title: Recombinant human interferon-beta (rHuIFN-beta) and radiation therapy for inoperable non-small cell lung cancer.
abstract: Fifteen patients with stage II, IIIA, and IIIB non-small cell lung cancer (NSCLC) received subcutaneous (s.c.) recombinant, glycosylated, human interferon-beta 1a (Rebif; rHuIFN-beta 1a) on each day of conventionally fractionated radiation therapy (RT) given in 2.0 Gy fractions to 60 Gy in 6 weeks. The rHuIFN-beta 1a was generated in CHO cells by recombinant DNA technology and is identical to natural IFN-beta produced by fibroblasts in primary sequence and glycosylation. Cohorts of three patients each were treated with escalating doses of rHuIFN-beta 1a: 1.5, 3, 6, 12, and 24 MIU/m2 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 in which dose-limiting toxicity occurred in > or = two 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, respectively. Fourteen of fifteen patients experienced grades 1-3 acute (early) toxicity (< or = 90 days), which was primarily gastrointestinal: dysphagia/esophagitis (14/15), nausea/vomiting (12/15), anorexia (7/15), and liver transaminasemia (6/15). One of three patients treated with 24 MIU/m2 per treatment day (total rHuIFN-beta 1a 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 grade 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 12 MIU/m2 per treatment day when given daily during conventional RT to 60 Gy in 6 weeks. Biologic response by rHuIFN-beta 1a alone was reflected by significant and dose-related increases in 2-5A synthetase, beta 2-microglobulin, and neopterin. Radiation therapy alone had no effect on these immune response parameters and did not diminish their augmentation by rHuIFN-beta 1a. There was no association of biologic modulation with clinical response or survival.
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee 53226, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Byhardt
authors.forename: L
authors.initials: L
authors.lastname: Vaickus
authors.forename: P L
authors.initials: PL
authors.lastname: Witt
authors.forename: A Y
authors.initials: AY
authors.lastname: Chang
authors.forename: T
authors.initials: T
authors.lastname: McAuliffe
authors.forename: J F
authors.initials: JF
authors.lastname: Wilson
authors.forename: C A
authors.initials: CA
authors.lastname: Lawton
authors.forename: J
authors.initials: J
authors.lastname: Breitmeyer
authors.forename: M E
authors.initials: ME
authors.lastname: Alger
authors.forename: E C
authors.initials: EC
authors.lastname: Borden
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D016899:Interferon-beta / Q000009:adverse effects / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007155:Immunologic Factors; D011838:Radiation-Sensitizing Agents; D011994:Recombinant Proteins; D016899:Interferon-beta