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New Frontiers and Paradigm Changes in Optimizing Supportive Care in Cancer Focus on Thrombosis Prevention, CINV, and Hematologic Complications of Malignancy.

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Presentation on theme: "New Frontiers and Paradigm Changes in Optimizing Supportive Care in Cancer Focus on Thrombosis Prevention, CINV, and Hematologic Complications of Malignancy."— Presentation transcript:

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2 New Frontiers and Paradigm Changes in Optimizing Supportive Care in Cancer Focus on Thrombosis Prevention, CINV, and Hematologic Complications of Malignancy Program Chairman Gary H. Lyman, MD, MPH, FRCP (Edin) Editor-In-Chief, Cancer Investigation Professor of Medicine and Director Health Services, Effectiveness and Outcomes Research Division of Medical Oncology, Department of Medicine Duke University School of Medicine and the Duke Comprehensive Cancer Center Senior Fellow, Duke Center for Clinical Health Policy Research Investigations Innovation Clinical Application

3 Program Faculty PROGRAM CHAIRMAN GARY H. LYMAN, MD, MPH, FRCP (Edin) GARY H. LYMAN, MD, MPH, FRCP (Edin) Editor-In-Chief, Cancer Investigation Professor of Medicine and Director Health Services, Effectiveness and Outcomes Research Research Division of Medical Oncology, Department of Medicine Medicine Duke University School of Medicine and the Duke Comprehensive Cancer Center Comprehensive Cancer Center Senior Fellow, Duke Center for Clinical Health Policy Research Policy Research Lee S. Schwartzberg, MD, FACP Lee S. Schwartzberg, MD, FACP Supportive Oncology Services, Memphis Accelerated Community Oncology Research Network Network Clinical Professor of Medicine University of Tennessee Medical Center Memphis, Tennessee Jeffrey Crawford, MD George Barth Geller Professor for Research In Cancer Chief of Division of Medical Oncology Department of Medicine Duke University Medical Center Editor-in-Chief, Supportive Care Oncology Oncology Durham, North Carolina Alok A. Khorana, MD, FACP Vice-Chief, Division of Hematology/Oncology Associate Professor of Medicine and Oncology Oncology James P. Wilmot Cancer Center University of Rochester Rochester, New York

4 An Evidence-Based Overview to Critical Issues in Supportive Care Overview Program Chairman Gary H. Lyman, MD, MPH, FRCP (Edin) Editor-In-Chief, Cancer Investigation Professor of Medicine and Director Health Services, Effectiveness and Outcomes Research Division of Medical Oncology, Department of Medicine Duke University School of Medicine and the Duke Comprehensive Cancer Center Senior Fellow, Duke Center for Clinical Health Policy Research Investigations Innovation Clinical Application

5 Complications of Cancer Chemotherapy Kuderer NM et al. Cancer 2006;106:2258–2266 Chirivella I et al. J Clin Oncol 2006;24;abstract 668 Bosly A et al. Ann Hematol 2007, advance access published 20 October 2007; doi:10.1007/s00277-007-0399-y Myelosuppressive chemotherapy Febrile neutropenia (FN) Chemotherapy dose delays and dose reductions Decreased relative dose intensity (RDI) Complicated life- threatening infection and prolonged hospitalization Neutropenia Reduced survival

6 Meta-analysis of Randomized Controlled Trials Relative risk of FN 0.10.20.51.02.05.010 Favours G-CSF Favours no G-CSF Combined filgrastim (n=9) Combined lenograstim (n=5) Combined pegfilgrastim (n=1) All G-CSF (n=15) RR 0.61 0.62 0.08 0.54 95% CI 0.53–0.72 0.44–0.88 0.43–0.67 0.03–0.18 p <.001 0.007 <.001 Kuderer et al. J Clin Oncol 2007;25:3158–3167 Febrile Neutropeonia (n = 3182)

7 Primary Prophylactic CSF Administration Required and recommended for dose dense regimens Required and recommended for dose dense regimens Recommended for the prevention of FN in patients who have a high risk of FN based on: Recommended for the prevention of FN in patients who have a high risk of FN based on: Age Age Medical history Medical history Disease characteristics Disease characteristics Myelotoxicity of the chemotherapy regimen Myelotoxicity of the chemotherapy regimen Clinical trial data support the use of CSF when the risk of FN is in the range of 20% or higher Clinical trial data support the use of CSF when the risk of FN is in the range of 20% or higher

8 Primary Prophylactic CSF Administration: Special Circumstances When the following clinical factors are present, primary prophylaxis with CSF is often appropriate even with regimens with FN rates of <20% : When the following clinical factors are present, primary prophylaxis with CSF is often appropriate even with regimens with FN rates of <20% : Age >65 yearsAge >65 years Poor performance statusPoor performance status Previous FNPrevious FN Poor nutritional statusPoor nutritional status Open wounds or active infectionsOpen wounds or active infections More advanced cancerMore advanced cancer Extensive prior treatment, including large XRT portsExtensive prior treatment, including large XRT ports Administration of combined chemoradiotherapyAdministration of combined chemoradiotherapy Cytopenias due to bone marrow involvement by tumorCytopenias due to bone marrow involvement by tumor Other serious comorbiditiesOther serious comorbidities

9 Evidence-based G-CSF Guidelines Key Recommendations Summary of Recommendations Summary of Recommendations EORTC 1 ASCO 2 NCCN 3 G-CSF primary prophylaxis with 20% overall FN risk FN risk associated with chemotherapy Consider patient risk factors for overall FN risk G-CSF primary prophylaxis to maintain chemotherapy RDI Dose-dense chemotherapy regimens G-CSF for ongoing FN episode G-CSF formulation and dosing Secondary prophylaxis with G-CSF 1. Aapro et al. Eur J Cancer 2006;42:2433–2453; 2. Smith et al. J Clin Oncol 2006;24:3187–3205; 3. NCCN. Myeloid growth factors V.1.2009

10 Chemotherapy-Induced Acute Emesis Classes of Antiemetic Highest therapeutic index antiemetic agents Highest therapeutic index antiemetic agents 5-HT 3 Serotonin Receptor Antagonists 5-HT 3 Serotonin Receptor Antagonists Corticosteroids (Dexamethasone) Corticosteroids (Dexamethasone) NK 1 Receptor Antagonists (Aprepitant) NK 1 Receptor Antagonists (Aprepitant) These classes of antiemetic agents These classes of antiemetic agents Highly effective Highly effective Few significant side effects (when used appropriately) Few significant side effects (when used appropriately) Safe in combination Safe in combination Emetic Risk of IV Administered Antineoplastic Agents High (>90%)Moderate (30% to 90%)Low (10% to 30%)Minimal (<10%) Carmustine Cisplatin Cyclophosphamide>1500mg/m 2 Dacarbazine Dactinomycin Mechlorethamine Streptozotocin Carboplatin Cyclophosphamide<1500 mg/m 2 Cytarabine >1 gm/m 2 Daunorubicin Doxorubicin Epirubicin Idarubicin Ifosfamide Irinotecan Oxaliplatin 5-Fluorouracil Bortezomib Cetuximab Cytarabine<1000mg/m 2 Docetaxel Etoposide Gemcitabine Methotrexate Mitomycin Mitoxantrone Paclitaxel Pemetrexed Topotecan Trastuzumab 2-Chlorodeoxyadenosine Bevacizumab Bleomycin Busulfan Fludarabine Rituximab Vinblastine Vincristine Vinorelbine

11 Chemotherapy-Induced Acute Emesis Antiemetic Agents 5-HT 3 Serotonin Receptor Antagonists Dexamethasone Aprepitant Yields greatest antiemetic protection in randomized- multicenter studies Chemotherapy of high emetic risk Anthracycline + Cyclophosphamide Indicated for patients receiving agents of moderate emetic risk other than anthracycline + cyclophosphamide 5-HT 3 Serotonin Receptor Antagonists Dexamethasone Kris M et al, JCO 2006:24: 2932-2947 Combinations of Antiemetics

12 Antiemetic Regimens Based on Emetic Risk ASCO Guidelines High (> 90%) High (> 90%) Moderate (30-90%) Moderate (30-90%) Low (10-30%) Low (10-30%) 5-HT 3 SRA: day 1 5-HT 3 SRA: day 1 Dexamethasone: days 1-4 Dexamethasone: days 1-4 Aprepitant: days 1-3 Aprepitant: days 1-3 5HT 3 SRA: day 1 5HT 3 SRA: day 1 Dexamethasone: day 1 (2,3)* (may omit days 2,3 s/p aprepitant) Dexamethasone: day 1 (2,3)* (may omit days 2,3 s/p aprepitant) (Aprepitant: days 1-3 for AC) (AC- anthracycline + cyclophosphamide) (Aprepitant: days 1-3 for AC) (AC- anthracycline + cyclophosphamide) Dexamethasone: day 1 Dexamethasone: day 1 Kris M et al, JCO 2006:24: 2932-2947

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14 Program Chairman Gary H. Lyman, MD, MPH, FRCP (Edin) Editor-In-Chief, Cancer Investigation Professor of Medicine and Director Health Services, Effectiveness and Outcomes Research Division of Medical Oncology, Department of Medicine Duke University School of Medicine and the Duke Comprehensive Cancer Center Senior Fellow, Duke Center for Clinical Health Policy Research Investigations Innovation Clinical Application Optimizing Management of Cancer Patients at Risk for Venous Thromboembolism

15 TumorCellsHemostaticSystem Procoagulant Activity Cytokines Growth Factors Fibrinolytic Activity GrowthInvasionMetastasesAngiogenesis Kuderer NM et al J Clin Oncol 2009; 27: 4902-4911

16 VTE Inpatient Risk and Mortality Hospitalized Cancer Patients* 0 2 4 6 8 10 12 14 16 18 20 199519961997199819992000200120022003 Inpatient Mortality (%) VTE No VTE P<0.0001 Khorana et al. Cancer 2007; 110: 2339-2346 VTE- patients on chemo VTE-all patients DVT-all patients PE-all patients 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 199519961997199819992000200120022003 Rate of VTE (%) P<0.0001 133 U.S. academic medical centers, 1995 – 2003 * n = 1,015,598

17 876543210876543210 Chemotherapy Risk in cancer population Remission Risk in general population Time Diagnosis Metastasis End of life Hospitalization Relative Risk Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007 Cancer and Venous Thromboembolism Risk of VTE Varies Over Natural History of Cancer

18 Risk Factors for VTE in Patients with Cancer Patient-related factors Older age Older age Race Race Higher in AA Higher in AA Lower in Asians Lower in Asians Major comorbidities Major comorbidities History of VTE History of VTE Treatment-related factors Major surgery Major surgery Hospitalization Hospitalization Chemotherapy Chemotherapy Central venous catheters Central venous catheters Hormonal therapy Hormonal therapy Antiangiogenic agents Antiangiogenic agents ESAs ESAs ?Transfusions ?Transfusions Cancer-related factors Site of cancerSite of cancer Advanced stageAdvanced stage Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007

19 Increased morbidity Increased morbidity Hospitalization Hospitalization Anticoagulation Anticoagulation Postphlebitic syndrome Postphlebitic syndrome Increased mortality Increased mortality Increased risk of recurrent VTE Increased risk of recurrent VTE Bleeding complications Bleeding complications Cancer treatment delays Cancer treatment delays Increased healthcare costs Increased healthcare costs Important Consequences of VTE in Cancer Patients

20 Ambulatory Cancer Patients Receiving Chemotherapy Cumulative Incidence of VTE Kuderer NM et al; J Clin Oncol 2008 All Cause Early Mortality HR = 4.90 [2.27-10.60], P<.0001 Prospective Study at 115 Randomly Selected US Practice Sites March 2002 – February 2006 [N = 4,458]

21 Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer ASCO Clinical Practice Guidelines Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

22 Clinical Questions 1.Should patients with cancer receive anticoagulation for VTE prophylaxis while hospitalized? 1.Should patients with cancer receive anticoagulation for VTE prophylaxis while hospitalized? 2.Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? 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? 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? 5.Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

23 Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation. Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation. ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

24 Anticoagulant Prophylaxis to Prevent Screen-Detected VTE 3 large, randomized, placebo-controlled, double-blind trials in medical patients at high risk including cancer 3 large, randomized, placebo-controlled, double-blind trials in medical patients at high risk including cancer MEDENOX (enoxaparin) 1 ~ 15% MEDENOX (enoxaparin) 1 ~ 15% PREVENT (dalteparin) 2 ~5% PREVENT (dalteparin) 2 ~5% ARTEMIS (fondaparinux) 3 ~15% ARTEMIS (fondaparinux) 3 ~15% Screening for asymptomatic DVT with venography or ultrasound Screening for asymptomatic DVT with venography or ultrasound 1 Samama MM, et al. N Engl J Med. 1999;341:793-800 2 Leizorovicz A, et al. Circulation. 2004;110:874-9 3 Cohen AT, et al. BMJ 2006; 332: 325-329 High Risk Hospitalized Medical Patients

