1-Introduction


1.1. Epidemiology
1.2. Risk factors for DVT and PE in cancer patients
1.3. Risk factors for catheter-related thrombosis in cancer patients
1.4. Context
1.5. Expectations
1.6. Aims

1.6.1. Clinical questions
1.6.2. Targeted users

1.7. Project management

1.7.1. Sponsors
1.7.2. Funding
1.7.3. Working group
1.7.4. Methodological support of INCat
1.7.5. Planning


1.1. Epidemiology

Cancer is an independent and major risk factor for venous thromboembolism (VTE) [LEVITAN1999] [HEIT2000]. Venous thromboembolism (VTE) is defined as deep-vein thrombosis (DVT), including catheter-related thrombosis (CRT), and pulmonary embolism (PE).
VTE occurs in 4 to 20% of cancer patients. In hospitalized patients included in the National Hospital Discharge Survey (USA), the rate of VTE was 2% in patients with cancer and 1% among patients without cancer [STEIN2006].
Although the association between cancer and thrombosis has been known since Trousseau’s first report [TROUSSEAU1865], cancer care providers now have increased awareness of the impact of thrombotic complications in patients with cancer. Several factors have contributed to this heightened awareness.
Firstly, cancer-associated VTE is increasingly prevalent. In an analysis of more than 1 million hospitalized patients with cancer, the rate of VTE increased by 28% from 1995 to 2003 (p <0.0001) [KHORANA2007]. In an exhaustive review of the literature, the frequency of symptomatic catheter-related thrombosis was 5%, a figure subsequently confirmed in prospective clinical trials [VERSO2003] [DEBOURDEAU2009].
Secondly, the consequences of VTE are better understood. Thrombosis is the second-leading cause of death in patients with cancer [KHORANA2007A]. Furthermore, VTE is an independent prognosis factor of worsened mortality in cancer patients. Cancer patients with VTE have a shorter global survival than cancer patients with similar tumoral stage and anti-cancer treatments but without VTE. Among 1 211 944 patients with cancer, global survival was 6% in patients with VTE compared to 58% in subjects without VTE [LEVITAN1999]. In a study of 235 149 cancer patients included in the California Cancer Registry, adjusting for age, race and stage, diagnosis of VT, was a significant predictor of decreased survival during the first year for all cancer types (hazard ratios, 1.6-4.2; p<0.01) [CHEW2006]. In addition, patients with cancer who suffer from VTE have an increased risk of recurrent VTE, bleeding complications, morbidity, and utilization of health care resources [PRANDONI2002] [ELTING2000]. In this last study, 525 of the 529 patients with venous thromboembolic events were hospitalized for initial anticoagulation therapy, for a mean of 11 days. The mean cost of hospitalization was 20 065 US $ [ELTING2000].
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1.2. Risk factors for DVT and PE in cancer patients

The high incidence of VTE in cancer patients is due to the presence of various simultaneous risk factors: the underlying neoplasm (histological type, stage and site), type of surgery, hospitalization, presence of a central venous catheter, and use of chemotherapy and/or erythropoiesis stimulating agents (ESA) [BOHLIUS2006] [BENNETT2008] [MARECBERARD2009].
Cancer-associated VTE is a multifactorial illness. A recently developed risk score
can identify cancer patients treated with chemotherapy who are at high risk for VTE by utilizing a combination of easily available clinical and laboratory variables (Table 1)

reco tab1

Table 1 Predictive model for cancer-associated/chemotherapy-associated VTE ([KHORHANA2008])

