Ay C, et al. ESMO Open 20172:e000188. doi:10.1136esmoopen-2017-000188Open Access [627567]

1
Ay C, et al. ESMO Open 2017;2:e000188. doi:10.1136/esmoopen-2017-000188Open Access
AbstrAct
The treatment of cancer-associated venous
thromboembolism (VTE) is difficult because cancer patients with VTE on anticoagulation are at an increased
risk of bleeding compared with patients without VTE. This
review summarises the evidence supporting the current standard of care and emerging treatment options. In
difficult-to-treat subpopulations, where clinical data are
often lacking, this review also provides the best clinical practice strategies based on the available data. The use of therapeutic doses of parenteral anticoagulants in
patients with cancer-associated VTE for at least 3 to 6
months is supported by the current clinical data. After major cancer surgery, extended thromboprophylaxis for approximately 1 month following hospital discharge is also
supported. In select populations of ambulatory cancer
patients with solid tumours, or in patients with myeloma
receiving immunomodulatory agents in combination with chemotherapy and/or corticosteroids, pharmacological prophylaxis could be considered. Although parenteral
anticoagulants may not be tolerated by some patients,
the data pertaining to the use of direct oral anticoagulants (DOACs) in cancer patients with VTE at this point can only be considered hypothesis generating. Clarity of the use of DOACs is awaiting the results of head-to-head
trials between DOACs and parenteral anticoagulants. In
addition, because of the lack of clinical trials, there are still unanswered questions on the optimal treatment regimens in subpopulations at increased risk of bleeding,
including cancer patients with thrombocytopenia and
those with brain metastases. For clinicians to balance the risk of recurrent thrombosis with the chance of bleeding, they need to assess the relevant clinical data. Current data support the use of parenteral anticoagulants
in cancer patients with VTE, but many unanswered
questions pertaining to the optimal regimens in special subpopulations and regarding the efficacy and safety of DOACs remain. To address this need, there are currently
several clinical trials under way.
IntroductIon
The estimated annual incidence of venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is 1 to 2 per 1000 person-years among the general population.
1 However, the
incidence of VTE is up to 6.5-fold higher in patients with cancer versus patients without cancer.
2 3 Overall, cancer accounts for an esti-
mated 18% of the total number of VTE cases, and VTE is a leading cause of death among patients with cancer.
4 5 The survival rates are
also lower, prognosis worse and healthcare costs higher in cancer patients with VTE compared with those without.
6–11
Vitamin K antagonists (VKAs) with initial
heparin treatment have long been consid-ered the mainstay for the management of VTE.
12 The treatment of cancer-associated
VTE, however, is especially difficult because patients with cancer treated with a VKA are at an approximately threefold higher risk of VTE recurrence and up to a sixfold higher risk of bleeding versus patients without cancer but with VTE.
13 14 Factors including potential
drug–drug interactions with oncology regi-mens as well as vomiting, thrombocytopenia and renal dysfunction associated with cancer and its treatment can also complicate anti-coagulation in patients with cancer.
15 16 This
review summarises the evidence supporting the current standard of care and emerging treatment options. In difficult-to-treat subpopulations where clinical data are often lacking, this review also provides the best clin-ical practice strategies based on the available data.
PArenterAl AntIcoAgulAnts
treatment and secondary prevention
Numerous clinical trials have assessed the
efficacy and safety of low-molecular-weight heparin (LMWH) for treatment and secondary prevention of cancer-associated VTE with generally favourable results (figure 1).
