Initial report of a clinical trial evaluating the safety and efficiency of neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas: A prospective, phase II, single-arm study

Fuhua Lin; Chengcheng Guo; Qunying Yang; Yinsheng Chen; Chao Ke; Ke Sai; Ji Zhang; Xiaobing Jiang; Wanming Hu; Shaoyan Xi; Jian Zhou; Depei Li; Zhihuan Zhou; Qinqin Zhao; Xi Cao; Zhong-ping Chen

doi:10.4103/glioma.glioma_6_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 5 | Issue : 1 | Page : 29-38

Initial report of a clinical trial evaluating the safety and efficiency of neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas: A prospective, phase II, single-arm study

Fuhua Lin, Chengcheng Guo, Qunying Yang, Yinsheng Chen, Chao Ke, Ke Sai, Ji Zhang, Xiaobing Jiang, Wanming Hu, Shaoyan Xi, Jian Zhou, Depei Li, Zhihuan Zhou, Qinqin Zhao, Xi Cao, Zhong-ping Chen
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, China

Date of Submission	15-Feb-2022
Date of Decision	10-Mar-2022
Date of Acceptance	15-Mar-2022
Date of Web Publication	30-Mar-2022

Correspondence Address:
Dr. Zhong-ping Chen
Department of Neurosurgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060
China

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_6_22

Abstract

Background and Aim: High-grade glioma is the most common malignant primary brain tumor in the central nervous system. Multiple strategies such as surgery, radiotherapy, and chemotherapy have been used, but the prognosis of patients with high-grade glioma remains poor. No standard treatment exists for recurrent gliomas; however, combination therapies of programmed cell death protein 1 blockades with antiangiogenic agents have demonstrated promising effects in different solid tumors. Therefore, since the end of 2020, a clinical trial designed to evaluate the safety and efficiency of neoadjuvant therapy using camrelizumab and apatinib in patients with recurrent high-grade gliomas has been carried out in our institution. Methods/Design: In this prospective, Phase II, single-arm study, patients with recurrent high-grade gliomas will receive single-dose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before reoperation for tumor resection. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab and 4 weeks after surgery with the daily administration of apatinib. Treatment of camrelizumab and apatinib will be continued until disease progression or unacceptable toxicity or death. The primary outcome measure will be the median overall survival rate. Secondary outcome measures will include progression-free survival rate at 6 months and at 12 months and other measures. The trial is planned to enroll 30 patients. This study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (Guangzhou, China; approval No. SL-B2020-149-01) on July 27, 2020. Results and Conclusions: Although an evaluation is still impossible to be conducted yet, 11 patients had been enrolled by the end of January 2022. Some patients have shown a promising outcome. These preliminary data suggest that this study would be worthwhile. We hope that this study will provide scientific evidence to better care of patients with recurrent high-grade glioma. Trial registration: This study was registered with ClinicalTrials.gov under identifier NCT04588987 on October 19, 2020.

Keywords: Apatinib, camrelizumab, neoadjuvant therapy, recurrent glioma

How to cite this article:
Lin F, Guo C, Yang Q, Chen Y, Ke C, Sai K, Zhang J, Jiang X, Hu W, Xi S, Zhou J, Li D, Zhou Z, Zhao Q, Cao X, Chen Zp. Initial report of a clinical trial evaluating the safety and efficiency of neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas: A prospective, phase II, single-arm study. Glioma 2022;5:29-38

How to cite this URL:
Lin F, Guo C, Yang Q, Chen Y, Ke C, Sai K, Zhang J, Jiang X, Hu W, Xi S, Zhou J, Li D, Zhou Z, Zhao Q, Cao X, Chen Zp. Initial report of a clinical trial evaluating the safety and efficiency of neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas: A prospective, phase II, single-arm study. Glioma [serial online] 2022 [cited 2023 Oct 2];5:29-38. Available from: http://www.jglioma.com/text.asp?2022/5/1/29/341379