[KHORANA2008].
The risk score for VTE was derived from a development cohort of 2701 patients and then validated in an independent cohort of 1365 patients from a prospective registry. The stageadjusted multivariate model identified five predictive variables. Observed rates of VTE in the development and validation cohorts were 0.8% and 0.3% in the low-risk category, 1.8% and 2% in the intermediate-risk category and 7.1% and 6.7% in the high-risk category, respectively.
This model has now been externally validated by the Vienna CATS study in 819 cancer patients [AY2010]. The 6-month cumulative probabilities of developing VTE in this study population were 1.5% (score of 0), 3.8% (score of 1), 9.4% (score of 2) and 17.7% (score ≥3). Several other retrospective and prospective studies have further validated this risk score, although rates vary between studies because of differences in patient selection and follow-up periods (Table 2).

reco tab2

Table 2 Rates of VTE according to Risk Score

In addition, the Vienna group has described an expansion of this original risk score with the inclusion of two additional biomarkers: D-dimer and soluble P-selectin (sP-selectin). This
further improved the prediction, specifically the positive predictive value. Patients with a score of 5 or higher had a risk/cumulative probability of 35% to develop thrombosis within 6 months after diagnosis of cancer. However, biomarker tests need to be available. This issue has already
been widely achieved with the D-dimer test, but still has to be further confirmed for the sP-selectin.

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1.3. Risk factors for catheter-related thrombosis in cancer patients

Several risk factors for CRT have been identified in cancer patients.
Risk factors that are related to patient’ characteristics and to catheter insertion modalities were studied in these guidelines because of their clinical consequences. Conversely, different types of thrombophilia are associated with CRT in cancer patients without any clinical implications (see Table 3) .

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Table 3 Studies on thrombophilia in catheter-related thrombosis

 

reco tab3b

Table 3 Studies on thrombophilia in catheter-related thrombosis ( follow)

The most common thrombophilias shown to be risk factors for CRT in cancer patients are
those involving factor II mutation

(G20210A prothrombin mutation) and factor V mutation
(Q 506 mutation factor V Leiden), in most cases as heterozygous mutations. The estimated
attributable risk of CRT conferred by the presence of factor V and factor II mutations was   about 13.1% and 4.5% respectively in the meta-analysis by Dentali et al. [DENTALI2007], but their clinical consequences cannot be assessed in the absence of dedicated studies. Similarly, few studies have analysed the respective incidence and role of protein S and protein C deficiency.

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1.4. Context

Venous thromboembolism (VTE) is a major therapeutic issue in cancer patients. VTE is an independent prognostic factor and a leading cause of death [KOHRANA2007A].
In this population,
– for the treatment of DVT and PE: Low-Molecular-Weight Heparins (LMWH) have been
shown to be superior to vitamin K antagonists (VKA) |MEYER2002] [LEE2003] [HULL2006];
– for the prophylaxis of VTE in surgical patients: use of LMWH has been validated
([AKL2008D] [AKL2008E];
– for the prophylaxis of VTE in medical cancer patients: many clinical trials have been
published or are about to be published, which will further inform our practice.
Therefore, the prevention and the treatment of VTE in cancer patients represent a major
therapeutic challenge since:
– implementation of specific prophylactic regimens in onco-hematology has recently
become an area of interest;
– the management of established VTE in cancer patients has changed over the last ten years,
given the results of comparisons between classical anticoagulation protocols using LMWH
and early VKA therapy and the long-term use of LMWH for 3 to 6 months. Because cancer
patients often present with a variety of risk factors and co-morbidities, specific oncology
guidelines on the subject were established using various methodological approaches.
These national guidelines for the treatment of VTE in cancer patients were successively
published by:
– the Italian Association of Medical Oncology (AIOM) [MANDALA2006],
– the American Society of Clinical Oncology (ASCO) [LYMAN2007],
– the French “Institut National du Cancer” (INCa) [FARGE2008] [DEBOURDEAU2009],
– the American College of Chest Physicians (ACCP) [GEERST2008] [KEARON2008],
– the National Comprehensive Cancer Network (NCCN) [NCCN2011].
Meanwhile, the European Society of Medical Oncology (ESMO) has published its own
recommendations [MANDALA2009] [MANDALA2011].
Despite the paucity of evidence-based data in hematology patients, recommendations were
also issued for the treatment of VTE in multiple myeloma patients [PALUMBO2008].

