Incidence of venous thromboembolism and the role of D-dimer as predictive marker in patients with advanced gastric cancer receiving chemotherapy: A prospective study

Table 1 Patients’ pretreatment characteristics and risk of venous thromboembolism on univariate analysis

Variable	Total patients	Patients with VTE	Risk of time to VTE
			HR	95%CI	P value
Total, n (%)	241 (100.0)	27 (11.2)
Age (yr)
< 65	178 (73.9)	18 (10.1)
≥ 65	63 (26.1)	9 (14.3)	1.632	0.732-3.641	0.231
Gender
Male	169 (70.1)	18 (10.7)
Female	72 (29.9)	9 (12.5)	1.052	0.472-2.345	0.9
ECOG PS
0-1	229 (95.0%)	27 (11.8)
2	12 (5.0%)	0	0.046	0.000-99.991	0.432
BMI
< 25	202 (83.8)	23 (11.4)
≥ 25	39 (16.2)	4 (10.3)	0.793	0.274-2.296	0.669
Previous CVC
No	233 (96.7)	25 (10.7)
Yes	8 (3.3)	2 (25.0)	3.13	0.738-13.266	0.122
Previous gastrectomy
No	209 (86.7)	26 (12.4)
Yes	32 (13.3)	1 (3.1)	0.196	0.027-1.448	0.11
Primary tumor site
Antrum/pylorus	94 (39.0)	10 (10.6)
Body	32 (13.3)	9 (11.0)	1.131	0.458-2.791	0.79
Cardia/fundus	28 (11.6)	3 (10.7)	1.138	0.313-4.144	0.844
Diffuse	25 (10.4)	5 (20.0)	2.413	0.823-7.073	0.108
Histology
W/D or M/D	84 (34.9)	6 (7.1)
P/D or SRC	154 (63.9)	21 (13.6)	2.084	0.840-5.166	0.113
Unclassified	3 (1.2)	0	NA
Peritoneal seeding
No	137 (56.8)	11 (8.0)
Yes	104 (43.2)	16 (15.4)	1.945	0.902-4.191	0.09
Liver metastasis
No	156 (64.7)	20 (12.8)
Yes	85 (35.3)	7 (8.2)	0.741	0.313-1.754	0.495
Lung metastasis
No	220 (91.3)	26 (11.8)
Yes	21 (8.7)	1 (4.8)	0.509	0.069-3.764	0.509
Bone metastasis
No	225 (93.4)	24 (10.7)
Yes	16 (6.6)	3 (18.8)	2.344	0.701-7.835	0.167
Number of metastatic sites
0-1	109 (45.2)	9 (8.3)
≥ 2	132 (54.8)	18 (13.6)	1.898	0.851-1.898	0.118
CEA (log) median (range, ng/mL)	2.5 (0.3-8070)		1.133	0.947-1.355	0.173
CA19-9 (log) median (range, U/mL)	19.3 (1.4-30800)		0.882	0.726-1.073	0.209
CA72-4 (log) median (range, U/mL)	5.1 (1.7-6490)		1.099	0.885-1.364	0.395
Hb median (range, g/dL)	12.0 (7.0-17.6)		0.956	0.786-1.163	0.653
WBC median (range, × 109/L)	7100 (2600-19300)		1	1.000-1.000	0.026
Platelet median (range, × 109/L)	274 (107-731)		1.001	0.998-1.005	0.508
CRP median (range, mg/dL)	2.01 (0.10-19.22)		1.056	0.952-1.053	0.302
Fibrinogen (log) median (range, × 109/L)	360 (66-897)		1.132	0.337-3.796	0.841
PAI-1 (log) median (range, × 109/L)	35.0 (2.0-112.0)		1.197	0.662-2.165	0.551
D-dimer (log) median (range, × 109/L)	1.02 (0.06-82.3)		1.401	1.069 1.836	0.015

BMI: Body mass index; CI: Confidence interval; CRP: C-reactive protein; CVC: Central venous catheter; log: Log-transformation; M/D: Moderate differentiation; P/D: Poor differentiation; SRC: Signet ring cell; VTE: Venous thromboembolism; W/D: Well-differentiated.

Table 2 Clinical features of venous thromboembolism in advanced gastric cancer patients receiving chemotherapy n (%)

	Total (n = 27)	Symptomatic VTE (n = 13)	Incidental VTE (n = 14)	P value
Time to VTE duration (median, mo)	6.1	7.5	4.7	0.16
VTE incidence
< 3	10 (37.0)	4 (30.8)	6 (42.9)
3-6	6 (22.2)	3 (23.1)	3 (21.5)
6-12	7 (25.9)	3 (23.1)	4 (28.6)
> 12	4 (14.8)	3 (23.1)	1 (7.2)	0.68
Types of VTE
DVT	19 (70.4)	8 (61.5)	11 (78.6)
PTE	4 (14.8)	3 (23.1)	1 (7.2)
PTE + DVT	4 (14.8)	2 (15.4)	2 (14.3)	0.608
Treatment of VTE
Medication (anticoagulation)	22 (81.4)	10 (76.9)	12 (75.7)
IVC filter	3 (11.1)	3 (23.1)	0
No treatment	2 (7.5)	0	2 (14.3)	0.031
Delay of chemotherapy
None	17 (62.9)	5 (38.5)	12 (85.7)
Yes	10 (37.1)	8 (61.5)	2 (14.3)	0.018

DVT: Deep vein thrombosis; PTE: Pulmonary thrombosis; VTE: Venous thromboembolism; IVC: Inferior venous cava.

Table 3 Multivariate analysis of risk factors for venous thromboembolism¹

Variable	HR	95%CI	P value
Prior gastrectomy (no vs yes)	0.25	0.03-1.89	0.178
History of CVC (no vs yes)	2.21	0.51-9.50	0.286
D-dimer (log)	1.32	1.00-1.75	0.051

¹All potential prognostic factors with a P value ≤ 0.15 on univariate analyses were entered into the multivariate Cox models. The final models were determined by backward elimination.

Table 4 Comparisons of D-dimer levels between baseline and time of venous thromboembolism development

	Total(n = 27)	Symptomatic VTE(n = 13)	Incidental VTE(n = 14)	P value
Baseline D-dimer	4.19	3.62	4.72	0.835
D-dimer at the time of VTE development	11.18	14.11	8.45	0.436
	P value	P value	P value
	0.004	0.01	0.198

VTE: Venous thromboembolism.

Table 5 Time to venous thromboembolism according to chemotherapeutic agent used for 1^st-line chemotherapy

Variable	Patients (n)	Patients with VTE n (%)	Risk of time to VTE
			HR	95%CI	P value
Fluoropyrimidine
SP	96	11 (11.5)
XP	22	3 (13.6)	1.67	0.47-6.18	0.422
Platinum
XP	22	3 (13.6)
XELOX	27	4 (14.8)	0.94	0.21-4.25	0.94
Addition of targeted agents
Conventional chemotherapy	158	17 (10.8)
+ targeted agents	83	10 (12.0)	1.21	0.56-2.65	0.627
Addition of VEGFR inhibitors
Conventional chemotherapy	217	27 (12.4)
+ VEGFR inhibitors	24	0	0.04	0.00-12.13	0.227

SP: TS-1 + cisplatin; XP: Capecitabine + cisplatin; XELOX: Capecitabine + oxaliplatin, targeted agents, Vorinostat, sorafenib, Bevacizumab, or trastuzumab +/- pertuzumab; VEGFR: Inhibitors, sorafenib or bevacizumab; VTE: Venous thromboembolism.