Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Regardless of ideal multidisciplinary treatment, including maximal surgical resection, followed by radiotherapy plus concomitant and maintenance temozolomide (TMZ), almost all patients experience tumor progression with nearly universal mortality and a median survival of less than 15 months. The addition of bevacizumab to standard treatment with TMZ revealed no increase in overall survival (OS) but improved progression-free survival (PFS). In newly diagnosed GBM, methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has been shown to predict response to alkylating agents, as well asgnosis. Therefore, MGMT promoter status may have a crucial role in the choice of single modality treatment in fragile elderly population. No standard of care is established in recurrent or progressive GBM. Treatment alternatives may include supportive care, surgery, re-irradiation, systemic therapies, and combined modality therapy. Despite numerous clinical trials, the identification of effective therapies is complex because of the lack of appropriate control arms, selection bias, small sample sizes, and disease heterogeneity. Tumor-treating fields plus TMZ represent a major advance in the field of GBM therapy, and should be considered for patients with newly diagnosed GBM with no contraindications. As a disease with such a poor prognosis, treatment of GBM should go beyond improving survival and aim at preserving and even improving the quality of life of both the patient and the caregiver.

Introduction

Glioblastoma (GBM) is the most common and devastating primary malignant brain tumor in adults, encompassing 16% of all primary brain and central nervous system neoplasms (1). Regardless of advanced diagnostic modalities and ideal multidisciplinary treatment that includes maximal surgical resection, followed by radiotherapy (RT) plus concomitant and maintenance temozolomide (TMZ) chemotherapy, almost all patients experience tumor progression with nearly universal mortality. The median survival from initial diagnosis is less than 15 months, with a 2-year survival rate of 26–33% (2, 3). The addition of bevacizumab to standard treatment revealed no increase in overall survival (OS), but improved progression-free survival (PFS). That finding caused considerable debate regarding whether the combination is cost-effective in first-line treatment (4, 5). In – newly diagnosed GBM (nGBM), methylation of O6-methylguanine-DNA methyltransferase (MGMT) promoter has been shown to predict response to alkylating agents; its status may play a crucial role in the choice of single modality treatment in fragile elderly population (6–8).

Currently, no standard of care is established for recurrent or progressive GBM (rGBM) (9). Despite numerous clinical trials, the identification of effective therapies is complex due to the lack of appropriate control arms, selection bias, small sample size, and disease heterogeneity (10). Treatment alternatives may include supportive care, reoperation, re-irradiation, systemic therapies, and combined modality therapy. Therapeutic options need to be carefully weighted, taking into account tumor size and location, previous treatments, age, Karnofsky performance score (KPS), patterns of relapse, and prognostic factors. The association of tumor-treating fields (TTFields) with TMZ represents the first major advance in the field of GBM therapy in approximately a decade and should be considered for newly diagnosed patients with no contraindications (11).As a disease with such a poor prognosis, treatment of GBM should go beyond improving survival and aim at preserving and even improving the quality of life (QoL) of both the patient and the caregiver.

Newly Diagnosed Glioblastoma

TARGETED THERAPY—IS THERE A PLACE IN NEWLY DIAGNOSED GLIOBLASTOMA?

Since GBM is one of the most vascularized tumors, antiangiogenic therapeutic strategies are very attractive. Bevacizumab is a monoclonal antibody that binds to circulating VEGF-A and inhibits its biological activity by preventing the interaction with the VEGF receptor. This leads to a reduction in endothelial proliferation and vascular growth within the tumor (52). Bevacizumab was approved by the FDA, based on unprecedented response rates (RRs) in rGBM, which led to its evaluation in the postoperative setting of nGBM (Table 1) (64, 65). Two large phase III, randomized, placebo-controlled trials, adding bevacizumab to standard treatment were conducted (4, 5). In the RTOG 0825 trial, median PFS was increased (10.7 vs. 7.3 months), although it did not reach the predefined significance level, and there was no difference in OS between the two treatment groups. The MGMT methylation status and recursive partitioning analysis (RPA) class were prognostic regardless of the study treatment. A decline in QoL and neurocognitive function (NCF) was more frequently observed with bevacizumab (5). In the AVAglio trial, there was a significant increase in PFS (10.6 vs. 6.2 months; P < 0.001), but not in OS. Baseline health-related QoL and PS were maintained longer in the bevacizumab group (4). Grade 3 or 4 toxicities occurred more often in the bevacizumab arms of both studies. In RTOG 0825, the crossover from placebo to bevacizumab, at disease progression, was planned and occurred in 48.3% of patients, and in AVAglio, the crossover was about 30%. This may have eliminated a potential survival benefit (4, 5). In both RTOG 0825 and AVAglio, efforts have been made to identify a subset of patients who could benefit from upfront treatment with bevacizumab, but no marker proved consistently effective in predicting either response or resistance to bevacizumab (4, 5).

