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New Dimensions and Landmark Advances in Supportive Care for the Cancer Patient Optimizing Prevention and Management of Drug-Related Side Effects and Thrombotic.

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Presentation on theme: "New Dimensions and Landmark Advances in Supportive Care for the Cancer Patient Optimizing Prevention and Management of Drug-Related Side Effects and Thrombotic."— Presentation transcript:

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2 New Dimensions and Landmark Advances in Supportive Care for the Cancer Patient Optimizing Prevention and Management of Drug-Related Side Effects and Thrombotic Complications in the Setting of Malignancy New Dimensions and Landmark Advances in Supportive Care for the Cancer Patient Optimizing Prevention and Management of Drug-Related Side Effects and Thrombotic Complications in the Setting of Malignancy Program Chairman Craig M. Kessler, MD Professor of Medicine and Pathology Georgetown University Medical Center Director of the Division of Coagulation Department of Laboratory Medicine Lombardi Comprehensive Cancer Center Washington, DC Innovation Investigation Application Steven Grunberg, MD Program Co-Chairman Professor of Medicine University of Vermont Burlington, Vermont

3 CME-accredited symposium jointly sponsored by University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Eisai, Inc. Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview

4 Program Educational Objectives As a result of this session, participants will: Learn about the prevalence and incidence of CINV in the setting of tumors across the cancer treatment and disease state spectrum. Learn about causes and treatment approaches to peripheral neuropathy. Learn to risk stratify cancer patients, evaluate their likelihood for incurring DVT, and learn how to assess and implement prophylaxis measures that can reduce the incidence of DVT in these patient populations. Learn how to apply current guidelines for pharmacologic prophylaxis of DVT issued by national professional organizations (ASCO, NCCN, ACCP, ASHP) in at-risk patients with cancer, medical and surgical conditions. Learn how to employ a cancer supportive care team approach, with oncologists, oncology nurses, and supportive care personnel to optimize management of CINV in both acute and delayed phases. As a result of this session, participants will: Learn about the prevalence and incidence of CINV in the setting of tumors across the cancer treatment and disease state spectrum. Learn about causes and treatment approaches to peripheral neuropathy. Learn to risk stratify cancer patients, evaluate their likelihood for incurring DVT, and learn how to assess and implement prophylaxis measures that can reduce the incidence of DVT in these patient populations. Learn how to apply current guidelines for pharmacologic prophylaxis of DVT issued by national professional organizations (ASCO, NCCN, ACCP, ASHP) in at-risk patients with cancer, medical and surgical conditions. Learn how to employ a cancer supportive care team approach, with oncologists, oncology nurses, and supportive care personnel to optimize management of CINV in both acute and delayed phases.

5 Program Faculty Craig M. Kessler, MD Program Co-Chairman Professor of Medicine and Pathology Georgetown University Medical Center Lombardi Comprehensive Cancer Center Chief, Division of Coagulation Washington, DC Charles Loprinzi, MD Professor of Oncology Director, NCCTG Cancer Control Program Co-Director Mayo Cancer Center Cancer Prevention and Control Program Mayo Clinic Rochester, MN Prevention and Control Program Mayo Clinic Rochester, MN Steven Grunberg, MD Program Co-Chairman Professor of Medicine University of Vermont Burlington, Vermont

6 Faculty COI Financial Disclosures Craig M. Kessler, MD - Co-Chairman Grant/Research Support: GlaxoSmithKline Consultant: Sanofi-Aventis, Eisai Pharmaceuticals Speakers Bureau: Sanofi-Aventis, GlaxoSmithKline Steven Grunberg, MD - Co-Chairman Grant/Research: Merck Consultant: Merck, GlaxoSmithKline Speakers Bureau: Merck, Eisai Charles Loprinzi, MD Charles Loprinzi, MD No information to disclose

7 Global Care of the Cancer Patient Symptom Management Steven Grunberg, MD Program Co-Chairman Professor of Medicine University of Vermont Burlington, Vermont Innovation Investigation Application

8 Symptom Management Interchangeable terms that do not mean the same thing Interchangeable terms that do not mean the same thing Symptom management Symptom management Supportive care Supportive care Palliative care Palliative care Symptom management is an integral part of cancer care throughout the disease course, not just at end- of-life Symptom management is an integral part of cancer care throughout the disease course, not just at end- of-life

9 Symptom Management and Palliative Care Palliative care concentrates on disease-related and late treatment-related symptom management. Observations and research are not complicated by acute treatment- related symptoms. Palliative care concentrates on disease-related and late treatment-related symptom management. Observations and research are not complicated by acute treatment- related symptoms. Symptom management concentrates on disease-related and acute treatment-related symptom management. Observations and research are not complicated by rapidly declining performance status. Symptom management concentrates on disease-related and acute treatment-related symptom management. Observations and research are not complicated by rapidly declining performance status. Survivorship concentrates on late treatment-related symptom management. Observations and research are not complicated by acute treatment or disease effects. Survivorship concentrates on late treatment-related symptom management. Observations and research are not complicated by acute treatment or disease effects. All of these areas can learn from each other. All of these areas can learn from each other.

10 Symptoms and Prognosis The sicker they get, the better they do The sicker they get, the better they do Older philosophy that assumes a lack of effective symptom management. May apply when a new treatment is devised since non-lethal toxicity will seldom stop approval of an effective cancer remedy. Older philosophy that assumes a lack of effective symptom management. May apply when a new treatment is devised since non-lethal toxicity will seldom stop approval of an effective cancer remedy. Challenge of symptom management is to block toxicity without compromising efficacy Challenge of symptom management is to block toxicity without compromising efficacy

11 Supportive Care Toxicity Targets Hematologic Hematologic Myelosuppression Myelosuppression Gastrointestinal Gastrointestinal Nausea/vomiting Nausea/vomiting Constipation/diarrhea Constipation/diarrhea Mucositis Mucositis Cardiovascular Cardiovascular Thrombosis Thrombosis Cardiac Cardiac Neurologic Neurologic Peripheral neuropathy Peripheral neuropathy Cognitive Cognitive Pulmonary Pulmonary Renal Renal Cutaneous Cutaneous Alopecia Alopecia Rash Rash

12 Cancer and Prevention of VTE Landmark Advances and New Paradigms of Care for the Oncologist and Clinical Support Specialist Cancer and Prevention of VTE Landmark Advances and New Paradigms of Care for the Oncologist and Clinical Support Specialist Program Co-Chairman Craig Kessler, MD MACP Director, Division of Coagulation Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC Program Co-Chairman Craig Kessler, MD MACP Director, Division of Coagulation Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC Innovation Investigation Application

13 VTE and CancerA Looming National Healthcare Crisis MISSION AND CHALLENGES MISSION AND CHALLENGES Recognizing cancer patients at risk for DVT and identifying appropriate candidates for long-term prophylaxis and/or treatment with approved and indicated therapies are among the most important challenges encountered in contemporary pharmacy and clinical practice. MISSION AND CHALLENGES MISSION AND CHALLENGES Recognizing cancer patients at risk for DVT and identifying appropriate candidates for long-term prophylaxis and/or treatment with approved and indicated therapies are among the most important challenges encountered in contemporary pharmacy and clinical practice.

14 COMORBIDITYCONNECTIONCAPUTICancer Heart Failure ABE/COPD Respiratory Failure Myeloproliferative Disorder ThrombophiliaSurgery History of DVT OtherCOMORBIDITYCONNECTIONCAPUTICancer Heart Failure ABE/COPD Respiratory Failure Myeloproliferative Disorder ThrombophiliaSurgery History of DVT OtherSUBSPECIALISTSTAKEHOLDERS Infectious diseases OncologyPHARMACISTSCardiology Pulmonary medicine HematologyOncology/hematology Interventional Radiology HospitalistSurgeonsEMPCPSUBSPECIALISTSTAKEHOLDERS Infectious diseases OncologyPHARMACISTSCardiology Pulmonary medicine HematologyOncology/hematology Interventional Radiology HospitalistSurgeonsEMPCP Comorbidity Connection

15 Epidemiology of First-Time VTE White R. Circulation. 2003;107:I-4 –I-8.) VariableFinding Seasonal Variation Possibly more common in winter and less common in summer Risk Factors 25% to 50% idiopathic 15%-25% associated with cancer 20% following surgery (3 months) Recurrent VTE 6-month incidence, 7%; Higher rate in patients with cancer Recurrent PE more likely after PE than after DVT Death After Treated VTE 30-day incidence 6% after incident DVT 30-day incidence 12% after PE Death strongly associated with cancer, age, and cardiovascular disease

16 Epidemiology of VTE White R. Circulation. 2003;107:I-4 –I-8.) One major risk factor for VTE is ethnicity, with a significantly higher incidence among Caucasians and African Americans than among Hispanic persons and Asian-Pacific Islanders. One major risk factor for VTE is ethnicity, with a significantly higher incidence among Caucasians and African Americans than among Hispanic persons and Asian-Pacific Islanders. Overall, about 25% to 50% of patient with first-time VTE have an idiopathic condition, without a readily identifiable risk factor. Overall, about 25% to 50% of patient with first-time VTE have an idiopathic condition, without a readily identifiable risk factor. Early mortality after VTE is strongly associated with presentation as PE, advanced age, cancer, and underlying cardiovascular disease. Early mortality after VTE is strongly associated with presentation as PE, advanced age, cancer, and underlying cardiovascular disease.

