In addition to seizures, motor or sensory deficits, and increased intracranial pressure, DLGG patients can present with cognitive complaints and deficits that negatively affect HRQOL [26]. With this respect, it is important to note that patients with tumors in the dominant hemisphere tend to have more symptoms than those with lesions in the non-dominant hemisphere [27, 28]. Patients with DLGG furthermore tend to have more global cognitive deficits, unlike patients with stroke who tend to have lesion site-specific deficits. This may be explained by a diffuse growth of tumor cells infiltrating normal brain tissue [29]. Additionally, acute neurotransmitter changes and chronic degeneration of fiber tracts [30] caused by tumor and treatment-related damage to certain brain areas may impair neuronal responses in remote undamaged cortical regions (i.e., diaschisis). Given the increasing evidence for redistribution of neural function, particularly in DLGG, taking advantage of this property is becoming an important aspect of surgical management of these patients. As extensively discussed elsewhere in this book, a number of groups have endorsed a strategy pioneered by Duffau which takes advantage of surgery-induced plasticity for DLGG [31]. Evidently, deterioration in functioning usually occurs at the time of anaplastic transformation, which occurs in the majority of DLGG patients [9].

With regard to the effect of tumor volume, location, and histological grade on preoperative HRQOL a study of 101 successive brain tumor patients [32] was performed using the Nottingham health profile (NHP) and Sintonen’s 15D scale [33]. Analyses showed tumor size not to be related to HRQOL scores. However, large tumors (>25 ml) were associated with poorer HRQOL than small tumors (< or = 25 ml). Surprisingly, patients with tumors in the right hemisphere or in the anterior region had poorer HRQOL than those with tumors in the left hemisphere or posteriorly. From this study the authors [32] conclude that large tumors apparently damage several parts of the brain and/or raise intracranial pressure to a level that exceeds the brain’s compensatory capacity. In this study tumors in the right hemisphere seemed to be related to poorer HRQOL, while other studies observed that patients with right-sided lesions perceived a better HRQOL [14, 27]. To add to the confusion and most likely due to methodological issues, two studies reported homogeneity of HRQOL of patients with right- and left-sided lesions [34, 35], another study reports a worse HRQOL in patients who have bilateral lesions [36] and one reports a better functional status (KPS) in patients with right-sided lesions, but without affecting HRQOL [37]. Awaiting analyses from large preoperative studies that systematically documented both HRQOL, information on tumor location, and on mood, since depressive symptoms are known to affect HRQOL ratings, definite conclusions regarding laterality of the tumor and HRQOL cannot be drawn.

In order to place HRQOL of DLGG survivors in an appropriate, interpretable context a healthy population control group, matched on key background characteristics such as age, sex and education is needed. In a 2011 study [38] related to a study by Klein et al. [26] 195 DLGG patients studied on average 6 years following diagnosis and initial treatment were compared with 100 hematological (non-Hodgkin lymphoma and chronic lymphatic leukemia cancer survivors (NHL/CLL) and 205 healthy controls, matched on age, sex and educational level. Generic HRQOL was assessed with the SF-36 Health Survey; condition-specific HRQOL with the Medical Outcomes Study Cognitive Function Questionnaire and the EORTC Brain Cancer Module. Objective cognitive functioning was assessed with a battery of neuropsychological tests. No statistically significant differences were observed between the DLGG and NHL/CLL groups in SF-36 scores. The DLGG group scored significantly lower than the healthy controls. Approximately one-quarter of the DLGG sample reported serious cognitive symptoms. Problems with vision and motor function were uncommon. Age (older), sex (female), number of objective cognitive deficits, and epilepsy burden were associated significantly with both generic and condition-specific HRQOL. Clinical variables, including time since diagnosis, tumor lateralization, extent of surgery, and radiotherapy, were not related significantly to HRQOL. From this the authors conclude that DLGG survivors experience significant problems across a broad range of HRQOL domains, most of which are not condition-specific. However, the cognitive deficits that are relatively prevalent among DLGG patients are associated with negative HRQOL outcomes, and thus contribute additionally to the vulnerability of this population of cancer survivors. Patients that remained stable (65 out of the initial 195 patients) for 12 years following diagnosis reported significantly worse physical functioning using the SF-36 Physical Component Summary and the physical functioning subscale at long-term than at midterm follow-up [39]. For this subgroup, further research is recommended to better aid patients in dealing with the consequences of DLGG.

