身体剂量参数对局部晚期鼻咽癌患者免疫细胞减少的影响分析：一项回顾性队列研究

doi:10.19401/j.cnki.1007-3639.2023.10.002

摘要/Abstract

摘要：

背景与目的： 调强适形放疗（intensity-modulated radiotherapy，IMRT）可显著提升局部晚期鼻咽癌患者的生存结局，然而该疗法仍未能满足局部晚期鼻咽癌（locally-advanced nasopharyngeal carcinoma，LANPC）患者的预后需求，因此，确定有效的预后预测标志物对于改善放疗的效果和实现个体化治疗至关重要。由于放疗相关的身体剂量参数和免疫炎性标志物在以往的研究中显示出潜在的预测价值，本研究旨在探讨局部晚期鼻咽癌患者放疗过程中身体剂量参数与免疫细胞减少及预后之间的关系。方法： 回顾性分析了2012年1月1日—2016年12月31日在复旦大学附属肿瘤医院接受根治性放疗的423例LANPC患者（Ⅲ ~ Ⅳa期）的临床资料，研究IMRT期间多种免疫细胞的百分比变化范围。采用Cox比例风险回归模型来确定患者总生存（overall survival，OS）、局部无复发生存（locoregional relapse-free survival，LRFS）和无远处转移生存（distant metastasis-free survival，DMFS）的独立预后因素。从剂量-体积直方图（dose-volume diagrams，DVH）中获取一系列身体剂量参数（body dose parameters），采用logistic回归确定与白细胞变化相关的影响因素。结果： 较高的淋巴细胞变化范围[ΔLYM%≥77.0%（high ΔLYM%）]和较高的单核细胞变化范围[ΔMONO%≥28.5%（high ΔMONO%）]是局部晚期鼻咽癌患者的两个不良预后因素。多因素分析结果显示，high ΔLYM%被证明是OS（HR = 1.672，P = 0.012）、LRFS（HR = 1.712，P = 0.006）和DMFS（HR = 1.971，P = 0.001）的不良预后因素；High ΔMONO%可作为OS（HR = 1.355，P = 0.015）和DMFS（HR = 1.704，P = 0.003）的不良预后因素。ΔLYM%变化值受身体剂量参数中的身体辐照总剂量（integral body dose，IBD）（OR = 1.004，P = 0.037）和body V₆₀（OR = 1.046，P = 0.036）的影响，而ΔMONO%受body V₅₅（OR = 1.144，P = 0.009）和V₇₀（OR = 0.734，P = 0.022）的影响。结论： IBD、body V₆₀和body V₅₅、V₇₀可作为放疗计划中的剂量限制区域，以减轻对淋巴细胞和单核细胞的消耗，进一步改善预后。

关键词: 队列研究, 回顾性研究, 局部晚期鼻咽癌, 淋巴细胞, 单核细胞, 身体剂量参数

Abstract:

Background and purpose: The implementation of intensity-modulated radiotherapy (IMRT) has significantly enhanced the survival outcomes for patients with nasopharyngeal carcinoma (NPC). However, this therapeutic approach still falls short in meeting the prognostic requirements of individuals with locally advanced NPC (LANPC). Therefore, it is imperative to identify effective prognostic markers to enhance the efficacy of radiotherapy and achieve personalized treatment. Given the potential predictive value demonstrated in previous studies regarding radiotherapy-related body dose parameters and immune blood cells, this study aimed to investigate the correlation between body dose parameters and reduced immune cells and patient prognosis during radiotherapy in LANPC patients. Methods: Clinical data of 423 patients with LANPC (stage Ⅲ-Ⅳa) treated in Fudan University Shanghai Cancer Center from Jan.1, 2012 to Dec. 31, 2016 were retrospectively analyzed. Percentage changes of different immune blood cells during radiotherapy were also collected. Cox proportional hazard model was used to determine prognostic factors for overall survival (OS), locoregional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). Body dose-based parameters were extracted from dose-volume histograms (DVHs). Logistic regression was applied to determine parameters that could predict white blood cells reduction. Results: High ΔLYM% (ΔLYM%≥7 7.0%) and high ΔMONO% (ΔMONO%≥2 8.5%) were identified as two adverse prognostic factors in LANPC patients. In multivariable analysis, high ΔLYM% was found to be a significant predictor of worse OS (HR = 1.672, P = 0.012), LRFS (HR = 1.712, P = 0.006), and DMFS (HR = 1.971, P = 0.001). High ΔMONO% was associated with worse OS (HR = 1.355, P = 0.015) and DMFS (HR = 1.704, P = 0.003). The change of ΔLYM% was influenced by the integral body dose (IBD) (OR = 1.004, P = 0.037) and body V₆₀ (OR = 1.046, P = 0.036). ΔMONO% was significantly affected by body V₅₅ (OR = 1.144, P = 0.009) and V₇₀ (OR = 0.734, P = 0.022). Conclusion: Integral body dose, V₆₀, and V₅₅, V₇₀ can serve as dose-volume constraints to retain sufficient immune cell populations to improve prognosis.

Key words: Cohort study, Retrospective study, Locally advanced nasopharyngeal carcinoma, Lymphocyte, Monocyte, Body dose parameter

中图分类号:

江健韵, 翟瑞萍, 应红梅. 身体剂量参数对局部晚期鼻咽癌患者免疫细胞减少的影响分析：一项回顾性队列研究[J]. 中国癌症杂志, 2023, 33(10): 898-907.

JIANG Jianyun, ZHAI Ruiping, YING Hongmei. Impact of body dose parameters on circulating immune cells in locally advanced nasopharyngeal carcinoma patients: a retrospective cohort study[J]. China Oncology, 2023, 33(10): 898-907.

