Clinical Updates for the Management of Lung Cancer Brain Metastases

Lilyana Angelov, MD

Nearly half of all brain tumors are associated with an underlying cancer diagnosis, and lung cancer is one of the most common of these. As improved cancer therapies are helping patients live longer, the safe and effective management of lung cancer brain metastases is coming to the fore. The goals we always keep in mind in these cases are to extend survival, prevent neurological dysfunction and improve quality of life. This article briefly reviews the progress made toward these goals made in recent years.

Surgery can be essential for making a diagnosis, maximizing resection of a solitary metastasis, and improving survival. It offers many advantages over other management strategies: Not only is the cancer locally removed, but the associated rapid resolution of mass effect and edema many times improves neurological issues and allows for faster tapering of corticosteroids used to treat symptomatic lesions.

Surgical risk can be reduced and neurological deficits minimized by using the following tools and strategies:

• Image-guided computer-assisted navigation
• Microsurgery and minimal-access craniotomy
• Cortical mapping and awake surgery if near critical areas

In most cases, adding whole brain radiation therapy (WBRT) or stereotactic radiosurgery to surgery has been essential to increase survival and reduce tumor recurrences. Sometimes open surgery is not necessary; however, a biopsy may be required to confirm the tumor diagnosis and guide patient management.

Evolving Roles of Radiation Therapies

For decades, whole brain radiation therapy (WBRT) was considered standard treatment for patients with brain metastases. Although 70% to 90% of patients experience improved symptoms in 1 to 3 weeks, toxicities including alopecia, fatigue, skin erythema, headache, otitis media, somnolence syndrome, and leukoencephalopathy are common.

Most importantly, WBRT is associated with neurocognitive decline, which becomes more evident as patients live longer than 1 year. This risk can be lowered by newer approaches such as medications (eg, memantine) or modified radiation delivery such as hippocampal sparing during WBRT; however, delayed impact on cognition continues to be a factor.

This concern regarding delayed toxicity has reduced the role of WBRT in recent years. WBRT is still considered necessary for leptomeningeal disease and for cases involving numerous metastatic lesions, although the threshold is not well defined and is rising as other therapies prove effective for multiple metastases. WBRT is also traditionally standard for small cell lung cancer (SCLC) brain metastases, but evidence now indicates that stereotactic radiosurgery alone may be sufficient, if not favored, for up to 10 lesions.

Stereotactic radiosurgery offers multiple advantages over many other therapies, including lower cost and, in most cases, avoidance of general anesthesia for surgery. It involves a minimally invasive or noninvasive outpatient procedure with no meaningful recovery time. Additionally, in contrast to some of the limitations encountered with open surgery, stereotactic radiosurgery can safely treat lesions that are small, deep, or near critical areas.

Already the standard for limited small brain metastases, stereotactic radiosurgery has increasingly been used over the past few years as primary treatment for patients with up to 15 tumors and for large lesions. It also can be used as salvage treatment for recurrence of metastases following WBRT. Comparable with WBRT in terms of overall survival and local and distant control, it allows for faster time to systemic therapy and causes fewer toxicities, including neurocognitive impairment.

For large brain metastases (≥ 2 cm), single-session radiosurgery does not consistently provide durable control. Instead, we recommend staged treatment (ie, 2 stereotactic radiosurgery treatments performed 1 month apart) effectively boosting the target and achieving approximately 90% 1-year local control. This strategy capitalizes on the tumor volume shrinkage that is often observed between sessions, reducing the irradiated volume, and possibly making the tumor more responsive to the next treatment. Systemic therapy is allowable between the 2 treatments. We have found this approach to be feasible, safe, and effective, obviating the need for surgical intervention even for large brain metastasis in select cases.

Radiation necrosis or radionecrosis (a delayed impact of radiation treatment seen in 5% to 10% of patients) remains a concern following both WBRT and stereotactic radiosurgery, especially as it can be clinically and radiologically difficult to distinguish from recurrent tumors. We closely monitor all patients with MRI after radiation therapy to detect suspicious lesions early, as well as radionecrosis when it is more likely to be limited and even reversible if treated promptly.

Systemic/Targeted Therapies Have Arrived

In recent years, we have changed how we treat non–small cell lung cancer (NSCLC) tumors driven by EGFR mutations or ALK rearrangements. This has had significant impact on control of lung cancer-related brain metastases.

Prior to 2015, the tyrosine kinase inhibitors (TKIs) used for targeted therapy of NSCLC offered very good systemic control but very little control of brain metastases. Since 2015, TKIs with central nervous system (CNS) activity have become available and have quickly moved from second-line to frontline therapy. We now even have data supporting adjuvant use of one TKI, osimertinib (Tagrisso), for EGFR-positive tumors. These developments have given us the welcome option of withholding WBRT in TKI-naïve patients.

How do we use these drugs?

In cases of EGFR- or ALK-driven tumors with brain metastases, virtually all patients who are TKI-naïve receive TKI therapy plus stereotactic radiosurgery. The first-line TKI is osimertinib for those with EGFR-positive tumors and alectinib (Alecensa) for those with ALK-positive tumors.

If disease progression occurs, for EGFR-positive tumors we will continue osimertinib if there are 2 or fewer lesions and extracranial control is being achieved. If there are multiple lesions and extracranial control is being lost, we continue with stereotactic radiosurgery alone and decide whether and when to add chemotherapy. For disease progression in patients with ALK-positive tumors, alectinib may be followed by the second-line TKI lorlatinib (Lorbrena) before considering switching to chemotherapy.

For patients with tumors with no driver mutations, immunotherapy with a checkpoint inhibitor with or without chemotherapy is used in addition to stereotactic radiosurgery.

Ongoing Questions and Future Directions

Whether and when we can use systemic therapy alone is a key research question currently under study. Given the known benefits from local therapy, many oncologists are understandably reluctant to use systemic therapy alone, even though the appeal of systemic therapy is compelling, given its potential impact on controlling the disease throughout the body. However, there continue to be multiple unknowns regarding the timing and sequence of systemic therapy in relation to stereotactic radiosurgery or WBRT, as well as regarding the advisability of trying another TKI if CNS progression occurs.

Even as the field grapples with these questions, the progress made in the past few years—particularly the advent of systemic therapies and improvements in the use of stereotactic radiosurgery—deserves recognition. These advances underscore the importance of multidisciplinary expertise in the management of lung cancer brain metastases. And with so much still unknown despite these advances, the need for a multidisciplinary team approach to optimize individual treatment strategies may be the greatest imperative of all.

Lilyana Angelov, MD, is director of the Gamma Knife Center in the Brain Tumor and Neuro-Oncology Center at Cleveland Clinic in Ohio.

Samuel Chao, MD, is a professor at Cleveland Clinic Lerner College of Medicine, and an oncologist at the Brain Tumor and Neuro-Oncology Center and the Department of Radiation Oncology at Cleveland Clinic in Ohio.

Marc Shapiro, MD, is an associate staff member in the Department of Solid Tumor Oncology at Cleveland Clinic in Ohio.