Multivariate analysis of factors influencing prognosis in IDH wild-type glioblastoma

doi:10.11958/20252243

Abstract

Abstract:

Objective To investige clinicopathological features and prognostic factors in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM). Methods A total of 137 patients with GBM diagnosed by surgical pathology at the General Hospital of Ningxia Medical University from January 2014 to July 2024 were retrospectively enrolled in this study. Clinical data, including age, gender, ethnicity, presence of epilepsy, neurological function status and Karnofsky Performance Status (KPS) score prior to radiotherapy, were collected. Tumor-related parameters, such as extent of resection, histological classification, tumor location, maximum tumor diameter, IDH mutation status, Ki-67 proliferation index, methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter and postoperative treatment regimens—including concurrent chemoradiotherapy and the number of adjuvant chemotherapy cycles were also recorded. Multivariate Cox proportional hazards regression analysis was conducted to identify independent prognostic factors. Kaplan-Meier survival curves were used to evaluate overall survival according to clinical characteristics. Results The median overall survival (OS) of the 137 GBM patients was 20.9 months, and their 1-year, 2-year and 3-year survival rates were 79.7%, 36.9% and 16.4%, respectively. Pre-radiotherapy KPS score, MGMT promoter methylation status, receipt of postoperative concurrent chemoradiotherapy and the number of adjuvant chemotherapy cycles were significantly associated with median survival of GBM patients (P<0.05). Multivariate Cox analysis revealed that absence of MGMT promoter methylation, lack of postoperative concurrent chemoradiotherapy after surgery and the number of adjuvant chemotherapy cycles<6 were independent risk factors for reduced survival in patients with GBM (P<0.05). Patients with a pre-radiotherapy KPS score<80, MGMT promoter unmethylation, lack of postoperative concurrent chemoradiotherapy and the number of adjuvant chemotherapy cycles<6 demonstrated significantly lower cumulative overall survival rates compared to those with these characteristics (P<0.05). Conclusion MGMT promoter unmethylation, lack of postoperative concurrent chemoradiotherapy and adjuvant chemotherapy cycles<6 are independent risk factors affecting overall survival in patients with IDH wild-type GBM.

Key words: glioblastoma, isocitrate dehydrogenase, O(6)-methylguanine-DNA methyltransferase, promoter regions, genetic, methylation, chemoradiotherapy, adjuvant

CLC Number:

R739.41

Figures/Tables 3

References 21

[1]	OSTROM Q T, PRICE M, NEFF C, et al. CBTRUS Statistical Report:primary brain and other central nervous system tumors diagnosed in the United States in 2016-2020[J]. Neuro Oncol, 2023, 25(12Suppl 2):iv1-iv99. doi:10.1093/neuonc/noad149.
[2]	LOUIS D N, PERRY A, WESSELING P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System:a summary[J]. Neuro Oncol, 2021, 23(8):1231-1251. doi:10.1093/neuonc/noab106.
[3]	李德培, 陈银生, 郭琤琤, 等. 脑胶质瘤的临床疗效和预后因素分析(附741例报告)[J]. 中华神经外科杂志, 2018, 34(9):905-909.
	LI D P, CHEN Y S, GUO Z Z, et al. The treatment effect of gliomas and prognostic factor analysis:a reports of 741 cases[J]. Chin J Neurosurg, 2018, 34(9):905-909. doi:10.3760/cma.j.issn.1001-2346.2018.09.009.
[4]	ZAPPE K, PÜHRINGER K, PFLUG S, et al. Association of MGMT promoter and enhancer methylation with genetic variants,clinical parameters,and demographic characteristics in glioblastoma[J]. Cancers(Basel), 2023, 15(24):5777. doi:10.3390/cancers15245777.
[5]	CHEHADE G, LAWSON T M, LELOTTE J, et al. Long-term survival in patients with IDH-wildtype glioblastoma:clinical and molecular characteristics[J]. Acta Neurochir(Wien), 2023, 165(4):1075-1085. doi:10.1007/s00701-023-05544-3.
[6]	INCEKARA F, SMITS M, VAN DER VOORT S R, et al. The association between the extent of glioblastoma resection and survival in light of MGMT promoter methylation in 326 patients with newly diagnosed IDH-wildtype glioblastoma[J]. Front Oncol, 2020,10:1087. doi:10.3389/fonc.2020.01087.
[7]	国家卫生健康委员会医政医管局, 中国抗癌协会脑胶质瘤专业委员会, 中国医师协会脑胶质瘤专业委员会. 脑胶质瘤诊疗指南(2022版)[J]. 中华神经外科杂志, 2022, 38(8):757-777.
	Medical Administration Bureau of the National Health Commission, Committee of Glioma of China Anti-Cancer Association, Society for Neuro-Oncology of China. Guidelines for the diagnosis and treatment of glioma(2022 Edition)[J]. Chin J Neurosurg, 2022, 38(8):757-777. doi:10.3760/cma.j.cn112050-20220510-00239.
[8]	STUPP R, HEGI M E, MASON W P, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study:5-year analysis of the EORTC-NCIC trial[J]. Lancet Oncol, 2009, 10(5):459-466. doi:10.1016/S1470-2045(09)70025-7.
[9]	GILBERT M R, WANG M, ALDAPE K D, et al. Dose-dense temozolomide for newly diagnosed glioblastoma:a randomized phase III clinical trial[J]. J Clin Oncol, 2013, 31(32):4085-4091. doi:10.1200/JCO.2013.49.6968.
[10]	ALEXANDER B M, CLOUGHESY T F. Adult Glioblastoma[J]. J Clin Oncol, 2017, 35(21):2402-2409. doi:10.1200/JCO.2017.73.0119.
[11]	STUPP R, MASON W P, VAN DEN BENT M J, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma[J]. N Engl J Med, 2005, 352(10):987-996. doi:10.1056/NEJMoa043330.
[12]	SKADELLY M, DANGEL E, GOHDE J, et al. Prolonged temozolomide maintenance therapy in newly diagnosed glioblastoma[J]. The Oncologist, 2017, 22(5):570-575. doi:10.1634/theoncologist.2016-0347.
[13]	田落意, 程传东, 钱中润, 等. 原发性胶质母细胞瘤的临床与分子病理学特征及其预后相关因素分析[J]. 临床神经外科杂志, 2024, 21(3):292-297.
	TIAN L Y, CHENG C D, QIAN Z R, et al. Clinical and molecular pathological characteristics of primary glioblastoma and analysis of prognostic factors[J]. J Clin Neurosurg, 2024, 21(3):292-297. doi:10.3969/j.issn.1672-7770.2024.03.010.
[14]	陈加贝, 漆松涛, 欧阳辉, 等. 影响胶质母细胞瘤患者预后的多因素分析[J]. 中华神经外科杂志, 2015, 31(1):48-53.
	CHEN J B, QI S T, OU Y H, et al. The analysis of prognostic factors for glioblastoma multiforme[J]. Chin J Neurosurg, 2015, 31(1):48-53. doi:10.3760/cma.j.issn.1001-2346.2015.01.014.
[15]	李凯新, 孔丹, 董百强, 等. 放疗联合替莫唑胺治疗术后高级别脑胶质瘤的临床分析[J]. 中华放射肿瘤学杂志, 2017, 26(2):133-137.
	LI K X, KONG D, DONG B Q, et al. A clinical analysis of radiotherapy combined with temozolomide for postoperative high·grade glioma[J]. Clin J Radiat Oncol, 2017, 26(2):133-137. doi:10.3760/cma.j.issn.1004-4221.2017.02.004.
[16]	LIANG H K, WANG C W, TSENG H M, et al. Preoperative prognostic neurologic index for glioblastoma patients receiving tumor resection[J]. Ann Surg Oncol, 2014, 21(12):3992-3998. doi:10.1245/s10434-014-3793-4.
[17]	黄国浩, 曹勇勇, 杨林, 等. 成人胶质母细胞瘤预后因素分析:单中心176例临床回顾[J]. 陆军军医大学学报, 2024, 46(17):2002-2008.
	HUANG G H, CAO Y Y, YANG L, et al. Prognostic factors for glioblastoma:a retrospective single-center analysis of 176 adults[J]. Journal of Army Medical University, 2024, 46(17):2002-2008. doi:10.16016/j.2097-0927.202402039.
[18]	LI H Y, SUN C R, HE M, et al. Correlation between tumor location and clinical properties of glioblastomas in frontal and temporal lobes[J]. World Neurosurg, 2018,112:e407-e414. doi:10.1016/j.wneu.2018.01.055.
[19]	HENKER C, KRIESEN T, SCHNEIDER B, et al. Correlation of Ki-67 index with volumetric segmentation and its value as a prognostic marker in glioblastoma[J]. World Neurosurg, 2019,125:e1093-e1103. doi:10.1016/j.wneu.2019.02.006.
[20]	许广智, 张佳乐, 伊西才, 等. IDH野生型胶质母细胞瘤患者预后影响因素分析[J]. 临床神经外科杂志, 2022, 19(2):130-134.
	XU G Z, ZHANG J L, YI X C, er al. Prognostic factors of IDH wild-type glioblastoma patients[J]. J Clin Neurosurg, 2022, 19(2):130-134. doi:10.3969/j.issn.1672-7770.2022.02.003.
[21]	HEGI M E, DISERENS A C, GORLIA T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma[J]. N Engl J Med, 2005, 352(10):997-1003. doi:10.1056/NEJMoa043331.

