乳腺癌患者新辅助化疗后凝血相关指标变化与化疗疗效的关系

doi:10.3877/cma.j.issn.1674-0807.2017.02.007

目的

评估乳腺癌患者新辅助化疗(NCT)前后凝血相关指标与化疗疗效的关系。

方法

回顾性分析2010年6 月至2012年5 月在第三军医大学西南医院乳腺外科行NCT 的146 例乳腺癌患者临床资料。 NCT 前后分别取患者静脉血5 ml,检测凝血相关指标[凝血酶原时间(PT)、凝血酶原活性(PT%)、凝血酶原时间国际标准化比例(PTINR)、部分活化凝血活酶时间(APTT)、部分活化凝血活酶时间比值(APTT ratio)、纤维蛋白原(Fib)、凝血酶时间(TT)、血小板(PLT)、D-二聚体(D-D)]。并按实体瘤治疗疗效评价标准评价化疗疗效。患者NCT 前后凝血相关指标的比较采用配对t 检验或配对秩和检验;患者NCT 前或NCT 后凝血相关指标与疗效关系的分析采用独立样本t 检验或秩和检验;患者NCT 后凝血相关指标的变化与疗效关系的分析采用秩和检验。

结果

(1)NCT 后,Fib 和PLT 水平均较NCT 前显著升高[(3.4±0.8) g/L 比(2.8±0.6) g/L, t=9.012,P＜0.001; (245.2±77.7)×10⁹/L 比(193.1±55.2)×10⁹/L, t=8.624,P＜0.001],而D-D 水平较NCT 前显著降低[M(P₂₅ ～ P₇₅): 104.0(74.5 ～162.3) ng/ml 比112.5(79.8 ～197.5) ng/ml, Z=-3.790,P＜0.001],并且,NCT 前后PT、PT%、PTINR、APTT、APTT ratio 和TT 水平的差异均无统计学意义(t=-0.223、0.524、0.347、0.134、0.348、-1.605, P 均＞0.050)。 (2)NCT 前,化疗有效组(80 例)D-D 水平较无效组(66 例)高[M(P₂₅ ～P₇₅):140.0(90.3 ～215.8) ng/ml 比94.5(72.0 ～168.8) ng/ml,Z=-3.201,P=0.001],但2 组间PT、PT%、PTINR、APTT、APTT ratio、Fib、TT 和PLT 水平差异均无统计学意义(t=4.453、2.891、1.782、1.542、0.736、0.104、1.635、0.054,P 均＞0.050)。 (3)NCT 后,化疗有效组与无效组间PT、PT%、PTINR、APTT、APTT ratio、Fib、TT、PLT 及D-D 水平差异均无统计学意义(t=0.112、0.202、0.134、1.784、1.125、0.643、0.435、2.892 及Z=-0.701,P 均＞0.050)。 (4)NCT 后,D-D 降低组92 例,其中化疗有效者61 例,有效率为66.3%,而D-D 升高组54 例,其中化疗有效者19 例,有效率为35.2%;NCT 后D-D 降低组患者化疗有效率更高(Z=-3.642, P＜0.001)。而NCT 后,PT、PT%、PTINR、APTT、APTT ratio、Fib、TT 及PLT的变化值在化疗有效组和无效组间差异均无统计学意义(Z=-0.311、-0.550、-0.214、-0.543、-0.672、-1.583、-0.286、-1.798,P 均＞0.050)。

结论

乳腺癌患者容易出现凝血相关指标异常;化疗可能导致Fib 升高,D-D 降低,PLT 变化,化疗期间有必要监测Fib、D-D 和PLT 水平。 NCT 后D-D 水平降低者化疗疗效更好。

关键词: 乳腺肿瘤, 化学疗法, 辅助, 血液凝固, 治疗结果

Objective

To evaluate the correlation between change of blood coagulation indexes and chemotherapy efficacy after neoadjuvant chemotherapy (NCT) in breast cancer patients.

