Cancer-related venous thromboembolic disease: current management and areas of uncertainty

Abstract

The relationship between cancer and venothromboembolic events is a complex, multifactorial process which is still not fully understood and therefore the use of current generic guidelines may be inadequate. Current management of cancer-related VTE may be suboptimal because of the lack of cancer-specific studies into the role of primary prophylaxis in both ambulant and non-ambulant cancer patients. Further research into developing cancer-specific risk assessment tools and the choice, dose and duration of prophylaxis is required. The management of confirmed symptomatic VTE in cancer patients is outlined but certain controversies remain. Areas for further research include the management of asymptomatic unsuspected VTE events, recurrent VTE events on treatment and the role of IVC filters and other treatment options are required. This paper attempts to cover some of the recent developments and areas of uncertainty surrounding the management of cancer-related VTE.

Keywords

cancer venous thromboembolism VTE prophylaxis

Introduction

The association between cancer and venothromboembolic events (VTE) has long been known. Trousseau described his eponymous syndrome of migratory thrombophlebitis in 1865 suggesting the association between malignancy and VTE.^1,2 Since then it has become clear that cancer can be associated with a hypercoagulable state and many different pathways have been uncovered in this complex relationship between cancer and VTE.^1–4

The annual incidence of VTE events in patients with cancer is around 0.5% with the incidence for inpatients approximately 2%, which is double that of the normal population.³ Approximately 1% of patients with cancer will die of a pulmonary emboli (PE).⁵ This syndrome tends to be associated with a poorer prognosis than matched cancer patients without VTE.^6–8 It is also accepted that both the risks of recurrence of VTE and bleeding on anticoagulation is higher in the cancer population than in the normal population.^9,10 It is apparent that the relationship between cancer and the risk of VTE events involve complex interactions between many factors,¹¹ including the primary histology, stage and treatments.³ This poses a management challenge for clinicians. In this article, we will attempt to unveil some of the treatment options and controversies surrounding this paraneoplastic phenomenon.

Primary prophylaxis

For the purpose of this paper, we define primary prophylaxis as any treatment used to reduce the risk of developing VTE events. This is an area that has generated much debate in cancer patients and the controversy around this has been fuelled by the publication of the CG92 National Institute of Clinical Excellence (NICE) guidance¹² in January 2010.

NICE guidance

The NICE guidance recommends that all patients coming into hospital should have a VTE risk assessment undertaken.¹² The risk assessment tool recommended by NICE states that if a medical patient's mobility is reduced for >3 days and has ‘active cancer or cancer treatment’ that patient is deemed to be at high risk of VTE. The document makes clear recommendations that patients with cancer, who are receiving oncological treatment and are ambulant, need not be offered prophylaxis. These recommendations were made on the basis of extrapolation from limited evidence in the general medical inpatient population. Therefore, most generic medical risk assessment tools score any cancer diagnosis highly.^13,14 This is due to the lack of studies looking specifically at the cancer population. The studies quoted in the NICE document also looked at asymptomatic events, detected on ultrasound scan, as their endpoints, or in some situations, an elevation in fibrinogen products, which are known to be elevated in cancer patients anyway.¹⁵ However, the role of thrombin generation and other degradation products may act as a useful predictive marker to identify cancer patients at higher risk for VTE.¹⁶

The document does not define the duration of treatment or, specifically, the term ‘active cancer’. The duration of therapy is pertinent because the actual period of high risk for VTE events is unknown. In some instances, the risk could be higher a few weeks post-discharge from hospital.^17,18

In appendix D of the CG92 document,¹² it acknowledges that some cancer subtypes pose less of a risk of VTE than the normal population. The guidance also suggests that, for the duration of their inpatient stay, prophylactic low doses of low molecular heparin or fondaparinux may be adequate, without any robust cancer-specific evidence to support this approach.

Newer evidence from retrospective databases from North America and Southern Europe would suggest that the risk for VTE in cancer patients involves a complex multifactorial association between primary histology, treatments and other factors.^19–23 What is still not clear is the choice, dose of therapeutic agent and duration of intervention to reduce these risks.