25 MEDENOX 1 StudyRRR Thromboprophylaxis Patients with VTE (%) 14.9 5.5 5.0 2.8 10.5 5.6 1 Samama MM, et al. N Engl J Med. 1999;341:793-800 2 Leizorovicz A, et al. Circulation. 2004;110:874-9 3 Cohen AT, et al. BMJ 2006; 332: 325-329 P < 0.001 P = 0.0015 RRR 63% 45% 47% Placebo Enoxaparin 40 mg Dalteparin 5,000 units Fondaparinux 2.5 mg ARTEMIS 3 PREVENT 2 Anticoagulant Prophylaxis to Prevent Screen- Detected VTE High Risk Hospitalized Medical Patients: VTE

26 0.49% 0.16% 0.2% 1.7% 1.1% Samama MM, et al. N Engl J Med. 1999;341:793-800 Leizorovicz A, et al. Circulation. 2004;110:874-9 Cohen AT, et al. BMJ 2006; 332: 325-329 Incidence of Major Bleeding (%) Study Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients: Major Bleeding

27 ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Lyman GH et al: J Clin Oncol 2007; 25:5490-5505 Routine prophylaxis with an antithrombotic agent in the ambulatory setting is not recommended. Routine prophylaxis with an antithrombotic agent in the ambulatory setting is not recommended. * This recommendation is based on extrapolation from studies of prophylaxis in other high risk cancer settings. NOTE: Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. LMWH or adjusted dose warfarin (INR~1.5) is recommended.* Ambulatory Cancer Patients

28 Characteristics of Prophylaxis Studies VTE – Prophylaxis with LMWH TrialYearStageN LMWH / DoseControlArmDuration Type of Pub Specific Chemo FAMOUS Solid Tumors2004III/IV385DalteparinPlacebo 12 months ManuscriptNo TOPIC-I Breast Cancer2005III/IV353CertoparinPlacebo 6 months Abstract+No TOPIC-2 NSCLC2005III/IV547CertoparinPlacebo 6 months Abstract+No PRODIGE Glioma2007Any186DalteparinPlacebo 6-12 months AbstractNo SIDERAS Solid Tumors2006IV141Dalteparin Non- Placebo IndefinitelyManuscriptNo PROTECHT Solid Tumors2008III/IV1166Nadroparin 2:1 Placebo < 4 months with chemo ManuscriptNo CONKO-04 Pancreatic Cancer2009Advanced312Enoxaparin Non- Placebo 3 months (to prog) AbstractYes* FRAGEM Pancreatic Cancer2009Advanced123 Dalteparin # Non- Placebo 3 months AbstractYes* (1000 mg/m2) # Higher dose than standard prophylactic dose *Gemcitabine-based chemotherapy (1000 mg/m2) # Higher dose than standard prophylactic dose

29 Cancer Type BenefitHarm Venous Thromboembolism Major Bleeding Overall 3.1% 3.1% 0.9% 0.9% Pancreatic 13.0% 13.0% 0.8% 0.8% Non-Pancreatic 1.4% 1.4% 0.8% 0.8% Systematic Review of LMWH Prophylaxis in Cancer Patients Kuderer NM et al. ASH Oral Presentation 2009 VTE Versus Major Bleeding: Absolute Risk

30 Clinical Risk Model for Chemotherapy-associated VTE Risk Score Based on Pretreatment Risk Factors Risk Factors Risk score 1. Site of cancer 1. Site of cancer a) Very high risk cancer (stomach, pancreas) a) Very high risk cancer (stomach, pancreas) 2 2 2 2 b) High risk (lung, lymphoma, gynecologic, bladder, testicular) b) High risk (lung, lymphoma, gynecologic, bladder, testicular) 1 1 1 1 2. Platelet count >350,000/mm 3 2. Platelet count >350,000/mm 3 1 1 1 1 3. Hemoglobin level < 10 g/dL or use of 3. Hemoglobin level < 10 g/dL or use of Red cell growth factors Red cell growth factors 1 1 1 1 4. Leukocyte count >11,000 /mm 3 4. Leukocyte count >11,000 /mm 3 1 1 1 1 5. BMI > 35 kg/m 2 5. BMI > 35 kg/m 2 1 1 1 1 Khorana AA et al. Blood. 2008; 111: 4902-4907

31 RISK SCORE: Low (0) Intermediate (1-2) High (>3) n=374 n=842n=149 Rate of VTE (%) 0% 1% 2% 3% 4% 5% 6% 7% 8% n=734 n=1,627n=340 0.3% 2.0% 6.7% 0% 1% 2% 3% 4% 5% 6% 7% 8% n=734 n=1,627n=340 0.8% 1.8% 7.1% 0.3% 2.0% 6.7% n=374 n=842n=149 VTE Prediction Risk Score Chemotherapy – Associated Thrombosis Khorana AA et al. Blood. 2008; 111:4902-4907 Development cohort Validation cohort

32 Mortality and Progression-Free Survival By VTE Risk Score Outcomes Outcomes Low Risk N=1,206 Intermediate Risk N=2,709 High Risk N=543AllN=4,458 Mortality Risk (%)1.2%5.9%12.7%5.6% HR [+/- CI]1.0 3.6 [1.9-6.7] 6.9 [3.5-13.6] - Progression-free survival Risk (%)93%82%72%84% HR [+/- CI]1.0 2.8 [2-3.9] 4.3 [2.9-6.3] - Kuderer NM et al. ASH 2008

33 ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Lyman GH et al: J Clin Oncol 2007; 25:5490-5505 LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the patient with cancer with established VTE. LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the patient with cancer with established VTE. LMWH for at least 6 months is also preferred for long-term anticoagulant therapy. LMWH for at least 6 months is also preferred for long-term anticoagulant therapy. After 6 months, indefinite anticoagulant therapy should be considered for patients with active cancer. After 6 months, indefinite anticoagulant therapy should be considered for patients with active cancer. NOTE: Vena cava filters are only indicated for patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite adequate long-term therapy with LMWH. Preventing Recurrence in Cancer Patients with Established VTE

34 0123456789101112 Time (months) 0 10 20 30 Recurrent VTE, % Hazard ratio 3.2 [1.9-5.4] Cancer 21% No Cancer 7% Prandoni P et al. Blood 2002; 100: 3484-3488 01234567891011 12 Time (months) 0 10 20 30 Major Bleeding, % Cancer 12% No Cancer 5% Hazard ratio 2.2 [1.2-4.1] Recurrent VTE and Bleeding During Anticoagulant Treatment Patients with cancer and venous thrombosis

35 RCTs of Long-term Treatment in Cancer Patients with VTE 1. Meyer G, et al. Arch Intern Med. 2002;162:1729-1735. 2. Lee AY, et al. N Engl J Med. 2003;349:146-153. 3. Deitcher SR, et al. Clin Appl Thromb Hemost. 2006;12:389-396. 4. Hull RD, et al. Am J Med. 2006;119:1062-1072. StudyNo. Long-Term Treatment Recurrent VTE, % Major Bleed, % Death, % Meyer 1 2002 71Warfarin21.1*22.7 67 Enoxaparin 1.5 mg/kg 10.5*11.3 Lee 2 2003 336Warfarin17*441 336 Dalteparin 200/150 IU/kg 9*639 Deitcher 3 2006 30Warfarin102.98.8 29 Enoxaparin 1.0 mg/kg 6.96.56.5 32 Enoxaparin 1.5 mg/kg 6.311.119.4 Hull 4 2006 100Warfarin10*719 100 Tinzaparin 175 IU/kg 6*720 * P <.05 RCTs of LMWH vs. Vitamin K Antagonists in Cancer

36 5 to 7 days Dalteparin 200 IU/kg OD Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo Control Group Dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo Experimental Group Randomization 1 month 1 month 6 months 6 months The CLOT Trial Study Schema Lee AY, et al. N Engl J Med. 2003;349:146-153.

37 0 5 10 15 20 25 Days Post Randomization 0306090120150180210 Probability of Recurrent VTE, % dalteparin, 9% VKA, 17% risk reduction = 52% HR 0.48 (95% CI 0.30, 0.77) log-rank p = 0.002 The CLOT Trial: Results: Symptomatic Recurrent VTE Lee AY, et al. N Engl J Med. 2003;349:146-153.

38 Anticoagulants are not recommended at this time as treatment to improve survival in patients with cancer without VTE. Anticoagulants are not recommended at this time as treatment to improve survival in patients with cancer without VTE. Participation in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies is encouraged. Participation in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies is encouraged. ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Lyman GH et al: J Clin Oncol 2007; 25:5490-5505 Improving survival in absence of established VTE

39 Systematic Review of Anticoagulants as Cancer Treatment Kuderer, N. M. et al. J Clin Oncol; 27:4902-4911 2009 Kuderer NM, et al. Cancer. 2007;110:1149-1161 Impact on All Cause Mortality

40 Kuderer, N. M. et al. J Clin Oncol; 27:4902-4911 2009 Kuderer NM, et al. Cancer. 2007;110:1149-1161 Systematic Review of Anticoagulants as Cancer Treatment Impact on Major Bleeding

41 Patient Group Recommended Not Recommended Hospitalized patients with cancer VTE prophylaxis with anticoagulants If bleeding or contraindication to anticoagulation Ambulatory patients with cancer receiving chemotherapy Myeloma patients receiving thalidomide or lenalidomide + chemotherapy/ dexamethasone. LMWH or adjusted dose warfarin. Otherwise, no routine prophylaxis Patients with cancer undergoing surgery Prophylaxis with low-dose UFH or LMWH Prophylaxis with mechanical methods for patients with contraindications to pharmacologic methods Consider mechanical methods when contraindications to anticoagulation. Patients with cancer with established VTE Anticoagulation for at least 6 months. Consider continued anticoagulation beyond 6 months in those with active cancer. - To improve survival- Not recommended ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Lyman GH et al: J Clin Oncol 2007; 25:5490-5505 Summary

42 Recommendations for Primary Prevention of VTE in Patients With Cancer Modified from Khorana AA et al J Clin Oncol 2009; 27: 4919-4926 Comparisons of Guideline Panels

43 Unanswered Questions A Call to Action for Future Research Prevention of VTE in the ambulatory patient with cancer: A role for targeted prophylaxis? Prevention of VTE in the ambulatory patient with cancer: A role for targeted prophylaxis? Prevention of VTE in the hospitalized patient with cancer: a need for cancer-specific studies? Prevention of VTE in the hospitalized patient with cancer: a need for cancer-specific studies? Optimal treatment of recurrent VTE Optimal treatment of recurrent VTE Management of incidental or screen-detected VTE Management of incidental or screen-detected VTE Impact of anticoagulation on survival of patients with cancer Impact of anticoagulation on survival of patients with cancer Khorana AA et al J Clin Oncol 2009; 27: 4919-4926

44 Cancer and Venous Thromboembolism Conclusions VTE is a common complication of cancer and cancer treatment and is associated with considerable morbidity, mortality and costs. VTE is a common complication of cancer and cancer treatment and is associated with considerable morbidity, mortality and costs. Hospitalized medical and surgical cancer patients are at increased risk for VTE and should be considered for pharmacologic prophylaxis if no contraindication to anticoagulation exists. Hospitalized medical and surgical cancer patients are at increased risk for VTE and should be considered for pharmacologic prophylaxis if no contraindication to anticoagulation exists. Cancer patients treated for documented VTE should be considered for continued anticoagulation, preferably with LMWH, for up to 6 months or longer in patients with active malignancy. Cancer patients treated for documented VTE should be considered for continued anticoagulation, preferably with LMWH, for up to 6 months or longer in patients with active malignancy. Routine thromboprophylaxis of ambulatory cancer patients is not currently recommended. Routine thromboprophylaxis of ambulatory cancer patients is not currently recommended.

