Recurrent glioblastoma has been reported to have a poor prognosis. Due to its therapeutic resistance and aggressiveness, its clinical management is challenging. GBM is a vascularized tumour that produces VEGF. Anti-VEGF treatments have been widely used in recurrent GBM. The mechanism of anti-VEGF treatments may have two aspects. First, inhibiting VEGF and its receptor reduces tumour angiogenesis to produce a hypoxic environment and inhibits tumour growth [6]. Second, the tumour vessel diameter was normalised, and the basement membrane was thin. A reduced volume of tumour microvessels has been reported to be related to longer survival [7].
Bevacizumab is approved for treating recurrent glioblastoma by the US Food and Drug Administration and has become a recommended treatment in the National Comprehensive Cancer Network (NCCN) guidelines, with several phase II and III randomized trials indicating a prolonged PFS compared with chemotherapy alone [8–10]. A phase III RCT reported a prolonged median PFS (4.2 vs. 1.5 months) in the bevacizumab and Lomustine groups compared with the Lomustine alone group. However, this trial did not find a difference in OS between the two groups. The grade 3 to 5 toxicity rate in the experimental group was 63.6% [10]. Friedman et al reported a phase II randomized controlled trial (RCT) in which a higher 6-month PFS rate (50.3% vs. 42.6%) and better ORR (37.8% vs. 28.2%) were observed in the bevacizumab with irinotecan group than in the bevacizumab alone group [9]. Other anti-angiogenic drugs, including sorafenib, pazopanib, sunitinib, etc., were reported in phase I and II trials treating rGBM. The ORR reported for anti-VEGF treatments for rGBM ranged from 6–30% (Table 3), and the 6-month PFS ranged from 3–63%. The treatment-related toxicity was mild for these anti-VEGF treatments. However, the efficacy seems to be unsatisfactory.
Anlotinib is an oral novel multi-target tyrosine kinase inhibitor targeting the VEGF1/2/3 receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor. It inhibits more targets than bevacizumab, sunitinib, sorafenib, etc. and has been reported to reduce both tumour proliferation and angiogenesis [3]. Lv et al published the first case report of the administration of 12 mg anlotinib to an rGBM patient. The patient achieved a PR after 26 days, but the tumour progressed in two months [4]. Wang et al reported a recurrent GBM patient with an FGFR-TACC3 fusion who was administered anlotinib 12 mg and temozolomide 100 mg/m2. The patient achieved a PR after 2 months and maintained stable disease for more than 17 months [11].
Several reports have suggested that re-irradiation has reasonable efficacy with acceptable safety profiles in selected patients with recurrent GBM. However, for rGBM, salvage treatment failure ultimately occurs. It is crucial to increase local treatment to reduce recurrence risk. In a meta-analysis, a highly conformal technique with a hypofractionated regimen (e.g. 25 Gy in 5 fractions or 35 Gy in 10 fractions) is recommended, taking into account the volume and location of the recurrent tumour. The RTOG 1205 trial reported a prolonged PFS with anti-VEGF treatment with HSRT compared with bevacizumab alone [5]. Philip et al theorized that additional anti-VEGF treatment sensitised the tumour endothelia to radiotherapy and induced apoptosis [12].
New-generation automated noncoplanar HSRT delivery systems can deliver high-dose treatment by limiting the dose to normal structures and can provide a higher local treatment intensity for recurrent tumours.
In this study, the ORR rate of salvage treatment was 100% in 2 CR and 3 PR patients. The ORR was higher than other results of anti-VEGF treatments [
13–
25], which ranged from 6–30% (Table 3). There may be several possible reasons. Patient selection may be a reason for good outcomes. All patients had a KPS of 70 or higher, and HSRT was performed after the first recurrence. Moreover, the administration of HSRT increased local treatment intensity. The preliminary result of RTOG 1205 also reported an increased PFS in the intensified treatment groups. Additionally, patients with a smaller tumour volume may have a better response. The two CR patients (Fig.
2A, Fig.
2B) in this study had a relatively smaller PTV (7.08 and 5.53 cm3) than the 3 PR patients (26.94, 44.33, and 54.41 cm3).
No treatment failure was observed until the last follow-up. Salvage HSRT was administered with a full dose of 25 Gy/5 fx for all five patients without and interruption. No radionecrosis occurred during the follow-up. Grade 2 hand-food syndrome was found in 2 patients (40%), and rash and hypertension were observed in 1 patient (20%). These adverse effects were considered related to anlotinib. In a phase II randomized trial of non-small-cell lung cancer patients, 28.33% of the subjects had grade 2 hand-foot syndrome, and grade 2 hypertension was observed in 55% of patients [26]. These toxicities were also observed in our study.
The study had some limitations due to its retrospective nature: inherent patient selection bias was created when the physicians chose eligible patients to receive the regimen. The treatment option was provided for patients with high KPS scores who were not willing to receive standard intravenous bevacizumab treatment. Thus, the cohort was enriched with patients with a better prognosis. Another limitation was that recurrence before salvage treatment was diagnosed by radiological parameters according to the RANO criteria, which is a common practice [27]. However, the lack of biopsy samples limited the information on tumour genomic characterizations. It is crucial to consider whether the previously detected mutation still presents as the dominant clone at the time of recurrence [28]. Further investigation is warranted to explain the potential treatment mechanisms and select good responders to the regimen. Additionally, although no patient died or had progressive disease at the last follow-up, a longer follow-up duration is needed to further evaluate the OS and PFS of patients.
Despite the limitations, this study provides initial evidence of a promising outcome using salvage HSRT with anlotinib in a real-world scenario. Responses were observed in all rGBM patients included in the study. Further investigation is needed to identify patients who can benefit from this regimen. A prospective phase II study HSCK-002 (ClinicalTrials.gov identifier: NCT04197492) is ongoing to further investigate the value of HSRT with anlotinib.