Does Arterial Spin-labeling MR Imaging–measured Tumor Perfusion Correlate with Renal Cell Cancer Response to Antiangiogenic Therapy in a Mouse Model?

Abstract

Purpose:To determine whether arterial spin-labeling (ASL) magnetic resonance (MR) imaging findings at baseline and early during antiangiogenic therapy can predict later resistance to therapy. Materials and Methods:Protocol was approved by an institutional animal care and use committee. Caki-1, A498, and 786-0 human renal cell carcinoma (RCC) xenografts were implanted in 39 nude mice. Animals received 80 mg sorafenib per kilogram of body weight once daily once tumors measured 12 mm. ASL imaging was performed at baseline and day 14, with additional imaging performed for 786-0 and A498 (3 days to 12 weeks). Mean blood flow values and qualitative differences in spatial distribution of blood flow were analyzed and compared with histopathologic findings for viability and microvascular density. t Tests were used to compare differences in mean tumor blood flow. Bonferroni-adjusted P values less than .05 denoted significant differences. Results:Baseline blood flow was 80.1 mL/100 g/min Ϯ 23.3 (standard deviation) for A498, 75.1 mL/100 g/min Ϯ 28.6 for 786-0, and 10.2 mL/100 g/min Ϯ 9.0 for Caki-1. Treated Caki-1 showed no significant change (14.9 mL/100 g/min Ϯ 7.6) in flow, whereas flow decreased in all treated A498 on day 14 (47.9 mL/100 g/min Ϯ 21.1) and in 786-0 on day 3 (20.3 mL/100 g/min Ϯ 8.7) (P ϭ .003 and .03, respectively). For A498, lowest values were measured at 28 -42 days of receiving sorafenib. Regions of increased flow occurred on days 35-49, 17-32 days before documented tumor growth and before significant increases in mean flow (day 77). Although 786-0 showed new, progressive regions with signal intensity detected as early as day 5 that correlated to viable tumor at histopathologic examination, no significant changes in mean flow were noted when day 3 was compared with all subsequent days (P Ͼ .99). Conclusion:ASL imaging provides clinically relevant information regarding tumor viability in RCC lines that respond to sorafenib.

Quantification of renal perfusion: Comparison of arterial spin labeling and dynamic contrast‐enhanced MRI

“…Although principally employed for cerebral blood flow quantification, ASL has begun to see applications outside of the brain, with the kidney being one of the first and most popular sites. Several studies have demonstrated the feasibility of ASL quantification of renal perfusion in both healthy and disease states (12)(13)(14)(15)(16). However, a number of quantification issues remain to be addressed, such as: how perfusion estimates may be confounded by different flow characteristics, the positioning and orientation of the tagging slab, and tissue and arterial transit times.…”

Magnetic resonance imaging as a biomarker in renal cell carcinoma

“…These findings correlated with the lack of response of Caki-1 tumors to sorafenib therapy, possibly suggesting that low levels of perfusion on ASL may be a useful biomarker for predicting poor responsiveness to certain types of antiangiogenic therapy. 75 Although blood flow changes on ASL after antiangiogenic therapy varied in these animal models, its regional distribution within the tumors corresponded tightly to their histopathologic appearance. Regions with high signal intensity on ASL correlated to viable tumor, with zones of absent or diminished signal (ie, <2 mL/100 mg/minute) representing necrosis.…”

“…Caki-1 (sorafenib resistant), A498 (sorafenib sensitive), and 786-0 (early response followed by rapid development of resistance by Day 5) tumors exhibited different levels of blood flow on ASL MRI at baseline. 75 Specifically, Caki-1 tumors demonstrated minimal blood flow at baseline (10.2 mL AE 9.0 mL/100 mg/minute) relative to 786-0 tumors (75.1 mL AE 28.6 mL/100 mg/minute) and A498 tumors (80.1 mL AE 23.3 mL/100 mg/minute). These findings correlated with the lack of response of Caki-1 tumors to sorafenib therapy, possibly suggesting that low levels of perfusion on ASL may be a useful biomarker for predicting poor responsiveness to certain types of antiangiogenic therapy.…”

“…75 Schor-Bardach et al recently studied the response rate to sorafenib therapy of 3 different human RCC xenografts implanted in nude mice. Caki-1 (sorafenib resistant), A498 (sorafenib sensitive), and 786-0 (early response followed by rapid development of resistance by Day 5) tumors exhibited different levels of blood flow on ASL MRI at baseline.…”

“…In those lines that responded to sorafenib, ASL provided important information regarding tumor viability with a tight radiologicpathologic correlation to induced intratumoral necrosis. 75 Thus, the potential to use ASL as a means to base therapeutic decisions for patients with well perfused tumors also can be appreciated.…”