The prognostic value of HRQOL was determined in a study by Mainio [40]. The postoperative survival of 101 brain tumor patients was followed from surgery (1990–1992) until the end of the year 2003. Depression was evaluated by the Beck Depression Inventory (BDI) and HRQOL with Sintonen’s 15D scale [33] before operation and at 1 year as well as at 5 years after operation. The mean survival times in years were significantly related to tumor malignancy, being the shortest, 1.9, for patients with high-grade gliomas, while patients with DLGGs or a benign brain tumor had mean survival times of 9.1 and 11.6, respectively. At all follow-ups, depressed DLGG patients had a significantly shorter survival time, 3.3–5.8 years, compared to non-depressed DLGG patients, 10.0–11.7 years. A decreased level of HRQOL in DLGG patients was significantly related to shorter survival. These results suggest that depression and decreased HRQOL among DLGG patients are related to shorter survival at long-term follow-up. Decreased HRQOL may therefore serve as an indicator for poor prognosis in DLGG patients. This finding is in line with a meta-analysis [41] that indicates depression diagnosis and higher levels of depressive symptoms predicted elevated mortality of cancer patients. This was true in studies that assessed depression before cancer diagnosis as well as in studies that assessed depression following cancer diagnosis. Associations between depression and mortality persisted after controlling for confounding medical variables. Research is needed on whether the treatment of depression could, beyond enhancing quality of life, extend survival of depressed cancer patients.

Surgery for brain tumors is used to establish the histological diagnosis and to alleviate neurological symptoms through the reduction of tumor mass. Data from multiple series have demonstrated the importance of aggressive surgical resection for improved outcomes in DLGG. In particular, increased volumetric extent of resection has been shown to directly improve survival [42–45]. The risks and benefits must be weighed carefully because the surgical intervention itself may result in a transient or permanent decline in neurological function [46]. Where the tumor involves critical functional regions of the brain (e.g., motor cortex or arcuate fasciculus), complete tumor removal would directly affect the patient’s functioning and is thus not feasible. Surgical debulking is often recommended for any patient with increased intracranial pressure, neurological deficits related to mass effects, or uncontrollable seizures. It is important for the patient to understand that gross total resection does not mean the tumor has been completely removed. Surgery and perioperative injuries may cause neurological deficits owing to damage of normal surrounding tissue. However, most of these deficits resolved within 3 months, presumably owing to the plasticity of the normal brain [47]. Nonetheless, many neurosurgeons are hesitant to operate on patients with tumors in eloquent brain areas. Studies that use intraoperative image guiding and functional mapping in patients with DLGG in eloquent brain locations showed that intraoperative electrostimulation mapping during awake procedures is the most reliable method for identifying eloquent regions [48, 49]. This is a safe, inexpensive, and reproducible technique that allows the identification of crucial (nonfunctionally compensable) structures at the level of the cortex, white matter pathways, and deep gray nuclei [50]. Nonetheless, surgery for glioma in eloquent areas can negatively affect neurocognitive functioning early after surgery. In a study [51] 28 patients with gliomas of the left hemisphere in language and non-language areas were assessed before and 3 months after surgery with a comprehensive neuropsychological test battery. The authors showed pre- and postoperative language, memory, and executive functioning to be worse than healthy controls. Postoperatively, a decline was found in language and executive functioning. Postsurgical change was determined by tumor location, with only patients with tumors in or close to language areas to have reduced language capacity. Tumor resection in language areas thus increases the risk of cognitive deficits in the language domain postoperatively. A comparable study into the subacute surgery-related changes in neurocognitive functioning in patients with left and right temporal lobe tumors yielded similar findings [52]. They showed patients with left temporal lobe tumor to have greater decline than patients with right temporal lobe tumor on verbal memory and confrontation naming tests. Nonetheless, over one-third of patients with right temporal lobe lesions also showed verbal memory decline.

