Reirradiation versus systemic therapy versus combination therapy for recurrent high-grade glioma: a systematic review and meta-analysis of survival and toxicity

High-grade gliomas (HGG) consist of glioblastoma multiforme (GBM) and anaplastic gliomas (anaplastic astrocytoma and anaplastic oligodendroglioma) [1]. Most HGGs are managed with a multimodal approach, incorporating maximal safe surgical resection, postoperative radiotherapy and temozolomide [2]. Despite this, HGGs have a poor prognosis with a median overall survival (OS) of 15 months and nearly all patients experiencing tumour recurrence [3]. Treatment options for recurrent HGG (rHGG) are limited and include reoperation, reirradiation (reRT), second-line chemotherapy, or a combination of these [4].

Notably, 90% of recurrences occur within 2 cm of the original tumour site, suggesting the need for improved local control [5]. To control local progression, surgical resection is one treatment option, with a median reported OS of 9.7 months. However, only 20–30% of patients with recurrent or progressive disease have resectable lesions, and reoperation is often limited by performance status and diffuse, infiltrative disease involving eloquent areas [4].

ReRT is another localised treatment option for recurrent or progressive disease. It generally benefits patients with a good performance status (KPS > 60), localised/unifocal disease, and a time interval between initial radiation and reRT of at least 6 months [6, 7]. Retrospective data suggests that reRT is safe and provides improved local control [8], with a median reported OS of 7.5–16 months [6] and an OS-12 rate of 36% in recurrent GBM (rGBM) [9]. ReRT is controversial given the tendency for in/near-field recurrences, and hence the increased risk for radiation necrosis (RN) from cumulative dose. The reported incidence of RN following reRT is 0–31.3% [10]. Risk factors associated with RN include fractionation schedule, dose (cumulative EQD2), treatment volume, time interval between initial radiation and reRT, and concomitant systemic therapy. Three external beam radiotherapy techniques are used based on fractionation schedule; stereotactic radiosurgery (SRS), hypofractionated stereotactic radiotherapy (HFSRT), and conventionally fractionated radiotherapy (conventional RT) [7].

Second-line chemotherapy is commonly required for durable tumour control. Literature reports a median OS of 6–9 months in patients with rGBM treated with salvage chemotherapy. No single agent or combination of systemic therapies has demonstrated superiority to the others [11‐13]. Bevacizumab has demonstrated efficacy in delaying tumour progression, albeit without an OS improvement, and hence has been approved by the FDA for treatment of rGBM [14]. Nevertheless, most patients with rHGG progress on bevacizumab after a median time of 3–5 months [15].

Several retrospective studies report the safety and efficacy of combining reRT with bevacizumab [16]. In a network meta-analysis of treatment options for progressive or rGBM, McBain et al. found limited evidence suggesting reRT with or without bevacizumab may improve survival in select individuals [17]. Bevacizumab is further postulated to reduce radioresistance and to lower the incidence of RN [18]. Temozolomide has also been studied in combination with reRT in rHGG due to its radio-sensitizing effect [19]. However, its value in this setting is uncertain given its widespread use in initial treatment and possible subsequent resistance [20].

Combination therapy with localised treatment and systemic therapy allows for the simultaneous targeting of macroscopic, microscopic, and diffuse disease, and hence may result in improvements in OS and progression-free survival (PFS). However, as the treatment of rHGG is of palliative intent, cumulative treatment-related toxicities must be balanced with the potential impact of disease progression on quality of life (QoL). This review aims to compare the impact of reRT, systemic therapy and combination therapy (reRT & systemic therapy) with regards to OS, PFS, adverse effects (AEs), and quality of life (QoL) in patients with rHGG.

This review was conducted in accordance with PRISMA guidelines.

Compared to reRT alone, combination therapy improved OS and PFS. While there was insufficient information to conduct a meta-analysis comparing AEs, Kazmi et al. reported no significant differences in toxicity between reRT alone and combination therapy (5% vs 9% respectively, p = 0.22) [9]. Further RCTs are required to confirm the survival benefit and safety of combination therapy compared to reRT alone.

Particularly, the addition of bevacizumab to reRT with/without non-bevacizumab-based systemic therapy improved OS and PFS and reduced RN. Grade 3 + AEs were also lower with bevacizumab compared to without (0–10% vs 0–50%, respectively), largely secondary to decreased rates of Grade 3 + RN. These findings differ from the AVAglio [55] and RTOG 0825 [56] trials which explored the supplementation of the Stupp protocol [2] with bevacizumab in primary GBM. Both RCTs found bevacizumab resulted in a PFS improvement and a modest increase in grade 3 + AEs. However, as neither trial demonstrated an OS benefit, bevacizumab is not routinely used for primary GBM. Bevacizumab is, however, commonly utilised for recurrent GBM in the absence of proven OS benefits due to reported PFS improvements and steroid sparing effects, both which are postulated to improve QoL [14]. This review supports further investigation into the addition of bevacizumab to reRT in the recurrent HGG context given the demonstrated OS and PFS improvements and lower rates of grade 3 + AEs secondary to decreased rates of grade 3 + RN.