17 Comorbidity Connection ComorbidityConnection Overview Overview

18 Acute Medical Illness and VTE Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164: Risk Factor Odds Ratio (95% CI) X2X2X2X2 Age > 75 years Cancer Previous VTE 1.03 ( ) 1.62 ( ) 2.06 ( ) Acute infectious disease 1.74 ( ) 0.02

19 Comorbid Condition and DVT Risk Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%. Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%. The individual attributable risk estimates for malignant neoplasm, trauma, congestive heart failure, central venous catheter or pacemaker placement, neurological disease with extremity paresis, and superficial vein thrombosis were 18%, 12%, 10%, 9%, 7%, and 5%, respectively. The individual attributable risk estimates for malignant neoplasm, trauma, congestive heart failure, central venous catheter or pacemaker placement, neurological disease with extremity paresis, and superficial vein thrombosis were 18%, 12%, 10%, 9%, 7%, and 5%, respectively. Together, the 8 risk factors accounted for 74% of disease occurrence Together, the 8 risk factors accounted for 74% of disease occurrence Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern Med Jun 10;162(11): Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study

20 VTE Recurrence Predictors of First Overall VTE Recurrence Heit J, Mohr D, et al. Arch Intern Med. 2000;160: Baseline Characteristic Hazard Ratio (95% CI) Age 1.17 ( ) Body Mass Index 1.24 ( ) Neurologic disease with extremity paresis 1.87 ( ) Malignant neoplasm With chemotherapy Without chemotherapy 4.24 ( ) 2.21 ( )

21 ICOPER Cumulative Mortality Mortality (%) Days From Diagnosis 17.5% Lancet 1999;353:

22 Stages of Chronic Venous Insufficiency 1.Varicose veins 2.Ankle/ leg edema 3.Stasis dermatitis 4.Lipodermatosclerosis 5.Venous stasis ulcer

23 Progression of Chronic Venous Insufficiency From UpToDate 2006

24 Rising VTE Incidence in Hospitalized Patients Stein PD et al. Am J Cardiol 2005; 95:

25 DVT Registry (N=5,451): Top 5 Medical Comorbidities 1.Hypertension 2.Immobility 3.Cancer 4.Obesity (BMI > 30) 5.Cigarette Smoking Am J Cardiol 2004; 93:

26 Implementation of VTE prophylaxis continues to be problematic, despite detailed North American and European Consensus guidelines. Implementation

27 SURGEON GENERAL: CALL TO ACTION TO PREVENT DVT AND PE September 15, 2008

28 Surgeon Generals Call to Action 42-Page Document Issued September 15, 2008 Issued September 15, 2008 Endorsed by Secretary, HHS Endorsed by Secretary, HHS Endorsed by Director, NHLBI Endorsed by Director, NHLBI Foreword by Acting Surgeon General, Steven K. Galson, MD, MPH (RADM, U.S. Public Health Service) Foreword by Acting Surgeon General, Steven K. Galson, MD, MPH (RADM, U.S. Public Health Service)

29 Call to Action for VTE Dr. Galsons 1 st Call To Action Dr. Galsons 1 st Call To Action > 350, ,000 Americans suffer VTE annually > 350, ,000 Americans suffer VTE annually > 100,000 U.S. deaths per year > 100,000 U.S. deaths per year Negative impact on QOL of survivors Negative impact on QOL of survivors Must disseminate info widely to address gap because were not applying knowledge systematically Must disseminate info widely to address gap because were not applying knowledge systematically Foreword

30 I. Major Public Health Problem II. Reducing VTE Risk III. Gaps in Application, Awareness of Evidence IV. Public Health Response V. Catalyst for Action Call to Action for VTE

31 Symposium ThemesCancer/DVT 1.Cancer rates are increasing as heart disease Rx improves and as cancer Rx improves. 2.Cancer increases VTE risk. 3.VTE is preventable (immunize!) 4.VTE prophylaxis may slow cancer 5.Increased emphasis on prophylaxis: OSG, NCCN, ASCO, ACCP, NATF 6.Facilitate prophylaxis with alerts.

32 Chemotherapy-Induced Nausea and Vomiting Causes, Challenges, and Optimal Treatment Steven Grunberg, MD Program Co-Chairman Professor of Medicine University of Vermont Burlington, Vermont Innovation Investigation Application

33 Perception of Chemotherapy (1983) Nausea and vomiting are the two most feared toxicities of chemotherapy. Coates, Eur J Cancer Clin Oncol 19:203, 1983

34 Sun, Gynecol Oncol 87:118, 2002 Median Time-Trade-Off Scores

35 Medical Costs of Emesis Why were we able to move most chemotherapy from an inpatient to an outpatient procedure? Why were we able to move most chemotherapy from an inpatient to an outpatient procedure? Indwelling venous catheter/Infusaport Indwelling venous catheter/Infusaport Effective antiemetics Effective antiemetics What are the direct costs of emesis? What are the direct costs of emesis? Few patients discontinue chemotherapy due to toxicity Few patients discontinue chemotherapy due to toxicity Antiemetic control decreases duration of hospitalization and frequency of rehospitalization Antiemetic control decreases duration of hospitalization and frequency of rehospitalization Grunberg, Eur J Cancer 36 Suppl:S28, 2000

36 Functional Living Index – Emesis (FLIE) FLIE is an 18-question questionnaire that evaluates the effect of vomiting (9 questions) and nausea (9 questions) on the ability to carry out Activities of Daily Living FLIE is an 18-question questionnaire that evaluates the effect of vomiting (9 questions) and nausea (9 questions) on the ability to carry out Activities of Daily Living Each question is scored from 0 (inability to function) to 7 (normal function) Each question is scored from 0 (inability to function) to 7 (normal function) A value of 6 or above is considered to indicate No Impact on Daily Living A value of 6 or above is considered to indicate No Impact on Daily Living Does Complete Protection from emesis improve quality of life by increasing the percentage of patients for whom emesis has No Impact on Daily Living? Does Complete Protection from emesis improve quality of life by increasing the percentage of patients for whom emesis has No Impact on Daily Living? Lindley, Qual Life Res 1:331, 1992

37 Correlation of Emesis Protection and Quality of Life Martin, Eur J Cancer 39:1395, 2003

38 Levels of Emetogenicity Highly Emetogenic Chemotherapy (HEC) (> 90%) Highly Emetogenic Chemotherapy (HEC) (> 90%) Cisplatin Cisplatin Mechlorethamine Mechlorethamine Moderately Emetogenic Chemotherapy (MEC) (30-90%) Moderately Emetogenic Chemotherapy (MEC) (30-90%) Cyclophosphamide Cyclophosphamide Doxorubicin Doxorubicin Low Emetogenic Chemotherapy (10-30%) Low Emetogenic Chemotherapy (10-30%) Paclitaxel Paclitaxel 5-Fluorouracil 5-Fluorouracil Minimally Emetogenic Chemotherapy (< 10%) Minimally Emetogenic Chemotherapy (< 10%) Vincristine Vincristine Bleomycin Bleomycin

39 Levels of Emetogenicity Modifying Factors Age Age Younger patients vomit more than older patients Younger patients vomit more than older patients Gender Gender Women vomit more than men Women vomit more than men Alcohol history Alcohol history Patients with a history of heavy alcohol use vomit less than those without such a history Patients with a history of heavy alcohol use vomit less than those without such a history Nausea/vomiting history Nausea/vomiting history Patients with a history of morning sickness or motion sickness are more likely to vomit Patients with a history of morning sickness or motion sickness are more likely to vomit

40 Definitions Vomiting – expulsion of stomach contents Vomiting – expulsion of stomach contents Nausea – subjective feeling of imminent vomiting Nausea – subjective feeling of imminent vomiting Complete Response – no vomiting or rescue medication Complete Response – no vomiting or rescue medication Complete Control – no vomiting, rescue medication or significant nausea Complete Control – no vomiting, rescue medication or significant nausea Total Control – no vomiting, rescue medication or nausea Total Control – no vomiting, rescue medication or nausea

41 Role of Emesis in Natural Selection Vomiting is a physiologic process, not a pathologic process. It is the bodys natural defense against ingestion of toxic substances.