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参考文献 36

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Characteristics	Overall (n = 423)	Characteristics	Overall (n = 423)
Gender n (%)		Concurrent chemotherapy n (%)
Female	110 (26.0)	Yes	104 (24.6)
Male	313 (74.0)	No	319 (75.4)
Age, median (IQR)	49 (40, 57)	Adjuvant chemotherapy n (%)
Overall stage n (%)		Yes	179 (42.3)
Ⅲ	168 (39.7)	No	244 (57.7)
ⅣA	255 (60.3)	Dose to PTV-G (Gy) n (%)
T stage		66.0	88 (20.8)
T₁	23 (5.4)	70.4	335 (79.2)
T₂	113 (26.7)	ΔWBC n (%)
T₃	176 (41.6)	<25.5%	211 (49.9)
T₄	111 (26.2)	≥25.5%	212 (50.1)
N stage		ΔLYM n (%)
N₀	6 (1.4)	<77.0%	206 (48.7)
N₁	76 (18.0)	≥77.0%	217 (51.3)
N₂	169 (40.0)	ΔMONO n (%)
N₃	172 (40.7)	<28.5%	211 (49.9)
Pathological type n (%)		≥28.5%	212 (50.1)
Non-keratinized differentiated	10 (2.4)	ΔNEU n (%)
Non-keratinized undifferentiated	413 (97.6)	<22.6%	211 (49.9)
Induction chemotherapy n (%)		≥22.6%	212 (50.1)
Yes	286 (67.6)	ΔPLT n (%)
No	137 (32.4)	17.0%	211 (49.9)
		≥17.0%	212 (50.1)

Characteristics	OS		LRFS		DMFS
Characteristics	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
Gender (male vs female) (male vs female)	-	-	-	-	1.81 (0.92-3.58)	0.087
Age	1.05 (1.02-1.07)	<0.001	1.02 (0.99-1.04)	0.144	-	-
TNM Ⅳa vs TMN Ⅲ (ⅣA vs Ⅲ)	3.08 (1.72-5.51)	<0.001	2.61 (1.32-5.17)	0.006	2.06 (1.56-4.40)	0.023
Induction chemotherapy	0.26 (0.15-0.46)	<0.001	0.39 (0.24-0.64)	<0.001	0.25 (0.15-0.41)	< 0.001
Concurrent chemotherapy	-	-	-	-	-	-
Adjuvant chemotherapy	0.50 (0.27-0.93)	0.028	-	-	-	-
PTV-G (70.4 vs 60.0 Gy)	-	-	-	-	-	-
ΔWBC%	-	-	-	-	-	-
ΔLYM%	1.18 (1.02-2.32)	0.043	1.13 (1.08-1.64)	0.028	1.31 (1.09-2.50)	0.011
ΔMONO%	1.03 (1.01-2.01)	0.047	-	-	1.17 (1.02-2.07)	0.021
ΔNEU%	-	-	1.60 (0.99-2.59)	0.055	-	-
ΔPLT%	-	-	-	-	-	-

Characteristics	Univariable analysis		Multivariable analysis
Characteristics	Odds ratio (95% CI)	P value	Odds ratio (95% CI)	P value
Gender
Female	Reference
Male	0.925 (0.587-1.458)	0.738	-	-
Age	1.070 (1.054-1.086)	<0.001	1.071 (1.054-1.087)	<0.001
Overall stage
Ⅲ	Reference
ⅣA	1.171 (0.778-1.761)	0.449	-	-
Induction chemotherapy
No	Reference
Yes	1.290 (0.838-1.984)	0.247	-	-
Concurrent chemotherapy
No	Reference
Yes	1.471 (0.925-2.339)	0.103	-	-
PTV-P
66.0	Reference
70.4	1.066 (0.629-1.806)	0.812	-	-
MBD	1.000 (1.000-1.000)	0.129	-	-
IBD	1.004 (1.001-1.009)	0.013	1.004 (1.001-1.010)	0.037
V₅	1.002 (0.970-1.009)	0.321	-	-
V₁₅	1.018 (0.967-1.111)	0.317	-	-
V₄₅	1.019 (0.964-1.078)	0.501	-	-
V₅₅	1.000 (0.937-1.067)	0.989	-	-
V₆₀	1.068 (1.006-1.169)	0.053	1.046 (1.030-1.154)	0.036
V₆₅	1.003 (0.892-1.105)	0.892	-	-
V₇₀	0.946 (0.765-1.171)	0.612	-	-

Characteristics	Univariable analysis		Multivariable analysis
Characteristics	Odds ratio (95% CI)	P value	Odds ratio (95% CI)	P value
Gender
Female	Reference
Male	0.881 (0.540-1.439)	0.612	-	-
Age	0.993 (0.976-1.010)	0.399	-	-
Overall stage
Ⅲ	Reference		Reference
ⅣA	0.668 (0.429-1.041)	0.075	0.512 (0.275-0.954)	0.035
Induction chemotherapy
No	Reference
Yes	0.899 (0.567-1.427)	0.653	-	-
Concurrent chemotherapy
No	Reference
Yes	1.386 (0.835-2.299)	0.207	-	-
PTV-P
66.0	Reference
70.4	1.082 (0.614-1.907)	0.786	-	-
MBD	1.000 (1.000-1.001)	0.224	-	-
IBD	0.997 (0.991-1.002)	0.228	-	-
V₅	1.010 (0.990-1.032)	0.327	-	-
V₅₅	1.068 (0.988-1.154)	0.097	1.144 (1.034-1.265)	0.009
V₇₀	0.827 (0.661-1.034)	0.096	0.734 (0.564-0.957)	0.022