubicin: 25 mg/m2 IV over 1 hour, daily x 3

Week 12 Evaluation followed by definitive Surgery Local control by amputation or limb-salvage procedure

Post-operative chemotherapy (Weeks 14-35) Ifosfamide, carboplatin, and doxorubicin in two-agent pairs for approximately 35 weeks.

Week 14 - Ifosfamide-Doxorubicin Ifosfamide: 2.65 gm/m2 IV daily over 15-30 minutes x 3 (Days 1, 2, 3) with MESNA, Doxorubicin: 25 mg/m2 IV over 1 hour, daily x 2 (Days 1 and 2)

Week 17 - Ifosfamide-Carboplatin Ifosfamide: 2.65 gm/m2 IV daily over 15-30 minutes x 3 (Days 1, 2, 3) with MESNA, Carboplatin: targeted to an AUC of 8 mg/mL/min given IV over 1 hour (Day 1 only)

Week 20 - Carboplatin-Doxorubicin Carboplatin: targeted to an AUC of 8 mg/mL/min given IV over 1 hour (Day 1 only), Doxorubicin: 25 mg/m2 IV over 1 hour, daily x 2 (Days 1 and 2)

Week 23 - Evaluation, followed by Ifosfamide:

Doxorubicin. Ifosfamide: 2.65 gm/m2 IV daily over 15-30 minutes x 3 (Days 1, 2, 3) with MESNA, Doxorubicin: 25 mg/m2 IV over 1 hour, daily x 2 (Days 1 and 2)

Week 26 - Ifosfamide-Carboplatin Ifosfamide: 2.65 gm/m2 IV daily over 15-30 minutes x 3 (Days 1, 2, 3) with MESNA, Carboplatin: targeted to an AUC of 8 mg/mL/min given IV over 1 hour (Day 1 only)

Week 29 - Carboplatin-Doxorubicin Carboplatin: targeted to an AUC of 8 mg/mL/min given IV over 1 hour (Day 1 only), Doxorubicin: 25 mg/m2 IV over 1 hour, daily x 2 (Days 1 and 2)

Week 32 - Evaluation, followed by Ifosfamide-Doxorubicin. Ifosfamide: 2.65 gm/m2 IV daily over 15-30 minutes x 3 (Days 1, 2, 3) with MESNA, Doxorubicin: 25 mg/m2 IV over 1 hour, daily x 2 (Days 1 and 2)

Week 35 - Carboplatin-Doxorubicin Carboplatin: targeted to an AUC of 8 mg/mL/min given IV over 1 hour (Day 1 only), Doxorubicin: 25 mg/m2 IV over 1 hour, daily x 2 (Days 1 and 2)

• Drug: Ifosfamide, Carboplatin, Doxorubicin
  See Detailed Description for treatment plan.
• Procedure: Limb Sparing
  See Detailed Description for treatment plan.

• Crews KR, Stewart CF, Liu T, Rodriguez-Galindo C, Santana VM, Daw NC. Effect of fractionated ifosfamide on the pharmacokinetics of irinotecan in pediatric patients with osteosarcoma. J Pediatr Hematol Oncol. 2004 Nov;26(11):764-7.
• Sanders RP, Drissi R, Billups CA, Daw NC, Valentine MB, Dome JS. Telomerase expression predicts unfavorable outcome in osteosarcoma. J Clin Oncol. 2004 Sep 15;22(18):3790-7.
• McCarville MB, Barton EH, Romano E, Cameron J, Kaste SC, Daw NC, Wu S, Glass JO, Xiong X, Reddick WE. The etiology and clinical significance of the thallium donut sign in pediatric osteosarcoma of the extremity. Am J Roentgenol 188:572-578, 2007.
• McCarville MB, Reddick WE, Xiong X, Kaste SC, Daw NC. Clinical significance of the 201Thallium donut-sign in primary extremity osteosarcoma. Presented at the 2006 Society of Pediatric Radiology and European Society of Paediatric Radiology's Fifth Conjoint Meeting, Montreal, Quebec, Canada, May 18-20, 2006.
• Kaste SC, Waszilycsak G, McCarville MB, Daw NC. Excess cancer mortality in pediatric thallium imaging. Presented at the 2006 Society of Pediatric Radiology and European Society of Paediatric Radiology's Fifth Conjoint Meeting, Montreal, Quebec, Canada, May 18-20, 2006.
• Freeman SS, Allen SW, Ganti R, Wu J, Ma J, Su X, Neale GA, Dalton JD, Billups CA, Dome JS, Daw NC, Khoury JD. EGFR expression and copy number gain are common in osteosarcoma. Presented at the US and Canadian Academy of Pathology Annual Meeting, San Diego, California, March 24-30, 2007.
• Reddick WE, Hoffer FA, Billups CA, Jenkins JJ, Wu J, Daw NC. Response assessment using dynamic MR imaging in non-metastatic osteosarcoma. To be presented at the ASCO Annual Meeting, Chicago, Illinois, June 2007.
• Rivera GK, Quintana J, Villarroel M, Rodríguez C, Santana VM, Ribeiro RC, Daw NC. Conduct of an international collaborative osteosarcoma trial at centers in a developed and developing country. To be presented at the ASCO Annual Meeting, Chicago, Illinois, June 2007.

Inclusion Criteria:

• All subjects with histologically proven high-grade osteosarcoma,chondrosarcoma, MFH, fibrosarcoma or chondrosarcoma of bone, whose tumors are potentially resectable (either by limb sparing, en bloc resection, or amputation) and have no evidence of metastasis.
• Adequate liver, renal and cardiac function.
• Age: Younger than 25 years old

Exclusion Criteria:

• Prior chemotherapy

• Immunex/Berlex
• National Institutes of Health (NIH)