Radiotherapy in Prostate Brain Metastases: A Review of the Literature

Brain Metastases in Prostate Cancer

The presence of brain metastases in patients with prostate cancer is infrequent. Intracranial dissemination of prostate cancer usually occurs in the late stage of the disease. It most commonly involves the epidural space as a result of local invasion of cranial metastases (6). However, since the dura mater serves as a barrier to the spread of tumor cells, intradural spread is most likely the result of hematogenous spread. Some risk factors for the development of brain metastases have been identified including elevated Gleason Score as well as long-standing disease (7). Magnetic resonance imaging (MRI) is the optimal method used to evaluate the location, number, size, and pattern of brain metastases (7).

The prognosis of patients with prostate cancer who develop brain metastases is poor, as is that of other brain metastases from other types of cancer. In addition, it is common for patients to have concurrent distant metastases. In the Tremont-Lukats et al. series of patients, they reported a median treatment-free survival of 1 month (8). The median survival time of prostate cancer patients with brain metastases has ranged from 1 to 7.7 months (5, 8–11).

Leptomeningeal dissemination. Lynes et al. described that the most common intracranial location of prostate cancer metastases was the meninges (65%), cerebrum (25%), and cerebellum (8%). However, many patients were diagnosed only by autopsy and/or computed tomography (CT) rather than MRI, and it is possible that before the introduction of MRI into clinical practice many intraparenchymal lesions in the brain went undetected (7, 11). In more modern studies, the development of dural metastases in prostate cancer is very rare, with an incidence of less than 0.1% (12). In the study by Kanilmaz et al., 60% of patients had pure intraparenchymal metastases, 20% had pure extensive dural metastases, and 20% had both. The exact mechanism of leptomeningeal dissemination is unknown, although several theories have been proposed. As the survival of metastatic castration-resistant prostate cancer (mCRPC) improves, the incidence of dural metastases is likely to increase, thus a differential diagnosis should be considered in those patients with mCRPC who present with neurological symptoms (13).

Intraparenchymal metastases. Intraparenchymal brain metastases are more frequent in men with prostate cancer with aggressive phenotypes such as mCRPC. The most common symptoms are dysphasia, dysarthria, diplopia, facial numbness, headache, weakness, delirium, and confusion (14–16).

In the Kayolmaz study, 75% of patients with intraparenchymal metastases had multiple metastatic lesions (7). As in the Memorial-Sloan-Kettering Cancer Center study, 71% of their patients had multiple intraparenchymal metastatic lesions (9). Bhambhvani et al. reported data from 31 patients with a median number of brain metastases of 2 (1–5). In this study, 61% of metastases were supratentorial, 10% infratentorial, and 29% were both supratentorial and infratentorial (16).

Brain metastasis from prostate cancer presenting as a cystic tumor is even rarer. Twelve cases of prostate cancer patients with cystic or partially cystic brain metastases have been published (17).

Radiotherapy for Brain Metastases

Treatment of brain metastases from prostate cancer includes systemic treatment along with local treatment with surgery, WBRT, radiosurgery or hypofractionated stereotactic radiotherapy. Surgical treatment is indicated in solitary symptomatic intracranial metastases, with controlled systemic disease and acceptable surgical risk (4). Treatment with WBRT includes whole brain parenchymal irradiation (18). Radiosurgery or FSRT allows irradiation of the metastasis in isolation, while limiting the dose to the healthy brain parenchyma.

Whole brain radiotherapy. The median survival in patients receiving WBRT in a systemic review was 4 to 9 months (19). The most commonly used doses are 20 Gy in 5 fractions and 30 Gy in 10 fractions (18). Some factors related to survival in elderly patients have been described, such as Karnofsky Performance Scale (KPS) >80% (20).

