High-grade gliomas (HGG) are aggressive neuroepithelial tumours which originate from glial cells, infiltrating the brain parenchima; they represent almost the 50% of primary malignant brain tumours and still have a poor prognosis of around 15 months [1], despite recent advances in treatments and personalized clinical pathways.
HGG may cause neurological and neuropsychological impairments with a significant impact on patients' autonomy and quality of life (QoL) [2–4], depending on their location and side, dimensions and associated edema or mass effects.
The actual standard treatment protocol for HGG is represented by a maximal safe resection surgery, followed by the Stupp protocol, a combination of concomitant chemo and radiotherapy [1, 5]; afterwards, a series of cycles of adjuvant chemotherapy are administered.
Whereas several studies in literature deal with the cognitive effects of cerebral radiotherapy in HGG [6, 7], little is known about the cognitive impact of chemotherapy for brain tumours.
Since the 80's chemotherapy neural adverse effects have been investigated in animal models [8] and in frequent non-cerebral tumours such as breast, colon-rectal and testicular cancer [9–11], reporting chemotherapy-related cognitive impairment (CRCI) in up to the 20–30% of patients after one year from the end of the therapy, with a significant impact on daily functioning and QoL. Among the most consistent findings, impairments in divided and sustained attention, language production, processing speed, reasoning and memory have been reported [12–15], also independently from therapy cessation. The significant percentages of CRCI led to expressions such as “chemobrain” or “chemofog” to refer to this phenomenon [16].
A wide literature is nowadays available about structural and functional abnormalities in the gray and white matter structures in oncological patients experiencing CRCI: for example, it is known that breast cancer survivors report frontal hypometabolism during executive tasks [17, 18], reduced event-related potentials [19] or abnormalities in the Default Mode Network functioning [20]. Moreover, tautopathies, hyppocampal dysfunctions and synaptical damages [21, 22, 23], demielinization and assonal degeneration have also been described [for a review see 19].
These alterations have been linked to the neurotoxicity induced by the chemotherapic treatments, which manage to overrun the blood-brain barrier besides their targets outside the brain.
In this view, chemotherapies for brain tumours, whose target is within the brain parenchima, are likely to induce more severe CRCI, but there is a generalized lack of studies addressing the relation between chemotherapy and cognition in brain tumour patients, as reported in a recent review [24].
In the late 2000s the DNA alkylating agent Temozolomide (TMZ), was approved for the management of gliomas, firstly as adjuvant treatment [25] and secondarily concomitant to radiotherapy [1]. TMZ is readily permeable to the blood-brain barrier through a mechanism of conversion into a metabolite (the 5 − 3(3-methyl)-1-triazen-1-yl-imidazole-4-carboxamide) which causes glioma cells apoptosis [23]. TMZ was linked to a significant improvement of the 2-year survival rate of patients from 10.4% (radiotherapy alone) to 26.5%, with low rates of toxicity and adverse clinical effects [25] and represents nowadays one of the most common treatments used in clinical practice for HGG.
Concerning the impact of TMZ on cognition, a negative effect has been described on memory functions in mice models, due to TMZ chemical mechanisms of action which may damage hyppocampal integrity [26]. Nevertheless, very little is known about its effects in glioma patients, due to the difficulties in separating the effects of TMZ from those of other treatments or drugs and the heterogeneity of patients and their clinical pathways: a few studies dealing with low-grade glioma (LGG) patients treated with TMZ report a slight improvement of memory over time [27] or stable cognitive performances before and after treatment, or after 3 months from the completion of the treatment protocol [28]. Hilverda and colleagues [29] describe that TMZ does not affect cognition in glioblastoma patients, with respect to radiotherapy, in the first six months of treatment, with a greater impact of TMZ during concomitant phase than the adjuvant cycles.
Starting from this generalized lack of precise data, aim of this work is to retrospectively study the effects of TMZ chemotherapy on cognition and daily autonomy in a population of adult HGG patients followed at our Institution.