Background

High-grade glioma is the most common malignant primary brain tumor in adults, and it accounts for >40% of all primary central nervous system malignant tumors.^[1] Multiple strategies such as surgery, radiotherapy, and chemotherapy with temozolomide have been applied, although the prognosis of patients with high-grade glioma remains poor with a median progression-free survival (PFS) of 6.9 months and a median overall survival (OS) of 14.6 months for patients with glioblastoma (GBM).^[2] No standard of treatment exists for patients with recurrent high-grade gliomas. Conventional treatment options include repeated surgery, reirradiation, systemic therapy, and supportive care. The targeted therapy of receptor tyrosine kinases is a hotspot in the treatment of different malignant tumors, including high-grade glioma. Apatinib, a novel small molecular antiangiogenic inhibitor, can highly and selectively bind to vascular endothelial growth factor receptor 2 (VEGFR-2). Apatinib inhibits the activation of VEGFR-2 to block vascular endothelial growth factor, mediate signal transduction, and inhibit angiogenesis to control tumor growth.^[3] Therefore, apatinib has been applied in the treatment of various tumors such as refractory gastric cancer and non-small-cell lung cancer.^[4],[5],[6] In recent years, several studies have reported encouraging results of treatment with apatinib in patients with recurrent GBM.^[7],[8]

In 2019, clinical trials^[9],[10] reported the efficacy of the neoadjuvant administration of PD-1 blockade in the treatment of patients with recurrent GBM. The results suggested that neoadjuvant PD-1 blockade therapy can activate tumor-associated T cells, which upregulates interferon-γ-related signaling pathways and downregulates tumor cell cycle-related genes. After surgery, tumor-associated T cells continue to kill the remaining tumor cells, and the T cells begin to transform into the memory T phenotype. This neoadjuvant therapy was associated with improved overall survival and enhanced local and systemic antitumor immune response, which indicated the potential of the application with PD1 blockade in progressive or recurrent GBM. Based on these limited studies, we hypothesized that apatinib combined with PD-1 blockade would prolong OS in patients with recurrent high-grade glioma. Thus, a prospective, phase II, single-arm trial was designed to assess the efficiency and tolerability of the combination of these drugs.

Methods/Design

Study design

This study is an investigator-initiated study and is designed as a prospective, phase 2, open-label, single-arm study to investigate the efficacy and safety of neoadjuvant therapy with PD-1 blockade (i.e., camrelizumab) and apatinib in patients with recurrent high-grade gliomas [Table 1]. The enrolled patients will receive a single-dose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before reoperation for tumor resection. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab (200 mg) and, 4 weeks after surgery, with the daily administration of apatinib (250 mg/day). Treatment of camrelizumab and apatinib will be continued until disease progression or unacceptable toxicity or death. The trial is planned to enroll an expected sample size of 30 patients. The flow diagram for the study is presented in [Figure 1].

Table 1: A flow chart of this study and the assessment schedule

Click here to view

Figure 1: Schedule of enrollment, interventions, and assessments

Click here to view

Screening and enrollment

Thirty patients with recurrent high-grade glioma, based on the response assessment in neuro-oncology (RANO) criteria, will be enrolled. Potential patients will be identified by a multidisciplinary tumor board and subsequently referred for enrollment and eligibility screening. All inclusion scans are assessed by a trained neuroradiologist.

Eligibility criteria

Inclusion criteria

Signed written consent form
Age between 18 years and 70 years
Male or female sex
Supratentorial tumor, histologically confirmed as the World Health Organization (WHO) Grade 3–4 glioma, based on biopsy or tumor resection
Completion of postoperative adjuvant radiotherapy with an interval ≥12 weeks between the last fraction of radiotherapy and enrollment
Completion of postoperative adjuvant chemotherapy with an interval ≥4 weeks between the last dose of chemotherapy and enrollment
Whole-brain magnetic resonance imaging (MRI), based on the consensus recommendations for a standardized brain tumor imaging protocol in clinical trials of not more than 4 weeks from the assessment, that indicates recurrence, based on the RANO criteria
Karnofsky Performance Score ≥60
When corticosteroid is necessary, the dosage should be stable or reduced within at least 5 days before the baseline MRI. Furthermore, the dosage of oral dexamethasone should be less than 2.25 mg/d within at least 5 days before the screening MRI
Estimated survival ≥12 weeks
Adequate organ function:

Adequate bone marrow function, defined as hemoglobin level ≥110 g/L, white blood cell count ≥3.0 × 10⁹/L, neutrophil count ≥1.5 × 10⁹/L, and platelet count ≥75 × 10⁹/L
Normal liver function and renal function, defined as bilirubin ≤1.5 upper limit of normal (ULN); alanine aminotransferase and aspartate transaminase ≤2.0 × ULN; and creatinine <1.5 × ULN or estimated creatinine clearance ≥50 mL/min (using the Cockcroft-Gault formula).

Normal coagulation function (i.e., cruor function), defined as an international normalized ratio ≤1.5 × ULN, activated partial thromboplastin time ≤1.5 × ULN, and prothrombin time ≤1.5 × ULN
Use of validated anticonception for fertile female participants and all male patients (fertile female participants will be required to take a validated pregnancy test for the evaluation of pregnancy within 7 days before enrollment, and voluntarily use validated anticonception during the investigation period and at least 8 weeks after the last dose of camrelizumab and apatinib. Male participants will be required to undergo surgical sterilization or voluntarily use validated anticonception during the investigation period and at least 8 weeks after the last dose of camrelizumab and apatinib)
Supply 25–30 pieces of tumor specimen sections
Good obedience to the follow-up flow.

Exclusion criteria

The presence of other malignant tumors in the past 5 years (except for patients with cervical carcinoma in situ, skin base cell carcinoma, or squamous cell carcinoma that has been completely cured)
History of allergy to therapeutic regimens in the trial or of severe hypersensitivity reactions to any monoclonal antibodies
Previous immunotherapy (including PD-1, programmed death ligand 1, or cytotoxic T lymphocyte-associated antigen blockade) or VEGFR-targeted therapy (except for patients who have previously received bevacizumab or other macromolecular monoclonal antibodies of VEGFR treatment for no more than three times only to relieve brain edema)
Patients who have had thrombotic events (such as brain stroke, deep venous thrombosis, or pulmonary embolism) within 12 months before enrollment
The presence of unstable systemic disease (including uncontrolled infection, uncontrolled hypertension, unstable angina pectoris, or angina with a recent episode within 3 months before enrollment; congestive heart failure or myocardial infarction within 12 months before enrollment; clinically significant arrhythmias, significant liver function impairment, significant renal impairment or severe metabolic diseases requiring treatment)
Known history of testing positive for human immunodeficiency virus or known to have acquired immunodeficiency syndrome
Active infection with hepatitis B virus or other hepatitis virus
The presence of other chronic disease requiring immunotherapy or corticosteroid treatment
Pregnant or nursing (fertile female participants will be required to take a validated pregnancy test for the evaluation of pregnancy)
Previous treatment with corticosteroid or any other immunosuppressive agent within 7 days before the first dose of the therapeutic regimens in this trial (except for patients treated with dexamethasone in a dosage not exceeding 4 mg/d or other form of corticosteroid with the equivalent dose limit, which should be stable or in reduction within at least 7 days^[11] before the adjuvant treatment)
Abnormal coagulation function or the presence of bleeding diathesis or undergoing thrombolytic or anticoagulant therapy
Other situation that may affect the completion of the treatment or follow-up and the evaluation of the result.

Blinding

This is an open label trial, and thus, the patients and investigators will not be blinded to the study design.

