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Romano, A.; Moltoni, G.; Blandino, A.; Palizzi, S.; Romano, A.; De Rosa, G.; De Blasi Palma, L.; Monopoli, C.; Guarnera, A.; Minniti, G.; et al. Radiosurgery for Brain Metastases. Encyclopedia. Available online: https://encyclopedia.pub/entry/50929 (accessed on 01 August 2024).
Romano A, Moltoni G, Blandino A, Palizzi S, Romano A, De Rosa G, et al. Radiosurgery for Brain Metastases. Encyclopedia. Available at: https://encyclopedia.pub/entry/50929. Accessed August 01, 2024.
Romano, Andrea, Giulia Moltoni, Antonella Blandino, Serena Palizzi, Allegra Romano, Giulia De Rosa, Lara De Blasi Palma, Cristiana Monopoli, Alessia Guarnera, Giuseppe Minniti, et al. "Radiosurgery for Brain Metastases" Encyclopedia, https://encyclopedia.pub/entry/50929 (accessed August 01, 2024).
Romano, A., Moltoni, G., Blandino, A., Palizzi, S., Romano, A., De Rosa, G., De Blasi Palma, L., Monopoli, C., Guarnera, A., Minniti, G., & Bozzao, A. (2023, October 30). Radiosurgery for Brain Metastases. In Encyclopedia. https://encyclopedia.pub/entry/50929
Romano, Andrea, et al. "Radiosurgery for Brain Metastases." Encyclopedia. Web. 30 October, 2023.
Radiosurgery for Brain Metastases
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15205092

Stereotactic radiosurgery (SRS) has transformed the management of brain metastases by achieving local tumor control, reducing toxicity, and minimizing the need for whole-brain radiation therapy (WBRT). Nevertheless, radiation treatment may induce brain changes, visible in neuroimaging, that are often difficult to distinguish from progressive disease.

stereotactic radiosurgery brain metastasis magnetic resonance imaging immunotherapy radiation necrosis

1. Introduction

Stereotactic radiosurgery (SRS) often represents the primary modality of choice in the treatment of intact brain metastases (BM), or it can be used as adjuvant treatment after surgical resection [1]. The role of SRS in BM treatment has significantly evolved, and its goal is not only to locally control tumoral growth but also to delay or avoid whole brain radiation therapy (WBRT), reducing the incidence of toxicity radio-induced delay [1][2][3].
MRI is the gold standard for the detection of BM and for studying their evolution after SRS [4]. Several imaging techniques are nowadays available for monitoring the response to treatment after brain irradiation, ranging from basic MR examinations to more advanced MR techniques, such as perfusion studies [5], up to nuclear medicine examinations [6]. Nevertheless, response assessment after radiation therapy (RT) remains challenging, and the question to be answered is if there are tools that can indicate if there has been or not a response to therapy and if there are post-treatment changes mimicking tumoral disease.
According to RANO criteria, the response to the therapy is based mostly on dimensional criteria, with a complete response if lesions disappear, a partial response with at least a 30% decrease in the sum longest diameter of Central Nervous System (CNS) target lesions, progressive disease with at least a 20% increase in the sum longest diameter of CNS target lesions, and stable disease if dimensional variation does not qualify for partial response nor progressive disease [7][8]. Therefore, a reduction or stability in lesion size has long been considered a marker for a good treatment response. Nevertheless, recent evidence has shown that nearly 50% of BM may transiently enlarge after treatment without disease progression. For this reason, size alone is not able to provide a realistic estimate of treatment response [9]. Nor could post-contrast enhancement alone be considered a valid marker to discriminate between related changes and disease persistence; indeed, an increase in contrast enhancement following radiation treatment may be related both to progressive disease, pseudoprogression, and radiation necrosis (RN) [10]. Also, if the patient has received concomitant immunotherapy, the appearance of new lesions may not constitute progressive disease [7].
Therefore, conventional imaging alone, based on the evaluation of T2 signal intensity changes, contrast enhancement pattern changes, and size assessment alone, is not able to correctly identify treatment response and distinguish it from therapy-induced related changes [7][11]. Other techniques—some routinely used, others innovative—could help: restriction of diffusion in Diffusion Weighted Imaging (DWI) is usually a biomarker for hypercellularity [12]; dynamic susceptibility contrast-enhanced (DSC) MR perfusion imaging is usually a marker of neoangiogenesis and reduction of its derived parameter rCBV (relative Cerebral Blood Volume) is often seen after SRS [10]; and dynamic contrast-enhanced perfusion (DCE) as a tool to evaluate permeability changes [10][13].