17–23
Antithrombotic therapy for
prophylaxis and treatment of venous thromboembolism in patients with
cancer: review of the literature on
current practice and emerging options
Cihan Ay,1 Pieter Willem Kamphuisen,2 Giancarlo Agnelli3 Review
To cite: Ay C, Kamphuisen PW,
Agnelli G. Antithrombotic therapy for prophylaxis and treatment of venous thromboembolism in patients with cancer: review of the literature on current practice and emerging options. ESMO Open 2017;2:e000188. doi:10.1136/esmoopen-2017-000188
Received 12 March 2017
Accepted 14 March 2017
1Department of Medicine,
Clinical Division of Haematology and Haemostaseology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
2Department of Internal
Medicine, Tergooi Hospital, Hilversum, The Netherlands
3Internal and Cardiovascular
Medicine-Stroke Unit, University of Perugia, Perugia, Italy
Correspondence to
Dr Cihan Ay, Department of Medicine I, Clinical Division of Haematology and Haemostaseology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; cihan. ay@ meduniwien.
ac. at

Open Access
2 Ay C, et al. ESMO Open 2017;2:e000188. doi:10.1136/esmoopen-2017-000188The Comparison of Low-Molecular-Weight Heparin
versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer study randomised 676 cancer patients with acute VTE to dalteparin (200 IU/kg/day) for 1 month followed by dose-reduced dalteparin (approximately 150 IU/kg/day) for 5 months, or to dalteparin (200 IU/kg/day) for 5 to 7 days and a VKA for 6 months (target interna-tional normalised ratio [INR] range 2.0–3.0).
17 The risk
of recurrent VTE was significantly lower with dalteparin
Figure 1 Incidence of (A) recurrent VTE and (B) major bleeding in select randomised clinical trials of LMWH for the
treatment and secondary prevention of VTE in patients with cancer. CANTHANOX, Secondary Prevention Trial of Venous Thromboembolism With Enxoaparin; CATCH, Comparison of Acute Treatments in Cancer Hemostasis; CLOT, Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer; LITE, Long-Term Innohep Treatment Evaluation; LMWH, low-molecular-weight heparin; ONCENOX, Oncology and Enoxaparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Open Access
3
Ay C, et al. ESMO Open 2017;2:e000188. doi:10.1136/esmoopen-2017-000188 Ay C, et al. ESMO Open 2017;2:e000188. doi:10.1136/esmoopen-2017-000188versus VKA (HR 0.48, 95% CI 0.30 to 0.77, p=0.002), with
no significant difference in the rate of major bleeding (6% vs 4%, respectively; p=0.27).
17 In the Comparison
of Acute Treatments in Cancer Hemostasis study, which assessed tinzaparin for the treatment of acute VTE with active cancer, 900 patients were randomised to tinzaparin (175 IU/kg/day) for 6 months or to tinzaparin (175 IU/kg/day) for 5 to 10 days and warfarin for 6 months (target INR of 2.0–3.0).
22 Tinzaparin non-significantly reduced
the risk of recurrent VTE (HR 0.65, 95% CI 0.41 to 1.03, p=0.07) and significantly reduced the risk of clinically relevant non-major bleeding (HR 0.58, 95% CI 0.40 to 0.84, p=0.004) but not major bleeding (HR 0.89, 95% CI 0.40 to 1.99, p=0.77) versus warfarin.
22 Overall, in a
recent meta-analysis, LMWH reduced the risk of recur –
rent VTE (relative risk [RR] 0.60, 95% CI 0.45 to 0.79, p <0.001) and had no effect on the risk of major bleeding (RR 1.07, 95% CI 0.66 to 1.73, p=0.08) versus VKA in cancer patients with acute VTE.
24
The risk of recurrence and bleeding associated with
long-term LMWH treatment beyond 6 months presum-ably continues to be high in cancer patients with VTE. The Dalteparin Sodium for the Long-Term Management of Venous Thromboembolism in Cancer Patients study followed 334 cancer patients with newly diagnosed VTE treated with dalteparin for 12 months.
25 All patients
initially received dalteparin (200 IU/kg/day) for 4 weeks and dose-reduced dalteparin (approximately 150 IU/kg/day) during months 2 to 12.
25 The incidence of new or
recurrent VTE with LMWH was similar at 2 to 6 months and 7 to 12 months (3.4% [95% CI 1.6% to 6.1%] vs 4.1% [95% CI 1.8% to 8.0%], respectively).
25 The incidence of
major bleeding was also similar (1.1% [95% CI 0.6% to 1.9%] vs 0.7% [95% CI 0.3% to 1.4%]).
