FDG-PET as a predictive biomarker for therapy with everolimus in metastatic renal cell cancer

James L Chen, Daniel E Appelbaum, Masha Kocherginsky, Charles L Cowey, Wendy Kimryn Rathmell, David F McDermott, Walter M Stadler, James L Chen, Daniel E Appelbaum, Masha Kocherginsky, Charles L Cowey, Wendy Kimryn Rathmell, David F McDermott, Walter M Stadler

Abstract

The mTOR (mammalian target of rapamycin) inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays renal cell carcinoma (RCC) progression. Preclinical evidence suggests that baseline elevated tumor glucose metabolism as quantified by FDG-PET ([(18)F] fluorodeoxy-glucose positron emission tomography) may predict antitumor activity. Metastatic RCC (mRCC) patients refractory to vascular endothelial growth factor (VEGF) pathway inhibition were treated with standard dose everolimus. FDG-PET scans were obtained at baseline and 2 weeks; serial computed tomography (CT) scans were obtained at baseline and every 8 weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, average SUVmax of all measured lesions and their corresponding 2-week relative changes were examined for association with 8-week change in tumor size. A total of 63 patients were enrolled; 50 were evaluable for the primary endpoint of which 48 had both PET scans. Patient characteristics included the following: 36 (72%) clear cell histology and median age 59 (range: 37-80). Median pre- and 2-week treatment average SUVmax were 6.6 (1-17.9) and 4.2 (1-13.9), respectively. Response evaluation criteria in solid tumors (RECIST)-based measurements demonstrated an average change in tumor burden of 0.2% (-32.7% to 35.9%) at 8 weeks. Relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable P = 0.01; clear cell subtype P = 0.02), with modest correlation. Baseline average SUVmax was correlated with overall survival and progression-free survival (PFS) (P = 0.023; 0.020), but not with change in tumor burden. Everolimus therapy decreased SUVs on follow-up PET scans in mRCC patients, but changes were only modestly correlated with changes in tumor size. Thus, clinical use of FDG-PET-based biomarkers is challenged by high variability.

Keywords: Kidney carcinoma; mTOR protein; pharmacological biomarkers; positron emission tomography.

Figures

Figure 1
Figure 1
Patient disposition of this clinical trial exploring FDG-PET as a predictive biomarker for therapy with everolimus in metastatic renal cell carcinoma.
Figure 2
Figure 2
(A) RECIST-based changes in tumor size at 8 weeks post treatment with everolimus are heterogeneous as seen in the waterfall plot. (B) FDG-PET uptake decreased after 2 weeks of treatment for most renal cancer patients.
Figure 3
Figure 3
Kaplan–Meier estimates of overall survival among patients with high (>4) and low (≤4) baseline avgSUVmax. (A) Significant difference in overall survival among all patients (n = 50). (B) The overall survival difference is no longer statistically significant among the clear cell subtype (n = 36).

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