A narrative review on the management of glioblastoma in China

Introduction

Glioma is the most common intracranial primary malignant tumor, and half of it is glioblastoma (also named IDHwt-GBM). The incidence rate of GBM increases with age, with rates highest in patients aged 75 to 84 years (1). According to the report of Central Brain Tumor Registry of the United States (CBTRUS), GBM has the lowest 1-year survival rate (40.9%) and 5-year survival rate (6.6%) compared with other primary brain tumors (2). A single center retrospective study in China included 1,285 patients with glioma, of which 254 were GBM. The 1- and 5-year survival rates were 61% and 9% respectively, in line with what is observed in other countries (3). Standard of care management for GBM involves maximum safe surgical resection, radiation therapy, temozolomide (TMZ) chemotherapy, and consideration of alternating electrical fields. The degree of surgical resection is the most important factor affecting the effect of radiotherapy and chemotherapy and survival. Despite this prognosis remains poor, however, there are promising treatments actively under investigation (4-6).

Systematic guidance is very important to help clinicians make appropriate treatment decisions. Good clinical practice guidelines can improve the overall quality of diagnosis and treatment. In this review we have included Chinese guidelines on the management of glioma. In addition, we also summarized the current situation regarding the surgical, targeted and immunotherapy therapy and tumor treating fields (TTF) of GBM treatment in China, in order to help clinicians and patients make appropriate treatment based on current evidences. We present the following article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-22-18/rc).

Guidelines for glioma management in China

Clinical practice guidelines play an important role in healthcare. Good clinical guidelines can improve the overall diagnosis and treatment level and limit unnecessary treatments and costs. Europe, America and other countries have successively formulated guidelines for glioma treatment (6,7). China has discussed the formulation of guidelines for glioma diagnosis and treatment since 2005 (8).

We systematically searched PubMed, China National Knowledge Infrastructure (CNKI) and Wanfang databases, with the terms “consensus” or “guideline” or “standard”, and “glioma” or “glioblastoma” or “glial tumor”, and “China”. The retrieval time was from the establishment of the database to 24 January 2022. The detailed search strategy was reported in Table 1. Finally, 19 guidelines (8-26) were included, including 8 subclassified as the guideline (8,10,12-15,17,23), 8 subclassified as the consensus (9,11,16,18-20,22,26) and 3 subclassified as the standard (21,24,25). There is 1 guideline focused on low-grade glioma (15), 1 focused on brainstem glioma (16) and 2 focused on pediatric glioma (24,25). Two guidelines (10,14) reported the contents of the system search, 4 guidelines (9,11,12,20) are updated, and 9 guidelines (10,13,14,16-18,20,22,23) reported the source of funding (Table 2). Up to now, the year with the largest number of published guidelines is 2018, with a total of 4 guidelines (17-20) published (Figure 1). Overall, China’s guidelines and expert consensus still need to be improved in terms of preciseness, applicability and editorial independence.

Figure 1 Number of glioma management guidelines published annually in China.

Surgical resection

Surgical treatment is the first choice for patients with GBM. On the premise of fully protecting the patient’s brain function, the tumor tissue can be removed to the greatest extent (27,28). Several assistive technologies, including intraoperative magnetic resonance imaging (MRI) scanning, intraoperative ultrasound, fluorescence contrast and neuro-navigation, can be used to observe and confirm whether there is residual tumor (7,29).

Neuro-navigation integrates the structural and functional image information obtained before operation into neuro-navigation, registers reference points and reference frames, and determines important anatomical structures, so as to shorten the time of intraoperative functional positioning. Neuro-navigation device have been equipped by many large academic hospitals in urban centers, for example Beijing, Shanghai, Guangzhou, Wuhan, and so on.

At present, the main problem of intraoperative neuro-navigation is brain displacement, but intraoperative MRI can correct brain displacement and update navigation in real time, which is helpful to improve the resection degree of glioma (30). In addition, intraoperative ultrasound can guide the operator to judge the lesion location and resection degree in real time through the bone window, which is easy to popularize, but its image is easy to be affected by section, air, edema, etc. (31). Because of the high price and high requirements for surgical instruments, only a few academic hospitals have equipped the intraoperative MRI, such as Beijing Tiantan Hospital, Huashan Hospital in Shanghai and so on.

