New Hope for VTE Burden in Ambulatory Cancer Patients

Transcription

1 New Hope for VTE Burden in Ambulatory Cancer Patients Essam Abo-El-Nazar MS, FRCS Consultant Liver Surgeon King Fahd Hospital Jeddah-KSA Prof. of Surgery Imperial College London-UK

2 My talk today What is the burden of VTE in cancer patients? What are the risk factors for VTE in cancer patients? What is the risk of VTE in cancer patients receiving chemotherapy? What is the new hope for VTE prophylaxis in those patients. VTE = venous thromboembolism.

3 KSA VTE Experts Meeting 2008 VTE epidemiology and risk factors in cancer patients

4 VTE and cancer Of all cases of VTE 1 ~20% of VTE occur in cancer patients Of all cancer patients % will experience VTE as many as 50% have VTE at autopsy Compared to patients without cancer 3.2-fold higher risk of recurrent VTE and rate as high as 21% at 1 year fold higher risk of bleeding with incidence of 12.5% at 1 year fold higher mortality 3 1. Lee AY, et al. Circulation. 2003;107:23 Suppl 1:I17-I Prandoni P, et al. Blood. 2002;100: Sorensen HT, et al. N Engl J Med. 2000;343:

5 Venous thromboembolism (VTE) is a major complication of cancer, occurring in 4% to 20% of patients, and is one of the leading causes of death in patients with cancer. The risk of VTE including deep venous thrombosis (DVT) and pulmonary embolism (PE) is increased several-fold in patients with cancer. Hospitalized patients with cancer and those receiving active therapy seem to be at the greatest risk for development of VTE.

6 Of all patients with VTE, patients with cancer account for 20%, with patients receiving chemotherapy accounting for as much as 13% of the total burden of VTE.

7 CONSEQUENCES OF CANCER-ASSOCIATED VTE Hospitalized patients with VTE have a greater in-hospital mortality rate (odds ratio, 2.01; 95% CI 1.83 to 2.22; P < 0001). The risk of fatal PE in patients with cancer undergoing surgery is three-fold greater than in patients without cancer undergoing similar surgery. Reducing VTE in patients with cancer could therefore have a significant impact on morbidity, outcomes, use of health care resources and mortality.

8 RISK FACTORS FOR CANCER-ASSOCIATED VTE In a population-based study, chemotherapy was associated with a 6.5-fold increased risk of VTE. The risk of VTE increases significantly when patients with cancer are hospitalized

9 Risk Factors for VTE in Patients With Malignant Disease

10 Venous thrombosis in cancer patients is increasing VTE rate in cancer the National Hospital Discharge Survey indicates VTE rates in hospitalized cancer patients doubled from VTE in hospitalized cancer and non-cancer patients(%) Year Cancer patients Non-cancer patients Stein PD. Am J Med. 2006;119:60-8.

11 Impact of cancer on PE frequency Cancer No cancer OR Surgical (%) Non-surgical (%) Total Adapted from Huber O, et al. Arch Surg. 1992;127:310-3.

12 Risk for VTE by type of malignancy Fold increase in risk vs patients without malignancy. Blom JW,et al. JAMA. 2005;293:

13 Activation of coagulation in cancer patients No cancer Cancer p (n = 72) (n = 106) value Tissue factor, pg/ml Factor VIIa, mu/ml TAT, μg/l PF 1+2, nmol/ml Factor XIIa, ng/ml PF = prothrombin factor; TAT = thrombin-antithrombin complex. Kakkar AK, et al. Lancet. 1995;346:

14 Risk factors for VTE in patients with malignant disease Patient-related factors older age (esp. > 65) race (Black/Asian > Hispanic/ Caucasian) comorbid conditions (obesity, infection, renal disease, pulmonary disease, arterial thrombosis) prior history of VTE heritable prothrombotic mutations Cancer-related factors primary site of cancer (pancreatic, GI, brain, lung, gynaecological, renal, haematological) initial 3 6 months after diagnosis current metastatic disease Treatment-related factors recent major surgery current hospitalization active chemotherapy active hormonal therapy current or recent antiangiogenic therapy (thalidomide, lenalidomide, bevacizumab) current erythropoiesis-stimulating agents presence of central venous catheters Lyman GH, et al. J Clin Oncol. 2007;25:

