Burden of venous thromboembolism in patients with pancreatic cancer

Table 1 Studies assessing the predictive values of risk assessment models in pancreatic cancer patients

Ref.	Study design	Country	Patients analyzed/included	VTE screening at study entry	RAMs	Number of patients in each group	Study or median observation period	Patients with VTE during the overall follow-up, n (%)	Rates of VTE
Pelzer et al[45], 2013	Retrospective analysis of theCONKO-004 RCT	Germany	144/312, APC included in the CONKO-004 trial (control arm)	No	Khorana score	Intermediate risk: 55/144 (38.2%); High risk: 89/144 (61.8%)	12 mo	21/144 (14.6%)	At 6 mo: Intermediate risk: 4/55 (7.2%); High risk: 17/89 (19.1%)
Muñoz Martín et al[25], 2014	Retrospective	Spain	73/84, ambulatory PC patientsreceiving chemotherapy	No	Khorana score	Intermediate risk: 36/84 (43%); High risk: 48/84 (57%)	2008-2011	30/84 (35.7%)	At 6 mo: Intermediate risk: 4/37 (10.8%); High risk: 10/36 (27.8%)
van Es et al[29], 2017	Retrospective	Netherlands	147/178, ambulatory PC patientsstarting chemotherapy	No	Khorana score	Intermediate risk: 101/147 (69%); High risk: 46/147 (31%)	2003-2014	20/147(13.6%)	At 6 mo: Intermediate risk: 9/101 (8.9%); High risk: 4/46 (8.7%)
Kruger et al[28], 2017	Retrospective	Germany	111/172, APC patients undergoing palliative chemotherapy	No	Khorana score	Intermediate risk: 69/111 (38%); High risk: 42/111 (62%)	2002-2012	16/111 (14.4%)	At 6 mo: Intermediate risk: 6/69 (8.6%)High risk: 5/42 (11.9%); During the overall observation period; Intermediate risk: 8/69 (11.6%); High risk: 8/42 (19.0%); P = 0.4
Berger et al[30], 2017	Retrospective	Germany	150, PC patients receiving chemotherapy	No	Khorana score	Intermediate risk: 87/150 (58%); High risk: 63/150 (42%)	2010-2014	37/150 (24.7%)	Unspecified; During the overall observation period: no difference between groups (P = 0.44)
Godinho et al[39], 2020	Retrospective	Portugal	165 newly diagnosed PC patients	No	Khorana score; Onkotev score	Khorana score: Intermediate risk: 106/165 (64%); High risk: 59/165 (36%). Onkotev score: Score 0: 30/165 (18.2%); Score 1: 63/165 (38.2%); Score 2: 55/165 (33.3%); Score ≥ 3: 17/165 (10.3%)	6.3 mo	51/165 (31%)	During the overall observation period: Khorana score: Intermediate risk: 28/106 (26.4%); High risk: 23/59 (38.9%). Onkotev score: Score 0: 1/30 (< 10%); Score 1: 8/63 (< 10%); Score 2: 28/55 (41.8%); Score ≥ 3: 14/17 (70.6%)
Kim et al[32], 2018	Retrospective	Korea	216 metastatic PC patients receiving palliative chemotherapy	No	Khorana score	Intermediate risk: 135/216 (62.5%); High risk: 81/21 (37.5%)	2005-2015	50/216 (23.1%)	During the overall observation period: Intermediate risk: 30/135 (22.2%); High risk: 20/81 (24.7%); P = 0.677
Frere et al[34], 2020	Prospective	France	675 newly diagnosed PC patients	Yes, patients excluded if VTE at diagnosis	Khorana score	Intermediate risk: 492/675 (73%); High risk: 183/675 (27%)	2014-2019; 19.3 mo	141/675 (20.8%)	During the total follow-up: Intermediate risk: 108/492 (22%); High risk: 33/183 (18%); P = 0.26
Vadhan-Raj et al[41], 2020	Retrospective subgroup analysis of the CASSINI RCT	International	138 PC patients undergoing chemotherapy included in the CASSINI trial (control arm)	Yes, patients excluded if VTE at diagnosis	Khorana score	Intermediate risk: 100/138 (72.5%); High risk: 38/138 (27.5%)	6 mo	18/138 (13.0%)	At 6 mo: Intermediate risk: 14/100 (14.0%); High risk: 4/38 (10.5%)

APC: Advanced Pancreatic cancer; PC: Pancreatic cancer; RAM: Risk assessment model; VTE: Venous thromboembolism.