2. How to Translate in Imaging the Effects of Stereotactic Radiosurgery on Tumoral Cells and Surrounding Brain Cells

It has been widely reported that the risk of radiation injury correlates partly with lesions size and location, volume of normal brain parenchyma receiving radiation, radiation dose, prior use of RT, and concurrent systemic treatments including either immunotherapy or targeted therapy [14][15][16].
SRS achieves its therapeutic effects in a time- and dose-dependent way by causing DNA damage, resulting in the inhibition of tumor cell division, induction of apoptosis or necrosis, and thrombosis of neoplastic vessels [2][17]. Mechanisms underlying the effectiveness of SRS and consequently the brain SRS-related changes are multiple, not merely related to tumoral cell killing but also involving the tumoral microenvironment. The main mechanisms involved are summarized below (the first one mostly affects tumoral cells; the others affect the tumoral microenvironment).
  • DNA injury and apoptosis: ionizing radiation produces oxygen-free radicals in tumor cells, inducing cell death mainly due to the breakage of the DNA double helix; DNA repair pathways are subsequently activated, leading to cell cycle arrest and apoptosis of cells with irreversibly damaged DNA [18][19].
  • Ceramide-induced apoptosis and fibrinoid necrosis: radiation directly damages the plasma membrane of several cell types (like endothelial cells), activating the enzymatic hydrolysis of sphingomyelin, which generates ceramide. Ceramide acts as a second messenger, stimulating ‘’ceramide-induced apoptosis’’ via the mitochondrial system [20]. This process leads to the production of more reactive oxygen species, which subsequently induce an inflammatory response involving cytokines and chemokines and then the formation of fibrin-platelet thrombi and fibrinoid necrosis [21].
  • Demyelination and diffuse edema: astrocytes, oligodendrocytes, and neural progenitor cells are extremely sensitive to radiation, and radiation damage in the brain results in foci of demyelination. Moreover, necrotic tumor debris, if not readily removed, causes an inflammatory response that induces a capillary permeability defect with consequent edema. The preferential sites of this phenomenon are represented by basal nuclei, cerebral peduncles and deep white matter [22][23].
  • HIF-1 and VEGF activation and neoangiogenesis: it has been demonstrated that radiation injury increases the release of HIF-1a and VEGF by astrocytes. The upregulation of HIF-1a leads to angiogenesis [24], with new fragile and leaking vessels causing perilesional edema.
  • Blood–brain barrier (BBB) disruption: the disruption of the BBB caused by radiation leads to cerebral vasogenic edema. Radiation furthermore induces transient vasodilatation, with variable alteration of capillary permeability generally reversible and transient [25].
In the radiological field, all these phenomena translate, respectively, into enhancement after contrast medium injection, hyperintensity on T2-weighted images related to vasogenic edema, and necrotic areas.

3. Early Post-Treatment Assessment of Stereotactic Radiosurgery

  • Key points
  • Increased diffusivity could be an early sign of radiation treatment efficacy.
  • The reduction of the rCBV DSC-derived parameter within the lesion has been generally considered a reference target for the effectiveness of RT.
  • The reduction of the K-trans DCE-derived parameters is related to a good response to treatment due to a reduction in the pathological vascular permeability of the treated area.
In the early post-SRS phase (typically within three months after treatment), the main neuroradiological goal is to correctly interpret the RT effects in order to identify well-responding patients with important prognostic implications and unresponsive patients who may benefit from further treatments [9][26].

3.1. Diffusion Weighted Imaging (DWI)

DWI and the derived apparent diffusion coefficient (ADC) are based upon water molecule mobility in tissue and provide indirect information on the tissue microenvironment. The role of DWI as a biomarker in the detection of early post-radiation effects has been extensively studied [4][12][27]. Based on the principle that restricted diffusion is a marker of hypercellularity, it could be speculated that as cells are killed by therapy in the BM, this could lead to increased diffusivity, which could potentially be an early sign of radiation treatment efficacy [4][12][27]. In this regard, Huang et al. showed how the ADC value in BM increased significantly already in the first days after SRS [13], whereas Chen et al. identified the Diffusion Index (tumor volume/ADC mean) as a valid biomarker with lower Diffusion Index values one month after SRS in responder patients compared to non-responder patients [27].