The surgical technique of resection of gliomas in brain functional areas in wake-up state is regarded as an important technique to safely remove gliomas in brain functional areas to the greatest extent. At present, it is still a hot and difficult issue in the field of surgery. In 2013, China first published the expert consensus on the surgical technology of removing gliomas in brain functional areas in wake-up state (11). Based on the release of new research results, the Chinese brain glioma group updated the guidelines in 2014 (12) and 2018 (17) respectively to further improve the standardization and standards of surgery. At present, the key to resection of gliomas in brain functional areas under wake-up anesthesia lies in the detection and protection of important functional structures. Although Chinese hospitals carried out wake-up surgery in the 1990s, considering the technical requirements of anesthesiologists, the cooperation of patients and the extension of operation time, this technology has not been well promoted at present. Only few neurosurgeons in the academic hospitals, such as Beijing Tiantan Hospital, Huashan Hospital in Shanghai, Zhongnan Hospital of Wuhan university, and so on, regularly performed the wake-up craniotomy for patients with GBM located in brain functional areas.

Although China’s guidelines recommend image technology to assist surgical treatment, it is difficult to completely remove the real tumor boundary due to the diffuse, invasive and special location of GBM. Further research is still needed to overcome this problem.

Targeted therapy and immunotherapy

The standard treatment of GBM includes maximum surgical resection, postoperative radiotherapy and TMZ chemotherapy, but these may have immunosuppressive effect. Coupled with the immune particularity of the central nervous system, GBM is a disease that is difficult to be treated by immune pathway. However, the new study found that the central nervous system has an appropriate immune response and is connected with the peripheral immune system (32). At the same time, GBM growth can destroy the blood-brain barrier and facilitate the entry and exit of lymphocytes into and out of brain tissue (33). These provide a theoretical basis for immunotherapy of GBM. In recent years, targeted therapy represented by bevacizumab (BEV) has been widely used in clinical treatment. New targeted therapy medicine for GBM, such as a MET kinase inhibitor PLB-1001, also demonstrated remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models in China (34). At present, a variety of GBM immunotherapy methods have entered the stage of clinical trials, mainly including immune checkpoint inhibitors, chimeric antigen receptor T (CAR-T) cells and vaccines.

Bevacizumab

BEV is a human clonal antibody that blocks tumor angiogenesis by inhibiting vascular endothelial growth factor. It can prevent epithelial growth factor receptor (EGFR) from binding to its receptor and reduce tumor cardiovascular formation, so as to inhibit tumor growth. The US Food and Drug Administration (FDA) first approved BEV for the treatment of recurrent GBM in 2009 (35). A systematic review included 5 randomized controlled trials (RCTs) with 834 patients provided clear proof of the beneficial effects of BEV treatment in recurrent GBM patients (36). However, two phase III randomized controlled trial of BEV combined with standard first-line radiotherapy and chemotherapy in the treatment of newly diagnosed GBM showed that BEV could not prolong the overall survival (OS), only could improve the progression free survival (PFS) (37-39). The study of BEV combined with TMZ in the treatment of recurrent GBM in China showed that the effect is better in the short term, but there was no significant difference in the long-term curative effect between China and foreign countries (40). Based on the current evidence, China’s guidelines (22) reported that BEV was not recommended in combination with standard treatment for newly GBM patients, except for the guidance of clear molecular markers and other test results. BEV was recommended for patients with recurrent GBM. In addition, clinical trials on BEV are combination therapy in China. For recurrent GBM, BEV combined with hypofractionated re-radiation, Camrelizumab, ASC40 tablets, Irinotecan plus re-radiotherapy, and Nimustine (ChiCTR2000035881, NCT04952571, NCT05201326, NCT05118776, NCT02698280). Most trials are in the recruitment stage. One ongoing clinical trial to explore the potential image biomarkers in newly GBM with BEV (NCT01939574) (Table 3)

