RECOMBINANT HUMAN INTERFERON-BETA (RHUIFN-BETA) AND RADIATION-THERAPYFOR INOPERABLE NONSMALL CELL LUNG-CANCER

Fifteen patients with stage II, IIIA, and IIIB non-small cell lung can cer (NSCLC) received subcutaneous (s.c.) recombinant, glycosylated, hu man interferon-beta 1a (Rebif; rHuIFN-beta 1a) on each day of conventi onally fractionated radiation therapy (RT) given in 2.0 Gy fractions t o 60 Gy in 6 weeks. The rHuIFN-beta 1a was generated in CHO cells by r ecombinant DNA technology and is identical to natural IFN-beta produce d by fibroblasts in primary sequence and glycosylation. Cohorts of thr ee patients each were treated with escalating doses of rHuIFN-beta 1a: 1.5, 3, 6, 12, and 24 MIU/m(2) per treatment day. Acute toxicity was assessed according to modified WHO criteria; late toxicity was graded using RTOG late toxicity criteria. The maximum tolerated dose (MTD) of rHuIFN-beta 1a was defined as the dose level immediately below that i n which dose-limiting toxicity occurred in greater than or equal to tw o of six patients. Immunomodulatory effects and antigenicity of rHuIFN -beta 1a were assessed by 2-5A synthetase, beta(2)-microglobulin, and neopterin levels and by measurement of anti-rHuIFN-beta antibodies, re spectively. Fourteen of fifteen patients experienced grades 1-3 acute (early) toxicity (less than or equal to 90 days), which was primarily gastrointestinal: dysphagia/esophagitis (14/15), nausea/vomiting (12/1 5), anorexia (7/15), and liver transaminasemia (6/15). One of three pa tients treated with 24 MIU/m(2) per treatment day (total rHuIFN-beta 1 a dose 672 MIU) died of complications secondary to pneumonia, sepsis, adult respiratory distress syndrome (ARDS), and radiation pneumonitis. Twelve patients were evaluable for late toxicity (>90 days). Maximum toxicity was grade 0 in five patients, grade 1 in four patients, and g rade 5 in one patient (radiation pneumonitis). Clinical responses from the combination were 1/15 CR, 6/15 PR, 6/15 stable disease, and 1/15 progressive disease. The MTD of rHuIFN-beta 1a has been estimated at 1 2 MIU/m(2) per treatment day when given daily during conventional RT t o 60 Gy in 6 weeks. Biologic response by rHuIFN-beta 1a alone was refl ected by significant and dose-related increases in 2-5A synthetase, be ta(2)-microglobulin, and neopterin. Radiation therapy alone had no eff ect on these immune response parameters and did not diminish their aug mentation by rHuIFN-beta 1a. There was no association of biologic modu lation with clinical response or survival.