Chapter 5. Prophylaxis of VTE in medical cancer patients

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5.1. Bibliographic strategy results
5.2. Data extraction
5.3. Data analysis
5.4. Discussion
5.5. Recommendations – prophylaxis of VTE in medical cancer patients

 


 

5.1. Bibliographic strategy results

For the prophylaxis of VTE in hospitalized medical cancer patients, no specific studies were found. For this reason, the main studies comparing LMWH and UFH in the general population were analyzed for this question. Thus, the clinical trials included [BERGMANN1996] [HARENBERG1996] [LECHLER1996] [KLEBER2003] in the ACCP guidelines, which previously addressed this question, were selected [GEERTS2008]. The percentage of cancer patients in these studies varied from 5% to 15%.
For children with acute lymphocytic leukemia (ALL) treated with L-asparaginase, we found two small studies [MEISTER2008] [MITCHELL2003].
For the studies that were only available in abstract form, the main author was contacted to make sure that the paper had been accepted by a peer-reviewed medical journal (in this case methodological limits were taken in account).

HTA Questions Studies included
HTA 1: Hospitalized patients

4 prospective randomized studies

[BERGMANN1996] [HARENBERG1996] [LECHLER1996] [KLEBER2003]

4 randomized double-blind studies

[DAHAN1986] [SAMAMA1999] [LEIZOROVICZ2004] [COHEN2006]

HTA 2: Children with ALL treated with L-asparaginase

1 prospective non-randomized study [MEISTER2008]

1 randomized study [MITCHELL2003]

HTA 3: Ambulatory patients treated with chemotherapy

2 prospective randomized studies [RIESS2009] [MARAVEYAS2011]

3 randomized double-blind trials [HASS2005] [AGNELLI2009] [PERRY2010[J1] ]

1 analysis of pooled data [VERSO2010]

HTA 3: Patients treated with thalidomide or lenalidomide

2 retrospective studies [ZANGARI2004] [IKHLAQUE2006]

1 prospective randomized study [PALUMBO2011 ]

2 meta-analyses [ELACCAOUI 2007] [HICKS2008]

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5.2. Data extraction

Data extraction: Cliquez pour télécharger
  


 

5.3. Data analysis

Hospitalized cancer patients

Studies

4 prospective randomized studies

[BERGMANN1996] [HARENBERG1996] [LECHLER1996] [KLEBER2003]

4 randomized double-blind studies

[DAHAN1986] [SAMAMA1999] [LEIZOROVICZ2004] [COHEN2006]

Agreement

Yes

Quality of evidence

Moderate (randomized studies but indirectness)

Results

For primary prophylaxis of VTE in hospitalized medical cancer patients:

  • LMWH and UFH have a similar efficacy and safety
  • LMWH and fondaparinux are superior to placebo with a non-significant trend towards increased bleeding (except for enoxaparin 20 [J1] or 40 mg and fondaparinux)
  • the rate of cancer patients included in these studies varies from 5 to 15%
  • no study reports a difference of efficacy between cancer and non-cancer patients

Conclusions
Primary prophylaxis with UFH, LMWH and fondaparinux has been shown to be effective
in studies including hospitalized cancer patients with reduced mobility.

 

 

Children with ALL treated with L-Asparaginase

Studies

1 prospective non-randomized study

[MEISTER2008]

1 randomized study

[MITCHELL2003]

Agreement

No: only two studies with few patients and different designs (ATIII + LMWH vs. ATIII, ATIII vs. observation)

Quality of evidence

Very low (observational, study limitations, inconsistency, imprecision)

Results

In children with ALL, the rate of symptomatic VTE is around 5%.

Conclusions
It seems difficult to draw any conclusions about the efficacy of antithrombin III (ATIII) and
the combination of LMWH with ATIII.

 

Ambulatory patients treated with chemotherapy

Studies

2 prospective randomized studies

[RIESS2009] [MARAVEYAS2011 ]

3 randomized double-blind trials

[HASS2005[J2] ] [AGNELLI2009] [PERRY2010]

1 analysis of pooled data

[VERSO2010]

Agreement

No, results depend on the type of cancer

Quality of evidence

Moderate (randomized, but serious inconsistency)

Results

Primary prophylaxis with LMWH in patients treated with chemotherapy:

  • increases non-significantly intracranial bleeding in patients with a brain tumor
  • decreases the rate of VTE without an excess of bleeding in patients with locally advanced or metastatic pancreatic (at subtherapeutic dosages) or locally advanced or metastatic lung cancers
  • has no effect on VTE in patients with metastatic breast cancer

 [J1]20 mg n’est pas plus efficace que le placebo. personnellement je n’en parlerai pas, car du coup son bleeding risk a peu d’intérêt

 [J2]??? HAAS2012 ?