Methods

Totally 146 patients in Department of Breast Surgery, Southwest Hospital, Third Military Medical University from June 2010 to May 2012 were enrolled and their clinical data were retrospectively analyzed. The 5 ml venous blood was drawn from breast cancer patients before and after NCT to detect blood coagulation related indexes,including prothrombin time (PT), prothrombin activity (PT%), prothrombin time international normalized ratio (PTINR), activated partial thromboplastin time (APTT), APTT ratio, fibrinogen (Fib), thrombin time(TT), platelet (PLT) and D-dimer (D-D). NCT efficacy was evaluated by Response Evaluation Criteria in Solid Tumors. Paired t-test and rank sum test were used to compare the blood coagulation indexes before and after NCT. Independent sample t-test and rank sum test were used to analyze the correlation of NCT efficacy with pre-NCT and post-NCT levels of blood coagulation indexes. Rank sum test was used to analyze the correlation between change of blood coagulation indexes and chemotherapy efficacy after NCT in breast cancer patients.

Results

(1) The levels of Fib and PLT after NCT were significantly higher than pre-NCT values[(3.4±0.8) g/L vs (2.8±0.6) g/L, t=9.012, P＜0.001; (245.2±77.7)×10⁹/L vs (193.1±55.2)×10⁹/L,t=8.624,P＜0.001]. D-D level after NCT was significantly lower than pre-NCT value [M(P₂₅-P₇₅): 104.0(74.5-162.3) ng/ml vs 112.5(79.8-197.5) ng/ml,Z=-3.790,P＜0.001]. There were no significant differences in PT, PT%, PTINR, APTT, APTT ratio and TT before and after NCT (t=-0.223, 0.524,0.347, 0.134,0.348, -1.605, all P＞0.050). (2) Before NCT, D-D level in NCT effective group (n=80)was significantly higher than that in non-effective group (n=66) [M(P₂₅-P₇₅): 140.0(90.3-215.8)ng/ml vs 94.5(72.0-168.8)ng/ml,Z=-3.201,P=0.001], while there were no significant differences in PT,PT%, PTINR, APTT, APTT ratio, Fib, TT and PLT(t=4.453,2.891,1.782,1.542,0.736,0.104,1.635,0.054, all P＞0.050). (3) After NCT, there were no significant differences in PT, PT%, PTINR, APTT,APTT ratio, Fib, TT, PLT and D-D level between NCT effective group and non-effective group (t=0.112,0.202,0.134, 1.784, 1.125, 0.643, 0.435, 2.892, Z= -0.701, all P ＞0.05). (4)D-D level was decreased in 92 cases after NCT (61 showed improvement after chemotherapy, with the efficacy of 66.3%).D-D level was increased in 54 cases after NCT (19 showed improvement after chemotherapy, with the efficacy of 35.2%). There was a significant difference in chemotherapy efficacy between D-D-decreased patients and D-D-increased patients(Z=-3.642, P＜0.001)after NCT. The changes of PT, PT%, PTINR, APTT, APTT ratio, Fib, TT and PLT were not significantly different between NCT effective group and non-effective group(Z=-0.311, -0.550,-0.214,-0.543,-0.672,-1.583,-0.286,-1.798,all P＞0.050).

Conclusions

Coagulation related indexes tend to be abnormal in breast cancer patients. Chemotherapy may lead to increased Fib, decreased D-D and change of PLT level, so it is necessary to monitor these three indexes during chemotherapy. The patients with decreased D-D after NCT are prone to obtain better chemotherapy response.

Key words: Breast neoplasms, Chemotherapy, adjuvant, Blood coagulation, Treatment outcome

表1 146 例乳腺癌患者NCT 前后凝血相关指标比较

组别	PT(s, $\bar{x}$ ±s)	PT%( $\bar{x}$ ±s)	PTINR( $\bar{x}$ ±s)	APTT(s, $\bar{x}$ ±s)	APTT ratio( $\bar{x}$ ±s)	Fib(g/L, $\bar{x}$ ±s)	D-D[ng/ml,M(P₂₅~P₇₅)]	TT(s, $\bar{x}$ ±s)	PLT(×10⁹/L, $\bar{x}$ ±s)
NCT前	10.8±0.7	106.3±13.4	0.9±0.1	24.0±3.4	0.9±0.1	2.8±0.6	112.5(79.8~197.5)	16.5±1.2	193.1±55.1
NCT后	10.8±0.6	106.9±15.5	0.9±0.1	24.1±3.4	0.9±0.1	3.4±0.8	104.0(74.5~162.3)	16.3±1.3	245.1±77.7
检验值	t=-0.223	t=0.524	t=0.347	t=0.134	t=0.348	t=9.201	Z=-3.790	t=-1.605	t=8.624
P值	0.861	0.633	0.801	0.924	0.773	＜0.001	＜0.001	0.121	＜0.001

