Efficacy of Anlotinib in Treating Progressive Glioblastoma: Insights From a Single-Center Study

Introduction

Glioblastoma (GBM) is the most prevalent tumor in the central nervous system [1]. Due to its high malignancy, patients with GBM experience lower progression-free survival (PFS), overall survival (OS), and 5-year survival rates [2,3]. At present, newly diagnosed GBM is treated with maximal safe resection, postoperative concomitant chemoradiation, and adjuvant chemotherapy using temozolomide (TMZ) [4,5]. Due to its malignancy, GBM progresses despite standard therapy [2]. This aggressive progression typically includes postoperative residual tumor cell invasion and migration, aberrant tumor vascularization, an immunosuppressive tumor microenvironment, genetic alterations, and treatment resistance, clinically reflected by symptom deterioration and evident radiological progression (eg, new or enlarging lesions on contrast-enhanced MRI). However, there are no treatment guidelines for progressive GBM [6]. Despite attempts by neurosurgeons to utilize various therapeutic measures such as second surgeries, radiotherapy and chemotherapy, patients with progressive GBM have a poor prognosis [7].

Glioma is characterized by several clinically significant molecular biomarkers, including but not limited to isocitrate dehydrogenase status, O-6-methylguanine-DNA methyltransferase, epidermal growth factor receptor (EGFR) copy number variation and mutation status, as well as 1p-19q co-deletion [8,9]. These diverse molecular biomarkers are closely associated with treatment modalities and patient prognosis [9]. Recently, targeted therapy for these markers and individualized treatment strategies tailored to specific patients have been gradually implemented in the management of glioma, particularly GBM [5,10]. However, when regards to target therapy for newly diagnosed GBM, only bevacizumab has progressed to phase III trials, and the research outcomes have not been ideal [11,12]. For recurrent glioblastoma (rGBM), bevacizumab may offer limited improvements in patients’ quality of life and PFS, but it does not appear to extend OS [13–15].

Anti-angiogenic therapy now plays a vital role in targeting the multifaceted mechanisms of glioma progression. Anlotinib, a novel oral molecular multi-target tyrosine kinase inhibitor (TKI), exerts its inhibitory effect by targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and stem cell factor receptor c-Kit [16,17]. As a newly developed molecular targeted therapy, anlotinib can suppress tumor angiogenesis and growth. For pharmacokinetics, anlotinib exhibits favorable bioavailability and membrane permeability, as well as notable blood–brain barrier permeability [17,18]. Given these advantages, anlotinib holds broader prospects in clinical application. Currently, anlotinib has been increasingly applied, expanding from treatment of refractory non-small cell lung cancer and small cell lung cancer to other malignant tumors such as medullary thyroid cancer and soft tissue sarcoma [19–21]. Beyond its use in these malignancies, the evidence on anlotinib in the treatment of GBM has progressed from case reports to clinical trials [22–25]. Due to its multi-target inhibition feature, we believe that this drug could exert a deeper antineoplastic effect on GBM.

This study aims to further investigate the clinical efficacy and safety profile of anlotinib in an expanded cohort of progressive glioblastoma patients. We conducted retrospective analysis of 10 progressive GBM patients and assessed the clinical outcomes after anlotinib was used.

Material and Methods

PATIENT INCLUSION:

We retrospectively included and analyzed 10 patients with progressive GBM in Tianjin Medical University General Hospital from March 2020 to December 2022. The patient inclusion criteria were: 1) age >18 years; 2) diagnosed as having GBM by integrated pathology and molecular biomarkers, including the latest WHO guidance; 3) previous first-line treatment measures with Stupp protocol; 4) tumor progression verified by neurosurgeons and radiologists using mRANO criteria [26]; 5) normal bone marrow, liver, and kidney function; 6) treatment with anlotinib after tumor progression; and 7) complete neuroimaging. Exclusion criteria were: 1) presence of other malignant tumors; 2) severe cardiovascular and cerebrovascular diseases; and 3) absence of clinical data. Additionally, we meticulously collected clinical data on all patients, including sex, age, surgical procedures, duration of anlotinib use, additional treatment measures, and toxicity. During the treatment process, we performed neuroimaging examinations every 2 months, and hemograms were performed monthly to assess clinical status of each patient. Neuroimaging follow-up was performed primarily with non-contrast and contrast-enhanced MRI, while blood tests included basic assessments of red blood cells, white blood cells, platelets, and key liver and kidney function tests. Postoperative glioma progression was primarily defined by new intracranial MRI contrast-enhancing lesions or progressive clinical worsening, assessed jointly by neurosurgeons and neuroradiologists.

