Brain Metastases in NSCLC Increasing and Require Personalized Treatment

Non—small 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.

Prognosis for Patients With NSCLC and 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

Management of Brain Metastases in NSCLC

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

Surgery, Whole Brain Radiotherapy, and Stereotactic Radiosurgery

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

Chemotherapy and Targeted Agents

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 studies—primarily phase II studies and case reports—also 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).

Conclusion

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

References

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