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Osteosarcoma

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Sarcoma

Soft Tissue Sarcoma

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Folate

Vitamin B9

Preoperative Chemotherapy Courses 1, 2, 3, 4: 750mg/m2; IV over 15 minutes on day 1

Postoperative Chemotherapy for Good Responders Courses 1 and 2: 750mg/m2 IV over 15 minutes on Day 1

Postoperative Chemotherapy for Poor Responders Courses 2 and 4: 750mg/m2 IV over 15 minutes on Day 1

Preoperative Chemotherapy Courses 1 and 3: 75mg/m2; IV push day 1 Courses 2 and 4: 75mg/m2; IV push day 1, hour 0

Postoperative Chemotherapy for Good Responders Course 1: 75mg/m2; IV push day 1 Course 2: 75mg/m2; IV push day 1, hour 0

Postoperative Chemotherapy for Poor Responders Course 2: 75mg/m2; IV push day 1 Course 4: 75mg/m2; IV push day 1, hour 0

Preoperative Chemotherapy Courses 1 and 3: 60mg/m2 daily x 2 days, in 1000 ml D5W NS + 10g/m2 mannitol

Postoperative Chemotherapy for Good Responders Courses 1 and 2: 60mg/m2 daily x 2 days, in 1000 ml D5W NS + 10g/m2 mannitol

Postoperative Chemotherapy for Poor Responders:

Course 2: 60mg/m2 daily x 2 days, in 1000 ml D5W NS + 10g/m2 mannitol

Preoperative Chemotherapy Courses 1, 2, 3, and 4: 5mcg/Kg; IV/SQ starting 24 hours after chemotherapy until WBC \>10,000

Postoperative Chemotherapy for Good Responders Courses 1, 2, and 3: 5mcg/Kg; IV/SQ starting 24 hours after chemotherapy until WBC \>10,000

Postoperative Chemotherapy for Poor Responders Courses 2, 4, and 5: 5mcg/Kg; IV/SQ starting 24 hours after chemotherapy until WBC \>10,000

G-CSF

Preoperative Chemotherapy Courses 1, 2, 3, and 4: 6mg; SQ starting 24 hours after chemotherapy

Postoperative Chemotherapy for Good Responders Courses 1, 2, and 3: 6mg; SQ starting 24 hours after chemotherapy

Postoperative Chemotherapy for Poor Responders Courses 2 and 4: 6mg; SQ starting 24 hours after chemotherapy

PEG-filgrastim

Preoperative Chemotherapy Courses 2 and 4: 50mg/m2 on days 1, 2, 3, 4

Postoperative Chemotherapy for Good Responders Course 2: 50mg/m2 on days 1, 2, 3, 4 Course 3: 50mg/m2 on days, 1, 2, 3, 4 Hour 0-1

Postoperative Chemotherapy for Poor Responders Course 4: 50mg/m2 on days 1, 2, 3, 4 Course 5: 50mg/m2 on days 1, 2, 3, 4

Preoperative Chemotherapy Courses 2 and 4: 3g/m2; IV over 1 hour Days 1, 2, 3, 4

Postoperative Chemotherapy for Good Responders Course 2: 3g/m2; IV over 1 hour Days 1, 2, 3, 4 Course 3: 3g/m2; IV over 1 hour Days 1, 2, 3, 4

Postoperative Chemotherapy for Poor Responders Course 4: 3g/m2; IV over 1 hour Days 1, 2, 3, 4 Course 5: 3g/m2; IV over 1 hour Days 1, 2, 3, 4

Preoperative Chemotherapy Courses 2 and 4: 600mg/m2, 1st dose in bag with ifosfamide, 2nd dose IV over 3 hours immediately post ifosfamide infusion, Subsequent doses - hour 5, 8, 11, 14 (IV push)

Postoperative Chemotherapy for Good Responders Courses 2 and 3: 600mg/m2, 1st dose in bag with ifosfamide, 2nd dose IV over 3 hours immediately post ifosfamide infusion, Subsequent doses - hour 5, 8, 11, 14 (IV push)

Postoperative Chemotherapy for Poor Responders Courses 4 and 5: 600mg/m2, 1st dose in bag with ifosfamide, 2nd dose IV over 3 hours immediately post ifosfamide infusion, Subsequent doses - hour 5, 8, 11, 14 (IV push)

