An Italian - Scandinavian treatment and research protocol for high-grade osteosarcoma of the extremities (localized disease and metastatic relapse).

Italian Sarcoma Group (ISG) and Scandinavian Sarcoma Group (SSG)

• Age <40 years.
• Histologically proven osteosarcoma of high malignancy grade (grade III or IV), and extremity localized.
• The diagnosis must be made by open or coarse needle biopsy.
• The tumor must arise in the marrow or the bone surface.
• Patients with localized disease are eligible. Patients with metastasis at diagnosis will be eligible when the corresponding protocol has ben activated.
• No previous treatment should have been given for osteosarcoma.
• Adequate bone marrow, hepatic and renal function.
• Chemotherapy must be started within four weeks from the histological diagnosis.
• The patient registration form must be accompanied by representative histology slides (for verification of diagnosis) and conventional anterior, posterior and lateral x–rays of the entire involved bone (for estimation of tumor volume).

Localized disease
Preoperative treatment:
Methotrexate: 12 000 mg/m2,  week 0 and 6
Cisplatin: 60 mg/m2/24 h as 48 h cont. i.v. inf., week 1 and 7
Adriamycin: 75 mg/m2 as 24 h cont. i.v. inf., week 1 and 7
Ifosfamide: 3000 mg/m2/24 h as 120 hours cont. i.v. inf., week 4 and 10
Surgery: between week 12 and 13

Postoperative – Good responders:
Adriamycin: 90 mg/m2 as 24 h cont. i.v. inf., week 14 and 23
Ifosfamide: Ifosfamide: 3000 mg/m2/24 h as 120 hours cont. i.v. inf., week 17 and 26
Methotrexate: 12 000 mg/m2, week 19 and 28
Cisplatin: 60 mg/m2/24 h as 48 hours cont. i.v. inf., week 20 and 29

Postoperative – Poor responders:
Adriamycin: 90 mg/m2 as 24 h cont. i.v. inf., week 14 and 23
Ifosfamide: 3000 mg/m2/24 h as 120 hours cont. i.v. inf., week 17, 26 and 32
Methotrexate: increased by 3000 mg/m2 above pre.op dose, week 19, 28 and 34
Cisplatin: 75 mg/m2/24 h as 48 hours cont. i.v. inf., week 20, 29 and 35

First metastatic relapse
Cyclofosfamide: 4000 mg/m2, day 1
Etoposide: 200 mg/m2/day, day 2, 3 and 4
PBSC-harvest: between week 1 and 2
HDEC = Etoposide 450 mg/m2/day and Carboplatin 375 mg/m2/day, day 21-24, 49-52
Peripheral blood stem cell (PBSC) rescue, week 3 and 7 at 72 hours after termination of chemotherapy
Metastasectomy – Histologic tumor response: week 10

Complete surgery: Observation
Incomplete if any surgery:

1. Consider supplemental localized high-dose RT and/or brachytherapy
2. Experimental treatment with 153Sm EDTMP, if Tc uptake on scintigraphy.
   

Primary
In patients with localized disease, to  evaluate histologic tumor response, relapse-free survival and overall survival rates.

Secondary
In all patients who relapse with distant metastases, to increase the 5-year overall survival rate from first metastatic event form 25% to 50% by using high-doses of chemotherapy with peripheral blood stem cell rescue.

1997-2000

187

Serra M, Pasello M, Manara MC, Scotlandi K, Ferrari S, Bertoni F, Mercuri M, Alvegard TA, Picci P, Bacci G, Smeland S: May P-glycoprotein status be used to stratify high-grade osteosarcoma patients? Results from the Italian/Scandinavian Sarcoma Group 1 treatment protocol. Int J Oncol. 2006; Dec 29(6):1459-68.

Ferrari S, Smeland S, Mercuri M, Bertoni F, Longhi A, Ruggieri P, Alvegard TA, Picci P, Capanna R, Bernini G, Müller C, Tienghi A, Wiebe T, Comandone A, Böhling T, Del Prever AB, Brosjö O, Bacci G, Saeter G; Italian and Scandinavian Sarcoma Groups: 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. J Clin Oncol. 2005; Dec1 23(34):8845-52. Epub 2005 Oct 24.