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1.5. Expectations

Despite some methodological variations and although few guidelines covered all the questions
to be assessed [KHORANA2007] [FARGE2010], the final recommendations were similar.
However, worldwide, there is still large heterogeneity in the clinical knowledge and
implementation of these recommendations. In addition, many clinicians are reluctant to
modify their practice or still have doubt on the tolerability and acceptance of long-term daily
subcutaneous treatment [DEBOURDEAU2008] when applying standard therapeutic
recommendations. A subset of cancer patients with either life-threatening thrombotic disease,
advanced cancer disease, renal insufficiency or thrombocytopenia may require alternative

therapeutic options, since specific precautions must be taken into consideration in the decision
to anticoagulate.
In addition, underuse of VTE prophylaxis still represents a major clinical challenge in the
general population, and use of adequate prophylaxis in the surgical or medical setting is even less frequent in the cancer subgroup than in other patients [COHEN2008]. Tolerance and cost effectiveness of long-term use of LMWH may account for large heterogeneity in daily clinical
practice and the implementation of specific recommendations for cancer patients is still low in daily clinical practice. VTE in cancer patients requires a multidisciplinary approach, but downstream of guidelines publication, the potential organizational barriers to applying these recommendations have not been discussed.
In a previous paper, the authors of the present guidelines called for a sustained research effort to investigate the clinical issues identified here to reduce the burden of VTE and its consequences in cancer patients. They highlighted the need for an homogenization of
guidelines by an international consensus working group followed by educational and active implementation strategies [KHORANA2009]. The aims of these international clinical practice guidelines (CPG) are:
– to pool the data of existing guidelines to reach consensus,
– to take into account the difficulties in order to make each CPG easier to use and
implement at each national level,
– to study clinical questions that are unanswered.


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1.6. Aims

1.6.1. Clinical questions

These CPG concern venous thrombosis management in cancer patients: treatment and
prophylaxis of deep venous thrombosis, pulmonary embolism and catheter-related
thrombosis.
Based on the context and the expectations, described above, the working group selected the following clinical questions because they remain unanswered and/or needed to be internationally homogenized:
Q1. Initial treatment (0 up to 10 days) of established VTE (specific cases excluded)
1. UFH followed by VKA
2. LMWH followed by VKA
3. LMWH vs. UFH
4. Fondaparinux
5. Thrombolytics
6. Vena cava filters
Q2. Early maintenance treatment (10 days to 3 months) and long-term treatment (beyond
3 months) of established VTE (specific cases excluded)
1. Early maintenance and long-term use of LMWH
2. Idraparinux
3. Duration of the treatment
Q3. Treatment of VTE recurrence (specific cases excluded)
1. VKA or LMWH
2. Vena cava filter
Q4. Prophylaxis of VTE in surgical cancer patients (specific cases excluded)
1. LMWH or UFH vs. placebo or no treatment
2. LMWH vs. UFH
3. Comparison of drugs
4. Dose of LMWH
5. Duration of prophylaxis and extended treatment
6. Use of external compression devices

Q5. Prophylaxis in medical cancer patients (specific cases excluded)
1. Hospitalized patients
2. Children with Acute Lymphoblastic Leukemia (ALL) treated with L-asparaginase
3. Patients treated with chemotherapy
4. Patients treated with thalidomide or lenalidomide
Q6. Treatment of established Catheter-Related Thrombosis (CRT)
1. LMWH+VKA
2. Withdrawal of CVC
3. Thrombolytics
Q7. Prophylaxis of CRT
1. VKA
2. UFH
3. LMWH
4. Thrombolytics
5. Type of CVC and insertion modalities
Q8. Specific cases: all these specific cases which were not studied in the above clinical
questions
1. Initial treatment (0-10 days), early maintenance treatment (10 days to 3 months) and
long-term treatment of established VTE in patients with brain tumors
2. Prophylaxis of VTE in cancer patients with neurosurgery
3. Treatment and prophylaxis of VTE in cancer patients with renal failure
4. Treatment and prophylaxis of VTE in patients with thrombocytopenia
5. Treatment and prophylaxis of VTE in pregnant women with cancer