Intervention

In this study, two main drugs, camrelizumab and apatinib, were involved in the intervention protocol. Camrelizumab (SHR-1210; Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, China) is an anti-PD-1 monoclonal antibody, which has been proven as safe and effective for different tumors.^[11],[12] Apatinib (Aitan^®, brand name in China, produced by Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, China; it is also called rivoceranib outside of China) is a novel and selective inhibitor of VEGFR-2 tyrosine kinase with broad antitumor profiles. As neoadjuvant therapy, the trial participants will receive a single-dose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before reoperation for tumor resection. For all participants, if a patient has no contraindications, surgery will be performed with the purpose of maximal safe tumor resection. A new postoperative MRI will be conducted preferably within 72 h after the repeated resection. If histopathology confirms the recurrence of high-grade glioma, based on the 2016 WHO classification criteria, the participants will continue with postoperative adjuvant therapy. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab (200 mg). Apatinib will be administered at a dose of 250 mg daily beginning 4 weeks after surgery. Treatment with camrelizumab and apatinib will be continued until disease progression, unacceptable toxicity, or death.

Medication adjustment

Drug doses will be withheld and/or reduced for intolerable Grade 2 or Grade 3–4 toxicity, until unacceptable toxicity or disease progression. If the delay is expected to be more than 1 week because of the toxicity of apatinib during the treatment, only camrelizumab will be applied alone until the toxicity is restored to the dosing standards of apatinib. The combination therapy of apatinib and camrelizumab would then be restarted. During the period of combination therapy, apatinib can be suspended for 2 weeks at most; if more than 2 weeks, the administration will be terminated. However, if a delay of more than 2 weeks because of toxicity caused by camrelizumab, the participant will receive only apatinib until the toxicity recovers to the standards for camrelizumab administration. The combination of apatinib and camrelizumab would then be applied again. A maximum of 12 weeks of continuous suspension of the camrelizumab is allowed. If the suspension exceeds 12 weeks, camrelizumab will be discontinued. In the situation of a delay, possibly no longer than 2 weeks, because of an unspecified drug-related situation, it can be resumed within 2 weeks, whereas apatinib and camrelizumab need to be suspended simultaneously [Table 2] and [Table 3].

Table 2: Medication adjustment due to camrelizumab

Click here to view

Table 3: Medication adjustment due to apatinib

Click here to view

If the indication is that the toxicity is primarily caused by one of the investigated drugs, then a reduction or suspension of a single drug will be acceptable. However, if uncertainty exists about whether the toxicity is caused by two or more drugs involved in the trial, then a reduction of or the simultaneous suspension of all investigated drugs may be considered.

Follow-up and response assessment

During the neoadjuvant and postoperative adjuvant treatment, patients will be followed up regularly as per local guidelines and with clinical examinations, laboratory tests every 2 weeks, and MRI every 8 weeks or with shorter intervals. Toxicity will be evaluated every 2 weeks. The follow-up regimen may be revised at the discretion of the treating physician. In particular, additional follow-up including clinical and neuroradiological investigations, quality of life assessments, toxicity evaluation, and neuroimaging may be conducted in connection with suspected or validated progression. Treatment response will be evaluated, based on the RANO criteria [Table 1].

Withdrawal from study

The study will be terminated when all enrolled participants have been excluded from the trial and the necessary data have been acquired. A patient may be excluded from the trial for one of the following reasons:

The tumor resection/biopsy findings do not support a high-grade glioma diagnosis
Death
Loss to follow-up
End-of-trial
Enrollment in another interventional clinical trial
Withdrawal of consent
The patient is no longer suitable for further participation because of ethical or medical safety reasons determined by the investigator.

Outcome measures

The primary outcome measure will be the median overall survival rate. Secondary outcomes will include progression-free survival rate at 6 months (PFS6) and at 12 months (PFS12), time to progression, and overall objective response rate, assessed with the modified RANO criteria (i.e., objective response rate), OS rate at 12 months, quality of life assessment, and Karnofsky Performance Score [Table 1]. Interim futility analysis will be conducted after 12 months of follow-up of the first 15 patients. The trial began in July 2020 and is expected to complete in June 2023. The inclusion period is expected to be the first 24 months of the trial.

