Treatment of Isolated Intracranial Progression of Lung Cancer During Treatment with Systemic Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs)

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are an effective treatment for non-small-cell lung cancer (NSCLC) harbouring EGFR mutations. The development of isolated central nervous system (CNS) metastases is a relevant clinical problem in patients who respond well to EGFR-TKIs. Methods: We present a patient with isolated progression of brain metastases during treatment of EGFRmutated NSCLC with an EGFR-TKI and review the treatment options in this setting, including the evidence for and toxicity of treatment with high-dose TKIs. Results: Oligometastatic CNS progression during TKI therapy may be treated locally. Both whole brain radiotherapy (WBRT) and stereotactic brain irradiation are well tolerated and effective in this setting. The use of high-dose pulsed TKIs is intended to increase the concentration of TKI in the brain and has been reported to be effective and without significant toxicity in case reports and small case series. These therapeutic options are illustrated in the case of a 44-year-old NSCLC patient who developed CNS progression after WBRT during second-line erlotinib and was treated locally with stereotactic radiosurgery (SRS) and, upon further CNS progression, with high-dose pulsed erlotinib. This resulted in intracerebral response; however, significant haemorrhage also occurred. Severe haemorrhage has not previously been described as a complication of high-dose pulsed erlotinib. Conclusion: Possible explanations for isolated CNS progression during TKI treatment include inadequate dosing across the blood—brain barrier and longer survival on TKIs. The efficacy and tolerability of high- dose pulsed TKIs for CNS metastases has been previously reported. None of the cases reported showed the severe haemorrhage and cerebral oedema that developed in our patient. Simultaneous anticoagulation as well as previous SRS may have predisposed our patient to haemorrhage and may prove to be relative contraindications to high-dose pulsed erlotinib. Most centres only see a few patients in this clinical situation, and co-operative efforts are needed to collect and analyse similar cases and to develop appropriate treatment strategies.