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

Balamurugan Vellayappan
Balamurugan Vellayappan
, 
Dennis Cheong
Dennis Cheong
, 
Salil Singbal
Salil Singbal
, 
Jeremy Tey
Jeremy Tey
, 
Yu Yang Soon
Yu Yang Soon
, 
Cheng Nang Leong
Cheng Nang Leong
, 
Alvin Wong
Alvin Wong
, 
Sein Lwin
Sein Lwin
, 
Chau Hung Lee
Chau Hung Lee
, 
Pravin Periasamy
Pravin Periasamy
, 
Simon Lo
Simon Lo
 y 
Naresh Kumar
Naresh Kumar
   | 13 dic 2022
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Article Category: Research Article
Publicado en línea: 13 dic 2022
Páginas: 525 - 534
Recibido: 24 ago 2022
Aceptado: 29 sept 2022
DOI: https://doi.org/10.2478/raon-2022-0046
© 2022 Balamurugan Vellayappan, Dennis Cheong, Salil Singbal, Jeremy Tey, Yu Yang Soon, Cheng Nang Leong, Alvin Wong, Sein Lwin, Chau Hung Lee, Pravin Periasamy, Simon Lo, Naresh Kumar, published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

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

Inclusion and exclusion criteria

Inclusion criteria Exclusion criteria
1. Age ≥ 21 years 1. Metastatic haematological and germ cell neoplasms
2. Proven metastatic disease 2. Inability to undergo MRI or receive gadolinium contrast
3. Life expectancy > 3 months 3. Prior radiotherapy to region of interest
4. Eastern Cooperative Oncology group (ECOG) 0–2 4. Recent immediate surgery surgical to affected intervention spinal levels, or patients requiring
5. ≤ 3 contiguous vertebral body segments, including para-spinal disease 5. Spinal instability score (SINS) > 12
6. Able to lie supine for ≥ 60 minutes 6. Symptomatic cord compression (Bilksy grade 2 or 3), or worsening neurological deficits

Clinical outcomes

Patient ID (Change Post-SBRT from VAS pre- SBRT baseline) Acute toxicity Late toxicity Response at 3 months assessment (MD Anderson criteria) Follow-up duration (months) Local recurrence at last follow-up Status of patient at last follow-up
1 0 (-8) G1 esophagitis Nil PR 39 No Dead
2 0 (-3) Nil Nil PR 54 Yes Alive
3 0 (-5) Nil G1 compression fracture PR 50 No Alive
4 0 (-8) G1 esophagitis Nil SD 15 No Dead
5 3 (-3) G1 esophagitis Nil PR 22 No Dead
6 0 (-3) Nil Nil SD 13 No Dead
7a 2 (-5) Nil G1 compression fracture PR 42 No Alive
7b 2 (-5) Nil Nil PR 42 No Alive
8a - Nil N/A - N/A N/A Dead
8b - Nil N/A - N/A N/A Dead
8c - Nil N/A - N/A N/A Dead
9 0 Nil G3 compression fracture SD 37 No Alive
10 0 (-3) Nil Nil PR 22 No Alive

Patient characteristics

Patient ID Age Gender Primary histology Level of spinal metastases Extraspinal disease site Baseline analgesia requirement: opioid/non- opioid/nil Prior chemotherapy anti-Prior VEGF therapy Prior immunotherapy ECOG treatment Pre- VAS SINS Indication SBRT
Dose (Gy) Fractions
1 69 M RCC C1 Lung Non-opioid No No Yes 1 8 6 Radioresistant histology, pain control 24 3
2 60 M RCC S1 Nil Nil No No No 0 3 3 Oligometatasis 27 3
3 60 M NSCLC-EGFR - T5 Brain, lung bone. Nil Yes No No 1 5 6 Oligometastasis 24 3
4 62 F NSCLC-EGFR - C5 Brain, bone nodal, Opioid No No No 1 8 7 Oligometastasis, pain control 24 2
5 75 M adenocarcinoma Prostate T1 Bone Nil No No No 1 6 5 Oligometastasis 24 3
6 62 M adenocarcinoma Colon L1 LN, lung Nil Yes No No 1 3 9 Oligometastasis 27 3
7a 52 M RCC L1 Bone Opioid No No Yes 1 7 7 Radioresistant histology, pain control 27* 3*
7b 52 M RCC L2 Bone Opioid No No Yes 1 7 7 Radioresistant histology, pain control 27* 3*
8a 69 F NSCLC-EGFR + T1 Brain, lung bone. Non-Opioid No No Yes 1 3 5 Oligometastasis 24 3
8b 69 F NSCLC-EGFR + T10 Brain, lung bone. Non-Opioid No No Yes 1 3 4 Oligometastasis 27* 3*
8c 69 F NSCLC-EGFR + T12 Brain, lung bone. Non-Opioid No No Yes 1 3 6 Oligometastasis 27 3
9 51 F ductal Breast carcinoma Invasive T4 Nil Nil Yes No No 1 0 2 Oligometastasis 27 3
10 72 M adenocarcinoma Prostate L3 Nil Nil No No No 2 3 2 Oligometastasis 24 2
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Medicine, Clinical Medicine, Internal Medicine, Haematology, Oncology, Radiology
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