25
thromboprophylaxis in patients receiving chemotherapyA number of studies have assessed LMWH prophylaxis in ambulatory patients with cancer receiving chemo-therapy.
26–32 In the Prospective, Randomised Trial of
Simultaneous Pancreatic Cancer Treatment with Enox-aparin and Chemotherapy (PROSPECT-CONKO 004) study, 312 patients with advanced pancreatic cancer were randomised to receive first-line chemotherapy in an outpatient setting with or without enoxaparin. The risk of symptomatic VTE within the first 3 months was significantly lower with enoxaparin versus without enoxaparin (HR 0.12, 95% CI 0.03 to 0.52, p=0.001), and the risk of major bleeding did not differ (HR 1.4, 95% CI 0.35 to 3.72).
26 Similarly, the SAVE-ONCO
trial randomised 3212 patients on chemotherapy for metastatic or locally advanced solid tumours to receive prophylactic anticoagulation with semuloparin, an ultra-LMWH or placebo for the duration of chemo-therapy.
27 Semuloparin significantly reduced the risk
versus placebo of symptomatic DVT, non-fatal PE or VTE-related death (HR 0.36, 95% CI 0.21 to 0.61, p<0.001), with no difference in the risk of major or clinically relevant non-major bleeding (HR 1.40, 95% CI 0.89 to 2.21).
27 In another randomised placebo-con-
trolled trial, a prophylactic course of nadroparin also reduced the incidence of VTE versus placebo in ambu-latory patients receiving chemotherapy for metastatic or locally advanced cancer.
28 Overall, in a Cochrane review
of pharmacological thromboprophylaxis in ambulatory patients with cancer receiving chemotherapy, which included a total of 9861 patients, LMWH significantly reduced the risk of VTE compared with placebo or inactive control (RR 0.53, 95% CI 0.38 to 0.75) without significantly increasing the risk of major bleeding (RR 1.30, 95% CI 0.75 to 2.23).
33
Perioperative thromboprophylaxisFollowing surgery, VTE risk is elevated postdischarge in patients with cancer.
34 In a prospective observational
study, the incidence of clinically overt VTE in patients with cancer after surgery was approximately 1% to 3% depending on the type of surgery.
35 Importantly, 40% of
VTE events occurred after >21 days postsurgery, and 46% of the deaths postsurgery were due to VTE.
35
Extended LMWH prophylaxis in patients with cancer
beyond the first week postsurgery reduces the rate of VTE relative to short-term prophylaxis.
36 37 In the Enoxaparin
and Cancer II trial, following open-label prophylaxis with enoxaparin 40 mg for approximately 1 week, 501 patients
who had undergone abdominal or pelvic surgery were randomly assigned to continued prophylaxis with enoxa-parin or placebo for an additional 19 to 21 days.
36 During
the double-blind period, the incidence of VTE was signifi-cantly lower in patients with continued enoxaparin versus placebo (4.8% vs 12.0%, respectively; p=0.02).
36 Similarly,
a prospective, open-label trial compared the incidence of VTE in 427 patients with cancer who underwent abdom-inal surgery and were randomised to receive no further thromboprophylaxis after 7 days with dalteparin 5000 IU patients or prolonged administration of dalteparin for a further 21 days.
37 The incidence of VTE was lower
in the prolonged prophylaxis group versus the short-term prophylaxis group (7.3% vs 16.3%, respectively; RR reduction 55%, 95% CI 15% to 76%, p=0.012), and major bleeding events were similar in the two groups (0.5% vs 1.8%, respectively).
37 However, in the Cancer, Bemiparin
and Surgery Evaluation study, 4 weeks of one time per day bemiparin 3500 IU prophylactic treatment in patients with cancer undergoing abdominal or pelvic surgery did not significantly reduce the combined incidence of DVT, non-fatal PE and all-cause mortality relative to 1 week of
bemiparin prophylaxis (RR reduction 24.4%, 95% CI −23.7% to 53.8%, p=0.26).
38
In patients with cancer undergoing surgery, unfraction-
ated heparin (UFH) appears to be as efficacious as LMWH in preventing VTE.
