Quantifying the changes in the tumour vascular micro-environment in spinal metastases treated with stereotactic body radiotherapy - a single arm prospective study

Abstract

Background: The primary objective was to quantify changes in vascular micro-environment in spinal metastases (SM) patients treated with stereotactic body radiotherapy (SBRT) with multi-parametric dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI). The secondary objective was to study plasma biomarkers related to endothelial apoptosis.

Patients and methods: Patients were imaged with DCE-MRI at baseline/1-week/12-weeks post-SBRT. Metrics including normalised time-dependent leakage (Ktrans), permeability surface product (PS), fractional plasma volume (Vp), extracellular volume (Ve) and perfusion (F) were estimated using distributed parameter model. Serum acid sphingomyelinase (ASM) and sphingosine-1-phosphate (S1P) were quantified using ELISA. Clinical outcomes including physician-scored and patient-reported toxicity were collected.

Results: Twelve patients (with varying primary histology) were recruited, of whom 10 underwent SBRT. Nine patients (with 10 lesions) completed all 3 imaging assessment timepoints. One patient died due to pneumonia (unrelated) before follow-up scans were performed. Median SBRT dose was 27 Gy (range: 24-27) over 3 fractions (range: 2-3). Median follow-up for alive patients was 42-months (range: 22.3-54.3), with local control rate of 90% and one grade 2 or higher toxicity (vertebral compression fracture). In general, we found an overall trend of reduction at 12-weeks in all parameters (Ktrans/PS/Vp/Ve/F). Ktrans and PS showed a reduction as early as 1-week. Ve/Vp/F exhibited a slight rise 1-week post-SBRT before reducing below the baseline value. There were no significant changes, post-SBRT, in plasma biomarkers (ASM/S1P).

Conclusions: Tumour vascular micro-environment (measured by various metrics) showed a general trend towards downregulation post-SBRT. It is likely that vascular-mediated cell killing contributes to excellent local control rates seen with SBRT. Future studies should evaluate the effect of SBRT on primary-specific spinal metastases (e.g., renal cell carcinoma).

Keywords: DCE-MRI; endothelial apoptosis; spine metastases; stereotactic body radiotherapy.

Figure 1

Schematic illustration of the DP model. Contrast agent (CA) concentration within the vessel decreases with position (x) along the vessel length (L), producing concentration gradients between the arterial (x = 0) and venous (x = L) capillary ends. During the CA passage, a portion of the CA molecules diffuses between the plasma and extracellular, extravascular space (EES) at a controlled permeability surface area product (PS) rate, so that the plasma, Cp(x, t), and EES, Ce(x, t), concentrations show both spatial and temporal dependence.

Figure 2

Normalized values of dynamic contrast enhanced (DCE) parameters (A) time-dependent leakage (Ktrans); (B) permeability surface product (PS); (C) fractional plasma volume (Vp); (D) extracellular volume (Ve); and (E) perfusion.

Figure 3

(A) Representative images for Patient 7a showing at L1 with reduction in dynamic contrast enhanced (DCE) parameters [i] time-dependent leakage (Ktrans); [ii] permeability surface product (PS); [iii] fractional plasma volume (Vp); [iv] extracellular volume (Ve); and [v] perfusion (F) across the 3 time points.

Figure 3

(B) [i] Metastatic deposit in L1 vertebral body (yellow arrow), as shown on T1 Axial MR (with gadolinium contrast); [ii] stereotactic body radiotherapy (SBRT) planning image (CT, MRI fused). SBRT 27 Gy in 3 fractions, delivered using volumetric modulated arc therapy. Clinical target volume (CTV) (blue outline), planning organ at risk volume (PRV)_cord (red outline), 95% isodose (orange colourwash).

Figure 4

Correlative plasma markers (A) acid sphingomyelinase (ASM); and (B) sphingosine-1-phosphate (S1P).