45 Prophylaxis may be considered in selective high risk settings such as multiple myeloma patients receiving thalidomide/lenalidomide. Prophylaxis may be considered in selective high risk settings such as multiple myeloma patients receiving thalidomide/lenalidomide. Consideration of prophylactic anticoagulation in cancer patients must always balance the risk of VTE with the increased risk of bleeding and other complications. Consideration of prophylactic anticoagulation in cancer patients must always balance the risk of VTE with the increased risk of bleeding and other complications. Improved methods for the identification of cancer patients at high risk for VTE and candidates for targeted thromboprophylaxis are needed and under active investigation. Improved methods for the identification of cancer patients at high risk for VTE and candidates for targeted thromboprophylaxis are needed and under active investigation. Cancer and Venous Thromboembolism Conclusions

46 Chemotherapy-Induced Nausea and Vomiting (CINV) Optimizing Clinical Management Lee S. Schwartzberg, MD, FACP Supportive Oncology Services, Memphis Accelerated Community Oncology Research Network Clinical Professor of Medicine University of Tennessee Medical Center Memphis, Tennessee Investigations Innovation Clinical Application

47 Taste Change Chemotherapy Experienced Patients Rank Severe CINV Near Death Sun C et al. Support Care Cancer. 2005 Thrombocytopenia Median VAS Scores Remission CINV 1 Current Health AlopeciaDepressionOtotoxicity Weight Gain Sexual Dysfunction Memory loss Constipation Leg pain FatigueFlu Peripheral Neuropathy DiarrheaDysuria CINV 4 CINV 6 CINV 5 Death Perfect Health CINV 2 Mucositis CINV 3 Febrile Neutropenia Complete Control Mucositis Death Moderate Delayed Nausea Poorly Controlled Acute & Delayed CINV

48 Types of CINV: Definitions Acute (posttreatment) Acute (posttreatment) Occurs within first 24 hours after administration of cancer chemotherapy Occurs within first 24 hours after administration of cancer chemotherapy Delayed Delayed CINV that begins after first 24 hours CINV that begins after first 24 hours May last for 120 hours May last for 120 hours Anticipatory Anticipatory Learned or conditioned response from poorly controlled nausea and vomiting associated with previous chemotherapy Learned or conditioned response from poorly controlled nausea and vomiting associated with previous chemotherapy Breakthrough Breakthrough CINV that occurs despite prophylaxis and requires rescue CINV that occurs despite prophylaxis and requires rescue

49 Emetogenic Potential of Single Antineoplastic Agents HIGH Risk in nearly all patients (> 90%) MODERATE Risk in 30% to 90% of patients LOW Risk in 10% to 30% of patients MINIMAL Fewer than 10% at risk

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51 Patient-Specific Risk Factors for CINV Age <50 years Age <50 years Women > men Women > men History of light alcohol use History of light alcohol use History of vomiting with prior exposure to chemotherapeutic agents History of vomiting with prior exposure to chemotherapeutic agents Other risks Other risks History of motion sickness History of motion sickness History of nausea or vomiting during pregnancy History of nausea or vomiting during pregnancy History of anxiety History of anxiety ASHP. Am J Health Syst Pharm. 1999:56:729-764; Balfour and Goa. Drugs. 1997:54:273-298

52 Other Causes of Nausea and Vomiting in Cancer patients Brain metastases Brain metastases Electrolyte disturbances Electrolyte disturbances Gastoparesis Gastoparesis Concurrent medications Concurrent medications Bowel obstruction Bowel obstruction Vestibular dysfunction Vestibular dysfunction

53 Pathophysiology of Chemotherapy-Induced Emesis

54 Pharmacologic Agents for Prevention of CINV Corticosteroids Corticosteroids Dopamine antagonists Dopamine antagonists Serotonin (5-HT3) antagonists Serotonin (5-HT3) antagonists NK-1 receptor antagonists NK-1 receptor antagonists

55 Key Milestones in Antiemetic Treatment 1960197019801990200020022004 Phenothiazines: first agents to demonstrate antiemetic effect High-dose metoclopramide shown to enhance antiemetic effect Combination therapy: addition of a corticosteroid shown to improve antiemetic response First clinical studies of 5-HT 3 antagonists Introduction of 5-HT 3 antagonists into clinical practice for CINV New class of drug: NK-1 antagonists in clinical development for CINV Aprepitant: March 2003 Palonosetron: July 2003 Viale PH. Clin J Onc Nurs. 2005;9(1):77-84 Hesketh PJ. Support Care Cancer. 2001;9:350-4 Grunberg SM, Hesketh PJ. New Engl J Med. 1993;329(24):1790-6 Hesketh PJ. Support Care Cancer. 2004;12:550-4

56 Controlling Cisplatin-induced Emesis: Progress Over the Past 30 Years 1978 100% - 75% - 75% - 50% - 50% - 25% - 25% - Complete Response: 0% 50% 1988 60% 1998 70% 2008 No Useful Rx HD-MCP/Dex 5-HT3/Dex 5-HT3/Dex/NK1 No Useful Rx HD-MCP/Dex 5-HT3/Dex 5-HT3/Dex/NK1 (24 hour control) (120 hour control)

57 Patterns of Emesis Cisplatin vs Cyclophosphamide and Carboplatin Martin M. Oncology. 1996;53(suppl 1): 26-31 CisplatinCyclophosphamide/Carboplatin Intensity of Emesis 012345 Days

58 1 st Generation 5HT 3 RAs are Therapeutically Equivalent Pts receiving MEC* (N=1,085) 80% of pts received prophylactic steroids *Cyclophosphamide 500 - 1200 mg/m 2, carboplatin 300 mg/m 2 59.0 60.0 71.0 58.0 72.0 TotalNausea Emesis Oral granisetron 2 mg IV ondansetron 32 mg Complete Control (%) Highest Level Evidence Highest Level Evidence MASCC 2009MASCC 2009 NCCN 2010NCCN 2010 ASCO 2006ASCO 2006 1 st Generation Agents are therapeutically equivalent 1 st Generation Agents are therapeutically equivalent DolasetronDolasetron OndansetronOndansetron GranisetronGranisetron 1 st Generation oral, IV & patch forms equally effective 1 st Generation oral, IV & patch forms equally effective Perez et al. J Clin Oncol 1998;16:754

59 Palonosetron Second generation 5-HT 3 antagonist Second generation 5-HT 3 antagonist Pharmacologic differences from older 5-HT 3 antagonists Pharmacologic differences from older 5-HT 3 antagonists Prolonged half-life (~40 hours) Prolonged half-life (~40 hours) Enhanced receptor binding affinity (30-fold ) Enhanced receptor binding affinity (30-fold ) FDA approved FDA approved IV formulation July 25, 2003 IV formulation July 25, 2003 Oral formulation August 22, 2008 Oral formulation August 22, 2008 Regimens Regimens IV 0.25 mg pre chemotherapy IV 0.25 mg pre chemotherapy acute/delayed HEC/MEC PO 0.50 mg pre chemotherapy PO 0.50 mg pre chemotherapy acute MEC

60 Palonosetron vs. 1 st gen HT-3RA: Complete Response on Day of Chemo & Beyond Palonosetron 0.25 mg (n=378) Ondansetron/Dolasetron 32/100 mg (n=376) 46.8 42.0 * 57.7 * 64.0 * 72.0 60.6 0 20 40 60 80 100 Time (hr) Acute: 0-24 (Day 1) Delayed: 24-120 (Days 2-5) Overall: 0-120 (Days 1-5) Complete Response (CR) (% of Patients) *p<0.025 for pairwise difference (2-sided Fishers exact test) between palonosetron and ondansetron/dolasetron. Gralla R et al. Ann Oncol. 2003; Eisenberg P et al. Cancer. 2003 Rubenstein EB et al. Proc Am Soc Clin Oncol. 2003. Abstract 2932 CR = no emetic episodes or use of rescue medications

61 Aapro M Support Care Cancer 2003:11:391 Palonosetron vs Ondansetron Palonosetron vs Ondansetron * * N=447 (67%) High Emetic Risk Chemotherapy Patients Also Receiving Dexamethasone

62 Phase III Trial of IV Palonosetron vs. IV Granisetron with Cisplatin or AC-Based Chemotherapy 1114 patients 1114 patients Cisplatin (57%) or anthracycline/cyclophosphamide (43%) Cisplatin (57%) or anthracycline/cyclophosphamide (43%) Single 0.75 mg dose of palo vs. single 40 μg/kg dose of granisetron Single 0.75 mg dose of palo vs. single 40 μg/kg dose of granisetron Dexamethasone 16 mg d1; 4mg/d d 2-3 (AC/EC); 8mg/d d 2-3 CDDP Dexamethasone 16 mg d1; 4mg/d d 2-3 (AC/EC); 8mg/d d 2-3 CDDP Objective: demonstrate non-inferiority d1 and superiority d 2-5 of palonosetron Objective: demonstrate non-inferiority d1 and superiority d 2-5 of palonosetron Primary endpoint complete response (no emesis/no rescue) Primary endpoint complete response (no emesis/no rescue) Saito M et al. Lancet Oncol. 2009;10(2):115-24

63 Phase III Trial Palonosetron vs. Granisetron both with Dexamethasone in HEC Outcome Palo+ Dex (n=555)% Grani+ Dex (n=558)%P Complete Response, Acute (0-24h)73.772.1ND CR, Delayed (24-120h)53.042.40.0003 CR, Overall (0-120h)47.938.10.0007 No Nausea: 0-120 hours32250.01 No Emesis: 0-120 hours58490.006 Saito M et al. Lancet Oncol. 2009;10(2):115-24

64 * 69.0 61.1 64.8 50.0 0 10 20 30 40 50 60 70 80 Acute (0-24 hrs) Delayed (24-120 hrs) Overall (0-120 hrs) 90 * 52.7 42.8 * Fishers exact test indicates a difference between PALO and GRAN Chi-square test indicates a difference between PALO and GRAN Chi-square test indicates a difference between PALO and GRAN * p = 0.0165 p = 0.030 Palonosetron 0.75 mg IV (n=239) Granisetron 40 mcg/kg IV (n=236) Complete Response (% of patients) Saito M, et al. Lancet Oncol 2009;10:115-124 Data on file, Taiho/Helsinn 2008 Please note that the EU approved dose is 0.25 mg Palonosetron + Dexamethasone vs Granisetron + Dexamethasone in Japanese Patients Complete Response – AC/EC Subset

65 5-HT3 Treatment-Related Adverse Reactions Adverse Reaction Palonosetron 0.25 mg IV (n=187) Palonosetron 0.75 mg IV (n=188) Ondansetron 32 mg IV (n=187) n%n%n% Headache94.8105.3105.3 Constipation31.663.231.6 Dizziness10.500.063.2 Adverse reaction = adverse event judged by the investigator to have a definite, probable, possible or unknown relationship to study medication n = number of patients with the adverse reaction *Reported in 2% of patients in any treatment group Gralla R, et al. Ann Oncol. 2003;14:1570-1577

66 Palonosetron: 5-HT 3 Antagonist of Choice? Palonosetron is a 5-HT 3 antagonist with strong receptor binding affinity and an extended half-life Palonosetron is a 5-HT 3 antagonist with strong receptor binding affinity and an extended half-life Comparable tolerability Comparable tolerability Ease of use and trends towards superiority in delayed CINV favor palonosetron as the preferred 5-HT 3 antagonist Ease of use and trends towards superiority in delayed CINV favor palonosetron as the preferred 5-HT 3 antagonist Definitive proof of superiority to first generation 5-HT 3 antagonists would require trials with control arms utilizing corticosteroids, NK 1 antagonists and repetitive dosing of the first generation agents Definitive proof of superiority to first generation 5-HT 3 antagonists would require trials with control arms utilizing corticosteroids, NK 1 antagonists and repetitive dosing of the first generation agents

67 Aprepitant Selective antagonist of the binding of Substance P to the neurokinin 1 (NK1) receptor Selective antagonist of the binding of Substance P to the neurokinin 1 (NK1) receptor FDA approved FDA approved Oral formulation: March 26, 2003 Oral formulation: March 26, 2003 IV formulation (fosaprepitant): January 31, 2008 IV formulation (fosaprepitant): January 31, 2008 Regimen Regimen 125 mg PO day 1, 80 mg PO days 2-3 acute/delayed HEC/MEC 125 mg PO day 1, 80 mg PO days 2-3 acute/delayed HEC/MEC 115 mg IV day 1, 80 mg PO days 2-3 acute/delayed HEC/MEC 115 mg IV day 1, 80 mg PO days 2-3 acute/delayed HEC/MEC

68 Aprepitant in Anthracycline/ Cyclophosphamide Chemotherapy *p<0.05 Complete response (CR): no emesis and no rescue medication. Warr DG et al. J Clin Oncol 2005; 23:2822-2830 * * 76 55 51 69 49 42 0 20 40 60 80 100 Acute: 0-24 (Day 1) Delayed: 24-120 (Days 2-5) Overall: 0-120 (Days 1-5) Complete Response (CR) (% of Patients) Aprepitant (n=433) Standard (n=424) Time (hr) Complete Response (N=857)