Sample size

The sample size calculations were based on a study of 35 recurrent GBM patients, which demonstrated that neoadjuvant treatment of PD-1 blockade (16 cases) significantly extended survival (median overall survival 13.7 months) compared to patients that were randomized to receive adjuvant (19 cases), postsurgical PD-1 blockade alone (7.5 months).^[9] We expected to achieve median overall survival of over 13.7 months, and thus, 30 patients have been proposed to enroll for this exploratory study.

Ethical approval and consent

This study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (Guangzhou, China; approval No. SL-B2020-149-01, July 27, 2020) and was registered in ClinicalTrials.gov (NCT04588987) on October 19, 2020. The trial was reported in line with the Standard Protocol Items: Recommendations for Interventional Trials checklist^[13] and the Transparent Reporting of Evaluations with Nonrandomized Designs statement.^[14] Participants will provide written informed consent before taking part in the study.

Data collection and management

All relevant information for each subject should be recorded in the Central Research Facilities (CRF) and inputted in an Internet-based electronic data capture system, timely and truly by trained research staff. The personal information of each subject is confidential. To promote participant retention, researchers will instruct subjects to take their medication as prescribed. Patients will also be informed of the follow-up visits by telephone in advance, and all items will be measured in strict accordance with the assessments schedule shown in [Table 1]. Two data entry staff are needed to input the data independently. After reviewing and confirming that the database is correct, electronic data will be conserved and backed up. As original material, the CRF is not easily changed. The researchers have to sign and date the CRF when it is necessary to modify. The locked electronic data files do not allow any changes to be made. The database will be statistically analyzed by statistical analysts as required by the statistical plan. The principal investigator has access to the final dataset, while other investigators are prohibited from entering. Except for the name-related data, the disclosure of the information to third parties is prohibited. After the completion of the trial, the responsible unit of the study has the right to publish contents related to the experiment in the form of a paper.

Data analysis

Outcome assessors undertake statistical analysis tasks and participate in the whole process from trial design and implementation to analysis and summary. The Kaplan–Meier method will be used to estimate median PFS and OS, and a log-rank test will be used to compare differences between the two arms. Furthermore, a Cox proportional hazards analysis will be done to estimate the hazard ratio and 95% confidence interval. Regarding prognostic factors, univariate and multivariate analyses, including age, histology, treatment method, IDH mutation, 1p/19q status, and MGMT promoter status will be used to analyze their impact on PFS and OS. Safety analysis, mainly for Advanced Encryption Standard, will be done in the safety set population. All effectiveness analysis (PFS, OS, cognitive function) will be done on an intention-to-treat set.

Primary Results

By the end of January 2022, 11 patients had been enrolled [Table 4]. While no detailed clinical results present yet, two patients have shown promising results. The first patient is a 5-year-old girl who had a GBM in the left parietal and temporal lobe. She underwent the first surgery in January 2019, followed by proton radiotherapy and adjuvant chemotherapy with temozolomide. One year later, she had to receive a second surgery for tumor progression. Several adjuvant chemotherapy regimens, including irinotecan in combination with temozolomide, were tried after the second surgery. However, in July 2021, she again experienced tumor progression. On account of her young age, she was not enrolled in this trial. However, her parents decided to have her receive treatment, as described in this protocol. She received a neoadjuvant therapy with camrelizumab and apatinib before the third surgery. Since the time of her third tumor resection, she has been treated with camrelizumab and apatinib as adjuvant therapy for 6 months with a good tumor control [Figure 2].

Table 4 Clinical data of the 11 enrolled patients

Click here to view

Figure 2: Combination of camrelizumab and apatinib as neoadjuvant and adjuvant therapy for a 5-year-old girl with recurrent glioblastoma. This patient had a tumor progression in the left temporal lobe before neoadjuvant therapy. Postoperative computed tomography scan indicated a small evaluable lesion near the surgical cavity (which is pointed by a blue arrow). Follow-up magnetic resonance scans in 11 weeks, 18 weeks, and 23 weeks demonstrated that the lesion became smaller and is in a stable control. CT: Computed tomography, MRI: Magnetic resonance, Postop: Postoperation, Preop: Preoperation

Click here to view

The second patient is a 28-year-old woman with recurrent GBM. She received adjuvant therapy with camrelizumab and apatinib because she refused to receive a reoperation when tumor progression was confirmed with brain MRI, based on the RANO criteria. After treatment, the lesion appeared gradually enlarged on enhancing (this change could be an immunoresponse) but stable on fluid-attenuated inversion recovery imaging. The clinical status remained well, and tumor is clinically stable. She is still in no progression survival until the last follow-up time (February 22, 2022) [Figure 3].

