|Year : 2022 | Volume
| Issue : 2 | Page : 69-76
Postoperative radiotherapy with concomitant temozolomide plus anlotinib for newly diagnosed glioblastoma: Study protocol for a multicenter, double-blind, randomized phase II trial
Yuanyuan Chen1, Baiqiang Dong1, Guihong Liu2, Pengfei Sun3, Meihua Li4, Xuejun Yang5, Shiyu Feng6, Liang Wang7, Yonghong Hua8, Ming Zhao9, Yanhui Liu10, Juntao Ran11, Li Qiao12, Xueguan Lu13, Hao Jiang14, Deqiang Mao15, Junxin Wu16, Xianming Li17, Wei Zheng18, Zhigang Liu19, Song Lin20, Meiling Deng1, Qunying Yang21, Chengcheng Guo21, Jing Li22, Zhong-ping Chen21
1 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, China
2 Department of Radiation Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
3 Department of Radiation Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu Province, China
4 Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
5 Department of Neurosurgery, Internet Hospital of Tianjin Medical University General Hospital, Tianjin, China
6 Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
7 Department of Neurosurgery, Tangdu Hospital, Xi'an, Shaanxi Province, China
8 Department of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang Province, China
9 Department of Neurosurgery, Henan Cancer Hospital, Zhengzhou, Henan Province, China
10 Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
11 Department of Radiation Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu Province, China
12 Department of Neurosurgery, Gansu Provincial Hospital, Lanzhou, Gansu Province, China
13 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
14 Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, China
15 Department of Neurosurgery, Chongqing University Cancer Hospital, Chongqing, China
16 Department of Radiation Oncology, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
17 Department of Radiation Oncology, Shenzhen People's Hospital, Shenzhen, Guangdong Province, China
18 Department of Neurosurgery, The Sixth Medical Center of PLA General Hospital, Beijing, China
19 Department of Radiation Oncology, The Fifth Affiliated Hospital Sun Yat-sen University, Zhuhai, Guangdong Province, China
20 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
21 Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, China
22 Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, China
|Date of Submission||02-Jun-2022|
|Date of Decision||18-Jun-2022|
|Date of Acceptance||23-Jun-2022|
|Date of Web Publication||26-Jul-2022|
Dr. Zhong-ping Chen
Department of Neurosurgery/Neuro-Oncology, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou 510060
Source of Support: None, Conflict of Interest: None
Background and Aim: Postoperative radiotherapy with concomitant temozolomide (TMZ) followed by ≤ six cycles of adjuvant TMZ chemotherapy (Stupp regimen) is the standard treatment for newly diagnosed glioblastoma (GBM); however, its effectiveness is limited. Anlotinib inhibits both tumor angiogenesis and tumor cell proliferation by targeting multiple kinases, and showing promising results in preclinical GBM models. We designed a Phase II trial to assess the efficacy and safety of the Stupp regimen plus anlotinib. Methods/Design: This is a multicenter, double-blind, randomized, placebo-controlled trial with an expected 150 patients randomly assigned 1:1 ratio to receive TMZ-based radiochemotherapy with anlotinib (Stupp regimen + anlotinib) or placebo (Stupp regimen + placebo). Postoperative patient recruitment will begin in July 2021, the analysis of primary outcome measures will be completed in July 2023, and the study will finish in July 2024. Major eligibility criteria include histologically confirmed newly diagnosed GBM and an Eastern Cooperative Oncology Group performance score ≤2. Other criteria for inclusion include age ≥18 years and lack of significant comorbidity. In this study, the primary endpoint will be the median progression-free survival (PFS). Secondary endpoints include 1-year overall survival rate, PFS at 6 months, overall response rate, duration of response, disease control rate, quality of life, and toxicity. The protocol has received approval from Sun Yat-sen University Cancer Center Ethics Committee (Approval No. B2021-073-01; approved on April 19, 2021). Discussion: Updated treatment modalities are required for newly diagnosed GBM. Our proposed treatment modality of the Stupp regimen combined with anlotinib therapy are waiting conclusion. Trial Registration: This study was registered with ClinicalTrials.gov under identifier NCT04959500 on July 13, 2021.
