Old Does Not Necessarily Mean Worse: Standard 6-Week Chemoradiation For Elderly Patients ( ≥ 70 Years) With Newly Diagnosed Glioblastoma

Results

Introduction Glioblastoma (GBM) is the most malignant and common primary brain tumor in adults [1]. The overall prognosis remains poor: around 12-15 months [2] [3]. The current therapeutics rely on surgical resection, radiotherapy (RT), chemotherapy (CT) and best supportive cares (BSC) [4]. The combination of 6 weeks of conventionally fractionated RT (CFRT) with radiosensitizing temozolomide (TMZ), followed by up to 6 cycles of maintenance TMZ (known as the standard chemoradiation regimen [3]) is the mainstay for < 65 year-old patients [4]. However, there are concerns about whether and/or which elderly patients may bene t from such post-operative treatment.
Focusing on the elderly population (e.g. aged ≥ 70 years) with newly-diagnosed GBM is relevant for the following reasons: i) the highest incidence rate is currently observed in patients aged 75 to 84 years [5] ; ii) neurological symptoms (following progression or treatment toxicities) may have dramatic consequences on independence and/or quality of life for such a frail population [6] [7]; iii) the life expectancy is extremely poor but has increased in the last decade with the development of post-operative treatments [2]; iv) GBM-speci c geriatric scales of frailty are still lacking. Age and performance status (PS) > 2 are common negative prognostic factors [8] [9]. MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene silencing and its consequence on therapeutics have been investigated considerably [10] [11]. In particular, MGMT methylation is associated with improved response to TMZ. The di culties in interpreting the results of the tests nevertheless mean that MGMT status not routinely assessed [12].
Over the last few years, both the indication for, and modalities of, post-operative treatments in elderly patients have been controversial [13] [33]. This type of regimen tends to be the current standard of care for elderly patients although there are no prospective trials comparing it to the standard 6-week protocol.
In this context, we present the tolerance data and outcomes for all the elderly patients (≥ 70 years) who were referred to our institution for the standard 6-week chemoradiation. The objective was to investigate whether common geriatric sources of frailty such as age or baseline neurological disabilities, had a negative impact on survival.

Patient selection
All ≥70-year-old, histologically-proven GBM patients referred to our radiation therapy department (Institut de Cancérologie de l'Ouest, Saint Herblain, France) for a standard 6-week chemoradiation from January 2004 to December 2018 were included. Patients with World Health Organisation (WHO) grade <4 gliomas were excluded [1]. All patients had surgical intervention -either complete (CR) or partial (PR) resection or biopsy (B) -and had been considered t for radiochemotherapy (RCT) by a multidisciplinary team (including neurosurgeons, medical and radiation oncologists), mainly based on PS ≤ 2. Speci c geriatric evaluation was not systematically performed in our institution at that time. The histomolecular isocitrate deshydrogenase (IDH) mutation was determined in each case, but after 2011. MGMT-methylation status was not considered informative for therapeutic decisions in our institution at that time and was not carried out routinely.
Post-operative treatment modalities and follow-up Immobilization in the treatment position was systematically achieved using custom thermoplastik mask contention during RT. An RT-dedicated computed tomography (CT) scan was registered with contrastenhanced T1-weighted brain magnetic resonance imaging (MRI) in order to guide tumor delineation [35] [36]. The gross tumor volume (GTV) was de ned as the contrast enhancement area in the T1-weighted MRI sequence and CT scan, including the tumor bed for patients with prior partial or complete resection. Following GBM guidelines [36], the clinical target volume (CTV) was de ned as the addition of a geometric tridimensional 10-20mm margin (depending on the tumor's topography) around the GTV that was corrected to the anatomical borders and had to include the hypersignal FLAIR-MRI around the GTV.
The planning target volume (PTV) was de ned as CTV+5mm. The dose prescribed to the PTV was 60 Gy in 30 fractions of 2 Gy per fraction, 5 days a week within conformal three-dimensional radiotherapy [3].
Concomitant daily TMZ (75 mg/m 2 , 7 days a week from the rst to the last day of RT) was prescribed during RT, with weekly blood samples.
All patients were examined by their medical oncologists one month after the last RT session to start up to 6 cycles of maintenance TMZ (150-200mg/m 2 , 5 consecutive days a month). During the RCT, treatment tolerance was evaluated once a week. Patients were followed up clinically and with blood tests once a month throughout the maintenance phase and then every three months. The rst brain MRI for evaluation was performed three months after the end of RT, then every three months for at least ve years.

Outcomes
The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), incidence rate for early adverse neurological events, and TMZ-related toxicity assessed by the CTCAE v5 classi cation.
Survivals (OS and PFS) were respectively de ned as the time from histological diagnosis to death from any cause, and neurological progression as assessed by MRI (at least T1 with gadolinium injection and FLAIR) or death from any cause. As it can be di cult to distinguish recurrence from pseudoprogression after RT and TMZ [37], repeated MRI over shorter time interval than planned were necessary in some cases. The date of progression assigned was the earlier date when progression was rst suspected. Early adverse neurological events were de ned as the occurrence of: symptoms of intracranial hypertension (ICHT) and/or the use of corticosteroids and/or the need for hospitalization for any cause in the absence of neurological progression or death (≤1 month after RCT).
For each patient, the presence of neurological disabilities (motor, visual, instability, cognitive and communication) was also retrospectively reviewed before and after RCT.

Early adverse neurological events
In the subgroup of patients without early neurological progression or death (80.5%; 103/128), 52.5% (54/103) of patients had early adverse neurological events. The occurrence of such events (HR = 1.69, p = 0.010) was signi cantly associated with death from any cause in this subgroup of patients. Regarding speci cally the ≥80-year-old cohort, the rate for early adverse neurological events was 61% (11/18).
Prognostic factors in the same subgroup (N = 103) for the occurrence of early adverse neurological events are summarized in Figure 3. Patients with pre-RCT neurological disabilities did not exhibit signi cantly higher occurrence for early adverse neurological events (OR = 1.19, p = 0.671) nor did ≥80- year-old patients (OR = 1.74, p = 0.313). The quality of the surgical resection (B versus CR; OR = 3.06, p = 0.017) and RPA class (III-IV versus I-II, OR = 2.89, p = 0.018) were signi cantly associated with higher incidence for such events.

Discussion
Around 80% of all the ≥ 70-year-old patients who were referred to our institution for standard 6-week chemoradiation, received the entire 6-week long treatment. In particular, all the ≥ 80-year-old patients completed this treatment. The RPA classi cation by Scott et al. [8] was prognostic for both the OS and occurrence of early adverse neurological events, but interestingly, the presence of neurologic disabilities at baseline was not associated with worsened outcomes.
In recent decades, several studies have investigated different treatment modalities to go further than the standard protocol: e.g. CT intensi cation with lomustine for MGMT-methylated patients [38], TMZ dose escalation [39] or the addition of irinotecan during the maintenance TMZ phase [40]; maintenance TMZ beyond 6 cycles [41]; the addition of antiangiogenic drugs such as bevacizumab [42] [43] or cilengitide [44]; immunotherapeutic approaches with vaccines such as Rindopepimut® for patients with a mutation in the epidermal growth factor receptor (EGFR) gene [45] or antiPD1 checkpoint inhibitors [46]; alternating electric elds to the brain called Tumor Treating Fields (TTF) during the maintenance phase [47]. At this time, none of these treatments except TTF has been able to demonstrate clear oncologic improvements compared to the original 6-week chemoradiation regimen, which remains the mainstay for ≤ 65-70-yearold patients with median PFS and OS of 6.9 and 14.6 months, respectively [3]. In comparison, median OS were 3.9-9.6 months with exclusive RT or TMZ [28] [30] [33] [48]. It is important to note that standard 6week chemoradiation has never been formally compared with hypofractionated chemoradiation.
Considering overall survival (MGMT methylated and unmethylated combined), the data of our study (median OS 11.7 months) compare favorably to the data by Perry et al [33] (median OS 9.3 months), with also comparable median age (74.1 years in our study versus 73 years Neurological de cits in elderly patients with GBM are sometimes used as a reason to avoid « aggressive » post-operative treatment. But this cohort of patients tolerated the treatment reasonably well. The presence of neurological disability at baseline was associated with neither worsened OS nor higher occurrence of early adverse neurological events. The presence of baseline neurological disability may re ect the extent of the surgical resection, and the survival was clearly improved in patients who had either a CR or a PR. Although often considered as a source of geriatric frailty, the presence of neurological disability alone should not be a reason for post-operative de-escalation.
Lastly, the treatment modalities and duration of treatment for the standard chemoradiation may respectively seem too heavy and too long compared to the life expectancy of elderly patients with GBM, but the overall survival in this study was actually similar to the life expectancy of younger patients with GBM. A surprising 81% of these elderly patients completed RCT. Only 28% of patients completed the full 6 cycles of maintenance temozolomide. However, around 50% of patients developed early adverse neurological events, which were correlated with lower OS as already described in the literature [9]. Various therapeutic options speci cally aimed at the elderly have emerged in this regard. Accelerated HFRT +/-TMZ is increasingly being used with signi cantly lower radiation doses but paradoxically comparable outcomes [28] [29] [30] [31] [32] [33]. The overall good tolerance and brain diffusion also make TMZ monotherapy an option [28] [48] [49], especially in the case of MGMT methylation [10] [11] [12]. The fear of therapeutic de-escalation arising from such protocols means they are not recommended for younger patients [26]. Some elderly patients could however appear suitable for the best and maybe most "aggressive" strategy, but reliable predictive biomarkers are lacking in order to identify which elderly patients would t into this category. The development of GBM-dedicated geriatric scales e.g. relying on the RPA classi cation, appears crucial for optimizing treatment algorithms [13] [14].
Our study has obvious limitations, mainly linked to its retrospective nature and the selection bias. The criteria for the patient selection in our study (ie based on the referral to our department for standard 6week chemoradiation) may seem unsatisfactory since not all the patients ≥ 70 years with GBM were thus analyzed. All the patients included have been considered t for 6-week chemoradiation mainly based on PS < 2 and before the implementation of a systematic geriatric assessment in our department. Nutrition and mood assessments are other important geriatric parameters, but the data were incomplete or missing from our recording. Speci c response assessment criteria in neuro-oncology (RANO) have been developed for GBM [50] but could not be used in our study because of the retrospective analysis. Overall prospective geriatric evaluation is needed to build GBM-dedicated treatment algorithms.

Conclusions
Standard 6-week chemoradiation was feasible for "real-life" elderly patients diagnosed with glioblastoma with unknown MGMT status, even in cases of post-operative neurological disabilities. GBM-dedicated geriatric scales are urgently needed to guide optimal therapeutics.

Declarations
Funding: Not applicable.
Con ict of interest: The authors declare that they have no known competing nancial interests or personal relationships that could have appeared to in uence the work reported in this paper.
Availability of data and material: Research data are stored in an institutional repository and will be shared upon request to the corresponding author.   Forest plot in univariate analysis for the occurrence of early adverse neurological events (de ned as the occurrence of intracranial hypertension symptoms and/or use of corticosteroids and/or hospitalization) for the subgroup of patients without neurological progression or death before the start of temozolamide maintenance (N = 103). RCT = radiochemotherapy; PS = performance status; C(P)R = complete (partial) resection; B = biopsy. Neurological disability = pre-RCT motor, visual, instability, cognitive or communication disability.