69 Aprepitant in Moderately Emetogenic Chemotherapy Warr DG et al. J Clin Oncol 2005; 23:2822-2830 *p<0.001 * * * 88 81 76 77 69 59 0 20 40 60 80 100 Acute: 0-24 (Day 1) Delayed: 24-120 (Days 2-5) Overall: 0-120 (Days 1-5) Emesis-Free (% of Patients) Aprepitant (n=433) Standard (n=424) Time (hr) Percent of Patients with No Emesis

70 Aprepitant in Moderately Emetogenic Chemotherapy No nausea: score <5 mm on 0-100 mm VAS. Warr DG et al. J Clin Oncol 2005; 23:2822-2830; Warr DG et al. Support Care Cancer. 2004. Abstract A027 61 37 33 59 36 33 0 20 40 60 80 100 Acute: 0-24 (Day 1) Delayed: 24-120 (Days 2-5) Overall: 0-120 (Days 1-5) Nausea-Free (% of Patients) Aprepitant (n=430) Standard (n=424) Time (hr) Percent of Patients with No Nausea

71 Phase III Aprepitant Study (801): Multiple-day Ondansetron Aprepitant Control Group Day 4 16 8 Day 1 3212125 3220 Days 2-3 808 16 ODADDA O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo PP P 16 P OO Schmoll et al: Ann Oncol 17:1000-6, 2006 Initial cycle cisplatin > 70 mg/m2Initial cycle cisplatin > 70 mg/m2 445 patients445 patients

72 Phase III Aprepitant Study (801): Multiple-day Ondansetron Identical design to Protocols 052 and 054 except ondansetron dosed days 1-4 Identical design to Protocols 052 and 054 except ondansetron dosed days 1-4 Primary endpoint: complete response on days 1 - 5 after cisplatin Primary endpoint: complete response on days 1 - 5 after cisplatin Aprepitant regimen superior to control regimen of protracted ondansetron and dexamethasone dosing, CR 72% vs. 61% respectively Aprepitant regimen superior to control regimen of protracted ondansetron and dexamethasone dosing, CR 72% vs. 61% respectively Schmoll et al: Ann Oncol 17:1000-6, 2006

73 Perception vs Reality: Emetogenic Chemotherapy Grunberg S. Cancer. 2004;100:2261-2268 Highly Emetogenic Chemotherapy Moderately Emetogenic Chemotherapy

74 Optimizing Supportive Care in Cancer The best treatment of delayed CINV is to prevent it!

75 671 pts receiving doxorubicin-based chemotherapy 671 pts receiving doxorubicin-based chemotherapy All treated w/ 1 st generation 5HT 3 + Dex on Day 1 of CT All treated w/ 1 st generation 5HT 3 + Dex on Day 1 of CT Pts then randomized for days 2 and 3: Pts then randomized for days 2 and 3: Arm 1: Prochlorperazine 10 mg p.o. three times daily (q 8 h) Arm 1: Prochlorperazine 10 mg p.o. three times daily (q 8 h) Arm 2: Any oral 5-HT 3 antiemetic, using standard dosing regimens Arm 2: Any oral 5-HT 3 antiemetic, using standard dosing regimens Arm 3: Prochlorperazine 10 mg p.o. as needed for nausea Arm 3: Prochlorperazine 10 mg p.o. as needed for nausea Rescue medications for control of symptoms were allowed Rescue medications for control of symptoms were allowed Are Oral Followup 5-HT 3 RAs Really Effective for Delayed CINV? Hickock et al ASCO 2005 Final Results URCC-CCOP

76 Oral 5HT 3 RAs: Majority of Patients Experience Nausea Patients randomized for days 2 and 3; rescue medications allowedPatients randomized for days 2 and 3; rescue medications allowed Hickock et al ASCO 2005 Final Results URCC-CCOP * p = 0.002 (overall comparison); p = 0.06 ( q 8 h vs 5-HT 3 ); * p = 0.002 (overall comparison); p = 0.06 (Prochlorperazine q 8 h vs 5-HT 3 ); p = NS ( prn vs 5-HT 3 ) p = NS (Prochlorperazine prn vs 5-HT 3 ) 10 20 30 40 50 60 70 80 90 100 Prochlorperazine q 8h* 3 * 5HT 3 * Prochlorperazine PRN* % Patients with Delayed Nausea 75 83 87

77 Oral 5HT 3 RAs Not Effective for Delayed CINV Vomiting Vomiting Significantly more patients vomited at least once during the delayed period (34%) than on the day of treatment (19%) p <0.01 Significantly more patients vomited at least once during the delayed period (34%) than on the day of treatment (19%) p <0.01 Nausea Nausea Nausea severity was significantly greater during the delayed period than on the day of treatment p < 0.01 Nausea severity was significantly greater during the delayed period than on the day of treatment p < 0.01 More patients getting oral 5HT 3 RAs required rescue medications (45%) than patients getting Compazine ® (27- 30%) p=0.002 More patients getting oral 5HT 3 RAs required rescue medications (45%) than patients getting Compazine ® (27- 30%) p=0.002 Hickock et al ASCO 2005 Final Results URCC-CCOP

78 Meta-Analysis of Efficacy of 5-HT 3 RA in Prevention of Delayed Emesis from Chemotherapy Reviewed 5 studies, 1,716 pts comparing 5-HT 3 RA to placebo, Reviewed 5 studies, 1,716 pts comparing 5-HT 3 RA to placebo, 5 studies, 2,240 pts comparing 5-HT 3 RA + dexamethasone to dexamethasone alone 5 studies, 2,240 pts comparing 5-HT 3 RA + dexamethasone to dexamethasone alone 5-HT 3 RA as monotherapy Absolute RR (95% CI) 8.2% (3.0-13.4) NNT 12.2 Number of doses per protected pt: 74.4 5-HT 3 RA as adjunct to dexamethasone Absolute RR (95% CI) 2.6% (-0.6-5.8) NNT 38.8 Number of doses per protected pt: 423 Geling and Eichler, JCO 2005; 23:1289-1294

79 Breakthrough Medications for CINV Antipsychotics Antipsychotics Cannabinoids Cannabinoids Benzodiazepines Benzodiazepines Phenothiazines Phenothiazines Dopamine Receptor Antagonists Dopamine Receptor Antagonists Consider other classes, alone or in combination

80 Emetic risk group Risk (% of patients) Acute prevention Delayed prevention High and AC combinations >90%5-HT 3 RA + DEX + aprepitant lorazepam H 2 blocker or proton pump inhibitor DEX + aprepitant lorazepam H 2 blocker or proton pump inhibitor NCCN Antiemesis Guidelines v.2.2010: HEC Recommendations DEX, dexamethasone; AC, anthracycline-cyclophosphamide For more information see: http://www.nccn.org

81 Emetic risk group Risk (% of patients) Acute prevention Delayed prevention Moderate30-90% 5-HT 3 RA + DEX lorazepam H 2 blocker or proton pump inhibitor 5-HT 3 RA or DEX lorazepam H 2 blocker or proton pump inhibitor Low10-30% DEX, prochlorperazine, or metoclopramide lorazepam H 2 blocker or proton pump inhibitor No preventive measures Minimal<10%No routine prophylaxisNo preventive measures NCCN Antiemesis Guidelines v.2.2010: MEC Recommendations DEX, dexamethasone For more information see: http://www.nccn.org

82 MASCC / ESMO Committees II-V Combined Statement #3 – Moderate* Prevention of nausea and vomiting following chemotherapy of moderate emetic risk: To prevent acute and delayed vomiting and nausea following chemotherapy of moderate emetic risk, we recommend a regimen of palonosetron and multiday dexamethasone beginning before chemotherapy June 2009 Multinational Association for Supportive Care in Cancer. www.mascc.org * Does not include AC given its higher risk of nausea and vomiting, in which an NK 1 RA is added to Dex + 5HT 3 RA

83 Summary 1 st generation 5HT 3 RAs therapeutically equivalent & major advance in supportive care for control of acute emesis 1 st generation 5HT 3 RAs therapeutically equivalent & major advance in supportive care for control of acute emesis Newer agents include 2 nd generation 5-HT3 RA palonosetron and NK-1 antagonist aprepitant Newer agents include 2 nd generation 5-HT3 RA palonosetron and NK-1 antagonist aprepitant Treatment guidelines have changed Treatment guidelines have changed Degree of nausea incurred has been refined for many agents Degree of nausea incurred has been refined for many agents Delayed CINV recommendations are updated Delayed CINV recommendations are updated Prevention of CINV has improved, but challenges remain Prevention of CINV has improved, but challenges remain Improving detection of CINV, especially after 24 hours Improving detection of CINV, especially after 24 hours Educating patients and oncology healthcare givers Educating patients and oncology healthcare givers The development and evaluation of clinically useful assessment tools The development and evaluation of clinically useful assessment tools Further development of regimens to treat delayed CINV Further development of regimens to treat delayed CINV

84 Risk Stratification Tools to Identify Patients for Primary and Secondary Prevention of VTE in the Setting of Malignancy Screening and VTE Risk Assessment Across the Complex Spectrum of Malignant DisordersWhat Works? What Doesnt? Investigations Innovation Clinical Application Alok A. Khorana, MD, FACP Vice-Chief, Division of Hematology/Oncology Associate Professor of Medicine and Oncology James P. Wilmot Cancer Center University of Rochester Rochester, New York

85 Risk Assessment for VTE In Cancer Patients Risk Assessment for VTE In Cancer Patients Risk Factors for VTE Risk Factors for VTE Biomarkers Biomarkers Risk Assessment Models Risk Assessment Models Implications for Study Design of Prophylaxis Trials Implications for Study Design of Prophylaxis Trials Secondary Prophylaxis Secondary Prophylaxis Optimizing Supportive Care in Cancer

86 Risk Factors for VTE Patient-related factors Older age Older age Race, gender Race, gender Comorbidities Comorbidities Treatment-related factors Hospitalization Hospitalization Chemotherapy Chemotherapy Anti-angiogenics Anti-angiogenics Major surgery Major surgery Erythropoiesis-stimulating agents Erythropoiesis-stimulating agents Transfusions Transfusions Cancer-related factors Site of cancer Site of cancer Advanced stage Advanced stage Initial period after diagnosis Initial period after diagnosis Rao et al., in Cancer-Associated Thrombosis. (Khorana and Francis, Eds) 2007

87 Type of cancer Adjusted OR (95% CI) Hematologic 28 (4-199.7) Lung 22.2 (3.6-136.1) GI 20.3 (4.9-83) Breast 4.9 (2.3-10.5) Prostate 2.2 (0.9-5.4) Blom JW et al. JAMA 2005 VTE and Site of Cancer

88 VTE in the REAL-2 Study: Oxaliplatin vs Cisplatin Starling et al JCO 2009 P=0.0003 HR for cisplatin 0.51; 95% CI, 0.34 to 0.76; P =.001

89 VTE With Bevacizumab Bevacizumab (n=1,196) Control (n=1,083) Nalluri SR, et al. JAMA. 2008;300:2277-2285. RR=1.29 (95% CI, 1.03-1.63) Rate of VTE (%) Rate of VTE (%) 13% 9.9% Bevacizumab (n=3,795) Control (n=3,167) 6.2% 4.2% RR=1.38 (95% CI, 1.12-1.70) All-Grade VTE (6 studies) High-Grade VTE (13 studies)

90 VTE in Myeloma Palumbo et al. JTH 2006: 4 1842-45 Months Cumulative Percentage MPT MPT and Enoxaparin RMP and Aspirin MP 0 5 10 15 20 25 0.20.10

91 Candidate Biomarkers Blood counts Blood counts Platelet count Platelet count Leukocyte count Leukocyte count Hemoglobin Hemoglobin Tissue factor Tissue factor Soluble P-selectin Soluble P-selectin D-dimer D-dimer C-reactive protein C-reactive protein Factor VIII Factor VIII

92 Incidence of VTE By Quartiles Of Pre-Chemotherapy Platelet Count Khorana AA et al. Cancer 2005 0% 1% 2% 3% 4% 5% 6% <250250-300300-350>350 Pre-chemotherapy Platelet Counts (x1000) Incidence Of VTE Over 2.5 Months(%) P =0.005

