Max is a 61-year-old male who works as a consultant cardiologist at your same institution and who has recently been diagnosed with locally advanced, small-cell lung cancer (SCLC). He is about to start treatment with chemotherapy and concurrent radiotherapy. Searching on the Internet for recent advances in the management of his disease, he has read about the possible antineoplastic effect of anticoagulant drugs. He asks you for advice regarding the potential benefits and drawbacks of the addition of prophylactic low-molecular-weight heparin as adjuvant therapy, with the aim of improving survival.
Many in vitro and animal studies have illustrated how anticoagulant drugs display a variety of antineoplastic properties which involve a variety of mechanisms, such as inhibition of tumor cell proliferation, neoangiogenesis disruption or metastasis avoidance. Although most studies have been performed with low-molecular-weight heparins (LMWH), oral anticoagulants – both vitamin K antagonists (VKA) and direct oral anticoagulants (DOAC) – have also shown interesting results.
Unfortunately, the pre-clinical evidence has not been clearly and uniformly confirmed by the multiple clinical trials conducted over the last few years. Although some studies found a positive impact on survival, with the addition of LMWH to standard cancer treatment, beyond venous thromboembolism (VTE) prevention, in other studies, no effect was observed. Recent study-level meta-analyses of randomized clinical trials (RCT) did not show a significant survival benefit [1]. However, due to the heterogeneous design of the RCT on this topic, it is difficult to obtain concrete conclusions. There are important variations across studies regarding study population (single vs multiple malignancies), disease stage (limited vs advanced cancer) or treatment schemes (type, dose and duration of LMWH). It seems that if any benefit exists, it would be limited to some specific tumors and probably at early stages.
Another recent individual participant data meta-analysis presented at the latest ASH meeting evaluated the impact of prophylactic use of heparin in more than 8,000 oncological patients included in 13 RCT. According to the analysis, LMWH reduced the risk of VTE without increasing major bleeding, but without improving survival across all patients [2]. The adjusted relative risk of mortality within one year was 0.99 (95% CI: 0.95- 1.03) and the hazard ratio after one year was 0.97 (95% CI: 0.82-1.14). The greatest benefit of LMWH treatment in terms of VTE occurrence was observed in patients with lung and pancreatic cancer, OR=0.52 (95% CI: 0.39-0.68) and OR=0.55 (95% CI: 0.35-0.88), respectively.
On the other hand, other recent studies have found that the reduction in the incidence of VTE events is counterbalanced by a higher risk of clinically relevant bleeding. Meanwhile, the evidence supporting DOAC is much weaker at the moment. On-going studies evaluating the use of these newer drugs for VTE prophylaxis in cancer patients will be of great value. A recent Cochrane review suggested that future research should investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer[3]. Independent investigator initiated studies are probably the only hope of illustrating further advances in this field, since the interest of pharmaceutical companies in this area has declined over time. Meanwhile, as the authors of the aforementioned review explained, the decision for a patient with cancer to start heparin therapy should be counterbalanced by a careful consideration of the benefits and drawbacks of the therapy; they also stated that treatment choice must also integrate the patient’s values and preferences.
Our patient described above had been diagnosed with limited-stage SCLC, probably the scenario in which LMWH has obtained the best results regarding survival improvement [4]. In addition, lung cancer as a whole is considered a high-risk malignancy both by the validated Khorana risk score for VTE in cancer patients and the Vienna prediction normogram. If other clinical or biological risk factors for thrombosis were present, the benefits of LMWH in terms of VTE prevention and uncertain improved survival would probably outweigh the risks (bleeding, inconvenience of daily subcutaneous injections). On the contrary, if no additional risk factors for thrombosis were identified, the weakness of the available evidence on cancer survival, together with a higher risk of bleeding, would probably favor a decision to advise against the use of LMWH.
References
- Sanford D, Naidu A, Alizadeh N, Lazo-Langner A. The effect of low molecular weight heparin on survival in cancer patients: an updated systematic review and meta-analysis of randomized trials. J Thromb Haemost. 2014 Jul;12(7):1076-85.
- Schünemann H, Ventresca M, Crowther M, Di Nisio M, et al. An Individual Participant Data Meta-Analysis of 13 Randomized Trials to Evaluate the Impact of Prophylactic Use of Heparin in Oncological Patients. ASH 59th anual meeting & exposition. 2017. Abstract 626.
- Akl EA, Kahale LA, Hakoum MB, Matar CF, Sperati F, Barba M, Yosuico VED, Terrenato I, Synnot A, Schünemann H. Parenteral anticoagulation in ambulatory patients with cancer. Cochrane Database Syst Rev. 2017 Sep 11;9:CD006652.
- Yu Y, Lv Q, Zhang B, Lan F, Dai Y. Adjuvant therapy with heparinin patients with lung cancer without indication for anticoagulants: A systematic review of the literature with meta-analysis. J Cancer Res Ther. 2016 Oct;12(Supplement):37-42.