Pourquoi une étude de 2012 est-elle référencée (fin de la recherche June 2011)

Conclusions
In cancer patients treated with chemotherapy, prophylaxis with LMWH:

  • could have a benefit in patients with locally advanced or metastatic pancreatic (at subtherapeutic dosages) or locally advanced or metastatic lung cancers,
  • has no effect on VTE in patients with metastatic breast cancer,
  • might be dangerous for patients with a brain tumor,
  • may increase the bleeding risk in the presence of thrombocytopenia.[J1]

 

Patients treated with thalidomide or lenalidomide

Studies

2 retrospective studies

[ZANGARI2004] [IKHLAQUE2006]

1 prospective randomized study [PALUMBO2011 ]

2 meta-analyses

[ELACCAOUI 2007] [HICKS2008]

Agreement

Yes

Quality of evidence

Low (1 randomized study with serious limitations and imprecision; meta-analyses did not take into account this study)

Results

Prophylactic doses of LMWH or aspirin (100 mg/day) or warfarin to maintain INR within the therapeutic range reduce the risk of thromboembolic events among multiple myeloma patients treated with lenalidomide or thalidomide with no increase in bleeding risk

Conclusions
The rate of VTE in patients treated with IMiDs (thalidomide, lenalidomide) combined with steroids and/or chemotherapy (doxorubicine) is very high. VTE prophylaxis in patients treated with thalidomide or lenalidomide produces similar results irrespective of whether LMWH, therapeutic VKA (INR 2-3), low-dose VKA or low-dose aspirin (100 mg/day) is used. In the absence of a placebo group the efficacy of these regimens remains elusive.

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5.4. Discussion

As there was no clear definition in the literature enabling distinction between inpatients and outpatients, we chose to use the term medical patients to denote both hospitalized and ambulatory patients. In the absence of specific studies, the results of primary VTE prophylaxis in hospitalized patients can be applied to cancer patients with reduced mobility. None of the included studies concerning prophylaxis in medical patients reported differences between non-cancer and cancer patients (5% to 15 % of the population). In this setting, the efficacy of both LMWH and fondaparinux is superior to that of placebo; UFH and LMWH have been shown to have the same efficacy.
The risk of VTE during hospitalization and after discharge is higher in medical cancer patients than in non-cancer patients, so the risk reduction in this population could be particularly important [KHORANA2008]. For this reason, in selected high-risk patients, continued prophylaxis after hospital discharge may be considered (best practice in view of the lack of specific data).

Only two non-randomized studies, including small numbers of patients and differing in design, were performed in children with ALL treated with L-asparaginase [MITCHELL2003] [MEISTER2008]. One study tested the value of adding LMWH to ATIII substitution

 [J1]est-ce un résultat ? je ne le vois pas dans la table 26 en tout cas

[MEISTER2008] and the other compared the prescription of ATIII to no treatment [MITCHELL2003]. There is no consensus supporting any particular prophylactic regimen in children and adults with ALL treated with L-asparaginase to prevent VTE and the experts of the Working group reported a wide divergence in practices in this case. So recommendations can only be based on local policy and individual patient characteristics.

The trials of primary prophylaxis of VTE in medical patients have included ambulatory cancer patients treated with chemotherapy and have used LMWH. The prevention of VTE with LMWH in medical cancer patients treated with chemotherapy could be restricted to a subgroup in which the rate of VTE is much higher than the bleeding risk. In the case of locally advanced or metastatic pancreatic cancer the risk of VTE is so high that the benefit of the LMWH used in a subtherapeutic regimen in two studies [RIESS2009] [MARAVEYAS2011] outweighed the bleeding risk. For locally advanced and metastatic pulmonary cancer, the benefit-risk ratio was lower in the studies included in this guideline [HAAS2012] [AGNELLI2009] [VERSO2010] and the recommandation is weak. The benefit of such prophylaxis could be restricted to non-small cell carcinoma (NSCC), because one study included only NSCC [HAAS2012] and the second probably included only  a small number of patients with small cell carcinoma (SCC) which is far less frequent than NSCC [AGNELLI2009]. Analysis of clinical trials shows that primary prophylaxis with LMWH might be dangerous for patients with a brain tumor [PERRY2009], because of an excess of intracranial bleeding, but it can decrease the rate of VTE without excess of bleeding in locally advanced or metastatic pancretic or lung cancers [RIESS2009] [MARAVEYAS2011] [AGNELLI2009] [VERSO2010] . The experts think there is a need for further studies before recommending routine prophylaxis with LMWH in cancer patients receiving chemotherapy.

