INHALED GM-CSF FOR FIRST PULMONARY RECURRENCE OF OSTEOSARCOMA; EFFECTS ON DISEASE FREE SURVIVAL AND IMMUNOMODULATION: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP

Purpose: Osteosarcoma most commonly recurs in lung. Based on preliminary data on antitumor effects of GM-CSF in animal models, and promising phase 1 trials, we embarked on a feasibility study of inhaled granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with first isolated pulmonary recurrence of osteosarcoma. Experimental Design: Forty-three eligible patients received inhaled GM-CSF at doses from 250-1750 μg twice daily on alternate weeks. Following two cycles, patients underwent thoracotomy to resect tumor and analyze pulmonary nodules for expression of Fas/Fas ligand (Fas/FasL), and presence of dendritic cells by immunostaining for CD1a, clusterin and S100. Following surgery, patients received 12 additional cycles of therapy on alternating weeks or until progression. Event free survival and survival, and feasibility of therapy delivery were evaluated. Results: Dose escalation to 1750 μg twice daily was feasible with no dose limiting toxicity. Mean scores for Fas /FasL in nodules from patients with bilateral recurrence who underwent unilateral thoracotomy pretreatment (using a scoring system of 0-3) were 1.3 and 0.88 respectively, compared to 0.78 and 0.62 in nodules resected following two cycles of therapy. Only 11 of 30 nodules post inhalation were positive for CD1a, 4 of 30 for S100 and 6 of 30 for clusterin. Event free and overall survival at 3 years were 7.8% and 35.4%, respectively. Conclusions: Inhalation of GM-CSF at doses from 250-1750 μg twice daily on alternate weeks was feasible with low toxicity. However, no detectable immunostimulatory effect in pulmonary metastases or improved outcome post relapse were seen..