Primary prevention and treatment of venous thromboembolic events in patients with gastrointestinal cancers - Review

Table 1 Some venous thromboembolic event risk factors in cancer patients

Cancer-related	Patient-related	Treatment-related
Reduced mobility
Primary cancer (e.g., pancreatic cancer > colo-rectal cancer)	Age	Operation
Stage (IV > III)	History of VTE	Chemotherapy
Histology (e.g., adeno- > squamous cell-carcinoma)	Infection/fever	Central line/ port-catheter
Grade (3 > 2)		Parenteral nutrition
Thrombocytosis		Radiation therapy
Leukocytosis
Acute phase (elevated CRP)
Elevated D-dimer

CRP: C-reactive protein; VTE: Venous thromboembolic event.

Table 2 Comprehensive outline of some guidelines focusing on the prevention and treatment of cancer associated venous thromboembolism

	Primary prophylaxis/prevention of VTE in cancer patients			Treatment of cancer-associated VTE
	Surgical patients	In-patients (non surgical)	Out-patients	Acute/initial	Long-term/secondary prevention
ASCO Guidelines 2013[15]	UFH, LMWH (Dalteparin, Enoxaparin), Fondaparinux	UFH, LMWH (Dalteparin, Enoxaparin), Fondaparinux	Not recommended routinely1 LMWH may be considered	UFH, LMWH (Dalteparin, Enoxaparin, Tinzaparin), Fondaparinux	LMWH (Dalteparin, Enoxaparin,Tinzaparin)
	A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy, especially in the highest risk patients.			VKA not recommended	VKA (INR 2-3) acceptable if LMWH is not available Use of NOACs is not recommended
	Patients undergoing major cancer surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 d and it should be considered an extension up to 4 wk in patients undergoing abdominal and pelvic surgery				Treatment of splanchnic or visceral vein thrombi diagnosed incidentally should be considered on a case-by-case basis, considering potential benefits and risks of anticoagulation
ESMO Guidelines 2011[16]	LMWH (Dalteparin, Enoxaparin), UFH Fondaparinux not recommended	LMWH (Dalteparin, Enoxaparin), Fondaparinux, UFH	Not recommended routinely May be considered in high risk patients	LMWH (Enoxaparin, Dalteparin), UFH	Treatment for a total of 6 mo. Initial dose of LMWH 100% for 1 mo, thereafter 5 mo with 75%-80% of the initial dose of LMWH
	Cancer patients undergoing elective major abdominal or pelvic surgery should receive in hospital and post-discharge prophylaxis with s.c. LMWH for up to 1 mo after surgery
International Consensus Groupe 2013[17]	LMWH (Dalteparin, Enoxaparin, Nadroparin, Tinzaparin), Fondaparinux, UFH For 10 ± 2 d or 25-31 d (28 d) extended use (Bemiparin sodium 3500 IU per day for 28 d)	LMWH (Dalteparin, Enoxaparin, Nadroparin, Tinzaparin), Fondaparinux, UFH	Not recommended routinely To be considered/recommended: Patients with locally advanced or metastatic lung or pancreatic cancer treated with chemotherapy and having a low bleeding risk	LMWH (Dalteparin, Enoxaparin), UFH	LMWH (Dalteparin, Enoxaparin) for 3 to 6 mo
British Committee for Standards in Haematology 2015[18]	Patients undergoing abdominal and pelvic surgery for cancer should be considered for extended thromboprophylaxis	Patients with active or recent cancer should receive thromboprophylaxis throughout their admission unless contraindicated Patients without a history of venous thromboembolism receiving adjuvant hormonal therapies for cancer should not routinely receive thrombo-prophylaxis	Patients should be assessed for thrombosis risk and although most do not routinely require thromboprophylaxis, it should be considered for high risk patients	Initial treatment should be with LMWH for six months	Warfarin and other oral anticoagulants are acceptable alternatives if LMWH is impractical and anticoagulation is indicated Anticoagulation should be continued, taking pt status and wishes and bleeding risk into consideration. There is a rationale but little direct evidence for preferring to continue to use LMWH
				Cancer patients with incidental pulmonary embolus or deep vein thrombosis should be therapeutically anticoagulated as for symptomatic disease
Australian Governments National Health and Medical Research Council 2009[19]	LMWH, continue for at least 7 to 10 d following major general surgery Consider using extended thromboprophylaxis with LMWH for up to 28 d after major abdominal or pelvic surgery for cancer, especially in patients who are obese, slow to mobilise or have a past history of VTE	LMWH, UFH		-	-
MAYO CLINIC VTE Prevention and Management Guidelines 2014[20]	UFH, LMWH (Enoxaparin, Dalteparin), Fondaparinux Cancer patients undergoing pelvic or abdominal surgery should receive 4 wk of LMWH	UFH, LMWH (Enoxaparin, Dalteparin), Fondaparinux		UFH, LMWH (Enoxaparin, Dalteparin), Fondaparinux VKA (INR2-3)	Anticoagulants are continued until there is no evidence of active malignant disease defined as any evidence of cancer on cross-sectional imaging or any cancer-related treatment (surgery, radiation, or chemotherapy) within the past 6 mo
ASH Guidelines 2013[21]	UFH, LMWH, Fondaparinux in all patients undergoing major surgical intervention for malignant disease Prolonged prophylaxis for up to 4 wk may be considered in patients undergoing major abdominal or pelvic surgery for cancer with high-risk features such as residual malignant disease, obesity, and prior history of VTE	UFH, LMWH, Fondaparinux	Routine VTE prophylaxis in ambulatory patients receiving chemotherapy is not recommended	LMWH	LMWH Continue treatment with LMWH is preferred for at least the initial 6 mo of treatment
German Guidelines[22,23]	LMWH, Fondaparinux, (UFH) Patients undergoing abdominal and pelvic surgery for cancer are recommended to get extended thromboprophylaxis (28 to 35 d)	LMWH, Fondaparinux, (UFH)	LMWH, Patients should be assessed for thrombosis risk and thromboprophylaxis should be considered for high risk patients	LMWH, Fondaparinux, UFH	LMWH for 3 to 6 mo If cancer persists extended secundary prophylaxis (with LMWH, VKA, or NOAC) is usefull (till death)