39 40 In a meta-analysis of clinical trials
evaluating the efficacy and safety of LMWH and UFH for thromboprophylaxis following cancer surgery, no differ –
ences were found in mortality with LMWH versus UFH treatment (RR 0.89, 95% CI 0.61 to 1.28) or in the risk of clinically suspected DVT (RR 0.73, 95% CI 0.23 to 2.28).
40

Open Access
4 Ay C, et al. ESMO Open 2017;2:e000188. doi:10.1136/esmoopen-2017-000188orAl AntIcoAgulAnts
treatment and secondary prevention
LMWH monotherapy is generally considered the first-line treatment for cancer-associated VTE.
41–47 Nevertheless,
VKAs remain a common treatment strategy,48 49 possibly
in part because of patients’ unease with long-term subcu-taneous injections or limited access to LMWH.
50
Unlike parenteral anticoagulants, direct oral anticoag-
ulants (DOACs)—such as direct thrombin inhibitors (ie, dabigatran) and direct factor Xa inhibitors (ie, apixaban, rivaroxaban and edoxaban)—offer the convenience of oral administration, and as opposed to VKAs, they have more predictable pharmacodynamics and require no routine laboratory monitoring in most patients.
51 As a
class, DOACs have similar efficacy and are associated with less major bleeding than warfarin for the treatment of acute VTE.
52 However, the efficacy and safety of DOACs in
cancer patients with VTE have not been directly assessed in large, head-to-head trials with LMWH or VKA.
In the phase 3 clinical trials for DOACs versus VKAs
in acute treatment of VTE, only 6% of patients had active cancer.
53 In addition, the patients with cancer in
these trials were not representative of patients at risk for cancer-associated VTE (eg, only approximately 15% to 30% had metastatic cancer and only approximately 30% were receiving chemotherapy).
54–57 Furthermore,
the criteria for defining cancer status at baseline in these studies differed from the clinical trials assessing LMWH for cancer-associated VTE.
24 Therefore, the results of the
cancer subgroup analyses of these trials can only be consid-ered hypothesis generating. Nevertheless, subgroup analyses demonstrated a similar risk of recurrent VTE and major bleeding for dabigatran, rivaroxaban, edox-aban and apixaban compared with LMWH/warfarin
54–57
(figure 2). Overall, in a network meta-analysis of all phase 3 trials, the risk of recurrent VTE in patients with cancer in the pooled DOAC group tended to be lower than that in the pooled VKA group (RR 0.65, 95% CI 0.38 to 1.09, p=0.10), without an increased risk of major bleeding (RR 0.72, 95% CI 0.39 to 1.35, p=0.31).
24
A small prospective study assessed the safety of dabig-
atran (dosed according to creatinine clearance) versus acenocoumarol in the secondary prevention of VTE in 46 patients with cancer and DVT.
58 In this study, dabigatran
had a safety and tolerability profile in patients with cancer consistent with those reported in the larger clinical trial population.
58
Since direct comparisons between DOACs and LMWH
in patients with cancer are not presently available, DOACs cannot be considered for routine treatment of VTE in these patients. However, there are currently ongoing head-to-head trials assessing the efficacy and safety of DOACs versus LMWH monotherapy for the treatment of VTE in patients with cancer, including for apixaban ( Clin-
icalTrials. gov: NCT02585713), edoxaban ( ClinicalTrials.
gov: NCT02073682; Hokusai-VTE Cancer) and rivarox-aban ( ClinicalTrials. gov: NCT02583191; CONKO_011/
AIO-SUP-0115/Ass and ISRCTN Registry: 86712308; Select-D).