93 Incidence of VTE by Pre-Chemotherapy Leukocyte Count Khorana AA et al. Blood 2008 0% 1% 2% 3% 4% 5% 6% <4.5 (n=342) 4.5-11 (n=3202) >11 (n=513) Pre-chemotherapy WBC Counts (x1000/mm 3 ) Incidence Of VTE Over 2.4 Months (%) P =0.0008

94 Incidence of VTE by Type of Leukocyte Absolute Neutrophil Count Absolute Monocyte Count P=0.0001 P<0.0001 Connolly et al ISTH 2009 Abs 1573 Proportion with VTE

95 Independent Effect of Platelet & Leukocyte Counts In A Multivariate Analysis Variable Odds Ratio* (95% CI) P value Platelet count >350,000/mm 3 1.8 (1.1-3.2) 0.03 Leukocyte count >11,000/mm 3 2.2 (1.2-4.0) 0.008 *Adjusted for site of cancer, stage, hemoglobin < 10g/dl or use of ESAs and obesity Khorana AA et al. Blood 2008

96 Effect of Leukocyte and Platelet Counts on VTE Risk In the Vienna CATS registry, platelet count >443,000 was associated with VTE (HR3.5) In the Vienna CATS registry, platelet count >443,000 was associated with VTE (HR3.5) Simanek et al, J Thromb Hemost 2009 Simanek et al, J Thromb Hemost 2009 In the RIETE registry, patients with leukocytosis had increased risk of recurrent VTE and death (OR 2.7) In the RIETE registry, patients with leukocytosis had increased risk of recurrent VTE and death (OR 2.7) Trujillo-Santos et al, Thromb Hemost 2008 Trujillo-Santos et al, Thromb Hemost 2008 In the REAL-2 study of advanced GEJ/gastric cancers, leukocytosis was associated with VTE during chemotherapy (HR 2.0) In the REAL-2 study of advanced GEJ/gastric cancers, leukocytosis was associated with VTE during chemotherapy (HR 2.0) Starling et al, J Clin Oncol 2009 Starling et al, J Clin Oncol 2009

97 Mortality by Pre-chemotherapy Leukocyte Count 14.0% (8.9%-21.6%) 4.4% (3.2%-6.1%) P <0.0001 MVA for early mortality: HR 2.0, p = 0.001 Kuderer et al ASH 2008 Connolly et al ISTH 2009 WBC>11x10 9 /L WBC<11x10 9 /L Time (Days) Proportion Died 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 0.200.180.160.140.120.100.080.060.040.020.00

98 Tissue Factor in Cancer: Lack of Standardized Assays Immunohistochemistry of tumor specimens Immunohistochemistry of tumor specimens TF ELISA TF ELISA TF MP procoagulant activity assay TF MP procoagulant activity assay Impedance-based flow cytometry Impedance-based flow cytometry

99 Tissue Factor Expression and VTE Khorana AA, et al. Clin Cancer Res. 2007;13:2870-2875. Rate of VTE (%) P = 0.04

100 Circulating Tissue Factor and VTE Khorana AA, et al. J Thromb Haemost. 2008;6:1983-1985. Plasma TF (pg/mL) P =.04 DVT DVT Fatal PE

101 Cumulative Incidence of VTE for Cancer Patients According to TF–bearing Microparticles Zwicker J I et al. Clin Cancer Res 2009;15:6830-6840 Log Rank P=0.002 Months Cumulative Incidence of VTE 0 5 10 15 20 25 0.60.50.40.30.20.10.0

102 FRAGEM and TF Biomarker Data Maraveyas, et al. Blood Coagul Fibrinolysis 2010 250200150100500-50 ControlDalteparin Boxplot of the percentage change of tissue factor antigen in the sera of pancreatic cancer patients in both the control and dalteparin groups

103 TF and Survival In Pancreatic Cancer Bharthuar et al ASCO GI 2010 Median Survival in pts with TF MP-PCA >2.5 and 2.5 and 2.5 pg/mL vs. 231 days for TF { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/1/678049/slides/slide_103.jpg", "name": "TF and Survival In Pancreatic Cancer Bharthuar et al ASCO GI 2010 Median Survival in pts with TF MP-PCA >2.5 and 2.5 and 2.5 pg/mL vs. 231 days for TF

104 Originally published in Ay C, et al. Blood. 2008;112:2703-2708. Copyright © 2008 American Society of Hematology. Soluble P-Selectin and VTE in Cancer 687 cancer patients followed for median of 415 days687 cancer patients followed for median of 415 days sP-Selectin independent predictor of VTEsP-Selectin independent predictor of VTE Cumulative 6-mo probability of VTE was 12% vs 4% for levels < 75 th percentileCumulative 6-mo probability of VTE was 12% vs 4% for levels < 75 th percentile Observation time (days) Cumulative probability of VTE (%) 0 100 200 300 400 500 600 700 0.250.200.150.100.050.00 > 75 th percentile < 75 th percentile

105 Ay, C. et al. J Clin Oncol; 27:4124-4129 2009 D-dimer, F1/2 and VTE in Cancer Elevated D-d Elevated D-d+F1/2 Elevated F1/2 alone Noneleva Nonelevated D-d and F1/2 Observation Time (Days) Cumulative Risk (probability) 0 100 200 300 400 500 600 700 0.250.200.150.100.05

106 Risk Assessment for VTE In Cancer Patients Risk Assessment for VTE In Cancer Patients Risk Factors Risk Factors Biomarkers Biomarkers Risk Assessment Models Risk Assessment Models Implications for Study Design of Prophylaxis Trials Implications for Study Design of Prophylaxis Trials Optimizing Supportive Care in Cancer

107 VTE in Cancer Outpatients The overwhelming majority of cancer patients are treated in the outpatient/ambulatory setting The overwhelming majority of cancer patients are treated in the outpatient/ambulatory setting Which patients are most at risk? Which patients are most at risk? Which patients will benefit most from prophylaxis? Which patients will benefit most from prophylaxis? How do you define high risk? Level of risk for which prophylaxis is considered acceptable by both patients and oncologists

108 Risk Model Patient Characteristic Score Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate)21 Platelet count > 350,000/mm 31 Hb < 10g/dL or use of ESA1 Leukocyte count > 11,000/mm 31 BMI > 35 kg/m 21 Khorana AA et al. Blood 2008

109 Risk Model Validation Risk Low (0) Intermediate(1-2) High(>3) 0% 1% 2% 3% 4% 5% 6% 7% 8% Rate of VTE over 2.5 mos (%) n=734 n=1627n=340 0.8% 1.8%7.1% Development cohort 0.3% 2.0%6.7% Validation cohort n=374 n=842n=149 Khorana AA et al. Blood 2008

110 Full data available in 839 patients Full data available in 839 patients Median observation time/follow-up: 643 days Median observation time/follow-up: 643 days Score 0 Score 1 Score 2 Score 3 6 months 1.5% 3.8% 9.4% 17.7% Number of PatientsEvents nn (%) Score 39616 (17%) Score 223125 (11%) Score 123314 (6%) Score 02797 (3%) Vienna CATS Validation Ay et al ISTH 2009 Abs

111 Expanded Risk Score with D-Dimer and sP-selectin Expanded Risk Score with D-Dimer and sP-selectin Score 5 Score 4 Score 3 Score 2 Score 1 Score 0 30.3% 1.0% 6 months Number of PatientsEvents n n (%) Score 5 31 9 (29%) Score 4 52 10 (19%) Score 3 137 15 (11%) Score 2 226 11 (5%) Score 1 192 13 (7%) Score 0 201 4 (2%) Ay et al ISTH 2009 Abs

112 Risk Model Is Highly Predictive of Short- Term Overall Survival Low Intermediate High P < 0.0001 Kuderer NM et al. ASH 2008 By VTE Risk Score Categories

113 Progression-Free Survival and Overall Survival by VTE Risk Category Outcomes Outcomes (at 4 months) Low Risk N=1,206 Intermediat e Risk N=2,709 High Risk N=543 All Patients N=4,458 Mortality Risk (%)1.2%5.9%12.7%5.6% HR [+/- CI]1.0 3.56 [1.91- 6.66] 6.89 [3.50- 13.57] - PFS Risk (%)93%82%72%84% HR [+/- CI]1.0 2.77 [1.97- 3.87] 4.27 [2.90-6.27] - Kuderer NM et al. ASH 2008

114 Risk Assessment for VTE In Cancer Patients Risk Assessment for VTE In Cancer Patients Risk Factors Risk Factors Biomarkers Biomarkers Risk Assessment Models Risk Assessment Models Implications for Study Design of Prophylaxis Trials Implications for Study Design of Prophylaxis Trials Optimizing Supportive Care in Cancer

115 Rates of VTE in Recent Prophylaxis Studies N=930N=312N=123N=1165 Agnelli et al Lancet Onc 2009 Palumbo et al ASH 2009 Riess et al ISTH 2009 Maraveyas et al ESMO 2009

116 VTE in Lung Cancer: PROTECHT and TOPIC studies sVTE LMWH sVTE Placebo All VTE LMWH All VTE Placebo PROTECHT3.5%5%4%6.2% TOPIC-23%5.7%4.5%8.3% All3.2%5.5%4.3%7.8% Verso et al. JTH 2010 online Major Bleeding LMWH Major Bleeding Placebo PROTECHT1%0% TOPIC-23.7%2.2% All2.5%1.7% NNT=50 (sVTE) NNT=28 (allVTE) RRR=46% NNH=125

117 International Myeloma Working Group Thromboprophylaxis Recommendations Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide associated thrombosis in myeloma. Leukemia. 2008 Feb;22(2): 414-23. Individual risk factors: obesity (BMI 30), prior VTE, central venous catheter Comorbid risk factors: cardiac disease, chronic renal disease, diabetes, acute infection, immobilization Surgery risk factors: trauma, general surgery or any anesthesia Medications: erythropoietin Myeloma-related risk factors: diagnosis, hyperviscosity Myeloma therapy risk factors: multiagent chemotherapy, doxorubicin, high-dose steroids Patients with 1 VTE risk factor: Aspirin (81-325 mg daily) Patients with 1 VTE risk factor: Aspirin (81-325 mg daily) Patients with 2 VTE risk factors: LMWH (enoxaparin 40 mg/d) or full-dose warfarin, although less existing supporting data for the latter Patients with 2 VTE risk factors: LMWH (enoxaparin 40 mg/d) or full-dose warfarin, although less existing supporting data for the latter Patients receiving thalidomide/lenalidomide concurrently with high-dose dexamethasone or doxorubicin should receive LMWH thromboprophylaxis Patients receiving thalidomide/lenalidomide concurrently with high-dose dexamethasone or doxorubicin should receive LMWH thromboprophylaxis Anticoagulant treatment can continue for 4 to 6 months or longer if additional risk factors are present Anticoagulant treatment can continue for 4 to 6 months or longer if additional risk factors are present

118 PHACS : Prophylaxis in High-risk Ambulatory Cancer Patients Study R Dalteparin prophylaxis x 12 weeks with 4-weekly screening US and start/end CT chest Observe x 12 weeks with 4-weekly screening US and start/end CT chest R01 HL095109-01, 9/2008 Patients deemed high-risk for VTE starting chemotherapy

119 Ongoing Clinical Trials Study (Agent) Criteria for inclusion* NEndpoints PHACS (dalteparin x 12 wks) -Risk score >=3 404 Asymptomatic and symptomatic VTE SAVE-ONCO (semuloparin up to 4 mos) -Lung, bladder, GI, ovary -Metastatic or locally advanced 3200 DVT, PE, VTE- related death MicroTEC (enoxaparin x 6 mos) -Lung, colon, pancreas -Metastatic or unresectable -Elevated TF MPs 227VTE * All studies enroll patients initiating a new chemotherapy regimen

120 Treatment of VTE in Cancer: The CLOT Study Lee, A. Y.Y. et al. N Engl J Med 2003;349:146-153

121 CLOT Study: Reduction in Recurrent VTE 0 5 10 10 15 15 20 20 25 25 Days Post Randomization 0306090120150180210 Probability of Recurrent VTE, % Risk reduction = 52% p-value = 0.0017 Dalteparin OAC Recurrent VTE Lee et.al. N Engl J Med, 2003;349:146

122 Summary of NCCN Guidelines Updates Summary of Major Changes in the 1.2009 Version of the NCCN Venous Thromboembolic Disease Guidelines

123 Changes in 2009 NCCN Guidelines Stage 1 Immediate: Stage 1 Immediate: Concomitant with diagnosis or while diagnosis and risk assessment (heparin phase) changed to Stage 1 Immediate: At diagnosis or during diagnostic evaluation Stage 1 Immediate: Concomitant with diagnosis or while diagnosis and risk assessment (heparin phase) changed to Stage 1 Immediate: At diagnosis or during diagnostic evaluation Low –molecular-weight-heparin: New footnote 6 was added that states, Although each of the low molecular weight heparins (LMWH), have been studies in randomized control trials in cancer patients, dalteparins efficacy in this population is supported by the highest quality evidence and it is the only LMWH approved by the FDA for this indication. Low –molecular-weight-heparin: New footnote 6 was added that states, Although each of the low molecular weight heparins (LMWH), have been studies in randomized control trials in cancer patients, dalteparins efficacy in this population is supported by the highest quality evidence and it is the only LMWH approved by the FDA for this indication. Unfractionated heparin (IV): target aPTT range changed from 2.0-2.9 x control) to 2.0-2.5 x control… (Also for VTE-H) in these patients. Unfractionated heparin (IV): target aPTT range changed from 2.0-2.9 x control) to 2.0-2.5 x control… (Also for VTE-H) in these patients.

