Impact of novel systemic treatments in patients with irradiated brain metastases

Chapter 2 presents the overall survival (OS) of a consecutive cohort of patients with brain metastases (BM). Tailoring and timing of the different local and systemic treatment (ST) modalities in BM patients are challenging. Therefore, in this chapter, we assess the impact of all treatment strategies and their relationship with OS. The cohort consists of patients that received radiotherapy after BM diagnosis, patients who awaited the effect of newly-started or switched STs and patients that received best supportive care. OS in the first group was 14 months, 32 months in the second group and 0 months in the third. In the multivariate Cox regression analysis, options for ST, KPS ≥70 and breast cancer were prognostic for a longer overall survival, while progressive extracranial metastases and WBRT were prognostic for shorter OS. Thirty-four percent of patients who awaited the effect of STs did not need radiotherapy in follow-up. Despite the fact that the study describes a retrospective cohort, the availability of ST options was an important prognostic factor. This factor should always be incorporated in decision-making in BM patients. In Chapter 3, we report the effects of the combined treatment with SRS and ST on local control of BM and toxicity. The median time to local failure of irradiated BM was 18 months. The results show that patients who did not receive any form of ST have worse local control. A diameter > 2.5 cm was associated with a higher risk of symptomatic cerebral radiation necrosis (sCRN). Having ST options therefore positively affects local control, without increasing sCRN. Chapter 4 describes the effect of ST on distant brain failure (DBF) in BM patients treated with SRS. Although novel STs, such as immunotherapy and targeted therapies, have shown better systemic disease control in the last decade, their effect on DBF in BM patients remains a topic of discussion. The Brain Metastasis Velocity (BMV), defined as the cumulative number of new brain metastases since initial SRS divided by the total time between initial SRS and new BM, correlates DBF to OS. This implies that better distant brain control can improve OS. In our study, the median time to DBF after radiotherapy was 21 months. Receiving immunotherapy or targeted therapy were associated with a lower hazard of DBF, compared with chemotherapy. The presence of >5 initial BM and progressive or stable extracranial disease were associated with increased DBF. BMV was significantly associated with OS. Chapter 5 reports local control of a cohort of patients with large BM, treated with SGKRS and different STs. Previous reports on SGKRS have shown its potency in establishing local control in these patients, although cohort sizes were small in different studies. This study reports on a large cohort of consecutive patients who were presented with large BM were included. The probability of local control at 12 months was 83%. OS at 12 months was 39%, underlining the poor prognosis that accompanies large BM. Patients receiving ST had better local control than patients who did not. Larger volume reduction between the first and second fraction was also associated with better local control. Larger volumes of the largest BM, and larger volume of all the irradiated BM were associated with worse local control. The rate of sCRN was 26% at 12 months, which is reasonably high. Although this study described a retrospective cohort, it is the largest cohort reporting on SGKRS, and the first including the effects of ST. In this patient population, with poor prognosis, SGKRS could potentially be a viable alternative for surgical resection.