Brain Metastases

Educational Objectives

The goal of this program is to improve the management of patients with brain metastases. After hearing and assimilating this program, the clinician will be better able to:

1. Identify primary malignancies and molecular subtypes commonly associated with brain metastases.

2. Review the efficacy and toxicities of radiation therapy, surgery, radiosurgery, and chemotherapy for treating brain metastases.

3. Compare and contrast the efficacy and safety of
whole-brain radiation therapy and stereotactic radio-surgery for the management of brain metastases.

4. Summarize the efficacy of new-generation targeted therapies and immunotherapies for inducing an
intracranial response.

5. Discuss the genetic alterations that occur between primary tumors, brain and extracranial metastases, and lymph nodes.

Summary

Incidence: in United States, ≈170,000 patients diagnosed with brain metastases (BM) each year (number increasing); most common intracranial malignancy (≈10 times more common than primary central nervous system [CNS] malignancies), and among most common oncologic disorders; most common primary malignancies associated with BM include melanoma and lung, breast, and gastrointestinal cancers

Prevalence by molecular subtype: molecular subtype influences risk for developing BM; occurrence of BM disproportionately high in patients with less common molecular subtypes (eg, ≤50% of patients with ALK-positive non-small cell lung cancer [NSCLC] and patients with triple-negative or HER2-positive breast cancer)

Origin and distribution: BM thought to originate from arterial microemboli derived from primary tumor and travel through vascular or lymphatic system to cortex; frequency of BM reflects arterial supply of different brain regions; subtle differences in regional locations of BM related to site of primary tumor

Symptoms: BM increasingly diagnosed earlier when patients asymptomatic or with subtle symptoms, because use of computed tomography and magnetic resonance imaging (MRI) increased; BM cause symptoms through increased intracranial pressure, direct tumor infiltration, and peritumoral edema

Role of antiepileptic therapy: few prospective randomized trials available and results inconclusive; Cochrane Review — no data to support empiric use of antiepileptic drugs to prevent seizures in patients with BM; many patients who develop seizures during treatment with antiepileptic therapy receive subtherapeutic doses; speaker’s recommendations — ensure patients receive full doses of drugs; patients with history of or who present with seizures require antiepileptic therapy; in most cases, empiric therapy not recommended for prevention of seizures, but consider for patients with melanoma, renal cell carcinoma, or choriocarcinoma (often associated with spontaneous hemorrhage and higher incidence of seizures)

Survival: without treatment, median survival with BM of 1 mo (older data); steroids prolong survival (considered empiric therapy in early stages of disease, particularly for patients with mass effect or peritumoral edema); radiation therapy plays key role for improving survival

Radiation therapy: yields quick and temporary benefit; however, progression occurs after median of 3 to 4 mo (radiation controls CNS disease, but patients succumb to systemic disease) dosing fractionation schemes — 30 Gy in 2 wk considered standard; if concerned about long-term survival of patient, consider lowering fraction size to reduce CNS toxicity; outcomes not improved with higher doses and longer periods of treatment; in select patients, possible role for single-fraction and reduced doses (but doses of ≤2000 cGy typically inadequate)

Radiation Therapy Oncology Group BM trials: recursive partitioning analysis stratified patients into 3 groups by performance status; with radiation therapy, median survival of 2 to 6 mo

Graded prognostic assessment (GPA): currently used in most prospective trials to determine similarities among groups of patients (eg, age, cancer subtype, performance status); study shows clear distinction in prognosis between groups of patients stratified by GPA; useful for clinicians to predict median survival

Surgery: indications — urgent need for decompression; hydrocephalus; diagnosis; concern for hemorrhage or infection; recurrent disease after nonsurgical therapy; solitary metastasis; classic study — in patients with solitary brain metastasis randomized to surgery before radiation therapy, median survival longer, neurologic status superior, and local rate of recurrence lower than in patients randomized to biopsy before radiation therapy; surgery associated with low rates of mortality and morbidity; in ≈11% of patients initially diagnosed with solitary brain metastasis, surgery or biopsy revealed different diagnosis (eg, primary tumor, infection)

Radiosurgery: treats small, discrete areas with high doses of radiation; generally administered as single fraction; gamma knife technique most precise (±0.1 mm of target)