42 Neurotransmitters Involved in Emesis Emetic center GABA Histamine Endorphins Cannabinoid Dopamine Substance P Serotonin

43 High Dose Metoclopramide – The First Highly Effective Antiemetic Gralla, NEJM 305:905, 1981 Metoclopramide(n=11) Placebo (n=10) P Metoclopramide (n=11) Prochlorperazine(n=10)P Emetic Episodes Hours of Vomiting NS Hours of Nausea NS

44 Phase I Study of Ondansetron 43 Patients Receiving Cisplatin > 60 mg/m 2 43 Patients Receiving Cisplatin > 60 mg/m 2 Grunberg, J Clin Oncol 7:1137, 1989 Dose Level CompleteMajorFailure 0.01 mg/kg mg/kg mg/kg mg/kg mg/kg 122 Total44%37%19%

45 Increase in Complete Protection with Dexamethasone 89 Patients Receiving Cisplatin > 50 mg/m 2 Roila, J Clin Oncol 9:675, 1991OndansteronOndansteron/DexamethasonepVomiting64%91% Nausea66%89% Nausea/Vomiting56%81% Preference14%39%0.003

46 Serotonin Antagonist Dose-Response Curve Grunberg, in Tonato, ESMO Monographs, 1996

47 Natural History of Delayed Nausea and Vomiting Kris, J Clin Oncol 3:1379, 1985 Hours after cisplatin Percent with nausea or vomiting

48 Perception vs Reality Highly Emetogenic Chemotherapy Grunberg, Cancer 100:2261, 2004 Percent of patients

49 Perception vs Reality Moderately Emetogenic Chemotherapy Grunberg, Cancer 100:2261, 2004 Percent of patients

50 *Log-scale In vitro data; clinical significance has not been established Half-Life and Binding Affinities of 5-HT 3 Receptor Antagonists 1. Aloxi ® package insert, Zofran ® package insert, Anzemet ® package insert, Kytril ® package insert, Wong EHF et al. Br J Pharmacol. 1995;114: Miller RC et al. Drug Dev Res. 1993;28: HT 3 Antagonist Half-Life (h) Binding Affinity (pKi)* Binding Affinity (pKi)* Palonosetron Ondansetron Dolasetron Granisetron Tropisetron

51 Palonosetron for Highly Emetogenic Chemotherapy Efficacy Results by 24 Hour Period

52 Palonosetron for Moderately Emetogenic Chemotherapy Efficacy Results by 24 Hour Period Poli-Bigelli, Ann Oncol 14:1570, 2003

53 Palonosetron for Moderately Emetogenic Chemotherapy Efficacy Results by 24 Hour Period Eisenberg, Cancer 98:2473, 2003

54 Inhibition of Serotonin-Induced Calcium Ion Flux Rojas, Anesth Analg 107:469, 2008

55 Neurotransmitters Involved in Emesis Emetic center GABA Histamine Endorphins Cannabinoid Dopamine Substance P Serotonin

56 L-758,298 vs Ondansetron for Cisplatin-Induced Emesis Cocquyt, Eur J Cancer 37:835, 2001

57 Ondansetron/Dexamethasone + Aprepitant for Cisplatin-Induced Emesis Hesketh, J Clin Oncol 21:4112, 2003

58 Time course of emesis following cisplatin with a 5-HT 3 antagonist or aprepitant Patients with no emesis (%) Time since cisplatin (hours) Gran + dex d1 / placebo d2–5 Gran + dex + aprepitant d1 / aprepitant d2–5 Aprepitant d0 / aprepitant + dex d1 / aprepitant d2–5 Aprepitant + dex d1 / aprepitant d2–5 Hesketh, Support Care Cancer 10:365, 2002

59 Palonosetron/Dexamethasone/Aprepitant for MEC-Induced Emesis (n=58) Palonosetron/Dexamethasone/Aprepitant for MEC-Induced Emesis (n=58) Grote, J Support Oncol 4:403, 2006

60 Palonosetron/Dexamethasone/Aprepitant for MEC-Induced Emesis – Single Day (n=41) Palonosetron/Dexamethasone/Aprepitant for MEC-Induced Emesis – Single Day (n=41) Grunberg, Support Care Cancer (In Press) 2009

61 Palonosetron/Dexamethasone + Aprepitant (3-day vs single day) (n=70) Palonosetron/Dexamethasone + Aprepitant (3-day vs single day) (n=70) Herrington, Cancer 112:2080, 2008

62 Guideline Organizations MASCC MASCC ASCO ASCO ASHP ASHP NCCN NCCN EONS EONS Consensus of Consensus Consensus of Consensus

63 Why do Guidelines Vary? Charge to the Committee Make the guidelines evidence-based Make the guidelines evidence-based Pro: high level of evidence Con: incomplete with variable compliance Make the guidelines comprehensive Make the guidelines comprehensive Pro: advice for all situations Con: variable level of evidence and compliance Make the guidelines acceptable Make the guidelines acceptable Pro: advice for all situations and good compliance Con: highly variable level of evidence

64 Antiemetic Consensus Guidelines Adapted from Koeller, Support Care Cancer 10:519, 2002 RiskAcuteDelayedHigh 5-HT3+DXM+NK1 DXM+NK1 Moderate 5-HT3+DXM+NK1 NK1 Low Single Agent None MinimalNoneNone

65 Effect of Physician Education on Antiemetic Guideline Compliance Distribution of written guidelines Distribution of written guidelines Improved compliance x 2 months Lecture by visiting expert Lecture by visiting expert No change in behavior Direct feedback of patient experiences Direct feedback of patient experiences Improved compliance x 4+ months Mertens, J Clin Oncol 21:1373, 2003

66 Its not really a Code Its actually more of a Guideline - Pirates of the Caribbean, 2003

67 Remaining Challenges Pharmacodynamics of antiemetics Pharmacodynamics of antiemetics Convenient schedule/extended efficacy Convenient schedule/extended efficacy Control of nausea Control of nausea Control of anorexia Control of anorexia

68 A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Linking Science and Evidence to Clinical Practice What Do Trials Teach? A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Linking Science and Evidence to Clinical Practice What Do Trials Teach? Program Co-Chairman Craig Kessler, MD MACP Director, Division of Coagulation Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC Program Co-Chairman Craig Kessler, MD MACP Director, Division of Coagulation Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC Innovation Investigation Application

69 VTE and Cancer: Epidemiology Of all cases of VTE: Of all cases of VTE: About 20% occur in cancer patients About 20% occur in cancer patients Annual incidence of VTE in cancer patients 1/250 Annual incidence of VTE in cancer patients 1/250 Of all cancer patients: Of all cancer patients: 15% will have symptomatic VTE 15% will have symptomatic VTE As many as 50% have VTE at autopsy As many as 50% have VTE at autopsy Compared to patients without cancer: Compared to patients without cancer: Higher risk of first and recurrent VTE Higher risk of first and recurrent VTE Higher risk of bleeding on anticoagulants Higher risk of bleeding on anticoagulants Higher risk of dying Higher risk of dying Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21 Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21

70 1.Ambrus JL et al. J Med. 1975;6: Donati MB. Haemostasis. 1994;24: Johnson MJ et al. Clin Lab Haem. 1999;21: Prandoni P et al. Ann Intern Med. 1996;125:1-7 DVT and PE in Cancer Facts, Findings, and Natural History VTE is the second leading cause of death in hospitalized cancer patients 1,2 VTE is the second leading cause of death in hospitalized cancer patients 1,2 The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer 2 The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer 2 Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE 3 Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE 3 Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years 4 Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years 4

71 Clinical Features of VTE in Cancer VTE has significant negative impact on quality of life VTE has significant negative impact on quality of life VTE may be the presenting sign of occult malignancy VTE may be the presenting sign of occult malignancy 10% with idiopathic VTE develop cancer within 2 years 10% with idiopathic VTE develop cancer within 2 years 20% have recurrent idiopathic VTE 20% have recurrent idiopathic VTE 25% have bilateral DVT 25% have bilateral DVT Bura et. al., J Thromb Haemost 2004;2:445-51

72 Thrombosis and Survival Likelihood of Death After Hospitalization DVT/PE and Malignant Disease Malignant Disease DVT/PE Only Nonmalignant Disease Number of Days Probability of Death Levitan N, et al. Medicine 1999;78:285