Postoperative Chemotherapy for Poor Responders Courses 1 and 3: 15 mg/m2/dose IV or PO every 6 hours, beginning 24 hours after start of methotrexate infusion and continuing until methotrexate level is \<0.1 uM

Stephen X. Skapek, MD

Andres Morales, MD

This is a pilot study that will allow investigators to collect data related to early and potentially more accurate response assessments using a chemotherapy protocol that eliminates methotrexate to maximize the dose intensity of doxorubicin. The pilot data will be used to seek funding to more fully address the hypotheses in a multi-institutional, Phase II or Phase III trial. The primary and secondary objectives are as follows:

Primary:

1. To evaluate the feasibility and potential usefulness of measuring early changes in tumor metabolic activity, assessed by Fludeoxyglucose-Positron Emission Tomography (FDG-PET) imaging and alkaline phosphatase activity, as early predictors of histological response rate at 12 weeks in osteosarcoma patients.
2. To explore whether histological response can be assessed by a computer algorithm using virtual microscopic images of pathology material, and whether quantifying necrosis in this way correlates with microscope slide-based review.

Secondary:

1. To gather pilot data on the histological response rate, 3-year event-free survival, and toxicity when children and young adults with resectable osteosarcoma are treated using a chemotherapy regimen of alternating courses of doxorubicin/cisplatin (DC) and doxorubicin/ifosfamide/etoposide (IDE).

All patients will receive 4 courses of preoperative chemotherapy courses. With the exception of high-dose methotrexate, which is given weekly, preoperative and postoperative chemotherapy courses are planned to begin every 21 days.

Patients with good histological response (those patients with \> 90% tumor necrosis at time of definitive resection) will receive three postoperative chemotherapy courses. The 1st will consist of doxorubicin, dexrazoxane, cisplatin and Granulocyte-Colony Stimulating Factor (G-CSF)(or Polyethylene Glycol filgrastim). The 2nd course will consist of doxorubicin, dexrazoxane, ifosfamide, MESNA, etoposide, G-CSF (or PEG-filgrastim). The 3rd course will consist of ifosfamide, MESNA, etoposide, G-CSF (or PEG-filgrastrim). The total doxorubicin dose will be 450 mg/m2.

Patients with poor response (those patients with \< 90% tumor necrosis found on pathology at time of definitive resection) will receive five postoperative chemotherapy courses. High Dose-Methotrexate will be administered during the 1st and 3rd postoperative chemotherapy courses as 4-weekly and 2-weekly doses, respectively. The 2nd course will consist of doxorubicin, dexrazoxane, cisplatin and G-CSF (or PEG-filgrastim). The 4th course will consist of doxorubicin, dexrazoxane, ifosfamide, Mesna, etoposide, G-CSF (or PEG-filgrastim). The 5th cycle will consist of ifosfamide, Mesna, etoposide, G-CSF (or PEG-filgrastrim). The total doxorubicin dose will be 450 mg/m2.

A Study of Pre-Operative Treatment of Newly-Diagnosed, Surgically-Resectable Osteosarcoma With Doxorubicin, Ifosfamide, Etoposide, and Cisplatin With Early Metabolic Assessment of Response

A Pilot Study of Pre-Operative Treatment of Newly-Diagnosed, Surgically-Resectable Osteosarcoma With Doxorubicin, Ifosfamide, Etoposide, and Cisplatin With Early Metabolic Assessment of Response

The feasibility and potential usefulness of measuring early changes in tumor metabolic activity will be assessed by early Fludeoxyglucose-Positron Emission Tomography imaging and alkaline phosphatase activity.

To gather pilot data on the histological response rate when children and young adults with resectable osteosarcoma are treated using a chemotherapy regimen of alternating courses of doxorubicin/cisplatin (DC) and doxorubicin/ifosfamide/etoposide (IDE).

To explore whether histological response can be measured by a computer algorithm using virtual microscopic images of pathology material, and whether quantifying necrosis in this way correlates with microscope slide-based review.

To gather pilot data on the 3-year event-free survival when children and young adults with resectable osteosarcoma are treated using a chemotherapy regimen of alternating courses of doxorubicin/cisplatin (DC) and doxorubicin/ifosfamide/etoposide (IDE).

To gather pilot data on toxicity when children and young adults with resectable osteosarcoma are treated using a chemotherapy regimen of alternating courses of doxorubicin/cisplatin (DC) and doxorubicin/ifosfamide/etoposide (IDE).

Spots Global Cancer Trial Database for surgically resectable high grade osteosarcoma