The focus of these guidelines is the treatment and prophylaxis of DVT, PE and CRT. The
following questions were not addressed either because they were beyond the scope of the
guidelines or because of the lack of data:
· Role of anticoagulation treatment on tumor response
· Treatment adherence
· Effect of anticoagulation on patient survival
· Search for underlying cancer in the case of new onset of idiopathic VTE
· Economic evaluation is too heterogeneous to be assessed as a specific question. Indeed,
the recommended drugs are not available in each country. Furthermore, the price of drugs
varies substantially in each country. The present CPG recommendations were elaborated
using medical data and could not be based on cost of anticoagulation approaches. In some
specific cases, where strong evidence is lacking, the price could have been taken into
account to elaborate a recommendation that was cheaper than another one.

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1.6.2. Targeted users

The professionals for whom the guidelines are intended are:
1. Health care providers
· oncologists
· hematologists
· surgeon-oncologists
· gynecologist-oncologists
· surgeons
· vascular disease specialists
· internal medicine specialists
· palliative medicine specialists
· gynecologists
· geriatricians
· radiation oncologists
· neurologists
· general practitioners
· pharmacists
· nurses
2. Stakeholders
· hospital directors
· public health institutions
· health networks
· medical societies
3. Although these recommendations were not specifically established for patients’ use,
members from patients’ associations were included in the reading group. They reviewed these
guidelines and patients’ preferences, opinions, expectations and needs were taken into
account.

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1.7. Project management

1.7.1. Sponsors

These international guidelines were elaborated by the International Society of Thrombosis and
Haemostasis (ISTH), following an initiative from the Groupe Francophone Thrombose et Cancer
(GFTC) with the collaboration of the Academic Medical Centre (AMC) and the University
Medical Center Groningen (UMCG) Netherlands, and the methodological support of the French
Institute of Cancer (INCa).

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1.7.2. Funding

Financial support was given by the Groupe Francophone Thrombose et Cancer
(www.thrombose-cancer.com), the Paris 7 Institut Universitaire d’Hématologie (IUH Saint
Louis Hospital), The International Society on Thrombosis and Haemostasis (ISTH) 2007
Presidential Fund, and the French Institute of Cancer (INCa).
The authors acknowledge the role of the ISTH, the IUH, the INCa and the GFTC for their
financial support.

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1.7.3. Working group

A multidisciplinary working group from different countries was set up to develop these
international guidelines according to INCa methodology.
The working group consisted of:
· 24 experts from the following specialities :
 Oncology, Hematology, Palliative medicine
 Internal medicine, Vascular disease
 Biology, Epidemiology
· Others:
 2 nurses: from Europe and USA;
 2 patient representatives
 2 methodologists
 2 coordinators
Three major working subgroups were constituted throughout the process:
1- VTE treatment in the general population and for specific patient groups
2- VTE prophylaxis:
2.1. Surgical patients
2.2. Medical patients
3- Catheter-related thrombosis: prophylaxis/treatment
Coordinators and methodologists were particularly assigned to each specific group, but could
of course cover every single subject.

Role of the working group members in the project

Role of the working group members in the project

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1.7.4. Methodological support of INCa

1.7.4. Methodological support of INCa
This support aimed:
· to advise on project management and the CPG method;
· to perform a professional literature search on EBM websites and in the Medline®
database;
· to review intermediate drafts and advise on the presentation of the data;
· to set up a collaborative website for the working group dedicated to the project.

1.7.5. Planning

1.7.5. Planning

Planning

Planning

Update
These guidelines will be updated every 4 years.

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