The response assessment after chemotherapy for DLGGs remains a difficult and non-consensual issue.

For many years, MacDonald criteria, created to evaluate WHO grade III and IV gliomas [57] and based on two dimensional enhanced tumor measurements on computed tomography or magnetic resonance imaging (in conjunction with clinical and steroid dosage evaluations) were used for DLGGs after adaptation (especially by considering the two largest diameters on T2-weighted or FLAIR slides and not on injected images and by abandoning the reference to steroids). This procedure does not allow to objectively monitor the evolution of a tumor under treatment and clearly underestimates the number of responders. This was the case for many initially reported studies [16–18].

New recommendations were proposed [58]. These latter do not appear optimal by considering that “published studies that have compared calculations based on single, multidimensional and true volumetric measurements and the strength of their correlations with the outcome (PFS, OS) are absent and thus that evidence-based data for the preferred measurement system are not available”. We disagree with this opinion (see the dedicated chapter), because we consider that the volumetric evaluation is absolutely necessary for monitoring DLGG patients receiving chemotherapy. Otherwise, the risk is to dramatically underestimate responses and thus to be in an absolute inability to properly monitor the treatment duration.

The papers by Hoang-Xuan et al. [22] and Ricard et al. [32] were the first most important considering the impact of chemotherapy on DLGGs. In the second one’s, authors were, indeed, among the first to report a longitudinal real volumetric assessment in a population of 107 patients treated exclusively with temozolomide. The method of the three diameters technique (ellipsoidal approximation) was used to obtain volumes and mean tumoral diameters (MTD) [59]. During the treatment, they found that more than 60% of patients achieved a minor or partial response. At the onset of TMZ treatment, the MTD decreased in 92% of patients, demonstrating an early initial chemosensitivity: 38 of 39 patients who had a pre-, per- and post-evaluation of the MTD slope experienced a breakdown of the MTD growth curves after chemotherapy onset. After the initial phase of MTD decrease and despite continuous administration of TMZ, the tumors of some patients started to resume growth again whereas others continued to decrease. Tumor regrowth occurred in 16.6% of 1p-19q codeleted tumors and in 60.6% in non-codeleted tumors (p < 0.0004). Tumors over-expressing p53 had also a much greater rate of relapse (70.5% versus 25%). The evolution of the MTD was also tested after discontinuation of TMZ. The greater part of the population remains stable or sometimes continues to decrease despite the interruption of treatment. Nevertheless, a majority of tumors starts to grow again: 59% rate of MTD regrowth after a median follow-up of 200 days after TMZ discontinuation (range, 60–630 days).

Our group has also published a retrospective study concerning chemotherapy followed by surgical resection for DLGGs. The impact of chemotherapy on the tumor volume was estimated using Volume Viewer^® software (General Electrics GE Healthcare, Milwaukee, WI, USA). For exams in which only printed images were accessible, a three diameters technique was used. We also demonstrated that chemotherapy induced a tumor shrinkage (median volume decrease of 35.6%) in 17/17 cases (ipsilateral in ten patients and in the contralateral hemisphere in seven patients) [43].

Peyre et al. [36] reported kinetics data concerning 21 patients treated with PCV protocol. During PCV treatment, all the patients presented a decrease of the mean tumoral diameter (MTD). During chemotherapy, the median MTD decrease was −10.2 mm/year (range, −23 to −1 mm/year). 20 of the 21 patients presented a persistent decrease after PCV discontinuation. The median duration of the MTD decrease was 3.4 years (range 0.8–7.7 years) after PCV onset and 2.7 years (range 0–7 years) after the end of PCV. At the time of maximal MTD decrease, the rates of partial and minor responses were 38% and 42%, respectively, according to adapted McDonald’s criteria. PCV treatment is associated with a prolonged response even in patients with no 1p19q codeletion. Taal et al. confirmed these results in a retrospective series of 32 patients [46].