59–61 These studies should provide clarity about
the role of DOACs in the treatment of cancer-associated VTE.
thromboprophylaxis
Data on the use of oral anticoagulants for the prevention of VTE in ambulatory patients with cancer are limited. In a double-blind randomised trial in women receiving chemotherapy for metastatic breast cancer, 315 patients were randomly assigned to receive placebo or a very-low-dose warfarin (1 mg) for 6 weeks, after which dose-adjusted
warfarin (INR 1.3–1.9) treatment was continued until
Figure 2 Forest plot of the HRs for DOACs vs warfarin for (A) new or recurrent VTE and (B) major bleeding based on the
published subanalyses of the patients with active cancer at baseline included in the major DOAC phase 3 clinical trials for VTE. BID, two times per day; DOAC, direct oral anticoagulant; OD, one time per day; VKA, vitamin K antagonist; VTE, venous thromboembolism.
aRivaroxaban 15 mg BID for the first 21 days followed by 20 mg OD. bApixaban 10 mg BID for 7 days
followed by 5 mg BID. cRelative risk. dPatients with a creatinine clearance of 30 to 50 mL/min, a bodyweight of <60 kg or who
were receiving concomitant treatment with select P-glycoprotein inhibitors received edoxaban 30 mg OD.

Open Access
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Ay C, et al. ESMO Open 2017;2:e000188. doi:10.1136/esmoopen-2017-000188 Ay C, et al. ESMO Open 2017;2:e000188. doi:10.1136/esmoopen-2017-0001881 week after the end of chemotherapy.62 The incidence
of VTE was significantly lower in the low-dose warfarin
group versus placebo (7 events vs 1 event; p=0.031).62
Major bleeding occurred in 2 placebo patients and 1 warfarin patient.
62
A secondary analysis of the of the Multicenter,
Randomised, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospital-ised Acutely Ill Medical Patients Comparing Rivaroxaban with Enoxaparin (MAGELLAN) trial and a phase 2 study are currently the only clinical data available pertaining to the efficacy of DOACs for thromboprophylaxis in patients with active cancer.
63 The MAGELLAN trial
compared a prophylactic treatment of rivaroxaban for 35 days with enoxaparin administered for 10 days followed by placebo in hospitalised, medically ill patients.
63 Among
the subgroup of patients with cancer, the incidence of VTE with rivaroxaban (9.9%) was similar to enoxaparin/placebo (7.4%) and the incidence of bleeding was higher (5.4% vs 1.4%).
63 Phase 2 pilot study assessed the safety of
apixaban (5, 10 or 20 mg one time per day) versus placebo
for preventing VTE in 125 patients with metastatic cancer receiving chemotherapy.
64 In this study, the incidence
of recurrent VTE was 1.1% with apixaban compared with 13.8% with placebo.
64 There is an ongoing trial to
directly evaluate the efficacy and safety of a prophylactic treatment of rivaroxaban versus placebo in ambulatory patients with cancer receiving chemotherapy ( Clinical-
Trials. gov: NCT02555878; CALLISTO).
61
sPecIAl PoPulA tIons A t IncreAsed rIsk of bleedIng
Patients with chemotherapy-induced thrombocytopeniaUp to 24% of patients with solid tumours treated with chemotherapy develop clinically significant thrombocy-topenia.
65 66 As these patients are at an increased risk of
major bleeding during chemotherapy,67 it is challenging
to find the balance between the risk of bleeding and thrombosis.
68 Furthermore, treatment decisions in these
patients are complicated by the lack of large randomised studies.
68 In the clinical trials assessing the efficacy and
safety of LMWH for the treatment of VTE, patients were generally excluded or treatment was interrupted if they had low platelet counts (ie, <30×10
9–100×109/L).17–23
Therefore, the available evidence about the use of anti-coagulants in these patients comes primarily from small retrospective studies and case reports.
In a case series of 5 patients with thrombocytopenia
and haematological malignancies treated with enoxa-parin for concomitant VTE, platelet transfusions were given for platelet counts <20×10
9/L, and enoxaparin
dose was reduced for platelet counts <50×109/L.69 There
were 2 major bleeding events (1 fatal) and 1 minor bleed; there were no incidences of recurrent or new VTE.
69
Conversely, there were no major bleeds reported in a small retrospective study of 10 patients with haemato-logical malignancies and thrombocytopenia undergoing intensive chemotherapy who received enoxaparin as thromboprophylaxis or for catheter-related central venous thrombosis.
70 As in the case series, during the
period of severe thrombocytopenia, the enoxaparin dose was generally reduced.