73 Hospital Mortality With or Without VTE Khorana, JCO, 2006 Mortality (%) N=66,016 N=20,591 N=17,360

74 Trends in VTE in Hospitalized Cancer Patients VTE- patients on chemotherapy VTE-all patients DVT-all patients PE-all patients Rate of VTE (%) P< Khorana AA et al. Cancer

75 Thrombosis Risk In Cancer Primary Prophylaxis Medical Inpatients Medical Inpatients Surgery Surgery Radiotherapy Radiotherapy Central Venous Catheters Central Venous Catheters

76 Risk Factors for Cancer-Associated VTE Cancer Cancer Type Type Men: prostate, colon, brain, lung Men: prostate, colon, brain, lung Women: breast, ovary, lung Women: breast, ovary, lung Stage Stage Treatments Treatments Surgery Surgery 10-20% proximal DVT 10-20% proximal DVT 4-10% clinically evident PE 4-10% clinically evident PE 0.2-5% fatal PE 0.2-5% fatal PE Chemotherapy Chemotherapy Central venous catheters (~4% generate clinically relevant VTE) Central venous catheters (~4% generate clinically relevant VTE) Patient Patient Prior VTE Prior VTE Comorbidities Comorbidities Genetic background Genetic background

77 VTE Risk And Cancer Type Solid And Liquid Malignancies Stein PD, et al. Am J Med 2006; 119: Relative Risk of VTE in Cancer Patients PancreasBrainMyeloprolStomachLymphomaUterusLungEsophagusProstateRectalKidneyColonOvaryLiverLeukemiaBreastCervixBladder Relative Risk of VTE Ranged From 1.02 to 4.34

78 Medical Inpatients Cancer and Thrombosis

79 Thromboembolism in Hospitalized Neutropenic Cancer Patients Retrospective cohort study of discharges using the University Health System Consortium Retrospective cohort study of discharges using the University Health System Consortium 66,106 adult neutropenic cancer patients between 1995 and 2002 at 115 centers 66,106 adult neutropenic cancer patients between 1995 and 2002 at 115 centers Khorana, JCO, 2006

80 Neutropenic Patients: Results 8% had thrombosis 8% had thrombosis 5.4% venous and 1.5% arterial in 1 st hospitalization 5.4% venous and 1.5% arterial in 1 st hospitalization Predictors of thrombosis Predictors of thrombosis Age over 55 Age over 55 Site (lung, GI, gynecologic, brain) Site (lung, GI, gynecologic, brain) Comorbidities (infection, pulmonary and renal disease, obesity) Comorbidities (infection, pulmonary and renal disease, obesity) Khorana, JCO, 2006

81 Predictors of VTE in Hospitalized Cancer Patients CharacteristicOR P Value Site of Cancer LungStomachPancreasEndometrium/cervixBrain < <0.001<0.001<0.001 Age 65 y Arterial thromboembolism Comorbidities (lung/renal disease, infection, obesity) <0.001 Khorana AA et al. J Clin Oncol. 2006;24:

82 Pharmacologic (Prophylaxis & Treatment) Nonpharmacologic(Prophylaxis) Antithrombotic Therapy: Choices Intermittent Pneumatic Compression Elastic Stockings Inferior Vena Cava Filter Oral Anticoagulants Unfractionated Heparin (UH) Low Molecular Weight Heparin (LMWH) New Agents: e.g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.?

83 Prophylaxis Studies in Medical Patients Francis, NEJM, 2007 Placebo Enoxaparin MEDENOX Trial Placebo Dalteparin PREVENT Placebo Fondaparinux ARTEMIS Rate of VTE (%) Relative risk reduction 63% Relative risk reduction 44% Relative risk reduction 47%

84 ASCO Guidelines 1. SHOULD HOSPITALIZED PATIENTS WITH CANCER RECEIVE ANTICOAGULATION FOR VTE PROPHYLAXIS? Recommendation. Hospitalized patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications to anticoagulation. Lyman GH et al. J Clin Oncol (25) 2007; 34:

85 Surgical Patients Cancer and Thrombosis

86 Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis: Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis: Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732 Incidence of VTE in Surgical Patients No Cancer N=16,954CancerN=6124P-value Post-op VTE 0.61%1.26%< Non-fatal PE 0.27%0.54%< Autopsy PE 0.11%0.41%< Death0.71%3.14%<0.0001

87 Natural History of VTE in Cancer Surgery: Registry Web-Based Registry of Cancer Surgery Web-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patients Tracked 30-day incidence of VTE in 2373 patients Type of surgery Type of surgery 52% General 52% General 29% Urological 29% Urological 19% Gynecologic 19% Gynecologic 82% received in-hospital thromboprophylaxis 82% received in-hospital thromboprophylaxis 31% received post-discharge thromboprophylaxis 31% received post-discharge thromboprophylaxis Findings Findings 2.1% incidence of clinically overt VTE (0.8% fatal) 2.1% incidence of clinically overt VTE (0.8% fatal) Most events occur after hospital discharge Most events occur after hospital discharge Most common cause of 30-day post-op death Most common cause of 30-day post-op death Agnelli, Ann Surg 2006; 243: 89-95

88 LMWH vs. UFH Abdominal or pelvic surgery for cancer (mostly colorectal) Abdominal or pelvic surgery for cancer (mostly colorectal) LMWH once daily vs. UFH tid for 7–10 days post-op LMWH once daily vs. UFH tid for 7–10 days post-op DVT on venography at day 7–10 and symptomatic VTE DVT on venography at day 7–10 and symptomatic VTE 1. ENOXACAN Study Group. Br J Surg 1997;84:1099– McLeod R, et al. Ann Surg 2001;233: Prophylaxis in Surgical Patients StudyNDesignRegimens ENOXACAN 1 631double-blind enoxaparin vs. UFH Canadian Colorectal DVT Prophylaxis 2 475double-blind enoxaparin vs. UFH

89 Canadian Colorectal DVT Prophylaxis Trial 13.9% 1.5% 2.7% 16.9% N=234 N=241 McLeod R, et al. Ann Surg 2001;233: P=0.052 Incidence of Outcome Event Incidence of Outcome Event VTEMajor Bleeding VTEMajor Bleeding (Cancer) (All) Prophylaxis in Surgical Patients

90 VTE Prox Any Major VTE Prox Any Major DVT Bleeding Bleeding DVT Bleeding Bleeding P= % 1.8% Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346: ENOXACAN II Incidence of Outcome Event Incidence of Outcome Event N=167 N=165 0% 0.4% 12.0% 4.8% NNT = % 3.6% Extended Prophylaxis in Surgical Patients

91 A multicenter, prospective, assessor-blinded, open-label, randomized trial: Dalteparin administered for 28 days after major abdominal surgery compared to 7 days of treatment A multicenter, prospective, assessor-blinded, open-label, randomized trial: Dalteparin administered for 28 days after major abdominal surgery compared to 7 days of treatment RESULTS: Cumulative incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3% after prolonged thromboprophylaxis (12/165) (relative risk reduction 55%; 95% confidence interval 15-76; P=0.012). RESULTS: Cumulative incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3% after prolonged thromboprophylaxis (12/165) (relative risk reduction 55%; 95% confidence interval 15-76; P=0.012). CONCLUSIONS: 4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTE, without increasing the risk of bleeding, compared with 1 week of thromboprophylaxis. CONCLUSIONS: 4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTE, without increasing the risk of bleeding, compared with 1 week of thromboprophylaxis. Major Abdominal Surgery: FAME InvestigatorsDalteparin Extended Rasmussen, J Thromb Haemost Nov;4(11): Epub 2006 Aug 1.