124 Changes in 2009 NCCN Guidelines Stage 3 Chronic: Third bullet: Consider indefinite anticoagulation…. changed to Recommend indefinite anticoagulation…. Third bullet: Consider indefinite anticoagulation…. changed to Recommend indefinite anticoagulation…. Fourth bullet: For catheter associated thrombosis, anticoagulate as long as catheter is in place and for at least 3 months after catheter removal. Fourth bullet: For catheter associated thrombosis, anticoagulate as long as catheter is in place and for at least 3 months after catheter removal.

125 Changes in 2009 NCCN Guidelines 6 Although each of the low molecular weight heparins (LMWH) have been studied in randomized controlled trials in cancer patients, dalteparins efficacy in this population is supported by the highest quality evidence and is the only LMWH approved by the FDA for this indication. 6 Although each of the low molecular weight heparins (LMWH) have been studied in randomized controlled trials in cancer patients, dalteparins efficacy in this population is supported by the highest quality evidence and is the only LMWH approved by the FDA for this indication. Lee AYY, Levine MN, Baker RI, Bowden C, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism on patients with cancer. New Eng J Med 2003;349(2): 146-153.

126 (VTE-D): Therapeutic Anticoagulation Treatment for VTE The NCCN panel recommends VTE thromboprophylaxis for all hospitalized patients with cancer who do not have contraindications to such therapy, and the panel also emphasized that an increased level of clinical suspicion of VTE should be maintained for cancer patients. Following hospital discharge, it is recommended that patients at high-risk of VTE (e.g. cancer surgery patients) continue to receive VTE prophylaxis for up to 4 weeks post-operation. Careful evaluation and follow-up of cancer patients in whom VTE is suspected and prompt treatment and follow-up for patients diagnosed with VTE is recommended after the cancer status of the patient is assessed and the risks and benefits of treatment are considered. The NCCN panel recommends VTE thromboprophylaxis for all hospitalized patients with cancer who do not have contraindications to such therapy, and the panel also emphasized that an increased level of clinical suspicion of VTE should be maintained for cancer patients. Following hospital discharge, it is recommended that patients at high-risk of VTE (e.g. cancer surgery patients) continue to receive VTE prophylaxis for up to 4 weeks post-operation. Careful evaluation and follow-up of cancer patients in whom VTE is suspected and prompt treatment and follow-up for patients diagnosed with VTE is recommended after the cancer status of the patient is assessed and the risks and benefits of treatment are considered.

127 Therapeutic Anticoagulation Failure Therapeutic INR Switch to heparin (LMWH preferred) or fondaparinux Increase warfarin dose and treat with parenteral agent until INR target achieved or consider switching to heparin (LMWH preferred) or fondaparinux Patient on warfarin Check INR Sub- therapeutic INR

128 Therapeutic Anticoagulation Failure Therapeutic aPTT Increase dose of heparin or Switch to LMWH or Switch to fondaparinux and Consider placement of IVC filter and Consider HIT Increase dose of heparin to reach therapeutic level Patient on heparin Check aPTT levels Sub- therapeutic aPTT

129 Conclusions Cancer patients are clearly at increased risk for VTE but risk is highly variable Cancer patients are clearly at increased risk for VTE but risk is highly variable TF is an emerging candidate biomarker predictive of VTE and survival TF is an emerging candidate biomarker predictive of VTE and survival ?generalizability to all cancers ?generalizability to all cancers Lack of standardized assay Lack of standardized assay A recently validated risk model can predict risk of VTE (and mortality) using 5 simple clinical and laboratory variables A recently validated risk model can predict risk of VTE (and mortality) using 5 simple clinical and laboratory variables

130 Conclusions Thromboprophylaxis is safe and effective in certain high-risk settings Thromboprophylaxis is safe and effective in certain high-risk settings LMWH-base prophylaxis is guideline-based standard of care LMWH-base prophylaxis is guideline-based standard of care Hospitalized and surgical patients Hospitalized and surgical patients Highly selected cancer outpatients (myeloma, ?pancreas, ?? lung) Highly selected cancer outpatients (myeloma, ?pancreas, ?? lung) Ongoing studies are adopting novel approaches to selecting patients for prophylaxis Ongoing studies are adopting novel approaches to selecting patients for prophylaxis

131 Hematologic Complications of Chemotherapy Balancing Benefits and Risks of Intervention Investigations Innovation Clinical Application Jeffrey Crawford, MD George Barth Geller Professor for Research In Cancer Chief of Division of Medical Oncology Department of Medicine Duke University Medical Center Editor-in-Chief, Supportive Care Oncology Durham, North Carolina

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133 APPRISE – Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs Doctors will be required to register and undergo training on risks and benefits of ESAs in order to continue prescribing. Doctors will be required to register and undergo training on risks and benefits of ESAs in order to continue prescribing. As part of the program, patients will be given a medication guide that outlines the risks and benefits of ESAs. As part of the program, patients will be given a medication guide that outlines the risks and benefits of ESAs. Enrollment of providers begins March 24, 2010. Enrollment of providers begins March 24, 2010.

134 Biological Characteristics of Erythroid Stimulating Agents (ESAs) Epoetin alfa – FDA approval for chemotherapy induced anemia (CIA) - 1993 Epoetin alfa – FDA approval for chemotherapy induced anemia (CIA) - 1993 In vivo half-life 8.5 h (IV) and 16-19 h (SC) in healthy subjects 1 In vivo half-life 8.5 h (IV) and 16-19 h (SC) in healthy subjects 1 Darbepoetin alfa – FDA approval for CIA -2002 Darbepoetin alfa – FDA approval for CIA -2002 Higher proportion of sialic acid-containing carbohydrate, resulting in a 3-fold longer half-life and a 4-fold weaker binding affinity for the EPO receptor 2 Higher proportion of sialic acid-containing carbohydrate, resulting in a 3-fold longer half-life and a 4-fold weaker binding affinity for the EPO receptor 2 Epoetin beta – Approved for CIA in Europe Epoetin beta – Approved for CIA in Europe Less sialated than epoetin alfa and a slightly longer half-life when given SC (~24 h in healthy subjects) 3 Less sialated than epoetin alfa and a slightly longer half-life when given SC (~24 h in healthy subjects) 3 Despite pharmacodynamic differences, efficacy/safety of ESAs in CIA patients appear similar Despite pharmacodynamic differences, efficacy/safety of ESAs in CIA patients appear similar 1 Procrit prescribing information 2002; 2 Egrie JC et al. Oncology (Huntingt) 2002; 3 Halstenson CE et al. Clin Pharmacol Ther 1991

135 Rescue by Transfusion vs an Improvement/ Maintenance Strategy with ESAs: a Conceptual Model ODAC Meeting, 5/20/07 Weeks of Chemotherapy Hb Level Transfusion Rescue Strategy Individualized patient trigger ESA improvement/ maintenance strategy Asymptomatic Zone

136 Modeled Probability of Receiving a Blood Transfusion as a Function of Baseline Hb 4 Phase 3, placebo-controlled CIA Studies, n=1641 (980297, 20000161, 20010145, 20030232) 56789101112131415 Baseline Hb (g/dL) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Predicted Probability TFN PlaceboDA OR=0.41, 95%CI (0.33, 0.51) ODAC Meeting, 5/20/07

137 Summary of HRQoL Data from Systematic Review of Randomized Placebo-controlled Trials QOL Scale (ESA vs control) Mean Change P-value FACT-F (5 studies, 1418 max pts) 3.6 vs -0.8 <0.001 LASA (4 studies, 1076 max pts) 4.8 vs -3.6 <0.001 Favors Control Favors EPO/DARB Source Difference in Standardized Mean FACT-F Values (95% CI) P Difference in Standardized Means (95% CI) 0.000.50-0.501.00 Littlewood 0.23 (-0.02 to 0.48) 0.076 Boogaerts 0.11 (-0.16 to 0.38) 0.428 Iconomou 0.44 (0.07 to 0.82) 0.021 Witzig 0.11 (-0.12 to 0.33) 0.360 Random-effects model 0.22 (0.10 to 0.36) 0.001 Fixed-effects model 0.22 (0.10 to 0.34) 0.000 Savonije 0.42 (0.12 to 0.71) 0.005 1 Cella D et al, J Pain Symptom Manage. 2002;24(6):547-561 Ross, S et al. Clin Ther. 2006; 28(6): 1-31 3-point difference in FACT-F defined as clinically important 1 3-point difference in FACT-F defined as clinically important 1

138 Higher Hb is Associated with Higher HRQoL Crawford J, et al. Cancer. 2002;95(4):888-895. 45 50 55 60 65 7891011121314 Hb level (g/dL) LASA Overall QOL Score 0 1 study (n=1580)

139 Across all studies, recommendation for transfusion was Hb <8 g/dL (or signs & symptoms of anemia) 9.2% When and Why do Physicians Transfuse? Data from 5 Phase 3 CIA Darbepoetin alfa Studies Prophylactic (1.2%) Medically Indicated (4.4%) 8 – 10 g/dL 54.3% <8 g/dL 35.9% Reasons Given for Transfusion (n=2227 CRF responses ) 10-12 g/dL 12 g/dL (0.7%)12 g/dL (0.7%) Hb at Time of Transfusion (n=2185 transfusion episodes) Hb Trigger 34.7% Therapeutic 46.0% Other 13.7% (n=2286)

140 Common Risks of Blood Product Infusions Upile, T, et al. Clinical Advances in Hematology & Oncology Volume 7, Issue 10 October 2009 Some of the Risks of Transfusion Febrile nonhemolytic Febrile nonhemolytic Acute transfusion reaction from mismatch Acute transfusion reaction from mismatch Acute hemolytic Acute hemolytic Delayed hemolytic Delayed hemolytic Allergic Allergic Anaphylactic Anaphylactic Human leukocyte antigen sensitization Human leukocyte antigen sensitization Red blood cell allosensitization Red blood cell allosensitization Graft-versus-host disease Graft-versus-host disease Clotting disturbances Clotting disturbances Electrolyte disturbances Electrolyte disturbances Volume overload in the young and elderly Volume overload in the young and elderly Transfusion-related acute lung injury Transfusion-related acute lung injury Peri-operative infection susceptibility Peri-operative infection susceptibility Blood borne infectoons – viral (HIV, hepatitis), bacterial, prions, parasites (malaria) Blood borne infectoons – viral (HIV, hepatitis), bacterial, prions, parasites (malaria) Increased tumor recurrence from peri- operative transfusion Increased tumor recurrence from peri- operative transfusion Worsensed cancer prognosis from peri-operative transfusion Worsensed cancer prognosis from peri-operative transfusion

141 Background: Erythropoiesis-stimulating agents (erythropoietin and darbepoietin) have been approved to reduce the number of blood transfusions required during chemotherapy; however, concerns about the risks of venous thromboembolism and mortality exist. Methods: Study of patients aged 65 years or older in the Surveillance, Epidemiology and End Results-Medicare database; with colon, non-small cell lung or breast cancer or with diffuse large B-cell lymphoma from 1991 through 2001; and who received chemotherapy. The main outcome measures were claims for use of an erythropoiesis-stimulating agent, blood transfusion, venous thromboembolism (i.e., deep vein thrombosis or pulmonary embolism), and overall survival. Patterns of Use and Risks Associated with Erythropoiesis- Stimulating Agents Among Medicare Patients with Cancer Hershman, D. JNCI 101 (23):1-9, 2009

142 Results 56,210 patients received chemotherapy 56,210 patients received chemotherapy 15,346 (27%) received an ESA 15,346 (27%) received an ESA 22% received transfusions 22% received transfusions 14.3% of ESA patients had VTE 14.3% of ESA patients had VTE 9.8% of nonESA patients had VTE 9.8% of nonESA patients had VTE ESA – erythroid stimulating agent VTE – venous thromboembolism Patterns of Use and Risks of ESAs

143 Hershman, D. JNCI 101 (23):1-9, 2009 Trends in ESA and Transfusion Use in All Patients % of Patients Receiving ESA % of Patients Receiving Blood Transfusion 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 706050403020100 % of Patients

144 Overall Survival Hershman, D. JNCI 101 (23):1-9, 2009 Proportion alive Time to death (years) EAS use ESA non-use 0 2 4 6 8 10 1.000.750.500.25

145 Khorana, Francis, Blumberg, Culakova, Refaai, Lyman. Arch Intern Med 2008;168:2377-2381. Blood Transfusions, Thrombosis and Mortality in Hospitalized Patients with Cancer Population 504,208 pts with cancer admitted between 1995- 2003 at 60 medical centers

146 Blood Transfusions, Thrombosis and Mortality in Hospitalized Patients with Cancer Khorana, Francis, Blumberg, Culakova, Refaai, Lyman. Arch Intern Med 2008;168:2377-2381.