TABLE 1

Clinical trials with bevacizumab in the newly diagnosed glioblastoma.

In summary, these trials have shown that the combination of bevacizumab with standard RT–TMZ for the treatment of nGBM resulted in improved median PFS, without gain in OS. Data regarding QoL and functional status are contradictory. Not surprisingly, there was an increase in adverse events associated with bevacizumab therapy. Cilengitide, a selective αvβ3-αvβ5-integrin inhibitor, had shown promising results in phase II trials, with more pronounced benefits in GBM with methylated MGMT promoter (66–68). Two prospective randomized trials evaluated the role of cilengitide in combination with standard treatment, in patients with a methylated MGMT gene promoter (CENTRIC) and in those with an unmethylated MGMT status (CORE). They both failed in demonstrating an OS gain (47, 48). Other agents, namely enzastaurin and temsirolimus, have been studied in phase II trials, without any improvement in OS or PFS (41).

Recurrent Glioblastoma

NITROSOUREA MONOTHERAPY AND COMBINATION REGIMENS

Nitrosoureas are DNA alkylating agents, namely carmustine (BCNU), lomustine (CCNU), nimustine (ACNU), and fotemustine. They are characterized by high lipophilicity and thus can cross the blood–brain barrier, making them useful in the treatment of brain tumors such as GBM (109). Table 2 summarizes nitrosourea-based trials in rGBM. Nitrosoureas, particularly BCNU, were the chemotherapeutic agents of choice for first-line treatment of GBM in the 1970s and 1980s. Based on two phase II trials, TMZ was approved for recurrent high-grade gliomas, and nitrosoureas were relocated into second-line therapy (126, 127). Two phase II trials and a retrospective study assessed the efficacy of BCNU monotherapy regimens in rGBM (110, 118, 125). They reported a PFS6 and a median OS of 13.0–17.5% and 5.1–7.5 months, respectively. RRs were limited and no complete remission was observed. The predominant side effects were hematologic and long-lasting hepatic and pulmonary toxicity. Although BCNU regimens have shown similar efficacy to other cytotoxic therapies, toxicity can be substantial, and the patient recovers slowly, such that the administration of other drugs in the case of further tumor progression can be infeasible (110). BCNU was also evaluated in combination with other agents, such as irinotecan and TMZ, in two phase II studies, with a median OS of 7.8–11.7 months (115, 116). These data demonstrate that BCNU is an effective agent in the treatment of rGBM, but at present its use in clinical practice is limited.

TABLE 2

Retrospective studies and clinical trials with nitrosourea in recurrent GBM (nitrosourea + bevacizumab combination studies are described in Table 4).

In a small retrospective study, with 32 patients pretreated with TMZ, ACNU was given alone (n = 14) or in combination with teniposide (n = 17) or cytarabine (n = 1), yielding a PFS6 of 20% and a median OS of 6.7 months (124). Hematological toxicity was substantial (grade 3 or 4 in 50% of patients). Three phase II–III randomized trials compared lomustine as monotherapy with investigational agents, namely enzastaurin, cediranib, or galunisertib (119–121). In all three trials, the results were comparable between arms, pointing toward relevant activity of the control arm or lack of efficacy of the investigational agent. PFS6 ranged from 11 to 34.5%, median OS from 6.6 to 9.8 months, and observed RRs were low (0–16%). Four prospective phase II trials, using different schedules of administration, evaluated fotemustine in TMZ pretreated patients at first recurrence/relapse of GBM (111–114). These four studies, encompassing 160 patients, showed a PFS6 of 20.9–61% and a median OS of 6 to 11 months. The best efficacy and toxicity profile was obtained with a low-dose induction regimen (fotemustine 80 mg/m² on days 1, 15, 30, 45, and 60, followed by a 4-week rest period) ensued by a maintenance therapy (80 mg/m² every 4 weeks) in nonprogressive patients (114). However, these data were derived from phase II trials with a small sample of patients. Phase III studies are required to determine the efficacy and safety of fotemustine, in the treatment of rGBM, after TMZ. The efficacy of PCV (procarbazine–lomustine–vincristine) was described in two retrospective studies (122, 123). They included 149 patients, of whom 16 received previous TMZ treatment. Similar results were described, with PFS6 of 29–38.4% and a median OS of 7.7–7.8 months. As expected, grade 3/4 hematologic toxicity was the most common (26%); pulmonary fibrosis was not reported (123). There is also suggestion that MGMT promoter methylation may be predictive of responsiveness to this class of agents (7, 128). In summary, different nitrosoureas show comparable efficacy in monotherapy, remaining an option in the treatment of rGBM. However, their toxicity profile, particularly hematological, limits the combination with other agents, as well as a more widespread use.

