【作者】 程金湘；

【导师】 章翔； 林伟；

【作者基本信息】 第四军医大学 ， 外科学， 2013， 博士

【摘要】 中枢神经系统肿瘤每年约有189,000新发病例和142,000死亡病例（分别占新发肿瘤的1.7%和因肿瘤死亡的2.1%）。胶质瘤是最常见的原发性中枢神经系统肿瘤，约占中枢神经系统肿瘤的40%，约占成人恶性中枢神经系统肿瘤的78%。胶质母细胞瘤（Glioblastoma，GBM，WHO IV级）的中位生存期为12~15个月，间变性胶质瘤（WHO III级）的中位生存期为2~5年，低级别胶质瘤（WHO I、II级）的中位生存期为4~10年。由于胶质瘤患者预后差，生存期短，功能损伤严重，因此提高生命质量对于他（她）们变得尤为重要。欧洲癌症研究与治疗组织（European Organzationfor Research and Treatment of Cancer，EORTC）的生命质量测定量表（QLQ-C30）和脑肿瘤模块（BCM），以及肿瘤治疗的功能性评估—脑问卷（FACT-Br）已被广泛地应用于临床试验。大多数的生命质量测定量表都系英语来源，且主要应用于以英语为母语的人群之中。目前，国内关于健康相关生命质量的研究也在逐步地进展当中。大多数国内应用的生命质量测定量表都通过翻译、回译及文化调适制定成中文版。标准中文版的EORTC QLQ-C30（3.0版）在国内评估乳腺癌、生殖系统肿瘤和肺癌患者时证明了其有效性，但是其有效性和可靠性并没有对脑肿瘤患者进行评估。到目前为止，没有针对脑肿瘤特异性的中文版生命质量测定量表。虽然健康相关生命质量已被广泛地作为评估脑肿瘤患者手术后其他辅助治疗效果的次要终点指标，但是尚缺乏对术前脑肿瘤患者的生命质量研究、以及评价其对预后的影响。国内尚未引进健康相关生命质量作为评估治疗效果的指标。1．标准中文版EORTC QLQ-C30（3.0版）评估脑肿瘤患者术前健康相关生命质量的应用评价由于脑肿瘤患者很差的预后，健康相关生命质量对肿瘤患者来说显得越来越重要。标准中文版EORTC QLQ-C30（3.0版）针对脑肿瘤患者的心理特征评估尚未得到证实，且目前缺乏手术前脑肿瘤患者的健康相关生命质量的基线数据。本研究纳入了2008年7月至12月、经过CT或MRI扫描怀疑或诊断为脑肿瘤、在第四军医大学西京医院神经外科入院接受手术的患者。对纳入研究的脑肿瘤患者在三个时间点进行标准中文版的EORTC QLQ-C30（3.0版）评估：T1，CT或MRI扫描怀疑或者诊断为脑肿瘤的患者，入院第一天或第二天；T2，T1时间点后的1~2天（T1和T2均在手术前）；T3，出院前一天。在T1时间点同时评估简易智能精神状态检查量表（Mini-Mental Status Examination，MMSE）和卡氏评分（Karnofsky performancestatus，KPS）。根据患者病史信息采集其基本情况。依据QLQ-C30评分手册进行分值的转换，然后施行量表的信度、效度、反应度评估。多条目的子量表克朗巴赫α系数均大于0.70，量表信度良好。多数条目与其对应领域（除了认知功能领域外）的相关性大（r>0.4），与其他领域相关性小，认为该量表结构效度良好。对T1时间点各个已知组间的差异进行方差分析，并对T1和T2时间点QLQ-C30对手术前、后的反应性改变进行方差分析。年龄>50岁和<50岁的患者进行比较，前者的生理功能、角色功能与认知功能、总体健康状况/生命质量均更差，且易于出现更严重的睡眠问题和食欲不振。根据MMSE量表评分，将患者分为认知功能正常组和异常组。认知功能正常与认知功能异常的患者相比，前者具有更好的生理功能和认知功能、总体健康状况/生命质量，较轻的疲劳和食欲不振等症状。KPS80-100的患者较KPS <80的患者具有更好的功能分值。脑转移瘤者表现出最差的功能评分、总体健康状况/生命质量，以及较为严重的症状，其后依次为胶质细胞瘤、脑膜瘤、垂体腺瘤和胆脂瘤。手术后患者的生理功能和角色功能评分降低。这些评估符合预期的假设，认为该量表具有良好的反应度。和所有的手术后辅助治疗前的肿瘤患者相比，手术前的脑肿瘤患者具有更好的生理功能、角色功能和情感功能，较轻的呼吸困难、失眠和腹泻等症状，但是认知功能和社会功能损害较为严重，总体健康状况/生命质量更差，以及恶心/呕吐症状更为严重。总体来说，标准中文版EORTC QLQ-C30是评估脑肿瘤患者健康相关生命质量信度、效度、反应度均良好的量表。本研究也提供了术前脑肿瘤的患者的基线参考数据。将来的研究应该进一步优化该中文版量表的认知功能子量表，以及选择其他时间点再次评估重测信度和治疗反应度。2．国人胶质瘤患者健康相关生命质量的研究健康相关生命质量在治疗胶质瘤的临床试验中已得到了高度的重视，但是尚缺乏手术前胶质瘤患者生命质量的基线报告以及其与预后的关系。本研究首次对国人胶质瘤患者健康相关生命质量进行分析研究。该部分只纳入第一部分研究中病理证实为胶质瘤的患者。对胶质瘤患者于手术后3个月、6个月分别进行信件或电话随访。总共有92例胶质瘤患者纳入分析。经描述性的统计学分析发现，具有情感功能损害、社会功能损害、认知功能损害、生理功能损害和角色功能损害的患者比例分别为：84.8%、75.0%、75.0%、70.7%和50.0%。具备有疲劳、疼痛、食欲不振、失眠及恶心/呕吐的患者比例分别为：82.0%、72.8%、50.0%、39.1%和36.9%，具有其他症状（如呼吸困难、腹泻、便秘等）的患者比例<30.0%。通过Spearman等级相关分析发现，总体健康状况/生命质量与疲劳和疼痛、以及所有的功能子量表显著相关。疲劳与所有的功能子量表、疼痛、食欲不振以及总体健康状况/生命质量相关。通过Mann Whitney U-检验或Kruskal-Wallis检验，比较不同特征胶质瘤患者的组间差异：胶质瘤患者手术前的健康相关生命质量无性别和肿瘤位置的差异，亦无MMSE评分区分的认知正常和异常组间的差异。年龄、KPS评分、WHO级别和肿瘤复发对胶质瘤患者手术前的生命质量有显著的影响。年龄≥50岁的患者较<50岁的患者有更差的生理功能、角色功能、总体健康状况/生命质量以及更严重的失眠和便秘症状。MMSE评分认知功能异常的患者在≥50岁的人群显著多于<50岁的人群。KPS <80者有更差的生理功能、角色功能、情感功能、认知功能、社会功能、总体健康状况/生命质量，更严重的疲劳、疼痛、失眠和食欲不振。更差的KPS也与MMSE评估的认知功能异常相关。和WHO II级和III级患者相比较，WHO IV级的患者具有显著统计学意义最差的生理功能、角色功能、情感功能、社会功能、总体健康状况/生命质量，更严重的疲劳和疼痛症状。患者胶质瘤复表现出显著恶化的生理功能、社会功能及总体健康状况/生命质量。Spearman等级相关性分析显示，KPS与QLQ-C30量表中的生理功能、疲劳、认知功能、角色功能、总体健康状况/生命质量显著相关，而年龄和WHO级别与QLQ-C30的任何子量表和条目无等级相关性。随访发现对健康相关生命质量失访率过高，无法进行手术前后健康相关生命质量的比较分析。本研究提供了国人胶质瘤患者手术前的健康相关生命质量基线数据。手术前多数胶质瘤患者已经有情感功能、社会功能、认知功能、生理功能和角色功能的损害。在这些患者中，疲劳、疼痛、食欲不振、失眠和恶心/呕吐等症状较为常见。疲劳、疼痛、各种功能状态均明显地影响总体健康状况/生命质量。年龄大、KPS评分差、WHO IV级和肿瘤复发，与胶质瘤患者手术前较差的生命质量密切相关。如何降低健康相关生命质量研究中的失访率是今后相关研究中需要高度重视的问题。更多还原

