The metastases in our patient were located deep in the brain parenchyma and at the gray-white matter junction pointing to hematogeneous spread of her lung adenocarcinoma. Her rapid neurologic deterioration associated with diffuse cerebral edema suggests that there were more metastases than could be visualized on MRI, indicating carcinomatous encephalitis as the likely diagnosis. However, the diagnostic criteria for this disease are poorly defined but clinicians often based their diagnosis on the presence of multiple non-enhancing parenchymal brain metastases in a miliary pattern as key findings. Such a narrowly defined criterion has limitations, and it does not incorporate clinical data and our understanding of tumor biology. First, gadolinium enhancement probably occurs when a tumor reaches a size large enough to promote angiogenesis (Folkman 2002
). Although miliary tumors in carcinomatous encephalitis are non-enhancing initially, they would enhance eventually on MRI as they grow over time. Second, rapid generalized neurologic deterioration is common in these patients. Lastly, given the rapid tumor progression, tumor cell infiltration into the subarachnoid space could be a natural progression of carcinomatous encephalitis.
In the United States, whole brain cranial irradiation at 300 cGy per fraction × 10 fractions is the standard treatment for patients with brain metastases, particularly for those patients with poor performance status. However, due to her rapid neurological deterioration, our patient needed a radiation schedule that would offer the quickest response. Borgelt et al (1980
) compared four treatment regimens, 200 cGy × 20, 250 cGy × 15, 200 cGy × 15, and 300 cGy × 10, and noted equivalent clinical radiobiological efficacy. We chose a high-dose fractionated schedule of 400 cGy × 5 (Borgelt 1981
) to achieve rapid tumor response and neurological improvement.
Gefitinib is a small molecule tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) that produced dramatic radiologic and clinical responses in 10% of patients with non-small cell lung cancer (Kris 2003
). Female gender, non-smokers, adenocarcinoma histology, and Asian descent were prognostic factors favoring a response (Fukuoka 2003
; Miller 2004
). Somatic mutations that led to in-frame deletions and missense substitutions in the ATB-binding pocket of EGFR were responsible for this exquisite sensitivity to gefitinib (Sordella 2004
; Han 2005
; Mitsudomi 2005
). We do not know the EGFR mutation status in our patient. But given her gender, adenocarcinoma histology, lace of a smoking history, and Asian decent, she would be likely to have EGFR mutations that confer a favorable response to gefitinib. Furthermore, at standard dose of 250 mg daily or higher, gefitinib has efficacy against metastases in the brain parenchyma and leptomeninges (Katz 2003
; Jackman 2006
We think that the combination of gefitinib and high-dose fractionated cranial irradiation was responsible for this patient’s rapid recovery and complete response in the brain. The neurological improvement seen in our patient was unlikely a result of gefitinib alone, since her liver and bone metastases had a limited response. There is preclinical data to support this notion because a combination of gefitinib and radiation had an additive cytotoxic effect on A431 cells (vulvar carcinoma cells that have high levels of EGFR) in vitro and a synergistic anti-tumor effect on GEO (human colon carcinoma), A549 (human non-small cell carcinoma), and MCF-7 (human breast carcinoma) xenografts in nude mice (Bianco 2002
; Giocanti 2004
). Interestingly, there was decreased tumor expression of transformation growth factor α, vascular endothelial growth factor, and basic fibroblast growth factor (Bianco 2002
), suggesting mechanisms other than inhibition of EGFR signaling may be at work.