The risk of VTE associated with first-line treatment of multiple myeloma patients with thalidomide and lenalidomide (IMiDs) is very high, especially when these drugs are combined with high doses of dexamethasone or with chemotherapy (doxorubicin). Multiple myeloma is a common disease and IMiDs are the gold standard for the treatment of patients not eligible for autologous haemopoietic stem-cell transplantation, but only one randomized study has been performed. In this study, patients with multiple myeloma treated with thalidomide-based regimens, aspirin and low-dose warfarin (1.25 mg/day) showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients in whom warfarin showed less efficacy than LMWH [PALUMBO2001]. The two meta-analyses indicate that administering prophylactic doses of LMWH or warfarin to maintain a therapeutic INR reduces the risk of thromboembolic events [ELACCAOUI2007] [HICKS2008]. As no study with a placebo or observation group has been performed to date, the efficacy of such regimen remains unclear. Furthermore, as the rate of non-multiple myeloma patients treated either with thalidomide or lenalidomide is very low in the studies selected, these recommendations can only apply to patients with multiple myeloma treated with IMiDs.

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5.5 Recommendations – prophylaxis of VTE in medical cancer patients

R1. We recommend prophylaxis with LMWH, UFH or fondaparinux in hospitalized medical patients with cancer and reduced mobility.

Quality of evidence

Moderate

Balance between desirable and undesirable effects

Favorable

Values and preferences

Subcutaneous injections

Costs (resource allocation)

In some countries price differences between LMWH, UFH or fondaparinux may influence the choice

Level of recommendation

Strong

 

R2. For children with ALL treated with L-asparaginase, depending on local policy and individual patient characteristics (platelet count, kidney function, fibrinogen and antithrombin III levels, etc.), prophylaxis may be considered in some patients. The same therapeutic option can be considered for adults

Quality of evidence

Very low

Balance between desirable and undesirable effects

Depends on individual patient characteristics

Values and preferences

Subcutaneous injections

Costs (resource allocation)

Not considered

Level of recommendation

Best practice

 

R3. In patients receiving chemotherapy, prophylaxis cannot be recommended routinely

Quality of evidence

Moderate

Balance between desirable and undesirable effects

Uncertain for all types of cancer

Values and preferences

Subcutaneous injections

Costs (resource allocation)

Not considered

Level of recommendation

Strong

 

R4. Primary pharmacological prophylaxis of VTE may be indicated in patient with locally advanced or metastatic pancreatic cancer treated with chemotherapy and having a low bleeding risk.

Quality of evidence

Moderate

Balance between desirable and undesirable effects

Favorable

Values and preferences

Subcutaneous injections

Costs (resource allocation)

Not considered

Level of recommendation

Strong

 

R5. Primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pulmonary [J1] cancer treated with chemotherapy and having a low bleeding risk.

Quality of evidence

Moderate

Balance between desirable and undesirable effects

Favorable

Values and preferences

Subcutaneous injections

Costs (resource allocation)

Not considered

Level of recommendation

Weak

 

R6. In patients treated with IMiDs combined with steroids and/or chemotherapy (doxorubicin), VTE prophylaxis is recommended. In this setting, VKA at low or therapeutic doses, LMWH at prophylactic dose and low-dose aspirin have shown similar effects with regard to preventing VTE. However, the efficacy of these regimens remains unclear.

Quality of evidence

Low

Balance between desirable and undesirable effects

Uncertain

Values and preferences

Subcutaneous injections

Costs (resource allocation)

Depending of the drug used for prophylaxis

Level of recommendation

Weak

 


 [J1]lung ?