季丽莉, 陈 晨, 张雪皎, 王伟光, 程志祥, 袁 玲, 魏 征, 承璐雅, 庄静丽, 王志梅, 李 锋, 邹善华, 刘 澎
复旦大学附属中山医院血液科,上海 200032
·论 著·
Frailty评分预测老年多发性骨髓瘤的临床分析
季丽莉, 陈 晨, 张雪皎, 王伟光, 程志祥, 袁 玲, 魏 征, 承璐雅, 庄静丽, 王志梅, 李 锋, 邹善华, 刘 澎*
复旦大学附属中山医院血液科,上海 200032
目的: 运用Frailty评分体系预测老年多发性骨髓瘤(multiple myeloma,MM)患者临床转归的研究分析。方法: 对复旦大学附属中山医院血液科2015年1月1日至2016年2月29日收治的29例65岁以上老年MM患者进行Frailty评分,以分析其与患者临床转归的关系。结果: Frailty评分高危组13例(44.8%)、中危组5例(17.2%)、低危组11例(37.9%),3组患者在ISS分期(P=0.281)和化疗强度(P=0.475)上的差异无统计学意义。Frailty高危组患者不良反应较多,血液学3级及以上不良发生率(69.2%)显著高于低危组(18.2%,P=0.014)和中危组(0.0,P=0.011);高危组非血液学3级及以上不良反应发生率(84.6%)显著高于低危组(18.2%,P=0.001)和中危组(20.0%,P=0.011)。高危组中有69.2%的患者中断、延缓化疗或减小化疗强度,显著高于低危组(9.1%,P=0.004),与中危组差异无统计学意义(40.0%,P=0.268)。高危组患者化疗后获完全缓解(CR)及极好的部分缓解(VGPR)的患者占30.8%、部分缓解(PR)者占23.1%、无效(NR)者占46.2%,显著低于低危组(CR及VGPR 63.6%、PR 36.4%、NR 0.0,P=0.027),与中危组比较差异无统计学意义(CR及VGPR 40.0%、PR 20.0%、NR 40.0%,P=0.751)。结论: Frailty评分体系可预测高危患者治疗的不良反应和疗效,高危患者预后差,但其对预后评估价值的大小有待更大样本量的阐明。
多发性骨髓瘤;Frailty评分;老年;不良反应
多发性骨髓瘤(multiple myeloma,MM)多发于40岁以上的人群,美国 1975—2007年的数据[1]表明,60%以上的MM患者是65岁以上的老年人。随着社会人口老龄化,在近几十年,老年人中MM发病率逐渐升高[2]。一项亚裔人群的调查[3]证实,75~79岁年龄段的MM发病率在20多年间增加了5.2倍。
高龄是MM独立的预后不良因素,其原因尚不明确,可能与老年患者化疗耐受性差相关[4-6]。老年评分系统(geriatric assessment,GA)是一个评估老年患者意识、功能状态和合并疾病的工具,已广泛用于评估老年恶性肿瘤患者的综合状态[7-8]。已有研究[1]将GA用于评价老年MM患者,并结合年龄因素组成新的MM老年患者Frailty评分体系。本研究将这一评分体系用于65岁及65岁以上MM患者的评价,以了解这一体系是否有助于预测其临床转归,为临床决策提供帮助。
1.1 一般资料 2015年1月1日至2016年2月29日,复旦大学附属中山医院血液科共收治年龄≥65岁MM患者29例。根据国际多发性骨髓瘤工作组2014年标准治疗指征[9],其中可评价患者29例(男性17例、女性12例),中位年龄69岁(65~82岁)。29例患者中,1例为复发MM患者,28例为新诊断患者。其中26例已完成4周期诱导化疗,3例患者诊断后1个疗程化疗后死亡。化疗方案包括以硼替佐米为基础的硼替佐米、环磷酰胺、地塞米松(VCD);硼替佐米、阿霉素、地塞米松(PAD);硼替佐米、沙利度胺、地塞米松(VTD)和硼替佐米、地塞米松(BD)方案以及来那度胺为基础的来那度胺、地塞米松(RD)方案。
1.2 随访参数 患者治疗前检测血清β2微球蛋白、清蛋白水平,完成ISS分期。完成4周期化疗患者按照美国国立综合癌症网络(National Comprehensive Cancer Network ,NCCN)多发性骨髓瘤指南(2016 V2)的疗效标准评价疗效[10]:分为完全缓解(CR)和非常好的部分缓解(VGPR)组,部分缓解(PR)组,其余为无效(NR)组。治疗过程中根据美国国家癌症研究所常见不良事件术语标准(National Cancer Institute Common Terminology Criteria for Adverse Events,NCI-CTCAE)评估患者血液学、非血液学不良反应,并记录患者由于不良反应导致治疗延缓、更改方案或中断治疗的情况。
1.3 Frailty评分 包含患者年龄和GA评分的3个工具,即Katz日常生活评分(Katz activity of daily living,ADL)、Lawton日常生活评分(Lawton instrumental activity of daily living,IADL)以及Charlson合并症指数(Charlson comorbidity index,CCI)[1]。 积分标准如下:年龄<75岁计0分,75~80岁计1分,80岁以上计2分;ADL≤4分者计1分,4分以上计0分;IADL≤5分者计1分,5分以上积0分;CCI≥2分者计1分,2分以下计0分。最后将年龄与3个工具所得积分相加,得到Frailty评分,Frailty评分≥2分者为高危组,1分者为中危组,0分者为低危组。
1.4 统计学处理 应用STATA 7.0软件完成统计分析。由于观察例数少,多组比较采用单因素方差分析和Kruskal Wallis检验;两组比较采用Wilcoxon Rank Sum 检验。检验水准(α)为0.05。