TREATMENT PROCESS:

All enrolled patients initially received the standard Stupp protocol. Upon confirmation of tumor progression, treatment was switched to a regimen consisting of anlotinib (12 mg once daily, administered orally in 3-week cycles: 2 weeks on, 1 week off) and TMZ (150–200 mg/m2 once daily, given on a 7-days-on/7-days-off schedule within a 28-day cycle). Treatment continued until the occurrence of second progression, grade III–IV toxicity, or death, in accordance with the standard Stupp criteria [4,27]. The dosage of anlotinib could be adjusted as appropriate (8–12 mg) according to adverse effects.

EFFICACY AND ADVERSE EFFECTS EVALUATION:

We evaluated treatment efficacy according to the mRANO criteria. For patients who maintain a stable condition, we conducted neuroimaging using magnetic resonance imaging (MRI) and systematic physical assessment every 2 chemotherapy cycles (2 months). For patients with new clinical symptoms presentation, we promptly conducted physical examinations and neuroimaging to assess their status. Based on clinical data and mRANO criteria, we systematically evaluated disease status and classified them as complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) [28]. Based on the above data and definitions, we calculated the overall response rate (ORR) and disease control rate (DCR). In accordance with the National Cancer Institute-Common Terminology Criteria Adverse Events (CTCAE, version 5.0), we systematically evaluated the adverse effects of each patient. In addition, the general condition of every patient was assessed using the European Organization for Research and Treatment core quality of life questionnaire (EORTC QLQ-C30, version 3.0) [29]. Lastly, we established the definitions of OS and PFS following the administration of anlotinib. The primary endpoints for assessing patient survival were 6-month PFS and 1-year OS.

STATISTICAL ANALYSIS:

The survival data of this cohort were analyzed after anlotinib use. Statistical analysis of KPS and QLQ-C30 was conducted using SPSS (version 26.0) with a 2-tailed t test. Because of the small sample size, no multivariate analysis was conducted.

ETHICS APPROVAL:

This study was authorized by the Ethics Committee of Tianjin Medical University General Hospital (approval no. IRB2023-wz-163). Informed consent has been obtained from all patients, and strict confidentiality measures have been implemented to protect patient data.

Results

PATIENT CHARACTERISTICS:

From March 2020 to December 2022, a total of 10 patients diagnosed with progressive GBM were enrolled (6 males and 4 females). Their mean age was 58 years, ranging from 41 to 70 years.

The mean preoperative KPS score was 70 (40–90), while the mean corresponding score for tumor progression was 50 (20–80). Although the histopathology of this cohort covered astrocytoma, anaplastic astrocytoma, pleomorphic xanthoastrocytoma, and GBM, GBM was diagnosed in all patients after the integration of molecular identification. Most patients underwent tumor resection (8 of 10), with 2 undergoing stereotactic biopsy (2 of 10) due to the deep tumor location. In addition, more patients had at least 1 negative prognostic factor, including unmethylated MGMT promoter, IDH wild type, and EGFR mutation. Patient clinical characteristics and detailed treatment information are presented in Tables 1 and 2.

