Maximal COX-2 immunostaining and clinical response to celecoxib and interferon alpha therapy in metastatic renal cell carcinoma.
BACKGROUND
Cyclooxygenase-2 (COX-2) plays a major role in the development of cancer through numerous mechanisms. COX-2 is expressed in the majority of renal cell carcinoma (RCC) tumors and correlates with stage, grade, and microvessel density. Based on potential additive or synergistic antitumor effects, interferon-alpha (IFNalpha) and celecoxib, an oral COX-2 inhibitor, were given to metastatic RCC patients in a Phase II trial.


METHODS
Patients with untreated, metastatic RCC received IFNalpha 3 million units (MU) daily and celecoxib 400 mg orally (p.o.) twice daily continuously until disease progression or unacceptable toxicity. Pretreatment, paraffin-embedded RCC tumor samples were immunohistochemically stained for COX-2 expression and plasma basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) levels were assayed to determine predictive or prognostic potential.


RESULTS
There were three partial responses among 25 patients treated (objective response rate, 12%; 95% confidence interval [CI], 3-31%). The observed median time to disease progression (TTP) for the entire cohort was 3.3 months. A significant association between maximal COX-2 staining and clinical response was observed: all patients who experienced an objective response demonstrated 3+ COX-2 tumor immunostaining (trend test: P=0.03). Therapy was well tolerated without cardiac or other notable toxicity.


CONCLUSIONS
The addition of celecoxib to IFNalpha did not increase the objective response rate or TTP of this unselected cohort. Maximal COX-2 tumor immunostaining may identify RCC patents more likely to achieve clinical benefit with COX-2 inhibition in combination with IFNalpha. Further investigation of this combination in 3+ COX-2-overexpressing RCC tumors is warranted.
Rini
Brian I
BI
Department of Hematology and Oncology, Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio 44195, USA. rinib2@ccf.org
Weinberg
Vivian
V
Dunlap
Sarah
S
Elchinoff
Alexandra
A
Yu
Nancy
N
Bok
Robert
R
Simko
Jeffery
J
Small
Eric J
EJ
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000096:biosynthesis*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011720:Pyrazoles / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016861:Cyclooxygenase Inhibitors; D016898:Interferon-alpha; D011720:Pyrazoles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D051546:Cyclooxygenase 2; D000068579:Celecoxib