15 Mechanisms of chemotherapyinduced VTE The prothrombotic effects of chemotherapy Chemotherapy TF Platelet activation TF VEGF Tumour cell cytokine secretion Direct vascular endothelial toxicity Monocyte/macrophage expression of TF Decrease protein C and S Decrease ATIII Increase PAI-1 Alterations in coagulation and fibrinolytic molecules Endothelial cell apoptosis and increase in TF activity TNF-α IL-1β TF TF TF Increase in endothelial TF expression Haddad TC, Greeno EW. Thromb Res. 2006;118:555-

16 Risk of VTE is highest in first months after cancer diagnosis The highest risk of venous thrombosis is in the first 3 months after diagnosis (adjusted OR, 53.5; 95% CI, ) Patients (%) to 3 months > 3 months to 1 year > 1 to 3 years > 3 to 5 years > 5 to 10 years > 10 to 15 years > 15 years 0 Time after diagnosis of malignancy Adjusted OR = odds ratio adjusted for age and sex. Blom JW, et al. JAMA. 2005;293:

17 Independent risk factors for DVT/PE Risk factor/characteristic Odds ratio Recent surgery with institutionalization Trauma Institutionalization without recent surgery 7.98 Malignancy with chemotherapy 6.53 Prior CVC or transvenous pacemaker 5.55 Prior superficial vein thrombosis 4.32 Malignancy without chemotherapy 4.05 Neurological disease with extremity paresis 3.04 Serious liver disease 0.10 CVC = central venous catheter. Heit JA, et al. Thromb Haemost. 2001;86:

18 Venous thromboembolic events with chemotherapy according to cancer type Pooled analysis of patients in randomized Phase II and III studies (N = 6,055 patients/10 RCT) Incidence of VTE (% patients) Bevacizumab all grade No bevacizumab all grade Bevacizumab grade 3 5 No bevacizumab grade 3 5 All Breast cancer NSCLC NSCLC = non-small-cell lung cancer; RCT = randomized controlled trial. Pancreatic cancer 5% Renal cell cancer 10% Colorectal cancer Hurwitz HI, et al. J Clin Oncol. 2011;29:

19 Risk for VTE in cancer patients with angiogenesis agents Tumour type Incidence and relative risk of all-grade VTE with bevacizumab among patients with various tumour types Number of studies All-grade VTE, n/n Bevacizumab Control Overall 6 155/1, /1,083 Colorectal cancer Non-small-cell lung carcinoma 3 108/564 85/ /66 3/32 Breast cancer 1 17/229 12/215 Renal cell carcinoma 1 20/337 6/304 Incidence, % (95% CI) 11.9 ( ) 19.1 ( ) 14.9 ( ) 7.3 ( ) 3.0 ( ) RR (95% CI) 1.29 ( ) 1.19 ( ) 1.59 ( ) 1.30 ( ) 3.00 ( ) Nalluri SR, et al. JAMA. 2008;300:

20 Cisplatin-associated VTE Retrospective analysis of 932 patients treated with cisplatin-based chemotherapy 169 (18.1%) patients had a thromboembolic event (TE) DVT alone: 49.7% PE alone: 25.4% DVT+PE: 13.6% TEs occurred within 100 days of initiation of treatment in 88% of patients Moore RA, et al. J Clin Oncol. 2011;29:

21 What is the true burden of VTE in medical oncology? IHCIS Database search on the same population as SAVE-ONCO N VTE rate 30, % at 3.5 months IHCIS = Integrated Health Care Information Solutions. Lyman GH, et al. The European Multidisciplinary Cancer Congress, Stockholm, Sweden, September 2011: [abstract 3002].

22 What is the true burden of VTE in medical oncology? Medical oncology versus other settings 60% to 70% of fatal PE detected post-mortem are not suspected or diagnosed 1,2 70% Picture modified f from Ralph A. Clevenger Fatal PE is the leading cause of sudden death among hospitalized patients and contributes to up to 10% of in-hospital deaths 3 1. Stein PD, et al. Chest. 1995;110: Sandler DA, et al. J R Soc Med. 1989;82: Nicolaides AN, et al. Int Angiology. 2006;25:

23 Atypical localization of VTE in cancer compared to major surgery setting Natural history following major surgery 1 Incidental VTE in cancer with chemotherapy 2 Retrospective, single institution cohort study N = 1,921 medical records of cancer patients (solid T + chemotherapy) 1/3 1/3 2/3 Upper limbs DVT 8% Iliac-cava vein 4% Lower limbs DVT + SVT* 6% Portal or splanchnic veins 10% Lower limbs DVT alone 31% PE alone 26% Renal veins 2% PE with lower limbs DVT 13% 1. Kakkar VV, et al. Lancet. 1969;2: DVT = deep vein thrombosis; SVT = superficial vein thrombosis. 2. Di Nisio M, et al. Thromb Haemost. 2010;104:

24 Conclusions Venous thromboembolism is an important complication Frequency may be underestimated Impact on clinical outcome frequently not appreciated Important opportunities for pharmacological prophylaxis

25 GUIDELINE QUESTIONS (1) Should hospitalized patients with cancer receive anticoagulation for VTE prophylaxis? (2) Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? (3) Should patients with cancer undergoing surgery receive perioperative VTE prophylaxis? (4) What is the best method for treatment of patients with cancer with established VTE to prevent recurrence? (5) Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival?

26 1. SHOULD HOSPITALIZED PATIENTS WITH CANCER RECEIVE ANTICOAGULATION FOR VTE PROPHYLAXIS? Recommendation: Hospitalized patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications to anticoagulation.

27 2. SHOULD AMBULATORY PATIENTS WITH CANCER RECEIVE ANTICOAGULATION FOR VTE PROPHYLAXIS DURING SYSTEMIC CHEMOTHERAPY? (1) Routine prophylaxis with an antithrombotic agent is not recommended. (2) Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis.

28 3. SHOULD PATIENTS WITH CANCER UNDERGOING SURGERY RECEIVE PERIOPERATIVE VTE PROPHYLAXIS? Recommendations (1) All patients undergoing major surgical intervention for malignant disease should be considered for thromboprophylaxis. (2) Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting greater than 30 minutes should receive pharmacologic thromboprophylaxis with either low-dose UFH or LMWH unless contraindicated because of a high risk of bleeding or active bleeding. (3) Prophylaxis should be commenced preoperatively, or as early as possible in the postoperative period. (4) Mechanical methods may be added to pharmacologic methods, but should not be used as monotherapy for VTE prevention unless pharmacologic methods are contraindicated because of active bleeding.

29 (6) Prophylaxis should be continued for at least 7 to 10 days postoperatively. (7) Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing major abdominal or pelvic surgery for cancer with high-risk features such as residual malignant disease after operation, obese patients, and those with a previous history of VTE.

30 4. WHAT IS THE BEST TREATMENT FOR PATIENTS WITH CANCER WITH ESTABLISHED VTE TO PREVENT RECURRENT VTE? Recommendations (1) LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the cancer patient with established VTE. (2) LMWH given for at least 6 months is also the preferred approach for long-term anticoagulant therapy. (3) Vitamin K antagonists with a targeted INR of 2 to 3 are acceptable for long-term therapy when LMWH is not available. (4) The insertion of a vena cava filter is only indicated for patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite adequate long-term therapy with LMWH.

31 (5) Anticoagulation should be avoided in the presence of active intracranial bleeding, preexisting bleeding diathesis such as thrombocytopenia (platelet count 50,000/L) or coagulopathy. (6) For elderly patients, anticoagulation is recommended for established VTE as described for other patients with cancer. Careful monitoring and dose adjustment is necessary to avoid excessive anticoagulation and further increase in the risk of bleeding.

32 American Society of Clinical Oncology Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer Recommendations of the American Society of Clinical Oncology VTE Guideline Panel include (1) all hospitalized cancer patients should be considered for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications. (2) routine prophylaxis of ambulatory cancer patients with anticoagulation is not recommended, with the exception of patients receiving thalidomide or lenalidomide (3) Patients undergoing major surgery for malignant disease should be considered for pharmacologic thromboprophylaxis. (4) low molecular weight heparin represents the preferred agent for both the initial and continuing treatment of cancer patients with established VTE. (5) The impact of anticoagulants on cancer patient survival requires additional study and cannot be recommended at present.