TEMOZOLOMIDE MONOTHERAPY AND COMBINATION REGIMENS

In both trials leading to the approval of TMZ, the sdTMZ schedule was used (126, 127). Four other prospective single-arm trials, all without previous TMZ treatment, used the same schedule and reached similar results with a PFS6 rate of 21–32% and a median OS of 7.0–9.9 months (129–132). Table 3 reviews TMZ-based trials in rGBM. Different schedules of TMZ were experimented to increase dose intensity, aimed at overcoming TMZ resistance by cumulative depletion of MGMT (165). The main alternative schedules were continuous low dose (40–50 mg/m² daily), 3 weeks on/1 week off (75–100 mg/m² for 21 days every 28 days), 1 week on/1 week off (150 mg/m² for 7 days every 14 days), but other dose-dense schedules are described (133–145). The toxicity profile did not vary between the different schemes. Besides the fact that the studies did not have a comparator arm, the heterogeneity in the inclusion criteria, regarding the number of recurrences and previous treatments, limits the comparison of efficacy data. The RESCUE phase II trial examined the best timing for TMZ rechallenge, by prospectively dividing the 91 GBM patients into three groups, according to the “TMZ-free interval”: early group (progression during the first six cycles of adjuvant TMZ); extended group (progression while receiving extended adjuvant TMZ, beyond the standard six cycles, but before completion of adjuvant treatment); and rechallenge group (progression after completion of adjuvant treatment and a treatment-free interval greater than 2 months). The “early” and “rechallenge” groups, respectively, showed comparable PFS6 rates of 27.3% and 35.7%, with median PFS of 3.6 and 3.7 months, experiencing most benefit than the “extended group” (PFS6 of 7.4%, median PFS of 1.8 months). The authors considered the possibility that the PFS6 results in the “early” group could be attributable to pseudoprogression (140).

TABLE 3

Retrospective studies and clinical trials with temozolomide in recurrent GBM (temozolomide + nitrosourea combination studies are described in Table 2).

Four randomized phase II clinical trials were conducted using single-agent TMZ (127, 159, 166, 167). A randomized trial comparing sdTMZ with procarbazine, in TMZ-naive patients, revealed a PFS6 of 21% versus 8%, with a median OS 1.5 months longer in the TMZ arm (127). Brada et al. compared two different TMZ schedules with PCV, before TMZ became first-line standard, in patients with recurrent high-grade glioma (no separate data for GBM patients were provided) (166). In this trial, TMZ (both arms combined) did not display a clear benefit compared with PCV. It also showed that TMZ dose-intense regimens do not provide a survival or PFS benefit compared with standard doses, in the treatment of TMZ-naive patients. The DIRECTOR trial compared two dose-dense regimens of TMZ (120 mg/m²/day, 1 week on/1 week off versus 80 mg/m²/day, 3 weeks on/1 week off), in patients with GBM at first progression, after TMZ chemoradiotherapy and at least two maintenance TMZ cycles (160). The outcome was comparable between arms regarding efficacy, safety, and tolerability. The most important result of this trial was the strong prognostic role of the MGMT promoter methylation status in patients rechallenged with TMZ. PFS6 was increased by 5.8-fold (39.7 % in patients with methylated MGMT versus 6.9 % in unmethylated tumours), and OS at 12 months by 2.4-fold. Also, a significantly improved outcome was demonstrated in patients with an interval above 2 months from previous TMZ, and largely confined to patients with MGMT methylated promoter (160). Wick et al. conducted a retrospective review of 80 patients with recurrent glioma (45 with GBM) rechallenged with various TMZ schedules (163). Upon progression, those who had stable disease and a TMZ-free interval of at least 8 weeks were treated with the same or an alternative regimen of TMZ; the group progressing under TMZ received an alternative regimen. The efficacy results were comparable between groups and no clear evidence of cumulative toxicity has emerged (163). Considering the small numbers of patients in most studies and the wide range of TMZ regimens tested, there was no evidence that one metronomic schedule was superior over the other in terms of efficacy or safety. Numerous other studies evaluated TMZ-based combination regimens in rGBM but have failed to deliver conclusive efficacy beyond single-agent activity of TMZ. Those combination partners prospectively evaluated in single-arm designs were bevacizumab, interferon-α2b, sorafenib, O6-benzylguanine, irinotecan, cisplatin, liposomal doxorubicine, and ABT-414 (146–156, 158).