147 Feinberg, B. Community Oncology, June 2009, 257-261 Community Oncology ESA Experience Timepoint Pre-NCD cohort Post NCD cohort P Value Number Hb level (SD) Number Baseline225 10.7 (0.9) 144 9.7 (0.8) <0.0001 Week 4206 11.0 (1.2) 138 10.2 (1.2) <0.0001 Week 8138 11.2 (1.3) 102 10.3 (1.1) <0.0001 Mean hemoglobin levels at different time points

148 Feinberg, B. Community Oncology, June 2009, 257-261 Community Oncology ESA Experience

149 Focused ESA Safety Data ENHANCE 2003 ENHANCE 2003 DAHANCA 12/06 DAHANCA 12/06 EPO-CAN-20 2007 EPO-CAN-20 2007 BEST 2005 BEST 2005 20000161 4/05, 4/07 20000161 4/05, 4/07 20010103 1/07 20010103 1/07 GOG-191 2007 GOG-191 2007 PREPARE 11/07 PREPARE 11/07 Survival, Tumor Progression, TVE * *8 trials selected by FDA for label inclusion out of 57 total, publication date, = date data reported to FDA Lancet 2003;632:1255-60. J Natl Cancer Inst 2006:98:708-14. J Clin Oncol 2005;23:5960-72. J Natl Cancer Inst 2005;97:489-98. J Clin Oncol 2007;25:1027- 32. http://www.fda.gov (accessed 3/20/08). JAMA 2008;299:914-24

150 EPO CAN-20 300 patients not on active treatment 300 patients not on active treatment Primary endpoint: QOL at 12 weeks Primary endpoint: QOL at 12 weeks Target hemoglobin 12-14 g/dL Target hemoglobin 12-14 g/dL Unplanned safety analysis 70 patients Unplanned safety analysis 70 patients Result : Survival decrement HR 1.84 Result : Survival decrement HR 1.84

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152 Wright J et al. JCO 2007 Mar 20;25(9):1027-32. Epub 2007 Feb 20 EPO-CAN-20 (Advanced NSCLC) Cause of Death Placebo (34 deaths) Epoetin Alfa (32 deaths) No. of Patients % % Progressive lung cancer3191.22887.5 Pneumonia12.913.1 Myocardial infarction12.91 Renal failure12.9- Hyponatremia-13.1 Bowel perforation-13.1 Unknown cause-13.1 Reported Causes of Death

153 Meta-analysis: Lung Cancer Trials Study Name Study Name No. of Deaths/Total Odds Ratio 95% CI ESAControl Lower Limit Upper Limit AoC NSCLC Wright 2007 (EPO-CAN-20)32/3334/372.820.2828.56 CIA NSCLC EPO-GER-22146/195159/1900.580.350.96 Vansteenkiste 2002 NSCLC72/10882/1140.780.441.38 Milroy 2003 (INT-49)136/214126/2101.160.791.72 Random Effects Model: NSCLC Random Effects Model: NSCLC0.830.541.27 CIA SCLC Vansteenkiste 2002 SCLC28/4737/450.320.120.83 Pirker 2007 (AMG 20010145)241/298251/2980.790.521.21 EPO-CAN-1528/5229/520.930.432.00 Thatcher 19997/863/441.210.304.93 Grote 2005 (N93-004)100/109101/1151.540.643.72 Random Effects Model: SCLC Random Effects Model: SCLC0.830.531.28 0.10.20.512510 Favors ESAFavors Control ODAC 2008 Supplement

154 Cochrane Meta Analysis – Summary of Results Study population N Hazard Ratio (95% CI) P-value On-study mortality 1 All cancer pts 13, 933 1.17 (1.06, 1.30) 0.002 Chemotherapy trials 10, 441 1.10 (0.98, 1.24) 0.12 Overall survival 2 All cancer pts 13, 933 1.06 (1.00, 1.12) 0.05 Chemotherapy trials 10, 441 1.04 (0.97, 1.11) 0.26 1 deaths during active study phase; 2 deaths during longest follow-up available Bohlius et al, (Lancet 2009)

155 Meta Analysis of Disease Progression Glaspy, Crawford, Vansteenkiste, Henry, Rao, Bowers, Berlin, Tomita, Bridges, Ludwig British Journal of Cancer 102, 301-315 (5 January 2010)

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157

158 A Randomized, Double-Blind, Placebo- Controlled Study to Evaluate the Long-Term Safety and Efficacy of Darbepoetin Alfa Administered at 500 µg Once-Every-3-Weeks in Anemic Subjects With Advanced Stage Non- Small Cell Lung Cancer Receiving Multi-Cycle Chemotherapy Clinical Trials Identifier NCT00858364

159 Sponsor Amgen Inc. Sponsor Amgen Inc. General Design Randomized, double-blind, placebo-controlled Phase 3, non-inferiority study intended to evaluate the long term safety and efficacy of darbepoetin alfa General Design Randomized, double-blind, placebo-controlled Phase 3, non-inferiority study intended to evaluate the long term safety and efficacy of darbepoetin alfa Intervention Aranesp or placebo administered Q3W (2:1 randomization) Intervention Aranesp or placebo administered Q3W (2:1 randomization) Study population Subjects with advanced stage non-small cell lung cancer and anemia (Hb <=11 g/dL) receiving or about to receive first-line chemotherapy Study population Subjects with advanced stage non-small cell lung cancer and anemia (Hb <=11 g/dL) receiving or about to receive first-line chemotherapy Sample size 3000 subjects Sample size 3000 subjects

160 Clinical Trials Identifier NCT00858364 Primary outcome measure Primary outcome measure Overall Survival (OS) Overall Survival (OS) Secondary outcome measures Secondary outcome measures Progression-free survival (PFS) Progression-free survival (PFS) Objective tumor response Objective tumor response Incidence of at least 1 RBC transfusion or hemoglobin less than or equal to 8.0 g/dL from week 5 (day 29) to end of efficacy treatment period Incidence of at least 1 RBC transfusion or hemoglobin less than or equal to 8.0 g/dL from week 5 (day 29) to end of efficacy treatment period Incidence of at least 1 RBC transfusion or hemoglobin less than or equal to 8.0 g/dL from study day 1 to end of treatment period Incidence of at least 1 RBC transfusion or hemoglobin less than or equal to 8.0 g/dL from study day 1 to end of treatment period Incidence of neutralizing antibody formation to darbepoetin alfa Incidence of neutralizing antibody formation to darbepoetin alfa Change in hemoglobin from baseline to end of efficacy treatment period Change in hemoglobin from baseline to end of efficacy treatment period Incidence of adverse events (AEs) such as thrombovascular events (TVE), venous thromboembolic events (VTE), and AEs associated with RBC transfusions Incidence of adverse events (AEs) such as thrombovascular events (TVE), venous thromboembolic events (VTE), and AEs associated with RBC transfusions

161 Study Status as of June 2010 Study start date: June 2009 Study start date: June 2009 Currently recruiting subjects in North America, Europe, Asia and Latin America Currently recruiting subjects in North America, Europe, Asia and Latin America Study sites planned for a total of approximately 400 sites in over 30 countries Study sites planned for a total of approximately 400 sites in over 30 countries

162 Chemotherapy-induced Neutropenia and Its Complications Kuderer NM et al. Cancer 2006;106:2258–2266 Chirivella I et al. J Clin Oncol 2006;24;abstract 668 Bosly A et al. Ann Hematol 2008;87:277-283 Myelosuppressive chemotherapy Febrile neutropenia (FN)Chemotherapy dose delays and dose reductions Decreased relative dose intensity (RDI) Complicated life-threatening infection and prolonged hospitalization Neutropenia Reduced survival

163 Risk of FN Increases with Duration of Severe Neutropenia* Adapted from Blackwell S, Crawford J. In: Morstyn G, Dexter TM. Filgrastim; (r-metHuG-CSF) in Clinical Practice. New York: Marcel Dekker; 1994 p 103–116 Crawford J et al. N Engl J Med 1991;325:164–170 Days of severe neutropenia Predicted probability of FN (%) (temperature >38.2 C and ANC 38.2 C and ANC <0.5 x 10 9 /L) 100 80 60 40 20 0 01234567890123456789 *ANC <0.5 x 10 9 /L

164 Most Initial FN Events Occur During the First Cycle of Chemotherapy Adapted from Crawford J et al. JNCCN 2008;6:109–118 Proportion of first FN events in cycle 1 by cancer type Events in cycle 1 (%) FN events documented in 287/2692 (10.7%) of adult cancer patients during the 1 st three cycles of chemotherapy NSCLC – non-small cell lung cancer; SCLC – small cell lung cancer; NHL - non-Hodgkins lymphoma; HD – Hodgkins disease

165 Death as a Result of FN Hospitalization Kuderer NM et al. Cancer 2006;106:2258–2266 OverallNo majorOne major>one major (n=41,779)comorbiditycomorbiditycomorbidity (n=21,386)(n=12,398)(n=7,995) 25 20 15 10 5 0 9.5 2.6 10.3 21.4 Mortality following hospital admission of adult cancer patients with FN* Inpatient mortality (percent patients admitted for FN) *Data based on a single admission per patient

166 Clinical Consequences of Neutropenia and Febrile Neutropenia Reduced RDI resulted in lower OS in patients with DLBCL receiving CHOP-21 chemotherapy 2Reduced RDI resulted in lower OS in patients with DLBCL receiving CHOP-21 chemotherapy 2 Reduced RDI resulted in lower OS in ESBC receiving anthracycline- containing chemotherapy 1Reduced RDI resulted in lower OS in ESBC receiving anthracycline- containing chemotherapy 1 Estimated Survival 012345678 Years Post Chemotherapy 0.0 0.2 0.4 0.6 0.8 1.0 85% 86–90% >90% ARDI OS, overall survival; ARDI, average relative dose intensity Suboptimal chemotherapy reduces survival Suboptimal chemotherapy reduces survival 1 Chirivella I, et al. Breast Cancer Res Treat 2009;114(3):479-484 2 Bosly A, et al. Ann Hematol 2008; 87:277–283 Disease-Free Survival (years) Cum Proportion Survival RDI < 85% 85% < 85%, censored 85%, censored 1.0 0.8 0.6 0.4 0.2 0.0 0 24 6810 + +++ + + + + + +

167 Myelosuppression Predicts for Survival Benefit of Adjuvant Chemotherapy in Breast Cancer Patients Mayers C, Tannock IF. Cancer 2001;91:2253 Lyman G. JNCCN 2009;7:99-108

168 Analysis of 4626 Hodgkins Lymphoma patients on German HDSG Trials 1988-1998 Klimm B. J Clin Oncol 2005;23:8003-8011 Hypothesis: The better outcome of female HL patients is due to greater systemic chemotherapy exposure. ResultsFemaleMale P value P value G3/4 leukopenia69.9052.20p<0.0001 FFTF at 66 months81%74% Neutropenia as a Pharmacodynamic Endpoint of Clinical Benefit

169 No neutropenia Mild neutropenia Severe neutropenia No neutropenia208150102684329201310 Mild neutropenia1389874543833211311 Severe neutropenia906950282114 84 104 0.8 0.6 0.4 0.2 0 917865523926130 1.0 Time From Landmark Day (Weeks) Probability of Survival Patients at Risk Log-rank P=0.0118 (stratified by treatment) Overall Survival by Grade of Chemotherapy-Induced Neutropenia for Advanced NSCLC Patients Di Maio M et al. Lancet Oncol 2005;6:669

