Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups.
OBJECTIVE
To explore the effect of high-dose ifosfamide in first-line treatment for patients < or = 40 years of age with nonmetastatic osteosarcoma of the extremity.


METHODS
From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m2), methotrexate (12 g/m2), cisplatin (120 mg/m2), and doxorubicin (75 mg/m2). Postoperatively, patients received two cycles of doxorubicin (90 mg/m2), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m2). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination.


RESULTS
No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI, 57% to 71%) and overall survival was 77% (95% CI, 67% to 81%), whereas seven patients (4%) experienced local recurrence.


CONCLUSIONS
The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.
Ferrari
Stefano
S
Chemotherapy Division of Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Via C. Pupilli 1, 40136 Bologna, Italy. stefano.ferrari@ior.it
Smeland
Sigbjorn
S
Mercuri
Mario
M
Bertoni
Franco
F
Longhi
Alessandra
A
Ruggieri
Pietro
P
Alvegard
Thor A
TA
Picci
Piero
P
Capanna
Rodolfo
R
Bernini
Gabriella
G
Müller
Cristoph
C
Tienghi
Amelia
A
Wiebe
Thomas
T
Comandone
Alessandro
A
Böhling
Tom
T
Del Prever
Adalberto Brach
AB
Brosjö
Otte
O
Bacci
Gaetano
G
Saeter
Gunnar
G
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000473:pathology / Q000628:therapy*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005121:Extremities; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000139:chemically induced; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects; D007558:Italy; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D009364:Neoplasm Recurrence, Local; D012516:Osteosarcoma / Q000473:pathology / Q000628:therapy*; D010349:Patient Compliance; D011446:Prospective Studies; D051437:Renal Insufficiency / Q000139:chemically induced; D012537:Scandinavian and Nordic Countries; D016896:Treatment Outcome
D004317:Doxorubicin; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate