Serum basic fibroblast growth factor and vascular endothelial growth factor in metastatic renal cell carcinoma treated with interferon alfa- 2b

Renal cell carcinoma accounts for 2% of all cancers, and the incidence of this cancer is rising ( 1 ). The most effective therapies are based on the administration of biologic response modifiers, such as interleukin 2 or interferon alfa (IFN α) and result in responses in up to 20%-30% of patients with this disease ( 2 , 3 ). Identification of patients with an increased probability of response to such therapy is needed ( 4 , 5 ). The antitumor effect of IFN α might be based in part on its ability to downregulate (i.e., reduce) the expression of basic fibroblast growth factor (bFGF) messenger RNA and protein, an effect that has been observed in an in vitro study of human carcinoma cells ( 6 ). The effectiveness of IFN α in the treatment of patients with hemangioma ( 7 ) and the changes that occur in the tumor stroma after IFN α treatment of patients with carcinoid tumors ( 8 ) also suggest that this peptide may have an antiangiogenic mode of action. The highly vascular nature of renal cell carcinoma is in accordance with the high level of expression of the vascular endothelial growth factor (VEGF) gene in the vast majority of renal cell carcinoma specimens ( 9 ). An association of elevated bFGF protein expression with poor survival was demonstrated for a cohort of patients with renal cell carcinoma ( 10 ). We, therefore, analyzed changes in serum bFGF and VEGF levels with the use of an enzyme-linked immunosorbent assay ( 11 ) prior to and during treatment of patients with renal cell carcinoma who had been included consecutively in a multicenter phase II study of the effectiveness of treatment of such patients with IFN α. Twelve patients with metastatic renal cell carcinoma treated during the period January 1994 through November 1996 at our institution had had a nephrectomy, had radiologically proven progressive disease, had received no prior systemic therapy except for hormonal treatment, and had bidimensional measurable disease. Seven of the 12 patients had lung metastases. All patients were treated with interferon alfa-2b (Intron A R [recombinant]; Schering Corp., Kenilworth, NJ) with a subcutaneous dose of 5 million international units three times a week. Treatment was continued until a first evaluation was done at 2 months. In patients without progressive disease, treatment was continued until progression was observed. Serum angiokine levels were determined before the start of the treatment and at the first evaluation after 2 months. Elevated levels were predefined as to be greater than the 95th percentile value of the normal control subject group described by R&D Systems, Inc. (Minneapolis, MN) (i.e., >7.5 pg/mL for bFGF and >500 pg/mL for VEGF). Of the 12 patients, seven progressed after 2 months of therapy, two had a minor response (i.e., a reduction of the sum of the product of the largest perpendicular diameters of all measurable lesions of gt;25% and <50% of the pretreatment value for ⩾1 month) that lasted for 4 and 6 months, respectively, and three had a partial response (i.e., a 50% reduction in the sum of squares of the two largest perpendicular diameters of all measurable lesions for ⩾1 month) that lasted for 6, 7, and greater than or equal to 8 months, respectively. We have considered the observation of a minor response in patients with documented progressive disease as antitumor activity. Initial serum levels of bFGF and VEGF were elevated in five of the 12 patients and in six of the 12 patients, respectively. For eight of the 12 patients, at least one angiokine serum level was elevated. There was no relationship between the serum angiokine levels and the volume of metastatic disease or the number of involved sites. These results are in accordance with our previous reports ( 11 , 12 ). Mean pretreatment bFGF levels were significantly higher in the group of patients who responded to interferon treatment ( Table 1 ). More responders (i.e., four of five patients) had elevated bFGF serum levels than nonresponders (i.e., one of seven patients) ( P = .023 from a two-sided chi-squared test). Elevated serum bFGF levels predicted response in four of five patients. Normal serum bFGF levels predicted progression in six of seven patients. Patients with progressive disease did not show a decrease in serum bFGF levels. Serum bFGF and VEGF levels of responding patients remained decreased after prolonged treatment periods. The decrease in serum bFGF and VEGF levels that occurred concurrently with response was not specific for interferon treatment, since we have observed this effect also after effective chemotherapy or hormonotherapy ( 12 ). The first hypothesis that should be tested in a larger study is that bFGF levels in the serum of patients with renal cell carcinoma are able to predict their response to interferon therapy. The second hypothesis that should be tested is that a higher dose intensity is needed for those patients with an increased bFGF level and tumors that fail to respond to an initial dose of IFN α.