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作为一种发病率最高的淋巴瘤类型,弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma, DLBCL)具有较高的异质性,患者对治疗的反应以及预后结果差异较大[1-2] 。利妥昔单抗+环磷酰胺+多柔比星+长春新碱+泼尼松(R-CHOP )作为DLBCL一线标准治疗方案被医学界证实可以有效延长患者的生存时间[3]。然而,仍然有30%~40%的患者最终出现复发和死亡[4]。目前,国际预后指数(international prognostic index,IPI)以及美国国家综合癌症网络(National Comprehensive Cancer Network, NCCN)-IPI等临床评价标准被临床广泛使用,但有研究者报道其预测预后的价值有限[5-7]。因此,建立一种有效的风险预测模型对DLBCL患者进行更加准确的预后评估十分必要,并可为患者精准个性化治疗提供依据。
18F-FDG PET/CT在淋巴瘤分期及疗效评价中的价值已被国内外医学界广泛认可和推荐[8]。有研究结果表明,PET代谢参数[如SUVmax、总肿瘤代谢体积(total metabolic tumor volume, TMTV)以及糖酵解总量(total lesion glycolysis, TLG)]能够有效预测DLBCL患者的预后[9-10]。本研究基于PET代谢参数及临床指标建立DLBCL患者预后的预测模型,并对模型进行验证和评价。
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训练组随访时间33.5(17, 49)个月(2~117个月),验证组随访时间29.0(15, 46)个月(4~96个月)。随访截止时,训练组患者疾病进展95例、死亡68例;验证组患者疾病进展41例、死亡33例。训练组ROC曲线分析结果显示,SUVmax、TMTV及TLG的最佳诊断阈值为21.6、220.6 cm3及1 282.8 g。
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训练组单因素分析结果显示,年龄、LDH水平、ECOG PS评分、Ann Abor分期、大包块、TMTV及TLG为预测PFS期的危险影响因素(均P<0.05);年龄、LDH水平、B症状、ECOG PS评分、Ann Abor分期、大包块、TMTV及TLG为预测OS期的危险影响因素(均P<0.05,表1)。训练组多因素分析结果显示,年龄、LDH水平、Ann Abor分期及TLG(图1)是预测PFS期和OS期的独立影响因素(均 P<0.05,表2)。
因素 例数 无进展生存期 总生存期 HR(95%CI) P值 HR(95%CI) P值 性别(男/女) 142/126 1.012(0.675~1.518) 0.953 0.894(0.555~1.439) 0.643 年龄(<60岁/≥60岁) 151/117 2.017(1.341~3.035) 0.001 2.549(1.548~4.197) <0.001 LDH水平(正常/升高) 157/111 2.065(1.375~3.101) <0.001 2.304(1.417~3.745) 0.001 B症状(无/有) 168/100 1.459(0.973~2.188) 0.068 1.661(1.031~2.677) 0.037 ECOG PS评分(0~1分/≥2分) 201/67 1.671(1.092~2.559) 0.018 1.755(1.066~2.888) 0.027 Ann Abor分期(Ⅰ、Ⅱ期/Ⅲ、Ⅳ期) 117/151 2.922(1.812~4.713) <0.001 3.600(1.965~6.596) <0.001 结外累及(无/有) 90/178 1.351(0.865~2.112) 0.186 1.209(0.723~2.023) 0.470 骨髓累及(无/有) 220/48 1.381(0.856~2.230) 0.186 1.687(0.983~2.897) 0.058 大包块(无/有) 195/73 1.670(1.096~2.545) 0.017 1.825(1.116~2.984) 0.016 病理分型(无/有) 138/130 1.287(0.860~1.925) 0.221 1.399(0.868~2.256) 0.168 SUVmax(<21.6/≥21.6) 162/106 1.734(1.157~2.599) 0.170 1.538(0.953~2.481) 0.164 TMTV(<220.6 cm3/≥220.6 cm3) 186/82 2.712(1.812~4.060) <0.001 3.293(2.040~5.316) <0.001 TLG(<1 282.8 g/≥1 282.8 g) 183/85 3.277(2.186~4.911) <0.001 4.193(2.574~6.829) <0.001 注:DLBCL为弥漫大B细胞淋巴瘤;LDH为乳酸脱氢酶;ECOG PS为美国东部肿瘤协作组行为状态;SUVmax 为最大标准化摄取值;TMTV为总代谢肿瘤体积;TLG为糖酵解总量;HR为危险比;CI为置信区间 表 1 影响训练组268例DLBCL患者无进展生存期和总生存期的单因素分析
Table 1. Univariate analysis of influencing of progression free survival and overall survival in the training group 268 patients with diffuse large B-cell lymphoma
因素 无进展生存期 总生存期 HR(95%CI) P值 HR(95%CI) P值 年龄 2.054(1.355~3.112) 0.001 2.760(1.652~4.611) <0.001 LDH水平 1.589(1.030~2.451) 0.001 1.679(1.005~2.804) 0.048 Ann Abor分期 2.099(1.268~3.476) 0.004 2.333(1.240~4.388) 0.009 TLG 2.603(1.669~4.058) <0.001 3.367(1.980~5.728) <0.001 注:DLBCL为弥漫大B细胞淋巴瘤;LDH为乳酸脱氢酶;TLG为糖酵解总量;HR为危险比;CI 为置信区间 表 2 影响训练组268例DLBCL患者无进展生存期和总生存期的多因素分析