Table 2 Studies assessing the clinical benefit of anticoagulants for the prevention of venous thromboembolism in ambulatory pancreatic cancer patients

	PROTECHT	SAVE ONCO	FRAGEM	CONKO-0004	CASSINI
	Agnelli et al[58], 2009	Agnelli et al[59], 2012	Maraveyas et al[54], 2012	Pelzer et al[55], 2015	Khorana et al[61], 2019 and Vadhan-Raj et al[41], 2020
Population	Ambulatory patients > 18 yr on chemotherapy with metastatic or locally advanced lung, gastrointestinal, breast, ovarian, or head and neck cancer	Patients with metastatic or locally advanced lung, pancreatic, gastric, colorectal, bladder, and ovarian cancer beginning to receive a course of chemotherapy	Patients aged 18 yr or older; Histologically/cytologically confirmed advanced or metastatic pancreatic cancer; KPS: 60-100	Patients with histologically proven advanced pancreatic cancer were randomly assigned to ambulant first-line chemotherapy	Adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for VTE (defined as Khorana score ≥ 2)
Study design	Randomized, placebo-controlled, double-blind, multicenter study	Randomized, placebo-controlled, double-blind, multicenter study	Randomized, controlled Phase 2b study	Prospective, open label, randomized, multicenter and group-sequential 2b trial	Double-blind, randomized, placebo-controlled, parallel-group, multicenter study
Intervention	Arm A: nadroparin 3800 IU/d; Arm B: placebo; For duration of chemotherapy (up to 4 mo maximum)	Arm A: Semuloparin, 20 mg/d; Arm B: placebo; For duration of chemotherapy (median: 3.5 mo)	Arm A: Gemcitabine + Dalteparin 200 IU/kg s.c., o.d., for 4 wk, followed by a step-down regimen to 150 IU/kg for a further 8 wk); Arm B: Gemcitabine alone; For up to 12 wk	Arm A: Enoxaparin 1 mg/kg per day; Arm B: No enoxaparin	Arm A: rivaroxaban 10 mg o.d. up to day 180; Arm B: placebo up to day 180
Number of patients analyzed	Overall population: Arm A: 769 patients; Arm B: 381 patients. PC subgroup: Arm A: 36 patients; Arm B: 17 patients	Overall population: Arm A: 1608 patients; Arm B: 1604 patients. PC subgroup: Arm A: 126 patients; Arm B: 128 patients	Arm A: 59 patients; Arm B: 62 patients	Arm A: 160 patients; Arm B: 152 patients	Overall population: Arm A: 420 patients; Arm B: 404 patients. PC patients: Arm A: 135 patients; Arm B: 138 patients
Follow-up	120 d	3 mo	3 mo	3 mo	6 mo
Thromboembolic endpoint events	Overall population: Arm A: 11/769 (1.4%); Arm B: 11/381 (2.9%); P = 0.02. PC subgroup: Arm A: 3/36 (8.3%); Arm B: 1/17 (5.9%); P = 0.755	Overall population: Arm A:20/1608 (1.2%); Arm B: 55/1064 (1.2%); HR 0.36 (95%CI: 0.21-0.60); P < 0.001. PC subgroup: Arm A: 3/126 (2.4%); Arm B: 14/128 (10.9%); HR 0.22 (95%CI: 0.06-0.76); P = 0.015. At 3 mo: Arm A: 2/59 (3%); Arm B: 14/62 (23%); RR 0.145 (95%CI: 0.035-0.612); P = 0.002	At 3 mo: Arm A: 2/160 (1.25%); Arm B: 15/152 (9.8%); HR 0.12 (95%CI: 0.03-0.52); P = 0.001. Entire study: Arm A: 7/59 (12%); Arm B: 17/62 (28%); RR 0.419 (95%CI: 0.187-0.935); P = 0.039	Cumulative incidence rates: Arm A: 6.4%; Arm B: 15.1%; HR 0.40 (95%CI: 0.19-0.83); P = 0.01	Overall population: Up-to-day-180 observation period: Arm A: 25/420 (5.95%); Arm B: 37/421 (8.79%); HR 0.66 (95%CI: 0.40-1.09); P = 0.101; NNT =3 5. Intervention period: Arm A: 11/420 (2.62%); Arm B: 27/421 (6.41%); HR 0.40 (95%CI: 0.20-0.80); P = 0.007; NNT = 26. PC subgroup: Up-to-day-180 observation period: Arm A: 13/135 (9.6%); Arm B: 18/138 (13.0%); HR 0.70 (95%CI: 0.34-1.43); P = 0.329. Intervention period: Arm A: 5/135 (3.7%); Arm B: 14/138 (10.1%); HR 0.35 (95%CI: 0.130-0.96); P = 0.043; NNT = 16
Bleeding	Overall population: Major bleeding: Arm A: 5/769 (0.7%); Arm B: 0/381; P = 0.18. Minor bleeding: Arm A: 57/769 (7.4%); Arm B: 30/381 (7.9%); P = not significant. PC subgroup: P = not significant	Overall population: Major bleeding: Arm A: 19/1589 (1.2%); Arm B: 18/1583 (1.1%); OR 1.05 (95%CI: 0.55-2.04). CRNMB: Arm A: 26/1589 (2.8%); Arm B: 14/1583 (0.9%); OR 1.86 (95%CI: 0.98-3.68). PC subgroup: P = not significant	ISTH severe: Arm A: 2/59 (3%); Arm B: 2/62 (3%). ISTH non severe: Arm A: 5/59 (9%); Arm B: 2/62 (3%)	Major bleeding: Arm A: 8.3%; Arm B: 6.9%; HR 1.23 (95%CI: 0.54-2.79); P = 0.63	Overall population: Major bleeding: Arm A: 8/405 (1.98%); Arm B: 4/404 (0.99%); HR 1.96 (95%CI: 0.59-6.49) P = 0.265; NNH = 101. CRNMB: Arm A: 2.72%; Arm B: 1.98%; HR 1.96 (95%CI: 0.59-6.49); P = 0.265; NNH = 101. PC subgroup: Major bleeding: Arm A: 2/130 (1.5%); Arm B: 3/131(2.3%); HR 0.67 (95%CI: 0.11-3.99); P = 0.654. CRNMB: Arm A: 3/131(2.3%); Arm B: 2/130 (1.5%); HR 2.47 (95%CI: 0.48-12.72); P = 0.264
Survival	Overall population: Arm A: 33/769 (4∙3%); Arm B: 16/381 (4.2%); P = not significant. PC subgroup: not significant	Not significant	Arm A: 8.7 mo; Arm B: 9.7 mo	Arm A: 8.2 mo; Arm B: 8.51 mo; HR 1.01 (95%CI: 0.87-1.38); P = 0.44	Overall population: All-cause mortality: Arm A: 20.0%; Arm B: 23.8%; HR 0.83 (95%CI 0.62-1.11); P = 0.213. PC subgroup: Arm A: 34/135 (25.2%); Arm B: 33/138 (23.9%)