BEVACIZUMAB MONOTHERAPY AND COMBINATION REGIMENS

The first documented use of bevacizumab in GBM was a small series of patients with rGBM treated by Stark-Vance et al. (Table 4) (168). The authors used the combination of bevacizumab with irinotecan, which showed activity, with acceptable toxicity profile. Several prospective phase II studies were subsequently conducted. Two phase II studies, by Vredenburg et al., using the same combination, achieved a RR of 57–60.9%, PFS6 rate of 30–46%, and a median OS of 9 to 10 months (171, 172). Previous reports on salvage therapy for rGBM showed inferior efficacy results, with RR of 5–10%, PFS6 rate of 9–25%, and median OS of 5 to 6 months (108, 202, 203). In 2009, FDA approved bevacizumab for patients with rGBM, based on the results of two phase II prospective studies (64, 65). However, in Europe, bevacizumab was not approved because of lack of a bevacizumab-free control arm. The BRAIN study, a phase II noncomparative trial, randomized patients to bevacizumab plus irinotecan or bevacizumab monotherapy (64). RR was 37.8 and 28.2% for the combination and monotherapy arms, respectively, and PFS6 was similar between the groups (50.3 and 42.6%), which compared favorably with historical controls. Numerous other retrospective studies addressing the combination of bevacizumab plus irinotecan described similar results (191–193, 196, 199, 201). Several phase II trials evaluated the combination of irinotecan with bevacizumab, and two trials added a third combination partner, cetuximab or carboplatin (171–173, 176, 178, 179). RR ranged from 25 to 60.9%, PFS6 between 28 and 46.5%, and median OS between 6.7 and 9.7 months. A retrospective analysis by Nghiemphu et al. compared two groups: one with bevacizumab in combination with different chemotherapy agents, and the other, a control group, without bevacizumab. The authors found a significant improvement in PFS (P = 0.01) and OS (P = 0.04) in favor of the group treated with bevacizumab (195).

TABLE 4

Retrospective studies and clinical trials with bevacizumab in recurrent GBM.