Table 2. Multivariate analysis of influencing of progression free survival and overall survival in the training group 268 patients with diffuse large B-cell lymphoma
图 1 弥漫大B细胞淋巴瘤患者(训练组)的临床参数及18F-FDG PET代谢参数TLG对其无进展生存期和总生存期预后的Kaplan-Meier生存分析曲线
Figure 1. Kaplan-Meier survival analysis curve of clinical parameters and 18F-FDG PET metabolic parameters total lesion glycolysis of patients with diffuse large B-cell lymphoma (training group) to progression free survival and overall survival
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利用多因素Cox比例风险回归分析筛选结果中的年龄、LDH水平、Ann Abor分期及TLG分别构建预测PFS期和OS期列线图生存预测模型(图2A、3A)。图2和图3中的校准曲线显示,预测PFS期和OS期模型在训练组和验证组中预测生存率和实际生存率之间均具有较好的一致性;时间依赖型ROC曲线显示,与传统预后工具(NCCN-IPI和IPI)相比,列线图生存预测模型在大多数时间点AUC均较大;临床DCA结果显示,与NCCN-IPI及IPI相比,列线图生存预测模型可以使患者有更多的临床获益。C-index显示,列线图生存预测模型分别与NCCN-IPI和IPI相比,在训练组和验证组中均具有更高的诊断准确率(训练组和验证组PFS期:0.724对0.703对0.707、0.762对0.739对0.728;训练组和验证组OS期:0.749对0.726对0.738、0.753对0.705对0.672)。
图 2 预测弥漫大B细胞淋巴瘤患者PFS期的列线图生存预测模型(A)及其在训练组(B)和验证组(C)中的校准曲线(左)、时间依懒型ROC曲线(中)和临床决策曲线(右)
Figure 2. The nomogram of model for predicting progression free survival in diffuse large B-cell lymphoma patients (A), calibration curves, time dependent receiver operating characteristic curve and clinical decision curve of the model for predicting progression free survival in the training group (B) and validation group (C)
图 3 预测弥漫大B细胞淋巴瘤患者OS期的列线图生存曲线模型(A)及其在训练组(B)和验证组(C)中的校准曲线(左)、时间依懒型ROC曲线(中)和临床决策曲线(右)
Figure 3. The nomogram of model for predicting overall survival in diffuse large B-cell lymphoma patients (A), calibration curves, time dependent receiver operating characteristic curve and clinical decision curve of the model for predicting overall survival in the training group (B) and validation group (C)
基于18F-FDG PET代谢参数及临床参数的列线图生存预测模型预测弥漫大B细胞淋巴瘤患者预后的价值
The prognostic value of nomogram survival prediction model based on 18F-FDG PET metabolic parameters and clinical parameters of patients with diffuse large B-cell lymphoma
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摘要:
目的 构建基于18F-氟脱氧葡萄糖(FDG)PET代谢参数及临床参数的列线图生存预测模型,并验证其对弥漫大B细胞淋巴瘤(DLBCL)患者预后的预测价值。 方法 回顾性分析2011年3月至2019年11月于南京大学医学院附属鼓楼医院以及南京医科大学第一附属医院经组织病理学检查确诊的383例未经治疗的DLBCL患者的18F-FDG PET/CT影像学资料和临床资料,其中男性204例、女性179例,年龄19~93(47.3±14.9)岁。按照7∶3的比例采用随机数字表法将患者分为训练组(n=268例)和验证组(n=115例)。勾画并计算患者总肿瘤代谢体积(TMTV)和病灶糖酵解总量(TLG)。采用Kaplan Meier生存分析、单因素和多因素Cox比例风险回归模型对患者无进展生存(PFS)期及总生存(OS)期进行预后分析并构建生存预测模型。通过训练组和验证组的校准曲线、一致性指数(C-index)以及临床决策曲线分析(DCA)对预测模型进行评估。 结果 训练组单因素分析结果显示,年龄、乳酸脱氢酶(LDH)水平、美国东部肿瘤协作组行为状态(ECOG PS)评分、Ann Abor分期、大包块、TMTV及TLG为预测PFS期的危险影响因素(HR=1.670~3.277,均P<0.05);年龄、LDH水平、B症状、ECOG PS评分、Ann Abor分期、大包块、TMTV及TLG为预测OS期的危险影响因素(HR=1.661~4.193,均P<0.05)。训练组多因素分析结果表明,年龄、LDH水平、Ann Abor分期及TLG是预测DLBCL患者PFS期和OS期的独立影响因素(HR=1.589~3.367,均P<0.05)。校准曲线显示,该预测模型具有较好的预测一致性;C-index评估结果显示,训练组和验证组预测模型具有较高的准确性(PFS期:0.724对0.762; OS期:0.749对0.753)。临床DCA结果表明,预测模型可以给患者带来更多的临床获益。 结论 基于18F-FDG PET代谢参数TLG及临床参数(年龄、LDH水平、Ann Abor分期)生存预测模型能够很好地对DLBCL患者进行预后评估,为精准个性化治疗提供可能。 -
