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A. Sun



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    E02 - Radiation Toxicity (ID 2)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      E02.4 - Neurotoxicity of Cranial Irradiation (ID 380)

      14:00 - 15:30  |  Author(s): A. Sun

      • Abstract
      • Presentation
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      Abstract
      Overview of acute and late toxicities of brain irradiation Acute side effects of brain irradiation (BI) include common effects such as scalp erythema, alopecia, and fatigue and less common effects such as otitis externa, impaired sense of taste, nausea, and headache. Early delayed and late side effects from BI may include hyperpigmentation of the scalp, alopecia, hearing loss, behavioral changes, somnolence syndrome, radiation necrosis and neurocognitive decline. Brain Metastases (BM) often have a devastating impact on neurocognitive function (NCF). BI has been shown to treat, prevent or delay the incidence of BM in lung cancer. However, it can also cause toxicity resulting in a decline in NCF. To date there is limited data available regarding the effects of BI on NCF in patients with lung cancer. This is due to the lack of intensive NCF testing in lung cancer trials. Mechanisms of injury The pathophysiology of late radiotherapy injury is a dynamic and complex interaction between the vasculature and the parenchyma. The vascular hypothesis of radiation-induced injury describes a process of accelerated atherosclerosis causing vascular insufficiency, resulting in a picture similar to small vessel disease seen with vascular dementia. For this reason there is interest in studying vascular dementia treatments to prevent or reduce radiation-induced NCF decline. Glutamate is the principle excitatory amino acid neurotransmitter in cortical and hippocampal neurons. One of the receptors activated by glutamate is the N-methyl-D-aspartate (NMDA) receptor, which is involved in learning and memory. Ischemia can induce excessive NMDA stimulation and lead to excitotoxicity, suggesting that agents that block pathologic stimulation of NMDA receptors may protect against further damage in patients with vascular dementia. Memantine, an NMDA receptor antagonist, has been shown to be neuroprotective in preclinical models. Additionally, two placebo-controlled phase III trials found memantine to be well-tolerated and effective in treatment for vascular dementia. On these basis, RTOG launched a placebo-controlled, double-blind, randomized trial to evaluate the potential protective effect of memantine on NCF in patients receiving whole brain radiation (WBRT). The results of this study (RTOG 0614) were recently reported. Predisposing factors It is the therapeutic ratio of benefits vs. risks that helps determine the advisability of a treatment such as BI. Clinical trials of prophylactic cranial irradiation (PCI) can enable us to develop strategies that can potentially increase the benefits and decrease the risks. Potential strategies that can increase the benefits of BI may require better ways of identifying a subgroup of patients with the highest risk of developing BM such as those with small cell lung cancer (SCLC), adenocarcinoma, young age, high volume of disease and predictive markers. These are the patients most likely to benefit from PCI. In order to develop strategies to decrease the risks, we must identify and understand those risks. Identifying a subgroup of patients with the highest risk of developing NCF toxicities, such as older age or other patient factors such as hypertension and diabetes, may also improve the therapeutic ratio. Dose volume determinants Due to the concerns with NCF with WBRT, stereotactic radiosurgery (SRS) approaches are being actively studied. Combined therapy (SRS+WBRT) for BM are favored based on Phase III findings that brain control with combined therapy is significantly better than with SRS alone or WBRT alone. On the other hand, a phase III study found that the risk of neurocognitive deficit is doubled with the addition of WBRT to SRS. The published data demonstrate continued evolution of clinical trials and different management strategies are currently being evaluated in prospective clinical trials to minimize the likelihood of cognitive decline following BI. To reduce cognitive injury of conventional WBRT, several groups are exploring modified WBRT approaches, such as hippocampal-avoidance WBRT (HA-WBRT). In this approach, complex planning techniques are used to reduce dose to bilateral hippocampal structures while treating the rest of the brain. Hippocampal-dependent functions of learning, memory, and spatial information processing seem to be preferentially affected by RT. It is argued that since <5% of BM occur within 5 mm of the hippocampus, reducing dose to the hippocampus is safe and feasible. The feasibility of this approach has been studied prospectively in a multi-institutional setting by the RTOG study 0933. Clinical features and diagnosis Publications on radiation-induced neurotoxicity have used different assessment methods, time to assessment, and definition of impairment, thus making it difficult to accurately assess the rate and magnitude of the NCF decline that can be expected. There is a paucity of data on neurocognitive impairment after BI, which has previously been assessed using various different neuropsychological tests, as well as different definitions of neurocognitive impairment. It must be remembered that NCF is affected by a number of factors (i.e. BM volume, disease progression (intra and/or extra-cranial progression), chemotherapy, hormonotherapy, surgery, radiation, prior neurologic disease, medications, paraneoplastic effects, etc.) which should be considered when evaluating of the actual neurocognitive effect of treatments such as BI. In addition, a challenge that plagues most studies in patients with advanced cancers, is the decline in compliance with NCF testing over time. Nevertheless, many studies have been completed and will be presented. Prevention and treatment. Because treatment of NCF decline after radiation is limited, treatments ideally would be developed to prevent the detrimental cognitive effects of BI as discussed above. Determining the impact of BI on NCF would provide support for therapeutic decision making for an individual patient, for which we need to use sensitive cognitive assessments to elucidate the incidence, time course, intensity, domains of NCF changes following BI and their actual impact on patient quality of life (QOL). Selected References Sun A, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: Neurocognitive and quality-of-life analysis. J Clin Oncol 2011;29:279-286. Chang EL, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncol 2009;10:1037-1044. Wolfson AH, et al. Primary analysis of a phase III randomized trial radiation therapy oncology group (RTOG) 0212: Impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with LD-SCLC. IJROBP 2011;81:77-84.

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