CAR-T cell therapy

CAR-T cell therapy, namely chimeric antigen receptor T cell therapy. By using the patient’s own T lymphocytes, they are remodeled in the laboratory, loaded with receptors and costimulatory molecules that recognize tumor antigens, amplified in vitro and then reinfused into the patient’s body, so as to identify and attack their own tumor cells. CAR-T therapy solves the problem of tumor heterogeneity. The transformed T cells can target tumor cells, but the toxic reactions of treatment need to be closely monitored and treated. The common targets of CAR-T therapy in GBM are EGFR variant type III (EGFRvIII), human epithelial growth factor receptor 2 (HER2) and interleukin 13 receptor alpha 2 (IL-13R α 2), etc. (41). In addition, there are some promising antigens characterized by high expression of GBM, such as B7-H3 and CSPG4 (42,43). The first CAR-T clinical trial directed to EGFRvIII in 10 recurrent GBM patients showed that the median OS time was 8 months, and the clinical benefit was not significant (44). Another CAR-T clinical trial with HER2 as the target indicated that the median OS after the first infusion of T-cell and diagnosis in 17 patients with progressive GBM were 11.1 and 24.5 months respectively, and 8 patients had clinical benefits (45). Besides, there are also some encouraging results in the research of CAR-T in the treatment of GBM, but further research is needed to achieve stable clinical benefits (46,47). Treatment of GBM with CAR-T is plagued by the lack of ideal tumor antigens as targets and serious side effects. There are six ongoing clinical trials of CAR-T therapy for recurrent GBM in China (NCT04385173, NCT02844062, NCT04045847, NCT04077866, NCT05241392, NCT02937844), of which 3 trials were treated with anti-B7-H3 CAR-T and 1 was treated with CD147 CAR-T (Table 3).

Dendritic cells (DC) vaccine

DC are derived from bone marrow hematopoietic progenitor cells or monocytes. They are the most powerful antigen-presenting cells known at present. They can activate the body’s specific immunity by efficiently ingesting, processing and presenting antigens to T and B lymphocytes. DC vaccine is to use DC to present antigen and activate immunity. DC that can specifically recognize tumors induced or constructed in vitro, can be imported back into tumor patients to activate the immune response of T cells to tumors. A multicenter phase III clinical trial showed that the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax^®-L) to standard treatment may improve the median survival of GBM (48). One phase II clinical trial in China reported that DC vaccine may significantly prolong the OS of GBM patients. GBM patients with IDH1 wild-type, TERT mutation and low expression of B7-H4 are more sensitive to specific active immunotherapy activated by Glioblastoma stem-like cell antigens-primed DC vaccines (GSC-DCV) (49). Based on the current research, China’s latest guidelines recommend that DC vaccine can be used in the relevant clinical trials of recurrent GBM. In recent years, the “personalized DC vaccine” was proposed according to tumor heterogeneity, which can provide more accurate treatment for different tumor patients. At present, there are two ongoing clinical trials (NCT02709616, NCT02808364) on personalized DC vaccine for the treatment of newly GBM and recurrent GBM in China, and five studies on DC vaccine combined with TMZ, programmed cell death 1 (PD-1) and interleukin 12 (IL-12) for the treatment of GBM (ChiCTR1900025835, NCT01567202, NCT04968366, NCT04888611, NCT04388033) (Table 3).

Tumor treating fields

TTF is a new type of physical therapy. It interferes with the mitosis of tumor cells by acting on the tubulin of proliferating cancer cells, causes the apoptosis of affected cancer cells and inhibits tumor growth. The Food and Drug Administration approved TTF product Optune^® to treat adult patients with recurrent and newly diagnosed GBM in 2011 and 2015 respectively, based on the positive clinical trial results (4,50,51). In 2015, TTF technology was incorporated into the guidelines for the diagnosis and treatment of glioma of the nervous system in China (14). In 2018, the National Health Commission of China published the standard for the diagnosis and treatment of glioma (2018 version) (21), and TTF was recommended for the treatment of new GBM (level I evidence) and recurrent high-grade glioma (Level II evidence). In May 2020, China’s Drug Administration approved the combination of TTF and TMZ for the treatment of newly diagnosed GBM patients and as a monotherapy for recurrent GBM patients. In 2021, experts such as the glioma Professional Committee of China Anti-Cancer Association prepared an expert consensus on electric field treatment of GBM, and made a detailed report on the action mechanism, influencing factors, clinical evaluation, use scheme and patient management of TTF in the treatment of GBM (26). However, the application research of TTF in China is limited. At present, clinical trials are promoting the combination of TTF with radiotherapy and chemotherapy, targeted therapy, immunotherapy and so on. In addition, six ongoing clinical trials in China are trying to determine the safety and efficacy of TTF combined with radiotherapy and chemotherapy (ChiCTR2100047049, ChiCTR2100041969, ChiCTR2000034706, ChiCTR2000034285, NCT04689087, NCT04902586). Two ongoing clinical trials in China explore the recurrent GBM with TTF treatment system (ChiCTR2000032655, NCT04417933) (Table 3).

Conclusions

In summary, glioma guidelines in China are increasing year by year, and the quality of guidelines is also gradually improving, but the preciseness, applicability and independence of guidelines still need to be further improved. At present, emerging immune and targeted therapy are under research in China. However, the cooperation in clinical research of GBM in multiple centers needs to be strengthened in China.

