Vascular Thromboembolism in Advanced Pancreatic Cancer

  Dr. Anthony Maraveyas and the FRAGEM trial team

Advanced pancreatic cancer (APC) has the worst prognosis of all adenocarcinomas in the human body and is the 4^th leading cause of cancer related death in the western world. A key additional contributor to morbidity and mortality in this group of patients is diagnosed and undiagnosed vascular thromboembolism (VTE).  This has been persistently highlighted by post-mortem, registry and epidemiological studies. Moreover this grave VTE legacy is ‘compressed’ into a short patient survivorship resulting in the highest possible impact in terms of VTE episodes per ‘person-time’; between 4 and 5 times worse in fact, than most of the other common malignancies. APC therefore lends itself as a ‘model’ for the study of this problem.

A first positive step was the landmark CLOT investigators trial demonstrating the safety and efficacy of the long-term use of weight adjusted low molecular weight heparin (WAL) (‘secondary’ prevention dosing) in advanced cancer patients with VTE. The second was the realisation by us and others, that the conventional ‘primary’ prophylaxis LMWH dosing schedules used in surgical trials may not be sufficient for the protection of patients with APC from VTE, especially during periods of prolonged exposure to the endothelial stress of chemotherapy, a practice that increases the risk of thrombosis by up to 4.8-fold in APC patients compared to the general population risk. The inordinately high risk of a VTE diagnosis being made within the first 3 months of the cancer diagnosis coincides with the most likely timing of anti-cancer therapy (Figure below).

 Risk of diagnosis of clinical VTE after diagnosis of malignancy.

These considerations have led to the design of two trials. CONKO-04 using enoxaparin at half-recommended WAL and the FRAGEM study using the full WAL recommended dosing for dalteparin. Both trials have now reported and both are positive in terms of their primary endpoints of reducing VTE in APC. The emerging message is that, weight–adjusted- LMWH-thromboprophylaxis in the ambulant APC patient receiving chemotherapy prevents VTE, is safe and should be considered a standard of care, at least in the west.

Many new questions arise. What is the impact of WAL with combination chemotherapy?  Do we need to treat patients for longer than 3 months with WAL? What about VTE outcomes?

The FRAGEM data suggest that up to 9% of APC patients may be dying of a VTE-related event. This is markedly more than the figure we found in the literature of 0.1% of all deaths being attributed to VTE in APC randomised trials. This chimes strongly with the recent realisation of the thrombosis risk of erythropoietin at pharmacovigilance stage rather than trial stage, with VTE being a possible associate of the now demonstrated increased mortality in some patient-groups receiving EPO. A new ‘VTE-assessment-tool’ should be devised based on validated clinical outcome criteria, already being used outside cancer medicine for common VTEs. Furthermore, the elusiveness of VTE symptoms in the symptomatic cancer patient means that even the most skilled clinician will often miss the diagnosis and hence its consequences. Thromboprophylaxis therefore, seems a logical clinical strategy.

So, should we go back and study some of the ‘failed’ agents with concurrent WAL thomboprophylaxis? Bevacizumab (Avastin) for example can increase the symptomatic thromboembolic risk by 33%. How confident can we be that the lack of benefit in a recent RCT in APC is not the product of type II error from VTE imbalance? 

With the advent of the new oral anti-FXa (e.g. rivaroxaban) and direct thrombin inhibitors (e.g. dabigatran) will it be possible to make thrompoprophylaxis more user-friendly? Will these agents work as well and be as safe as LMWH in APC patients? And what of the putative anti-cancer effect of LMWHs? Would a WAL-thromboprophylaxis schedule ‘provide for’ this effect or do we need to explore different dosing paradigms or even combination of anticoagulant agents to realise these ‘dual’ benefits?

Dr. Anthony Maraveyas, Hull and East Yorkshire NHS Trust, Academic Oncology,

Hull East Yorkshire, United Kingdom.