Use of Systemic Therapy Concurrent With Cranial Radiotherapy for Cerebral Metastases of Solid Tumors

Abstract

The incidence of brain metastases of solid tumors is increasing. Local treatment of brain metastases is generally straightforward: cranial radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiosurgery) or resection when feasible. However, treatment becomes more complex when brain metastases occur while other metastases, outside of the central nervous system, are being controlled with systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies). It is known that some anticancer agents can increase the risk for neurotoxicity when used concurrently with radiotherapy. Increased neurotoxicity decreases quality of life, which is undesirable in this predominantly palliative patient group. Therefore, it is of utmost importance to identify the compounds that should be temporarily discontinued when cranial radiotherapy is needed.This review summarizes the (neuro)toxicity data for combining systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies) with concurrent radiotherapy of brain metastases. Because only a limited amount of high-level data has been published, a risk assessment of each agent was done, taking into account the characteristics of each compound (e.g., lipophilicity) and the microenvironment of brain metastasis. The available trials suggest that only gemcitabine, erlotinib, and vemurafenib induce significant neurotoxicity when used concurrently with cranial radiotherapy. We conclude that for most systemic therapies, the currently available literature does not show an increase in neurotoxicity when these therapies are used concurrently with cranial radiotherapy. However, further studies are needed to confirm safety because there is no high-level evidence to permit definitive conclusions. The Oncologist 2017;22:222-235 Implications for Practice: The treatment of symptomatic brain metastases diagnosed while patients are receiving systemic therapy continues to pose a dilemma to clinicians. Will concurrent treatment with cranial radiotherapy and systemic therapy (chemotherapeutics, molecular targeted agents, and monoclonal antibodies), used to control intra-and extracranial tumor load, increase the risk for neurotoxicity? This review addresses this clinically relevant question and evaluates the toxicity of combining systemic therapies with cranial radiotherapy, based on currently available literature, in order to determine the need to and interval to interrupt systemic treatment.

Cognitive effects of stereotactic radiosurgery in adult patients with brain metastases: A systematic review

“… 1 , 5 , 55 , 56 , 57 The combination of SRS and immunotherapy is promising because radiation therapy may enhance both local and systemic anti-tumor immune responses. 58 , 59 , 60 However, the safety (neurotoxicity), dosage, and timing/scheduling of concurrent immunotherapy with SRS remains a topic of research, 61 , 62 and prospective randomized trials including standardized neuropsychological assessments are needed to investigate the effects of these targeted therapies in combination with SRS on the cognition in patients with BM. 63 , 64 …”

Contemporary practice patterns of stereotactic radiosurgery for brain metastasis: A review of published Australian literature

“…whereby a large proportion of patients received targeted therapy or immunotherapy (median OS of 14.2 months). However, there are still many unanswered questions regarding the combination of SRS and systemic therapy, for example the best sequencing of systemic therapy and SRS, and the potential toxicities with concurrent use of systemic therapy with SRS, among others. Hence, it is important for any future studies reporting on the outcomes of SRS to include details on systemic therapy received by the patients.…”

Current multidisciplinary management of brain metastases

“…Interestingly, an analysis of a recent phase 3 trial of WBRT in brain metastasis suggests that ten 300‐cGy fractions may be superior to fifteen 250‐cGy fractions . Attempts to improve WBRT's treated metastasis control by combining systemic agents have demonstrated increased intracranial response rates, although with minimal, if any, survival benefit and increased AEs . Because of a lack of high‐level evidence regarding the toxicity of concurrent systemic therapies with WBRT, they are typically delivered sequentially to avoid neurotoxicity.…”