In the study of Kaloshi et al., they reported 38 patients treated with CCNU alone [44]. CCNU was delivered at the dose of 130 mg/m² every 6 weeks. The median time to obtain a radiographic response was 6 months and the maximum response was reached after a median of 12 months. 17 (45%) patients achieved a partial response, 9 (23%) patients a minor response, 8 (21%) were stable and 4 (11%) progressed. The maximal objective response rate was also 68%. Then, Kaloshi et al. analyzed growth kinetics in these 38 patients before, during and after CCNU treatment. During CCNU treatment, the median MTD decrease was −5.1 mm/year (range −8.9 to −1 mm/year) (after excluding patients with progression) [60]. The median duration of response was 1.7 years. Response was significantly longer in oligodendroglial tumors than in astrocytic tumors (median 2.8 years versus about 1 year, respectively, p = 0.003). The profile of CCNU response seems similar to PCV treatment. Otherwise, we have only limited data [37] on response rates after the restart of chemotherapy (low-grade stage) after a break of several months or years. It is thus difficult to provide guidance on this topic.

Seizures are the most common initial symptom in patients with DLGG. Their occurrence strongly depends on the tumor location including insular and central topography [61, 62]. Some authors have also suggested a link between IDH 1/2 mutation (frequent in DLGGs) and the onset of metabolic changes capable of promoting seizures [63].

For a long time, chemotherapy and irradiation were considered having just some minor beneficial effects on the patients’ seizure disorder using the argument that overall 60–70% of patients may experience recurrent epilepsy during long-term follow-up [64].

The progressive development of this therapeutic modality, its conceptual changes (prolongation of treatment time) and more precise analysis of the impact of such therapy on seizures have radically changed the view of many authors. Thus, it is now considered (despite the usual difficulties with seizure quantification in retrospective studies) that (1) the negative course of seizure frequency was mostly correlated to tumor progression (2) surgery had almost always a favorable effect on epilepsy (3) chemotherapy (such as radiation therapy) had a mostly favorable effect with acceptable tolerance [2, 65–67].

Seizure improvement is usually associated with radiological response. Nevertheless, some patients with a “stable disease” according to RANO criteria (defined by a FLAIR decrease inferior to 25%) reported significant seizure reduction [68]. Although it may be due to an underestimation of the response with this method, seizure reduction seems well to precede the radiological response given that a ≥ 50% seizure reduction at 6 months of TMZ initiation is associated with the occurrence of an objective MRI response (according to RANO criteria) at 12 months and 18 months. Likewise, seizure improvement seems to be independent prognostic factor for “PFS” and OS after 6, 12 and 18 months of TMZ onset [48, 69].

The improvement in seizure frequency during treatment with temozolomide seems, moreover, independent of antiepileptic drug adjustment [70].

An extensive experience with insular DLGGs (topography considered as the most epileptogenic) was also reported by our group. We confirmed the interest of a surgical removal and supported the role of chemotherapy from an epileptological point of view [35].

We need to address in this chapter, regarding the relationship between chemotherapy and DLGGs, the special place of antiepileptic treatments. Recommendations in this area are identical to the recommendations for all brain tumors. Most authors recommend first-line non-inducing drugs such as lamotrigine, levetiracetam or lacosamide [71, 72]. These new antiepileptic drugs seem better tolerated even if they are no more effective [67] The place of valproate remains debated. A clear efficiency is reported [72]. Combined antiproliferative activity through its inhibitory properties of histone deacetylase could improve survival as it was evoked for glioblastomas [73]. Nevertheless there are potential side effects (weight gain, thrombocytopenia, tremor, fetotoxicity) and enzyme inhibition may increase the hematologic toxicity of chemotherapy.

Finally, it seems possible to use amino acid Positon Emission Tomography to predict the impact of chemotherapy on epilepsy. The reduction of seizure frequency seems so well correlated with the reduction of metabolically active tumor volumes [74].

