SRS/fSRT for brain metastasis
Based on advances in chemotherapy and radiotherapy against cancer in the modern era, physicians have more options for treating brain metastases. Brain metastasis is the most common intracranial malignant tumor in adults, occurring in up to 8–35% of all cancer patients.
Treatment for brain metastasis includes whole brain radiotherapy, surgery, and SRS/fSRT. In particular, to manage smaller brain metastases, SRS is the first-line option. SRS/fSRT for brain metastasis are linked to good tumor control and fewer complications[1,2,3].In our previous studies, SRS and fSRT, using a frameless fixation system for brainstem metastasis and large brain metastasis with unsuitable surgical resection, showed good tumor control with the possibility of reducing RN[19,20].
Recurrence after SRS/fSRT for brain metastasis
SRS is an effective, routinely used treatment modality for brain metastasis, achieving high local tumor control (LTC) rates and typically avoiding the neurocognitive toxicities associated with whole brain radiation therapy. Based on a recent systematic review, the reported 1-year LTC rates vary from 71% to >90%. Nevertheless, the efficacy of SRS using a Gamma Knife (GK), in terms of LTC and complications, depend on the tumor size. In a large cohort treated with SRS, patients whose tumors at first SRS had a maximal diameter >10 mm or a volume of 0.25 cm3 were associated with shorter overall survival. McKay et al. reported the recurrence of brain metastasis after GK SRS. Among 738 patients treated with GK SRS, 58 (7.85%) patients had a recurrence with local failure. Of these 58 patients, 32 underwent a second course of GK SRS.Among them, 24% developed symptomatic RN and the 1-year control rate was 79%. Rana et al. reported that 32 brain metastases with recurrence after linac-based SRS/fSRT were treated with linac-based salvage SRS. The median interval time between initial SRS/fSRT and second SRS was 9.7 months. The overall control rate was 84.4% with 18.8% RN.Balermpas et al. reported 32 recurrent brain metastasis after GK SRS and Cyber Knife SRS. The one-year local control rate was 79.5%, and the overall rate of radiological RN was 16.1%. Repeated SRS for the recurrent brain metastasis after SRS or SRT are summarized in Table 2 [4,6,7,10,11,12,13].
Radiation necrosis after SRS/fSRT for brain metastasis
RN is an inflammatory reaction that occurs between a couple of months and several years following SRS and is one of the most common adverse effects after SRS/fSRT. In previous studies, RN occurred in 5-25% patients[21,22,23,24,25].The definition of RN varies across studies and is based on radiological findings including MRI perfusion, MR spectroscopy, and positron emission tomography with fluorodeoxyglucose and other tracers, and pathological findings after surgical resection. Therefore, it is difficult to compare the reported incidence of RN in each study.
Kohutek et al. reported that the median time from initial SRS to RN was 10.7 months (2.7–47.7 months) .RN is seen as a contrast-enhancing lesion with peri-lesional edema at the site of previous SRS radiologically and can be asymptomatic or cause neurological symptoms. Commonly cited risk factors for RN include target dose and volume, previous radiotherapy, and the concurrent use of systemic agents.
For the management of symptomatic RN including headache, cognitive impairment, seizures, or focal deficits related to the location of RN, oral steroids are the first line of treatment.Some patients need oral steroids for a long duration, but cannot continue to take steroids because of the unfavorable side effects. When RN following SRS/fSRT is resistant to oral steroids, bevacizumab–a humanized antibody inhibiting the vascular endothelial growth factor—may improve patient status and reduce the use of corticosteroids.For symptomatic patients with RN resistant to medication including oral steroids and bevacizumab or those with suspected recurrence, we performed SSR.
Cyst formation after SRS/SRT for brain metastasis
Alattar et al. reported that cyst formation after linac-based SRS occurred in 0.9% of 1106 treated lesions. Among the nine patients, four who had neurologic deterioration despite steroid treatment underwent surgical fenestration and biopsy of the cyst wall.Ishikawa et al. reported that the incidence of cyst formation was estimated as 10% in long-term survivors (>3 years) without tumor recurrence.
In the present study, there were two cases with cyst formation. The time from initial SRS/fSRT to cyst formation was 85 months and 96 months, respectively. We performed fenestration of the cyst wall and removed the necrotic tissue surrounding the cyst wall. No recurrence of cyst formation occurred in these two cases. Aizawa et al. reported that cyst formation occurred 10 years after initial SRS.In the long-term survivors treated with SRS/fSRT, even though follow-up MRI revealed no new brain metastasis and no recurrence, physicians should pay more attention to the development of cyst formation >10 years after SRS/fSRT. Cyst formation after SRS or SRT is summarized in Table 3.
The mechanism of development of cyst formation is unclear. Ishikawa et al. hypothesized that cyst formation is essentially the same as or very similar to those in patients treated with SRS for arteriovenous malformation and thus are not the result of disease progression. Breakdown of the blood-brain barrier appears to play an important role in the cyst formation process. The relatively high blood flow volumes and increased permeability of injured blood vessel walls in the irradiated lesion, may also promote cyst formation within the area of radiation-induced degeneration continuing for several years after SRS/fSRT.
The small sample size included in the present study and retrospective analyses do not allow us to evaluate the proper treatment for recurrence, RN, and cyst formation after SRS/fSRT. Although similar clinical studies have been recently conducted, each study involved different criteria, such as for the definition of RN and treatment modalities, hence lacking consistency in analysis.