New Dimensions and Landmark Advances in Supportive Care for the Cancer Patient Optimizing Prevention...

New Dimensions New Dimensions and and Landmark Advances Landmark Advances in in Supportive Care Supportive Care for the for the Cancer PatientCancer Patient

Optimizing Prevention and Management of Drug-Related Side Optimizing Prevention and Management of Drug-Related Side Effects and Thrombotic Complications in the Setting of MalignancyEffects and Thrombotic Complications in the Setting of Malignancy

New Dimensions New Dimensions and and Landmark Advances Landmark Advances in in Supportive Care Supportive Care for the for the Cancer PatientCancer Patient

Optimizing Prevention and Management of Drug-Related Side Optimizing Prevention and Management of Drug-Related Side Effects and Thrombotic Complications in the Setting of MalignancyEffects and Thrombotic Complications in the Setting of Malignancy

Program ChairmanProgram ChairmanCraig M. Kessler, MDCraig M. Kessler, MDProfessor of Medicine and PathologyProfessor of Medicine and PathologyGeorgetown University Medical CenterGeorgetown University Medical CenterDirector of the Division of CoagulationDirector of the Division of CoagulationDepartment of Laboratory MedicineDepartment of Laboratory MedicineLombardi Comprehensive Cancer CenterLombardi Comprehensive Cancer CenterWashington, DCWashington, DC

Innovation ● Investigation ● ApplicationInnovation ● Investigation ● Application

Steven Grunberg, MDSteven Grunberg, MDProgram Co-ChairmanProgram Co-Chairman

Professor of MedicineProfessor of MedicineUniversity of VermontUniversity of Vermont

Burlington, VermontBurlington, Vermont

CME-accredited symposiumCME-accredited symposium jointly sponsored by University of jointly sponsored by University of Massachusetts Medical Center, office of CME and CMEducation Massachusetts Medical Center, office of CME and CMEducation Resources, LLCResources, LLC

Commercial Support:Commercial Support: Sponsored by an independent educational grant Sponsored by an independent educational grant from Eisai, Inc.from Eisai, Inc.

Mission statement:Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes:Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI:COI: Full faculty disclosures provided in syllabus and at the beginning Full faculty disclosures provided in syllabus and at the beginning of the programof the program

CME-accredited symposiumCME-accredited symposium jointly sponsored by University of jointly sponsored by University of Massachusetts Medical Center, office of CME and CMEducation Massachusetts Medical Center, office of CME and CMEducation Resources, LLCResources, LLC

Commercial Support:Commercial Support: Sponsored by an independent educational grant Sponsored by an independent educational grant from Eisai, Inc.from Eisai, Inc.

Mission statement:Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes:Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI:COI: Full faculty disclosures provided in syllabus and at the beginning Full faculty disclosures provided in syllabus and at the beginning of the programof the program

Welcome and Program OverviewWelcome and Program Overview

Program Educational ObjectivesProgram Educational Objectives

As a result of this session, participants will: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: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.

Program FacultyProgram Faculty

Craig M. Kessler, MDCraig M. Kessler, MDProgram Co-ChairmanProgram Co-ChairmanProfessor of Medicine and PathologyProfessor of Medicine and PathologyGeorgetown University Medical CenterGeorgetown University Medical CenterLombardi Comprehensive Cancer CenterLombardi Comprehensive Cancer CenterChief, Division of CoagulationChief, Division of CoagulationWashington, DCWashington, DC

Charles Loprinzi, MDCharles Loprinzi, MDProfessor of OncologyProfessor of OncologyDirector, NCCTG Cancer Control ProgramDirector, NCCTG Cancer Control ProgramCo-Director Mayo Cancer Center Cancer Co-Director Mayo Cancer Center Cancer Prevention and Control ProgramPrevention and Control ProgramMayo ClinicMayo ClinicRochester, MNRochester, MN

Steven Grunberg, MDSteven Grunberg, MDProgram Co-ChairmanProgram Co-ChairmanProfessor of MedicineProfessor of MedicineUniversity of VermontUniversity of VermontBurlington, VermontBurlington, Vermont

Faculty COI Financial DisclosuresFaculty COI Financial Disclosures

Craig M. Kessler, MD - Co-ChairmanCraig M. Kessler, MD - Co-ChairmanGrant/Research Support: Grant/Research Support: GlaxoSmithKlineGlaxoSmithKlineConsultant: Consultant: Sanofi-Aventis, Eisai PharmaceuticalsSanofi-Aventis, Eisai PharmaceuticalsSpeaker’s Bureau: Speaker’s Bureau: Sanofi-Aventis, GlaxoSmithKlineSanofi-Aventis, GlaxoSmithKline Steven Grunberg, MD - Co-ChairmanSteven Grunberg, MD - Co-ChairmanGrant/Research: Grant/Research: MerckMerckConsultant: Consultant: Merck, GlaxoSmithKlineMerck, GlaxoSmithKlineSpeaker’s Bureau: Speaker’s Bureau: Merck, EisaiMerck, Eisai Charles Loprinzi, MDCharles Loprinzi, MDNo information to discloseNo information to disclose

Global Care of the Cancer PatientGlobal Care of the Cancer Patient

Symptom ManagementSymptom Management


Professor of MedicineProfessor of MedicineUniversity of VermontUniversity of VermontBurlington, VermontBurlington, Vermont


Symptom ManagementSymptom Management

► Interchangeable terms that do not mean the same Interchangeable terms that do not mean the same thingthing● Symptom managementSymptom management● Supportive careSupportive care● Palliative carePalliative care

► Symptom management is an integral part of cancer Symptom management is an integral part of cancer care throughout the disease course, not just at end-care throughout the disease course, not just at end-of-lifeof-life

Symptom Management and Palliative CareSymptom Management and Palliative Care

► Palliative care concentrates on disease-related and late Palliative care concentrates on disease-related and late treatment-related symptom management. Observations treatment-related symptom management. Observations and research are not complicated by acute treatment-and research are not complicated by acute treatment-related symptoms.related symptoms.

