Subdural collections arising from calvarial metastases following discontinuation of anti-angiogenic therapy
Authors: A L Wong, N Chou, K M Lee, B W Ang, C L Cheng, S C Lee
Journal: Annals of Oncology (2009)

We report two metastatic breast cancer patients with diffuse calvarial involvement who developed symptomatic subdural collections shortly after discontinuing anti-angiogenic therapy. The first patient had metastatic disease in the liver, skin, and bones, including the calvarium (Figure 1A), and developed subdural collections 3 weeks after discontinuing a 9-week course of sunitinib at 37.5 mg daily as part of a clinical trial. Sunitinib was discontinued after 9 weeks of treatment because of grade 3 leukopaenia. Three weeks later, she developed right upper limb weakness and slurred speech. Magnetic resonance imaging of the brain (Figure 1B) showed subdural reactive collections. She was treated with whole-brain radiotherapy with complete neurological recovery. The second patient had metastatic disease in the lungs and bone, including the calvarium (Figure 1C), and developed bilateral chronic subdural haematoma 13 weeks after discontinuing a 63-week course of bevacizumab 15 mg/kg, 3 weekly, which was initially administered with oral capecitabine 1000 mg/m2 twice a day, days 1–14, every 3 weeks, for 54 weeks before progressive lung and liver disease. She then received three additional cycles of bevacizumab with subcutaneous goserelin and oral letrozole, after which she developed new lung metastases and bevacizumab was discontinued. Thirteen weeks later, the patient was noted to have subtle slowness in mentation, which, in retrospect, may have pre-existed for several weeks. Contrast-enhanced computed tomography of the brain (Figure 1D) revealed bilateral chronic subdural haematomas. She underwent surgery with burr-hole drainage, mini-craniectomy, membranectomy, and subdural-peritoneal shunting because of repeated haematoma accumulation. Histology of the skull bone marrow (Figure 1E) revealed metastatic invasive ductal carcinoma (hematoxylin and eosin, ×400). Neither patient had a history of trauma or coagulopathy. Subdural collections or haematomas are rare complications of breast cancer that are largely limited to case reports [1.Tseng S.H. Liao C.C. Lin S.M. et al.Dural metastasis in patients with malignant neoplasm and chronic subdural hematoma.Acta Neurol Scand. 2003; 108: 43-46Crossref PubMed Scopus (30) Google Scholar]. Anti-angiogenic agents have recently been incorporated into the treatment armamentarium of solid tumours, including breast cancer [2.Hayes D.F. Miller K. Sledge G. Angiogenesis as targeted breast cancer therapy.Breast. 2007; 16: S17-S19Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. Bevacizumab is a monoclonal antibody that binds to the vascular endothelial growth factor (VEGF) ligand, while sunitinib and sorafenib are small-molecule tyrosine kinase inhibitors that block the receptor, VEGFR2. We postulate that our two patients experienced a transient pro-angiogenic state upon discontinuation of anti-angiogenic therapy due to a rebound phenomenon [3.Verheul H.M. Pinedo H.M. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition.Nat Rev Cancer. 2007; 7: 475-485Crossref PubMed Scopus (433) Google Scholar] that promoted capillary leakage from existing diffuse calvarial metastatic disease resulting in subdural collections. In the first patient treated with sunitinib, VEGFR blockade would have resulted in compensatory high circulating levels of VEGF [4.Deprimo S.E. Bello C.L. Smeraglia J. et al.Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins.J Transl Med. 2007; 5: 32Crossref PubMed Scopus (287) Google Scholar], and discontinuation of VEGFR blockade resulted in a transient pro-angiogenic state before VEGF levels normalised. Similarly, the patient who was treated with bevacizumab had chronic low levels of VEGF ligand that may have resulted in VEGFR up-regulation; the ensuing high levels of circulating VEGF ligand upon bevacizumab discontinuation would bind to the abundant VEGFR, resulting in a transient pro-angiogenic state. As bevacizumab has a long half-life of 3 weeks [5.Lu J.F. Bruno R. Eppler S. et al.Clinical pharmacokinetics of bevacizumab in patients with solid tumors.Cancer Chemother Pharmacol. 2008; 62: 779-786Crossref PubMed Scopus (279) Google Scholar], it may take approximately 4–6 weeks before VEGF levels rebound, and this, together with the patient’s subtle neurological symptoms, accounted for the delayed diagnosis 13 weeks after bevacizumab discontinuation. Calvarial metastases are generally regarded as clinically non-significant but may predispose to subdural collections from capillary leak upon withdrawal of anti-angiogenic therapy due to a rebound effect.