33 Summary of recommendations

34 Summary of recommendations

35 Summary of recommendations

36 Prophylaxis Guidelines in cancer patients Guidelines recommend VTE prophylaxis in «hospitalized medical patients» & by NCCN only for «ambulatory cancer patients receiving chemotherapy» NCCN V ASCO 2007 ESMO May 2010 ACCP 2008 ICS 2006 Hospitalized medical patients VTE prophylaxis with anticoagulants if no contra indication from admission to discharge [I] VTE prophylaxis with anticoagulants if no contra indication or bleeding Prophylaxis with UFH, LMWH or Fonda for cancer patients confined to bed with an acute medical complication [I, A] Routine thromboprophylaxis in bedridden patient with an acute medical illness [Grade 1A) For patients with acute medical illness, thrombopx based on the risk of VTE (acute medical co-morbidity) LMWH or LDUH should be used [Grade A] Ambulatory patients receiving chemotherapy VTE prophylaxis in high risk settings (antiangiogenic therapy = myeloma patients thalidomide/lenalidomide + high dosedexamethasone) VTE prophylaxis in high risk outpatients on chemotherapy with risk factors [IIa] -Active cancers associated with high incidence of VTE: stomach, pancreas, lung, lymphoma, gynecologic, bladder and testicular -Prechemotherapy platelet count > 300,000/mcL -Hemoglobin < 10g/Dl -Use of erythropoietic stimulating agents -Body mass index 35kg/m2 -Prior VTE No routine prophylaxis. Multiple myeloma patients receiving thalidomide or lenalidomide with CT or dexamethasone are at high risk of thrombosis and warrant VTE prophylaxis with LMWH or adjusted-dose warfarin (INR~1.5) Extensive, routine prophylaxis for advanced cancer patients receiving CT not recommended. Consider LMWH or adjusted-dose warfarin in myeloma patients receiving thalidomide + dexamethasone or thalidomide + chemotherapy [IIB] Px in cancer patients receiving adjuvant chemotherapy and/or hormone therapy not recommended [I, A] Recommendation against routine thromboprophylaxis for the primary prevention of VTE in patients receiving CT or hormonal therapy [Grade 1C] Value of routine primary thromboprophylaxis not yet established (only for those with advanced breast cancer: use of AVK) [Grade B] NCCN: National Comprehensive Cancer Network/ ASCO: American Society of Clinical Oncology/ ESMO: European Society of Medical Oncology / AOIM: Italian Association of Medical Oncology/ SOR: Standards, Options: Recommendations, from the French National Cancer Institute/ ACCP: American College of Chest Physicians/ ICS: International Consensus Statement

37 The ultra-low-molecular-weight heparin (ULMWH) Semuloparin for prevention of Venous Thromboembolism (VTE) in Cancer patients receiving Chemotherapy: SAVE-ONCO study

38 Study rationale Patients with cancer are at increased risk for VTE 1,2 Chemotherapy represents an additional risk factor for VTE 3,4 Certain tumor types and late-stage disease are associated with even higher VTE risk 2,3,5,6 Currently, routine thromboprophylaxis in ambulatory patients with cancer receiving chemotherapy is not recommended 7,8,9,10 due to several randomized controlled trials reporting inconclusive results 11 Large, randomized, placebo-controlled, VTE-prevention trials are needed 1 Heit JA, et al. Arch Intern Med. 2000;160:809-15; 2 Khorana AA, et al. Cancer. 2007;110: ; 3 Blom JW, et al. J Thromb Haemost. 2006;4:529-35; 4 Kröger K, et al. Ann Oncol. 2006;17: ; 5 Chew HK, et al. Arch Intern Med. 2006;166:458-64; 6 Stein PD, et al. Am J Med. 2006;119:60-8; 7 Lyman G, et al. J Clin Oncol. 2007;34:1-16; 8 Geerts WH, et al. Chest. 2008;133:381S-453S; 9 Mandalà M, et al. Ann Oncol. 2010;21 Suppl 5:v274-6; 10 National Comprehensive Cancer Network (2010) 11 Kuderer N, et al. J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition); 27(15S): 9537.

39 Semuloparin Ultra-low-molecular-weight heparin (ULMWH): Molecular weight Da High anti-factor Xa activity with anti-factor IIa activity Half-life hours 98% bioavailability after subcutaneous injection C max reached at 3 hours Excretion mainly renal

40 Study objectives In patients with locally advanced or metastatic solid tumor receiving chemotherapy to: Compare the efficacy of semuloparin with placebo for the prevention of VTE Evaluate the safety of semuloparin

41 Study design Multinational, randomized, double-blind, parallel-group study N = 3200 Standard of care chemotherapy Placebo sc once daily Post-treatment follow-up Randomization Stratified by: - Cancer type - Cancer stage - Geographical location 1:1 Standard of care chemotherapy Semuloparin 20mg sc once daily End of treatment Treatment Duration: End of treatment + 1 month Patients were treated for the length of chemotherapy If chemotherapy changed prior to 3 months, patients were allowed to continue semuloparin or placebo treatment If chemotherapy changed or stopped after 3 months then semuloparin or placebo treatment was discontinued clinicaltrials.gov: NCT