Unfortunately, NICE guidance may potentially hamper the development of future study into this area because of the need to comply with the guidance. The generic risk assessment tool places cancer as a major risk factor for the development of VTE and a cursory assessment applying this tool may lead to the unnecessary and potentially hazardous prescriptions of prophylaxis. There is a need for an oncology-specific assessment tool for patients who can only be developed by prospective multicenter well-structured observation studies in this population.

Areas of uncertainty

Although many oncologists do not dispute the need for VTE risk assessments to take place,¹⁹ the NICE recommendations for cancer patients are open to misinterpretation and this introduces the potential for flawed practices, as outlined previously. This is evident in the document itself, acknowledging the lack of specific data in the cancer population and that further research is required. In appendix D of the NICE document, there is a breakdown of VTE risk based on cancer sites compared with the normal population.¹² It is clear that the authors factored this into their recommendations and even suggested the need for further research in this area.

However, because of Trusts’ need to comply with the guidance document, rather than promoting research, it may actually stifle research into this area. This is particularly relevant in the current situation where emerging evidence suggests that some ambulatory patients should be considered for primary prophylaxis.^16,21 Current guidance would, for example, suggest that a patient with head and neck squamous cell cancer (who may have a lower risk than the normal population for VTE), who may be admitted while receiving curative chemoradiotherapy and considered less mobile than normal, should receive prophylaxis, as opposed to a patient with advanced pancreatic cancer (higher risk of VTE) receiving chemotherapy as an outpatient. There is also increasing evidence that certain commonly used systemic chemotherapy agents, e.g. the commonly used cisplatin (Hospira UK Ltd., Leamington Spa, Warwickshire, UK) may increase the risk of VTE,^24,25 and, therefore, the relationship between cancer and VTE is also complicated by the treatments involved as well.

Recent retrospective analyses from large cancer databases have been used to develop risk stratification scoring systems to identify patients who are ambulant and receiving chemotherapy and who are at high risk of developing VTE.¹⁵ It may be that specifically identifying these patients for prophylaxis may reduce their risk of developing VTE. Newer studies are looking at defining molecular markers that may predict the risk of VTE and utilizing these for targeting patients most likely to benefit from intervention. A risk stratification system developed for ambulant cancer patients receiving systemic therapy by Khorana et al.²¹ suggests that by identifying basic parameters from a full blood count and type of cancer, a predictive risk of VTE can be produced. By using this score, oncologists may be able to identify high-risk groups of ambulant patients for consideration for prophylaxis. Ay et al.¹⁶ have validated this risk scoring system recently. Newer studies²⁰ looking at other markers, e.g. thrombin generation, etc. are also being studied and, in time, there may be a more robust predictive tool available. However, the intervention required is yet to be defined.

The current option for prophylaxis is using low doses of one of the low-molecular-weight heparin (LMWH) agents, but the dose and duration of therapy remain controversial. The PROTECHT²⁶ study, a blinded randomized placebo-controlled study, which studied the use of low-dose nadroparin, showed a reduction in VTE events from 2.9% in the placebo group to 1.4% in the nadroparin group. However, there was no survival advantage. The incidence of incidental thromboembolic events, which was not included in the primary analysis, was equivalent in both groups (1% in nadroparin group versus 0.8% in the placebo group), which is of interest. The prevalence of thromboembolism was highest in the lung cancer group.

Further study is urgently required into primary prophylaxis, including the dose and the duration of prophylaxis in cancer patients. These studies should, ideally, have a non-treatment group to ascertain a definite benefit from the intervention. However, this latter aspect is now virtually impossible to carry out in light of the NICE guidance. Any future studies should require careful planned subgroup analysis, with relevant endpoints of symptomatic VTE events, quality-of-life measures and overall survival.

Secondary prophylaxis

In this article, this has been defined as therapeutic intervention and/or anticoagulation for a radiological confirmed VTE.