Toxicities of radiation therapy: acute — nausea and vomiting; possible increased requirement for steroids; alopecia; transient disruption of blood-brain barrier; subacute — delayed lethargy and somnolence-type syndrome observed with higher doses; delayed — leukoencephalopathy (rare; destruction of white matter that occurs several months to years after radiation; related to fraction size and total dose); recent studies identify more subtle decline in cognitive function (typically memory) common in patients with BM treated with radiation therapy

Hippocampal avoidance: radiation to hippocampus (contains large volume of neural stem cells; responsible for memory) may contribute to decline in cognitive function and memory; in trial of patients who received hippocampus-sparing whole-brain radiation therapy (WBRT), neurocognitive testing at ≈4 mo shows incidence of cognitive decline only ≈3% (vs ≈30% for historical controls who received standard WBRT)

Stereotactic radiosurgery (SRS): in phase 3 study of ≈200 patients with one resected brain metastasis and cavity treatable with radiosurgery, greater frequency of cognitive decline after WBRT than SRS (85% vs 52%), with no difference in overall survival, but longer cognitive deterioration-free survival after SRS

Laser interstitial thermal therapy: useful for primary and metastatic tumors that cannot be reached or removed with surgery; involves stereotactic insertion of directional laser probe to craft zone of heat to kill irregularly shaped lesions; stereotactic approach uses combination of operating room and real-time MRI; can be used to treat radiation necrosis; procedure causes less edema than other therapies; clinical trials ongoing; MRI data show no evidence of mass effect or edema 3 wk after procedure

Chemotherapy: studies show that most conventional agents ineffective for treating BM because of limited ability to penetrate multiple barriers in brain (blood-brain, blood-tumor, and blood-cerebrospinal fluid [CSF] barriers); systemic delivery of many agents, including doxorubicin and paclitaxel (eg, Taxol), results in poor penetration of brain tissue and BM, while penetration of other agents (eg, vorinostat) into brain and BM moderately good (although heterogeneous); some systemic agents (eg, paclitaxel) neurotoxic, so penetration into CNS potentially harmful

Assessment of CNS lesions: measurement of single diameter (standard method for assessing systemic tumors) not appropriate for CNS lesions because steroids and radiation can affect appearance of tumors on radiologic scans, and sites of new disease may show T2 or flare changes but do not appear as contrast-enhancing nodules; Response Assessment in Neuro-Oncology scales — developed for neuro-oncologic sets of tumors (including BM) to assess improvement or progression; account for target and non-target lesions, steroid dosing, and clinical status

Lung cancer

Epidermal growth factor receptor (EGFR) inhibitors: early agents (erlotinib, gefitinib, and afatinib) — minimal penetration of CNS; ineffective for treating BM; osimertinib — 3rd-generation EGFR-tyrosine kinase inhibitor (TKI) active against T790M mutation in EGFR and designed to penetrate brain; randomized study in patients with stable, asymptomatic CNS metastases who progressed on first-line EGFR-TKI shows treatment with osimertinib improved progression-free survival (vs pemetrexed plus platinum chemotherapy); AZD3759 — EGFR-TKI designed to cross blood-brain barrier; BLOOM study shows that drug well-tolerated, with ratio of concentration of drug in CSF to plasma of 1:1 (for active metabolite, ratio of 0.5:1) and overall rate of response of ≈65% (in many patients, significant response in brain)

Anaplastic lymphoma kinase (ALK) inhibitors: alectinib — pooled data from 2 studies of patients with previous exposure to crizotinib show responses in heterogeneous group of patients robust, with rate of response in brain <58%; ceritinib — study shows rate of response of 45% and rate of intracranial disease control of 80%

Immunotherapy: study shows that in patients with NSCLC and BM treated with pembrolizumab, rate of response of ≈33%

Melanoma

Vemurafenib: study in patients with untreated or previously treated BM shows rate of response of ≈18% with single-agent therapy (however, usually used as part of combination therapy); in most patients, size of lesions decreased, but majority did not meet criteria for partial response; median overall survival of 10 to 14 mo

Dabrafenib: phase 2 trial — in previously untreated patients, rate of intracranial response of ≈40% (most showed some degree of response), with intracranial duration of response of 12 to 16 mo and overall survival of 16 to 21 mo (many participants had multiple BM); study of dabrafenib plus trametinib — shows rate of intracranial disease control of 78%, with median duration of response 6 to 7 mo

