A phase I/II study of doxorubicin, ifosfamide, etoposide and interval methotrexate in patients with poor prognosis osteosarcoma.
BACKGROUND
The prognosis for patients with metastatic or axial-skeletal osteosarcoma is poor. A phase I/II study was conducted of intensive chemotherapy with interval methotrexate, to assess the feasibility, response rate and toxicity in this group of patients.


METHODS
Thirteen patients, median age 18 (range: 8-34), with metastatic or axial-skeletal osteosarcoma were treated with ifosfamide 2.5 g/m(2), etoposide 150 mg/m(2), and doxorubicin 20 mg/m(2) on days 1-3, every 21 days, with interval methotrexate 12 g/m(2) given on day 14, for a maximum of eight cycles. Surgery to the primary was considered after four cycles for those with operable disease, or together with metastatic disease at completion of chemotherapy in those with inoperable tumours.


RESULTS
A total of 85 cycles were given, median 6 per patient (range: 4-8). Only 6 of the 13 patients completed all 8 cycles of chemotherapy. Forty-eight cycles (56%) required a dose reduction. The principal toxicity was myelosuppression, with a median nadir neutrophil count of 0.1 (range: 0-4.1). Grade 3 or 4 infection was seen in 41 cycles (48%). Histological response was assessable in seven patients, all of whom achieved a >or=90% necrosis. Radiological response rate, evaluable in seven patients with lung metastases, was 43%. All but one patient has had subsequent disease progression or relapse, with a median event free survival of 13 months (range: 5-53).


CONCLUSIONS
This regimen was associated with responses, but these were not sustained. Substantial toxicity was seen, preventing optimal delivery. More effective, less toxic regimens are needed in this group of patients.
McTiernan
Anne
A
Meyerstein Institute of Oncology, Middlesex Hospital, UCL Hospitals NHS Trust, London, United Kingdom.
Meyer
Tim
T
Michelagnoli
Maria P
MP
Lewis
Ian
I
Whelan
Jeremy S
JS
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002648:Child; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D012516:Osteosarcoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology
D000970:Antineoplastic Agents; D005047:Etoposide; D004317:Doxorubicin; D007069:Ifosfamide