Dr Alder on Clinical Decision-Making Around Local vs Systemic Therapy for Metastatic Lung Cancer With CNS-Only Disease

“The caveat is we have to look at what's going on systemically and also at the CNS. How big are the brain lesions? Are they symptomatic? What's the location of these brain lesions. Are they in very sensitive areas of the brain where any growth could be catastrophic? What's the associated edema? Is it single. Is it multiple? [Within] all of these conversations we always like to get multidisciplinary involvement because at the end of the day, we want to make sure that we're giving the patients the very best outcomes and that we really limit toxicities and think long term.”

Laura Alder, MD, an assistant professor of medicine and a member of theDuke Cancer Institute, discussed clinical decision-making around prioritizing local vs systemic therapy for patients with lung cancer who present with central nervous system (CNS)–only disease, during the Bridging the Gaps Brain Metastases meeting.

Alder explained that treatment selection in this setting is highly patient dependent and increasingly influenced by the availability of modern systemic therapies with robust CNS activity. In molecularly-defined lung cancers, particularly those harboring actionable alterations such as EGFR, ALK, ROS1, or RET, next-generation TKIs demonstrate high rates of CNS penetration, often achieving intracranial response rates in the range of 80% to 90%. In patients with access to these CNS-active agents, Alder noted that initiating systemic therapy upfront is often preferred, as it offers the potential to control both intracranial and extracranial disease while deferring or avoiding radiation-related toxicity.

However, Alder stressed that the decision to prioritize systemic therapy must be guided by a careful evaluation of CNS disease characteristics. Key factors include the size and number of brain metastases, the presence and severity of neurologic symptoms, lesion location, particularly involvement of eloquent or high-risk brain regions—and the degree of associated edema. Lesions in anatomically sensitive areas or those causing significant symptoms may necessitate immediate local intervention, regardless of the availability of CNS-penetrant systemic options.

Multidisciplinary collaboration is central to this decision-making process, Alder emphasized, highlighting the importance of involving medical oncology, radiation oncology, neurosurgery, and neuroradiology to balance disease control, toxicity mitigation, and long-term neurologic outcomes. When systemic therapy is initiated first, her practice routinely incorporates early surveillance imaging, with repeat brain MRI performed approximately 4 to 6 weeks after treatment initiation. This interval is generally sufficient to assess intracranial response, as responsive tumors treated with TKIs often demonstrate early radiographic improvement.

If follow-up imaging reveals suboptimal response or progression within the CNS, Alder noted that patients are typically rediscussed in a multidisciplinary setting to reassess treatment strategy. In such cases, local therapy, most commonly stereotactic radiosurgery is frequently employed to achieve focal disease control while minimizing neurocognitive impact.