Cancer and Thrombosis Epidemiology Diagnosis Prophylaxis Therapy

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Cancer and ThrombosisEpidemiologyDiagnosisProp
hylaxisTherapy

• A. Matzdorff
• Dpt. of Hematology, Oncology
• Caritasklinik St. Theresia, Saarbruecken, Germ.

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Cancer and Hemostasis
Cancer
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Cancer and Hemostasis

• Armand Trousseau (1801-1867)
• thrombosis always has, as its primary cause,
  a special alteration of the blood. An alteration
  which exists in the puerperal state and in
  cachexia
• Clinique Medical de l'Hotel-Dieu de Paris. 1865

Trousseau's Syndrom (Werner Syndrom!?!) Thrombophl
ebitis migrans is a sign of occult abdominal
cancer.
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Incidence of DVT with Cancer
10-15 of all cancer patients will experience DVT
and PE during the course of their disease.
Rickles et al. Blood 1983
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Incidence of DVT with Cancer
Enoxaparin 1.5-2 mg/kg
Sallah Thromb Haemost 2002 Blom J Thromb Haemost
2006
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DVT and Cancer
Cancer patients with DVT have shorter OS. Sallah
Thromb Haemost 2002
No DVT/PE
with DVT/PE
Sallah 2002
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Diagnosis
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Patients at RiskAll Cancer Patients!
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DiagnosisThrombophilia

• Hereditary thrombophilia increases risk of DVT in
  cancer patients (Nowak-Göttl, Blood 1999, Eroglu,
  J Thromb Haemost 2006) and for catheter-related
  thrombosis (Mandala, Ann Oncol 2004).
• Thrombophilia testing with positive familiy or
  personal history (Dicato, Blood 2003, Abstr.).

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DiagnosisDVT and occult cancer

• The risk of cancer after a first episode of
  venous thromboembolism is elevated during the
  following 2 years.
• the risk seems to be lower among patients treated
  with prolonged anticoagulation.
• Schulman N Engl J Med 2000
• Taliani J Thromb Haemost 2003 (6-8/1 Jahr)

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DiagnosisDVT and occult cancer

• Screening
• Limited Extensive
• Prandoni N Engl J Med 1992
• Sørensen N Engl J Med 1998
• Otten. Thromb Research 2001
• Piccioli. Haemostasis 2001
• Piccioli. Acta Haematologica 2001
• Piccioli. J Thromb Haemost 2004
• Di Nisio. J Thromb Haemost 2005

?
?
?
?
?
?
Screening (n99) ? 14 cancers ? 10 T1/2 No
Screening (n99) ? 10 cancers ? 2 T1/2
?

• Limited complete physical exam (breast, abdomen,
  prostate), routine-lab chest X-ray
• Extensive tumor markers, abdominal/pelvic CT,
  mammography, endoscopy, sputum cytology

• It is not clear whether early tumor detection
  translates into better overall survival
• Recommended cancer screening

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ProphylaxisMedical Cancer Patients
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Prophylaxis Surgical Cancer Patients
Enoxacan II Studie 332 pts. with abdominal
cancer Enoxaparin 40 mg qd x 1 week vs. 4
weeks Bilateral venography
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Prophylaxis Central Venous Catheters

• Levine. Thromb Haemost 1997
• 2500 E Dalteparin/d
• Boraks. Br J Haematol 1998
• 1 mg Warfarin/d
• ACCP Guidelines
• Geerts. Chest 2001
• Agnelli ASCO 2004 (Abstr.)
• - 40 mg Enoxaparin x 6 wks.

Lee AYY JCO 2006 lt 4 symptomat. DVT ? no
prophylaxis Karthaus Ann Oncol 2006 3.6
catheter related complications with/without
heparin ? no prophylaxis
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Prophylaxis Central Venous Catheters

• Abdelkefi JCO 2005
• Fewer catheter related infections (16 ? 8)
• Van Roode J Thromb Haemost 2005
• 15 PE (V/Q scan) with CVC-related thromboses
• Rare fatal PE.
• Huisman J Thromb Haemost 2006
• Prophylaxis with (1) thrombophilia or (2)
  previous DVT
• Agnelli J Thromb Haemost 2006
• Prophylaxis (1) CVC tip misplacement in the upper
  half of superior vena cava and (2) left side CVC
  insertion.