Current evidence base

The interaction between certain cancer-related pro-coagulants and heparin has led to some large studies utilizing LMWH.²⁷ The CLOT study,²⁸ published in 2003, showed a reduction in rate of recurrent VTE in cancer patients when utilizing the low-molecular-weight heparin, dalteparin, over a coumarin vitamin K antagonist (VKA). In the CLOT study, patients were randomized to receive dalteparin at 200 IU/kg for four weeks followed by 150 IU/kg for the subsequent five months versus a coumarin with a target INR of 2.5 for six months. The coumarin arm involved intensive INR control and follow-up. The probability of recurrent VTE was 17% in the coumarin arm versus 9% in the LMWH arm. There was no difference in the bleeding rate or survival.

Another study, the Canthanox study,²⁹ which failed to achieve its target accrual due to the higher bleeding rate in the VKA group, also compared LMWH (enoxaparin) with a vitamin K antagonist, warfarin, in the cancer patient population. The risk of bleeding complications (including fatal bleeding) was higher in the warfarin arm than in the LMWH arm, and the incidence of VTE events was also higher in the VKA group. The Cancer LITE study that compared three months of tinzaparin (LMWH) with VKA for confirmed DVTs in cancer patients showed a 16% recurrence rate after one year in the VKA arm as opposed to 7% in the LMWH arm. Once again, these studies did not show a survival benefit from the choice of anticoagulation.

An ongoing study, the CATCH study, is comparing tinzaparin and VKA for extended duration therapy but is specifically prospectively looking at quality-of-life measures and cancer-specific outcomes as well.³⁰ We await the results of this study with interest.

These studies have resulted in a change in the management pathways for cancer-related VTE with the increased use of LMWH as first-line anticoagulation.^31,32 It has been shown to have a clinical benefit and is cost-effective.³³

Although safer than VKA, these drugs still require monitoring for the risk of heparin-induced thrombocytopenia³⁴ following initiation and monitoring of the renal function of patients is required while they are on it.³⁵ The monitoring of renal function is required especially in cancer patients who have risks of renal dysfunction from nephrotoxic agents used, the side-effects of anticancer agents causing acute renal impairment (e.g. profuse diarrhoea) and the primary effects from the cancer itself (e.g. obstructive uropathy).

Following on from these studies, which have shown a benefit of LMWH in reducing the risk of VTE, more recent studies have looked at the role of therapeutic dose LMWH in specific high-risk cancers. These studies include the FragGem study³⁶ in pancreatic cancer which has shown a reduction in the incidence of VTE when patients are on LMWH treatment with gemcitabine chemotherapy for six months versus gemcitabine alone, but this does not appear to have an impact on overall cancer survival. There are further studies ongoing looking at the role of LMWH in lung cancers.

Consensus guidelines

Following these trials, national and international oncology bodies have issued consensus guidelines for the management of cancer-related VTE. The British Haematological Society,^34,37 European Society of Medical Oncologists (ESMO)³⁸ and the American Society of Clinical Oncologists (ASCO)³⁹ all recommend the use of a minimum of six months of anticoagulation, ideally with LMWH, for patients with cancer-related VTE. There is a suggestion that patients who have ‘active’ cancer should have longer durations of treatment.⁴⁰ This latter point is contentious because of the lack of a consistent definition of ‘active cancer’ and what the actual benefit to patients’ quality-of-life measures and cancer-specific outcomes are.

The National Comprehensive Cancer Network (NCCN)⁴¹ recommends a shorter duration of anticoagulation for DVT of three months for the first event. Although most oncologists would prescribe LMWH as their choice of treatment for confirmed VTE, there are some who still use VKA. The duration of treatment remains an area of significant controversy.

In the UK, a consensus meeting was held in London 2010, attended by oncologists, surgeons, haematologists and others and issued a joint recommendation published in the British Journal of Cancer in 2010.⁴² In this document, the recommendation was for LMWH or fondaparinux as the agent of choice in most episodes of VTE occurring in patients with cancer. The document suggested prolonging the duration of therapy in ‘active cancer’ or when ongoing risk factors remained beyond six months but acknowledged the paucity of evidence to support this approach.

