Inhaled granulocyte-macrophage colony stimulating factor for first pulmonary recurrence of osteosarcoma: effects on disease-free survival and immunomodulation. a report from the Children's Oncology Group.
OBJECTIVE
Osteosarcoma most commonly recurs in the lung. Based on preliminary data on the antitumor effects of granulocyte-macrophage colony stimulating factor (GM-CSF) in animal models, and promising phase I trials, we embarked on a feasibility study of inhaled GM-CSF in patients with first isolated pulmonary recurrence of osteosarcoma.


METHODS
Forty-three eligible patients received inhaled GM-CSF at doses from 250 to 1,750 microg 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 the 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 1,750 microg 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 with 0.78 and 0.62 in nodules resected following two cycles of therapy. Only 11 of 30 nodules postinhalation 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 to 1,750 microg twice daily on alternate weeks was feasible with low toxicity. However, no detectable immunostimulatory effect in pulmonary metastases or improved outcome postrelapse was seen.
Arndt
Carola A S
CA
Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. carndt@mayo.edu
Koshkina
Nadya V
NV
Inwards
Carrie Y
CY
Hawkins
Douglas S
DS
Krailo
Mark D
MD
Villaluna
Doojduen
D
Anderson
Peter M
PM
Goorin
Allen M
AM
Blakely
Martin L
ML
Bernstein
Mark
M
Bell
Sharon A
SA
Ray
Kaylee
K
Grendahl
Darryl C
DC
Marina
Neyssa
N
Kleinerman
Eugenie S
ES
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002648:Child; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008297:Male; D012516:Osteosarcoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D055815:Young Adult
D000970:Antineoplastic Agents; D016178:Granulocyte-Macrophage Colony-Stimulating Factor