92 ASCO Guidelines: VTE Prophylaxis All patients undergoing major surgical intervention for malignant disease should be considered for prophylaxis. All patients undergoing major surgical intervention for malignant disease should be considered for prophylaxis. Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receive pharmacologic prophylaxis. Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receive pharmacologic prophylaxis. Prophylaxis should be continued at least 7 – 10 days post-op. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing major surgery for cancer with high-risk features. Prophylaxis should be continued at least 7 – 10 days post-op. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing major surgery for cancer with high-risk features. Lyman GH et al. J Clin Oncol (25) 2007; 34:

93 Thrombosis is a potential complication of central venous catheters, including these events: –Fibrin sheath formation –Superficial phlebitis –Ball-valve clot –Deep vein thrombosis (DVT) Central Venous Catheters Geerts W, et al. Chest Jun 2008: 381S–453S

94 Placebo-Controlled Trials StudyRegimenN CRT (%) CRT (%) Reichardt* 2002 Dalteparin 5000 U daily placebo (3.7) 11 (3.7) 5 (3.4) 5 (3.4) Couban*2002 Warfarin 1mg daily placebo (4.6) 6 (4.6) 5 (4.0) 5 (4.0) ETHICS ETHICS 2004 Enoxaparin 40 mg daily placebo (14.2) 28 (18.1) * symptomatic outcomes ; routine venography at 6 weeks Prophylaxis for Venous Catheters Reichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G, et al. Proc ASCO 2004;23:730

95 Tolerability of Low-Dose Warfarin Tolerability of Low-Dose Warfarin 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily INR measured at baseline and four time points INR measured at baseline and four time points 10% of all recorded INRs >1.5 10% of all recorded INRs >1.5 Patients with elevated INR Patients with elevated INR 2.0–2.9 6% 3.0–4.919% >5.0 7% Central Venous Catheters: Warfarin Masci et al. J Clin Oncol. 2003;21:

96 Summary Recent studies demonstrate a low incidence of symptomatic catheter-related thrombosis (~4%) Recent studies demonstrate a low incidence of symptomatic catheter-related thrombosis (~4%) Routine prophylaxis is not warranted to prevent catheter-related thrombosis, but catheter patency rates/infections have not been studied Routine prophylaxis is not warranted to prevent catheter-related thrombosis, but catheter patency rates/infections have not been studied Low-dose LMWH and fixed-dose warfarin have not been shown to be effective for preventing symptomatic and asymptomatic thrombosis Low-dose LMWH and fixed-dose warfarin have not been shown to be effective for preventing symptomatic and asymptomatic thrombosis Prophylaxis for Central Venous Access Devices

97 8 th ACCP Consensus Guidelines No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) Chest Jun 2008: 454S–545S

98 Primary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient No recommendations from ACCP No recommendations from ACCP No data from randomized trials (RCTs) No data from randomized trials (RCTs) Weak data from observational studies in high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, ovarian) Weak data from observational studies in high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, ovarian) Recommendations extrapolated from other groups of patients if additional risk factors present (e.g., hemiparesis in brain tumors, etc.) Recommendations extrapolated from other groups of patients if additional risk factors present (e.g., hemiparesis in brain tumors, etc.)

99 Ambulatory Chemotherapy Patients Cancer and Thrombosis

100 Risk Factors for VTE in Medical Oncology Patients Tumor type Tumor type Ovary, brain, pancreas, lung, colon Ovary, brain, pancreas, lung, colon Stage, grade, and extent of cancer Stage, grade, and extent of cancer Metastatic disease, venous stasis due to bulky disease Metastatic disease, venous stasis due to bulky disease Type of antineoplastic treatment Type of antineoplastic treatment Multiagent regimens, hormones, anti-VEGF, radiation Multiagent regimens, hormones, anti-VEGF, radiation Miscellaneous VTE risk factors Miscellaneous VTE risk factors Previous VTE, hospitalization, immobility, infection, thrombophilia Previous VTE, hospitalization, immobility, infection, thrombophilia

101 Independent Risk Factors for DVT/PE Risk Factor/Characteristic O.R. Recent surgery with institutionalization Trauma12.69 Institutionalization without recent surgery 7.98 Malignancy with chemotherapy 6.53 Prior CVAD or pacemaker 5.55 Prior superficial vein thrombosis 4.32 Malignancy without chemotherapy 4.05 Neurologic disease w/ extremity paresis 3.04 Serious liver disease 0.10 Heit JA et al. Thromb Haemost. 2001;86:

102 VTE Incidence In Various Tumors Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 Oncology Setting VTE Incidence Breast cancer (Stage I & II) w/o further treatment 0.2% Breast cancer (Stage I & II) w/ chemo 2% Breast cancer (Stage IV) w/ chemo 8% Non-Hodgkins lymphomas w/ chemo 3% Hodgkins disease w/ chemo 6% Advanced cancer (1-year survival=12%) 9% High-grade glioma 26% Multiple myeloma (thalidomide + chemo) 28% Renal cell carcinoma 43% Solid tumors (anti-VEGF + chemo) 47% Wilms tumor (cavoatrial extension) 4%

103 Primary VTE Prophylaxis Recommended for hospitalized cancer patients Recommended for hospitalized cancer patients Not recommended or generally used for outpatients Not recommended or generally used for outpatients Very little data Very little data Heterogeneous Heterogeneous Need for risk stratification

104 Ambulatory Cancer plus Chemotherapy Study Methods Study Methods Prospective observational study of ambulatory cancer patients initiating a new chemotherapy regimen, and followed for a maximum of 4 cycles Prospective observational study of ambulatory cancer patients initiating a new chemotherapy regimen, and followed for a maximum of 4 cycles 115 U.S. centers participated 115 U.S. centers participated Patients enrolled between March, 2002 and August, 2004 who had completed at least one cycle of chemotherapy were included in this analysis Patients enrolled between March, 2002 and August, 2004 who had completed at least one cycle of chemotherapy were included in this analysis Khorana, Cancer, 2005

105 Ambulatory Cancer plus Chemotherapy VTE events were recorded during mid-cycle or new- cycle visits VTE events were recorded during mid-cycle or new- cycle visits Symptomatic VTE was a clinical diagnosis made by the treating clinician Symptomatic VTE was a clinical diagnosis made by the treating clinician Statistical analysis Statistical analysis Odds ratios to estimate relative risk Odds ratios to estimate relative risk Multivariate logistic regression to adjust for other risk factors Multivariate logistic regression to adjust for other risk factors Khorana, Cancer, 2005 Study Methods Study Methods

106 Incidence of VTE VTE / 2.4 months VTE/month VTE /cycle Cumulative rate (95% CI) 1.93%0.8%0.7% 2.2% ( ) 0.0% 0.5% 1.0% 1.5% 2.0% 2.5%3.0%Baseline Cycle 1 Cycle 2 Cycle 3 Rate of VTE (%) Khorana, Cancer, 2005

107 Risk Factors: Site of Cancer All patients Breast Colon Lung Upper GI Hodgkins NHL Others Site of Cancer VTE (%) / 2.4 months Khorana, Cancer, 2005

108 Incidence of Venous Thromboembolism By Quartiles of Pre-chemotherapy Platelet Count p for trend= % 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% 3.5% 4.0% 4.5%5.0% <217 < >337 Pre-chemotherapy Platelet Count/mm 3 (x1000) (x1000) Incidence Of VTE Over 2.4 Months(%) Khorana, Cancer, 2005

109 Risk Factors: Multivariate Analysis CharacteristicOR P value Site of Cancer Upper GI LungLymphoma Pre-chemotherapy platelet count > 350,000/mm Hgb < 10g/dL or use of red cell growth factor Use of white cell growth factor in high- risk sites Khorana, Cancer, 2005

110 Predictive 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 3 1 Hgb < 10g/dL or use of ESA 1 Leukocyte count > 11,000/mm 3 1 BMI > 35 1 Khorana AA et al. JTH Suppl Abs O-T-002

111 Risk Score 01234N1, VTE(%) /2.4 mos Incidence of VTE Over 2.4 Months Predictive Model

112 Predictive 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= % 1.8%7.1% Development cohort 0.3% 2.0%6.7% Validation cohort n=374 n=842n=149 Khorana AA et al. JTH Suppl Abs O-T-002

113 Oral Anticoagulant Therapy in Cancer Patients: Problematic Warfarin therapy is complicated by: Warfarin therapy is complicated by: Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. Frequent interruptions for thrombocytopenia and procedures Frequent interruptions for thrombocytopenia and procedures Difficulty in venous access for monitoring Difficulty in venous access for monitoring Increased risk of both recurrence and bleeding Increased risk of both recurrence and bleeding Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why? Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?

