Adjuvant High-Dose Thiotepa and Stem Cell Rescue Associated With Conventional Chemotherapy in Relapsed Osteosarcoma

Overview

Approximately 150 new cases of osteosarcoma are reported each year in France, of which 15 to 20% are metastatic. Further to the initial standard care, about 45% of the patients relapse within a median duration of 20 months. Result of the OS94 study results and of the investigation performed within the CRLCC, indicate that 25 to 30 patients (children and adults) experience an osteosarcoma relapse each year in FRANCE. According to several studies, the 5-year overall survival rate of patients in first relapse is 23-28%,with a median post relapse survival of 10 to 17 months. Multiple relapse cases are also reported in the COSS study, with a median time to second relapse of 0.8 year. At present, there is no reference treatment for the standard care of osteosarcoma relapse in FRANCE. Thiotepa is known for its antitumor effect in numerous malignant tumors. In 2007, a study from our institution reported that about 35% of all osteosarcoma relapses are treated with a high-dose thiotepa while the efficacy and tolerance of this therapeutic strategy have never been assessed. These results highlight the need to the evaluate the efficacy and tolerance of this high-dose of thiotepa within a clinical trial and its inclusion in the standard care of the osteosarcoma at relapse.

Despite the absence of tumor registry, approximately 150 new cases of osteosarcoma are reported each year in France (100 cases per year in children and 50 cases in adults), of which 15 to 20% are metastatic. The standardized impact rate in the world population is estimated at 3 per million inhabitants per year. Further to the initial standard care, about 45% of the patients relapse within a median interval of 20 months (range 3 months - 10 years). Results of the OS94 study and of the investigation performed within the CRLCC indicate that 25 to 30 patients (children and adults) experience an osteosarcoma relapse each year in FRANCE. Results of the five major published series indicate that the 5-year overall survival rate of patients in first relapse is between 23 and 28%, with a median post-relapse survival of 10 to 17 months. Multiple relapse cases are also reported in the COSS study, with a median time to second relapse of 0.8 year. At present, there is no reference treatment for the standard care of osteosarcoma relapse in FRANCE. Some recommendations have been given in the OS94 protocol, but they are generally not followed or they are implemented in a heterogeneous manner. Thiotepa (N N' N'' triethylenethiophosphoramide), an alkylating agent of the chemical family of ethylene-imines, is known for its antitumor effect in a number of malignant tumors. Its efficacy in osteosarcoma has been reported in the literature. A retrospective study of the SFCE (French Society for Childhood Cancer, results not yet published) in 45 patients presenting with refractory osteosarcoma or relapse has shown a radiological reaction rate of 30%. Moreover, a preliminary investigation performed by the CLB in 2007 within the framework of the SFCE study explored all relapse cases diagnosed between the beginning of 2004 and the end of 2006. Results showed that about 35% of the patients with osteosarcoma relapses are treated with high-dose thiotepa while the efficacy and tolerance of this therapeutic strategy have never been assessed. Altogether, these results led the SFCE osteosarcoma group to propose the evaluation of the efficacy and tolerance of this high-dose thiotepa chemotherapy within a clinical trial and to include the drug in the standard care of osteosarcoma in relapse.