Brain Radionecrosis Treated with Bevacizumab in a Patient with Resected Squamous Cell Carcinoma of the Lung
Authors: Jordi Remon, Cécile Le Péchoux, Caroline Caramella, Frederic Dhermain, Guillame Louvel, Jean-Charles Soria, Benjamin Besse
Journal: Journal of Thoracic Oncology (2016)

In April 2013, cT4N0M0 lung cancer was diagnosed in a 78-year-old female former smoker with peripheral vascular disease; it was diagnosed on the basis of thoracic, abdominal, and brain computed tomography (CT) and fludeoxyglucose F 18 positron emission tomography scans. A lobectomy with mediastinal dissection showed squamous carcinoma (pT4N2). The results of testing of the tumor tissue were positive for KRAS G12D and negative for EGFR, erb-b2 receptor tyrosine kinase 2 gene (HER2), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA). Chemotherapy was not offered because of the patient's age and stage. A unique left cerebellum brain metastasis was discovered within 2 months of surgery, and stereotactic radiotherapy (33 Gy in three fractions) was administered. In June 2014, a fludeoxyglucose F 18 positron emission tomography scan showed isolated uptake in the right lung and radical radiotherapy was initiated. In October, she experienced cerebellar disorders (imbalance) and a magnetic resonance imaging (MRI) scan showed progression of the treated metastasis. Neurosurgical excision was ruled out. Stereotactic radiotherapy (25 Gy, five fractions) with steroids gave clear clinical improvement. In September 2015, the patient again experienced imbalance with deterioration to performance status 3 and MRI revealed central hyposignal and peripheral enhancement on the irradiated region, suggesting radionecrosis (Fig. 1A). No extracranial progression was evident on CT scan. Steroids were prescribed but clinical improvement was not seen. After discussion of the risk-benefit ratio of bevacizumab in extrathoracic squamous cell carcinoma, bevacizumab, 5 mg/kg every 3 weeks, was initiated. After three cycles, meaningful improvement in the cerebellum syndrome was apparent and corticosteroids were stopped, and MRI showed a clear reduction of the peripheral metastatic enhancement (Fig. 1B). Clinical and radiological benefit was confirmed after six cycles (Fig. 1C). Treatment was discontinued on account of a femoral arterial ischemia related to atrial arrhythmia. The patient was monitored regularly (Fig. 1D). The cumulative incidence of brain metastasis in NSCLC is 16% to 35%, and it is linked to significant morbidity and poor prognosis.1Nayak L. Lee E.Q. Wen P.Y. Epidemiology of brain metastases.Curr Oncol Rep. 2012; 14: 48-54Crossref PubMed Scopus (726) Google Scholar For patients with NSCLC with fewer than four brain metastases measuring less than 4 cm, stereotactic radiotherapy improves survival compared with whole brain radiotherapy.2Halasz L.M. Uno H. Hughes M. et al.Comparative effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for patients with brain metastases from breast or non-small cell lung cancer.Cancer. 2016; 122: 2091-2100Crossref PubMed Scopus (48) Google Scholar Radionecrosis constitutes the main complication of stereotactic radiotherapy. It is reported in up to 34% of cases in the years after treatment and is associated with significant morbidity in 10% to 17% of patients. Increased radionecrosis risk is linked to larger lesion volume, prior whole brain irradiation, and higher radiation dose.3Le Rhun E. Dhermain F. Vogin G. Reyns N. Metellus P. Radionecrosis after stereotactic radiotherapy for brain metastases.Expert Rev Neurother. 2016; 16: 903-914Crossref PubMed Scopus (56) Google Scholar The delay of asymptomatic or symptomatic radionecrosis after stereotactic radiotherapy varies from 10 to 16 months, and radionecrosis can be responsible for crippling clinical manifestations in 2% to 32% of cases.3Le Rhun E. Dhermain F. Vogin G. Reyns N. Metellus P. Radionecrosis after stereotactic radiotherapy for brain metastases.Expert Rev Neurother. 2016; 16: 903-914Crossref PubMed Scopus (56) Google Scholar Pathogenesis is related to endothelial cell dysfunction with increased release of vascular endothelial growth factor (VEGF) and subsequent damage of the blood-brain barrier. Deregulation of VEGF levels causes vascular permeability, brain edema, neuronal demyelination, and necrosis.4Nonoguchi N. Miyatake S.-I. Fukumoto M. et al.The distribution of vascular endothelial growth factor-producing cells in clinical radiation necrosis of the brain: pathological consideration of their potential roles.J Neurooncol. 2011; 105: 423-431Crossref PubMed Scopus (120) Google Scholar The current clinical practice for radionecrosis treatment is administration of corticosteroids. Corticosteroid dependence may be observed in 10% to 50% of cases, and because of the adverse events and limited activity, alternative therapeutic approaches are awaited.3Le Rhun E. Dhermain F. Vogin G. Reyns N. Metellus P. Radionecrosis after stereotactic radiotherapy for brain metastases.Expert Rev Neurother. 