Trial Information

Protocol for Patients With Newly-Diagnosed Non-Metastatic Osteosarcoma - A POG/CCG Pilot Intergroup Study

OBJECTIVES: I. Compare the efficacy of three intensification regimens (doxorubicin vs
doxorubicin plus ifosfamide vs doxorubicin plus ifosfamide and etoposide) in patients with
newly diagnosed, previously untreated, nonmetastatic osteosarcoma. II. Determine the effect
of postoperative dose intensification on outcome in patients with standard response to
preoperative chemotherapy. III. Determine the effect of dexrazoxane cardioprotection during
standard induction therapy on histologic response in these patients. IV. Evaluate biological
factors that may predict outcome in these patients. V. Determine the safety of dexrazoxane
administered with doxorubicin in combination with cisplatin or cisplatin and ifosfamide in
these patients. VI. Determine the effect of dexrazoxane on cytotoxicity as measured by tumor
necrosis at definitive surgery in these patients. VII. Assess the feasibility of
administering doxorubicin with dexrazoxane cardioprotection or high dose ifosfamide with
etoposide to standard risk patients who are also receiving methotrexate and cisplatin.

OUTLINE: This is a multicenter study. Patients are enrolled sequentially on 1 of 3 pilot
intensification regimens. After surgery to completely remove the primary tumor, patients are
assigned to 1 of 2 adjuvant chemotherapy groups based on percent necrosis at limb salvage.
Pilot 1: (Closed to accrual as of 6/2/2000) Patients receive dexrazoxane IV followed
immediately by doxorubicin IV over 20 minutes plus cisplatin IV over 4 hours on days 1 and 2
of weeks 1 and 6. Methotrexate IV over 4 hours is administered on day 1 of weeks 4, 5, 9,
and 10. Patients undergo surgery on week 11. Adjuvant chemotherapy begins on day 1 of week
13. Group 1 (good response to neoadjuvant chemotherapy): Patients receive methotrexate IV
over 4 hours every 3 weeks for 6 courses, beginning on week 13. Patients also receive
dexrazoxane and doxorubicin every 3 weeks for 4 courses, beginning on week 14. Cisplatin is
administered with the first 2 courses of dexrazoxane and doxorubicin. Group 2 (standard
response to neoadjuvant chemotherapy): Patients receive methotrexate and cisplatin as in
group 1 plus dexrazoxane and doxorubicin for 6 courses. Pilot 2: Patients receive
preoperative therapy comprised of dexrazoxane, doxorubicin, and methotrexate as in pilot 1.
Ifosfamide IV over 4 hours is also administered on days 1-5 of week 1. Patients undergo
surgery on week 11, then begin adjuvant chemotherapy on week 13. Group 1: Patients receive
methotrexate, dexrazoxane, and doxorubicin as in pilot 1, group 1. Ifosfamide is also
administered on weeks 14 and 20. Cisplatin is administered on weeks 17, 23, and 26. Group 2:
Patients receive methotrexate, dexrazoxane, and doxorubicin as in pilot 1, group 2.
Ifosfamide is administered on weeks 14, 20, 26, and 31. Cisplatin is administered on weeks
17, 23, and 29. Pilot 3: (Open to accrual as of 6/2/2000) Patients receive preoperative
therapy comprised of methotrexate, dexrazoxane, doxorubicin, ifosfamide, and cisplatin as in
pilot 2. Patients undergo surgery on week 11, then begin adjuvant chemotherapy on week 13.
Group 1: Patients receive methotrexate, dexrazoxane, doxorubicin, ifosfamide, and cisplatin
as in pilot 2, group 1. Group 2: Patients receive methotrexate on weeks 13, 19, 29, 32, 35,
and 36, high dose ifosfamide and etoposide IV over 4 hours on days 1-5 of weeks 14, 23, and
26, and cisplatin on weeks 20, 30, and 33. Dexrazoxane and doxorubicin are administered on
weeks 17, 20, 30, and 33. Patients are followed every 3 months for 1 year, every 6 months
for 4 years and then annually thereafter.

PROJECTED ACCRUAL: Approximately 180 patients will be accrued for this study within 2 years.