PALLIATIVE AND SUPPORTIVE CARE

Tratamentul antitrombotic la pacienţii cu cancer

 Specificity of antithrombotic treatment in cancer patients

First published: 24 octombrie 2015

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/OnHe.32.3.2015.4316

Abstract

Thromboembolic complications in cancer is a leading cause of morbidity and mortality. Therefore, prevention and treatment of this complications are contributing to increasing the survival and quality of life in cancer patients. Prevention can be achieved by identifying patients at high risk of developing thromboembolic complications and prophylaxis and treatment of recurrence must be properly chosen. Treatment with low molecular weight heparin in cancer patients is a safe treatment option and do not increase the risk of major bleeding. In correctly selected cases, oral anticoagulants have indication of replacement therapy with low molecular weight heparins.
 

Keywords
cancer, tromboembolic event, low molecular weight heparin

Rezumat

Complicaţiile tromboembolice în cancer sunt cauza principală de morbiditate şi mortalitate. Prin urmare, prevenirea şi tratamentul acestei complicaţii contribuie la creşterea supravieţuirii şi calitatea vieţii la pacienţii cu cancer. Prevenirea poate fi realizată prin identificarea pacienţilor cu risc crescut de apariţie a complicaţiilor tromboembolice şi profilaxia şi tratamentul recurenţei trebuie să fie ales în mod corespunzător. Tratamentul cu heparină de greutate moleculară mică la pacienţii cu cancer este o opţiune sigură de tratament şi nu creşte riscul de sângerare majoră. În cazurile selectate corect, anticoagulantele orale sunt indicate în terapia de substituţie cu heparine cu greutate moleculară mică.
 

Introduction

Venous thromboembolism is the leading cause of morbidity and mortality in cancer(1). Moreover, cancer is a major risk factor for venous thromboembolism, with an increased incidence of 4-7 times(2,3). The close association between cancer and venous thromboembolism is well known, it was first reported in 1865 by Trousseau(4).

At one in seven patients hospitalized and who died of cancer it was demonstrated at autopsy that the cause of death was pulmonary thromboembolism and also 60% of patients that had died by venous thromboembolism suffered from cancer in localized stage or metastatic limited(5).

The occurrence of venous thromboembolism in patients with cancer is caused by a hypercoagulable state by activation of coagulation by tumor cells, due to the synthesis of pro-coagulant factors, cytokines (TNF, IL-1b, VEGF) or by stimulating direct intercellular interaction with endothelial cells, leucocytes or platelets. Tumor cells constitutively express tissue factor, the main activator of coagulation, which initiates angiogenesis and vascular endothelial penetration by tumor cells(3,6). Another pro-coagulant factor produced by tumor cells is a cysteine proteinase that activates Factor X in a Factor VIIa independent manner. TNF and IL-1b stimulate endothelial expression of tissue factor and inhibit expression of thrombomodulin. VEGF stimulates angiogenesis and inhibits apoptosis. Also, tumor cells express cell surface adhesion molecules which fosters direct interaction with endothelial cells, platelets, white blood cells, fibronectin and von Willebrand factor(3,7,8).

The emergence of venous thromboembolism phenomena in patients with cancer severely affects disease prognosis, especially if this complication is experienced early (within the first month after diagnosis), high­lighting an aggressive evolution of the disease or metastatic disease. Also, these patients have an increased risk of relapse of embolic phenomena, especially in the first months after diagnosis, and keep up even a few years(9). During chemotherapy, cancer patients show a 7 times higher risk of developing thromboembolism than patients without cancer(9).

Background

Clinicians often underestimate the prevalence of embolic phenomena and their negative impact on patients. All patients known with venous thrombosis developed during neoplastic disease, who present at admission in the Departments of Oncology and Palliative Care in Romania, were in treatment with oral anticoagulants coumarins (acenocumarol), requiring frequent therapeutic dose adjustment. Most commonly, due to reduced accessibility of the patient to health care, especially in rural areas, the possibility of weekly assessment and precise adjustment of the dose of oral anticoagulants is reduced, resulting in increased risk of bleeding by overdosing, but also risk of ineffective therapeutics by suboptimal doses. In these conditions we wanted to evaluate the indications and benefits of the treatment with low molecular weight heparin compared with oral anticoagulant therapy in patients with cancer at increased risk of thromboembolic events or who have experienced at least one such event during the course of the disease.