2.1 患者临床分期及Frailty分组概况 患者治疗前按照Frailty积分体系,分为高危组13例(44.8%)、中危组5例(17.2%)、低危组11例(37.9%)。按NCCN多发性骨髓瘤指南(2016 V2)进行ISS分期[10],ISSⅠ期患者1例(3.4%),ISS Ⅱ期患者6例(20.7%),ISSⅢ期患者22例(75.9%)。Frailty评分3个组患者的ISS分期差异无统计学意义(P=0.281),见表1。所有患者均给予硼替佐米、来那度胺作为基础药物,3组均有患者接受两药或三药方案,仅高危组1例患者接受硼替佐米单药治疗,3组治疗方案差异无统计学意义(P=0.475,表1)。
2.2 Frailty高危组血液学不良反应、非血液学不良反应发生率更高 分析3组3级及3级以上化疗不良反应的发生率,血液学不良反应、非血液学不良反应,以高危组发生率最高,差异均具有统计学意义(血液学不良反应P=0.007, 非血液学不良反应P=0.002),见表2。进一步进行两两比较发现,高危组患者3级及以上血液学不良反应发生率分别高于低危组(P=0.014)和中危组(P=0.011),而中危组和低危组的血液学3级及以上级别不良反应发生率间的差异无统计学意义(P=0.324);非血液学3级及以上级别不良反应发生率的比较发现,高危组显著高于低危组(P=0.001)和中危组(P=0.011),中危组和低危组间的差异无统计学意义(P=0.933)。
表1 3组患者的基本临床数据 n(%)
表2 3组患者化疗的相关不良反应 n(%)
2.3 Frailty高危组中较多患者无法坚持初始方案治疗 高危组患者中3例化疗1疗程后死亡,4例因不良反应严重而延缓治疗,2例因无法耐受三药方案改为两药方案,以上9例患者无法坚持初始方案治疗,发生率达69.2%;中危组有2例患者因不良反应严重而延缓治疗,无法坚持初始方案治疗发生率为40.0%;低危组患者1例因不良反应三药方案改为两药方案,无法坚持初始方案治疗发生率为9.1%,差异有统计学意义(P=0.014)。高危组无法坚持初始方案治疗的患者数显著高于低危组(P=0.004),与中危组比较差异无统计学意义(P=0.268);中危组和低危组间差异亦无统计学意义(P=0.155)。
2.4 Frailty高危组患者疗效较差 29例患者中,3例高危组患者化疗1疗程后病死,按本研究标准视为无效。26例完成4周期诱导治疗的患者按NCCN多发性骨髓瘤指南(2016 V2)进行疗效评价。本研究分为CR+VGPR组、PR组和NR组,3组间疗效差异无统计学意义(P=0.080),见表3。但各组两两比较发现,高危组与低危组间差异有统计学意义(P=0.027),其余各组间差异无统计学意义(高危组与中危组P=0.751,中危组与低危组P=0.182)。
表3 3组患者化疗效果的评价 n(%)
MM的治疗在最近几十年间有了重要的进步。20世纪80年代引入自体干细胞移植使得适合移植的MM患者生存时间显著延长[11];2000年后推出的新药方案(包括硼替佐米、来那度胺为基础的化疗方案)进一步改善了MM患者的生存时间[4,12-15]。但是,一项瑞典的流行病学调查数据[16]显示,几十年来新药受益的5年相关生存率(relative survival rate, RSR)仅局限在70岁以下患者,10年RSR改善也只体现在60岁以下患者。英国的一项研究[17]表明,虽然60岁以上老年患者的5年RSR有所改善,但差异无统计学意义。
大多数学者认为无法耐受化疗的不良反应是影响MM老年患者预后的重要因素[4-6],部分体能状态好的MM老年患者,采用高剂量化疗、甚至自体干细胞移植生存期可获得显著改善[18-20];一些耐受性差的MM老年患者,给予不良反应较小的治疗方案,甚至以支持治疗为主,可能更为妥当[21]。MM作为一种老年疾病,65岁以上患者占据相当大的比例,有效地评估这些患者的预后及其对化疗的耐受性,给予个体化的治疗,将有可能改善预后[22]。
GA评分是有效评价恶性肿瘤老年患者综合情况的体系[23],在MM老年患者中结合年龄因素,采用Frailty积分体系,能更好地预测患者的生存时间和化疗相关的不良反应。国外大样本量的研究[1]证实,Frailty积分体系能有效评估预后及化疗耐受性。我们首次将Frailty积分系统用于评估中国MM老年患者预后。本研究数据显示,Frailty评分3个组患者的ISS分期差异无统计学意义(P=0.281),且三组患者的治疗方案差异无统计学意义(P=0.475),因此,患者的分期和治疗强度在各Frailty分组是平衡的,对本研究无实质影响。
本研究中,Frailty高危组患者占44.8%,这群患者对化疗的耐受性较差,血液学和非血液学3级及以上不良反应发生率较高,同时无法耐受原方案化疗的比例也高,由此更换了强度较低的方案,甚至延缓治疗,这两个因素可能造成高危组患者疗效差。基于经验,Frailty高危组患者化疗耐受性差,治疗时更需要关注安全性,而盲目追求疗效、增加化疗强度是不合适的。中危组患者观察例数较少,还不足以得出有说服力的结论。低危组患者一般状况好,不良反映较轻,且都能坚持按时完成治疗疗程,因此63.6%的患者得到了VGPR以上的疗效,与国外报道的MM患者总体疗效接近[24]。对于这一类患者是否能进一步增加化疗强度以得到更好的疗效,还需要大规模临床试验来阐明。
综上所述,Frailty积分体系在我中心29例患者中得到了初步试用,所得结果与国外研究报道相符合:Frailty积分体系能反映患者的综合状态,可有效预测患者化疗的耐受性;Frailty高危患者需要减轻化疗强度、降低化疗不良反应发生率,以提高这部分患者的生活质量。当然,该积分系统对中国老年多发性骨髓瘤患者的预后评估价值有待通过更大样本量的研究来明确。
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[本文编辑] 叶 婷, 晓 璐
Clinical analysis of the Frailty score in the prognosis of elderly multiple myeloma
JI Li-li, CHEN Chen, ZHANG Xue-jiao, WANG Wei-guang, CHENG Zhi-xiang, YUAN Ling, WEI Zheng, CHENG Lu-ya, ZHUANG Jing-li, WANG Zhi-mei, LI Feng, ZOU Shan-hua, LIU Peng*
Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Objective: To analyze the Frailty score in the prognosis of elderly multiple myeloma. Methods: Twenty nine multiple myeloma patients aged above 65 year-old admitted from January 1, 2015 to February 29, 2016 were enrolled in the study. Frailty score assessment was performed and its relation with clinical outcome was analyzed. Results: The 13 patients were classified into high risk group (44.8%), 5 cases in mediate group (17.2%), and 11 cases in low risk group (37.9%). There were no statistical significance in the aspects of ISS stage (P=0.281) or chemotherapy intensity (P=0.475) found among the three groups. More patients (69.2%) in the Frailty high risk group suffered severe hematologic adverse events (≥grade 3), which was significantly higher than low risk group (18.2%,P=0.014) and mediate risk group (0.0,P=0.011). The occurrence of adverse reaction in severe non-hematologic group (≥grade 3) (84.6%) was higher than that of low risk group(18.2%,P=0.001) and that of mediate risk group(20.0%,P=0.011). There were 69.2% of patients in high risk group had chemotherapy discontinuation, delay or chemotherapy intensity reduction, which was significantly higher than low risk group (9.1%,P=0.004), and no statistical significance was observed in the mediate risk group (40.0%,P=0.268). In the terms of therapy efficacy, 30.8%, 23.1%, and 46.2% patients obtained complete remission or very good remission(CR+VGPR), partial remission (PR), and no remission (NR) in the high risk group, which were significantly lower than low risk group(CR+VGPR 63.6%, PR 36.4%, NR 0.0,P=0.027). No statistical significance of the efficacy was found between high risk group and mediate risk group (CR+VGPR 40.0%, PR 20.0%, NR 40.0%,P=0.751).Conclusions: The Frailty score can predict the adverse reaction and treatment efficacy, but with poor prognosis in high risk patients, and its clinical value in prognosis required further research.
multiple myeloma; Frailty score; elderly; adverse event
2016-06-01 [接受日期] 2016-08-06
国家自然科学基金(81300381, 81570123),上海市卫计委青年科研项目(20134y117). Supported by National Natural Science Foundation of China (81300381, 81570123) and Youth Research Projects of Shanghai Municipal Commission of Health and Family Planning(20134y117).
季丽莉,博士,主治医师. E-mail: ji.lili@zs-hospital.sh.cn
*通信作者(Corresponding author). Tel: 021-60267405, E-mail: liu.peng@zs-hospital.sh.cn
10.12025/j.issn.1008-6358.2016.20160734
R 733.3
A