Figure 3: A 28-year-old woman received adjuvant therapy with camrelizumab and apatinib at recurrence. The lesion in right temporal lobe appeared gradually enlarged on enhancing but stable on fluid-attenuated inversion recovery imaging. CT: Computed tomography, MRI: Magnetic resonance, Postop: Postoperation

Click here to view

Discussion

To date, no standardized treatment exists for recurrent high-grade glioma. Effective treatment modalities are highly required. Conventional treatment modalities including surgery, radiotherapy, and chemotherapy are still the most often applied options. The main purpose of surgery is maximum safe resection (i.e., reduction of tumor burden), obtaining histological confirmation of recurrence, and distinguishing progression from pseudo-progression. Another feasible option for patients with local recurrence is stereotactic radiosurgery or the low-fractionated stereotactic radiotherapy. For patients with relatively large recurrent lesions, conventional fractionated radiotherapy is commonly applied, although it is often unavoidable to cause damage to normal brain tissue previously treated with high-dose radiotherapy or radioactive brain injury. Variable median survival times of 6–12 months and neurological toxicity rates of 5%–20% have been reported.^{[15],[16],[17]} In addition, survival benefit has been reported after re-irradiation in combination with temozolomide or bevacizumab, compared to re-irradiation alone.^[18] For patients with recurrent GBM who receive salvage systemic treatment, the antiangiogenic agent bevacizumab and the alkylating agents temozolomide or lomustine represent the most common options which resulted in median survival times of 6–12 months.^[19],[20] Bevacizumab has been the standard therapeutic option for patients with recurrent GBM in the United States since its approval in 2009 by the Food and Drug Administration (Silver Spring, MD, USA). By contrast, lomustine is the recommended second-line chemotherapy in the European Union, according to the result of a large randomized trial of 437 patients with progressive GBM.^[21]

PD-1 blockade alone has not demonstrated satisfactory efficacy in patients with high-grade glioma;^[22],[23] however, compared to anti-PD-1 monotherapy, combination therapy of PD-1 blockade with antiangiogenic agents activate immune checkpoints that result in more potent antitumor activity.^[24] More recently, some researchers have reported that apatinib in combination with anti-PD1 therapy demonstrates synergistic antitumor effects in progressive malignant tumors such as advanced hepatocellular carcinoma and metastatic colorectal carcinomas.^[11],[12] Combined antiangiogenic agents and PD-1 blockade may provide synergistic effects by inducing T-cell function and activating the immune checkpoints of tumor cells, thereby improving the tumor-induced immunosuppressive microenvironment.^[25] In clinical practice, the effect of this treatment protocol in some patients who were not enrolled in this study seems to be encouraging. The meaning of the neoadjuvant administration of PD-1 blockade combined with antiangiogenic agent applied in this trial for recurrent glioma hopefully could be worthwhile, which is awaiting evaluation.

Conclusion

Although an evaluation is still impossible to be conducted yet, some patients have shown a promising outcome. These preliminary data suggest this study would be worthwhile. We hope that this study will provide scientific evidence to better care of patients with recurrent high-grade glioma.

Trial status

This study is currently still ongoing. The enrollment will not be terminated until all 30 participants are included or until the end of June 2023.

Acknowledgments

Nil.

Financial support and sponsorship

This study is partially supported by Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, China.

Institutional review board statement

The study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (Guangzhou, China; First approval number: SL-B2020-149-01, approval date: July 27, 2020, and was conducted in full compliance with all principles of the Declaration of Helsinki.

