Brain metastases are the most common intracranial tumor diagnosed in adults with an incidence that far outpaces that of primary malignant brain tumors (1). The incidence rate of brain metastases is approximately 9%-17%, and rates appear to be increasing particularly for patients with breast cancer, colorectal cancer, lung cancer, and melanoma due to improvements in systemic therapies, cancer surveillance, and overall patient survival (2, 3). Historical management of brain metastases with radiotherapy consisted of whole brain radiation therapy (WBRT), which delivers a uniform, low dose of radiation to the entire brain but is also associated with cognitive decline, fatigue, and alopecia among other symptoms (4). The development of stereotactic radiosurgery (SRS) in 1961 allowed a combination of precise localization with a steep dose gradient to treat brain metastases with a much higher biologically effective dose (BED) while sparing the uninvolved brain from a substantial radiation dose, altering the paradigm of brain radiotherapy (5, 6).

Today, SRS is utilized as a monotherapy as well as in conjunction with both WBRT and surgical resection (7, 8). Despite the higher rates of distant intracranial failure associated with SRS, local control is similar or better than with WBRT and salvage SRS can be offered if new intracranial metastases develop after treatment (9, 10). Unfortunately, SRS carries an increased risk of radionecrosis, with an incidence of approximately 20-30%, compared to the negligible incidence in patients treated with WBRT (11–13). Radionecrosis is a delayed toxicity of radiotherapy which can occur months to years following administration of SRS (14). While the precise pathophysiology of radionecrosis remains imperfectly characterized, the process is likely mediated through a combination of vascular insult, glial cell damage, and aggressive inflammatory response (15, 16). Furthermore, definitive diagnosis can be elusive due to similarities in appearance between radionecrosis and recurrent tumor (17, 18).

To date, several patient-related risk factors for radionecrosis have been identified. Evidence suggests that different areas of the brain may be more radiosensitive and therefore more prone to radionecrosis than others. Extrapolating from treatment of arteriovenous malformations (AVMs), the brainstem appears to be more resistant to the development of radionecrosis, while the frontal cortex may be more radiosensitive (19). Furthermore, radiosurgical treatment of peripheral metastases has also been associated with lower rates of radionecrosis, likely secondary to radiation “dose-dumping” into the non-neuronal tissues such as the calvarium (20). Limited data may suggest that certain tumor histologies are more susceptible to radionecrosis than others (21). In addition, increasing tumor size was identified early as a negative prognostic factor for development of radionecrosis, and consequently has been included as a stratification factor in every landmark randomized trial on the topic (22–25).

Treatment-related risk factors have also been identified including radiosurgical dose as a well-established predictor of radionecrosis (26–28). Rather than delivering radiation in a single dose, fractionated SRS may lower rates of radionecrosis when treating lesions over 2 cm, according to retrospective data, especially when the volume of normal brain receiving less than 18 Gy can be limited to 30 cc or less (29–31). Given the use of SRS in combination with WBRT and as a salvage treatment in the setting of recurrent disease, a history of prior radiation treatment and the time interval between treatments can also influence the incidence of radionecrosis (32, 33). Regarding concurrent immunotherapies, particularly with the increases in indications for immunotherapies and the long half-lives of many new therapeutic agents, multiple observational studies have shown that concurrent immunotherapies may improve local and regional disease control but also exacerbate the risk of radionecrosis (34–44).

However, it is not known whether increasing the time interval between diagnosis of brain metastases and radiosurgery is associated with changes in the incidence of radionecrosis or regional disease control and there are limited data available on changes in the incidence of local disease control (45). As asymptomatic brain metastases are not considered an oncologic emergency, there is no standardized time frame between diagnosis and radiation treatment. Furthermore, this time frame may vary by patient preference, insurance authorization time, receipt of recent chemotherapy, and availability of the radiation oncologist, neurosurgeon, dosimetrist, and radiation physicist. Brain metastases may significantly increase in size within days to weeks with average growth rates ranging from approximately 0.012 to 0.040 cm³ per day depending on histology (46–48). In this report, we seek to identify an optimal time interval between diagnosis of brain metastases and treatment that maximizes local and regional control while minimizing the incidence of radionecrosis.

In this patient cohort, a relationship between an increased treatment delay after diagnostic MRI or CT simulation and incidence of radionecrosis could not be demonstrated ( Table 1 ). Furthermore, a relationship between increased treatment delay after diagnostic MRI or CT simulation and local failure could also not be reliably demonstrated ( Table 3 ). Increased treatment delay after diagnostic MRI and after CT simulation were also not associated with regional failure ( Table 4 ). While previous research on treatment delays prior to WBRT after diagnostic CT or MRI also demonstrated a non-significant relationship with overall survival (51), limited research has been conducted to date on the relationship between treatment delays prior to SRS and local control (45), and there is no published research on the relationship between treatment delays and regional control or the incidence of radionecrosis.