表1 146 例乳腺癌患者NCT 前后凝血相关指标比较

组别	PT(s, $\bar{x}$ ±s)	PT%( $\bar{x}$ ±s)	PTINR( $\bar{x}$ ±s)	APTT(s, $\bar{x}$ ±s)	APTT ratio( $\bar{x}$ ±s)	Fib(g/L, $\bar{x}$ ±s)	D-D[ng/ml,M(P₂₅~P₇₅)]	TT(s, $\bar{x}$ ±s)	PLT(×10⁹/L, $\bar{x}$ ±s)
NCT前	10.8±0.7	106.3±13.4	0.9±0.1	24.0±3.4	0.9±0.1	2.8±0.6	112.5(79.8~197.5)	16.5±1.2	193.1±55.1
NCT后	10.8±0.6	106.9±15.5	0.9±0.1	24.1±3.4	0.9±0.1	3.4±0.8	104.0(74.5~162.3)	16.3±1.3	245.1±77.7
检验值	t=-0.223	t=0.524	t=0.347	t=0.134	t=0.348	t=9.201	Z=-3.790	t=-1.605	t=8.624
P值	0.861	0.633	0.801	0.924	0.773	＜0.001	＜0.001	0.121	＜0.001

表2 146 例乳腺癌患者化疗疗效与NCT 前凝血相关指标的关系

组别	例数	PT(s, $\bar{x}$ ±s)	PT%( $\bar{x}$ ±s)	PTINR( $\bar{x}$ ±s)	APTT(s, $\bar{x}$ ±s)	APTT ratio( $\bar{x}$ ±s)	Fib(g/L, $\bar{x}$ ±s)	D-D[ng/ml,M(P₂₅~P₇₅)]	TT(s, $\bar{x}$ ±s)	PLT(×10⁹/L, $\bar{x}$ ±s)
有效组	80	10.7±0.6	106.7±12.2	0.9±0.1	24.0±3.2	0.8±0.1	2.8±0.6	140.0(90.3~215.8)	16.6±1.2	200.4±54.3
无效组	66	10.8±0.7	105.7±14.9	0.9±0.1	24.1±3.6	0.9±0.1	2.8±0.6	94.5(72.0~168.8)	16.4±1.3	184.3±55.3
检验值		t=4.453	t=2.891	t=1.782	t=1.542	t=0.736	t=0.104	Z=-3.201	t=1.635	t=0.054
P值		0.782	0.650	0.534	0.784	0.423	0.871	0.001	0.332	0.081

表2 146 例乳腺癌患者化疗疗效与NCT 前凝血相关指标的关系

组别	例数	PT(s, $\bar{x}$ ±s)	PT%( $\bar{x}$ ±s)	PTINR( $\bar{x}$ ±s)	APTT(s, $\bar{x}$ ±s)	APTT ratio( $\bar{x}$ ±s)	Fib(g/L, $\bar{x}$ ±s)	D-D[ng/ml,M(P₂₅~P₇₅)]	TT(s, $\bar{x}$ ±s)	PLT(×10⁹/L, $\bar{x}$ ±s)
有效组	80	10.7±0.6	106.7±12.2	0.9±0.1	24.0±3.2	0.8±0.1	2.8±0.6	140.0(90.3~215.8)	16.6±1.2	200.4±54.3
无效组	66	10.8±0.7	105.7±14.9	0.9±0.1	24.1±3.6	0.9±0.1	2.8±0.6	94.5(72.0~168.8)	16.4±1.3	184.3±55.3
检验值		t=4.453	t=2.891	t=1.782	t=1.542	t=0.736	t=0.104	Z=-3.201	t=1.635	t=0.054
P值		0.782	0.650	0.534	0.784	0.423	0.871	0.001	0.332	0.081

表3 146 例乳腺癌患者化疗疗效与NCT 后凝血相关指标的关系

组别	例数	PT(s, $\bar{x}$ ±s)	PT%( $\bar{x}$ ±s)	PTINR( $\bar{x}$ ±s)	APTT(s, $\bar{x}$ ±s)	APTT ratio( $\bar{x}$ ±s)	Fib(g/L, $\bar{x}$ ±s)	D-D[ng/ml,M(P₂₅~P₇₅)]	TT(s, $\bar{x}$ ±s)	PLT(×10⁹/L, $\bar{x}$ ±s)
有效组	80	10.7±0.6	107.5±14.8	0.9±0.1	24.1±3.7	0.9±0.1	3.4±0.8	109.5(75.3,177.8)	16.4±1.4	242.3±65.9
无效组	66	10.8±0.6	106.2±16.3	0.9±0.1	24.0±3.0	0.9±0.1	3.5±0.8	99.5(72.3,147.5)	16.1±1.2	248.6±90.4
检验值		t=0.112	t=0.202	t=0.134	t=1.784	t=1.125	t=0.643	Z=-0.701	t=0.435	t=2.892
P值		0.281	0.620	0.153	0.924	0.583	0.711	0.461	0.150	0.632