关键词:
- 淋巴瘤,大B细胞,弥漫性 /
- 正电子发射断层显像术 /
- 体层摄影术,X线计算机 /
- 氟脱氧葡萄糖F18 /
- 预后 /
- 预测模型
Abstract:Objective To construct prognostic nomogram models of 18F-fluorodeoxyglucose (FDG) PET-based metabolic and clinical parameters and validate their importance to survival prediction of patients with diffuse large B-cell lymphoma (DLBCL). Methods 18F-FDG PET image and clinical characteristics of 383 patients with DLBCL who received no treatments and underwent histopathology in the Affiliated Drum Tower Hospital, Medical School of Nanjing University, and the First Affiliated Hospital of Nanjing Medical University from March 2011 to November 2019 were retrospectively analyzed. The patients included 204 males and 179 females, aged 19–93(47.3±14.9) years old. The patients were randomly allocated as the training group (n=268) and validation group (n=115) at a 7∶3 ratio. The total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) were computed. Kaplan-Meier survival analysis, univariate and multivariate Cox proportional hazard regression models were used to evaluate progression-free survival (PFS) and overall survival (OS). The models were construct, and performance was assessed and validated with regard to calibration, discrimination, and clinical usefulness by calibration curve, concordance index (C-index), and decision curve analysis (DCA). Results Univariate analysis indicated that age, lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance status (ECOG PS) score, Ann Abor stage, bulky, TMTV, and TLG were factors for predicting PFS in the training group (HR=1.670–3.277, all P<0.05). Age, LDH level, B symptoms, ECOG PS score, Ann Abor stage, bulky, TMTV, and TLG were factors for predicting OS in the training group (HR=1.661–4.193, all P<0.05). Multivariate Cox regression analyses showed that age, LDH level, Ann Arbor stage, and TLG were independent predictors of PFS and OS of DLBCL patients in the training group (HR=1.589–3.367, all P<0.05). Calibration curves showed that the models had good consistency for survival. The C-index showed that the models exhibited significant prognostic superiority in training and validation group (PFS: 0.724 vs. 0.762; OS: 0.749 vs. 0.753). Clicinal DCA showed that the prediction model could bring more clinical usefulness to patients. Conclusion 18F-FDG PET metabolic (TLG) and clinical (age, LDH level, and Ann Abor stage) parameters can successfully predict patient prognosis, which may promote precision medicine. -
图 1 弥漫大B细胞淋巴瘤患者(训练组)的临床参数及18F-FDG PET代谢参数TLG对其无进展生存期和总生存期预后的Kaplan-Meier生存分析曲线