Immunotherapy: ipilimumab monotherapy — studies show rate of response low; nivolumab plus ipilimumab combination therapy — small study shows response durable in majority of patients (time to response typically ≤2 mo; median duration of response not reached), with response maintained at follow-up (median of ≈9 mo) in 93% of responders (in some patients, complete response in brain); in Australian study, intracranial response to nivolumab plus ipilimumab less likely in patients with previous exposure to combination therapy with BRAF and MEK inhibitors than those without

Breast cancer

Lapatinib: theoretically active in brain, but shows low efficacy for treating HER2-positive disease; some data show activity increased when combined with capecitabine (eg, one study shows rate of CNS response of 66%)

Neratinib: study shows CNS volumetric rate of response of ≈50% when combined with capecitabine

Development of BM

Study using whole-exome sequencing: analysis of matched samples of BM, primary tumors, non-CNS metastases, and normal tissue shows that in 53% of cases, clinically relevant genetic alterations detected in BM but not in primary tumor; BM spatially and temporally separated genetically homogeneous, but distal extracranial samples (lymph nodes, primary tumor, and liver) genetically heterogeneous

Study of breast cancer samples: BM associated with breast cancer typically lose expression of PTEN, and genetic signatures of primary tumor and metastases in brain, bone, and lung differ; complex series of data show that microenvironment of brain (through exosomal transfer of astrocyte-derived microRNA) delivers RNA into tumor cells that regulates growth of tumors

Current paradigms: patients living longer, and more treatment options available; improvements in control of systemic disease increase development of BM; with increase in life expectancy, ameliorating neurocognitive toxicities of therapies important; selecting treatment strategy requires consideration of systemic options, systemic disease burden, molecular phenotype, and physical and cognitive fitness

Questions and Answers

SRS vs WBRT for patients with small number of BM: often institution-specific; speaker’s institution performs SRS whenever possible, regardless of size, shape, or number of lesions; multiple trials investigating this question; in older studies, overall survival similar; with SRS, neurocognitive function typically preserved and local control effective, but rates of distant brain failure high; speaker prefers to perform SRS and repeat as needed for distant BM that develop subsequently

Efficacy of temozolomide (eg, Temodar): extensive literature shows that temozolomide penetrates brain, but yields low rates of response for BM in patients with lung cancer, breast cancer, or melanoma

Genetic testing of BM: evidence may support sequencing of BM to identify new targets to treat, but insurance may not cover additional sequencing or targeted therapy; furthermore, results of sequencing not useful unless targeted agent able to penetrate blood-brain barrier

Ability of mTOR inhibitors to penetrate brain: everolimus approved for treating subependymal giant cell astrocytoma (yields good response and long-term survival), but efficacy for treating other primary brain tumors and ability to penetrate blood-brain barrier unclear

Intrathecal delivery of targeted agents: either safe or lethal; yields minimal penetration of standard agents into solid tumors; useful for intrathecal disease, but generally ineffective for delivery into brain

Surveillance: depends on individual patient, treatment options, and risk for recurrent BM; for patients at high risk for CNS metastases (eg, with ALK-positive NSCLC), more frequent surveillance and early treatment may be warranted; future guidelines may indicate need for empiric screening of high-risk patients

Readings

Brown PD et al: Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1049-1060; Chamberlain MC et al: Systemic therapy of brain metastases: non-small cell lung cancer, breast cancer, and melanoma. Neuro Oncol. 2017 Jan;19(1):i1-i24; Davies MA et al: Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017 Jul;18(7):863-873; Gadgeel SM et al: Pooled analysis of CNS response to alectinib in two studies of pretreated patients with ALK-positive non-small-cell lung cancer. J Clin Oncol. 2016 Dec;34(34):4079-4085; Goldberg SB et al: Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):976-983; Gondi V et al: Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. 2014 Dec 1;32(34):3810-6; Mok TS et al: Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640; Patchell RA et al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990 Feb 22;322(8):494-500; Sinha R et al: The evolving clinical management of cerebral metastases. Eur J Surg Oncol. 2017 Jul;43(7):1173-1185; Tremont-Lukats IW et al: Antiepileptic drugs for preventing seizures in people with brain tumors. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD004424.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose. In his lecture, Dr. Lesser presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Lesser was recorded at the Charles L. Spurr Piedmont Oncology Symposium, held September 15-16, 2017, in Asheville, NC, and presented by the Wake Forest School of Medicine. For information on future CME programs from this sponsor, please visit wakehealth.edu/office-of-continuing-education. The Audio Digest Foundation thanks the speakers and sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

ON091601

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.