Materials and method

We conducted a review of Anglo-Saxon literature and therapeutic international guidelines, by extensive research of Medline and Pubmed database, using the following search terms: thrombosis, venous thrombosis, cancer, Coumarin, Warfarin, Heparin, Low Molecular Weight Heparin, anticoagulant treatment, anti-thrombosis treatment. There were excluded from the review the articles that we could access only the abstract. We have identified major risk factors for thromboembolic events in cancer patients, and therapeutic indications (treatment initiation, type of treatment, period of treatment).

Results and discussion

The optimal approaches for preventing and treating thrombosis remains an open question regarding thromboprophylaxis in high-risk patients, treatment options and optimal treatment period in the acute or recurrent thrombotic events.

Many factors are associated with the risk of developing venous thrombosis and are classified into general causal factors (age, previous history of VTE, hospitalization and immobilization for longer than 3 days, major medical conditions, obesity, hereditary thrombophilia), cancer related factors (primary site - high risk: stomach, pancreas; intermediate risk: lung, lymphomas, gynaecological;  low risk: breast, colorectal, head and neck; cancer stage: metastatic)(9,10,11) and treatment - related factors: surgery, chemotherapy, hormonal therapy, antiangiogenic agents - bevacizumab, thalidomide, lenalidomide, erythropoiesis stimulating factors, transfusions(9,11).

VTE rate was up to 34% in patients with myeloma treated with thalidomide and doxorubicin and also in patients with relapsed myeloma treated with lenalidomide and high dose dexamethasone. The use of bevacizumab was associated  with 33% relative increase of thrombotic events(9).

Recently, in determining the risk of VTE, some bio­markers were associated: leukocyte count, platelet count, low hemoglobin level, high D-dimer level, elevated soluble P-selectin level, high C-protein reactive level(11,12).

In current clinical practice, the routine thrombo­pro­phy­laxis in ambulatory patients with cancer with che­mo­therapy,even with high risk factors, is not recommanded. An exception is made for patients with multiple myeloma who have received  thalidomide or lenalidomide and dexamethasone regimens(1,9).

The PROTECHT study (Prophylaxis of Thromboembolism during chemotherapy) of 1150 ambulatory cancer patients showed a 50% reduction in venous and arterial events in patients treated with nadroparin versus placebo group(1).

The initial therapy of VTE in cancer patients is low-molecular-weight heparin (LMWH) followed by oral anticoagulant (warfarin or related oral anticoagulants).  The long-term use of warfarin or acenocoumarol  is problematic due to achieving and maintaining the international normalized ratio (INR) of 2-3.

The analysis of 33 studies of patients with VTE  who received oral anticoagulant therapy longer than 3 months indicates a case fatality for major bleeding of 9.1% and the cancer patients have higher risk of major bleeding - hazard ratio of 4.07 compared with patients without cancer(5,13,14). The therapeutic levels in the treatment with oral anticoagulants may not be reached due to drug interactions (ex.: Warfarin - fluorouracil infusions(15)), vomiting, liver dysfunction or malnutrition and subsequently increasing the risk of overdose and bleeding.

Several trials have compared LMWHs with anticoagulants for long term prevention of VTE. A study of 146 cancer patients with VTE who received 3 months of LMWH or warfarin showed a risk of major bleeding or recurrent VTE of 10.5%, respectively 21.1%(5,16) and a meta-analysis demonstrated also a reduction of recurrence of VTE and major bleeding in favor of LMWHs(17). But, this were not statistical significant.

The benefits of using the LMWHs are: more predictable bioavailability, dose-independent renal clearance, not affected by diet, other drugs, anorexia or vomiting; greater flexibility when the treatment must be interrupted, less likely to cause heparin-induced thrombocytopenia(5,9).