Areas of uncertainty

Optimizing the management of cancer-related VTE poses a difficult challenge for clinicians. In essence, there needs to be a balance of risk of VTE weighed against any benefit in terms of quality of life and survival from instigating any intervention. Although LMWH reduces the recurrence of VTE events, it has not been shown to improve survival when compared with oral VKA therapy. The interventions need to be balanced against the patients’ cancer-specific prognosis, patient choice and potential interventions (including thrombolysis).⁴³

The use of LMWH has enabled an outpatient management for VTE, especially those who are deemed to have a lower risk of complications from anticoagulation.^44–48 The development of certain risk scores can be beneficial to facilitate this process, but once again these criteria tend to identify cancer as a increased risk factor.^49,50 The development of a cancer-specific outpatient scoring system should be developed. In our centre, the majority of patients with VTE are managed in the outpatient setting with clear guidelines with respect to monitoring. The development of shared care pathways with local general practitioners has led to the safe and effective anticoagulation of cancer patients as outpatients.

There is some debate over anticoagulation in patients in the terminal phase of their cancer. LMWH has been shown, however, to be favoured to VKA, based on a study of palliative care patients’ preferences for choice of anticoagulation.⁵¹

Some of the other areas are reviewed below.

Duration of therapy and choice of agent for longterm treatment

Although there is agreement that the first choice for anticoagulation in patients with cancer with confirmed VTE events is a LMWH, the duration of treatment remains unclear.

The duration of prophylaxis for DVT versus PE is uncertain. The Cancer LITE⁵² study suggested that for duration of anticoagulation with LMWH in cancer patients, three months was adequate in reducing the risk of recurrent VTE when compared with a VKA.

Most of the published studies have used a period of 3–6 months of anticoagulation at therapeutic doses of LMWH. The survival and/or quality-of-life benefit gained from continuing anticoagulation beyond this period is unclear.

The decision on prolonged anticoagulation is now subject to some ongoing clinical studies. However, the question for prolonged anticoagulation in patients with active cancer is fraught with complex competing factors, including a consistent accepted definition of ‘active cancer’, interaction with oncological interventions, choice and doses of the agent used, estimated cancer-specific survival time and patient choice.^3,30

Further studies looking into this question are now underway and we await these results. Newer studies are also looking at newer agents and centres should be encouraged to participate in these studies to maximize accruement.

Management of unsuspected pulmonary emboli

The advent of higher-resolution computed tomography scanning and the increased frequency of ‘routine’ scanning of cancer patients either undergoing active treatment or as part of their cancer surveillance has led to the discovery of this new phenomenon: the unsuspected PE (UPE).

Also known as incidental PE, these are events which are detected on routine scanning in patients who do not have any specific VTE-related symptoms. New research in this suggests that these events are fairly common. Our series over a one-year period suggested that we would expect to pick one event a week over the course of a year.⁵³

There are two emerging themes from this new diagnosis. The first is defining the event as asymptomatic. This is usually taken as the absence of the cardinal symptoms and signs of a PE, e.g. dyspnoea, pleuritic chest pain and signs of right ventricular strain among others. However, in a retrospective analysis it was found that fatigue was also a common symptom for PE in cancer patients, with a high sensitivity.⁵⁴ Fatigue is an extremely common symptom in cancer patients, especially those on treatment, and the specificity of this symptom for a PE must be questionable. It is therefore critical that a clear symptom and treatment history is taken over the time period preceding the scan to make this diagnosis.

The second issue is the clinical relevance of these events. Increasingly, the site of the embolus, either central or proximal versus subsegmental/peripheral, is being applied to reports. A clear and consistent definition of the extent and site of these emboli is required. We would suggest the number of emboli and the use of proximal and segmental in all reports of UPE events. Recent data would suggest that in cases of UPE in segmental/peripheral locations, cancer patients do not have a worse prognosis than patients without PEs.⁵⁵ This is very interesting because it may suggest that these events are probably occurring without any significant clinical sequelae and therefore may not require prolonged or any anticoagulation. The duration of the central PEs, as does symptomatic VTE, remains unclear. In our series, we found that the PE resolved after three months.⁵³ The rate of recurrence of VTE,⁵⁶ on and off anticoagulation, requires further study with prospective subgroup analysis depending on tumour subtype, stage and whether they are receiving active anticancer therapy or not. The role of prolonged anticoagulation needs to be weighed up against the risks and morbidity associated, especially in patients with a limited cancer-specific prognosis.