A follow-up study [53], suggests not only that most patients will have recovered 1 year after surgery, but also that recovery of neurocognitive functioning, specifically regarding language, might take longer than 3 months, as is generally assumed.

As noted earlier, treatment for low-risk patients may be deferred [11] and a watchful waiting policy in these patients with suspected DLGG does not appear to have negative effect on cognitive performance and HRQOL [22]. HRQOL and cognitive status of 24 patients suspected of having a DLGG, in whom treatment was deferred, and 24 patients with proven DLGG, who underwent early surgery were compared [22]. These patients were matched with healthy control subjects for educational level, handedness, age, and gender. The two patient groups were also matched for tumor laterality, use of AEDs, and interval between diagnosis and testing. HRQOL and cognitive status were compared between the three groups. Both patient groups scored worse on HRQOL scales than healthy control subjects. Unoperated patients with suspected DLGG scored better on most items than patients with histologically proven DLGG. Cognitive status was worse in both groups than in healthy control subjects, but, again, patients with suspected DLGG performed better than patients with proven DLGG. A much larger study [54] compared biopsy and watchful waiting that was favored in one hospital to early resection guided with three-dimensional ultrasound that was favored in the other regarding HRQOL outcome. Using generic (EQ-5D) and disease specific (EORTC QLQ-C30 and BN20) questionnaires They found no evidence that an early aggressive surgical approach in long-term DLGG survivors is associated with reduced HRQOL compared to a more conservative surgical approach. This finding weakens a possible role for watchful waiting in DLGG.

Prior research has shown that conventional (photon) radiotherapy, the standard treatment for most patients with high-risk DLGG, has a favorable impact on survival, but may negatively affect neurocognitive functioning and thus HRQOL. The risk of permanent central nervous system toxicity owing to radiotherapy, which typically becomes detectable after an asymptomatic latency period, continues to influence clinical treatment decisions. Interindividual differences in sensitivity result in a certain variability of the threshold dose and preclude administration of a guaranteed safe dose, even in the current era of high-precision image-guided (photon) radiotherapy. The therapeutic index in the nervous system is low, because the radiation dose required for tumor control is very close to, if not higher than, the toxic dose for neighboring tissues.

In contrast to the early complications of radiotherapy, the so-called late-delayed encephalopathy is an irreversible and serious disorder. This complication follows radiotherapy by several months to many years and may take the form of local radionecrosis or diffuse leukoencephalopathy and cerebral atrophy. Cognitive disturbances are the hallmark of the diffuse encephalopathy [55]. The severity of cognitive deficits ranges from mild or moderate cognitive deficits all the way to cognitive deterioration leading to dementia. It is not hard to imagine that these limitations in functioning have profound effects on HRQOL.

A commonly overlooked late complication of cranial radiotherapy in adults is endocrine dysfunction caused by damage to the hypothalamic–pituitary axis. Only a few studies have been done in adults, and these indicate that most patients who have clinical or subclinical endocrine dysfunction also show a significant decrease in well-being [56]. Emerging data indicate that these effects might be reversed by growth hormone therapy that could have a role in improving cognitive function by interacting with specific receptors located in areas of the CNS that are associated with the functional anatomy of learning and memory, by affecting excitatory circuits involved in synaptic plasticity, and by its protective effect on the CNS, as exemplified by its beneficial effects in patients with spinal cord injury [57].

Taphoorn et al. [58] described HRQOL in 20 patients who had been treated with early radiotherapy and 21 patients who had undergone surgery or biopsy only. In addition, 19 patients with hematological malignancies were included as a control group. The patients were evaluated for HRQOL through an interview, a multidimensional questionnaire that included physical status, social status, overall well-being, and treatment experiences and through the Profile of Mood States. Results showed that patients with brain tumors, regardless of whether they had received radiotherapy, had greater fatigue, memory loss, lack of concentration, and speech disorders than the control group. Patients were less satisfied with their condition and felt more restricted in daily activities than the control groups.