114 CLOT: Landmark Cancer/VTE Trial CANCER PATIENTS WITH ACUTE DVT or PE Randomization Randomization [N = 677] Primary Endpoints: Recurrent VTE and Bleeding Primary Endpoints: Recurrent VTE and Bleeding Secondary Endpoint: Survival Secondary Endpoint: Survival Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146 Dalteparin Oral Anticoagulant

115 Landmark CLOT Cancer Trial Reduction in Recurrent VTE Days Post Randomization Probability of Recurrent VTE, % Risk reduction = 52% p-value = Dalteparin OAC Recurrent VTE Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

116 Dalteparin N=338 N=338OACN=335 P-value* P-value* Major bleed 19 ( 5.6%) 19 ( 5.6%) 12 ( 3.6%) 12 ( 3.6%)0.27 Any bleed 46 (13.6%) 46 (13.6%) 62 (18.5%) 62 (18.5%)0.093 * Fishers exact test Bleeding Events in CLOT Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

117 Treatment of Cancer-Associated VTE StudyDesign Length of Therapy (Months)N Recurrent VTE (%) Major Bleeding (%)Death(%) CLOT Trial (Lee 2003) DalteparinOAC CANTHENOX (Meyer 2002) EnoxaparinOAC LITE (Hull ISTH 2003) TinzaparinOAC ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) OAC NS 0.03 NS NS NR

118 Treatment and 2° Prevention of VTE in Cancer – Bottom Line New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendationACCP) New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendationACCP) NOTE: Dalteparin is only LMWH approved (May, 2007) for both the treatment and secondary prevention of VTE in cancer NOTE: Dalteparin is only LMWH approved (May, 2007) for both the treatment and secondary prevention of VTE in cancer Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation ACCP) Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation ACCP) Chest Jun 2008: 454S–545S New Development New Development

119 CLOT 12-month Mortality All Patients Lee AY et al. J Clin Oncol. 2005; 23:

120 Days Post Randomization Probability of Survival, % OAC Dalteparin HR = 0.50 P-value = 0.03 Anti-Tumor Effects of LMWH CLOT 12-month Mortality CLOT 12-month Mortality Patients Without Metastases (N=150) Lee AY et al. J Clin Oncol. 2005; 23:

121 84 patients randomized: Chemo +/- LMWH (18 weeks) 84 patients randomized: Chemo +/- LMWH (18 weeks) Patients balanced for age, gender, stage, smoking history, ECOG performance status Patients balanced for age, gender, stage, smoking history, ECOG performance status LMWH for Small Cell Lung Cancer Turkish Study Altinbas et al. J Thromb Haemost 2004;2:1266. Chemotherapy plus Dalteparin Chemo alone P-value 1-y overall survival, % y overall survival, % Median survival, m CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily

122 VTE Prophylaxis Is Underused in Patients With Cancer 1.Kakkar AK et al. Oncologist. 2003;8: Stratton MA et al. Arch Intern Med. 2000;160: Bratzler DW et al. Arch Intern Med. 1998;158: Cancer: FRONTLINE Survey Clinician Respondents Rate of Appropriate Prophylaxis, % Major Surgery 2 Major Abdominothoracic Surgery (Elderly) 3 Medical Inpatients 4 Confirmed DVT (Inpatients) 5 Cancer: Surgical Cancer: Medical 4.Rahim SA et al. Thromb Res. 2003;111: Goldhaber SZ et al. Am J Cardiol. 2004;93:

123 Conclusions and Summary Risk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, surgery, thrombocytopeniaRisk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, surgery, thrombocytopenia Long-term secondary prevention with LMWH has been shown to produce better outcomes than warfarinLong-term secondary prevention with LMWH has been shown to produce better outcomes than warfarin Guidelines and landmark trials support administration of LMWH in at risk patientsGuidelines and landmark trials support administration of LMWH in at risk patients Cancer patients are under-prophylaxed for VTECancer patients are under-prophylaxed for VTE Health system pharmacists can play a pivotal role in improving clinical outcomes in this patient populationHealth system pharmacists can play a pivotal role in improving clinical outcomes in this patient population

124 Mayo/NCCTG Symptom-Control Trials: Innovation Investigation Application Charles Loprinzi, MD Professor of Oncology Director, NCCTG Cancer Control Program Co-Director Mayo Cancer Center Cancer Prevention and Control Program Mayo Clinic Rochester, MN Prevention and Control Program Mayo Clinic Rochester, MN Chemotherapy-induced Neuropathy and Hot Flashes

125 Topics Overview: Sx control studies can be accomplished Overview: Sx control studies can be accomplished Chemotherapy induced peripheral neuropathy Chemotherapy induced peripheral neuropathy Hot flashes Hot flashes

126 Symptom Control Trials Anorexia/cachexia Hot flash Anemia Skin toxicity Sexual health Fatigue Pain Antiemetic Mucosal toxicity Neuropathy Bone health

127 Symptom Control Trials Anorexia/cachexia Hot flash Anemia Skin toxicity Sexual health Fatigue Pain Antiemetic Mucosal toxicity Neuropathy Bone health

128 Topics Overview: Sx control studies can be accomplished Overview: Sx control studies can be accomplished Chemotherapy induced peripheral neuropathy Chemotherapy induced peripheral neuropathy Hot flashes Hot flashes

129 Mayo/NCCTG CIPN Program Treatment of established CIPN Treatment of established CIPN Prevention of CIPN Prevention of CIPN Paclitaxel acute pain syndrome Paclitaxel acute pain syndrome

130 Treatment of Established CIPN Nortriptyline Nortriptyline Gabapentin Gabapentin Lamotrigene Lamotrigene Baclofen/amitriptyline/ketamine Baclofen/amitriptyline/ketamine

131 Treatment of Established CIPN Nortriptyline Nortriptyline Gabapentin Gabapentin Lamotrigene Lamotrigene Baclofen/amitriptyline/ketamine Baclofen/amitriptyline/ketamine

132 Audience Poll How many practices are How many practices are commonly using gabapentin commonly using gabapentin (Neurontin) or pregabalin (Lyrica) (Neurontin) or pregabalin (Lyrica) for pts with CIPN? for pts with CIPN?

133 Efficacy of Gabapentin in the Management of Chemotherapy-Induced Peripheral Neuropathy: A Phase 3 Randomized, Double-Blind, Placebo- Controlled, Crossover Trial (N00C3) Rao R, Michalak J, Sloan J, Loprinzi C, Soori G, Nikcevich D, Warner D, Novotny P, Kutteh L, Wong G Cancer 110(9):2110, 2007

134 Study Schema R R 6 wk Gabapentin 2700 mg/day Placebo 6 wk Placebo Gabapentin 2700 mg/day 2 wk Washout Chemotherapy-induced neuropathy

135 Placebo Gabapentin Mean pain intensity Mean pain intensity Week P=0.21 P=0.37 First period Wash- out Second period Mean Pain Intensity Placebo Gabapentin

136 Cancer 110(9):2110, 2007 Mean value at the end of the first 6-week phase (expressed as a percentage of baseline score) POMS Uniscale SDS WHO ECOG Average pain (NRS) Worst pain (NRS) Placebo Gabapentin Gabapentin for CIPN

137 Conclusions Regarding Treatment of CIPN from this Experience 2 small tricyclic antidepressant studies – but cant rule out a small benefit 2 small tricyclic antidepressant studies – but cant rule out a small benefit Gabapentin doesnt appear to work – but what about pregabalin? Gabapentin doesnt appear to work – but what about pregabalin? Lamotrigine doesnt appear to work Lamotrigine doesnt appear to work Topical BAK looks like it is worth pursuing further Topical BAK looks like it is worth pursuing further

138 Mayo/NCCTG CIPN Program Treatment of established CIPN Treatment of established CIPN Prevention of CIPN Prevention of CIPN Paclitaxel acute pain syndrome Paclitaxel acute pain syndrome

139 Prevention of CIPN Calcium/magnesium Calcium/magnesiumOxaliplatin Vitamin E Vitamin E

140 Audience Poll How many are routinely using How many are routinely using Ca/Mg for pts receiving FULFOX? Ca/Mg for pts receiving FULFOX?

141 DA Nikcevich, A Grothey, JA Sloan, JW Kugler, PT Silberstein, T Dentchev, DB Wender, PJ Novotny, HE Windschitl, CL Loprinzi J Clin Oncol 2008; May 20 suppl (abstract 4009) Intravenous Calcium and Magnesium for Oxaliplatin-Induced Sensory Neurotoxicity (N04C7) For the North Central Cancer Treatment Group DA Nikcevich, A Grothey, JA Sloan, JW Kugler, PT Silberstein, T Dentchev, DB Wender, PJ Novotny, HE Windschitl, CL Loprinzi

142 Cumulative peripheral sensory neurotoxicity is the dose-limiting toxicity of oxaliplatin Cumulative peripheral sensory neurotoxicity is the dose-limiting toxicity of oxaliplatin In a retrospective, non-randomized study, intravenous administration of calcium and magnesium salts (CaMg) was associated with reduced oxaliplatin-induced PSN (Gamelin: Clin Cancer Res, 2004) In a retrospective, non-randomized study, intravenous administration of calcium and magnesium salts (CaMg) was associated with reduced oxaliplatin-induced PSN (Gamelin: Clin Cancer Res, 2004) Background

143 N04C7 Cancer Control Phase III Trial – Study Design Patients to receive adj FOLFOX R R IV CaMg IV placebo % of grade 2+ sNT

144 Primary Endpoint Grade 2+ sNT (CTCAE Scale) Primary Endpoint Grade 2+ sNT (CTCAE Scale) NeurotoxicityCaMgPlacebo graden=50n=52P Grade 2+22%41%0.038 NeurotoxicityCaMgPlacebo graden=50n=52P Grade 2+22%41%0.038

