MET-11 Recent advances in targeted therapies and immunotherapy for metastatic brain tumors

This presentation outlines CQ2 of Chapter 2 from the forthcoming updated version of the Clinical Practice Guidelines for Brain Tumors, edited by the Society. These guidelines discuss chemotherapy and other drug therapies for metastatic brain tumors in adult patients. First, there is no noteworthy change in the principle of prioritizing local treatment of symptomatic metastatic brain tumors or those that require local treatment in the near future. However, with recent advances in molecular-targeted drugs and/or immune checkpoint inhibitors, many physicians now consider starting systemic treatment prior to local treatment of brain metastases, even in patients with solid tumors that were once considered insensitive to chemotherapy, given that their symptoms are well-controlled and do not require urgent treatment. In the treatment of non-small cell lung cancer (NSCLC), the molecular subtypes of metastatic brain tumors with EGFR mutations and ALK fusion genes have yielded favorable responses to molecular-targeted drugs. Because small molecule drugs are well delivered to the central nervous system, systemic drug therapy with such targeted drugs is commonly selected for patients with untreated metastatic brain tumors. A recent phase II trial has shown the effectiveness of anti-PD-1 antibody pembrolizumab monotherapy for metastatic brain tumors from NSCLC. Because untreated metastatic brain tumors from renal cell carcinoma are prone to bleeding, local treatment of brain metastases should be prioritized before systemic treatment, even if the patient is asymptomatic. Regardless of BRAF mutation status, immune checkpoint inhibitors alone or in combination (nivolumab and ipilimumab) are effective against malignant melanoma with brain metastases; moreover, a combined treatment with BRAF and MEK inhibitors is effective against BRAF mutation-positive malignant melanoma with brain metastases. A novel HER2 inhibitor, tucatinib (unapproved), is expected to be effective against metastatic brain tumors from HER2-positive breast cancer.

Intraoperative Radiotherapy in Brain Malignancies: Indications and Outcomes in Primary and Metastatic Brain Tumors

Despite the continued controversy over defining an optimal delivery mechanism, the critical role of adjuvant radiation in the management of surgically resected primary and metastatic brain tumors remains one of the universally accepted standards in neuro-oncology. Local disease control still ranks as a significant predictor of survival in both high-grade glioma and treated intracranial metastases with radiation treatment being essential in maximizing tumor control. As with the emergence and eventual acceptance of cranial stereotactic radiosurgery (SRS) following an era dominated by traditional radiotherapy, evidence to support the use of intraoperative radiotherapy (IORT) in brain tumors requiring surgical intervention continues to accumulate. While the clinical trial strategies in treating glioblastoma with IORT involve delivery of a boost of cavitary radiation prior to the planned standard external beam radiation, the use of IORT in metastatic disease offers the potential for dose escalation to the level needed for definitive adjuvant radiation, eliminating the need for additional episodes of care while providing local control equal or superior to that achieved with SRS in a single fraction. In this review, we explore the contemporary clinical data on IORT in the treatment of brain tumors along with a discussion of the unique dosimetric and radiobiological factors inherent in IORT that could account for favorable outcome data beyond those seen in other techniques.

SURG-01. CYSTIC BRAIN METASTASES MANAGED WITH RESERVOIR PLACEMENT AND STEREOTACTIC RADIOSURGERY

BACKGROUND Stereotactic radiosurgery (SRS) has become a mainstay of treatment for patients with metastatic brain tumors. However, metastatic tumors with a large cystic component often exceed the size limit for safe and effective SRS. In such cases, surgical resection may not be the preferred first method of treatment, due to tumor location, patient co-morbidities, and patient preference. In such cases volume reduction by cyst aspiration followed by SRS may be a preferred option. OBJECTIVE To present the treatment of patients with cystic metastases using reservoir placement followed by SRS. METHODS Seven patients were treated with this method. We performed reservoir insertion for the aspiration of cystic component in each patient and followed that with outpatient SRS. RESULTS Mean overall volume reduction from this treatment method was 80% (range 46.5-94.9). Mean volume reduction from the cyst aspiration alone was 60.7% (range 3.5-90.9), and after SRS a further 71.6% (range 34.6-94.4), accounting for some cyst reaccumulation between the time of surgery and SRS. The interval between those two procedures were 24 days on average (range 11-58 days). Repeat reservoir aspiration was done a total of 10 times in 5 patients. CONCLUSION Cyst aspiration with reservoir placement followed by SRS is a good option for patients with large cystic brain metastases. The reservoir allows for repeat aspiration if needed. Catheter placement at the center of the cyst, and SRS within 2-3 weeks of surgery, can maximize the likelihood of a successful outcome.

Modulation of the blood-tumor barrier to enhance drug delivery and efficacy for brain metastases

The blood-brain barrier is the selectively permeable vasculature of the brain vital for maintaining homeostasis and neurological function. Low permeability is beneficial in the presence of toxins and pathogens in the blood. However, in the presence of metastatic brain tumors, it is a challenge for drug delivery. Although the blood-tumor barrier is slightly leaky, it still is not permissive enough to allow the accumulation of therapeutic drug concentrations in brain metastases. Herein, we discuss the differences between primary brain tumors and metastatic brain tumors vasculature, effects of therapeutics on the blood-tumor barrier, and characteristics to be manipulated for more effective drug delivery.

Treatment of epilepsy associated with primary and metastatic brain tumors

There is a number of unsolved issues in management of epilepsy associated with primary and metastatic brain tumors (BTs). In particular, no consensus approaches to treatment of patients with epilepsy associated with BTs have been proposed regarding use of current anti-epileptic drugs (AEDs). The review presents the relevant data on epidemiology, features of clinically manifested epilepsy at varying stages of BTs, aspects of drug-drug interaction between AEDs and anti-tumor agents, AED-related effects on cognitive functions as well as quality of life in patients with epilepsy associated with BTs. Levetiracetam and valproic acid comprise the first-line drugs for treating seizures in patients with BTs. It is unreasonable to use AEDs acting as hepatic microsomal enzyme inducers for therapy of epileptic seizures in BTs, because it may decrease efficacy of chemotherapy agents and glucocorticoids along with elevated rate of side effects. Perampanel acting as a selective noncompetitive AMPA receptor antagonist, may be one of the drugs of choice for the adjunctive therapy of epileptic seizures associated with BTs.