In view of the long survival of patients with DLGG and retrospective data suggesting a decline in cognitive function after radiotherapy in these patients [26, 59–61], both the EORTC and the NCCTG did companion studies assessing HRQOL outcomes. The randomized phase III trial EORTC 22844 [60] where low RT dose (45 Gy) was compared to high RT-dose (59.4 Gy) in DLGG after biopsy or surgery showed no difference in OS. A subset of patients answered questionnaires on physical, psychological, social, and symptom domains before radiotherapy and at various times after treatment. Comparisons between the high-dose and low-dose radiotherapy groups could be made for two time points: from the completion of radiotherapy to 6 months, and from 7 to 15 months after radiotherapy. During the initial postradiotherapy interval of 6 months, patients in the high-dose group reported poorer functioning and more symptoms than patients in the low-dose group. Significant differences were noted between the high-dose and low-dose groups for the symptoms of fatigue, malaise, and insomnia. During the 7–15-months after radiotherapy, significant differences favoring the low-dose group were noted in leisure time activity and emotional functioning. No significant differences between the baseline scores were seen. A phase III prospective randomized trial of low- versus high-dose radiation therapy for adults with supratentorial low-grade astrocytoma, oligodendroglioma, and oligoastrocytoma found somewhat lower survival and slightly higher incidence of radiation necrosis in the high-dose RT arm [62] potentially explaining why patients in the high-dose arm of EORTC 22844 experienced poorer HRQOL. A more recent study showed that although DLGG patients may have significantly lower scores on the Mental Component Summary of the SF-36 the use of radiotherapy was not consistently associated with lower HRQOL self-ratings [38]. Given the relatively long survival of considerable numbers of DLGG patients, the follow-up study of the Klein et al. cohort yields interesting results. At a mean of 12 years after their first diagnosis, this study [63] reports on the radiological and cognitive abnormalities in DLGG survivors with stable disease since the first assessment [26]. Of the 65 patients 32 patients (49%) patients had received radiotherapy and these patients had more attentional deficits at the second follow-up than those who did not have radiotherapy. Furthermore patients who had radiotherapy had poorer attentional functioning, executive functioning, and lower information processing speed between the two assessments. In total, 17 (53%) patients who had radiotherapy developed cognitive disabilities deficits in at least 5 of 18 neuropsychological test parameters compared with 4 (27%) patients who were radiotherapy naive. White-matter hyperintensities and global cortical atrophy were associated with worse cognitive functioning in several domains. These results suggest that the risk of long-term cognitive and radiological compromise that is associated with radiotherapy should be considered when treatment is planned. The findings of the previously mentioned study of the same group [20] that poorer cognitive functioning is related to lower generic and disease-specific HRQOL stresses this notion.

Relative to conventional (photon) radiotherapy, proton radiotherapy reduces entrance dose and eliminates the exit dose, with the advantage of sparing normal tissue, while having comparable biological effects on the targeted tissue as do photons. Although a few small studies show promising results [64, 65], whether this technique also compares favorably to photon therapy regarding neurocognitive functioning and HRQOL has to be demonstrated in large multi-center studies. Twenty patients were evaluated at baseline and at yearly intervals for up to 5 years regarding neurocognitive functioning, mood, and functional status [64]. Overall, patients exhibited stability in neurocognitive functioning with those with tumors in the left hemisphere versus in the right hemisphere being more impaired at baseline on verbal measures. Greater improvement in verbal memory over time was seen in patients with left than with tumors in the right hemisphere. There was no change on average in the emotional well-being of patients over time and there was no significant decline in HRQOL over time following radiotherapy completion. The same group [65] demonstrated that while all 20 patients (median age, 37.5 years) tolerated treatment without difficulty, new endocrine dysfunction was detected in six patients. Since no follow-up studies on neurocognitive functioning have been performed beyond the median survival of these patients, no definite conclusions can be drawn as to the preferred treatment of these patients.