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Value of P-Glycoprotein and Clinicopathologic Factors as the Basis for New Treatment Strategies in High-Grade Osteosarcoma of the Extremities

Massimo Serra, Katia Scotlandi, Gemma Reverter-Branchat, Stefano Ferrari, Maria C. Manara, Stefania Benini, Marina Incaprera, Franco Bertoni, Mario Mercuri, Antonio Briccoli, Gaetano Bacci, Piero Picci

From the Laboratorio di Ricerca Oncologica, Sezione di Chemioterapia, Servizio di Anatomia Patologica, Va Divisione, and Unita’ di Chirurgia Generale, Istituti Ortopedici Rizzoli, Bologna, Italy.

Address reprint requests to Massimo Serra, Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy; email: massimo.serra{at}ior.it.

Purpose: To evaluate the prognostic value of P-glycoprotein and clinicopathologic parameters in a large series of high-grade osteosarcoma (OS) patients treated at the Rizzoli Institute.

Patients and Methods: With the use of immunohistochemistry, P-glycoprotein was assessed in 149 patients with primary, nonmetastatic, high-grade OS who were homogeneously treated with chemotherapy protocols based on doxorubicin, high-dose methotrexate, and cisplatin and the addition of ifosfamide in the postoperative phase.

Results: P-glycoprotein positivity was found in 47 of 149 cases (32%) and was significantly associated with a higher incidence of relapse and a worse outcome, as was age younger than 12 years and tumor volume greater then 150 mL at diagnosis. Multivariate analysis further confirmed the prognostic value of these parameters, which all were independent adverse prognostic factors. Event-free survival and proportional hazards regression analyses confirmed that overexpression of P-glycoprotein at clinical onset is the most important adverse prognostic factor for high-grade OS patients treated with these chemotherapy protocols.

Conclusion: Increased P-glycoprotein levels, together with tumor volume and age, should be taken into consideration to identify, at time of diagnosis, subgroups of OS patients with a higher risk of recurrence. This subgroup identification will constitute the basis for drawing individualized treatment protocols on the basis of risk evaluation, with the aim of using more aggressive chemotherapy, or combination chemotherapy with other adjuvants, only in those patients for which more aggressive regimens are strictly necessary and warranted.

Supported by grants from the Istituti Ortopedici Rizzoli (Ricerca Corrente), Associazione Italiana per la Ricerca sul Cancro (AIRC), Italian Ministry of Health (Ricerca Finalizzata), and Italian Ministry for Education, University, and Research (MURST).

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