70 Similarly, in another study of 4
patients receiving chemotherapy for leukaemia who had VTE and a mean platelet count <60×10
9/L, enoxaparin
was not associated with haemorrhagic complications, and there were no incidences of recurrent VTE.
71 In the
absence of direct evidence, treatment decisions in this patient population may be determined on a case-by-case basis.
Patients with brain metastases
Patients with malignant brain tumours are at an esti-mated 3% to 60% increased risk of VTE during the postoperative period.
72 A prophylactic anticoagulant
regimen is effective in preventing VTE in patients under –
going neurosurgery.73 However, the prophylactic use of
anticoagulation in patients with malignant brain tumours undergoing surgery is controversial with some, but not all,
74–76 studies suggesting a possible increased risk of
intracranial haemorrhage.77 78
In a retrospective cohort study of 293 cancer patients
with brain metastases, there were no differences in the 1 year cumulative incidence of significant intracranial
haemorrhage in patients receiving therapeutic doses of enoxaparin compared with those not receiving anticoag-ulation (21% vs 22%; p=0.87).
79 To date, the PRODIGE
study is the largest randomised trial to assess the use of LMWH thromboprophylaxis in these patients.
78 In
the study, 186 patients with newly diagnosed malignant glioma were randomised to either dalteparin (5000 IU) or placebo for a total of 12 months starting within 4 weeks of surgery.
78 This study was prematurely closed for recruit-
ment because of lower-than-anticipated recruitment and because of the expiration of the study drug.
78 During the
first 6 months, there was a non-significant trend toward decreased incidence of VTE with LMWH versus placebo (HR 0.51, 95% CI 0.19 to 1.4, p=0.17).
78 However, during
this time, there were 3 major bleeds (all intracranial, 1 fatal) with LMWH and none with placebo. Over the full 12 months of the study, there were a total of 5 major bleeds on LMWH versus 1 on placebo (HR 4.2, 95% CI 0.48 to 36).
78 Overall, at present, there is no consistent clinical
evidence to indicate long-term primary pharmacological thromboprophylaxis in this high-risk patient population.
summAry of treA tment guIdelInes
treatment and secondary prevention
Parenteral anticoagulants are considered first-line therapy
for the treatment and prevention of VTE in patients with active cancer. Treatment guidelines—including from the American College of Chest Physicians, the Amer –
ican Society of Clinical Oncology (ASCO), the British Committee for Standards in Haematology (BCSH), the European Society of Medical Oncology, the National Comprehensive Cancer Network and the International

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6 Ay C, et al. ESMO Open 2017;2:e000188. doi:10.1136/esmoopen-2017-000188Clinical Practice Guidelines—recommend LMWH for the
short-term and long-term management of VTE in patients with cancer.
41–47 Due to of the lack of clinical trial data,
most guidelines do not recommend the use of DOACs for the acute or long-term management of VTE. However, ASCO and BCSH guidelines state that oral anticoagulants could be considered for long-term treatment of VTE in patients with cancer based on patient preference or when LMWH is not available.
42 46 47 The International Clinical
Practice Guidelines state that DOACs can be considered for early maintenance (10 days to 3 months) and long-term therapy (>3 months) in patients with VTE and stable cancer not receiving anticancer therapy.
45 In general,
treatment guidelines recommend that anticoagulation should be continued for at least 3 to 6 months as long as there is clinical evidence of active malignant disease in cancer patients with established VTE.
41–47
thromboprophylaxisRoutine thromboprophylaxis is not recommended in outpatients with cancer,
42 46 47 especially those deemed at
low risk for VTE.80 However, in select populations of cancer
patients with solid tumours or in patients with myeloma receiving immunomodulatory agents, prophylaxis could be considered.
41–47 80 81 In patients with myeloma taking
immunomodulatory agents, the European Myeloma Network recommends that the LMWH prophylaxis be continued for at least 4 months, after which patients may be switched to aspirin.
81
For the prevention of VTE in patients with cancer in
an inpatient setting or perioperatively, treatment guide-lines recommend parenteral anticoagulants for primary thromboprophylaxis.
