br performance status women also may
performance status (women also may have a reduced risk of Hexa His tag peptide relapse compared with men, but this association only trended to significance). This finding aligns with a large body of literature showing superior survival in women compared with men in many different cancer types.36-38
Patients who received BBB-permeable or BBB-impermeable therapies had a reduced risk of brain relapse compared with those not receiving any treatment (Table 4). However, this exploratory result must be interpreted with caution. In addition to the small sample size of our study, defining a drug as either
BBB permeable or BBB impermeable is an oversimplification. BBB permeability, often measured as the ratio of drug concentration in the cerebrospinal fluid (CSF) relative to plasma,
is a continuous variable with a wide range. Cyclophosphamide, for instance, has a CSF/plasma permeability of 20%,11 whereas erlotinib has one of 4%.16 Both drugs are classified as CSF permeable, but our analysis does not account for differences in the degree of permeability. Complicating the analysis, BBB permeability estimates for many drugs vary from study to study, have been studied only in rodents, or are unknown altogether. Perhaps the most significant complicating factor is the observation that drugs classified as BBB impermeable, such as nivolumab and other antibody-based treatments, can reduce the
size of brain metastases, likely by crossing the disrupted and leaky BBB within metastases.39 These possibilities may explain the reduced risk of brain relapse observed in patients receiving BBB-impermeable treatments. Accurately estimating the effect on BBB permeability on relapse risk is thus a challenging goal.
Our exploratory analysis also hinted at differences between systemic therapy types in affecting relapse risk and death. Compared with those receiving other treatments, patients
receiving kinase inhibitors had a reduced risk of systemic relapse, but, surprisingly, had a higher risk of death (Table 5). A higher risk of death was also seen in patients receiving
immunotherapies. These results are surprising given that both kinase inhibitors, such as erlotinib,40 and immunotherapies, such as ipilimumab,41 have been shown to increase overall survival in patients with cancer. In our sample, kinase inhibitors and immunotherapies may have been prescribed to patients who had a greater burden of disease and thus a higher baseline risk
of death. Future studies should further investigate the efficacy of different treatment classes on relapse risk and death.
Why was no association observed between post-SRS systemic therapy and overall survival, especially given the association be-tween post-SRS systemic therapy and reduced brain relapse? Failure to observe a survival benefit could be attributed to drug toxicity and patient selection bias. Toxicity may mitigate any benefit of systemic therapy on overall survival. Given that our study was retrospective and nonrandomized, patients selected to receive post-SRS systemic therapy may have had a higher baseline risk of death than those not receiving systemic therapy, thereby eliminating any benefit on overall survival.
Our study has several limitations. The definition of systemic therapy after SRS combined many different systemic therapy types, including DNA damaging agents (e.g., carboplatin), endocrine-based agents (e.g., tamoxifen), kinase inhibitors (e.g., erlotinib), and immunotherapies (e.g., nivolumab). Although we attempted to parse the relative efficacies of these different treat-ment types, our sample size was too small to make definitive conclusions. In addition, patients receiving the same treatment may have received it for different durations or at different dosages, and our analysis did not account for this variability. Moreover, some cancer types, such as ovarian cancer, were too rare to individually include in our Cox regression models. Given the retrospective and nonrandomized nature of our study, our ana-lyses may suffer from selection bias and confounding that limit the generalizability of the results.
Giving post-SRS systemic therapy to patients with brain metas-tases and controlled extracranial disease may be an effective prophylaxis to reduce the risk of future brain relapse. The benefits of this approach on patients’ quality of life must be weighed against the costs of drug toxicity and the financial burden of treatment. Future studies should compare different treatment types to see if particular drug classes are more effective at reducing relapse risk and death. Additional randomized prospective trials are needed to further delineate the role of systemic therapy after SRS.
1. Choong ES, Lo S, Drummond M, et al. Survival of patients with melanoma brain metastasis treated with stereotactic radiosurgery and active systemic drug therapies. Eur J Cancer. 2017;75:169-178.