【Abstract】 Cancers of the brain and nervous system account for189,000new cases and142,000deaths annually (1.7%of new cancers and2.1%of cancer deaths). Gliomas are the mostcommon primary central nervous system (CNS) tumors; they account for over40%ofCNS tumors and78%of CNS malignancies in adults. The median survival is only12-15months for patients with glioblastomas (GBMs)(WHO grade IV),2-5years for patientswith ana plastic gliomas (WHO grade III) and4-10years for patients with low-gradegliomas (LGG, including WHO grades I and II). Hence, quality of life (QoL) issues are ofspecial importance for glioma patients. The European Organization for Research andTreatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and theBrain Cancer Module (BCM), as well as the Functional Assessment of CancerTherapy-Brain (FACT-Br) were developed and extensively used in clinical trials. Themajority of QoL instruments were developed in English and used predominantly inEnglish-speaking populations. However in China, the study of health-related quality of life (HRQOL) is still in the developing stage. Most of QoL instruments used in China aretrans-lated from those used in developed English-speaking and western Europeancountries. The standard Chinese version of EORTC QLQ-C30(version3.0) is, overall, avalid instrument to assess HRQOL in Chinese breast, gynecological, and lung cancerpatients; nevertheless, its reliability and validity have not yet been evaluated in brain tumorpatients. To date, there is no specific brain tumor questionnaire available to assess HRQOLin China. Although HRQOL was extensively used as secondary endpoint to assess theefficacy of new treatments after surgery, the baseline HRQOL in brain tumor patientsbefore surgery has never been investigated, especially in China.1. The validation of the standard Chinese version of the European Organization forResearch and Treatment of Cancer Quality of Life Core Questionnaire30(EORTCQLQ-C30) in pre-operative patients with brain tumor in ChinaHealth related quality of life (HRQOL) has increasingly emphasized on cancerpatients. The psychometric properties of the standard Chinese version of the EuropeanOrganization for Research and Treatment of Cancer Quality of Life Core Questionnaire30(EORTC QLQ-C30, version3.0) in brain tumor patients wasn’t proven, and there was nobaseline HRQOL in brain tumor patients prior to surgery. A consecutive series of patientswith either suspected brain tumor or diagnosed by MRI or CT were recruited from July2008to December2008in the Department of Neurosurgery, Xijing Institute of ClinicalNeuroscience, Xijing Hospital, Fourth Military Medical University, China. Thequestionnaire EORTC QLQ-C30(version3.0) was administered at three time points: T1,the first or the second day that patients were hospitalized after the brain tumor suspected ordiagnosed by