41–47 80 81 After major cancer surgery
(abdominal and pelvic cancer surgery), extended thromboprophylaxis for approximately 1 month is recom-
mended following hospital discharge
42 43 46 because VTE
is frequently observed in these patients more than 3 weeks after discharge.
35
Patients with chemotherapy-induced thrombocytopeniaIn the absence of clinical trials specifically in cancer patients with thrombocytopenia, treatment guidelines are generally based on the platelet count exclusion thresh-olds used in the clinical trials assessing anticoagulants in patients with cancer. In general, the guidelines recom-mend that a full anticoagulant dose be used in patients with cancer with platelet counts >50 x 10
9 L.42 44–47 82 Anti-
coagulants may be considered in patients with platelet counts <50 x 10
9 L on a case-by-case basis, considering risk
of bleeding and risk associated with VTE.42 44–47 However,
ASCO, BCSH and International Society on Thrombosis and Haemostasis (ISTH) state that anticoagulation is contraindicated in patients with severe thrombocyto-penia (platelet counts <20 x 10
9/L [ASCO] or 25 x 109/L
[BCSH and ISTH]).46 47 82 BCSH and ISTH also recom-
mend the use of platelet transfusions to allow for full-dose anticoagulation or a 50% dose reduction in patients with platelet counts between 25 x 10
9 and <50 x 109/L.47 82Patients with brain metastasesThere are limited data available on the use of antico-agulants in patients with brain metastases who develop VTE. That said, ASCO and International Clinical Practice Guidelines note that anticoagulants are not absolutely contraindicated in patients with brain tumours per se.
42 45 46 However, an ISTH guidance statement indicates
that outpatient pharmacological thromboprophylaxis is not recommended in patients with a diagnosis of primary brain tumour.
80
treA tment PrActIces
A significant number of patients with cancer-associated VTE may not be managed according to established treatment recommendations.
83 Of the 275 physicians
responding to a survey of members of various German oncology and haematology clinics, only approximately 75% reported treating acute VTE in cancer patients with LMWH. In this survey, only 55% of specialists reported continuing LMWH treatment for 3 to 6 months, of whom most reported a dose reduction to 50% to 75% of the initial dose during this period.
84 However, in an inter –
national survey of 141 physicians, the long-term use of LMWH monotherapy to treat cancer-associated VTE was higher among thrombosis specialists versus other physi-cian specialists and among European physicians versus physicians from the USA.
85
In a retrospective analysis of health insurance claims
in the USA collected between 2009 and 2014, warfarin was the most commonly prescribed anticoagulant in cancer patients with acute VTE (warfarin, 50%; LMWH, 40%; other anticoagulants, 10%).
86 Of note, LMWH
was prescribed more often in patients with cancer types associated with a high risk of VTE (eg, pancreatic and stomach cancers). Similarly, in a retrospective cohort study of hospitalised patients with PE between 1998 and 2008, LMWH was prescribed in only 13.7% of patients with cancer.
87 In both studies, the relatively low use of
LMWH occurred even though LMWH monotherapy is considered the first-line treatment for cancer-associated VTE. However, in a cross-sectional study of patients with newly diagnosed acute VTE in Canada in 2013, approx-imately 85% of patients with cancer were prescribed LMWH monotherapy for the subsequent treatment of VTE.
88
Pharmacological thromboprophylaxis may also be
underused in patients with cancer at high risk for VTE.89–91
In a cross-sectional study of 775 hospitalised cancer patients with VTE admitted between January and June 2013, only 50.6% of patients received pharmacological prophylaxis during their hospital stay.
90 However, 31.9%
of patients were deemed to have at least 1 relative contra-indication for an anticoagulant, including active bleeding (5.5%) and severe thrombocytopenia (20.8%).
90 Among
patients not contraindicated for an anticoagulant, 74.2% received pharmacological thromboprophylaxis.
90 Patients
with cancer undergoing cancer-specific therapy were

Open Access
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Ay C, et al. ESMO Open 2017;2:e000188. doi:10.1136/esmoopen-2017-000188 Ay C, et al. ESMO Open 2017;2:e000188. doi:10.1136/esmoopen-2017-000188significantly less likely to receive thromboprophylaxis
versus patients with cancer admitted for other reasons (OR 0.37, 95% CI 0.22 to 0.61, p <0.001).