145 Placebo Ca/Mg Time to Grade 2+ sNT (CTC scale) % Free 2+ sNT % Free 2+ sNT Weeks P=0.05

146 Endpoint: Grade 2+ sNT (Oxaliplatin Scale) Endpoint: Grade 2+ sNT (Oxaliplatin Scale) NeurotoxicityCaMgPlacebo graden=50n=52P Grade 2+28%51%0.018 NeurotoxicityCaMgPlacebo graden=50n=52P Grade 2+28%51%0.018

147 Placebo Ca/Mg Time to Grade 2+ sNT (Oxaliplatin scale) Weeks P=0.03 % Free 2+ sNT % Free 2+ sNT

148 Concept Trial Story Hochster HS, Grothey A, Childs BH. Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. Journal of Clinical Oncology 2007;25(25):

149 French NEUROXA Study French NEUROXA Study 144 patients with colorectal cancer in the adjuvant and palliative setting 144 patients with colorectal cancer in the adjuvant and palliative setting Randomized, in a double-blind manner, to get CaMg versus a placebo Randomized, in a double-blind manner, to get CaMg versus a placebo Early analyses of data from this trial have become available Early analyses of data from this trial have become available Gamelin L et al: J Clin Oncol 26(7):1188, 2008

150 French NEUROXA Study French NEUROXA Study Objective response rates and survivals were equivalent in the two arms Objective response rates and survivals were equivalent in the two arms Substantially less neurotoxicity in one group vs the other (5% vs 24% of grade 3 NCI Common Toxicity Criteria, P<0.001) Substantially less neurotoxicity in one group vs the other (5% vs 24% of grade 3 NCI Common Toxicity Criteria, P<0.001) The blind for this trial has not yet been broken The blind for this trial has not yet been broken Gamelin L et al: J Clin Oncol 26(7):1188, 2008

151 The Use of Calcium and Magnesium for Prevention of Chemotherapy- Induced Peripheral Neuropathy A Phase III Double-Blind Placebo- Controlled Study N08CB

152 Placebo – 2 doses FOLFOX R* CaMg – 2 doses CaMg – 1 dose

153 Conclusions Regarding Prevention of CIPN from this Experience CaMg looks like it works for oxaliplatin, but confirmation needed to convince the troops CaMg looks like it works for oxaliplatin, but confirmation needed to convince the troops Vitamin E does not appear to work for CIPN, across different drugs Vitamin E does not appear to work for CIPN, across different drugs

154 Mayo/NCCTG CIPN Program Treatment of established CIPN Treatment of established CIPN Prevention of CIPN Prevention of CIPN Paclitaxel acute pain syndrome Paclitaxel acute pain syndrome

155 Audience Poll What is the etiology of the transient acute pain that commonly occurs a couple days after paclitaxel? What is the etiology of the transient acute pain that commonly occurs a couple days after paclitaxel? Myalgia Myalgia Arthralgia Arthralgia Something else Something else

156 Paclitaxel Acute Pain Syndrome Nerve injury hypothesis Nerve injury hypothesis Glutamine Glutamine (aka arthralgia/myalgia)

157 Animal Data As early as one day following infusion of paclitaxel, a subset of large, medium and small sensory neurons increased their expression of activating transcription factor 3 (ATF3)

158

159 The Paclitaxel Acute Pain Syndrome: Sensitization of Nociceptors as the Putative Mechanism Loprinzi et al: J Cancer 13(6):399, 2007

160 Methods With IRB approval, eighteen patients with cancer receiving paclitaxel, who complained of acute pain, were questioned, using a structured interview

161 Goal To identify the pain descriptors used, the anatomical distribution of symptoms, the severity of the pain, the factors that influenced the pain, and the time course of the pain

162 Patient Characteristics Age42-77 Tumor type Breast10 Gyn 5 Lung 2 Tonsil 1 Tumor type Breast10 Gyn 5 Lung 2 Tonsil 1 M/F2/16 Dose (mg/m 2 ) Dose (mg/m 2 )

163 Patient Descriptions Aching Aching, pain, bad ache Joint pain, growing pains Pulsating, electricity, discomfort Aching, tired pain Aching Aching, pain, bad ache Joint pain, growing pains Pulsating, electricity, discomfort Aching, tired pain Sharp deep pain Aching Pain, achiness Shooting pain Dull ache progressing to shooting pains Sharp deep pain Aching Pain, achiness Shooting pain Dull ache progressing to shooting pains

164 Patient Descriptions Real deep bone pain, not in the joints Deep bone pain Dull constant ache Joint, aching, what I think arthritis would be like Real deep bone pain, not in the joints Deep bone pain Dull constant ache Joint, aching, what I think arthritis would be like Shooting pain Deep pain like the flu Joint pain, muscle aches Low level flu, body ache, muscle Shooting pain Deep pain like the flu Joint pain, muscle aches Low level flu, body ache, muscle

165 Location Low back, then hips, legs, knees, whole body Knees Started at top of legs, down to ankles All over From the top of the knees to front of shin and top of feet, bilaterally Low back, then hips, legs, knees, whole body Knees Started at top of legs, down to ankles All over From the top of the knees to front of shin and top of feet, bilaterally Front of legs (shins); ankles/feet Hips, butt, thighs, knees, ankles, and feet Radiating from the legs down to ankle Radiates down from shoulders, radiates down legs Knees, ankles, feet Front of legs (shins); ankles/feet Hips, butt, thighs, knees, ankles, and feet Radiating from the legs down to ankle Radiates down from shoulders, radiates down legs Knees, ankles, feet

166 Location Legs and shoulders Legs Hands, feet, pelvis/back Mainly hips, knees, back; moved from joint to joint; jaw to feet, but not arms Legs and shoulders Legs Hands, feet, pelvis/back Mainly hips, knees, back; moved from joint to joint; jaw to feet, but not arms Mainly hip, also knees ankle, femur; usually bilateral Hamstring back of legs from mid thigh through knee Traveled through the body majority in hips/legs, also neck, shoulders, chest Mainly hip, also knees ankle, femur; usually bilateral Hamstring back of legs from mid thigh through knee Traveled through the body majority in hips/legs, also neck, shoulders, chest

167 Patient Descriptions Severity Mild3 Mild-moderate2 Moderate3 Severe9 Not stated1 Severity Mild3 Mild-moderate2 Moderate3 Severe9 Not stated1 Aggrevating factors None noted12 Walking 3 Sitting 1 Worse as day 1 went on Worse at night 1 Aggrevating factors None noted12 Walking 3 Sitting 1 Worse as day 1 went on Worse at night 1 Deep vs 100% surface deep

168 Patient Descriptions Onset after drugs (days)Pt Onset after drugs (days)Pt Duration (days)Pt Duration (days)Pt

169 Conclusion The nature and time course of P-APS, supported by the notation that paclitaxel frequently results in a distal sensorimotor polyneuropathy with longer term use, suggests that the P-APS is caused by a widely distributed sensitization of nociceptors, their fibers, or the spinothalamic system

170 Paclitaxel-Associated Acute Pain Syndrome Natural History Study Patients scheduled to receive IV paclitaxel at 1 of 2 dose/schedules 175+ mg/m 2 q 2-4 wk70-90 mg/m 2 weekly Patients scheduled to receive IV paclitaxel at 1 of 2 dose/schedules 175+ mg/m 2 q 2-4 wk70-90 mg/m 2 weekly Patient questionnaires looking at the incidence and severity of paclitaxel-associated acute pain and sensory neuropathy

171 Goals Detail the incidence, timing, severity, and characteristics of the P-APS in patients receiving paclitaxel Detail the incidence, timing, severity, and characteristics of the P-APS in patients receiving paclitaxel Describe differences between patients getting weekly versus less frequent, higher dose treatment Describe differences between patients getting weekly versus less frequent, higher dose treatment Study whether individuals with more prominent P-APS have more prominent later term distal neuropathy problems Study whether individuals with more prominent P-APS have more prominent later term distal neuropathy problems

172 Topics Overview: Sx control studies can be accomplished Overview: Sx control studies can be accomplished Chemotherapy induced peripheral neuropathy Chemotherapy induced peripheral neuropathy Hot flashes Hot flashes

173 Placebo (n=420) Soy (n=78) Clonidine (n=75) Megestrol (n=74) Fluoxetine (n=36) Venlafaxine (n=48) Vitamin E (n=53)

174 Placebo (n=420) Soy (n=78) Clonidine (n=75) Megestrol (n=74) Fluoxetine (n=36) Venlafaxine (n=48) Vitamin E (n=53) Black Cohosh (n=58) Ven (vs MPA) (n=94) MPA 400 mg (n=94)