Seymour et al. found that a time interval longer than or equal to 14 days in between treatment planning MRI and SRS was associated with a shorter time period before local failure compared to a time interval less than 14 days in between treatment planning MRI and SRS (45). However, given the median time in between MRI and SRS in Seymour et al. was 11 days with an interquartile range of 6 to 23 days compared to the median time in between MRI and SRS in this patient cohort of 34 days with an interquartile range of 28 to 48.5 days ( Table 1 ), it is possible that the association between local failure and increase in treatment delay is less significant when treatment delay increases beyond a certain point. It is also possible that the inclusion of margins during the treatment planning of this cohort compared to the relative lack of margins in 94.04% of metastases in Seymour et al. may have accounted for most tumor growth during the time interval between MRI and SRS in this cohort, resulting in the lack of association between treatment delay and local failure. In fact, another study found a 2mm margin was sufficient to cover 100% of tumor growth for 78% of metastases after a mean of 23 days in between consecutive MRI scans (48). In this cohort, an advantage to a shorter interval between diagnosis of brain metastases and treatment that minimizes radionecrosis and maximizes local and regional control was not identified. Regardless, delays in starting radiotherapy should be minimized whenever possible.

In this study, MRI maximum axial dimension and a history of prior WBRT ( Table 2 ) predicted radionecrosis, both of which are well-established risk factors (11, 22–25, 32). An increase in GTV was also associated with local failure on multivariate analyses ( Table 3 ), also concordant with the published literature (52, 53). While differences in histology were not associated with radionecrosis in this patient population ( Table 1 ), NSCLC was associated with a lower risk of local failure compared to other histologies after multivariate analyses ( Table 3 ). While this is also reflected in other studies (54, 55), contradictory reports suggest that breast cancer may be more radiosensitive (56). Unfortunately, details of histology subtype (e.g. triple negative breast cancer, squamous cell carcinoma of the lung) were not readily available that may shed additional light on these findings. Additionally, NSCLC was also associated with a lower risk of regional failure ( Table 4 ) compared to other histologies after multivariate analyses, with one study suggesting a lower risk of regional failure for NSCLC compared to SCLC (55), and another study suggesting a relationship between melanoma histology and regional failure with NSCLC demonstrating a nonsignificant relationship with regional failure (57).

Male gender was associated with greater risk of local failure on multivariate analyses ( Table 3 ), a finding also supported by numerous other studies (36, 58, 59), although the biological mechanism for this finding is not understood. A lower risk of regional failure was also identified with increasing Rx IDL and previous SRS to another lesion, findings that are neither intuitive nor observed in other studies to the best of the authors’ knowledge ( Table 4 ). While one might suspect that prior off-target failure would predict additional sites of intracranial failure following SRS, it is possible that such patients have more advanced disease and died before regional failure was established. Contrarily, those patients undergoing initial radiosurgery are likely earlier in their disease course and have a higher risk of regional failure due to a longer life expectancy.

Interestingly, while concurrent ITX was not associated with radionecrosis ( Table 1 ), it was associated with better local control ( Table 3 ). Metastases treated with concurrent ITX also demonstrated significantly better local failure-free survival compared to metastases treated without concurrent ITX ( Figure 1 ). These findings add to the growing body of literature suggesting that the use of concurrent immunotherapies with SRS is not only safe, but enhances the efficacy of radiosurgery (34–37), though much of the existing literature is in the context of melanoma brain metastases (38–43). A potential mechanism for the synergistic effect of combining concurrent immunotherapy and SRS is the abscopal effect, in which tumor neoantigens are generated by radiation and are subsequently absorbed by antigen-presenting cells (APCs) that then activate CD8⁺ T cells (60–63). While the immune response can typically be modulated by proteins such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed death-ligand 1 (PD-L1), immunotherapies inhibit these proteins and act as immune checkpoint inhibitors, thereby increasing immune system activation (60, 61).

Limitations of this study include the retrospective nature and exclusion of some patients due to lack of follow-up imaging. Histopathologic confirmation of radionecrosis was also not available for all metastases. Furthermore, concurrent immunotherapies were not separated based upon the targets of the inhibitors and analysis was not separated based upon tumor histology. Other systemic therapies may have also been utilized during treatment that were not recorded or analyzed. Nonetheless, this study is the first to the authors’ knowledge assessing the impact of treatment delays on radionecrosis and regional failure, and this study adds to the limited published data on the relationship between treatment delays and local failure.

In this patient cohort, there was no relationship between treatment interval from either diagnostic MRI or CT simulation to treatment and incidence of radionecrosis, local failure, and regional failure; consequently, an optimal interval between diagnosis of intact brain metastases and radiosurgery could not be identified. Concurrent ITX was not associated with radionecrosis, but was associated with a lower risk of local failure, suggesting a synergistic oncologic effect without an attendant increase in toxicity.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study involved human participants and was reviewed and approved by the NYU Langone Long Island Institutional Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

TC, PD, LT, and MCR conceived the project. JL, CM, and MCR collected the data and constructed the dataset. Statistical analysis was performed by MA. JL, MA, and MCR wrote an initial draft of the manuscript. All authors had approval over the final copy of the manuscript. All authors contributed to the article and approved the submitted version.