Venous thromboembolism (VTE), comprising of deep vein thrombosis (DVT) and pulmonary embolus (PE), is a common phenomenon which occurs in 1 in 1,000 patients and annually affects 6.5 million people worldwide [1, 2]. Within the UK, the cost of managing VTE has been estimated at £640 million per year, and the prevention of VTE has become a health service priority . Individuals with cancer are at particular risk of VTE due to the local release of procoagulants, such as tissue factor, and the prothrombotic nature of oncological treatments including surgery, chemotherapy and radiotherapy . Up to 18% of patients with cancer will develop VTE, requiring anticoagulation . The standard treatment of VTE is well established, consisting of five days anticoagulation with low molecular weight heparin (LMWH), followed by three to six months warfarin [4, 5]. However, the management of cancer associated thrombosis (CAT) presents several challenges due to a higher rate of both re-thrombosis and bleeding amongst patients with cancer when compared to those with a non-malignant disease .
The impact of VTE on patients with cancer is substantial; conferring a worse prognosis when compared with similar stage cancer patients without VTE [7, 8]. Furthermore, anticoagulation with warfarin is complicated by drug-drug interactions, variable drug absorption, and changing nutritional status . This inevitably has a practical impact on the delivery of anti-cancer therapies. Maintaining stable coagulation with warfarin is difficult and requires more frequent monitoring with blood tests, which adversely affects patients’ quality of life . Three randomized controlled trials (RCTs) have compared LMWH with warfarin in the treatment of CAT, demonstrating superior efficacy with LMWH without statistical difference in bleeding complications [11–13]. Consequently, national and international clinical guidelines recommend the gold standard treatment of CAT to be six months treatment with weight adjusted LMWH [6, 14–16].
The management of CAT beyond six months is less clear; in patients with locally advanced or metastatic cancer there is an ongoing prothrombotic state which may warrant anticoagulation beyond the recommended period. In support of indefinite anticoagulation are data suggesting the prothrombotic risk increases with disease progression, due to a greater tumor burden, reduced performance status and increased use of palliative chemotherapy [17–19]. However, with cancer progression also comes an increased bleeding risk during anticoagulation, and the decision to anticoagulate indefinitely will need to balance the benefits of preventing recurrent VTE against the risks of major bleeding [20, 21]. Furthermore, it is important to consider the impact of long term LMWH use on patients’ quality of life.
Currently, clinical guidelines recommend clinicians consider continuing anticoagulation indefinitely in patients with locally advanced or metastatic cancer [15, 16, 22]. Such recommendations are based largely on consensus opinion and, to date, have been supported by limited clinical evidence beyond case series and observational studies [23, 24]. In the recently reported DALTECAN (Dalteparin sodium for the long-term management of venous thromboembolism in cancer patients) study, 334 patients with VTE and locally advanced or metastatic cancer were treated with dalteparin, of whom 185 (55.4%) completed six months of therapy and 109 (33%) completed twelve months . The authors reported a 10.2% overall frequency of major bleeding and an overall incidence of new or recurrent VTE of 11.1%. In patients treated during the extended anticoagulation period, new or recurrent VTE was reported in 4.1% of patients and major bleeding at a rate of 4.2%. It is notable that both bleeding and recurrent thrombosis rates were higher in the first six months of anticoagulation (1.3% and 1.4% per patient-month respectively) compared with months seven to twelve (0.7% and 0.7% per patient-month respectively) . In the absence of a control arm in which patients received placebo/ceased anticoagulation at six months, the study offers no further guidance as to whether anticoagulation beyond six months provides any net benefit. However, it offers valuable data, which can be used to inform future clinical studies. Firstly, with 96% trial adherence, it suggests that the use of LMWH beyond six months is feasible within the trial setting. Secondly, it suggests that safety concerns regarding bleeding in this patient group may be less of an issue than previously believed. Furthermore, with the rate of VTE recurrence being lower during the extended anticoagulation period than the initial six months, it would seem reasonable to question what degree of added clinical benefit is gained through extended treatment, rather than ceasing anticoagulation at six months . Finally, the trial did not formally evaluate quality of life aspects of LMWH administration over an extended time period.