170 Strategies For Management of Chemotherapy-Induced Neutropenia Prevention Prevention Chemotherapy Dose reduction/delay Chemotherapy Dose reduction/delay Myeloid growth factors Myeloid growth factors G-CSF (filgrastim, lenograstim) G-CSF (filgrastim, lenograstim) GM-CSF (sargramostim, molgramostim) GM-CSF (sargramostim, molgramostim) Pegfilgrastim Pegfilgrastim - Antibiotics Treatment Treatment Observation if afebrile Observation if afebrile Antibiotics Antibiotics Myeloid growth factors (limited benefit) Myeloid growth factors (limited benefit)

171 Meta-Analysis: Antibiotic Prophylaxis Reduces Mortality in Neutropenic Patients 95 randomized controlled trials, 1973-2004 (n=9283) 95 randomized controlled trials, 1973-2004 (n=9283) 79 studies were on inpatients with hematologic malignancies and/or PSCT 79 studies were on inpatients with hematologic malignancies and/or PSCT 52 trials involved quinolone prophylaxis 52 trials involved quinolone prophylaxis 7 trials included CSFs 7 trials included CSFs Gafter-Gvili, A. Ann Intern Med. 2005:142(12):979-995

172 Meta-Analysis: Antibiotic Prophylaxis Reduces Mortality in Neutropenic Patients Results of Prophylaxis with Fluoroquinolones Outcome Relative Risk (CI) Relative Risk (CI) Fever.67 (.56-.81) Documented Infection.50 (.35-.70) Infection Related Death.38 (.21-.69) All cause mortality.52 (.35-.77) Adverse Events1.30 (.61-2.76) Development of resistant bacteria1.69 (.73-3.92) Gafter-Gvili, A. Ann Intern Med. 2005:142(12):979-995

173 Meta-Analysis: Antibiotic Prophylaxis Reduces Mortality in Neutropenic Patients Insufficient number of outpatient solid tumor/chemotherapy patients to be applicable Insufficient number of outpatient solid tumor/chemotherapy patients to be applicable Not recommended by IDSA guidelines because of concerns regarding antibiotic resistance Not recommended by IDSA guidelines because of concerns regarding antibiotic resistance Routine application limited to high risk inpatients with hematologic malignancies/stem cell transplants Routine application limited to high risk inpatients with hematologic malignancies/stem cell transplants Limitations of Prophylactic Antibiotics Gafter-Gvili, A. Ann Intern Med. 2005:142(12):979-995 Gafter-Gvili, A. Ann Intern Med. 2005:142(12):979-995

174 Role of Prophylactic Antibiotics in the Prevention of Infection after Chemotherapy SIGNIFICANT Trial Solid tumor/lymphoma patients (n-1565) receiving standard dose multicycle chemotherapy Solid tumor/lymphoma patients (n-1565) receiving standard dose multicycle chemotherapy Randomized to levofloxacin 500 mg qd x 7 day vs placebo Randomized to levofloxacin 500 mg qd x 7 day vs placebo Primary endpoint – reduction in febrile episodes attributed to infection Primary endpoint – reduction in febrile episodes attributed to infection SIGNIFICANT Trial. Cullen, et al. NEJM 2005; 353:988-998 SIGNIFICANT Trial. Cullen, et al. NEJM 2005; 353:988-998

175 Role of Prophylactic Antibiotics in the Prevention of Infection after Chemotherapy OutcomeLevofloxacinPlacebo RR Reduction (95% CI) Number Needed to Treat (CI) In first cycle Febrile episode3.57.9 56 (32-72) 23 (15-46) Probable infection1419 28 (10-43) 19 (11-58) Hospitalization6.710 36 (10-54) 28 (16-109) In any Cycle Febrile episode1115 29 (8.1-45) 23 (13-91) Probable infection3441 18 (6.3-27) 14 (9-410 Hospitalization1622 27 (9.9-410) 18 (11-52) Severe Infection or Death12 50 (-14 to 78) Not significant SIGNIFICANT Trial Values are percentages unless otherwise specified. Moon, S. et al. Supportive Cancer Therapy, 2006 3(4):207-13

176 Primary Prophylaxis with MGFs Reduces Febrile Neutropenia RR = 0.538 95% CI (0.430-0.673) 46% reduction in risk of febrile neutropenia with primary prophylaxis Kuderer NM et al. J Clin Oncol. 2007;25:3158-3167

177 Primary Prophylaxis with MGFs Reduces Infection-related Mortality RR = 0.552 95% CI (0.338-0.902) 45% reduction in risk of infection- related mortality with primary prophylaxis Kuderer NM et al. J Clin Oncol. 2007;25:3158-3167

178 Primary Prophylaxis with MGFs Reduces Early Mortality RR = 0.599 95% CI (0.4330.830) 40% reduction in risk of early mortality with primary prophylaxis Kuderer NM et al. J Clin Oncol. 2007;25:3158-3167

179 What impact does pegfilgrastim have on early, all- cause mortality in patients receiving chemotherapy? Design Inclusion criteria Patient population Endpoints Time to febrile neutropenia, progression-free and overall survival Lyman GH, et al. J Clin Oncol 2008; May 20 suppl:6552 Community-based, prospective observational study Eligibility was not restricted on the basis of older age or major co-morbidities; 3 month life expectancy and 4 cycles chemotherapy planned 4,458 consecutive adult patients initiating chemotherapy at 115 U.S. practice sites

180 Pegfilgrastim Primary Prophylaxis Demonstrates Significant Impact on Early Overall and Progression-free Survival Lyman GH, et al. J Clin Oncol 2008; May 20 suppl:6552 010203040 50 60708090 0.75 0.80 0.85 0.90 0.95 1.00 Survival Time (Days) Hazard Ratio = 0.412 [0.210,0.211] P = 0.010 Pegfilgrastim Primary Prophylaxis No Pegfilgrastim Prophylaxis 90 0 10203040 50 607080 0.75 0.80 0.85 0.90 0.95 1.00 Progression Free Survival Time (Days) Hazard Ratio = 0.554 [0.453,0.923] P = 0.015 Pegfilgrastim Primary Prophylaxis No Pegfilgrastim Prophylaxis

181 Impact of Pegfilgrastim on Overall and Disease Free Survival was Apparent in Major Prognostic Subgroups Lyman GH, et al. J Clin Oncol 2008; May 20 suppl:6552 C Pegfilgrastim No Pegfilgrastim Hazard Ratio = 0.383 [0.192,0.761] P = 0.006 ECOG 1 N = 2,024 0102030405060708090 0.75 0.80 0.85 0.90 0.95 1.00 Survival Time (Days) D Hazard Ratio = 0.274 [0.110,0.684] P = 0.006 Liver Dysfunction N = 1,045 Pegfilgrastim No Pegfilgrastim 0102030405060708090 0.75 0.80 0.85 0.90 0.95 1.00 Survival Time (Days) Hazard Ratio = 0.310 [0.133,0.723] P = 0.007 Planned RDI 85% N = 2,623 Pegfilgrastim No Pegfilgrastim A 0102030405060708090 0.75 0.80 0.85 0.90 0.95 1.00 Survival Time (Days) B Hazard Ratio = 0.346 [0.125,0.954] P = 0.040 Pegfilgrastim No Pegfilgrastim Lung Cancer N = 907 0102030405060708090 0.75 0.80 0.85 0.90 0.95 1.00 Survival Time (Days)

182 Risk of Mortality in Patients with Cancer Experiencing Febrile Neutropenia Barron, R. Abstract 9561, ASCO 2009 Kaplan-Meier Survival Curve for Early Mortality Length of Follow-up in Months Non febrile neutropenia patients Febrile neutropenia patients 0 2 4 6 8 10 12 Survival 1.000.990.980.970.960.95 Log rank test: Chi2(1)=4.79, p=0.0287

183 Risk of Mortality in Patients with Cancer Experiencing Febrile Neutropenia Barron, R. Abstract 9561, ASCO 2009 Kaplan-Meier Survival Curve for Overall Mortality Log rank test: Chi2(1)=23.15, p<0.0001 Length of Follow-up in Months Non febrile neutropenia patients Febrile neutropenia patients Survival 1.000.950.900.850.800.75 010203040506070

184 Guidelines at a Glance: Primary Prophylactic CSF Administration Neutropenic Event Risk EORTC2006ASCO 2006 2006NCCN2007 Moderate to High Use CSF 20% Use CSF ~ 20% Use CSF > 20% Intermediate Consider CSF 10 - 20% with risk factors Recommend < 20% (with risk factors) Consider CSF 10 - 20% with risk factors Low CSF is not recommended < 10% Not specified CSF is not recommended for most patients < 10% Risk Factor Assessment++++++++ NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors. v.1.2007. Available at: http://www.nccn.org, accessed May 23, 2007 Smith TJ, et al. J Clin Oncol. 2006;24(19):3187-3205 Aapro MS, et al. European J Cancer. 2006;42:2433-2453

185 NCCN Practice Guidelines in Oncology v.1.2010 Myeloid Growth Factors Patient Risk Factors for Developing Febrile Neutropenia In addition to the risk of the chemotherapy regimen and the specific malignancy being treated, these factors need to be considered when evaluating a patients overall risk for febrile neutropenia. Older patient, notably patients age 65 and older (see NCCN Senior Adult Oncology Guidelines) Older patient, notably patients age 65 and older (see NCCN Senior Adult Oncology Guidelines) Previous chemotherapy or radiation therapy Previous chemotherapy or radiation therapy Pre-existing neutropenia or bone marrow involvment with tumor Pre-existing neutropenia or bone marrow involvment with tumor Pre-existing conditions Pre-existing conditions Neutropenia Neutropenia Infection/open wounds Infection/open wounds Recent surgery Recent surgery Poor performance status Poor performance status Poor renal function Poor renal function Liver dysfunction, most notably elevated bilirubin Liver dysfunction, most notably elevated bilirubin

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188 Adverse Events Associated with Myeloid Growth Factors Common Bone/musculoskeletal pain (25-50%) Less Common Splenomegaly (3%) Headache, nausea Fever (1%) Rare Allergic reaction Sweets syndrome Controversial Acute myeloid leukemia – epidemiologic association, but not confirmed in randomized prospective trials Myeloid Growth Factor Guidelines v.1.2008, www.NCCN.org Filgrastim/Pegfilgrastim

189 Relative Risk for AML/MDS by Cancer Type Acute Myeloid Leukemia or Myelodysplastic Syndrome and Overall Mortality with Chemotherapy and Granulocyte Colony-Stimulating Factor Meta-Analysis of Randomized Controlled Trials Lyman, G. ASCO Abstract 9524, 2009

190 AML/MDS by Planned CT Regimen Category Lyman, G. ASCO Abstract 9524, 2009 Acute Myeloid Leukemia or Myelodysplastic Syndrome and Overall Mortality with Chemotherapy and Granulocyte Colony-Stimulating Factor Meta-Analysis of Randomized Controlled Trials

191 All-Cause Mortality by Tumor Type Lyman, G. ASCO Abstract 9524, 2009 Acute Myeloid Leukemia or Myelodysplastic Syndrome and Overall Mortality with Chemotherapy and Granulocyte Colony-Stimulating Factor Meta-Analysis of Randomized Controlled Trials

192 All-Cause Mortality by Regimen Category Lyman, G. ASCO Abstract 9524, 2009 Acute Myeloid Leukemia or Myelodysplastic Syndrome and Overall Mortality with Chemotherapy and Granulocyte Colony-Stimulating Factor Meta-Analysis of Randomized Controlled Trials

193 Neutropenia / Management Summary Neutropenia is the major risk factor for fever and infection, as well as reduced chemotherapy dose delivery; both of which can be associated with reduced survival of the cancer patient. Neutropenia is the major risk factor for fever and infection, as well as reduced chemotherapy dose delivery; both of which can be associated with reduced survival of the cancer patient. In patients at significant risk of febrile neutropenia (>20%) prophylactic CSFs are warranted in the first and all subsequent cycles of chemotherapy. In patients at significant risk of febrile neutropenia (>20%) prophylactic CSFs are warranted in the first and all subsequent cycles of chemotherapy. Prophylactic antibiotics may add to the benefit of CSFs in selected settings, but cannot replace them. Prophylactic antibiotics may add to the benefit of CSFs in selected settings, but cannot replace them. Further prospective studies evaluating chemotherapy RDI and outcomes in cancer patients are needed. Further prospective studies evaluating chemotherapy RDI and outcomes in cancer patients are needed.


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