90 In addition,
79% of patients eligible for thromboprophylaxis and clas-sified as being at a high VTE risk by their Padua Prediction Score were prescribed prophylaxis; 63% of those consid-ered as low risk also received prophylaxis.
90
conclusIonsMany of the treatment suggestions for the management of cancer-associated VTE are derived from retrospec-tive studies or are extrapolated from studies on patients without cancer because of a lack of randomised controlled trials focused on specific subpopulations.
92 Therefore,
treatment recommendations may differ slightly based on differences in treatment practices between nations and on how much weight is put on the available clinical trial data or lack thereof. Nevertheless, there is a general consensus (figure 3).
Cancer-associated VTE should be treated for at least 3 to
6 months with a therapeutic dose of LMWH. In patients with complete remission, treatment can be stopped after 6 months. In patients with active cancer (eg, presence of metastatic disease and/or ongoing anticancer treatment), treatment with LMWH at prophylactic doses or oral anti-coagulants, depending on patient preference, can be continued beyond 6 months. In patients with cancer with platelet counts <50 x 10
9 L or in patients with brain tumours, anticoagulants should be considered on a case-by-case basis. After major cancer surgery (abdominal and pelvic cancer surgery), extended thromboprophylaxis for approximately 1 month is recommended following hospital discharge. In
select populations of ambulatory cancer patients with solid tumours or in patients with myeloma receiving immuno-modulatory agents in combination with chemotherapy and/or corticosteroids, primary pharmacological thrombo-prophylaxis (primarily LMWH) could also be considered.
29
In practice, for clinicians to balance the risk of recur –
rent thrombosis with the chance of bleeding, they need to assess the relevant clinical data. Unfortunately, because of the lack of clinical trials, there are still unanswered questions on the optimal treatment regimens; which may affect adherence to treatment recommendations. There-fore, treatment decisions are often made on a case-by-case basis per individual bleeding and thrombotic risk. In addition, anticoagulant options are currently limited to parenteral anticoagulants, which may not be tolerated by some patients. To address the lack of data, several clinical trials are under way, including those assessing the relative efficacy and safety of DOACs in the treatment and preven-tion of cancer-associated VTE. DOACs may provide more convenient anticoagulation compared with LMWH, when their efficacy and safety are proven in patients with cancer.
Acknowledgements Assistance in medical writing and editorial support was
provided by Stefan Kolata, PhD, of AlphaBioCom, LLC (King of Prussia, PA), and funded by Daiichi Sankyo, Inc. (Parsippany, NJ).
Figure 3 Treatment and secondary prevention strategy diagram for VTE in patients with active cancer based on the
treatment guidelines for cancer-associated VTE. DOAC, direct oral anticoagulant; LMWH, low-molecular-weight heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.
aThere is an evidence gap regarding which dose of LMWH to choose for
extended therapy beyond 6 months; in clinical practice, some experts continue with full therapeutic dose and others reduce to a prophylactic dose.

Open Access
8 Ay C, et al. ESMO Open 2017;2:e000188. doi:10.1136/esmoopen-2017-000188Contributors All authors fulfil ICMJE authorship criteria.
Competing interests CA received honoraria for lectures from Sanofi, Pfizer/BMS,
Daiichi Sankyo, Boehringer Ingelheim and Bayer. PWK has served as a consultant
for Daiichi Sankyo, Bayer, Boehringer Ingelheim, CSL Behring and Ablynx and has
received investigator-initiated research grants from Daiichi Sankyo, Bayer, Leo
Pharma, Pfizer and CSL Behring. GA has received personal fees from Boehringer
Ingelheim, Sanofi, Daiichi Sankyo and Bayer.
Provenance and peer review Commissioned; internally peer reviewed.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http:// creativecommons. org/
licenses/ by- nc/ 4.0/
© European Society for Medical Oncology (unless otherwise stated in the text of the
article) 2017. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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