The addition of bevacizumab to reRT may also allow for safe dose escalation and for the treatment of larger volume disease due to its radioprotective properties. While bevacizumab is routinely used for the treatment of RN [57], it is not regularly used as a prophylactic agent [18]. In 2012, Sminia and Mayer found that RN occurred with a cumulative EQD2 dose > 100 Gy for conventional RT, > 105 Gy for HFSRT, and > 135 Gy for SRS. [58] In this review, 17 studies reported RN rates ranging from 0 to 9.5% (Supplementary Material; Table 2). 9 of these 17 studies escalated their cumulative EQD2 (a/b = 2) beyond Sminia and Mayer’s recommendation. Importantly, of these 9 studies, the rate of RN in the subset of patients that received bevacizumab with reRT was 0%, while the rate of RN in the subset of patients that did not receive bevacizumab ranged from 4.3 to 25.0%. Hence, bevacizumab may allow for safe dose escalation with acceptable rates of RN. Further studies are required to confirm if dose escalation confers improved local control or survival outcomes. RN is also a concern in the treatment of large volume disease. In 2021, Minniti et al. recommended SRS or high dose HFSRT (≥ 5 Gy/#) for smaller volume tumours (≤ 15 cc), high-dose HFSRT (≥ 5 Gy/#) for 8.5–34 cc tumours, and conventional RT or moderately HFSRT (1.8–3.5 Gy/#) for larger tumours (33–145 cc) to appreciate a low risk of RN [7]. In this review, 10 of 17 studies reporting RN rates also reported median PTV (Supplementary Material; Table 2). Of these 10 studies, 8 had median PTV > 34 cc. Importantly, in these 8 studies, the rate of RN in the subset of patients that received bevacizumab with reRT ranged from 0 to 4.8%, while the rate of RN in the subset of patients that did not receive bevacizumab ranged from 0 to 66.7%. Notably, all 8 studies utilised conventional RT or moderately HF-SRT, as recommended by Minniti et al. for larger volume tumours. Hence, reRT with concomitant bevacizumab may allow for the safer treatment of larger volume disease with acceptable rates of RN, particularly if the appropriate fractionation schedule is utilised.

Compared to systemic therapy alone, combination therapy (particularly with bevacizumab-based systemic therapy) improved OS and PFS with no difference in grade 3 + AEs. Two RCTs investigated bevacizumab with/without reRT in rHGG [27, 33]. Tsien et al. [27] compared bevacizumab with/without HFSRT (35 Gy/10#) in patients with bevacizumab-naïve rGBM. The study found that HFSRT improved PFS and 6-month PFS rates, though no improvements in OS were observed. However, due to low accrual, the study was amended to extend eligibility resulting in the inclusion of a large number of patients less likely to experience a survival benefit from focal HFSRT. Bergman et al. [33] compared bevacizumab-based systemic therapy with/without intervening HFSRT (32 Gy/4#) in patients with bevacizumab-resistant rHGG. Patients assigned to intervening HFSRT reported improved PFS and a nonsignificant improvement in OS, despite the study also failing to meet accrual goals to detect an OS difference. Interestingly, while Bergman et al. targeted FLAIR abnormalities in their CTV delineation, Tsien et al. did not. FLAIR abnormalities are non-enhancing regions that likely contain microscopic disease. Studies targeting FLAIR abnormalities have demonstrated improved locoregional control, suggesting that the deterioration of patients with rGBM may be due to insufficient reRT dose to these regions [59]. Further RCTs comparing systemic therapy with combination therapy, particularly with bevacizumab-based systemic therapy, are required. Importantly, the limitations of previous RCTs must be addressed; namely the inadequate accrual of appropriate patients, and the exclusion of FLAIR abnormalities from CTV delineation. Studies comparing QoL and neurocognitive function are needed as well.

Subset analyses of rGBM-only studies demonstrated similar improvements in OS and PFS with combination therapy across all comparative treatment groups, though no significant OS benefit was observed compared to systemic therapy alone. These findings are of particular clinical significance as there is no widely accepted standard-of-care for this patient cohort with the poorest prognosis [17]. Hence, further RCTs comparing combination therapy to systemic therapy or reirradiation alone in patients with rGBM are especially warranted.

This review has some limitations. There were insufficient studies to conduct a meta-analysis on QoL, and the impact of resection on survival could not be ascertained. Studies were also mainly of retrospective cohort methodology, hence conferring a greater risk of confounding and selection bias potentially favouring combination treatment. Furthermore, most studies incompletely reported molecular information (IDH/MGMT) and were conducted prior to the changes in WHO glioma classification in 2021. Of note, grading largely informs the management approach at initial diagnosis and relapse, and MGMT methylation status is a vital prognosticator in an era where most gliomas are treated with alkylating agents [4]. Further RCTs are therefore required to address these limitations and confirm this review’s findings. Additionally, the diagnosis of tumour progression/recurrence varied between studies; radiological diagnosis vs biopsy-proven. Notably, it is difficult to differentiate tumour progression with treatment-related changes using conventional MRI [60].

This review found that combination therapy may improve OS and PFS with acceptable toxicity in select patients with rHGG compared to reirradiation or systemic therapy alone. Hence, further RCTs are warranted although the limitations of previous RCTs must be addressed; namely the inadequate accrual of appropriate patients to detect an OS difference, and the exclusion of FLAIR abnormalities from CTV delineation. Additional studies comparing QoL and neurocognitive function are needed as well. This review also found that the addition of bevacizumab to reRT reduced RN and may allow for safer dose escalation and treatment of larger volume disease. Further studies are required to determine if dose escalation confers improved local control or survival outcomes.