Several clinical studies are currently attempting to clarify CAT management beyond six months anticoagulation. In the LONGHEVA (Long-term Treatment for Cancer Patients With Deep Venous Thrombosis or Pulmonary Embolism)  study patients who have completed six to twelve months of treatment for VTE and still have an indication for further anticoagulation (metastatic cancer and/or ongoing cancer treatment) will be randomized to receive a further six months of vitamin K antagonist (VKA) or LMWH. The primary efficacy outcome is recurrence of confirmed symptomatic DVT with secondary outcomes including safety. Driven by the belief that patients with metastatic cancer or receiving cancer treatment require extended anticoagulation, the investigators seek to establish the most efficacious anticoagulant between VKAs and LMWHs . Whilst the driving hypothesis feels intuitively sensible, this belief is yet to be quantified within the trial setting. Without robust data identifying the VTE risk of not continuing anticoagulation it becomes conceptually challenging to justify a therapeutic intervention that is yet to be proven beneficial.
SELECT-D (Anticoagulation therapy in SELECTeD cancer patients at risk of recurrence of venous thromboembolism.) is a pilot study comparing dalteparin versus rivoraxaban in the treatment of CAT with a second placebo-controlled randomization comparing the duration of anticoagulation therapy (six months versus twelve months treatment) in residual vein thrombosis [RVT] positive patients . It is wholly appropriate that this study is piloted before proceeding to a full RCT since several key factors within the study design will need clarification in advance. Firstly, the investigators have chosen to compare dalteparin with rivaroxaban, a drug that is yet to demonstrate non-inferiority in the CAT setting. Secondly, the utility of RVT as a predictor of VTE recurrence specifically in the cancer-associated thrombosis setting is yet to be established [27, 28].
It is arguable that when considering anticoagulation beyond six months, one should quantify the clinical need for prolonged anticoagulation before evaluating the most appropriate drug. Scientifically, such an approach has merit since it informs future studies from a basis of fact and not supposition. However, clinical practice has developed in such a way that many clinicians will continue anticoagulation regardless of the evidence deficit. For this reason, a study to identify whether patients with CAT and ongoing cancer should cease or continue anticoagulation at six months may be difficult to recruit to, since such practice feels counter intuitive to clinicians. Whether such a study would be feasible regardless of scientific merit is unclear. The authors therefore propose such a study to identify the feasibility of conducting a RCT comparing six months LMWH with indefinite anticoagulation in CAT patients with ongoing malignancy.
Research aim and objectives
The ALICAT (Anticoagulation Length in Cancer Associated Thrombosis) study was developed in response to a National Institute for Health Research (NIHR) Health Technology Assessment (HTA) commissioned call considering duration of treatment of venous thromboembolism in malignant disease (reference: 10/145), to address a specific gap in the evidence base for the management of CAT in patients with ongoing malignant disease.
The aim of this study is to examine the feasibility of conducting a phase three randomized controlled trial determining the length of anticoagulation for patients with cancer associated thrombosis.
The objectives are to: (1) Identify the practicalities of conducting a full RCT with regard to recruitment, retention and outcome measurement, specifically: the number of eligible patients that can be recruited within a one year timeframe, the dropout rate, the practical utility of measuring primary outcome measures, reporting processes, and assessment tools within the context of a full RCT. (2) Explore the logistical and attitudinal barriers to progressing to a full RCT, in particular: how and where to identify patients for recruitment, the attitudes of clinicians towards entering patients on to the ALICAT trial and prescribing anticoagulation for patients with CAT, patients’ attitudes to taking part in the trial, including individuals who consented, those who refused to participate and people who withdrew post-randomization.