In the study by Kanilmaz et al., 60% of patients had distant metastases at the time of diagnosis of prostate cancer. The median survival of patients with brain metastases was 4.5 months (7). In the study by Schröder et al., 12 patients treated with WBRT for intracranial metastases were identified. Median survival from first diagnosis of intracranial metastases was 14 weeks (0-126 weeks) and 6 weeks (0-47 weeks) from initiation of radiotherapy. In univariate analysis, survival was better in patients with ECOG 1 compared to ECOG 2-3 (p=0.030) and RPA class 2 compared to class 3 (p=0.045) (21). In the study by Dziggel et al., 18 patients were included. In a multivariate analysis, a longer time from prostate cancer diagnosis to WBRT showed a trend towards better local control (hazard ratio=2.77, p=0.098). Better KPS (hazard ratio=5.64, p=0.021) and longer time from prostate cancer diagnosis to WBRT (hazard ratio=5.64, p=0.013) were significantly associated with better survival (18). In the study by Nguyen et al., 21 elderly patients (≥65 years) were evaluated. In univariate analyses, KPS ≥80% resulted in better survival than KPS ≤70% (log-rank p=0.018). In the Cox model, KPS maintained significance (hazard ratio=3.18, p=0.031), and thus, the authors, as in the Dziggel’s study, concluded that KPS is a significant prognostic factor for survival in elderly patients with prostate cancer receiving WBRT for brain metastases (20). These predictors of survival should be taken into account when designing personalized treatment regimens and clinical trials.

Radiosurgery. SRS is a safe and effective option for the treatment of brain metastases from other more common primary diseases, such as melanoma, lung cancer and breast cancer.

In addition, SRS has shown promise in increasing the overall survival (OS) of patients with intracranial metastases from prostate cancer, with three small studies reporting survivals of between 9 and 13 months (8, 22, 23). Two studies with larger numbers of patients have recently been published (16, 24).

Bhambhvani et al. analyzed 31 patients and correlated an increase in median survival from 1.2 months to 4.6 months to treatment with radiosurgery (p<0.001) and surgical resection plus radiotherapy at 13 months (p<0.001) (16). Pikis et al. performed a multicenter study to evaluate the safety and efficacy of SRS. Data from nine institutions from 2005 to 2020 were analyzed. Forty-six patients were included in 51 SRS procedures for 120 intracranial prostate cancer metastases. The median time interval from prostate cancer diagnosis to SRS was 4.82±4.89 years, and extracranial dissemination was observed in 73.9% patients. The median KPS was 80, and neurological symptoms attributed to intracranial involvement were present in 76%. Single-fraction SRS was used in 49 procedures. SRS with 6 Gy in five sessions was used in two procedures. At a median radiological follow-up of 6 (0-156) months, local progression was observed in 14 lesions. The median survival after SRS was 15.18 months, and the overall 1-year intracranial progression-free survival was 44%. KPS score at the time of SRS was associated with better overall (p=0.02) and progression-free (p=0.03) survival. Age ≥65 years at the time of SRS was associated with lower OS (p=0.04). The authors conclude that SRS appears to be a safe, well-tolerated, and effective treatment option for patients with intracranial metastases from prostate cancer (24). Table I summarizes studies of brain metastases in prostate cancer treated with SRS and WBRT.

SRS Indications

Indications are based on data from studies involving patients with metastases of multiple origins (25). SRS or FSRT is indicated in patients diagnosed with brain metastases by MRI who are not candidates for surgery. In the case of multiple metastases, it is necessary to individualize each case according to the volume of each lesion and total volume (26). The number of metastases treated has not shown differences in neurological studies or in complications, when comparing 1, 2-5 or 5-10; however, the intracranial tumor volume is gaining importance due to its impact on disease control when radiosurgery of all lesions is considered (27, 28). It is recommended to offer radiosurgery treatment if there are more than 5 lesions if these do not exceed a total intracranial tumor volume of >16-20 cc, with the largest metastasis being <10 cc or <1.6 cm. In case of multiple metastases, assessment of dosimetric parameters V12 (in SRS) or V19 (in FSRT) and V5 should be performed (27).

Radiosurgery of brain metastases after WBRT is an option for overdosing macroscopic disease, as well as sequential adjuvant treatment for lesions that do not respond to WBRT, or for lesions that appear after a course of WBRT throughout follow-up. The prescribed doses will be adapted to the doses received and the time elapsed.

All treatments must consider the general condition of the patient, recommending a KPS ≥70%, an expected survival for extracranial disease greater than 6 months (controlled systemic disease or pending active treatment), and an expected OS greater than 3-6 months calculated with RPA (28, 29).

Limitations. Limitations of this review include the nature of the studies; most were retrospective series with a very small number of patients due to the low incidence of brain metastases in patients with prostate cancer. In addition, limited and ambiguous information makes interpretation of the data difficult.