临床特征	n	中位OS/月	Log-rank χ²
年龄
<60岁	98	21.9（18.7~25.0）	2.099
≥60岁	39	17.8（17.1~18.5）	2.099
性别
男	87	20.9（17.5~24.3）	0.110
女	50	22.4（14.1~30.8）	0.110
民族
汉族	105	20.9（16.1~25.8）	0.085
回族	32	22.4（11.9~32.9）	0.085
肿瘤最大径
≤4 cm	62	21.4（17.2~25.7）	0.032
>4 cm	75	20.9（15.7~26.2）	0.032
切除程度
全切除	53	23.8（21.1~26.6）	0.901
次全切除	84	19.4（16.3~22.5）	0.901
肿瘤侧别
左侧	67	20.9（15.4~26.5）	1.182
右侧	66	20.9（15.9~26.0）	1.182
双侧/中央	4	9.5
肿瘤位置
单叶	101	21.9（18.4~25.3）	2.375
多叶	36	17.6（13.6~21.7）	2.375
癫痫
有	25	19.4（10.0~28.7）	0.237
无	112	20.9（17.2~24.8）	0.237
神经功能受损
有	80	17.9（14.0.~21.5）	0.047
无	57	22.8（19.7~25.9）	0.047
放疗前KPS评分
<80分	13	17.9（1.4~34.4）	5.282^＊
≥80分	124	21.4（18.6~24.3）	5.282^＊
MGMT启动子甲基化
未甲基化	66	20.6（16.2~24.9）	5.610^＊
甲基化	71	22.4（14.7~30.2）	5.610^＊
Ki-67
≤20%	44	23.8（18.9~28.6）	1.941
>20%	93	20.6（16.0~25.2）	1.941
术后同步放化疗
是	131	21.9（18.7~25.1）	65.737^＊＊
否	6	6.3（5.4~7.2）	65.737^＊＊
辅助化疗周期数
<6个	90	15.3（12.7~17.9）	33.895^＊＊
≥6个	47	27.2（23.7~30.6）	33.895^＊＊

临床特征	n	中位OS/月	Log-rank χ²
年龄
<60岁	98	21.9（18.7~25.0）	2.099
≥60岁	39	17.8（17.1~18.5）	2.099
性别
男	87	20.9（17.5~24.3）	0.110
女	50	22.4（14.1~30.8）	0.110
民族
汉族	105	20.9（16.1~25.8）	0.085
回族	32	22.4（11.9~32.9）	0.085
肿瘤最大径
≤4 cm	62	21.4（17.2~25.7）	0.032
>4 cm	75	20.9（15.7~26.2）	0.032
切除程度
全切除	53	23.8（21.1~26.6）	0.901
次全切除	84	19.4（16.3~22.5）	0.901
肿瘤侧别
左侧	67	20.9（15.4~26.5）	1.182
右侧	66	20.9（15.9~26.0）	1.182
双侧/中央	4	9.5
肿瘤位置
单叶	101	21.9（18.4~25.3）	2.375
多叶	36	17.6（13.6~21.7）	2.375
癫痫
有	25	19.4（10.0~28.7）	0.237
无	112	20.9（17.2~24.8）	0.237
神经功能受损
有	80	17.9（14.0.~21.5）	0.047
无	57	22.8（19.7~25.9）	0.047
放疗前KPS评分
<80分	13	17.9（1.4~34.4）	5.282^＊
≥80分	124	21.4（18.6~24.3）	5.282^＊
MGMT启动子甲基化
未甲基化	66	20.6（16.2~24.9）	5.610^＊
甲基化	71	22.4（14.7~30.2）	5.610^＊
Ki-67
≤20%	44	23.8（18.9~28.6）	1.941
>20%	93	20.6（16.0~25.2）	1.941
术后同步放化疗
是	131	21.9（18.7~25.1）	65.737^＊＊
否	6	6.3（5.4~7.2）	65.737^＊＊
辅助化疗周期数
<6个	90	15.3（12.7~17.9）	33.895^＊＊
≥6个	47	27.2（23.7~30.6）	33.895^＊＊

因素	β	SE	Wald χ²	P	HR（95%CI）
放疗前KPS评分	0.687	0.394	3.045	0.081	1.988（0.919~4.303）
MGMT启动子甲基化	0.475	0.233	4.163	0.041	1.609（1.019~2.540）
术后同步放化疗	2.353	0.493	22.814	<0.001	10.513（4.004~27.606）
辅助化疗周期数	1.241	0.250	24.646	<0.001	3.458（2.119~5.643）

因素	β	SE	Wald χ²	P	HR（95%CI）
放疗前KPS评分	0.687	0.394	3.045	0.081	1.988（0.919~4.303）
MGMT启动子甲基化	0.475	0.233	4.163	0.041	1.609（1.019~2.540）
术后同步放化疗	2.353	0.493	22.814	<0.001	10.513（4.004~27.606）
辅助化疗周期数	1.241	0.250	24.646	<0.001	3.458（2.119~5.643）