Non-Small cell lung cancer intracranial metastases treatment
📌 Background
- Brain metastases (BM) occur in up to 40% of NSCLC patients.
- Historically associated with poor prognosis (median survival ~3–6 months untreated).
- Treatment has evolved with targeted therapies, immune checkpoint inhibitors, and advanced radiotherapy techniques.
🔍 Treatment Strategies
🧠 Local Therapies
a. Stereotactic Radiosurgery (SRS)
- First-line for patients with 1–10 brain metastases.
- Preferred over WBRT due to better cognitive outcomes.
- May be combined with systemic therapy.
b. Whole Brain Radiotherapy (WBRT)
- Used for diffuse disease, leptomeningeal involvement, or SRS-ineligible patients.
- Declining use due to neurotoxicity.
c. Surgical Resection
- Indicated for solitary symptomatic lesions or diagnostic uncertainty.
- Often followed by SRS or WBRT.
💊 Systemic Therapies
a. Targeted Therapy (if driver mutations present)
| Mutation | CNS-active drugs |
|---|---|
| EGFR | Osimertinib |
| ALK | Alectinib, Brigatinib, Lorlatinib |
| ROS1 | Entrectinib, Lorlatinib |
| KRAS G12C | Adagrasib, Sotorasib |
| MET exon 14 | Capmatinib, Tepotinib |
b. Immunotherapy (ICI)
- Agents: Pembrolizumab, Nivolumab, Atezolizumab
- Shown efficacy in PD-L1 ≥ 1% tumors, some activity against BMs.
- Often combined with platinum chemotherapy (e.g., KEYNOTE-189 regimen).
c. Chemotherapy
- Poor CNS penetration.
- Still relevant in non-targetable tumors or combined regimens.
🧪 Emerging Therapies
- KRAS G12C inhibitors (adagrasib, sotorasib): CNS-active, ongoing trials.
- Combinations: KRAS inhibitors + CDK4/6 (e.g., abemaciclib) or checkpoint inhibitors.
- Research on blood-brain barrier modulation to improve CNS delivery.
🧠 Key Clinical Considerations
- Evaluate if BM are symptomatic vs asymptomatic.
- CNS penetration is key when selecting systemic therapy.
- Perform molecular profiling (EGFR, ALK, KRAS, etc.) early.
- Involve multidisciplinary team (oncology, neurosurgery, radiation).
📚 Conclusion
The management of NSCLC with brain metastases now relies on personalized treatment guided by genomic alterations. Advances in targeted and immune therapies with CNS activity have improved outcomes. Radiotherapy remains crucial for local control, particularly in symptomatic or high-burden cases.
Surgical resection, stereotactic radiosurgery, and whole-brain radiation therapy have historically been the primary treatment modalities for patients with non-small-cell lung cancer (NSCLC) and BMs. The treatments for BMs have become complex with the discovery of targetable molecular drivers and the development of an astonishing number of tyrosine kinase inhibitors. Many of these tyrosine kinase inhibitors have robust and durable efficacy against CNS metastases. In many circumstances, these drugs can defer local therapy and even reduce the risk of CNS progression.Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are frequently utilized in this setting 1).
Brain metastases are common in patients with non-Small-cell lung cancer (NSCLC). Because of associated poor prognosis and limited specific treatment options, there is a real need for the development of medical therapies and strategies for affected patients 2).
A KPS score ≥ 70, RPA class I/II, and postoperative chemotherapy could benefit post-metastasectomy patients with brain metastases (BM) from Non-Small-cell lung cancer (NSCLC). Conversely, the initial onset of intracranial lesions is an unfavorable factor that increases the risk of death. These findings support the use of personalized therapy for patients with BM from NSCLC 3).
A article of Preusser et al., is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose was to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non-Small-cell lung cancer. The authors propose a series of recommendations for research and treatment within the discussed context 4).
PUBMED, EMBASE, the Cochrane Library, Web of Knowledge, Current Controlled Trials, Clinical Trials, and 2 conference websites were searched to select NSCLC patients with only single brain metastases (SBM) who received brain surgery or SRS. SPSS 18.0 software was used to analyze the mean median survival time (MST) and Stata 11.0 software was used to calculate the overall survival (OS).
A total of 18 trials including 713 patients were systematically reviewed. The MST of the patients was 12.7 months in surgery group and 14.85 months in SRS group, respectively. The 1, 2, and 5 years OS of the patients were 59%, 33%, and 19% in surgery group, and 62%, 33%, and 14% in SRS group, respectively. Furthermore, in the surgery group, the 1 and 3 years OS were 68% and 15% in patients with controlled primary tumors, and 50% and 13% in the other patients with uncontrolled primary tumors, respectively. Interestingly, the 5-year OS was up to 21% in patients with controlled primary tumors.
There was no significant difference in MST or OS between patients treated with neurosurgery and SRS. Patients with resectable lung tumors and SBM may benefit from the resection of both primary lesions and metastases 5).
Patients with NSCLC and synchronous brain metastases, presenting neurological symptoms showed no survival benefit from neurosurgical resection, although quality of life was improved due to early control of neurological symptoms 6).