TREATMENT PROCESS AND CLINICAL OUTCOME:

All patients in this cohort received anlotinib, and all except 1 were also treated with TMZ at the same time. The 1 exception discontinued TMZ due to hyperemesis induced by the drug. At the statistical endpoint, 7 patients had died and 3 were alive, with no censoring. The dosage of anlotinib administered was 12 mg/QD for 8 out of 10 patients and 8 mg/QD for the remaining 2. Each patient was followed up until 31 December 2022. According to mRANO criteria, there were 3 cases of CR, 3 cases of PR, 1 case of SD, and 3 cases of PD. Furthermore, the DCR was 70% and the ORR was 60%. Survival analysis showed the median PFS was 5.42 months (range 0.80–27.40 months) and the median OS was 6.30 months (range 4.17–27.40 months). Figure 1 illustrates the patient outcomes, ranging from anlotinib treatment to tumor progression or death.

To estimate the physical status during treatment, we conducted an analysis of KPS and QLQ-C30 scores. Firstly, a line chart was systematically presented for KPS scores at 4 different time points (preoperative, postoperative, tumor progression and anlotinib use) using GraphPad (version 9.4.0) (Figure 2). A 2-tailed paired t test revealed a significant difference between tumor progression and anlotinib use conditions (P<0.05). The results of the analysis suggested that there are benefits to using KPS scores. Secondly, QLQ-C30 scores in tumor progression and anlotinib use were analyzed and are presented in Table 3. The analysis showed statistically significant differences between tumor progression and anlotinib use across most items of the questionnaire.

ADVERSE EFFECTS:

Some patients experienced treatment-related adverse effects, but no severe toxic events (CTCAE °III–IV) occurred. Adverse effects were observed in the hematological, gastrointestinal, cardiovascular, and mucocutaneous systems. The most frequent adverse effect was decrease in white blood cells (8 out of 10, 80%), as well as elevations in AST and ALT levels (2 out of 10, 20%), increased GGT (2 out of 10, 20%), and hypertension (3 of 10 patients, 30%). There were no adverse effects over CTCAE 3. For lower-grade adverse events, symptomatic management was implemented. Other adverse effects can be found in Table 4. No deaths were deemed to be treatment-related. We cannot confirm whether the adverse effects were attributable to anlotinib or TMZ.

CASE 1: Case 1, a 40-year-old man had glioma located in frontal lobe. This patient underwent tumor resection, and histopathology confirmed the GBM diagnosis. He had seizure and weakness 4.07 months after surgery, and radiological examination showed tumor progression. After the use of anlotinib combined with TMZ as the new treatment strategy, he achieved CR. Presently, this patient is still alive, with improved quality of life. The main neuroimaging in treatment process is shown in Figure 3.

CASE 2: Case 2 was a 58-year-old woman with a tumor located in the callosum. Due to its deep location, biopsy was necessary, and GBM diagnosis was confirmed through histopathology and molecular identification. Tumor progression was detected by MRI, and syndromes appeared 3.33 months after tumor resection. She received anlotinib without TMZ because of emesis. At present, she is in good health. Interestingly, this illustrative case showed that anlotinib can restrain GBM progression without combined use of TMZ (the main neuroimaging in treatment is shown in Figure 4).

CASE 3: Case 3 was a 69-year-old man with tumor widely located in the temporo-parietal occipital lobe. After tumor resection, GBM was diagnosed through the integration of histopathology and molecular identification. He had tumor progression 4.07 months after surgery, presenting seizure and weakness. He died in 2022 because of coronary heart disease. Until his death, we observed no second progression of tumor (the main imaging during treatment is shown in Figure 5).

Discussion

LIMITATIONS:

The present study has several limitations. Firstly, as a single-center retrospective study, it had a small sample size and limited generalizability to other settings. Second, differences in patient conditions upon admission may have affected not only the clinical outcomes, but also caused heterogeneity in the statistical analysis. Thirdly, certain patients within the cohort had either undergone or were currently undergoing additional therapeutic interventions (such as tumor treating fields, gamma knife radiosurgery, or bevacizumab), which may have affected clinical outcomes.

Conclusions

Anlotinib, a multi-target tyrosine kinase inhibitor, is a promising new option for patients with progressive glioblastoma. This exploratory study provides preliminary evidence of therapeutic efficacy and good tolerability, highlighting its potential clinical efficacy. To gain deeper insights into the clinical potential of this drug, large-scale studies are needed.