Keywords: Anlotinib, glioblastoma, progression free survival, stupp, temozolomide
|How to cite this article:|
Chen Y, Dong B, Liu G, Sun P, Li M, Yang X, Feng S, Wang L, Hua Y, Zhao M, Liu Y, Ran J, Qiao L, Lu X, Jiang H, Mao D, Wu J, Li X, Zheng W, Liu Z, Lin S, Deng M, Yang Q, Guo C, Li J, Chen Zp. Postoperative radiotherapy with concomitant temozolomide plus anlotinib for newly diagnosed glioblastoma: Study protocol for a multicenter, double-blind, randomized phase II trial. Glioma 2022;5:69-76
|How to cite this URL:|
Chen Y, Dong B, Liu G, Sun P, Li M, Yang X, Feng S, Wang L, Hua Y, Zhao M, Liu Y, Ran J, Qiao L, Lu X, Jiang H, Mao D, Wu J, Li X, Zheng W, Liu Z, Lin S, Deng M, Yang Q, Guo C, Li J, Chen Zp. Postoperative radiotherapy with concomitant temozolomide plus anlotinib for newly diagnosed glioblastoma: Study protocol for a multicenter, double-blind, randomized phase II trial. Glioma [serial online] 2022 [cited 2022 Aug 8];5:69-76. Available from: http://www.jglioma.com/text.asp?2022/5/2/69/352258
| Introduction|| |
Glioblastoma (GBM) is the most aggressive intracranial tumor, accounting for 48.3% of malignant primary brain tumors. Treatment for GBM is currently based on the Stupp regimen, which includes maximal resection followed by radiotherapy with concurrent temozolomide (TMZ) and subsequent adjuvant TMZ. Despite the multimodal therapy, patients with GBM have a median progression-free survival (PFS) of only 6.9 months and a median overall survival (OS) of 14.6 months. The poor prognosis is attributed to the biological properties of GBM, including high invasion, intense apoptosis resistance, propensity for necrosis, rampant genomic instability, and robust angiogenesis, which result in the limited efficacy of adjuvant therapy. Therefore, suppressing tumor progression by targeting tumor angiogenesis might be possible.,,
Anlotinib is a novel multi-kinase inhibitor of vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptors (FGFRs) which suppresses tumor growth by inhibiting c-Kit, c-FMS, Aurora-B, and has a broader inhibitory spectrum than that of bevacizumab. Antiotinib, the first effective monotherapy to prove effective in treating advanced nonsmall cell lung cancer, has a more comprehensive spectrum of angiogenesis inhibitors than that of bevacizumab, as it targets VEGFR1/2/3, PDGFRα/β, and FGFR1/2/3, avoiding drug resistance caused by complementary signaling pathways and achieving effective angiogenesis inhibition.,, Thus, we assumed that the first-line treatment with the Stupp regimen plus anlotinib might prolong the survival of patients with newly diagnosed GBM, and the current proposed Phase II trial is intended to assess this hypothesis in a randomized comparative setting.
| Methods/Design|| |
This study was designed as an investigator-initiated, prospective, multicenter, 1:1 randomized, comparative, double-blind Phase II trial to investigate the efficacy of the proposed intervention. Control arm patients receive standard therapy according to the Stupp regimen, whereas patients in the experimental arm will receive anlotinib and Stupp regimen therapy. An expected sample size of 150 patients from 20 hospitals [the list of 20 hospitals can be seen in the Supplementary File 1] will be enrolled in the trial, with Sun Yat-sen University Cancer Center as the coordinating and sponsor site. The primary outcome will be the median PFS assessed by the Independent Review Committee. In this trial, a 5-month increase in PFS is expected in the experimental arm compared with the control arm (from 7 months in the control arm to 12 months in the experimental arm). Secondary outcomes will include 1-year OS, PFS at 6 months, objective response rate (ORR), duration of response, disease control rate (DCR), toxicity, and quality of life. The trial started in July 2021 and is expected to conclude in July 2024, and the inclusion period for this trial is expected to be the first 24 months. The trial schedule of enrolment, interventions, assessments, and visits for participants can be seen in [Table 1].
|Table 1: Schedule of enrollment, interventions, assessments, and visits for participants|
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Recruitment and eligibility criteria
One hundred and fifty patients with pathologically confirmed GBM and IDH1/2 wild-type after surgery will be enrolled. The institutional neuro-oncological tumor board will identify the potential study participants, and then referred to the enrollment and eligibility screening process. An experienced neuroradiologist evaluates all inclusion scans. Immediately ineligible patients, for example, those with poor performance status, significant comorbidities, multifocal disease, a primary tumor located extracranially, or other excluding conditions, will not be encouraged to undergo screening.