Figure 1. Kaplan-Meier survival analysis curve of clinical parameters and 18F-FDG PET metabolic parameters total lesion glycolysis of patients with diffuse large B-cell lymphoma (training group) to progression free survival and overall survival
图 2 预测弥漫大B细胞淋巴瘤患者PFS期的列线图生存预测模型(A)及其在训练组(B)和验证组(C)中的校准曲线(左)、时间依懒型ROC曲线(中)和临床决策曲线(右)
Figure 2. The nomogram of model for predicting progression free survival in diffuse large B-cell lymphoma patients (A), calibration curves, time dependent receiver operating characteristic curve and clinical decision curve of the model for predicting progression free survival in the training group (B) and validation group (C)
图 3 预测弥漫大B细胞淋巴瘤患者OS期的列线图生存曲线模型(A)及其在训练组(B)和验证组(C)中的校准曲线(左)、时间依懒型ROC曲线(中)和临床决策曲线(右)
Figure 3. The nomogram of model for predicting overall survival in diffuse large B-cell lymphoma patients (A), calibration curves, time dependent receiver operating characteristic curve and clinical decision curve of the model for predicting overall survival in the training group (B) and validation group (C)
表 1 影响训练组268例DLBCL患者无进展生存期和总生存期的单因素分析
Table 1. Univariate analysis of influencing of progression free survival and overall survival in the training group 268 patients with diffuse large B-cell lymphoma
因素 例数 无进展生存期 总生存期 HR(95%CI) P值 HR(95%CI) P值 性别(男/女) 142/126 1.012(0.675~1.518) 0.953 0.894(0.555~1.439) 0.643 年龄(<60岁/≥60岁) 151/117 2.017(1.341~3.035) 0.001 2.549(1.548~4.197) <0.001 LDH水平(正常/升高) 157/111 2.065(1.375~3.101) <0.001 2.304(1.417~3.745) 0.001 B症状(无/有) 168/100 1.459(0.973~2.188) 0.068 1.661(1.031~2.677) 0.037 ECOG PS评分(0~1分/≥2分) 201/67 1.671(1.092~2.559) 0.018 1.755(1.066~2.888) 0.027 Ann Abor分期(Ⅰ、Ⅱ期/Ⅲ、Ⅳ期) 117/151 2.922(1.812~4.713) <0.001 3.600(1.965~6.596) <0.001 结外累及(无/有) 90/178 1.351(0.865~2.112) 0.186 1.209(0.723~2.023) 0.470 骨髓累及(无/有) 220/48 1.381(0.856~2.230) 0.186 1.687(0.983~2.897) 0.058 大包块(无/有) 195/73 1.670(1.096~2.545) 0.017 1.825(1.116~2.984) 0.016 病理分型(无/有) 138/130 1.287(0.860~1.925) 0.221 1.399(0.868~2.256) 0.168 SUVmax(<21.6/≥21.6) 162/106 1.734(1.157~2.599) 0.170 1.538(0.953~2.481) 0.164 TMTV(<220.6 cm3/≥220.6 cm3) 186/82 2.712(1.812~4.060) <0.001 3.293(2.040~5.316) <0.001 TLG(<1 282.8 g/≥1 282.8 g) 183/85 3.277(2.186~4.911) <0.001 4.193(2.574~6.829) <0.001 注:DLBCL为弥漫大B细胞淋巴瘤;LDH为乳酸脱氢酶;ECOG PS为美国东部肿瘤协作组行为状态;SUVmax 为最大标准化摄取值;TMTV为总代谢肿瘤体积;TLG为糖酵解总量;HR为危险比;CI为置信区间 表 2 影响训练组268例DLBCL患者无进展生存期和总生存期的多因素分析
Table 2. Multivariate analysis of influencing of progression free survival and overall survival in the training group 268 patients with diffuse large B-cell lymphoma
因素 无进展生存期 总生存期 HR(95%CI) P值 HR(95%CI) P值 年龄 2.054(1.355~3.112) 0.001 2.760(1.652~4.611) <0.001 LDH水平 1.589(1.030~2.451) 0.001 1.679(1.005~2.804) 0.048 Ann Abor分期 2.099(1.268~3.476) 0.004 2.333(1.240~4.388) 0.009 TLG 2.603(1.669~4.058) <0.001 3.367(1.980~5.728) <0.001 注:DLBCL为弥漫大B细胞淋巴瘤;LDH为乳酸脱氢酶;TLG为糖酵解总量;HR为危险比;CI 为置信区间 -
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