Acknowledgments

We express our gratitude to Xian-Tao Zeng from Zhongnan Hospital of Wuhan University for his support and help in database system search.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-22-18/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (https://cco.amegroups.com/article/view/10.21037/cco-22-18/coif).The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Miller KD, Ostrom QT, Kruchko C, et al. Brain and other central nervous system tumor statistics, 2021. CA Cancer J Clin 2021;71:381-406. [Crossref] [PubMed]
2. Ostrom QT, Cioffi G, Waite K, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018. Neuro Oncol 2021;23:iii1-iii105. [Crossref] [PubMed]
3. Yang P, Wang Y, Peng X, et al. Management and survival rates in patients with glioma in China (2004-2010): a retrospective study from a single-institution. J Neurooncol 2013;113:259-66. [Crossref] [PubMed]
4. Stupp R, Taillibert S, Kanner A, et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA 2017;318:2306-16. [Crossref] [PubMed]
5. Lukas RV, Wainwright DA, Ladomersky E, et al. Newly Diagnosed Glioblastoma: A Review on Clinical Management. Oncology (Williston Park) 2019;33:91-100. [PubMed]
6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Central Nervous System Cancers, version 2. 2021-November 29, 2021. Available online: https://www.nccn.org/professionals/physician_gls/pdf/cns-poland.pdf
7. Weller M, van den Bent M, Preusser M, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol 2021;18:170-86. [Crossref] [PubMed]
8. Chen ZP, Zhou WN. Guidelines for diagnosis and treatment of single disease of gliomas (2005 discussion draft). Proceedings of the 4th annual meeting of Neuro Oncology Committee of Guangzhou Anti-cancer Association; 2005 July 8; Guangdong: Sun Yat sen University; 2005:9-18.
9. Society for Neuro‐Oncology of China. Chinese consensus for diagnosis and treatment in central nervous system malignant gliomas (simplified version). National Medical Journal of China 2009;89:3028-30.
10. Chinese Glioma Guideline Working Committee. Zhou L, Wang R. Chinese guidelines for diagnosis and treatment in central nervous system malignant gliomas (2012). National Medical Journal of China 2013;93:2418-49.
11. Chinese Glioma Cooperative Group. Expert consensus for the removal of functional brain during awake glioma surgery. Chinese Journal of Minimally Invasive Neurosurgery 2013;18:143-9.
12. Chinese Glioma Cooperative Group. Guidelines for the removal of functional brain during awake glioma surgery (2014 version). Chinese Journal of Minimally Invasive Neurosurgery 2014;19:479-85.
13. Chinese Glioma Cooperative Group. Guidelines for molecular diagnosis and treatment of glioma in China. Chinese Journal of Neurosurgery 2014;30:435-44.
14. Chinese Glioma Guideline Working Committee. Guidelines for diagnosis and treatment of central nervous system glioma in China (2015). National Medical Journal of China 2016;96:485-509.
15. Chinese Glioma Cooperative Group. Guidelines for surgical treatment of adult supratentorial low-grade gliomas. Chinese Journal of Neurosurgery 2016;32:652-8.
16. Society for Neuro‐Oncology of China. Expert consensus for the comprehensive management of brainstem glioma in China. National Medical Journal of China 2017;97:964-75.
17. Chinese Glioma Cooperative Group. Expert consensus for the removal of functional brain during awake glioma surgery (2018 version). Chinese Journal of Minimally Invasive Neurosurgery 2018;23:383-8.
18. Society for Neuro‐Oncology of China. Expert consensus for the multidisciplinary diagnosis and treatment of glioma in China. Chinese Journal of Neurosurgery 2018;34:113-8.
19. China Society for Radiation Oncology. Expert consensus of China on radiation therapy for gliomas in 2017. Chinese Journal of Radiation Oncology 2018;27:123-31.
20. Glioma Professional Committee of Chinese Medical Association. Expert consensus on immune and targeted therapy of central nervous system gliomas in China. National Medical Journal of China 2018;98:324-31.
21. Bureau of Medical Administration of National Health Commission. Guidelines for diagnosis and treatment of glioma (2018 version). Chinese Journal of Neurosurgery 2019;35:217-39.
22. Glioma Professional Committee of Chinese Medical Association. Expert consensus on immune and targeted therapy of central nervous system gliomas in China (Second Edition). National Medical Journal of China 2020;100:3388-96.
