Tackling Radionecrosis After SRS for Brain Metastases

Kate M. O'Rourke

Disclosures

November 20, 2019

The preferred line of treatment for breast cancer brain metastases has shifted from whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) on the promise of similar control with fewer side effects.[1] Yet, with the more frequent use of SRS in patients with these metastases, a challenging new clinical problem has emerged: radiation-induced brain necrosis, also known as radionecrosis.[2,3]

"SRS is generally very well tolerated, but if we do see a delayed complication from treatment, it is most commonly radionecrosis," said Trevor Royce, MD, MS, MPH, assistant professor in the Department of Radiation Oncology, University of North Carolina at Chapel Hill. "Patients with radionecrosis are often asymptomatic, and the condition is only seen radiographically—on a brain MRI, for example. However, it can present with neurologic symptoms."

Radionecrosis is a noncancerous condition in which an area of dead tissue in the brain is surrounded by inflamed tissue. It occurs in up to 34% of patients treated with SRS, presents at least 3 months after treatment, and can cause headaches, nausea, vomiting, weakness and other neurologic symptoms.[2,4,5] Here, we look at the challenges of diagnosis and the treatment options for this condition.

SRS: A Game-Changer

SRS provides dose-escalated radiation therapy over a shortened course, minimizing normal brain tissue exposure, and thus toxicities, while maintaining survival equivalent to that with WBRT.[6,7,8] Today, 10 or more tumors are routinely treated with SRS alone at most academic medical centers. In a single SRS session, clinicians can treat patients with cumulative tumor volumes of 25 cm3, even if they have more than 10 metastases.[9]

"SRS has been a tremendous improvement for patients. Traditionally, many patients would get their entire brain irradiated in the setting of brain metastases. Now, we are much more targeted and specific with where we aim our radiation. This avoids giving radiation, and its associated side effects, to otherwise normal and healthy brain tissue," said Royce. "SRS is generally very well tolerated and has resulted in improved quality of life for countless patients. It has fundamentally changed how we treat a patient with cancer who has metastases to the brain." 

Maciej Mrugala, MD, PhD, associate professor and director of the Comprehensive Neuro-Oncology Program at the Mayo Clinic, in Phoenix, Arizona, said clinicians started using SRS more frequently over the past several years because the technology became more available and studies highlighted the downsides of WBRT.[7,8] "More centers have CyberKnife or Gamma Knife technology, and we started treating patients with more than one lesion because of what we know whole-brain radiation can do to patients," added Mrugala. "Whole-brain radiation can be quite devastating for patients' cognition. Patients who have had whole-brain radiation may develop quite significant cognitive impairment—mostly short-term memory deficits that affect quality of life, the way they function at home and in society."

Fatima Cardoso, MD, director of the Breast Unit of the Champalimaud Clinical Centre in Lisbon, Portugal, agreed that SRS has been a game-changer. There is still some fatigue associated with SRS, but the neurologic side effects, which can be very severe with WBRT, are absent or minor.[8]

Diagnosing Radionecrosis

With the more pervasive use of SRS, however, clinicians have begun to see a number of cases of radionecrosis in long-term survivors; the side effect can occur months to years after radiation.[10] "In the past, there weren't that many long-term survivors with brain metastases, but today it's different," said Cardoso. "For example, sometimes we find a breast cancer patient with brain metastases that can be treated with SRS, and the disease outside the brain is very well controlled with anti-HER2 therapy. The patient then lives for several years after the treatment of their brain metastases."

"Radionecrosis is an inflammation in the area of the brain that received the radiation," explained Cardoso. "You have a sore that creates liquid, which is the edema. In the brain, there isn't much space, so anything that occupies space will cause symptoms. Patients will start having symptoms that are very similar to brain metastases, such as dizziness, nausea and vomiting, and problems walking."

Typically, added Mrugala, radionecrosis involves infiltration by immune cells and it can translate into brain swelling. "If the area is small, it is typically not a big deal, but sometimes it can cause significant swelling, and this, in turn, can cause symptoms," said Mrugala. "Patients can be hemiparetic and have a weakness of an arm, a leg, or the face. One can have headache or seizures. There are a lot of potential symptoms that can be associated with radiation necrosis, depending on where radionecrosis is in the brain and how extensive it is."