175 Placebo (n=420) Soy (n=78) Clonidine (n=75) Megestrol (n=74) Fluoxetine (n=36) Venlafaxine (n=48) Vitamin E (n=53) Black Cohosh (n=58) Ven (vs MPA) (n=94) MPA 400 mg (n=94)

176 Favors antidepressantFavors placebo Loprinzi, Fluoxetine 20 mg/g HR (fixed) 95% CI Study Stearns, Paroxetine 10 mg/d Stearns, Paroxetine 20 mg/d Stearns, Paroxetine 12.5 mg/d Stearns, Paroxetine 25 mg/d Paroxetine total Gordon, Sertraline 50 mg/d Kimmick, Sertraline 50 mg/d Grady, Sertraline 100 mg/d Sertraline total Loprinzi, Venlafaxine 37.5 mg/d Loprinzi, Venlafaxine 75 mg/d Loprinzi, Venlafaxine 150 mg/d Venlafaxine total Antidepressants total

177 Favors gabapentinFavors placebo Pandya 300 mg/d Pandya 900 mg/d Guttuso 900 mg/d Reddy 2400 mg/d Total HR (fixed) 95% CI Study

178 Hot Flash Conclusions Newer antidepressants decrease hot flashes Newer antidepressants decrease hot flashes Gabapentin decreases hot flashes Gabapentin decreases hot flashes

179 Case Studies

180 Case #1 48 year old woman with Stage II breast cancer treated with lumpectomy and radiotherapy – now scheduled for adjuvant chemotherapy with cyclophosphamide and doxorubicin 48 year old woman with Stage II breast cancer treated with lumpectomy and radiotherapy – now scheduled for adjuvant chemotherapy with cyclophosphamide and doxorubicin Non-smoker, non-drinker Non-smoker, non-drinker Has 2 children and had severe morning sickness with each pregnancy Has 2 children and had severe morning sickness with each pregnancy Experiences motion sickness on ships but not on airplanes Experiences motion sickness on ships but not on airplanes Taking coumadin for DVT that developed during her hospitalization for lumpectomy Taking coumadin for DVT that developed during her hospitalization for lumpectomy

181 Case #1 - Management What would the initial antiemetic management be? What would the initial antiemetic management be? What is her expected response to antiemetic therapy? What is her expected response to antiemetic therapy? What risk factors are pertinent in estimating her response? What risk factors are pertinent in estimating her response? Are there any other changes to be made in her medical management? Are there any other changes to be made in her medical management?

182 Case #2 24 year old man with metastatic testicular cancer 24 year old man with metastatic testicular cancer Being treated with PVB (cisplatin, vinblastine, bleomycin) Being treated with PVB (cisplatin, vinblastine, bleomycin) Smokes 1 pack per day of cigarettes; drinks beer on weekends Smokes 1 pack per day of cigarettes; drinks beer on weekends Used marijuana while in college but has since discontinued use Used marijuana while in college but has since discontinued use

183 Case #2 - Management What would the initial antiemetic management be? What would the initial antiemetic management be? How would you approach emesis occurring How would you approach emesis occurring One day after chemotherapy One day after chemotherapy 3 days after chemotherapy 3 days after chemotherapy 10 days after chemotherapy 10 days after chemotherapy 20 days after chemotherapy 20 days after chemotherapy How would you evaluate refractory emesis? How would you evaluate refractory emesis?

184 Case #3 Active 50 year old Caucasian male with charley horse of RLE for >6 days Active 50 year old Caucasian male with charley horse of RLE for >6 days Pain, swelling, erythema spreads to thigh over this time Pain, swelling, erythema spreads to thigh over this time 36 pack year history of cigarette smoking 36 pack year history of cigarette smoking Developed superficial thrombophlebitis 6 months ago after IV placement for routine colonoscopy Developed superficial thrombophlebitis 6 months ago after IV placement for routine colonoscopy

185 Hypercoagulability work up negative for: Hypercoagulability work up negative for: Factor V Leiden Factor V Leiden Prothrombin gene mutation Prothrombin gene mutation Antithrombin III activity Antithrombin III activity Protein C and S Protein C and S LAC LAC Duplex doppler ultrasound was positive for bilateral DVT s extending from popliteal to superficial femoral veins Duplex doppler ultrasound was positive for bilateral DVT s extending from popliteal to superficial femoral veins Patient hospitalized for UFH and coumadin transition Patient hospitalized for UFH and coumadin transition Case #3

186 CBC-WNL except platelets=650K CBC-WNL except platelets=650K CMP-WNL CMP-WNL Coagulation studies-WNL except for fibrinogen=758 mg/dL Coagulation studies-WNL except for fibrinogen=758 mg/dL D-dimers >2800 ng/mL ( 2800 ng/mL (<200) Case #3

187 Coumadin discontinued after 6 months Coumadin discontinued after 6 months Follow up labs: Follow up labs: D-dimers = 1000 ng/ml D-dimers = 1000 ng/ml Fibrinogen = 570 mg/mL Fibrinogen = 570 mg/mL FVIII = 650% FVIII = 650% Repeat Duplex dopplers = residual DVTs Repeat Duplex dopplers = residual DVTs

188 Case #3 - Conclusions Unprovoked DVT in patient >50 years old with negative family history and particularly large clot burden requires look for occult malignancy Unprovoked DVT in patient >50 years old with negative family history and particularly large clot burden requires look for occult malignancy Development of superficial thrombophlebitis in past and bilateral proximal DVT are significant Development of superficial thrombophlebitis in past and bilateral proximal DVT are significant Elevated FVIII and D-dimers and residual DVT post adequate anticoagulation are indicators of hypercoagulability Elevated FVIII and D-dimers and residual DVT post adequate anticoagulation are indicators of hypercoagulability CT scan of chest (hx of smoking) reveals 3 cm mass and bronchogenic washings confirm bronchogenic Ca CT scan of chest (hx of smoking) reveals 3 cm mass and bronchogenic washings confirm bronchogenic Ca

189 45 yo F Stage IB Endometrial Carcinoma 45 yo F Stage IB Endometrial Carcinoma TAH, BSO, LND TAH, BSO, LND Received prophylactic post op IV heparin x 4 days Received prophylactic post op IV heparin x 4 days Post-op Day 6 - chest pain and SOB, collapsed, cyanotic Post-op Day 6 - chest pain and SOB, collapsed, cyanotic VQ scan (+) for PE & 5mm tip of CVC VQ scan (+) for PE & 5mm tip of CVC IV Heparin re-initiated + urokinase given for thrombolysis with initial improvement in signs and symptoms IV Heparin re-initiated + urokinase given for thrombolysis with initial improvement in signs and symptoms Post-op Day 9 - sudden PLT drop 238,000 to 39,000mcL Post-op Day 9 - sudden PLT drop 238,000 to 39,000mcL HIT suspected, heparin d/c'd HIT suspected, heparin d/c'd Aida H, Aoki Y, Ohki I, & Tanaka K. Anticoagulation with a selective thrombin inhibitor in a woman with heparin-induced thrombocytopenia. Obstet Gynecol. 2001;98: Case #4

190 POD 10, CVC thrombus larger. Underwent successful thrombectomy POD 10, CVC thrombus larger. Underwent successful thrombectomy Argatroban was administered intra- and postoperatively Argatroban was administered intra- and postoperatively PLT post-op Day ,000/mcL PLT post-op Day ,000/mcL Oral warfarin and ASA initiated Oral warfarin and ASA initiated PLT post-op Day ,000/mcL PLT post-op Day ,000/mcL Patient was discharged home without further complications on hospital Day 32 Patient was discharged home without further complications on hospital Day 32 Case based on an actual patient. Individual results may vary. Aida H, Aoki Y, Ohki I, & Tanaka K. Anticoagulation with a selective thrombin inhibitor in a woman with heparin-induced thrombocytopenia. Obstet Gynecol. 2000;98: Case #4

191 Potential Causes Potential Causes Drug therapy Drug therapy anesthesia, pain meds, heparin, urokinase anesthesia, pain meds, heparin, urokinase Patient Factors Patient Factors obese, carcinoma obese, carcinoma Events Events surgery surgery Timing of PLT drop Timing of PLT drop re-exposure of heparin re-exposure of heparin day 3 day 3 Degree of PLT fall Degree of PLT fall 238,000 to 39,000mcL 238,000 to 39,000mcL Concurrent events Concurrent events CVC thrombosis CVC thrombosis PE PE Lab findings Lab findings elevated IgG antibody by immunoassay elevated IgG antibody by immunoassay Aida H, Aoki Y, Ohki I, & Tanaka K. (2001). Anticoagulation with a selective thrombin inhibitor in a woman with heparin-induced thrombocytopenia. Obstet Gynecol. 2001;98: Case #4


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