Toxicity and efficacy of escalating dosages of recombinant human interleukin-6 after chemotherapy in patients with breast cancer or non-small-cell lung cancer.
OBJECTIVE
To evaluate the safety, tolerability, and efficacy of varying doses of recombinant human interleukin-6 (rhIL-6) after chemotherapy.


METHODS
In this phase I/II study, 19 breast (stage III to IV) or non-small-cell lung cancer (NSCLC) patients received mitoxantrone (10 mg/m2) and thiotepa (40 mg/m2) every 3 weeks, followed by rhIL-6 subcutaneously (days 5 to 15) at six dose levels: 0.5, 1.0, 2.5, 5.0, 10.0, and 20.0 micrograms/kg/d body weight/d (micrograms/kg/d). rhIL-6 was increased to the next level in the individual patient in case of incomplete bone marrow recovery (leukocyte count < 3 x 10(9)/L and/or platelet count < 100 x 10(9)/L at day 22) and/or platelet nadir less than 25 x 10(9)/L in two consecutive cycles.


RESULTS
Flu-like symptoms were observed in most of the patients. Nausea and vomiting were reported in seven of 48 and 19 of 48 cycles, respectively. Dose-limiting toxicity at 20.0 micrograms/kg/d of rhIL-6 consisted of World Health Organization (WHO) grade 3 to 4 flu-like symptoms, nausea, and vomiting. Platelet recovery was faster in cycle 1 at 10.0 and 20.0 micrograms/kg/d of rhIL-6 than at lower dose levels (P < .05); thrombocytopenia grade 4 was observed at most levels. However, only two patients needed platelet transfusions (1.0 and 2.5 micrograms/kg/d rhIL-6). rhIL-6 effects on leukocytes were not dose-related, with a trend for the neutrophil nadir to increase with rhIL-6 up to 10 micrograms/kg/d. rhIL-6 dose escalation did not affect hematologic parameters and chemotherapy cycle duration. Hemoglobin (P < .001) and cholesterol (P < .05) levels decreased, while acute-phase proteins increased.


CONCLUSIONS
rhIL-6 following chemotherapy is tolerable up to 10 micrograms/kg/d; flu-like symptoms and nausea were dose-limiting at 20 micrograms/kg/d. Platelet nadir did not differ for the various rhIL-6 doses. However, a faster platelet recovery was observed at 10.0 and 20.0 micrograms/kg/d of rhIL-6.
Veldhuis
G J
GJ
Department of Internal Medicine, University Hospital of Gröningen, The Netherlands.
Willemse
P H
PH
Sleijfer
D T
DT
van der Graaf
W T
WT
Groen
H J
HJ
Limburg
P C
PC
Mulder
N H
NH
de Vries
E G
EG
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002097:C-Reactive Protein / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006261:Headache / Q000188:drug therapy; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D015850:Interleukin-6 / Q000008:administration & dosage* / Q000009:adverse effects; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein / Q000032:analysis
D006454:Hemoglobins; D015850:Interleukin-6; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein; D002097:C-Reactive Protein; D002784:Cholesterol; D007770:L-Lactate Dehydrogenase