MRI or CT; T2,1to2days after T1,(T1and T2were both before surgery);T3, the day before discharge. At T1, Mini-Mental State Examination (MMSE) andKarnofsky Performance Status (KPS) were also performed. The raw scores for eachdomain and single item were transformed to give a value between0-100. The ananlysis ofreliability and valibility of the scale was performed. Cronbach’s alpha coefficients formulti-item scales were greater than0.70and multitrait scaling analysis showed that most of the item-scale correlation coefficients met the standards of convergent and discriminantvalidity, except for the cognitive functioning scale. All scales and items exhibitedconstruct validity. Comparison of differences within known-groups was calculated byANOVA (for cross-sectional analysis of T1), and the responsiveness of the QLQ-C30tochanges in health status over surgery was evaluated by repeated measures ANOVA (foranalysis of the change between T1and T3). Patients older than50reported worse physical,role and cognitive functioning, worse global health status/QoL, more symptoms of sleepand appetite loss than those younger than50. Patients with normal cognition had betterphysical and cognitive function, better global health status/QoL, less fatigue and appetiteloss symptoms than those with abnormal cognition Patients with KPS80-100showedstatistically significant higher functional and lower symptom scores than those with KPSless than80There was a trend that patient with metastatic brain tumors reported thelowest levels for most functioning, worst global health status/QoL, and highest levels formost symptoms, followed by glioma, meningioma, pituitary adenoma and cholesteatoma.Score decrease after operation were observed in physical and role functioning scales.Compared with mixed cancer patients assessed after surgery but before adjuvant treatment,brain tumor patients assessed pre-surgery presented better physical, role and emotionalfunctions and less dyspnea, insomnia and diarrhea symptoms, worse cognitive and socialfunction and global health status/QoL, more nausea and vomiting symptoms. The standardChinese version of the EORTC QLQ-C30was overall a valid instrument to assessHRQOL in brain tumor patients in China. Future study should modify cognitivefunctioning scale and examine test-retest reliability and responsibility.2. Health-related quality of life in glioma patients in ChinaHealth-related quality of life (HRQOL) has been increasingly emphasized in theclinical trials of glioma patients. There are no reports comparing baseline HRQOL ofdifferent subgroups of glioma patients prior to surgery. This study was part of apreliminary study on HRQOL in brain tumor patients in China. Only patients withpathologically confirmed glioma were included in the analysis. Ninety-two pathologically confirmed glioma patients were recruited. There were84.8%patients with emotionalimpairment,75%with social and cognitive impairment,70.7%with physical impairment,and50%with role impairment. Eighty-two percent of patients reported