title: Intrapleural administration of interleukin 2 in pleural mesothelioma: a phase I-II study.
abstract: Twenty-three patients with pleural mesothelioma stage I-IIA were entered in a study of continuous daily intrapleural infusion of interleukin 2 (IL-2) for 14 days, repeated every 4 weeks. IL-2 was administered according to a groupwise dose escalation schedule (group A, 3 x 10(4); group B, 3 x 10(5); group C, 3 x 10(6); group D, 6 x 10(6); group E, 18 x 10(6); and group F, 36 x 10(6) IU day-1). Each group consisted of at least three patients. Intrapleural administration of IL-2 was associated with acceptable toxicity. All patients were treated on an outpatient basis except for the patients at dose levels E and F. Dose-limiting toxicity was observed at level F, 36 x 10(6) IU daily, and consisted of catheter infection, fever and flu-like symptoms. Intrapleural IL-2 levels were high (> 20,000 IU ml-1) at levels E and F, while serum levels in most patients were not or barely detectable (< 3-30 IU ml-1). Intrapleural IL-2 levels were up to 6000-fold higher than systemic levels. Intrapleural tumour necrosis factor alpha (TNF-alpha) levels varied greatly and did not correlate with IL-2 dosage. Intrapleural mononuclear cells (MNCs) displayed IL-2-induced lymphokine-activated killer (LAK) activity in all patients. Two patients were not evaluable for response owing to catheter-related problems which precluded the delivery of IL-2. Partial response (PR) occurred in 4 of 21 evaluable patients (19%; 95% confidence interval 5-42%) with a median time to progression of 12 months (range 5-37). Stable disease (SD) occurred in seven patients with a median time to progression of 5 months (range 2-7). There were no complete responses (CRs). The median overall survival was 15.6 months (range 3.0-43). No relationship between the dose of IL-2 and response rate was observed. We conclude that IL-2 given intrapleurally is accompanied with acceptable toxicity and has anti-tumour activity against mesothelioma. In view of the refractory nature of the disease IL-2 may be a treatment option for mesothelioma. A formal phase II study is warranted. Based on the observed toxicity, the lack of dose-response relationship and the immunomodulatory effects seen at relatively low-dose IL-2, the recommended dose for a phase II study is 3 x 10(6) IU day-1 using the present treatment schedule.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), The Netherlands.
authors.forename: S H
authors.initials: SH
authors.lastname: Goey
authors.forename: A M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: C J
authors.initials: CJ
authors.lastname: Punt
authors.forename: R
authors.initials: R
authors.lastname: Slingerland
authors.forename: J W
authors.initials: JW
authors.lastname: Gratama
authors.forename: R
authors.initials: R
authors.lastname: Oosterom
authors.forename: R
authors.initials: R
authors.lastname: Oskam
authors.forename: R L
authors.initials: RL
authors.lastname: Bolhuis
authors.forename: G
authors.initials: G
authors.lastname: Stoter
mesh_terms: D000368:Aged; D002408:Catheters, Indwelling / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007239:Infections / Q000209:etiology; D007263:Infusions, Parenteral; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D008297:Male; D008654:Mesothelioma / Q000401:mortality / Q000628:therapy*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D010994:Pleura; D010996:Pleural Effusion / Q000737:chemistry; D010997:Pleural Neoplasms / Q000401:mortality / Q000628:therapy*; D016019:Survival Analysis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D007155:Immunologic Factors; D007376:Interleukin-2; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha