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Recurrent Glioblastoma Treatment: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Francesco Carbone.

The treatment guidelines for the management of recurrent glioblastoma (rGBM) are far from definitive, and the prognosis remains dismal. Despite recent advancements in the pharmacological and surgical fields, numerous doubts persist concerning the optimal strategy that clinicians should adopt for patients who fail the first lines of treatment and present signs of progressive disease. With most recurrences being located within the margins of the previously resected lesion, a comprehensive molecular and genetic profiling of rGBM revealed substantial differences compared with newly diagnosed disease.

  • recurrent glioblastoma
  • brain tumor
  • glioblastoma treatment
  • chemotherapy
  • regorafenib
  • target therapy
  • immunotherapy

1. Introduction

Glioblastoma (GBM) represents the most common, yet deadly, brain tumor in the adult population. Despite novel surgical and pharmacological treatments, its prognosis remains dismal, with the median survival not exceeding 14 months and the 5-year mortality rate being 97% [1]. Currently, the standard of care (SOC) for newly diagnosed patients (Stupp’s protocol) comprises gross total surgical resection (GTR) followed by radiation therapy (RT) plus concomitant chemotherapy (CT) with temozolomide (TMZ) for six weeks and adjuvant chemotherapy of six cycles with an alkylating agent [2]. Nevertheless, an analysis of patients treated by such a protocol showed no significant reduction in the recurrence rates between individuals treated with RT alone and RT plus concomitant and adjuvant CT, suggesting that combination therapy, although effectively reducing tumor aggressiveness at the initial stage, does not significantly alter the disease course [3]. Therefore, the management of recurrent GBM (rGBM) continues to challenge neurosurgeons and neuro-oncologists, since no standard treatment has yet been validated, and solely empirical indications exist (Figure 1).
Figure 1.
Current diagnostic and therapeutic management for rGBM.
The recurrence of high-grade gliomas is nearly ubiquitous [4], with most recurrences presenting within 2 cm of the initial tumor margin [5] and approximately one-third of rGBMs resurging in the contralateral hemisphere, a different lobe, and rarely infratentorially [6]. Attempts to compare the genomic and molecular profiles of primary GBM (pGBM) with rGBM have largely demonstrated inconsistencies and significant disparities between the two tumors that therefore appear as separate molecular entities [7]. This confounding factor could be the reason why targeted molecular therapies have partially failed to achieve auspicated results, such as those obtained for non-small-cell lung cancer and colorectal cancer [8,9][8][9]. Notwithstanding the urgent need to investigate rGBM’s molecular profile to elucidate its unique features, current studies mostly focus on pGBM, possibly due to the scarce tissue accessibility and availability of rGBM. As a matter of fact, only 30% of recurrences are surgically treated, and most patients succumb during the first cycle of adjuvant chemotherapy due to an undiagnosed recurrence [10,11][10][11].

2. Locoregional Treatment of rGBM

Less than 50% of newly diagnosed patients with pGBM are deemed eligible for radical or cytoreductive surgery due to tumor inoperability or poor candidacy for surgery [14][12]. These numbers drop even lower for patients presenting with rGBM, where reintervention rates do not exceed 30%, with some studies reporting the ability to perform a second surgery in less than 10% of patients [15,16][13][14]. In addition, even when feasible, the impact of repeat surgery on prognosis remains controversial [17][15]. In their comprehensive review, Robin et al. [18][16] examined previously reported findings for a total of 2717 patients undergoing a second or third surgery for rGBM. Among the 33 studies considered, only 20 saw a role for reoperation in the case of progressive GBM, whereas ten studies saw either no benefit from reoperation or adopted alternative treatment strategies, including radiation therapy and chemotherapy. Finally, amid the abovementioned publications that contemplated repeat surgery for rGBM, thirteen articles with the addition of three other reports deemed the extent of resection of both initial and second surgery to be of prognostic value. Despite there being less available evidence for rGBM when compared with pGBM, GTR is estimated to provide a similar survival benefit of 3–5 months in both cases [19][17]. This could be associated with the generally accepted knowledge that less residual tumor corresponds to longer PFS; nonetheless, it should be considered that patients elected for reoperation are relatively fitter and present higher Karnofsky scores (KPS) when compared with non-eligible patients [19][17]. Furthermore, reoperation for rGBM has been associated with higher complication rates for morbidity (13–69%) and mortality (0–11%), precluding further treatment options, such as systemic chemotherapy, due to insufficient postoperative performance status [15,18,20][13][16][18]. As a consequence, more attention is given to minimally invasive salvage techniques, such as stereotactic radiotherapy (SRT), which represents a viable treatment option, especially in patients with long time-to-recurrence. Recently, Yaprak et al. [21][19] showed the benefits of SRT in a cohort of 42 patients diagnosed with rGBM following a first-line treatment consisting of resective surgery plus adjuvant TMZ and radiation therapy, who underwent salvage stereotactic treatment. With a median of three fractions at a prescription dose of 20 Gy (range, 18–30), the group was able to demonstrate a statistically significant difference in the survival time between the SRT-treated population (mean, 30 months; range, 9–123) and the patients who could not receive SRT (mean, 14 months; range, 1–111) (p = 0.001). Despite growing evidence and promising results, locoregional therapy for rGBM does not yield the desired benefits, also since no targeted surgical or radiotherapy protocols have been proposed based on the biological features hosted by this malignancy so far.

3. Molecular Footprints of rGBM

Similar to the advancements witnessed in the fields of oncology, immunology, and dermatology, neuro-oncological treatments have recently shifted from unspecific protocols based on cytotoxic systemic drugs toward a more precise and patient-specific approach. The search for targeted and safer therapies has heightened the urgent need for preclinical and clinical studies on pGBM and progressive GBM models and patients to gather practical insights that could lead to better drug engineering and assure multiple pharmacological options for different molecular subtypes. As highlighted by the 2021 WHO classification of brain tumors, the classification paradigm once based solely on histological, immunohistochemical, and radiological appearance characterizing the lesion now integrates previous models with molecular tumor profiling technologies for the recognition of its distinctive and patient-specific footprints, which appear to be better markers of prognostic and therapeutical value [22][20]. In the following section, a summary of the peculiar molecular trademarks of rGBM is presented, along with a description of the latest pharmacological advancements, taking advantage of recent knowledge gained from preclinical and clinical studies.

3.1. O-6Methylguanine-DNA Methyltransferase

Although the DNA repair protein O-6Methylguanine-DNA methyltransferase (MGMT) gene is ubiquitously expressed throughout most human tissues, the regulation of protein production varies greatly based on the degree of epigenetic silencing through gene promoter methylation. Given the ability of MGMT to encode a DNA-repair protein that is established to reduce the therapeutic effects of alkylating agents (i.e., TMZ), its methylation and, therefore, its suppression have long been considered a positive predictive factor of treatment response and OS in patients diagnosed with pGBM [23,24,25,26][21][22][23][24]. Furthermore, the silencing or downregulation of MGMT, occurring in 45% of GBMs, appears to correlate with post-recurrence survival, with MGMT-promoter methylated patients showing longer survival times than their unmethylated counterparts (mean, 3–4 months) [27,28,29][25][26][27]. Given the high genetic variability that exists between pGBM and rGBM, it is worth mentioning that the epigenetic silencing of MGMT is preserved through tumor progression in 70–90% of cases, thereby serving as a relatively stable prognostic marker [30,31][28][29]. In their meta-analysis of clinical trials, Binabaj et al. [26][24] reported a significant correlation between OS and MGMT promoter methylation assessed with univariate analysis (p = 0.001), although PFS was not observed to be related to MGMT silencing in the 10 studies explored. On the other hand, Cantero et al. [32][30] showed that MGMT methylation, along with isocitrate dehydrogenase (IDH) mutation, is not detected in a notable proportion of long-term survivors examined by next-generation sequencing, leaving concerns over its prognostic value. Notwithstanding the controversial prognostic significance, MGMT remains an attractive molecular marker for systemic chemotherapy for both pGBM and rGBM. As a matter of fact, TMZ, an alkylating agent capable of adding alkyl groups to guanines, represents the current standard chemotherapy treatment for newly diagnosed GBM, and it is administered as a concomitant therapy to surgical resection followed by adjuvant TMZ maintenance for six cycles, showing significantly better results in MGMT-methylated populations across various studies [33,34,35][31][32][33]. Recent evidence also advocates for MGMT promoter methylation as a predictive biomarker reflecting treatment response to alkylating agents in progressive disease. For instance, the AVAREG trial, assessing fotemustine and bevacizumab, and the BELOB trial, assessing the role of single-agent bevacizumab/lomustine or a combination of the two in patients with rGBM, confirmed the predictive value of MGMT silencing in the estimation of OS in this population [36,37,38][34][35][36]. For patients that do not present MGMT promoter methylation, however, new ways to improve response rates are currently under review. A phase-II trial investigating the role of O(6)-benzylguanine in adults with progressive, TMZ-resistant gliomas reported favorable results for anaplastic glioma, but was rather inconclusive in the case of rGBM, notwithstanding the relatively high hematopoietic toxicity of this combination, therefore prompting further research for the assessment of the real-life role of this irreversible inhibitor of the DNA repair protein coded by the MGMT gene [38][36]. In a recent study, Yamada et al. [39][37] demonstrated the time- and dose-dependent role of riluzole, a metabotropic glutamate receptor 1 inhibitor, in slowing the growth of human GBM cell lines. Moreover, they showed the independent ability of riluzole to suppress MGMT expression in MGMT methylated cells and TMZ-induced MGMT upregulation (p < 0.01).

3.2. Vascular Endothelial Growth Factor

Another distinctive molecular feature of rGBM is represented by the overexpression of vascular endothelial growth factor (VEGF). Through the activation of peculiar molecular pathways, this protein plays a crucial role in regulating complex biochemical mechanisms, including the proliferation, migration, and differentiation of vascular endothelial cells following hypoxic stress [38,39,40,41][36][37][38][39]. Its overexpression is considered pivotal in GBM progression, and the inhibition of various components of the angiogenetic axis has, therefore, been extensively investigated in various clinical trials. Bevacizumab, a VEGF-A targeting monoclonal antibodies, was the first drug to be approved for the treatment of newly diagnosed and progressive GBM for its ability to downregulate VEGF expression [36][34]. Although bevacizumab alone did not significantly improve OS in rGBM when compared with lomustine [28][26], various trials have investigated the possibility of adding cetuximab, tandutinib, and sorafenib, a chimeric antibody targeting the epidermal growth factor receptor (EGFR), a platelet-derived growth factor receptor (PDGFR), and VEGF receptor (R), respectively, to improve survival rates and PFS. Unfortunately, these phase-II trials failed to show statistical significance, since these combinations achieved similar results to bevacizumab alone [42,43,44][40][41][42]. D’alessandris et al. recently conducted a triple-armed, prospective cohort study investigating the administration of bevacizumab alone or in combination with erlotinib or sirolimus, taking into consideration the tissutal expression of VEGF, epidermal growth factor receptor variant III (EGFRvIII), and phosphatase and tensin homolog (PTEN) in patients presenting with rGBM [45][43]. They were able to demonstrate higher clinical benefits (mean, 71% of patients) than those achieved in the EORTC 2016 trial in terms of PFS at 6 and 12 months [28][26]. These results showed that a personalized therapy tailored to the molecular and genetic profile of rGBM could sensibly improve patients’ outcomes and should, therefore, become SOC after the foreseen randomized controlled trials (RCTs).

3.3. Epidermal Growth Factor Receptor

EGFR belongs to the family of erythroblastic oncogene B (ErbB) transmembrane tyrosine kinase receptors and is known to regulate a complex signaling cascade driving cell proliferation, differentiation, division, and survival [43,44,45,46,47,48][41][42][43][44][45][46]. Its role in oncogenesis and progression has been confirmed in various types of solid tumors, and its pharmacological regulation is currently SOC for several of these malignancies [49,50][47][48]. Since the first description of gene amplification and overexpression in human GBM in 1985 [51][49], EGFR structure and regulating function, along with its most-frequently mutated form (EGFRvIII), have been the focus of both pre- and clinical trials exploring different drug generations [52,53][50][51]. Nonetheless, despite gene amplification being reported in more than half of GBMs [54][52], promising early results have failed to keep up with expectations. As a matter of fact, first-generation EGFR inhibitors (erlotinib and lapatinib) that compete with ATP, thus blocking the activation of the receptor, as well as second-generation drugs, including afatinib and dacomitinib, that irreversibly bind the tyrosine kinase domain demonstrated only limited efficacy in phase-II clinical trials [55,56,57,58][53][54][55][56]. Future directions involve third-generation irreversible EGFR inhibitors, such as osimertinib and rociletinib, which are currently under investigation in phase-II RCT in EGFR-activated rGBM (NCT03732352). Interesting results were shown by the INTELLANCE-2/EORTC 1410 study [59][57]. In this randomized phase-II study, the role of depatuxizumab mafodotin (Depatux-M), an antibody conjugated with toxin monomethylauristatin-F that inhibits microtubule polymerization in EGFR-amplified rGBMs was investigated as the sole agent or in combination with TMZ versus SOC with Lomustine or TMZ in progressive EGFR-positive GBM. Although the primary endpoint of efficacy was not achieved at a 15-month follow-up, the combined administration showed a positive trend with regard to survival at longer follow-up times (28.7 months), with a statistically significant difference in OS between the two arms (hazard ratio, 0.66) and corneal epitheliopathy being reported as the most common adverse effect (25% of cases).

3.4. Telomerase Reverse Transcriptase

Mutations of the telomerase reverse transcriptase (TERT) promoter show the highest retention rates from pGBM to rGBM (~90%) among several genetic abnormalities investigated to date [27,60][25][58]. Encoding a catalytic subunit of the enzyme telomerase, TERT controls a rate-limiting de novo addition of telomere repeats at chromosomal ends, serving as a prognostic factor for pGBM and progressive disease [61][59]. As a matter of fact, TERT promoter mutation, in combination with IDH wild-type status, has been demonstrated to correlate with poor OS in patients with primary and rGBM [61,62,63][59][60][61]. Despite rGBM frequently hosting TERT promoter mutations supporting tumor cells’ immortalization, the pharmacological inhibition of TERT abnormal transcription has not yet been considered for extensive investigation, let alone sparse preclinical studies on GBM models [64,65,66][62][63][64].

3.5. Platelet-Derived Growth Factor Receptor

Platelet-derived growth factor receptors (PDGFRs) are tyrosine kinase receptors located on the cell’s surface, exploiting their regulatory role in cell proliferation, cellular differentiation, cell growth, development, and promoting tumor growth through autocrine stimulation [67][65]. For more than twenty years, the hyperexpression of PDGFRɑ (one of the four types of receptors belonging to this family) has been considered an initiating event in the development of gliomas, particularly in high-grade tumors [68][66]. To elucidate a possible therapeutic benefit derived from the inhibition of PDGFR-mediated activity, several RCTs have been conducted exploring imatinib, a tyrosine kinase inhibitor, alone or in combination with hydroxyurea [69,70,71][67][68][69]. However, apart from a few promising therapeutic results, cases of intratumoral hemorrhage, possibly due to iatrogenic pericyte recruitment, as well as the lack of sound efficacy, suggest that new ways to benefit from PDGFR-dependent metabolic processes regulation are warranted.

3.6. Regorafenib, a Multi-Targeted Tyrosine Kinase Inhibitor

Regorafenib is an oral multikinase receptor inhibitor regulating different molecular pathways, including tyrosine kinase receptor with immunoglobulin and EGF homology domain 2 (TIE2), proto-oncogene receptor tyrosine kinase (KIT), rearranged during transfection gene (RET), VEGFR1–3, PDGFR, proto-oncogene, serine/threonine kinase 1 (RAF1), fibroblast growth factor receptor 3 (FGFR), and proto-oncogene, serine/threonine kinase (BRAF). It is currently a viable option as a monotherapy for the treatment of gastrointestinal stromal tumors, colorectal cancer, and hepatocellular carcinoma [72,73,74][70][71][72]. Since its first preclinical assessment by Wilhelm et al. [75][73] in 2011, the administration of regorafenib in animal models and patients with rGBM has been evaluated either as a single therapy or in combination with other agents, such as lapatinib, sorafenib, and lomustine [76,77,78][74][75][76]. In line with the previously reported promising results, Lombardi et al. [79][77] aimed to investigate the efficacy and safety of regorafenib, comparing it against lomustine in patients with documented disease progression after surgical resection followed by radiotherapy and TMZ chemoradiotherapy. Their randomized, multicentric, open-label, phase-2 trial demonstrated a statistically significantly longer OS in patients treated with regorafenib, with similar results with regard to PFS and disease control. Nonetheless, the difference in quality of life did not show statistical significance between the two arms. It is worth mentioning that these results refer to patients with higher KPS, as usually seen in clinical practice, since the trial only enrolled subjects with performance status scores ≥ 70. After the REGOMA trial, the National Coalition for Cancer Survivorship (NCCS) 2021 guidelines followed the AIOM and included regorafenib as the first line of pharmacological treatment in patients with progressive disease [80,81][78][79]. Recently, a large monocentric, real-life retrospective study further reported promising results with the administration of regorafenib as monotherapy, with grade-3 drug-related adverse events occurring in 18% of patients, and one patient (2%) reporting a grade-4 adverse event (maculopapular rash) [82][80].

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