CI: Confidence interval; CRNMB: Clinically relevant non-major bleeding; HR: Hazard ratio; ISTH: International society of thrombosis and haemostasis; KPS: Karnofsky performance status; o.d.: Once daily; NTT: Number needed to treat; OR: Odds ratio; PC: Pancreatic cancer; RR: Risk ratio.

Table 3 Randomized trials assessing the efficacy and safety of direct oral anticoagulants in cancer patients with venous thromboembolism

	HOKUSAI-CANCER VTE[68] (n = 1050)		SELECT-D[69] (n = 406)		ADAM-VTE[70] (n = 300)		CARAVAGGIO[71] (n = 1155)
	Edoxaban	Dalteparin	Rivaroxaban	Dalteparin	Apixaban	Dalteparin	Apixaban	Dalteparin
Dose	LMWH × 5 d, then 60 mg OD	200 IU/kg × 1 mo, then 150 U/kg daily	15 mg BID × 3 wk, then 20 mg OD × 6mo	200 IU/kg × 1 mo, then 150 U/kg daily	10 mg BID × 7 d, then 5 mg BID × 6 mo	200 IU/kg × 1 mo, then 150 U/kg daily	10 mg BID × 7 d, then 5 mg BID × 6 mo	200 IU/kg × 1 mo, then 150 U/kg daily
Patients	Patients with active cancer and symptomatic or incidental popliteal, femoral or iliac or IVC DVT, symptomatic or incidental PE		Patients with active cancer and symptomatic DVT, symptomatic PE, or incidental PE		Active cancer patients with acute DVT (including upper extremity), PE, splanchnic or cerebral vein thrombosis		Patients with active or recent cancer and acute DVT or PE
PrimaryEndpoint	Composite of recurrent VTE/major bleeding at 12 mo		VTE recurrence over 6 mo		Primary safety: Major bleeding at 6mo; secondary efficacy: VTE at 6 mo		Efficacy: Recurrent VTE at 6 mo; Safety: Major bleeding at 6 mo
Follow-up	12 mo		6 mo		6 mo		6 mo
Recurrent VTE (%)	41/525 (7.9)	59/525 (11.3)	8/203 (4)	18/203 (11)	1/145 (0.7)	9/142 (6.3)	32/576 (5.6)	46/579 (7.9)
HR (95%CI) for recurrent VTE	0.71 (0.48-1.06), P = 0.006		0.43 (0.19-0.99)		0.099 (0.013-0.780), P = 0.03		0.63 (0.37-1.07, P < 0.001)
Major bleeding (%)	36/525 (6.9)	21/525 (4.0)	11/203 (4)	6/203 (6)	0/145 (0)	2/142 (1.4)	22/576 (3.8)	23/579 (4)
HR (CI) for major bleeding	1.77 (1.03-3.04)		1.83 (0.68-4.96)		Not estimable		0.82 (0.40-1.69, P = 0.6)
CRNMB (%)	76/525 (14.6)	58/525 (11.1)	25/203 (12.3)	7/203 (3.4)	9/145 (6.2)	7/142 (4.9)	52/576 (9)	35/579 (6.0)
HR (95%CI) for CRNMB	1.38 (0.98-1.94)		3.76 (1.63-8.69)		0.931 (0.43-2.02), P = 0.88		1.42 (0.88-2.30)

DVT: Deep vein thrombosis; PE: Pulmonary embolism; VTE: Venous thromboembolism; CI: Confidence interval; CRNMB: Clinically relevant non-major bleeding; HR: Hazard ratio; LMWH: Low-molecular-weight heparin.