23. Jiang T, Nam DH, Ram Z, et al. Clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 2021;499:60-72. [Crossref] [PubMed]
24. National Health Commission of the People's Republic of China. Guidelines for the management of pediatric brain gliomas in China (2021 version). Journal of Multidisciplinary Cancer Management 2021;7:22-31. (Electronic Version).
25. National Health Commission of the People's Republic of China. Guidelines for the management of pediatric ependymoma in China (2021 version). Clinical Education of General Practice 2021;19:773-6.
26. Glioma Professional Committee of China Anti-Cancer Association. Expert consensus on tumor electric field therapy for glioblastoma in China. Chinese Journal of Neurosurgery 2021;37:1081-9.
27. Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery 2008;62:753-64; discussion 264-6. [Crossref] [PubMed]
28. Sanai N, Berger MS. Operative techniques for gliomas and the value of extent of resection. Neurotherapeutics 2009;6:478-86. [Crossref] [PubMed]
29. Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 2006;7:392-401. [Crossref] [PubMed]
30. Senft C, Bink A, Franz K, et al. Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial. Lancet Oncol 2011;12:997-1003. [Crossref] [PubMed]
31. Bai HM, Wang WM, Li TD, et al. Three core techniques in surgery of neuroepithelial tumors in eloquent areas: awake anaesthesia, intraoperative direct electrical stimulation and ultrasonography. Chin Med J (Engl) 2011;124:3035-41. [PubMed]
32. Keskin DB, Anandappa AJ, Sun J, et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 2019;565:234-9. [Crossref] [PubMed]
33. Hilf N, Kuttruff-Coqui S, Frenzel K, et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 2019;565:240-5. [Crossref] [PubMed]
34. Hu H, Mu Q, Bao Z, et al. Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor. Cell 2018;175:1665-1678.e18. [Crossref] [PubMed]
35. Moen MD. Bevacizumab: in previously treated glioblastoma. Drugs 2010;70:181-9. [Crossref] [PubMed]
36. Zhang T, Xin Q, Kang JM. Bevacizumab for recurrent glioblastoma: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci 2021;25:6480-91. [PubMed]
37. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 2014;370:699-708. [Crossref] [PubMed]
38. Chinot OL, de La Motte Rouge T, Moore N, et al. AVAglio: Phase 3 trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastoma multiforme. Adv Ther 2011;28:334-40. [Crossref] [PubMed]
39. Weller M, Yung WK. Angiogenesis inhibition for glioblastoma at the edge: beyond AVAGlio and RTOG 0825. Neuro Oncol 2013;15:971. [Crossref] [PubMed]
40. Lu Y, Qi S, Ouyang H, et al. Preliminary clinical evaluations of bevacizumab for recurrent malignant glioma in Chinese patients. Zhonghua Yi Xue Za Zhi 2014;94:1165-8. [PubMed]
41. McGranahan T, Therkelsen KE, Ahmad S, et al. Current State of Immunotherapy for Treatment of Glioblastoma. Curr Treat Options Oncol 2019;20:24. [Crossref] [PubMed]
42. Nehama D, Di Ianni N, Musio S, et al. B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres. EBioMedicine 2019;47:33-43. [Crossref] [PubMed]
43. Pellegatta S, Savoldo B, Di Ianni N, et al. Constitutive and TNFα-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: Implications for CAR-T cell therapy. Sci Transl Med 2018;10:eaao2731. [Crossref] [PubMed]
44. O'Rourke DM, Nasrallah MP, Desai A, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 2017;9:eaaa0984. [Crossref] [PubMed]
45. Ahmed N, Brawley V, Hegde M, et al. HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial. JAMA Oncol 2017;3:1094-101. [Crossref] [PubMed]
46. Brown CE, Alizadeh D, Starr R, et al. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. N Engl J Med 2016;375:2561-9. [Crossref] [PubMed]
47. Choe JH, Watchmaker PB, Simic MS, et al. SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma. Sci Transl Med 2021;13:eabe7378. [Crossref] [PubMed]
48. Liau LM, Ashkan K, Tran DD, et al. First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med 2018;16:142. [Crossref] [PubMed]
49. Yao Y, Luo F, Tang C, et al. Molecular subgroups and B7-H4 expression levels predict responses to dendritic cell vaccines in glioblastoma: an exploratory randomized phase II clinical trial. Cancer Immunol Immunother 2018;67:1777-88. [Crossref] [PubMed]
50. Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 2012;48:2192-202. [Crossref] [PubMed]
51. Stupp R, Taillibert S, Kanner AA, et al. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA 2015;314:2535-43. [Crossref] [PubMed]