fatigue symptoms,72.8%reported pain,50%reported appetite loss,39.1%reported insomnia, and36.9%reported nausea/vomiting, whereas other symptoms (dyspnea, diarrhea, constipation) inthe QLQ-C30were reported by fewer than30%of patients. Differences between or withinsub-groups at baseline with respect to each patient characteristic variable were assessedfor all QoL subscales or items using the Mann Whitney U-test or Kruskal-Wallis test.Spearman’s rank correlation was used to investigate relationships between the age, KPS,WHO grade and QLQ-C30subscales and items. A chi-square test estimated the constituentratio of MMSE scores between different age subgroups. Global health status/quality of life(QoL) were strongly correlated with fatigue and pain symptoms and all "functioning"scales. Fatigue was strongly related to all functioning scales, pain, appetite loss, and globalhealth status/QoL. No difference in baseline HRQOL prior to surgery was reportedbetween females and males, among different lesion locations, or between normal-andabnormal-cognition subgroups of glioma patients. Patients older than50reported worsephysical and role functioning, worse global health status/QoL, and more insomnia andconstipation symptoms than those younger than50. The proportion of patients diagnosedwith abnormal cognition by MMSE was significantly larger in patients older than50thanin patients younger than50. Patients with KPS less than80reported worse physical, role,emotional, cognitive, and social functioning, worse global health status/QoL, and moresymptoms of fatigue, pain, insomnia and appetite loss than those with KPS80-100.Abnormal cognition according to MMSE was associated with worse KPS compared withnormal cognition. Compared with patients with grade II and III tumors, patients withgrade IV tumors reported significantly worst physical, role, emotional and socialfunctioning scores, worse global health status/QoL, and more fatigue and pain symptoms.Patients with recurrent glioma showed worse physical and social function and worseglobal health status/QoL than newly diagnosed glioma patients. Spearman correlationanalyses showed a significant relationship between KPS and physical functioning, fatigue, cognitive functioning, role functioning and global health status/QoL in the QLQ-C30.Neither age nor WHO grade was related to any scale or item in the QLQ-C30. It wasimpossible to compare the HRQOL between pre-surgery and post-surgery as there was toomuch of loss to follow these data provided the baseline HRQOL in glioma patients prior tosurgery in China. Most pre-surgery glioma patients indicated emotional, social, cognitive,physical, and role impairment. Fatigue, pain, appetite loss, insomnia, and nausea/vomitingwere common in these patients. The fatigue and pain symptoms and all types offunctioning strongly affected global health status/QoL. Old age, worse performance status,WHO grade IV and tumor recurrence had deleterious effects on HRQOL. It is important tominimize loss to follow-up in future study of HRQOL.更多还原