Cognitive functioning is correlated with quality of life, itself linked with return to work or to normal social life [75]. This point is absolutely crucial in general neuro-oncology and, still more, in the management of patients with DLGG. Approximately one quarter of patients with DLGG reported serious neurocognitive symptoms [76]. Neurocognitive deficits are far more frequent than previously thought and can be caused by the tumor itself, tumor-related epilepsy, treatments and psychological distress [52]. For some authors, the role of radiotherapy and chemotherapy in the treatment of DLGG remains controversial regarding their effect on survival and the development of neurotoxicity. 40 DLGG patients participated in the study of Correa et al. 16 patients had RT ± chemotherapy and 24 patients had no treatment. In this series, RT ± chemotherapy, disease duration, and antiepileptic treatment contributed to mild cognitive difficulties. It is, however not possible in this work to isolate the precise role of chemotherapy alone in the toxicity [77]. The same team published a new paper with 25 DLGG patients who underwent neuropsychological evaluations at study entry, 6 and 12 months subsequently. Nine patients had RT ± chemotherapy prior to enrollment and 16 had no treatment [78]. Longitudinal follow-up showed that both disease duration and treatment with RT ± chemotherapy contributed to a mild decrement in non-verbal recall and in some aspects of executive functions and quality of life. In these two articles, the widespread use of combined strategies (radiotherapy + chemotherapy) makes difficult to analyze the specific contribution of chemotherapy in the cognition modulation. Our group [39] reported a retrospective work with a neuropsychological assessment (NPA) of ten patients who underwent a strategy with a first chemotherapy followed by functional surgery. Nine patients were right-handed and one left-handed. No one presented with premorbid intelligence deterioration. Three patients did not show any neuropsychological deficit. Seven patients failed at three or less out of the eighteen cognitive tests that were applied. The three others failed at least four tests. The main cognitive domains where deficits were observed concern episodic memory, especially verbal modality (five patients), and executive functions (five patients). Interestingly, the patients who did not continue to work were not the same who presented the most severe cognitive impairment. Our conclusion was that this combined strategy is highly likely to preserve cognitive function.

A recent observational study RTOG 0925 evaluated the “Natural History of Brain Function, Quality of Life, and Seizure Control in Patients in Supratentorial Low-Risk Grade II Glioma”. The primary endpoint concerns neurocognitive functions assessed by four neurocognitive tests (which do not represent a robust and subtile neurocognitive assessment): Detection DET (psychomotor function), Identification IDN (visual attention), One Card Learning test OCTL (visuoperceptual learning and memory), Groton Maze Learning test GML (spatial learning and executive functions). Quality of life was measured by the EORTC QOL-30, EORTC QOL-BN20, EQ-5D questionnaires. Finally, seizure was analyzed using patient seizure diary. Results have not yet been published.

Donepezil could improve several cognitive functions (especially among patients with greater pretreatment impairments) in brain tumor survivors presented neurotoxic effects of radiotherapy [79]. Comprehensive neurocognitive rehabilitation has also demonstrated its benefit in DLGG patients [80]. The future researches have to develop systemic agents that allow to delay radiotherapy, to identify patients at major risk of neurotoxicity, to evaluate potential radioprotective agents [81].

As already mentioned, quality of life is correlated with cognitive functioning with, itself linked with return to work or to a normal social life [75]. Works on these three fundamental aspects of DLGG patient’s evaluation are very rare. We know, generally, that female sex, epilepsy burden, and number of objectively assessed neurocognitive deficits were associated significantly with both generic and condition-specific HRQOL [76]. The major impact of PCV on HRQOL is on nausea/vomiting, loss of appetite, and drowsiness during and shortly after treatment. There are few but severe no long-term effects of PCV chemotherapy. Majority of patients recover a “normal” state when they move away from the treatment period [82]. Some of them develop myelodysplasia or permanent sterility.

Liu et al. described the quality of life (QOL) of DLGG patients at baseline prior to chemotherapy and through 12 cycles of temozolomide. The Functional Assessment of Cancer Therapy-Brain (FACT-Br) was obtained at baseline (prior to chemotherapy) and at 2-month intervals under chemotherapy. Patients at baseline had higher reported social well-being scores (mean difference = 5.0; p < 0.01) but had lower reported emotional well-being scores (mean difference = 2.2; p < 0.01) compared with a normal population. Patients with right hemisphere tumors reported higher physical well-being scores (p = 0.01): 44% could not drive, 26% did not feel independent, and 26% were afraid of having a seizure. Difficulty with work was noted in 24%. Mean change scores at each chemotherapy cycle compared with baseline for all QOL subscales showed either no significant change or were significantly positive (p < 0.01). Authors concluded that DLGG patients on therapy were able to maintain their QOL in all realms. Patients’ QOL may be further improved by addressing their emotional well-being and their loss of independence in terms of driving or working [83].

In our work concerning patients treated with presurgical chemotherapy [39], the Karnofsky Performance Scale (KPS) scores ranged from 80 to 100 (median 90) and were globally stable during the whole follow-up period. The main domain that presented with significant impairment in the QOL assessment was role functioning (feeling of independence and socio-professional life) with a median score of 66.7% (range 50–100). The global QOL score was preserved after chemotherapy and surgery for most patients with a median value of 66.7% (range 33.3 to 83.3%). Cognitive, emotional, physical and social well-being scores were also relatively preserved (median scores 83.3, 79.2, 100 and 100%, respectively). Among the general symptoms, the main complains were fatigue (median score 33.3% range 11.1–100%) and pain (median score = 16.6%, range 0–66.7%) due to different associated diseases like osteoarthritis and arteriopathy. Sleeping troubles (mean score = 20 ± 30.6%), financial impact (mean score = 23.3 ± 39.6%) and digestive troubles (mean score = 20 ± 30.6%) seemed to have a moderate influence on the QOL. No patient reached the cut-off of 15 in the inventory for signs or symptoms of depression (BDI) with a mean score of 8.7 ± 3.6. However, seven subjects showed a tendency for “mild depression”, characterized by a score between 8 and 14.

We can therefore consider that TMZ alone or combined with surgery is able to maintain or even to improve the quality of life [84] and that PCV alters transiently the QOL, with a return to the “normal” situation when we move away from the treatment period.

We have to note that, nonetheless, more than one third of long DLGG survivors present an impaired quality of life (one or more Health Related Quality of Life scales) despite long-term post-therapeutic (including chemotherapy) stable disease [85]. It should make us particularly attentive about potentially incriminating therapeutic factors. It would also be interesting, in the future, to focus more specifically on the impact of chemotherapy on other quality of life parameters marginally explored like sexuality [86]. However, it could be difficult to specifically address the impact of each therapy given a multistage and individualized therapeutic approach in the current management of DLGG patients. Most studies have investigated the role of only one specific treatment without a global view of managing the cumulative time while preserving quality of life versus time to anaplastic transformation [84, 87]. Quality of life represents an individual and personal concept, which has to be taking into account and anticipate at each time of the management [88].

To date, there is no direct evidence for DLGG patients that confirms the impact of chemotherapy on patients’ survival. Only RTOG 9802 (randomized trial with RT alone or RT followed by six cycles of PCV for supratentorial adult DLGGs) and RTOG 0424 (phase II study of temozolomide-based chemoradiation therapy for high-risk DLGGs) trials demonstrated a benefit of chemotherapy on survival in “high-risk” DLGGs [4]. For RTOG 9802, median OS increased from 7.8 years to 13.3 years, with a hazard ratio of death of 0.59 (log rank: p = 0.002) [89]. For RTOG 0424, the 3-year OS rate was 73.1% (95% confidence interval: 65.3%–80.8%), which was significantly improved, compared to that of prespecified historical control values (p < 0.001) [90] (see Sect. 25.4.6.1). We know, however, that presumed eloquent location of DLGGs is an important but modifiable risk factor predicting disease progression and death [91] and that the risk of malignant transformation and subsequent survival may be predicted by pretreatment but also by treatment-related factors [92].

We are thus entitled to imagine that indirectly, this treatment modality may have an impact on patient survival.

In a retrospective selected series, seventeen patients considered at diagnosis or recurrence as “non operable” because of a functional areas infiltration or a too large contralateral extension, underwent temozolomide-based chemotherapy inducing tumor volume decrease immediately followed by a radical surgery. The median follow-up since initial radiological diagnosis was 5.9 years (range 1.4–11). The median time to malignant transformation was 99.6 months. We demonstrated that age, volume at diagnosis, 1p19q, IDH and MGMT promoter status had no impact on time to malignant transformation. Chemotherapy reduced tumor volume (median − 35.6%, range −61.6% to −5.1%) and significantly decreased the imaging tumor growth whatever 1p19q, IDH and MGMT status. We confirmed that a tumor volume decrease of more than 20% was significantly correlated with a lower postoperative residual tumor (median = 2 cc, p = 0.04), a greater extent of resection (whithout reaching statistical significance) and a better prognosis (p = 0.04). We thus concluded that, regardless of the molecular status, neoadjuvant chemotherapy could optimize surgical resection of DLGGs and could have an impact on their natural history and particular on the survival [43].

For more objective assessment of the impact of chemotherapy, it is conventional in neurooncology to use parameters such as overall survival and progression-free survival.

Overall survival is sensitive to all instituted treatments including “salvage” therapies. In this type of disease, treatments are often multiple and repeated. That makes difficult to analyze the specific impact of a given treatment (chemotherapy in our case) on survival. Progression-free survival could be an interesting parameter to use if and only if (1) there is longitudinal and rigorous volumetric assessment (2) these morphological parameters are associated with quality of life data [108]. The same remark can be made for the classical time to malignant transformation.

It was recently pointed out that clinical trials for DLGGs “need to consider other measures of patient’s benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged well-being” [58] should move in this direction also emphasized by Klein and colleagues “the multidimensional scales used to study changes in HRQOL studies in brain tumor patients provide a more comprehensive view of what is important to the patient concerning living with their disease and receiving treatment” [109].

To date, most radiologists and physicians analyze the images and decide the direction of treatment for gliomas and especially DLGGs via a side-by-side comparison of images. This procedure can be considered as very imperfect and even dangerous. It was indeed clearly demonstrated that automated change detection and image subtraction are superior to side-by-side image comparison for brain tumors in general [110] and more obviously for DLGGs [111].

In the same manner, the majority of dedicated centers simply monitored patients with conventional MRI without volumetric assessment and a fortiori without multiparametric examinations able to assess tumor cellularity, hypoxia, disruption of normal tissue architecture, changes in vascular density and vessel permeability [112]. However, today, these parameters seem absolutely essential [113].

RANO criteria [58] for DLGGs seem not appropriate to monitor treatment and follow-up. Detailed volume assessment is crucial in slow-growing tumors like DLGGs. Indeed, it may be difficult to highlight a tumor growth in this kind of tumors. RANO criteria correspond to a two-dimensional evaluation (the product of the two perpendicular diameters) whereas three-dimensional evaluation, is clearly superior and more accurate. 3D volumetric tumor measurement represents the gold standard [111, 114, 115]. In our group, we have demonstrated that manual MRI segmentation of DLGG tumor volumes (Osirix^® free software) was reproducible, independently of the practitioner, nor the medical specialty or experience [116]. Volumetric assessment is also feasible in clinical practice.

Finally, some authors have attempted to model the response to chemotherapy in order to predict the response to treatment. Results have to be confirmed and stated in the future [42, 47, 117].