The higher cost of the treatment with LMWHs can be annihilated by reducing hospitalization costs necessary to adjust the warfarin dose(3,5).

In the Malignancy and Low Molecular Weight Heparin Therapy (MALT), trial reported by Klerk et al., approximately 300 patients with incurable solid tumors were randomly assigned to the low molecular weight heparin or placebo for 6 weeks. A statistically significant improvement in overall survival was observed for LMWH relative to placebo. The reduction in mortality was also in favor of LMWH in the subgroup of patients who were identified as having a life expectancy of greater than 6 months(18).

The CONKO-004 trial found a 87% risk reduction of VTE using enoxaparin at 1 mg/kg once daily for 3 months compared to no prophylaxis (9.9% vs. 1.3%), while the FRAGEM study reported a 62% risk reduction in VTE using the CLOT therapeutic regimen of dalteparin (31% vs. 12%)(11,19,20).

A multicentre study demonstrated that a high prophylactic dosage of LMWH( 2500UI versus 5000UI) increases the protective effect without enhancing the bleeding risk(9,21).

A recent meta-analysis evaluated the anticoagulant treatment  on survival in cancer patients without VTE, finding a significant reduction in overall mortality with anticoagulant therapy. The clinical effect was most pronounced for LMWH, which produced a relative risk reduction in mortality of 13.3% compared with a non-significant reduction with warfarin of 5.8%(9,22).

Conclusion

The aim of the anticoagulant treatment in cancer patients is to prevent recurrence, extension and complications  of venous thromboembolism while minimizing the risk of major bleeding.

In cases carefully selected, long-term therapy with LMWH is the alternative for the oral anticoagulation therapy. 

Bibliografie

1. Connors JM, Prophylaxis against venous thromboembolism in ambulatory patients with cancer, N Engl J Med., 2014 Jun 26;370(26):2515-9. doi: 10.1056/NEJMra1401468.
2. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon W, Melton L, III. Risk Factors for Deep Vein Thrombosis and Pulmonary Embolism: A Population-Based Case-Control Study. Arch Intern Med. 2000;160(6):809-815
3. Linkins L-A. Management of venous thromboembolism in patients with cancer: role of dalteparin. Vascular Health and Risk Management. 2008;4(2):279-287.
4. Trousseau A. Phlegmasia alba dolens. Clin Med Hotel-dieu Paris. 1865;3:654-712.
5. Zacharski LR, Pradoni P. Monreal M.,Warfarin versus low-molecular-weight heparin therapy in cancer patients, Oncologist, 2005 Jan;10(1):72-9.
6. Rickles FR, Patierno S, Fernandez PM. Tissue factor, thrombin, and cancer. Chest. 2003;124:58S–68S.
7. Rak J, Yu JL, Luyendyk J, Mackman N., Oncogenes, trousseau syndrome, and cancer-related changes in the coagulome of mice and humans. Cancer Res. 2006;66:10643–6.
8. Nierodzik M, Chen K, Takeshita K, Li J.J., Huang J.Q., Feng X.S., Andrea M., Gordon P.A., Karpatkin S., Protease activated receptor 1 (PAR-1) is required and rate-limiting for thrombin-enhanced experimental pulmonary metastasis. Blood. 1998;92(10):3694-3700
9. Mandalà M., Falanga A., Roila F., Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines, Ann Oncol 2011; 22 (Suppl 6): vi85-vi92.
10. Khorana AA, Connolly GC, Assessing risk of venous thromboembolism in the patient with cance,. J Clin Oncol., 2009,  27:4839–4847.
11. Lee AY.,Thrombosis in cancer: an update on prevention, treatment, and survival benefits of anticoagulant. Hematology Am Soc Hematol Educ Program, 2010;2010:144-9s.
12. Sallah S, Husain A, Sigounas V, Plasma coagulation markers in patients with solid tumors and venous thromboembolic disease receiving oral anticoagulation therapy,  Clin Cancer Res., 2004,  10:7238–7243.
13. Hutten BA, Prins MH, Gent M ,Ginsberg J., Tijssen JG., Büller H.R., Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000;18:3078–3083.
14. Prandoni P, Lensing AWA, Piccioli A, Bernardi E., Simioni P., Girolami B., Marchiori A., Sabbion P., Prins M., Noventa F., Girolami A., Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood2002;100:3484–3488
15. Masci G, Magagnoli M, Zucali PA, Castagna L., Carnaghi C., Sarina B., Pedicini V.,  Fallini M., Santoro A., Minidose warfarin prophylaxis for catheter-associated thrombosis in cancer patients: can it be safely associated with fluorouracil-based chemotherapy? J Clin Oncol2003;21:736–739.
16. Meyer G., Marjanovic Z., Valcke J., Lorcerie B., Gruel Y., Solal-Celigny P., Le Maignan C., Extra J.M., Cottu P,, Farge D., Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer. Arch Int Med 2002;162:1729–1735.
17. Iorio A, Guercini F, Pini M. Low-molecular-weight heparin for the long-term treatment of symptomatic venous thromboembolism: meta-analysis of the randomized comparisons with oral anticoagulants. J Thromb Haemost 2003;1:906–1913.
18. Lee AY, Rickles F., Julian J., Gent M., Baker R., Bowden C., Kakkar A., Prins M., Levine M., Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005 Apr 1;23(10):2123-9.
19. Maraveyas, A., et al. "6503 Gemcitabine with or without prophylactic weight-adjusted dalteparin in patients with advanced or metastatic pancreatic cancer (APC): a multicentre, randomised phase IIB trial (the UK FRAGEM study)." European Journal of Cancer Supplements 7.2 (2009): 362.
20. Riess H., Pelzer U., Deutschinoff G., Opitz B., Stauch M., Reitzig P., Hahnfeld S.,  Hilbig A., .Stieler J, Oettle H., A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): results of the CONKO 004 trial. J Clin Oncol, 2009,27:LBA4506.
21. Bergqvist, David, et al. "Low molecular weight heparin started before surgery as prophylaxis against deep vein thrombosis: 2500 versus 5000 Xal units in 2070 patients." British Journal of Surgery 82.4 (1995): 496-501.
22. Kuderer, Nicole M., et al. "A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment." Cancer 110.5 (2007): 1149-1161.