2016; 16: 903-914Crossref PubMed Scopus (56) Google Scholar The monoclonal anti-VEGF antibody bevacizumab has been proposed as a potential therapeutic option but its use has not yet been validated.3Le Rhun E. Dhermain F. Vogin G. Reyns N. Metellus P. Radionecrosis after stereotactic radiotherapy for brain metastases.Expert Rev Neurother. 2016; 16: 903-914Crossref PubMed Scopus (56) Google Scholar In high-grade glioma, bevacizumab can provide palliation for symptomatic radionecrosis and peritumor edema5Kruser T.J. Mehta M.P. Kozak K.R. Identification of patients who benefit from bevacizumab in high-grade glioma—an easy question turned difficult: treat the scan or the patient?.J Clin Oncol. 2016; 34: 1281-1282Crossref PubMed Scopus (5) Google Scholar. In a pooled analysis (n = 71), 15% of brain metastatic tumors), 97% of patients had radiographic improvement after bevacizumab treatment for radionecrosis and 79% of cases had an improvement in their performance status leading a reduction of the corticosteroids dosage.6Tye K. Engelhard H.H. Slavin K.V. et al.An analysis of radiation necrosis of the central nervous system treated with bevacizumab.J Neurooncol. 2014; 117: 321-327Crossref PubMed Scopus (66) Google Scholar Radiological responses with bevacizumab have been reported 2 to 3 months after the start of treatment.3Le Rhun E. Dhermain F. Vogin G. Reyns N. Metellus P. Radionecrosis after stereotactic radiotherapy for brain metastases.Expert Rev Neurother. 2016; 16: 903-914Crossref PubMed Scopus (56) Google Scholar Brain metastases are associated with a risk for spontaneous hemorrhage at rate of 1.4% to 10%.7Besse B. Le Moulec S. Mazières J. et al.Bevacizumab in patients with nonsquamous non-small cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized, phase II study.Clin Cancer Res. 2015; 21: 1896-1903Crossref PubMed Scopus (169) Google Scholar However, in a retrospective exploratory analysis, patients with brain metastasis were at similar risk for development of cerebral hemorrhage independent of bevacizumab. Moreover, in a prospective phase II trial, bevacizumab combined with standard first-line platinum-based chemotherapy demonstrated efficacy and safety in patients with advanced nonsquamous NSCLC with untreated and asymptomatic brain metastasis.7Besse B. Le Moulec S. Mazières J. et al.Bevacizumab in patients with nonsquamous non-small cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized, phase II study.Clin Cancer Res. 2015; 21: 1896-1903Crossref PubMed Scopus (169) Google Scholar Patients with a predominantly squamous NSCLC histologic subtype are often excluded from bevacizumab clinical trials on account of increased risk for severe pulmonary hemorrhage (31%). However, grade 3 or higher pulmonary hemorrhage was reported in 3.2% of the 31 patients with bevacizumab-treated squamous NSCLC in the phase II BRIDGE trial, and no other serious bleeding effects occurred.8Hainsworth J.D. Fang L. Huang J.E. et al.BRIDGE: an open-label phase II trial evaluating the safety of bevacizumab + carboplatin/paclitaxel as first-line treatment for patients with advanced, previously untreated, squamous non-small cell lung cancer.J Thorac Oncol. 2011; 6: 109-114Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Although we cannot rule out a nonsquamous component owing to the presence of a KRAS mutation, tolerance of bevacizumab was as expected in our patient. We suggest that for patients with squamous NSCLC with no baseline risk factors for pulmonary hemorrhage8Hainsworth J.D. Fang L. Huang J.E. et al.BRIDGE: an open-label phase II trial evaluating the safety of bevacizumab + carboplatin/paclitaxel as first-line treatment for patients with advanced, previously untreated, squamous non-small cell lung cancer.J Thorac Oncol. 2011; 6: 109-114Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar or other contraindications to bevacizumab (excluding histologic subtype),9Reck M. Barlesi F. Crinò L. et al.Predicting and managing the risk of pulmonary haemorrhage in patients with NSCLC treated with bevacizumab: a consensus report from a panel of experts.Ann Oncol. 2012; 23: 1111-1120Crossref PubMed Scopus (74) Google Scholar bevacizumab could be used as experimental treatment for radionecrosis after individualized risk-benefit assessment. To our knowledge, this is the first report of management of radionecrosis with bevacizumab in an NSCLC with squamous histologic features, and it suggests that the efficacy and safety of this agent is independent of NSCLC subtype. This needs to be validated and optimal dose schedule and therapy duration need to be defined.