Maximum dose of radiation does not appear to be associated with the risk for radionecrosis, but volume does increase the risk.[11,12] Lesions receiving a dose of V12 Gy > 8.5 cm3 carry a risk for radionecrosis of more than 10% and should be considered for hypofractionated SRS.[13] The combination of SRS and checkpoint immunotherapy slightly increases the risk for radionecrosis compared with SRS alone.[14]

"The gravity of the symptoms of radionecrosis has to do with the size of the lesion. Sometimes the condition can be exacerbated by concomitant therapies," explained Mrugala. "If someone is on chemotherapy or immunotherapy at the same time, the risk of developing radionecrosis can be higher."

Because the features of radionecrosis overlap considerably with tumor recurrence, symptomatic radionecrosis is notoriously hard to diagnose and manage.[3] Radionecrosis requires very specialized imaging experts—neuroradiologists—to conduct a differential diagnosis.[10,15,16,17]

"Radiation necrosis on MRI can look like tumor. Sometimes it is very difficult to distinguish what is what," added Mrugala. "We frequently use secondary imaging like PET scans to help us distinguish progression of the tumor from radiation necrosis."

Misdiagnosing radionecrosis as tumor recurrence can lead to deleterious treatment and detrimental effects in patients.[3] "The symptoms are very similar and that is why the differential diagnosis is so hard," said Cardoso. "Sometimes radionecrosis looks like progression, but it's not. The lesion is a little bit bigger, and it can have more edema. It's, of course, very important to differentiate whether it is a true progression of the disease or a side effect of the treatment, because the approach is different. If it's a side effect of radiation, you actually need to withhold radiation and you should not give it again."

According to Mrugala, one way to minimize radionecrosis is to pay attention to the size of the metastases that you are considering irradiating. "Typically, three centimeters is the limit[18] for SRS," said Mrugala. "For anything bigger than that, the efficacy of the treatment may go down and the risk of necrosis can be higher."

According to Royce, careful radiation planning and delivery of SRS, supervised by clinicians with expertise, is essential when treating brain metastases. "Technological advancements have allowed these tremendous new treatments to become widely available, and they should be delivered by physicians with the appropriate expertise," said Royce. "We take great care to minimize the risk to nontumor tissues, and therefore minimize the risk of side effects from treatment."

Current and Emerging Therapies

Treatment options for radionecrosis are limited. Surgery can provide symptomatic relief, but it is associated with the risk for complications.[2] Corticosteroids, which can reduce inflammation, are standard of care, despite limited efficacy and a plethora of adverse effects.[2] Current guidelines from the European Society for Medical Oncology suggest that the vascular endothelial growth factor inhibitor bevacizumab may be an option to decrease surrounding edema, usually at a dose of 7.5 mg/kg every 2 weeks for a median of four cycles.[19] Bevacizumab may help reduce inflammation and lessen the symptoms of radionecrosis by reducing leaking of the blood vessels.[5] The BEST Trial is evaluating how well corticosteroids combined with bevacizumab work compared with corticosteroids alone in improving symptoms in patients with radionecrosis.[20]

"The primary line of treatment is steroids, and typically they need to be used for a period of several weeks, occasionally for several months, in increasing doses to control symptoms. Many patients respond very well to steroids just by themselves, and they have a nice outcome," said Mrugala. "In a certain population of patients, steroids don't work very well or patients develop a lot of side effects from the steroids, including weight gain, insomnia, and irritability, among other things, and in those patients we use bevacizumab." The downside of bevacizumab is that patients need to come in to the clinic for infusions, whereas steroids are given orally, Mrugala noted.

A third way to treat radionecrosis is with laser interstitial thermal therapy, otherwise known as laser ablation, which involves placing a probe within the area of radiation necrosis and destroying it.[21,22] "Laser ablation can work very well for radiation necrosis, but it is much more invasive," said Mrugala.

"In general, if a lesion looks like radiation necrosis in patients who have had SRS, we don't treat unless there are symptoms," said Mrugala. "But in patients who have symptoms, such as headaches, seizures, or weakness, treatment is definitely indicated."

Drs Royce, Mrugala, and Cardoso have disclosed no relevant financial relationships.

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