¹It may be considered for highly select high-risk patients. VTE: Venous thromboembolic event; LMWH: Low molecular weight heparins; UFH: Unfractionated heparin; VKA: Vitamin K antagonist; INR: International normalized ratios; NOAC: New oral anticoagulants.

Table 3 Primary prevention of cancer-associated venous thromboembolic event in gastrointestinal cancers

Study	Cancer	n	VTE placebo	VTE LMWH	VTE U-LMWH	RR
PROTECHT1	Gastorintestinal2	148/272	2.7%	1.5%		-44%
Agnelli et al[68], 2009	Pancreas	17/36	5.9%	8.3%		40%
SAVE-ONCO	Colo-rectal	461/464	2.0%		1.1%	-45%
Agnelli et al[69], 2012	Pancreas	128/126	10.9%		2.4%	-78%
	Stomach	207/204	1.9%		0.5%	-75%
FRAGEM	Pancreas	60/63	23%	3.4%		-85%
Maraveyas et al[70], 2012
CONKO 004	Pancreas	152/160	9.9%	1.3%		-87%
Pelzer et al[71], 2015

¹Randomization 1:2;

²Gastric (n = 40/58), colon (n = 79/156) and rectal (n = 29/58) cancers. LMWH: Low molecular weight heparin; U-LMWH: Ultra-LMWH; RR: Relative risk; VTE: Venous thromboembolic event.

Table 4 Assessment scores for prediction of the venous thromboembolic event-risk in cancer out-patients receiving chemotherapy, according to Khorana et al[73], Pabinger et al[75] and Verso et al[76]

Khorana score criteria[73]	Score
Primary cancer
With very high risk (pancreas, stomach) (high grade glioma1)	2
With high risk (lung, lymphoma, gynecologic, bladder, testicular)	1
Platelet count prior to chemotherapy > 350000/μL	1
Hb < 10 g/dL or ESA-application	1
Leukocyte count prior to chemotherapy > 11000/μL	1
Body mass index > 35 kg/m²	1
High risk	> 3
Vienna prediction score (additional parameters to Khorana score)[75]
D-dimer > 1.44 μg/mL	1
Soluble P-selectin > 153.1 μg/mL	1
High risk	> 4
Protecht prediction score (additional parameters to Khorana score)[76]
Cisplatin or carboplatin	1
Gemcitabine	1
High risk	> 3

¹High grade glioma are considered very high risk site of cancer in the Vienna prediction score only. ESA: Erythropoiesis stimulating agents.

Table 5 The CLOT and CATCH studies[80,81]: Study-population characteristics and study outcomes

	CLOT	CATCH	VKA	Dalteparin	P	VKA	Tinzaparin	P
Study-population characteristics
n	676	900
Women	52%	59%
Median age (yr)	63	59
ECOG 0-1	63%	77%
Metastasized cancer	67%	55%
Brest cancer	17.6%	9%
Colo-rectal cancer	17.8%	13%
Lung cancer	14.8%	12%
Gynecological cancer	11.2%	23%
Pancreatic cancer	4.8%
Urogenital cancers	14.2%
Brain cancers	5.5%
Hematological cancers	10%	10%
Study outcomes
VTE			15.8%	8.0%	0.002	10.0%	6.9%	0.07
DVT			11.0%	4.2%		5.3	2.7	0.04
Fatal PE			2.1%	1.7%		3.8%	3.8%
Non-fatel PE			2.7%	2.7%		0.7%	0.4%
Major bleeding			4%	6%	0.25	2.7%	2.9%
CRNM-bleeding						16%	11%	0.03
Any bleeding			19%	14%	0.09
6-mo mortality			41%	39%		41%	40%
INR < 2			30%			26%
INR 2-3			46%			47%

VKA: Vitamin K antagonist; VTE: Venous thromboembolic event; DVT: Deep vein thrombosis; PE: Pulmonary embolism; INR: International normalized ratios.

Table 6 Take home messages

Patients with gastrointestinal cancers are among those with the highest cancer-associated VTE risk (e.g., pancreatic cancer, gastric cancer)

Primary prevention of VTE should be considered according to an individual risk-benefit estimation

Scoring systems help to identify patients at high VTE risk. These patients may benefit from prophylactic anticoagulation

Usual prophylactic dosages of LMWH may not be effective enough in patients with the highest risk (e.g., pancreatic cancer)

Gastrointestinal cancer patients with VTE should have medical anticoagulation therapy with LMWH for at least three to six months

In patients with gastrointestinal cancers splanchnic vein thrombosis, portal hypertension, hepatopathy-associated coagulation defects (e.g., decreased prothrombin time) and thrombocytopenia may complicate anticoagulation strategies

VTE: Venous thromboembolic event; LMWH: Low molecular weight heparins.