Researchers are now searching for chemical or genetic biomarkers that could be used to identify lung cancer patients more likely to develop brain metastases.
Nonsmall cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases.1An estimated 24% to 44% of patients with NSCLC will develop brain metastases during the course of their disease.2Up to 10% of patients have brain metastases at diagnosis3; the brain is also a frequent site of recurrence in patients treated for advanced NSCLC.1
A growing number of patients with lung cancer are being diagnosed with brain metastases, which may be attributable to improvements in imaging techniques or longer survival due to therapeutic advances.3Factors reported to increase the risk of brain metastases include younger age at diagnosis, larger tumor size, greater lymphovascular space invasion, and hilar nodal involvement.1Some studies have associated nonsquamous histology with a greater likelihood of brain metastases, whereas others have found no clear relationship.1The data show a weak association between most of the reported predictors and brain metastases, limiting their usefulness for identifying patients at greater risk.1Researchers are now searching for chemical or genetic biomarkers that could be used to identify the patients with lung cancer who are more likely to develop brain metastases.
Several prognostic indexes for patients with metastatic brain disease exist.4Most factor in variables such as Karnofsky performance score, patient age, how well the primary tumor is controlled, extracranial disease, and the number and volume of metastatic brain lesions. The prognosis for patients with NSCLC-related brain metastases is poor, particularly for individuals with brain metastases at diagnosis.3Patients with untreated brain metastases survive an average of 1 to 2 months.5Whole brain radiation therapy (WBRT) was introduced in the 1950s6and became standard treatment for brain metastases in different types of cancer.7However, the median overall survival (OS) for treated patients treated with WBRT is only 3 to 6 months.6
Although prompt intervention contributes to better outcomes, many patients with brain metastases are asymptomatic, leading to treatment delays. The National Comprehensive Cancer Network (NCCN) guidelines for the diagnostic work-up of NSCLC recommend the use of imaging to look for brain metastases in certain groups of patients.8Patients with symptomatic brain metastases often exhibit signs and symptoms of neurologic injury and may experience seizures, memory loss, and cognitive decline.9,10Without treatment, the condition of individuals with brain metastases deteriorates quickly. Controlling brain metastases has been found to slow or even improve neurocognitive function, which corresponds with better quality of life.8,11
In some cases, managing brain metastases is limited to supportive approaches like corticosteroids (typically dexamethasone) to relieve intracranial pressure, antiseizure medications, or surgical resection to relieve symptoms. For some patients, especially with early-stage NSCLC, interventions for brain metastases may help control their disease. The selection of therapy depends on the stage of disease, the number and volume of the metastatic brain lesions, the patient's fitness level, and the patient’s preferences and goals.8
Select patients with a single brain metastasis appear to benefit from surgical resection followed by WBRT.7In a systematic review of studies on managing single brain metastases in various types of cancer, Gaspar et al found that the combination of surgical resection plus WBRT was superior to either approach alone in patients with good performance status and who had few sites of extracranial disease.7The NCCN guidelines for treating a single brain metastasis in NSCLC call for surgery followed by either WBRT or stereotactic radiosurgery (SRS), SRS followed by WBRT, or SRS alone, depending on the individual patient.8
The ideal approach for patients with multiple brain metastases is controversial.9,10Although WBRT is widely used, no randomized, controlled clinical trials have established a survival benefit from WBRT in patients with NSCLC and concomitant brain metastases.12The theory behind WBRT is that it helps control undetected microscopic metastatic lesions in addition to visible metastases.9However, WBRT’s neurotoxic risks, such as memory impairment or radiation necrosis, have led to growing reliance on SRS for patients who have a limited number of brain metastases (usually 1-3).9While the debate over whether to use SRS or WBRT as frontline treatment for brain metastases continues, it is becoming increasingly clear that although using WBRT and SRS sequentially reduces the recurrence of brain metastases, pairing the modalities does not improve survival and contributes to cognitive decline.4,8,10,13In 2014, the American Society for Radiation Oncology issued a statement recommending against the routine use of adjuvant WBRT with SRS for patients with limited brain metastases.14
Systemic chemotherapy and targeted agents are not routinely used to treat brain metastases. This is partly due to concerns that their large, hydrophilic molecules cannot permeate the blood-brain barrier (BBB).15Drug efflux mechanisms or intracranial pressure also appear to inhibit the effectiveness of chemotherapy for brain metastases.16However, evidence from preclinical studies suggests the poor quality of the neovasculature that feeds the brain metastases may compromise the integrity of the BBB and allow some of these agents to enter.16
Limited evidence from human studiesprimarily phase II studies and case reportsalso suggests systemic agents commonly used to treat NSCLC can cross the BBB.17In a phase II study, patients with NSCLC and brain metastases, who had not undergone WBRT (N = 43) received up to 6 cycles of pemetrexed and cisplatin. Brain metastases in 42% of patients responded to treatment, and the cerebral disease control rate was 84%.17
Studies have shown concordantEGFRstatus between patients’ primary NSCLC tumors and brain metastases.18,19Jamal-Hanjani and Spicer reviewed the literature for studies regarding the efficacy of EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib in controlling brain metastases.20Response rates of CNS metastases to the EGFR TKIs among patients with a confirmed or probableEGFRmutation ranged from 27% to 89%.
InALK-positive patients who develop resistance to the ALK TKI crizotinib, the CNS is a leading site of disease progression.21Data showing much lower concentrations of crizotinib in cerebrospinal fluid (CSF) versus serum indicate the drug’s weak penetration of the BBB. Although EGFR TKIs also produce lower drug concentrations in CSF than in plasma, the EGFR TKIs achieve higher levels relative to crizotinib.21
One strategy being studied is whether combining TKIs or chemotherapy agents with other drugs, like the VEGF inhibitor bevacizumab, can enhance their effectiveness against brain metastases. Preclinical studies have linked an elevated level of VEGF to an increased risk of brain metastases and to the spread of brain metastases in different cancers, possibly due to the way VEGF promotes neoangiogenesis.16
In the prospective phase II BRAIN study, patients with stage IV nonsquamous NSCLC and untreated asymptomatic brain metastases received a regimen of bevacizumab, carboplatin, and paclitaxel (n = 67) or a regimen of bevacizumab and erlotinib (n = 24). The OS rate of brain metastases was 61% compared with 64% for extracranial lesions. In the 29 patients with measurable brain disease, the median duration of brain metastases response was 8 months. Median progression-free survival was 7 months and median OS was 16 months, which is better than the duration of OS observed in trials of WBRT.2The safety profile for the bevacizumab-based regimen was consistent with that observed in other trials of the drug. One patient did experience an intracranial hemorrhage thought to be related to bevacizumab, but the authors said the incidence of intracranial hemorrhage was similar to historical NSCLC controls without brain metastases.2Controlled studies are needed before these findings are ready for practical application.
Numerous ongoing trials are evaluating approved and investigational targeted therapies for control of brain metastases in NSCLC. Targeted agents being studied alone or in combination with other agents or different treatment modalities include alectinib, bevacizumab, ceritinib, crizotinib, AP26113, and erlotinib (with and without WBRT).
Although WBRT and SRS may have improved outcomes for people with NSCLC who have brain metastases, OS remains poor. Many studies are evaluating whether chemotherapy or targeted agents, alone or in combination with other therapies, may have a role in managing NSCLC-related brain metastases. No randomized, controlled studies have established that chemotherapy or targeted agents can prolong OS. Thus, current guidelines for managing NSCLC call for an individualized approach to managing brain metastases, weighing the benefits and risks for each patient.8