Neurocognitive Function Changes in Patients With LD Small Cell Lung Cancer Undergoing Prophylactic Whole Brain Radiotherapy With Hippocampal Sparing - a Pilot Study

Background and rational Prophylactic cranial irradiation Small cell lung cancer (SCLC) is an aggressive type of lung cancer, with high sensitivity to chemotherapy and radiotherapy but with high incidence of local and distant recurrences. The brain is a common site of metastases from SCLC with a risk of up to 70% for brain involvement [1]. Prophylactic cranial irradiation (PCI) is the standard treatment for patients with limited disease (LD) SCLC after completing chemo-radiotherapy to the chest. The treatment includes whole brain radiotherapy (WBRT), reduces the incidence of brain metastases and improves overall survival (OS) by 5% [1]. The down side of WBRT is that the central nervous system (CNS) is vulnerable to radiotherapy (RT) and its related toxicity may be associated with irreversible cognitive dysfunction [2].

Radiotherapy and neuro-cognitive function It has been demonstrated that there are two main regions of human containing multipotent neural stem cells (NSCs): the subgranular zone (SGZ) within the dentate gyrus of the hippocampus, and the subventricular zone (SVZ) on the lateral aspect of the lateral ventricles [3,4,5,6,7,8]. These NSCs are capable of replacing adult neuron loss caused by various forms of harm (e.g. local ischemia, brain trauma, and radiation exposure and neurodegenerative diseases). However, they are extremely sensitive to X-rays, and thus reduction of NSCs may play an important role in radiation-induced neurocognitive impairment [6,7,8]. Neurocognitive function (NCF) has a major impact on QOL and has been actively studied in brain tumor patients treated with radiotherapy. Many studies have evaluated the neurocognitive outcome of patients treated with radiation for brain metastases and primary brain tumors [9,10,11,12,13,14]. Radiation primarily causes coagulation necrosis of the white matter tracts and cerebral vasculature by axonal demyelination and damage to vascular endothelial cells. Radiation has been shown to negatively affect various neuropsychological domains. WBRT has been shown to have greater neuropsychological impairment than focused radiation treatment [14]. Correlation, between radiation dosage to the bilateral hippocampi and impairment of NCF, was found in adult patients with benign or low-grade brain tumors treated with fractionated stereotactic radiotherapy (FSRT) [14].

An ongoing clinical trial of the radiation oncology group (RTOG) is testing the applicability of hippocampal sparing and its impact on neurocognitive changes in cancer patients with brain metastases.

Neuro-cognitive function testing Even though many studies have evaluated NCF in relation to radiation, there is no consensus regarding standardization of tests selection, time points for evaluation and correlations with biomarkers. Many studies use the Folstein Mini-Mental State Examination (MMSE) to assess neurocognitive function [15,16]. The MMSE is not a sensitive tool for detecting cognitive impairment and does not measure the cognitive functions affected by radiation. The NeuroTrax system is described elsewhere [17]. In brief, Mindstreams consists of custom software that resides on the local testing computer and serves as a platform for interactive cognitive tests that produce accuracy and reaction time (millisecond time-scale) data. In case of conducting several trails for a single patient, Mindstreams uses a different version of the tests in each trial, in order to avoid a learning bias. Tests are available in multiple languages, and equivalence among English and Hebrew versions has been shown [17]. After tests are run on the local computer, data are automatically uploaded to a central server, where calculation of outcome parameters from raw single-trial data and report generation occurs. All responses are made with the mouse or with the number pad on the keyboard. Participants are familiarized with these input devices at the beginning of the battery, and practice sessions prior to the individual tests instruct them regarding the particular responses required for each test.

Hippocampal sparing during PCI Recent data suggest minimal risk for hippocampal involvement in patients with SCLC and brain metastases suggesting that reduced radiation dose to these areas during PCI would not significantly compromise the control in the brain [18]. There is no published data thus far testing the effect of hippocampal sparing during PCI on the patient's neuro-cognitive function, QOL, and survival. Volumetric arc radiotherapy (VMAT) and intensity modulated radiotherapy (IMRT) use advanced radiation planning software with computerized algorithms of inverse planning to allow differential radiation dose distribution within the same radiation field. A preliminary dosimetric work in the radiation oncology unit at Sheba medical center has proved the feasibility of generating WBRT plans using these techniques while reducing the dose to the hippocampi. The investigators compared 3 radiotherapy plans (standard 2 lateral field plan, IMRT plan and a VMAT plan) aiming to give 30Gy to the brain, with 40Gy integrated boost to evident brain metastases (using magnetic resonance imaging - MRI scan) and reduced dose to the hippocampi (<10Gy) according to RTOG 0933 protocol. IMRT achieved better results in general then the VMAT plans, especially in patients with brain metastases located closer to the hippocampi. The work has been presented in the EANS European Association of Neuro-Surgeonsmeeting last year.