Cancer Res Treat.  2016 Oct;48(4):1210-1221. 10.4143/crt.2015.374.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a Surrogate Biomarker for Bevacizumab in Colorectal Cancer Liver Metastasis: A Single-Arm, Exploratory Trial

• Kim YE
• Joo B
• Park MS
• Shin SJ
• Ahn JB
• Kim MJ

• KMID: 2356223
• DOI: http://doi.org/10.4143/crt.2015.374

Abstract

PURPOSE
The purpose of this study is to investigate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and plasma cytokines and angiogenic factors (CAFs) as pharmacodynamic and prognostic biomarkers of bevacizumab monotherapy in colorectal cancer with liver metastasis (CRCLM).
MATERIALS AND METHODS
From July 2011 to March 2012, 28 patients with histologically confirmed CRCLM received bevacizumab monotherapy followed by combined FOLFOX therapy. The mean age of the patients was 57 years (range, 30 to 77 years). DCE-MRI (K(trans) and IAUC₆₀) was performed at baseline, first follow-up (3 days after bevacizumab monotherapy), and second follow-up (3 days after combined therapy). CAF levels (vascular endothelial growth factor [VEGF], placental growth factor [PlGF], and interleukin-8) were assessed on the same days. Progression-free survival (PFS) time distributions were summarized using the Kaplan-Meier method and compared using log-rank tests.
RESULTS
The median PFS period was 11.2 months. K(trans), IAUC₆₀, VEGF, and PlGF values on the first follow-up day were significantly different compared with baseline values. No differences were observed on the second follow-up day. A > 40% decrease in K(trans) from baseline to first follow-up was associated with a longer PFS (hazard ratio, 0.349; 95% confidence interval, 0.133 to 0.912; p=0.032). Changes in CAFs did not show correlation with PFS time.
CONCLUSION
DCE-MRI parameters and CAFs are pharmacodynamic biomarkers of bevacizumab for CRCLM. In our study, change in K(trans) at 3 days after bevacizumab monotherapy was a favorable prognostic factor; however, the value of CAFs as a prognostic biomarker was not found.

Keyword

Dynamic contrast enhanced-magnetic resonance imaging; Bevacizumab; Colorectal neoplasms

MeSH Terms

Angiogenesis Inducing Agents
Bevacizumab*
Biomarkers
Colorectal Neoplasms*
Cytokines
Disease-Free Survival
Endothelial Growth Factors
Follow-Up Studies
Humans
Liver*
Magnetic Resonance Imaging*
Methods
Neoplasm Metastasis*
Plasma
Vascular Endothelial Growth Factor A
Angiogenesis Inducing Agents
Bevacizumab
Biomarkers
Cytokines
Endothelial Growth Factors
Vascular Endothelial Growth Factor A

Figure

• 

  Fig. 1. Study design. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies and blood sampling for plasma cytokine and angiogenic factors (CAFs) were performed 1 day before treatment (day 0). Patients were treated with bevacizumab (5 mg/kg intravenously) alone on day 1 and the first follow-up DCE-MRI and blood sampling for plasma CAFs were performed 3 days after the monotherapy treatment (day 4). A concurrent FOLFOX-6+B regimen (bevacizumab/oxaliplatin/5-fluorouracil/leucovorin) was administered on day 7 and the second follow-up DCE-MRI and blood sampling for plasma CAFs were performed 3 days after combined chemotherapy (day 10).

• 

  Fig. 2. (A-G) Changes in the values of the dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and plasma cytokine and angiogenic factors (CAFs) parameters from baseline, first follow-up after treatment with bevacizumab alone, and second follow-up after treatment with combined therapy. VEGF, vascular endothelial growth factor; VEGFR-2, vascular endothelial growth factor receptor 2; IL-8, interleukin 8; PlGF, placental growth factor.

• 

  Fig. 3. Kaplan-Meier estimates for progression-free survival time for patients with low and high baseline IAUC60 values (A), and a Ktrans reduction at the first follow-up (B).

• 

  Fig. 4. A 39-year-old male patient had rectal cancer with one hepatic metastatic lesion. (A) On the baseline image the IAUC60 value was 22.29, which was a higher baseline group value. The baseline Ktrans value was 0.187. (B) On the first follow-up image after bevacizumab monotherapy, the patient had a 66% reduction in Ktrans (0.037). The dynamic contrast enhancedmagnetic resonance imaging results indicated that there were no significant changes in the perfusion parameters between the first and second follow-up (C) (0.031). Based on the large reduction in Ktrans, and the high baseline IAUC60 level, this patient was expected to have a good response to the treatment and to have a good prognosis. Compared with the baseline computed tomography (CT) image (D), the metastatic lesion had decreased in size by the 3-month CT follow-up (E).

Reference

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