Articole din ediţiile anterioare

GYNECOLOGICAL CANCERS | Ediţia 1 / 2015

Tipuri de cancer vaginal şi HPV

Payam Behzadi, Elham Behzadi, Reza Ranjbar, Esmaiel Saberfar

Cancerul este cunoscut ca o boală gravă cu grad înalt al morbidităţii şi mortalităţii în rândul populaţiei adulte. Există diferite tipuri de cancer...

24 martie 2015
REVIEW | Ediţia 3 40 / 2017

Imunoterapia cancerului pulmonar

Alexandru C. Grigorescu

Neoplasmul pulmonar rămâne principala cauză de deces prin cancer în întreaga lume. Din acest motiv, cercetătorii au considerat o prioritate cerceta...

27 octombrie 2017
CASE PRESENTATION | Ediţia 1 50 / 2020

Toxicitate cutanată excesivă la o pacientă care a primit doxorubicină lipozomală pegilată, asociată cu sindrom Nicolau, exacerbat de obezitatea morbidă

Petra Curescu, Alexandra G. Stan

Doxorubicina lipozomală pegilată (PLD) este o antraciclină uti­lizată în tratamentul cancerului ovarian. Deşi prezintă mai puţină cardiotoxicitate ...

30 martie 2020
REVIEW | Ediţia 1 38 / 2017

Imunoterapia în cancer: mecanismele imunologice şi rolul lor în terapie

Conf. dr. Dana Lucia Stănculeanu, Carmen Ardeleanu, Daniela Zob, Raluca Ioana Mihăilă, Oana Cătălina Toma, Şef lucrări dr. Laurenţiu Simion

Termenul „glonț magic” a fost folosit pentru prima dată de Paul Ehrlich la începutul secolulului XX, când a descris anticorpii care ținteu atât cel...

04 aprilie 2017