The actual reasons and pathophysiological factors that cause the development of this asymptomatic central PEs and why this results in poorer prognosis than patients without PEs require further study. These events may reflect a patient and cancer-specific interaction and understanding this may lead to potential further improvements in reducing VTE events and improving cancer-specific survival in these patients.

Management for recurrent VTE on treatment

Even with the use of LMWH in cancer patients with confirmed VTE, there are still approximately 5–10%^28,52 of these patients who will have further recurrence or progression of their VTE while on treatment. The optimal management of these patients can be very challenging.

A potential option would be to increase the dose of the LMWH and assess the patient clinically for signs of improvement. This can be carried out in a stepwise escalation of the therapeutic dose of the LMWH by 25% of the dose and/or dividing the delivery to a bi-daily regimen (in the case of once-a-day preparations).⁵⁷ It is generally suggested that anti-Xa levels are measured to ascertain if these levels are within the therapeutic range. However, it is possible that these patients may have an element of resistance and therefore higher ranges of therapeutic doses of LMWH are required. It is therefore important to correlate the measured ranges of anti-Xa levels directly with symptomatic responses.

An alternative strategy is the insertion of an inferior vena cava (IVC) filter.⁵⁸ This may reduce the risk of emboli but patients remain with a risk of DVT.⁵⁹ This is also principally based on the premise that emboli are only generated by lower-limb DVTs that may not necessarily be the case in cancer patients, who are also susceptible to upper-limb DVTs. It is therefore recommended that patients remain on anticoagulation following the insertion of the IVC filter. There are some who would advocate the conversion to a VKA and using higher INR ranges. This approach must be viewed with caution because of the significant elevated bleeding risks associated with patients with cancer, which may be elevated further while on a VKA. Closer monitoring and more erratic interactions with many oncological treatments would make this a high-risk option in our view.

Management of VTE in the bleeding patient

This is a particularly challenging problem. Sadly, tumour bleeds can be difficult to treat and are associated with a high morbidity.

Management decisions are made based on the individual clinical situation and require a complex clinical decision-making process weighing the risks posed by the bleeding and the VTE.

The initial management would be to stabilize the patient and identify the source and cause of the bleed. In the event that bleeding may be stemmed, then this intervention should be carried out post haste. In cases of major or difficult to manage bleeding, anticoagulation may need to be stopped and/or reversal agents used where appropriate to control the bleeding. In cases where the bleeding is not severe and the VTE carries a higher risk of complications, the use of unfractionated heparin (UFH) may be considered until the bleeding has been dealt with. The shorter half-life and available reversal agent for UFH may enable the VTE to be treated while still enabling the bleeding source to be dealt with.

In these cases, there may be a role for the insertion of an IVC filter until the bleeding source can be controlled.^58,59 In cases of tumour-associated bleeding, especially in cases where there is a slow bleed, intervention to stem the bleeding may be pursued using options such as radiation therapy or embolization. In cases where these measures are successful, it may be possible to reinstitute anticoagulation and potentially remove the IVC filter if there is no further significant bleeding risk. Some of the newer filters may potentially be removed even beyond six months postinsertion.

Conclusion

Cancer-related VTE is a complex disease process and requires specialist care. The increasing interest in VTE as whole is welcomed but the application of generic management algorithms may not be beneficial in the cancer population. Our understanding of this disease process is poor and requires more in-depth research, ideally led by multidisciplinary cancer clinicians to develop and optimize treatment options. There is a need for more active involvement from oncologists in the management of cancer-related VTE and also in defining the role and need for primary prophylaxis in specific cancer populations. Fortunately, this group of cancer ‘clotters’ is increasing and their expertise should be utilized in the development of future studies and guidelines.

Footnotes

Conflicts of interest: None declared.

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