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From survival to survivorship: late side effects become an issue in high-grade glioma

Gliomas are the most common primary brain tumors. In adults, the most frequent subtype is glioblastoma, an aggressive and lethal tumor characterized histologically by frequent mitoses, rich angiogenesis and necrosis. Multimodality treatment is the standard of care: maximal safe resection followed by partial brain irradiation combined with temozolomide. Resection followed by radiation produces a median survival of 2–3 years in anaplastic astro cytoma [1], but only 5–12 months in patients with glioblastoma, depending on the population studied [2]. The addition of temozolomide, while only increasing median survival by 2.5 months [3], produces a marked increase in long-term survival, with 9.8% of patients who received combination treatment living 5 years, as opposed to 1.9% with radiation alone [4]. Longer survival is associated with host factors (performance status and age [5]), molecular characteristics (O-methylguanine-DNA methyltransferase [MGMT] methylation [6], isocitrate dehydrogenase mutations [7] and poly morphisms in DNA repair enzymes [8]), and treatment factors (more radical resection [9] and use of temozolomide [4]). The cardinal non-molecular factors have been combined to define the Radiation Therapy Oncology Group (RTOG) recursive partitioning ana lysis class [5]. There is circumstantial evidence that survival may be improving further – in recent single-arm trials run by the New Approaches to Brain Tumor Therapy Consortium, median survival was nearly 20 months [10]. Whether this survival increase is a reflection of the activity of the various therapeutic agents tested, the results of a more aggressive approach, the increased use of secondand third-line treatments or some other factor is not clear. The expectation is that newer therapies will further lengthen survival. As glio blastoma shifts from being a rapidly fatal to slowly progressive disease, we are obligated to consider the long-term side effects of present and future treatments. In addition to the ‘classical’ side effects, such as neurological deficits and brain necrosis, research now emphasizes neurocognitive function and quality of life. These ‘newer’ end points are complex, since both the tumor and the treatment impact upon them. The long-term effects of radiation on the brain have been well described [11–14]. Pathological changes range from transient demyelination to irreversible vascular damage with resultant necrosis. A recent meta-ana lysis suggested that the brain is able to tolerate high doses of ionizing radiation (approximately 70 Gy) before undergoing necrosis [15]; however, more subtle cognitive changes occur at lower doses. Memory deficits following irradiation follow a biphasic pattern – in the initial months an initial decrement with rebound, followed by a secondary permanent decline [16–18]. Radiation-induced