Cytokines associated with toxicity in the treatment of recurrent glioblastoma with aflibercept.
Plasma profiling of patients treated with antiangiogenic agents may identify markers that correlate with toxicity. Objectives were to correlate changes in cytokine and angiogenic factors as potential markers of toxicity to aflibercept. Circulating cytokine and angiogenic factors were measured in 28 patients with recurrent glioblastoma in a single-arm phase II study of aflibercept. Plasma samples were analyzed at baseline, 24 h, and 28 days using multiplex assays or ELISA. We evaluated log-transformed baseline biomarker expressions with Cox proportional hazard regression models to assess the effect of markers on any grade II-IV (Gr II-IV) toxicity, on-target toxicity (hypertension, proteinuria, thromboembolism), and fatigue. All tests were two sided with a statistical significance level of p = 0.05. Among 28 pts, there were 116 Gr II-IV events. Changes in IL-13 from baseline to 24 h predicted on-target toxicities. Increases in IL-1b, IL-6, and IL-10 at 24 h were significantly associated with fatigue. Progression-free survival was 14.9 months for patients in the all-toxicity group and 9.0 months for patients in the on-target toxicity group compared to 4.3 months for those who did not develop any Gr II-IV toxicity (p = 0.002 and p = 0.045, respectively). Toxicity from antiangiogenic therapy remains an important cause of antiangiogenic treatment discontinuation and patient morbidity. Changes in IL6, IL10, and IL13 were repeatedly correlated with toxicity. Profiling of IL-13 as a surrogate for endothelial dysfunction could individualize patients at risk during antiangiogenic therapy, as could identifying those at higher risk for fatigue using IL-6 and IL-10.
Division of Oncology and Hematology, University of Nebraska Medical Center, 987680, Omaha, NE, 68198-7680, USA. nshonka@unmc.edu
Nicole
N
Shonka
Yuji
Y
Piao
Mark
M
Gilbert
Alfred
A
Yung
Susan
S
Chang
Lisa M
LM
DeAngelis
Andrew B
AB
Lassman
Jun
J
Liu
Timothy
T
Cloughesy
H Ian
HI
Robins
Rita
R
Lloyd
Alice
A
Chen
Michael
M
Prados
Patrick Y
PY
Wen
John
J
Heymach
John
J
de Groot
D000328:Adult; D000368:Aged; D042501:Angiogenic Proteins / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood; D001932:Brain Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood*; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005909:Glioblastoma / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D016016:Proportional Hazards Models; D040262:Receptors, Vascular Endothelial Growth Factor / Q000009:adverse effects* / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects* / Q000627:therapeutic use*; D016019:Survival Analysis
D042501:Angiogenic Proteins; D014408:Biomarkers, Tumor; D016207:Cytokines; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor