Post radiotherapy changes

Summary

Verma 2013.pdf

Differentiating among treatment necrosis, pseudoprogression, and tumor recurrence is expected to become even more complicated as additional treatment modalities (such as immunotherapy, antivascular agents, and gene therapy) are included for brain tumor treatment.

The addition of immunotherapy and chemical agents may enhance multiple apoptotic pathways through several metabolic pathways, resulting in an increased risk of developing treatment necrosis and pseudoprogression.

This may be one of the reasons behind the higher incidence of treatment effects and pseudoprogression with multimodality therapies.
The inclusion of additional treatment methods also reduces the specificity of contrast enhancement as a surrogate marker for defining disease progression, thereby requiring appropriate adjustments in the imaging criteria, as discussed in the next section.

	Radiation necrosis	Tumour progression	Pseudoprogression	Pseudoresponse (Generally for post chemo rather than post radiotherapy-I add it here just for comparison sake)
Timing	3 months to years post radiation		Up to 12 weeks after Post RT
MRI
-T1+C	Increase in enhancement in the tumour bed but without actual tumour	Increase in enhancement in the tumour bed with actual tumour Does not diminish with time	Increase in the nontumoral enhancing area Diminish with time	Decrease in the enhancing area
		Increase perilesional oedema Does not diminish with time	Increased peritumoral oedema that diminish with time	Increase peritumoural oedema does not diminish with time
-Flair		Flair shows hyperintensity	Flair shows hyperintensity	Flair shows hyperintensity
DWI (not consistent)	Generally Less cells, less restriction, higher ADC values (but gliosis can decrease ADC values in radiation necrosis	Generally more cells, more restriction, lower ADC values
MRS	Compared to tumour -Raised Cho/NAA ratio -Raised Cho/Creatine ratio Compared to normal brain -Reduced NAA/Creatine ratio	Compared to tumour Very Raised Cho/NAA ratio Very Raised Cho/Creatine ratio Compared to normal brain Very Reduced NAA/Creatine ratio
MR Perfusion	Reduced rCBV (>2.6) Reduced enhancement rate (dI/dt)	Raised rCBV (>2.6) Raised enhancement rate (dI/dt)
PET	Decrease metabolic activity (glucose uptake)	Increase metabolic activity (glucose uptake)
Pathology	Percentage of tumour cells present low Blood vessel damage → ischemia → necrosis → increased capillary permeability → fluid transudation → consequent brain oedema.	Percentage of tumour cell present high Progressive growth	Vasodilation → disruption of the BBB → oedema	◦ Antiangiogenic agents such as bevacizumab, an anti-VEGF antibody, and cediranib, a VEGF receptor tyrosine kinase inhibitor → reduce angiogenesis → reduce vascular permeability → falsely reduce contrast enhancement ◦ Reversibility of this vascular normalization, with rebound enhancement and edema, was noted when patients required a “drug holiday,” mostly due to toxicity, with a “re-response” after restart.
Differentiate	Biopsy (Tumour progression vs Radiation necrosis)	Biopsy (Tumour progression vs Radiation necrosis) Repeat MRI (Pseudoprogression vs Tumour progression)	Repeat MRI (Pseudoprogression vs Tumour progression)
Notes			If MRI changes stay for more than 12 weeks then call it radiation necrosis

3 different types of effects of brain RT can be identified on the basis of the time

Acute

Timing

During the period of radiotherapy

Pathology

Due to

Vasodilation → disruption of the BBB → oedema → raised ICP

Clinical features

Headache
Nausea
Somnolence

No changes

Management

Spontaneously resolve and do not require additional treatment
Symptomatic management

Corticosteroids

Pseudoprogression (Subacute or early-delayed)

General

Mimics tumor progression
Early necrosis

Do not use the term necrosis

As no cell death here just disruption of BBB from radiation

These types of necrotic lesions should not be considered strictly radionecrosis because they are included in the treatment effects, implying a potential difference in patient outcome.

Treatment necrosis

When using concurrent chemotherapies, such as temozolomide (TMZ), development of radiation necrosis is more likely and often occurs sooner during the early-delayed period.

Therefore, researchers have interchangeably used the terms treatment necrosis and pseudoprogression in the literature.

However, pseudoprogression is different from radiation necrosis, because these lesions and associated clinical symptoms recover spontaneously.

Shortly after completion of RT, patients with high-grade brain tumors can present with an increase in contrast-enhancing lesion size, followed by subsequent improvement or stabilization without any further treatment

MacDonald criteria (updated by Response Assessment in Neuro-Oncology working group)

Based on 2D tumour measurements made in MR imaging scans, in conjunction with clinical assessment and corticosteroid dose.
Differentiating progression and pseudo-progression:

Definition of disease progression (tumour recurrence) within the first 3 months (early-delayed time period) only

If the new enhancement is observed outside the radiation field OR

Tumour progression is considered to have occurred when an increase of >25% in the size of the contrast-enhancing lesion is observed.

If any histopathological confirmation exists.

Association between the incidence of pseudoprogression and increased survival;

Perhaps pseudoprogression = an active “inflammatory” response against the tumour

Timing

Up to 12 weeks after radiation ends

Pathology

Due to

Vasodilation → disruption of the BBB → oedema → raised ICP

Correspond to gliosis and reactive radiation-induced changes without evidence of viable tumour

Clinical features

Asymptomatic
Headache
Nausea
Somnolence

Non-enhancing white matter T2-signal hyperintensities and new or enhancing contrast-enhancing lesions in proximity to the irradiated tumour site on imaging
Vary from oedema to new lesions or increased size of contrast-enhancing lesions within the immediate vicinity of the irradiated tumor volume
Only method of distinguishing pseudoprogression and early progression of disease is to perform follow-up examinations of the patients because conventional MR imaging is unable to differentiate the 2 and alternative techniques have not yet been validated in prospective trials.

Management

Rescan in 4-6 weeks

When pseudoprogression is likely to resolve

Spontaneously resolve and do not require additional treatment

In some cases, appears to progress with time into radiation necrosis or treatment-related necrosis

Symptomatic management

Corticosteroids

MGMT promoter

Cells that are deficient in MGMT have shown an increased sensitivity to TMZ → Patients with low MGMT expression (due to methylation of the promoter) benefit more from adjuvant TMZ.
MGMT promoter status may predict pseudoprogression in >90% of patients with methylated glioblastoma.
60% probability of early true tumour progression was observed in unmethylated MGMT promoter tumours
Although it can occur following RT alone, pseudoprogression is widely believed to be more frequent following concomitant RT-TMZ

Radiation necrosis

Late: 3 months to years after radiation treatment,

Incidence

3%–24%

< 5% of patients treated with conventional fractionation regimes,

But a higher proportion when large doses per fraction are used and when larger volumes of normal brain are included.

Post radiosurgery incidence of radionecrosis 25%.

Pathology

Marked enhancement in the tumour bed but without actual tumour

Blood vessel damage → ischemia → necrosis → increased capillary permeability → fluid transudation → brain oedema

JSG:

There is always tumour cell but the percentage of tumour cells is lower than tumour progression

Occurrence directly related to

Total Radiation dose

Inc. risk if total radiation dose exceeds 64.8 Gy

Overall treatment duration

Irradiated brain volume.

Fraction size

Concurrent and adjuvant use of chemotherapy + radiation therapy

Increase the risk by at least 3x.
This is partially attributable to the breakdown of blood-brain barrier by radiation injury, which enhances the effectiveness of chemotherapeutic agents and causes unintended injury to tissue surrounding tumour.

Clinical features: variable

Asymptomatic

Significant neurological deficits

Due to

Raised intracranial pressure
Damage to normal functioning brain

Radiology

CT-not good at differentiating

Shared by radiation-induced adverse effects and tumour recurrence

Diffuse hypo-intensity of the white matter extending into and compressing the overlying cortex likely caused by oedema
Enhancing focal areas of lucency suggesting necrosis,
Irregular and/or extensive contrast enhancement
Mass effect

MRI-not good at differentiating

Difficult to distinguish from recurrence.

Increased incidence in white matter and manifests on conventional imaging similar to a malignant tumour with contrast enhancement, oedema, and mass effect

Some of the imaging features most commonly reported to be shared by tumour recurrence and treatment necrosis include

Origin near the primary tumour site
Contrast-agent enhancement
Vasogenic oedema
Growth over time
Mass effect

Treatment necrosis > tumour recurrence

Conversion from a non-enhancing to an enhancing lesion after radiation therapy,
Lesions appearing distant from the primary resection site,
Corpus callosum or peri-ventricular white matter involvement,
“Swiss cheese” or “soap bubble” shape patterns

DWI-a lot of limitations still

ADC estimates the mean diffusivity of water molecules within each voxel (in mm2 /s), assuming isotropy along each direction of movement
Tumour recurrence has greater cellularity than treatment necrosis, and therefore, lower ADC values are expected, compared with treatment necrosis → this has not been consistently shown in studies

One study reported significantly higher ADC values in tumor recurrence than in treatment necrosis, which could be attributable to greater extracellular space or necrotic regions within high-grade tumours.
The ADC values in treatment necrosis can also be lower because of scarring (from gliosis or fibrosis) within the lesion, whereas oedema can elevate the ADC values, possibly because of pure vasogenic oedema, which would have greater water-molecule mobility, compared with oedema associated with tumour recurrence.

FA captures the directionality of diffusion inside the tissue.
FA values are typically high in healthy, normal white matter, because water molecules rapidly diffuse parallel to the white matter tracts
White matter abnormalities that cause the loss of axonal organization produce lower FA and higher ADC values

Factors that can affect FA values: Vascularity, cellular density, and fibre structure

Treatment necrosis, which causes loss of cell structures and normal fibres, should produce even lower FA values than should tumour recurrence.

Perfusion

Tumour recurrence: formation of complex networks of abnormal blood vessels with increased permeability around the tumour site that appear as regions of hyper-perfusion with higher blood volume.

Treatment necrosis: is associated with regions of reduced perfusion because of treatment-induced vascular endothelial damage and coagulative necrosis.

MR perfusion methods:

Dynamic susceptibility-weighted contrast-enhanced (DSC) MR imaging

Relies on the T2* signal drop caused by the susceptibility effect of gadolinium based contrast agents in brain tissue.
The drop in signal correlates with the concentration of the contrast agent and can be used to measure the hemodynamic parameters.
The hemodynamic characteristics of the tissue are quantified using 3 measures:

Relative cerebral blood volume (rCBV)

rCBV has been consistently reported to be promising for differentiating between tumour recurrence and treatment necrosis
Tumour progression: Tumour has abnormal and highly permeable blood vessels growing → higher rCBV values than in normal brain tissue
Treatment necrosis: hinders blood flow → lower rCBV values

Relative peak height (rPH)

Maximum change in signal intensity during the transit period of a contrast agent
Quantitatively measure tumour vasculature and has been reported to strongly correlate with rCBV
Higher rPH values are expected to be associated with tumor recurrence, because progressing tumours have greater vasculature than does treatment necrosis

Percentage of signal-intensity recovery (PSR).

Measures the degree of contrast agent leakage through the tumour microvasculature and, thus, directly reflects capillary permeability
Growing tumors recruit abnormally formed and leaky blood vessels that are expected to increase vascular permeability and, thus, lower PSR values. PSR should therefore be lower in tumor recurrence than in treatment necrosis

Dynamic contrast-enhanced (DCE) MR imaging

Uses a rapid sequence of T1-weighted images to measures changes in signal intensity as a bolus of contrast agent passes through a brain tumour.
Tumour signal intensity in DCE-MRI reflects a combination of factors, including overall perfusion, vascular permeability, and extracellular volume
Quantitative hemodynamic parameters

Volume transfer of contrast between the blood plasma and extracellular space (Ktrans)

Represents the permeability of the tumour vasculature
Shown to be higher in tumour recurrence than in treatment necrosis

Extravascular extracellular space (Ve),

No statistically significant differences have been reported between the 2 lesion types

Area under the curve (iAUC)

Provides insight into the kinetics of contrast agent accumulation by integrating the concentration of the agent observed in brain tissue over time
Vascular dilation present in treatment necrosis, the iAUC values have been reported to be higher for treatment necrosis than for tumour recurrence.

CT Perfusion

Advantages over MR imaging:

CT scanners are more widely available
Unlike MR scanners, CT scanners do not suffer from magnetic susceptibility artifacts
CT is less prone to errors when quantifying hemodynamic parameters because of the linear relationship between tissue attenuation and contrast agent concentration and the presence of an arterial input function.

Disadvantage

Ionizing radiation,
The toxicity associated with the iodinated contrast agents,
Lower resolution, and
Limited image-slice volumes.
Require an additional imaging session in a different scanner, and these requirements further limit its feasibility for use in the clinical setting.
CT perfusion is also incapable of imaging regions outside the preselected slice(s), and therefore, the data obtained from a single scan do not permit reconstruction of other imaging planes for a more detailed study;

PET or MR perfusion does not suffer from this problem.

Magnetic Resonance Spectroscopy

Measures the relative compositions of various metabolites, most commonly including

N-acetylaspartate (NAA)
Choline
Creatine
Lipid
Lactate

Tumour progression (when compared with normal tissue)

Lower levels of NAA and creatine
Higher levels of choline and lactate, and different lipid compositions

NAA, Choline, and Creatine Ratios

Tumour recurrence:

Higher choline to creatine and choline to NAA ratios

When compared to

Radionecrosis
Normal surrounding brain

Lower NAA to creatine ratios

When compared to normal appearing white matter

Radionecrosis

Decreased NAA
Variable changes in choline and creatine intensities over time

Choline has been reported to increase during the first few months after radiation therapy and then decrease as treatment necrosis begins to appear

Lipid and Lactate

Are released with cell destruction and, therefore, are typically absent in normal brain tissue
Pure tumour progression

Low amount of lipid and lactate

But most tumour progression have areas of tumour necrosis

Tumour necrosis

Increased amount of lipid and lactate

An increased amount of lipid and lactate can be found inside regions of treatment necrosis, when compared with pure tumour recurrence with no necrosis.

Nuclear Medicine Imaging

Uses weakly radioactive medicinal compounds known as radiopharmaceuticals to image the physiological properties of organs.

Theory

Radiation necrosis: lower metabolism → lower tracer uptake
Tumour progression: increased metabolism → higher tracer uptake

2 types of methods used for metabolic imaging of intracranial lesion

Positron emission tomography (PET)

Fludeoxyglucose (FDG)

A commonly used analogue of glucose,
Has been reported to be capable of distinguishing treatment necrosis from tumour recurrence with

Sensitivity 65%–81%
Specificity 40% –94%

Cons

FDG uptake in normal cortex is variable and may make it difficult to distinguish tumour from surrounding normal Gray matter and
Low-grade tumours appear to be metabolically similar to their surrounding normal tissues, thus hindering the detection and accurate delineation of observed lesions

Amino acid analogs

3,4-dihydroxy-6–18F-fluoro-L-phenylalanine (18F-FDOPA)
O-2-18F-fluoroethyl-L-tyrosine (18F–FET)
L-methyl-11C-methionine (11C-MET)

May perform better than FDG, because amino acids exhibit lower uptake in the normal cortex than does glucose → better contrast than FDG → more accurate detection of growing tumours.

Limitations

Some conditions (e.g. epilepticus) can increase glucose metabolism in areas of the brain and may be misinterpreted as a progressing tumour
Radiation injury can trigger repair mechanisms that increase glucose metabolism in the brain and give the false impression of tumour recurrence,
PET images have generally low spatial resolution (5 mm) that limits their sensitivity in early detection of recurrence, and
There are risks to patients associated with exposure to ionizing gamma radiation.

Single photon emission CT (SPECT)

Similar to conventional planar nuclear medicine imaging but provides additional 3-dimensional information about an organ by imaging from multiple angles with use of gamma rays
Several radiotracers

Thallium-201 (201Tl)
99mTc-sestamibi
Iodine-123-a-methyl tyrosine ( 123I-IMT)
999mTc-glucoheptonate
99mTc-tetrofosmin

201Tl

Is not incorporated into healthy brain tissue
Has been reported to be superior to more powerfully differentiate treatment necrosis from tumour recurrence, compared with conventional structural imaging

Sensitivity ranging from 43% to 100%
Specificity ranging from 25% to 100%

Cons

Low spatial resolution
Requires relatively large radiation doses.

Several 99mTechnetium based tracers

Higher photon flux →

Better spatial resolution
Requiring lower radiation doses than 201Tl

Cons

Tracer uptake in the normal tissues of the choroid plexus and pituitary gland has limited their clinical use.
Sensitivity of these tracers is also low when attempting to detect tumour recurrence in the posterior fossa region
P-glycoproteins may also remove these tracers from tumour cells, thereby reducing their sensitivity to detect growing tumours

Cons

SPECT has poor spatial resolution (7 mm) and low SNR.
The localization of radiotracer uptake is also difficult in SPECT, because its low spatial resolution does not allow accurate registration of the functional images with the anatomical images

Management

Supportive

Steroid to reduce accompanying oedema,
Antiseizure medication as required
Close clinical and radiological surveillance.

VEGF inhibition

Bevacizumab, a humanized anti-VEGF monoclonal antibody in patients with symptomatic radionecrosis who do not respond to steroids.
Nobel 2025

Nobel 2025.pdf

926.0KB

Bevacizumab for the treatment of SRS-induced RN was associated with a

High initial response rate,
Significant lesion reduction
Prolonged clinical improvement.
High rate of lesion regrowth of RN (50%) at around 7 months

Poor response to Bev re-challenge

Hyperbaric oxygen therapy (HBO)

Enhancing oxygen delivery to damaged tissue by increasing plasma oxygen carriage enhances recovery.

Surgery

Indicated for mass effect that does not respond to steroid treatment or other medical management.

Pseudoresponse

Characterized by a marked decreased in the enhancing portion of the lesion some months after initiation of treatment. However, in some such cases, the FLAIR sequence shows a clear expansion of the lesion