Declaration of participant consent

The authors certify that they will obtain the patient consent forms. In the form, patients will give their consent for their images and other clinical information to be reported in the journal. The patients will understand that their names and initials will not be published and due efforts will be made to conceal their identity.

Conflicts of interest

There are no conflicts of interest.

Editor note: ZC is an Editorial Board member of Glioma. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board member and their research groups.

References

1.	Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2014-2018. Neuro Oncol 2021;23:i1-105.
2.	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.
3.	Tian S, Quan H, Xie C, Guo H, Lü F, Xu Y, et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci 2011;102:1374-80.
4.	Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol 2016;34:1448-54.
5.	Wu F, Zhang S, Xiong A, Gao G, Li W, Cai W, et al. A phase II clinical trial of apatinib in pretreated advanced non-squamous non-small-cell lung cancer. Clin Lung Cancer 2018;19:e831-42.
6.	Roviello G, Ravelli A, Polom K, Petrioli R, Marano L, Marrelli D, et al. Apatinib: A novel receptor tyrosine kinase inhibitor for the treatment of gastric cancer. Cancer Lett 2016;372:187-91.
7.	Wang L, Liang L, Yang T, Qiao Y, Xia Y, Liu L, et al. A pilot clinical study of apatinib plus irinotecan in patients with recurrent high-grade glioma: Clinical trial/experimental study. Medicine (Baltimore) 2017;96:e9053.
8.	Zhang H, Chen F, Wang Z, Wu S. Successful treatment with apatinib for refractory recurrent malignant gliomas: A case series. Onco Targets Ther 2017;10:837-45.
9.	Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med 2019;25:477-86.
10.	Zhao J, Chen AX, Gartrell RD, Silverman AM, Aparicio L, Chu T, et al. Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nat Med 2019;25:462-9.
11.	Ren C, Mai ZJ, Jin Y, He MM, Wang ZQ, Luo HY, et al. Anti-PD-1 antibody SHR-1210 plus apatinib for metastatic colorectal cancer: A prospective, single-arm, open-label, phase II trial. Am J Cancer Res 2020;10:2946-54.
12.	Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: An open-label, dose escalation and expansion study. Clin Cancer Res 2019;25:515-23.
13.	Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 statement: Defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200-7.
14.	Des Jarlais DC, Lyles C, Crepaz N; TREND Group. Improving the reporting quality of nonrandomized evaluations of behavioral and public health interventions: The TREND statement. Am J Public Health 2004;94:361-6.
15.	Ryu S, Buatti JM, Morris A, Kalkanis SN, Ryken TC, Olson JJ, et al. The role of radiotherapy in the management of progressive glioblastoma: A systematic review and evidence-based clinical practice guideline. J Neurooncol 2014;118:489-99.
16.	Ziu M, Goyal S, Olson JJ. Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of radiation therapy in the management of progressive and recurrent glioblastoma in adults. J Neurooncol 2021. doi: 10.1007/s11060-021-03857-w.
17.	Straube C, Kessel KA, Zimmer C, Schmidt-Graf F, Schlegel J, Gempt J, et al. A second course of radiotherapy in patients with recurrent malignant gliomas: Clinical data on re-irradiation, prognostic factors, and usefulness of digital biomarkers. Curr Treat Options Oncol 2019;20:71.
18.	Botros D, Dux H, Price C, Khalafallah AM, Mukherjee D. Assessing the efficacy of repeat resections in recurrent glioblastoma: A systematic review. Neurosurg Rev 2021;44:1259-71.
19.	Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27:4733-40.
20.	Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009;27:740-5.
21.	Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med 2017;377:1954-63.
22.	Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, et al. Effect of nivolumab vs. bevacizumab in patients with recurrent glioblastoma: The CheckMate 143 phase 3 randomized clinical trial. JAMA Oncol 2020;6:1003-10.
23.	Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol 2016;34:2206-11.
24.	Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott DF, Cho DC, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: A non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol 2018;19:405-15.
25.	Allen E, Jabouille A, Rivera LB, Lodewijckx I, Missiaen R, Steri V, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med 2017;9:eaak9679.