42 Eligibility Criteria Main inclusion criteria Metastatic or locally advanced solid tumor of lung, pancreas, stomach, colon/rectum, bladder or ovary Initiating a chemotherapy regimen with a minimum intent of 3 months* Main exclusion criteria ECOG (Eastern Cooperative Oncology Group) Performance status of 3 or 4 Estimated creatinine clearance < 30mL/min Contraindication to anticoagulation Requirement for systemic anticoagulation or thrombolysis *Prior chemotherapy was allowed

43 Study endpoints Primary efficacy endpoint: Time to first occurrence of: Any symptomatic DVT Any PE Non-fatal VTE-related deaths (fatal PE or unexplained death) Primary safety endpoint Clinically relevant bleeding, composite of Major bleeding* Clinically relevant non-major bleeding (CRNM)** *Major bleeding defined as any of the following: fatal bleeding, bleeding in a critical area or organ, or clinically overt and causing a drop in hemoglobin 2 g/dl, or requiring 2 units of blood transfusion 1 **CRNM defined as bleeding requiring medical intervention and not meeting criteria for major bleeding 1 ISTH criteria DVT = deep-vein thrombosis, PE = pulmonary embolism

44 Statistical assumptions VTE event rate ~4% in placebo group Risk reduction (RR) with semuloparin ~50% Power = 90% Alpha = 0.05 Intent-to-treat analysis of primary efficacy endpoint

45 Analysis populations Randomized n = 3212 Placebo n = 1604 (100%) Efficacy population Intent-to-treat Semuloparin n = 1608 (100%) Treated n = 1583 (98.7%) Safety population Treated n = 1589 (98.8%)

46 Baseline characteristics Placebo Semuloparin n = 1604 n = 1608 Median age (range), years 60.0 (18-87) 60.0 (20-89) Male, % Median BMI (range), kg/m² 24.1 (13-54) 24.4 (12-57) CVL at baseline, n (%) 302 (18.8) 316 (19.7) Metastatic / locally advanced, % 68.3 / / 31.8 Primary tumor location, % Lung Colon / Rectum Stomach Ovary Pancreas Bladder

47 Treatment duration Treatment duration was approximately 3.5 months, with no difference between the semuloparin and placebo groups

48 Primary efficacy endpoint Composite of symptomatic DVT and any PE Cumulative incidence (%) 5.0% 4.0% 3.0% 2.0% 1.0% Placebo : 3.4% (55/1604) Semuloparin 1.2% (20/1608) HR : 0.36 [ ]; p < Placebo RR 64% Semuloparin 0.0% Time (Months) Number at Risk Placebo Semuloparin HR = hazard ratio

49 Components of the primary efficacy endpoint OR 0.32 [ ] Placebo Semuloparin 2.1 OR 0.41 [ ] OR 0.20 [ ] OR 0.77 [ ] / / / /1604 3/1608 9/1604 7/1608 Symptomatic DVT Any PE Non-fatal PE VTE-related death OR = odds ratio [95% CI]

50 Bleeding Placebo OR 1.41 [ ] 2.8 OR 1.05 [ ] OR 1.86 [ ] / / / / / /1589 Clinically relevant Major* Non-major** *Includes 6 fatal bleedings (4 [0.3%] in placebo and 2 [0.1%] in semuloparin),and 5 (0.3%) non-fatal bleedings into critical area or organ in the semuloparin group **6 events in placebo and 9 in semuloparin caused study drug discontinuation; 2 events in placebo and 3 in semuloparin were serious and caused study drug discontinuation; 13 events in placebo and 25 in semuloparin recovered

51 Summary Semuloparin, compared to placebo, showed: 64% risk reduction in the composite of symptomatic DVT and any PE (p < ) 59% risk reduction in any PE; OR 0.41, [ ] Incidence of clinically relevant bleeding of 2.8% vs 2.0% Similar low incidence of major bleeding; 1.2% vs 1.1%

52 Conclusions Semuloparin 20 mg demonstrated a favourable benefit-risk profile for VTE prevention in cancer patients receiving chemotherapy Which cancer patients should we now consider for thromboprophylaxis? Undergoing surgery Hospitalized/acutely ill Receiving chemotherapy : Semuloparin is efficient and safe for VTE prophylaxis in ambulatory cancer patients receiving chemotherapy.

53 Thank you