表3 146 例乳腺癌患者化疗疗效与NCT 后凝血相关指标的关系

组别	例数	PT(s, $\bar{x}$ ±s)	PT%( $\bar{x}$ ±s)	PTINR( $\bar{x}$ ±s)	APTT(s, $\bar{x}$ ±s)	APTT ratio( $\bar{x}$ ±s)	Fib(g/L, $\bar{x}$ ±s)	D-D[ng/ml,M(P₂₅~P₇₅)]	TT(s, $\bar{x}$ ±s)	PLT(×10⁹/L, $\bar{x}$ ±s)
有效组	80	10.7±0.6	107.5±14.8	0.9±0.1	24.1±3.7	0.9±0.1	3.4±0.8	109.5(75.3,177.8)	16.4±1.4	242.3±65.9
无效组	66	10.8±0.6	106.2±16.3	0.9±0.1	24.0±3.0	0.9±0.1	3.5±0.8	99.5(72.3,147.5)	16.1±1.2	248.6±90.4
检验值		t=0.112	t=0.202	t=0.134	t=1.784	t=1.125	t=0.643	Z=-0.701	t=0.435	t=2.892
P值		0.281	0.620	0.153	0.924	0.583	0.711	0.461	0.150	0.632

表4 146 例乳腺癌患者NCT 后凝血相关指标的变化与化疗疗效的关系

凝血相关指标变化	例数	NCT(例)		Z值	P值
凝血相关指标变化	例数	有效	无效	Z值	P值
PT
减少	68	38	30	-0.311	0.746
不变	14	8	6
增加	64	34	30
PT%
减少	70	40	30	-0.550	0.590
增加	76	40	36	-0.550	0.590
PTINR
减少	69	37	32	-0.214	0.843
不变	12	7	5
增加	65	36	29
APTT
减少	73	38	35	-0.543	0.591
不变	4	3	1
增加	69	39	30
APTT ratio
减少	66	34	32	-0.672	0.496
不变	12	7	5
增加	68	39	29
Fib
降低	28	12	16	1.583	0.113
不变	1	0	1
升高	117	68	49
D-D
降低	92	61	31	-3.642	＜0.001
升高	54	19	35	-3.642	＜0.001
TT
降低	80	42	38	-0.286	0.774
不变	5	5	0
升高	61	33	28
PLT
降低	27	19	8	-1.798	0.073
升高	119	61	58	-1.798	0.073

表4 146 例乳腺癌患者NCT 后凝血相关指标的变化与化疗疗效的关系

凝血相关指标变化	例数	NCT(例)		Z值	P值
凝血相关指标变化	例数	有效	无效	Z值	P值
PT
减少	68	38	30	-0.311	0.746
不变	14	8	6
增加	64	34	30
PT%
减少	70	40	30	-0.550	0.590
增加	76	40	36	-0.550	0.590
PTINR
减少	69	37	32	-0.214	0.843
不变	12	7	5
增加	65	36	29
APTT
减少	73	38	35	-0.543	0.591
不变	4	3	1
增加	69	39	30
APTT ratio
减少	66	34	32	-0.672	0.496
不变	12	7	5
增加	68	39	29
Fib
降低	28	12	16	1.583	0.113
不变	1	0	1
升高	117	68	49
D-D
降低	92	61	31	-3.642	＜0.001
升高	54	19	35	-3.642	＜0.001
TT
降低	80	42	38	-0.286	0.774
不变	5	5	0
升高	61	33	28
PLT
降低	27	19	8	-1.798	0.073
升高	119	61	58	-1.798	0.073

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Relationship between change of blood coagulation indexes and efficacy after neoadjuvant chemotherapy in breast cancer patients

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Relationship between change of blood coagulation indexes and efficacy after neoadjuvant chemotherapy in breast cancer patients