There are several factors clearly related to the prognosis of DLGGs. These factors formed the “EORTC scoring system” [118] or the “UCSF LGG prognostic scoring system” [119] by combining different parameters (1) location of tumor in presumed eloquent cortex (UCSF) (2) tumor crossing the midline (EORTC) (3) presence of neurological deficit (EORTC) (4) Karnofsky Performance Scale score < or =80 (UCSF) (5) age > 50 years (UCSF)/ > or =40 years (EORTC) (6) maximum diameter (> or =6 cm for EORTC/ >4 cm for UCSF) and (7) histology (astrocytoma histology subtype for EORTC). Patients that combine two or more factors are classified in the high-risk group for the EORTC scoring system. For UCSF, the stratification of patients is based on scores generated groups (0–4) with statistically different OS and PFS estimates (p < 0.0001, log-rank test). It has more recently been shown by a multivariate analysis constructed on the basis of two European Organisation for Research and Treatment of Cancer radiation trials for low-grade gliomas that tumor size and MMSE score were significant predictors of OS whereas tumor size, astrocytoma histology, and MMSE score were significant predictors of “PFS” [120]. Finally, Gorlia et al. validated prognostic models and prognostic calculators [121] after pooling data from two large studies. The presence of baseline neurological deficits, a shorter time since first symptoms (>30 weeks), an astrocytic tumor type and tumors larger than 5 cm in diameter were negatively influenced both “PFS” and OS.

It is so far difficult if not impossible to determine whether these factors are only prognostic factors or predictors of treatment response, including chemotherapy response.

Dynamic Susceptibility-weighted Contrast-enhanced perfusion imaging can identify progression and can also predict treatment failure during follow-up of DLGGs with, for some authors, the best diagnostic performance [122].

Concerning spectroscopy, Murphy et al. reported in 2004 that there was interest to evaluate the reduction in the tumour choline/water signal in parallel with tumour volume change and that this marker could reflect the therapeutic effect of temozolomide [123]. In addition and very interestingly, Guillevin et al. demonstrated that the mean relative decrease of metabolic ratio −Δ(Cho/Cr)(n)/(Cho/Cr)(o)− 3 months after the start of a TMZ-based chemotherapy was predictive of tumour response over the 14 months of follow-up. The (1) H-MRS profile changes more widely and rapidly than tumor volume and represents an early non-invasive predictive factor of outcome under temozolomide-based chemotherapy [113].

The diagnostic criteria, in particular for oligoastrocytoma but also for “simple” astrocytomas or oligodendrogliomas, are highly subjective [124]. Most authors have proposed to go beyond the pathological (morphological) classification by including other criteria, notably molecular, to refine the prognostic significance of the diagnosis [125, 126]. Due to these important limitations of the morphological analysis of DLGGs, it was difficult to build clinical trials for chemotherapy.

The WHO classification of Central Nervous System tumors has been revised in 2016 [127] and integrates molecular parameters in addition to histology. Thus, IDH and 1p19q status are now used to define diffuse astrocytomas and oligodendrogliomas. Oligoastrocytomas “are now designated as NOS (not otherwise specified) categories, since these diagnoses should be rendered only in the absence of diagnostic molecular testing or in the very rare instance of dual genotype oligoastrocytoma”. For instance, we think that these modifications will not changed our attitude in daily practice in DLGGs, especially in chemotherapy decision making. Indeed, as we mentionned previously (Sect. 25.3.5), chemotherapy could induced a significant tumor volume reduction whatever molecular status, at the individual level [43, 45]. A positive point is that this modified classification incites to systematically perform molecular analyses, although there is no precision concerning the technique for 1p19q assessment (loss of heterozygosity LOH or fluorescence in situ hybridization FISH or comparative genomic hybridization CGH). However, in this new classification, a diagnosis of glioblastoma GBM is retained even without necrosis on histological analysis of oligodendrogliomas, leading to an overdiagnosis of GBM in DLGGs harboring anaplastic micro- or macrofoci, as defined by Pedeutour-Braccini et al. [128] Finally, this new classification will not solve the problem of the heterogeneity of DLGGs and it will be again difficult to draw conclusions from the various series to be published.