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TherapyOral Anticoagulants vs. LMWH
Fewer re-thromboses and bleeding with LMWH
compared to OA
Reduced mortality (ASCO 2003)
Cave 5FU/Capecitabine impair warfarin/phenprocoum
on metabolism ? INR increases (Magagnoli Br J
Haematol 2005, Magagnoli Ann Oncol 2006, Giunta
Ann Oncol 2006)
LMWH are superior to OA because they can be
adjusted to changing clinical situations in
cancer patients (cytopenia, anorexia, bleeding).
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TherapyOral Anticoagulants vs. LMWH
Wittkowsky J Thromb Haemost 2006 Why do 80 of
cancer patients receive warfarin instead of
heparin? 30 costs not covered by health
insurance 30 physicians preference 18 patients
refuse long-term injections 2 HIT
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Problems

• Thrombocytopenia from cancer or after
  chemotherapy
• CNS tumors/metastases with or without
  intratumoral bleeds
• Tumors that infiltrate the vertebral spine
• Cancer of GI or urogenital tract with active
  bleeding
• Impaired liver function from metastases
• Impaired renal function (age, cisplatinum, etc.)
• How we treat these patients
• Start LMWH with half-therapeutic dose, increase
  dose only when clinically stable.
• Vena cava filter, compression devices
• Anti Xa only with impaired renal function,
  bleeding or re-thrombosis

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Immobilization?

• Bedrest vs. Mobilization
• Acute DVT with pain and swelling bedrest,
  elevate leg, compression.
• Patients benefit from early mobilization.
• Aschwanden et al. Thromb Haemost 2001
• How we treat these patients
• Ambulatory patients should remain ambulatory
  with compression and LMWH.
• Bed rest only as required for pain relief.
• Problem free floating thrombus in inferior Vena
  cava.
• Bedrest for 5-7 days, no repeat venogram.

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Effects of Hemostasis on Cancer

• Heparin ? Remission of Cancer
• (Case Reports)
• Albert-Weil Rev Pathol Gen Comparée 1954
• Astedt J Am Med Ass 1977
• Astedt Acta Med Scand 1977
• Sadoff Am J Clin Oncol 1999

• Case Report
• Loynes et al. Thromb Haemost 2002
• ? Adenocarcinoma of lung.
• ? DVT
• ? LMWH
• Regression of tumor

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Effects of Coagulation Factorson Cancer

• Tissue Factor
• Triggers VEGF release (Zhang J Clin Invest 1994)
• Supports tissue invasion by cancer cells (Kakkar
  Br J Surg 1999)

• Heparin
• Inhibits thrombin and fibrin generation
• Induces release of TFPI (NMH, Amirkhosravi Thromb
  Haemost 2001 Suppl. P1409)
• modulates u-PA (Espana Thromb Haemost 1993
  Tyagi. J Mol Cell Cardiol 1997)
• Inhibits migration of cancer cells through vessel
  wall (Lapierre. Glycobiology 1996)
• Modulates binding of growth factors to receptors
  on tumor cells (Norrby. In J Microcirc Clin Exp
  1996 Jayson. Br J Cancer 1997)

• Thrombin
• Growth factor for cancer cells (Zain. Blood 2000)
• Protects against cytotoxic drugs (Schiller. Int J
  Clin Pathol Ther 2002, Maia. Cancer 1996)

• Fibrin
• Tumors are surrounded by fibrin (Billroth, 1878).
  
• Supports adhesion of tumor cells (Chew Cancer Res
  1976)
• Supports vascular proliferation (Shoji. Am J
  Pathol 1998)

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Effects of Platelets on Cancer

• Platelets
• Release VEGF (Verheul. Clin Cancer Res 1997)
• Bind to circulating cancer cells and protect them
  against immune attacks (Nieswandt. Cancer Res
  1999)
• Support adhesion of circulating cancer cells to
  vessel wall (McCarty. Blood 2000)
• Antimetastatic effects
• With thrombocytopenia (Gasic. PNAS 1968)
• Aspirin (Gasic. Lancet 1972)
• Dipyridamole (Tzanakakis. Cancer 1993)
• Tinzaparin (Stevenson. Clin Cancer Res 2005)

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Unfractionated Heparin (UFH) and Cancer

• Lebeau Cancer 1994738-45
• 277 pts. with SCLC
• Chemotherapy
• /- Heparin (500 U/kg/d)
• Median OS 317 vs. 261 days

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LMWH vs. UFH and Cancer

• Hettiarachchi Thromb Haemost 1999
• Meta-Analysis, 629 pts. in 9 studies
• LMWH superior to UFH

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LMWH and Cancer

• Kakkar AK, et al (FAMOUS STUDIE). Low molecular
  weight heparin therapy and survival in advanced
  cancer. J Clin Oncol 2004221944-1948

• Pts. with cancer of breast, colorectum, pancreas,
  ovary and no VTE received 5000 U dalteparin
  (Fragmin) or placebo for 10 months.

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LMWH and Cancer
Survival benefit from dalteparin only for good
prognosis patients
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Conclusions

• There are numerous interactions between cancer
  and hemostatic system.
• Cancer supports thromboses
• Cancer patients require prolonged postoperative
  prophylaxis.
• Treatment of VTE should be with LMWH instead of
  OA.
• Dosing and duration of anticoagulant treatment
  needs to be individualized. Risk of recurrent
  thrombosis must be balanced against the risk of
  bleeding in each individual patient.