- Age 18–75 years
- Eastern cooperative oncology group performance score: 0–2
- Estimated survival ≥3 months
- Histologically confirmed GBM
- Randomized trials can be initiated within 28–49 days of the last invasive procedure (biopsy, surgical resection, or other intracranial surgeries), with adequate healing of the cranioplasty wound
- Use of stable or decreased glucocorticoid doses within 5 days before the initiation of randomization
- Adequate organ function:
- Acceptable blood coagulation levels as follows: hemoglobin level ≥90 g/L, platelet count ≥90 × 109/L, and neutrophil count ≥1.5 × 109/L
- Normal liver and renal function defined as total bilirubin ≤1.5 × upper limit of normal (ULN); alanine transaminase and aspartate aminotransferase ≤2.5 × ULN or ≤5 × ULN for patients with liver metastasis; serum creatinine level ≤1.5 × ULN or creatinine clearance rate ≥60 mL/min
- Normal coagulation function (i.e., cruor function) defined as prothrombin time, international normalized ratio, and activated partial thromboplastin time ≤1.5 × ULN, or stable anticoagulant application within 2 weeks before enrolment.
Signed informed consent.
- Pregnancy or nursing (Female participants who are fertile will need to undergo a validated pregnancy test to determine whether they are pregnant)
- Other malignancies previously diagnosed or currently present that may affect the treatment protocol or comparisons
- Previous systemic radiotherapy, chemotherapy, or use of Chinese patent medicine for GBM
- Tumor located in the brainstem or multiple intracranial lesions of diffuse meningeal dissemination
- Factors affecting the usage of oral medications (chronic diarrhea, intestinal obstruction, or inability to swallow)
- High risk of fatal hemorrhage or other bleeding tendencies
- Contraindications for cerebral magnetic resonance imaging (MRI) examination
- Uncontrollable symptomatic epilepsy or refractory or severe cognitive impairment
- Other significant co-morbidities that may pose a greater risk or affect compliance with trial procedures
- Active participation in another therapeutic interventional clinical trial.
| Randomization and blinding|| |
A random allocation rule of the central randomization grouping system will be used to generate simple sequence randomization with 1:1 allocation, by a person who is not involved in the enrollment, and the assignment to either of the two arms will then be done according to closed envelopes. The MGMT promoter status (methylation versus nonmethylation) and recursive partitioning analysis will be used for stratification. Trial-independent Sun Yat-sen University Cancer Center central randomization grouping system administrator is the only person who knows the frequency of various block sizes, and once randomization is performed, editing is impossible.
Stupp regimen combined with anlotinib or placebo therapy
The flow chart for the study can be seen in [Figure 1]. All postoperative trial patients with confirmed GBM will be administered the Stupp regimen combined with anlotinib or placebo (placebo: made by starch) therapy and will be started between two and 6 weeks after surgery. Participants receive concurrent TMZ (75 mg/m2 qd, 42–49 days) and anlotinib/placebo (10 mg qd, 1–14 days every 3 weeks for two cycles) during radiotherapy. Subsequently, anlotinib/placebo is administered alone during a 28-day treatment break.
|Figure 1: Schedule of enrollment, interventions, and assessments. DCR: Disease control rate, DOR: Duration of response, ORR: Objective response rate, OS: Overall survival, PD: Progressive disease, PFS: Progression-free survival, q3 weeks: Every 3 weeks, RANO: Response assessment in neuro-oncology, RT: Radiotherapy, TMZ: Temozolomide|
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During adjuvant chemotherapy, patients receive TMZ at an initiation dose of 150 mg/m2 for 5 consecutive days of the 28-day cycle, which is increased to 200 mg/m2 in five subsequent cycles if no Grade ≥2 treatment-related adverse events are observed, concurrent with anlotinib/placebo (the same dose and scheme as before) for 24 weeks. This is followed by maintenance of anlotinib/placebo monotherapy until the unacceptable side effects occur or disease progression.
Both study arms have the same radiation dose, target delineation, and risk organ volum definitions. All patients will receive intensity-modulated radiotherapy or conformal radiotherapy (fractionated focal irradiation in daily fractions of 1.8–2.0 Gy, 5 days/week for 6 weeks, totaling 54–60 Gy). Gross tumor volume is defined as any residual T1 tumor enhancement, postoperative cavity, or the surrounding edema (or fluid-attenuated inversion recovery abnormality defined by MRI). The clinical target volume includes gross tumor volume + 1–2 cm anatomically constrained margin (i.e., excluded bone, fascia, and other anatomical barriers), followed by a dose boost to the enhancement area plus cavity and a 1–2 cm margin. The clinical target volume was expanded by 3–5 mm to create the planning target volume.
The mean PFS assessed by the Independent Review Committee. PFS is calculated from the date of randomization until disease progression, no matter whether the patient stopped the trial treatment, but the period of re-receiving other systemic anticancer treatment is not included.