3.2. Dynamic Susceptibility Contrast (DSC) Perfusion MRI

DSC perfusion imaging is the most widely used perfusion technique. It is suitable to be performed routinely in the follow-up of irradiated BM as it only takes about 2–3 min to be acquired and is highly sensitive in discriminating tumors from post-treatment changes [10][26].
DSC perfusion MRI relies on the T2 and T2* shortening effects of gadolinium-based contrast agents. It is performed using a series of T2*-weighted gradient echo-planar images acquired during the passage of a standard dose (0.1 mmol/kg) of contrast agent intravenously administered at a rate of at least 3 mL/s.
The main parameters derived from DSC MRI are the rCBV and the relative cerebral blood flow (rCBF), which represent, respectively, the volume of blood within the lesion and the volume of blood passing through the lesion per unit of time normalized to the contralateral normal parenchyma; those parameters are strictly related to tumoral neoangiogenesis. Other DSC parameters, derived from the T2* signal-intensity time curve, are the relative peak height (rPH) and the percentage of signal-intensity recovery (PSR).
A reduction in the rCBV parameter within the lesion has been generally considered a reference target for the effectiveness of RT, even in the early stages [4].
Although DSC theoretically can early discriminate responders from non-responders, it is important to remind about some issues concerning this technique, first of all the limit related to paramagnetic artifacts that in several cases hamper DSC in predicting tumor response after SRS; the difficulty of evaluating lesions in highly vascularized cortical areas; and the issue related to extravascular leakage of contrast agent [10].

3.3. Dynamic Contrast Enhanced (DCE) Perfusion MRI

An alternative, less commonly employed, perfusion technique is DCE MRI, which involves serial T1-weighted images before, during and after gadolinium-based contrast agent injection over a prolonged time of acquisition, typically 5 min or longer. DCE MRI is a multiparametric perfusion whose data analysis can be performed using both qualitative, semi-quantitative and quantitative methods in order to achieve information about tumor microvasculature and microarchitecture. Particularly, it assesses tumor microvasculature and is able to evaluate permeability changes within the treated lesion [13]. The transfer constant (Ktrans) is the most used parameter, reflecting flow and permeability [28]. Other permeability parameters include volume fraction of extracellular extravascular space (Ve), reflux rate (Kep), and vascular plasma volume (Vp). Ve depends on cellular density, tissue architecture and the presence of necrotic areas; Kep represents the reflux rate of gadolinium from the extracellular extravascular space back into plasma and depends on both Ktrans and Ve (Kep = Ktrans/Ve). Vp reflects the blood plasma volume per unit volume of tissue, and it is related to neoangiogenesis and vascular density [29].
Regarding the role of early-stage DCE perfusion, Taunk et al. have shown that lower values of the K-trans after SRS are related to a good response to treatment due to a reduction in the pathological vascular permeability of the treated area [30], and according to Knitter et al., an increase in the K-trans values, even in the early stage, is related to the progression of disease [4].

4. The Role of Neuroimaging in Distinguishing True Disease Progression from Post-Treatment Radiation Effects (PTRE) Mimicking Disease Progression

Key points
  • Radionecrosis and pseudoprogression are possible post-SRS treatment changes.
  • An enhancing lesion may represent both tumor recurrence and post-treatment radiation effects; T1 mapping could help in differential diagnosis with continuous but slow accumulation of contrast agent in RN in contrast to the rapid contrast agent accumulation and relatively fast clearance in tumor recurrence.
  • In DWI/ADC images, “The centrally restricted diffusion sign” appeared to be due to hypercellularity in coagulative necrosis and theexpression of RN.
  • DSC helps in differentiating pseudoprogression, or RN, from progressive disease, with the highest value of rCBV in progressive disease.
  • Ktrans and Vp DCE-derived parameters seem to help in differentiating progressive disease from radiation injuries; anyway, the role of DCE is still debated in the literature.
  • ASL seems to be useful only in monitoring metastatic lesions characterized by high vascularity and increased CBF values, including renal cell carcinoma, melanoma and thyroid carcinoma.
  • PET imaging, with 18F-fluorodeoxyglucose or amino acid tracers, represents an additional tool. Typically, high uptake of tracers is observed in tumor recurrence, while low uptake is considered a hallmark of radiation effects.
  • Radiomics and AI are showing promising results in differentiating true progression from treatment effects, but they still must be validated.

References

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Andrea Romano
,
Giulia Moltoni
,
Antonella Blandino
,
Serena Palizzi
,
Allegra Romano
,
Giulia de Rosa
,
Lara De Blasi Palma
,
Cristiana Monopoli
,
Alessia Guarnera
,
Giuseppe Minniti
,
Alessandro Bozzao
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Revisions: 2 times (View History)
Update Date: 31 Oct 2023
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