• Coagulation factors support cancer.
• Cancer patients that receive adequate
  anticoagulation have a significant survival
  benefit.

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Cancer and Hemostasis
Bleeding

• Thrombocytopenia MDS, Lymphoma, Leukemia,
  Chemother., u.a.
• DIC Infektions, AM3L
• Hyperfibrinolysis AM3L, Prostate Cancer
• Etc. Paraproteinemia, acquired Hemophilia,
  acquired von Willebrand Syndrome,
  Moschcowitz-Syndrom

• Thrombosis
• Solid Tumors
• Central Lines

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Cancer and Hemostasis

• Virchows Triad
• Alterations of the vessel wall
• Expression of tissue factor and PAI
• Downregulation of thrombomodulin
• Endothelial damage bei direct invasion of the
  tumor into the vessel wall
• Vascular Obstruction
• Immobilisation, bedrest
• Altered composition of the blood
• Increased prothrombotic factors (FGN, F.VIII,
  platelet count)
• Downregulation of inhibitors (Protein S, act.
  Protein C)

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Cancer Therapy and Hemostasis

• Tamoxifen ? 1.8x increase in risk of DVT
• (Anastrozole no risk)
• Direct effect of cytotoxic drugs on coagulation
  factors
• (Asparaginase ? Fibrinogen ?, protein C ?, AT
  III ?)
• 4x increased risk of DVT with thalidomide
• Enoxaparin 40 mg (warfarin not sufficient)
• New agents Bevacizumab (Avastin),
  VEGF-inhibitors, Metalloproteinases

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Patients at RiskAll Medical Patients!

• DVT is the most common secondary diagnosis in
  medical patients
• 234 consecutive patients (pts. with DVT or
  anticoagulant use excluded)
• admitted to an internal medicine ward
• duplex during the first 2 days
• All patients 5.5 DVT, 1 proximal DVT
• Older patients gt 80 18 DVT
• Oger E, Bressolet L, Nonent M, et al. Thromb
  Haemost 200288592-597

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DiagnosisCancer Patients

• Few patients have typical symptoms (swelling,
  pain, edema, tenderness)
• If symptoms are present they are attributed to
  the cancer.
• Check legs daily!
• Low probability and neg d-dimer ? no further
  testing
• Intermediate or high probability ? ultrasound
  imaging or venography

Cancer Patients
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Duration of Anticoagulation

• 3-6 months with completely resected cancer or
  cancer in CR
• Indefinite with tumor not in CR
• Prandoni et al. Blood 20021003484
• 181 cancer patients with VTE and
• adequate anticoagulation
• 21 Re-thromboses in 12 months
• 12 severe bleeds
• Complications correlate with cancer
• stage.

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Home Therapy

• Cost
• Enoxaparin 2 x 80 mg ? 800 /mo.
• Innohep 20.000 1 x 0,7 ml/d ? 750 /mo.
• Phenprocoumon 1,5 Tbl./tgl. ? 10 /mo.
• Patient not able to perform injections (elderly,
  visual impairment).
• Stable disease for prolonged periods (prostate
  and breast cancer)
• Always LMWH with chemotherapy, impaired
  nutrition.

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Effects of Hemostasis on Cancer
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Effects of Anticoagulation on Cancer

• Elias et al. Cancer 197536129-136
• 28 pts. with lung cancer
• Chemotherapie /- Heparin
• 2 patients with progression during chemotherapy
  showed regression when they received the same
  chemotherapy plus heparin
• Zacharski et al (VA Cooperative Study 75).
  Cancer 1984532046-2052
• 320 pts. with cancer of lung, colon, headneck,
  prostate
• Chemoth. /- Warfarin
• Benefit for SCLC (Median Survival 50 vs. 24
  Wochen)
• Chahinian et al (CALGB). J Clin Oncol
  198997993-1002
• 294 with SCLC-ED
• Chemoth. /- Warfarin
• Median OS 38 vs. 32 Weeks

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Prophylaxis Missing the Boat

• Gillies TE, et al. (Scotland)
• Still missing the boat with fatal pulmonary
  embolism - Audit of Surgical Mortality. Br J Surg
  1996831394-5
• 56 of surgical patients who die from PE had no
  prophylaxis, despite multiple risk factors and no
  contraindications to antithrombotic regimens .
• 50 of surgeons reported that they initiated
  thromboprophylaxis routinely, while most medical
  oncologists reported using thromboprophylaxis in
  less than 5 of medical patients (Kakkar et al.,
  FRONTLINE-Studie, Oncologist 2003).
• OConnell CL, JCO 2006
• Symptoms of DVT and PE are often missed. Dyspnea
  and fatigue can be signs of PE.