- 1-year OS. OS is calculated from the date of randomization until death due to any cause
- PFS at 6 months
- ORR assessed using the response assessment in neuro-oncology (RANO) criteria; ORR is defined as complete plus partial response,
- Duration of response assessed using the RANO criteria. Duration of response is defined as the date from the first record of tumor remission to the progression or death from any cause
- DCR assessed using the RANO criteria. DCR is defined as complete plus partial response plus stable disease
- Adverse event recorded and analyzed based on the Common Terminology Criteria for Adverse Events (CTC-AE) version 5.0
- Quality of life assessment (The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30 and QLQ-BN20).,
Follow-up and response assessment
Patients will be followed up every 3 months for 3 years and every 6 months thereafter. Clinical examinations, neuroimaging, hematological assessments, and toxicity evaluation (CTCAE version 5.0) will be performed at each visit. Quality of life will be assessed using EORTC QLQ-C30 and QLQ-BN20. Additional follow-up will be conducted in the event of validated or suspected progression, and RANO criteria will be used to evaluate the treatment response.
A trained independent neuroradiologist will conduct a centrally retrospective review of all MRI scans based on the recent consensus recommendation for brain tumor imaging. A third independent neuroradiologist will review the images, if there is a discrepancy between the local and central neuroradiologist observations. According to the local response assessment, decisions regarding the treatment and eligibility for trials will be continuously made by local investigators. Post hoc data quality assurance will be provided by the central review.
Sample size and statistical considerations
Blinded researchers will perform all statistical analyses. The input data will be checked periodically for completeness and consistency. Analyzing data will be performed after verifying the consistency and plausibility of the reported data. The study is powered on the basis of the primary outcome. The sample size is based on the assumption that the experimental arm's PFS will increase to 12 months, as the Stupp and AVAGlio trials reported a median PFS of 7 months., According to a one-sided log-rank test at a significance level of 0.025 and a power of 80%, the required sample size is 120 patients. Due to 36 months of accrual and 24 months of follow-up, we determined that 150 patients (75 in each arm) are required for accrual, allowing for a 10% dropout rate.
The analyses will be conducted as intention-to-treat analyses, and per-protocol analysis will be performed. Kaplan–Meier analysis is used to calculate the cumulative incidence of late toxicities and survival rates. The chi-square test for categorical variables or Student's t-test for continuous variables is used to assess the difference between the two groups. Multivariate Cox regression analyses are used to identify possible prognostic factors that influence the survival outcomes. Statistical significance is set at P < 0.05. Statistical analyses will be performed using IBM SPSS Statistics for Windows (version 24.0; IBM Corp., Armonk, NY, USA).
Withdrawal or termination criteria
The study termination will occur once all enrolled participants have been excluded from the trial and the necessary data have been collected. The following reasons may result in a patient's exclusion from the trial:
- Disease progression
- Inappropriate for further participation because of ethical or medical safety concerns, as determined by the investigator
- Loss to follow-up
- Without impacting clinical care at any time, patients may withdraw from the trial at any time.
Trial monitoring and oversight
During the study, telephone and on-site monitoring visits will be conducted at each site, and data monitoring and trial steering are carried out by the Good Clinical Practice Independent Ethics Committee. The trial management group coordinates and manages the daily activities of the trial.
Ethical approval and consent
This study protocol was approved by the Ethics Committee of the Sun Yat-sen University Cancer Center, Guangzhou, China (approval No. B2021-073-01) on April 19, 2021 and conducted in full compliance with the principles of the Declaration of Helsinki. The protocol has been registered on ClinicalTrials.gov (identifier: NCT04959500, registered on July 13, 2021). The trial was reported in line with the Consolidated Standards of Reporting Trials 2010 guidelines and the Standard Protocol Items: Recommendations for Interventional Trials checklist. The patients must provide written informed consent before participating in the study.
| Discussion|| |
Novel and effective therapeutic strategies are urgently needed owing to the poor efficacy of existing treatments for newly diagnosed GBM. In our preliminary multicenter, single-arm, Phase II trial of anlotinib combined with radiotherapy and TMZ as initial GBM treatment, 33 patients were enrolled and followed up for 16.3 months. The median PFS and OS were 10.9 and 17.4 months, respectively, which exceeded the trial expectations. All patients tolerated concurrent chemoradiotherapy, and more than half received eight cycles of adjuvant therapy. Major adverse events were Grade 1 or 2 and that of Grade ≥3 was hypertension (6.1%), and no treatment-related deaths were observed during the treatment and follow-up periods. This trial suggests that anlotinib combined with the Stupp regimen might be an effective and safe treatment for patients with newly diagnosed GBM and mild adverse reactions.