Numerous studies have assessed bevacizumab in combination with other agents, namely etoposide, TMZ, fotemustine, dasatinib, temsirolimus, erlotinib, sorafenib, panobinostat, or vorinostat (154, 158, 175, 177, 179–181, 183, 184, 187–189). In randomized trials involving two arms—one with bevacizumab in combination with experimental agents (irinotecan, carboplatin, vorinostat, or dasatinib) and the other with bevacizumab alone—it was found that both arms showed comparable efficacy, leading to the conclusion of poor efficacy of the experimental agent, without valid evidence regarding the single-agent activity of bevacizumab. A recent Dutch, open-label, three-group multicenter phase II trial (BELOB) reported promising results with bevacizumab combined with lomustine (128). Improved OS at 9 months (59% vs. 43% vs. 38%) and PFS6 (41% vs. 13% vs. 16%) were seen in the combination arm compared with single-agent lomustine and single-agent bevacizumab, respectively. Effectively, this was the first trial with bevacizumab in rGBM to demonstrate an improvement in a primary OS endpoint, suggesting increased effectiveness with the combination of bevacizumab and lomustine versus each of these agents alone. Therefore, a randomized phase III trial was performed, comparing bevacizumab–lomustine with single-agent lomustine (189). Unfortunately, a benefit in OS was not observed, while the improvement in PFS for the combination arm was maintained. A crossover to bevacizumab occurred in 35.5% of patients, which may account for these results. To evaluate the efficacy of bevacizumab beyond the second-line treatment, Piccioni et al. performed a retrospective analysis of 468 GBM patients treated at different recurrences (first, second, third, or more), including 80 who were treated upfront. The authors found that PFS and OS were similar for all three recurrence groups (median 4.1 and 9.8 months, respectively) (204). These data suggest that bevacizumab could have a role in the treatment of GBM independent of the line of therapy, and that a deferred use of bevacizumab seems not to decrease effectiveness. When comparing the results of available phase II trials on bevacizumab, alone or in combination with irinotecan, with those of standard cytotoxic chemotherapy, in rGBM, several findings are clear: bevacizumab alone has activity and increases RR, PFS6, and median PFS; on the other hand, the impact on OS is less clear.

Tumor-Treating Electric Fields for Glioblastoma

Glioblastoma in the Elderly

GBM is diagnosed at a median age of 64 years, and the incidence peaks between 75 and 84 years (15.24/100,000) (211). With aging population, this incidence is expected to increase. The poor survival rates associated with GBM (about 5% at 5 years) get even poorer in patients over 65 years (less than 2.1% at 5 years) (212). Age has long been recognized as the most important prognostic factor. Elderly patients tend to have more comorbidities and worse PS than their younger counterparts diagnosed with GBM. Similarly, their tumors seldom have favorable molecular features (IDH mutations occur in less than 2% of the tumors) (213). As a result, these patients have frequently been undertreated and underrepresented in clinical trials.

Supportive Care

The patient with GBM is, simultaneously, a patient with cancer and one with a progressive neurological disease. As such, there are certain specificities regarding not only the most frequent symptoms exhibited but also some end-of-life (EOL) care issues. Patients with primary brain tumors were found to have poorer PS, higher levels of nursing and social support, and more family overburden than other palliative care patients. Disorientation and confusion were also more frequent. Conversely, general EOL symptoms, such as dyspnoea, nausea, vomiting, anorexia, constipation, and pain, were experienced less frequently (227). Palliative care should aim at improving QoL, both for the patient and the caregiver, and is not limited to the EOL stage. The timing of its introduction, in the management of GBM patients, is an understudied issue. The experience with metastatic nonsmall cell lung cancer indicates improvements in QoL, mood, and symptom burden, as well as better EOL care and even extended survival, with early initiation of palliative care (228). Disease itself, along with GBM treatment side effects and symptomatic medication (namely antiepileptic drugs), affects cognition and impairs decision-making, very often early in the disease course (229, 230). As such, timely involvement of the patient in treatment decisions (including supportive measures ahead) is of paramount importance. Two systematic reviews of studies addressing the EOL phase, in high-grade gliomas, showed a high burden of symptoms, namely reduced consciousness (44–90%), dysphagia (10–85%), headache (36–62%), seizures (10–56%), focal neurological deficits (>50%), cognitive disturbances (>30%), confusion (15–51%), and poor communication (64–90%) (227, 231–236).

Conclusion

Despite maximal safe surgical resection and combined chemotherapy and RT, GBM retains a poor prognostic value. To date, excluding TTFields, no new agents improve survival when added to standard therapy. Although MGMT promoter methylation is predictive of response to TMZ, its role in the choice of first-line therapy is currently limited to the elderly GMB patients. No standard of care is established in the recurrent setting. Bevacizumab clearly impacts PFS, although its role in OS is less certain. TMZ rechallenge is a treatment option, especially for MGMT promoter-methylated rGBM. All in all, while efforts are being put in strategies to prolong OS, enhancing QoL for these patients must be a priority.

Conflict of interest: The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this manuscript.

Copyright and permission statement: We confirm that the materials included in this chapter do not violate copyright laws. Where relevant, appropriate permissions have been obtained from the original copyright holder(s). All original sources have been appropriately acknowledged and/or referenced.

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Doi: http://dx​.doi.org/10​.15586/codon.glioblastoma.2017.ch11