Overall, 65 patients, 35 (53.8%) male and 30 (46.2%) female, were treated with SIDCA. The first patient underwent SRS in November 2017 and the last patient in June 2019. The median age at the time of SRS was 61.5 years (range 22–85 years). With 40 (61.5%) patients, the most frequent entity was non-small-cell lung cancer (NSCLC), including 34 adenocarcinomas, 2 squamous cell carcinomas and 4 neuroendocrine carcinomas, followed by melanoma with 10 (15.4%) patients and breast cancer with 7 (10.8%) patients. Figure 2 shows the entities of the cohort. 25 (38.5%) patients had no extracranial metastases and 40 (61.5%) patients had extracranial metastases at the time of treatment. The median Karnofsky Performance Status at the time of radiosurgery was 90% (range 50–100%). The median follow-up at the time of data analysis was 13 months (95% CI: 11.1–14.9 months). Details of the patient characteristics are listed in table 1.
Overall, 254 lesions were treated. 2 (0.8%) were located in the brainstem. Details on the location of metastases are given in table 1. The number of treated lesions per patient per therapy session was median 3 (range 2–12). The median beam-on time of the simultaneous treatment of all metastases at once was 23 minutes (range 12–38 minutes). There was a significant correlation between number of metastases and beam-on time (Pearson 0.516; 95%-CI 0.324–0.676; p < 0.001). The median dose to each metastasis was 19 Gy (range 15–20Gy). Figure 3 shows a successful treatment of a patient with 5 metastases.
In total, 32 (49.2%) patients experienced AEs. In the first month after treatment, 7 (10.8%) patients experienced acute AEs CTCAE grade 1, such as fatigue, vertigo or cephalgia, all of which could all be related to the SRS. One (1.5%) patient, who received irradiation of 4 melanoma-metastases, experienced seizures CTCAE grade 2 due to intralesional hemorrhage a week after treatment. Overall, no acute AEs CTCAE grade 3 were reported. During follow-up, 28 (43.1%) patients presented AEs: 22 (33.8%) patients experienced CTCAE grade 1 (11 of them therapy-related (16.9%)), 4 patients (6.2%) experienced CTCAE grade 2 (one of them therapy-related (1.5%)) and 3 (4.6%) patients CTCAE grade 3 (none of them therapy related). The AEs are listed in detail in table 2.
Until December 2019 30 (46.2%) patients had died, 5 of them with cerebral progressive disease. Most of the patients (26.2%) died within the first 3 months after radiosurgery. Detailed information is given in Fig. 4. The median overall survival (OS) was 15 months (95% CI 7.7–22.3). In the follow-up period 36 (55.4%) patients had neither a malignant progressive lesion nor new metastases in the brain after radiosurgery.
14 (5.5%) lesions of 11 (16.9%) patients were progressive in size after treatment. Local control of the irradiated lesions after 6 months was 97.5%. 1 (0.4%) lesion, irradiated with 15 Gy, had a histopathologically verified tumor progression 6 months after radiosurgery. This patient additionally had multiple new metastases one year after therapy and was then treated with WBRT (30 Gy in 10 fractions). 21 months after SRS and 6 months after WBRT, the patient developed 3 new metastases: 1 was surgically resected and the rest were treated with a further SRS treatment.
Moreover, 18 (27.7%) patients developed new brain metastases after their first radiosurgery during the follow-up period. After the first intracranial progression, 8 patients received WBRT and 8 patients received a second series of SRS. 2 patients also received a third radiation series: one of them was treated with SRS after a WBRT and the other one was treated with a third SRS course. 2 patients are still under active surveillance after showing only limited progression. The median cerebral progression-free survival was 18 months (95% CI 11.1–24.9). The intracranial control rate was 73.0% after 6 months.
A symptomatic radiation necrosis (RN) was diagnosed in 3 (4.6%) patients, of which 2 (0.8%) lesions in 2 (3.1%) patients were histopathologically verified. One of them was treated with steroids due to symptoms such as vertigo CTCAE grade 2 with nystagmus, which were almost identical to the initial symptoms. The other patient experienced vertigo and cephalgia CTCAE grade 1, but did not require any antiedematous treatment. Another patient developed a symptomatic RN in two metastases, which was clinically and radiologically diagnosed, but no biopsy was performed. Both lesions were irradiated with 20 Gy. The patient suffered from paresis of his left arm and was first treated with dexamethasone and then with bevacizumab in analogy to Levin et al. after insufficient response[30, 31]. 9 lesions (3.5%) in 7 (10.8%) patients were interpreted as pseudo-progression by an experienced neuroradiologist.
A total of 38 (58.5%) patients were treated with immunotherapy at some point during the course of their disease. 12 patients (18.5%) received immunotherapy within a time-period of 4 weeks before and after treatment. 14 patients (21.5%) received tyrosine kinase inhibitors (TKI). 4 of these patients (6.2%) were treated throughout the course of disease, during and after radiotherapy. Overall, these patients had only few AE, most of which were unrelated to the cranial irradiation (such as thyroiditis in 1 patient, or alopecia in 2): 2 patients (3.1%) experienced cephalgia CTCAE°I, and 2 patients (3.1%) fatigue CTCAE°I. However, 1 patient with malignant melanoma, who received nivolumab until shortly before radiotherapy, suffered from a cranial hemorrhage in the irradiated metastases a week after radiotherapy and died a month later. The symptoms included aphasia CTCAE°I and seizure CTCAE°II. No RN was detected among the patients who received immunotherapy at the time of radiation. Detailed information about immunotherapy and small molecule treatment is listed in table 1.