Wang et al. reported a case of recurrent GBM treated with anlotinib. In this report, after the failure of multiline therapy with TMZ and bevacizumab, the patient was treated with a combination of TMZ and anlotinib. After 2 months of therapy, the patient achieved a partial response that was maintained for >17 months, and brain edema was well controlled. A retrospective study reported that 23 patients with recurrent high-grade GBM who were treated with anlotinib alone or in combination with TMZ showed ORR and DCR of 34.8% and 73.9%, respectively. The median PFS was 3.5 months in the anlotinib alone group and 4.5 months in the anlotinib plus TMZ group. Severe toxicity was uncommon; the incidence of Grade 1 and 2 adverse events was 65.2%, and no Grade ≥3 adverse events occurred. Hematotoxicity only occurred in the anlotinib plus TMZ group, and no treatments were terminated due to adverse events. Because anlotinib was effective and safe for patients with recurrent high-grade Glioma, further study of the Stupp regimen combined with anlotinib therapy will likely provide more survival benefits to patients with newly diagnosed GBM.
The limitation of the present study is small sample size.
| Conclusions|| |
Updated treatment modalities are required for newly diagnosed GBM. Our current clinical trial will answer whether the Stupp regimen combined with anlotinib provide more survival benefits to newly diagnosed GBM patients.
This is protocol version 1.1 (March 16, 2021). Postoperative patient recruitment began in July 2021 and is expected to be completed by the end of July 2023. The study procedures are expected to be completed by the end of July 2024. This study is currently ongoing. The enrollment will not be terminated until all 150 participants are included, or until the end of July 2023.
By the end of April 2022, 76 patients were enrolled [Table 2]. Although no detailed clinical results have been presented, two patients have shown promising results. The first patient is a 64-year-old male with GBM in the right parietal and temporal lobes. He underwent surgery in July 2021, followed by the Stupp regimen plus anlotinib or placebo as adjuvant therapy for 6 months, which resulted in good tumor control [Figure 2]. The second patient is a 58-year-old female with a newly diagnosed GBM. After adjuvant Stupp regimen plus anlotinib or placebo treatment, the clinical status remained stable, and no progression was observed at the last follow-up (March 29, 2022) [Figure 3].
|Figure 2: Stupp regimen plus anlotinib or placebo therapy in a 64-year-old male with newly diagnosed GBM on the right temporal lobe before surgery. Follow-up magnetic resonance imaging scans after anlotinib cycles 2, 5, and 11 indicate that the lesion is stable (shown by the red arrow). C-NO.: Number of anlotinib/placebo cycles, GBM: Glioblastoma, Postop: Postoperation, Preop: Preoperation, RT: Radiotherapy|
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|Figure 3: A 58-year-old female with newly diagnosed GBM received adjuvant Stupp regimen combined with anlotinib or placebo treatment. The lesion (shown by the red arrow) in the left temporal lobe appears stable on fluid-attenuated inversion recovery images. C-NO.: Number of anlotinib/placebo cycles, GBM: Glioblastoma, Postop: Postoperation, RT: Radiotherapy|
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Supplementary materials are available at Glioma online (http://www.jglioma.com/).
We are thankful to the patients enrolled in this study.
Financial support and sponsorship
This study is partially supported by Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Jiangsu, China.
Institutional review board statement
The study was approved by the Sun Yat-sen University Cancer Center Ethics Committee (approval No. B2021-073-01) on April 19, 2021 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 forms, the 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
The authors declare that there is no conflict of interest. No conflicts of interest exist between Chia Tai Tianqing Pharmaceutical Group Co., Ltd. and publication of this paper.
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.
Supplementary File 1: The list of 20 hospitals
- Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong Province, China
- The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
- Lanzhou University Second Hospital, Lanzhou, Gansu Province, China
- The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
- Internet Hospital of Tianjin Medical University General Hospital, Tianjin, China
- Chinese PLA general Hospital, Beijing, China
- Tangdu Hospital, Xi'an, Shaanxi Province, China
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China
- Henan Cancer Hospital, Zhengzhou, Henan Province, China
- West China Hospital, Chengdu, Sichuan Province, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu Province, China
- Gansu Provincial Hospital, Lanzhou, Gansu Province, China
- Fudan University Shanghai Cancer Center, Shanghai, China
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, China
- Chongqing University Cancer Hospital, Chongqing, China
- Fujian Cancer Hospital, Fuzhou, Fujian Province, China
- Shenzhen people's Hospital, Shenzhen, Guangdong Province, China
- The Sixth Medical Center of PLA General Hospital, Beijing, China
- The Fifth Affiliated Hospital Sun Yat-sen University Zhuhai, Guangdong Province, China
- Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]