► Symptom management concentrates on disease-related Symptom management concentrates on disease-related and acute treatment-related symptom management. and acute treatment-related symptom management. Observations and research are not complicated by Observations and research are not complicated by rapidly declining performance status.rapidly declining performance status.

► Survivorship concentrates on late treatment-related Survivorship concentrates on late treatment-related symptom management. Observations and research are symptom management. Observations and research are not complicated by acute treatment or disease effects.not complicated by acute treatment or disease effects.

► All of these areas can learn from each otherAll of these areas can learn from each other..

Symptoms and PrognosisSymptoms 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 Older philosophy that assumes a lack of effective symptom management. May apply when a new symptom management. May apply when a new treatment is devised since non-lethal toxicity will treatment is devised since non-lethal toxicity will seldom stop approval of an effective cancer remedy.seldom stop approval of an effective cancer remedy.

► Challenge of symptom management is to block Challenge of symptom management is to block toxicity without compromising efficacytoxicity without compromising efficacy

Supportive Care Toxicity TargetsSupportive Care Toxicity Targets

► HematologicHematologic● MyelosuppressionMyelosuppression

► GastrointestinalGastrointestinal● Nausea/vomitingNausea/vomiting● Constipation/diarrheaConstipation/diarrhea● MucositisMucositis

► CardiovascularCardiovascular● ThrombosisThrombosis● CardiacCardiac

► Neurologic Neurologic ● Peripheral neuropathyPeripheral neuropathy● CognitiveCognitive

► PulmonaryPulmonary

► RenalRenal

► CutaneousCutaneous● AlopeciaAlopecia● RashRash

Cancer and Prevention of VTECancer and Prevention of VTE

Landmark Advances and New Paradigms of Care Landmark Advances and New Paradigms of Care for the Oncologist and Clinical Support Specialistfor the Oncologist and Clinical Support Specialist

Cancer and Prevention of VTECancer and Prevention of VTE

Landmark Advances and New Paradigms of Care Landmark Advances and New Paradigms of Care for the Oncologist and Clinical Support Specialistfor the Oncologist and Clinical Support Specialist

Program Co-ChairmanProgram Co-ChairmanCraig Kessler, MD MACPCraig Kessler, MD MACP

Director, Division of CoagulationDirector, Division of CoagulationLombardi Comprehensive Cancer CenterLombardi Comprehensive Cancer Center

Georgetown University Medical CenterGeorgetown University Medical CenterWashington, DCWashington, DC





VTE and Cancer—A Looming VTE and Cancer—A Looming National Healthcare CrisisNational Healthcare Crisis

MISSION AND CHALLENGESMISSION AND CHALLENGES

Recognizing cancer patients at risk for DVT and Recognizing cancer patients at risk for DVT and identifying appropriate candidates for long-term identifying appropriate candidates for long-term prophylaxis and/or treatment with approved and prophylaxis and/or treatment with approved and indicated therapies are among the most important indicated therapies are among the most important challenges encountered in contemporary pharmacy challenges encountered in contemporary pharmacy and clinical practice.and clinical practice.

MISSION AND CHALLENGESMISSION AND CHALLENGES

Recognizing cancer patients at risk for DVT and Recognizing cancer patients at risk for DVT and identifying appropriate candidates for long-term identifying appropriate candidates for long-term prophylaxis and/or treatment with approved and prophylaxis and/or treatment with approved and indicated therapies are among the most important indicated therapies are among the most important challenges encountered in contemporary pharmacy challenges encountered in contemporary pharmacy and clinical practice.and clinical practice.

COMORBIDITYCOMORBIDITYCONNECTIONCONNECTION

CAPCAPUTIUTICancerCancerHeart Failure Heart Failure ABE/COPDABE/COPDRespiratory FailureRespiratory Failure Myeloproliferative DisorderMyeloproliferative DisorderThrombophiliaThrombophiliaSurgerySurgeryHistory of DVTHistory of DVTOtherOther

COMORBIDITYCOMORBIDITYCONNECTIONCONNECTION

CAPCAPUTIUTICancerCancerHeart Failure Heart Failure ABE/COPDABE/COPDRespiratory FailureRespiratory Failure Myeloproliferative DisorderMyeloproliferative DisorderThrombophiliaThrombophiliaSurgerySurgeryHistory of DVTHistory of DVTOtherOther

SUBSPECIALISTSUBSPECIALISTSTAKEHOLDERSSTAKEHOLDERS

Infectious diseasesInfectious diseasesOncologyOncologyPHARMACISTSPHARMACISTSCardiology Cardiology Pulmonary medicinePulmonary medicineHematologyHematologyOncology/hematologyOncology/hematologyInterventional RadiologyInterventional RadiologyHospitalistHospitalistSurgeonsSurgeonsEMEMPCPPCP

SUBSPECIALISTSUBSPECIALISTSTAKEHOLDERSSTAKEHOLDERS

Infectious diseasesInfectious diseasesOncologyOncologyPHARMACISTSPHARMACISTSCardiology Cardiology Pulmonary medicinePulmonary medicineHematologyHematologyOncology/hematologyOncology/hematologyInterventional RadiologyInterventional RadiologyHospitalistHospitalistSurgeonsSurgeonsEMEMPCPPCP

Comorbidity ConnectionComorbidity Connection

Epidemiology of First-Time VTEEpidemiology of First-Time VTE

White R. White R. CirculationCirculation. 2003;107:I-4 –I-8.). 2003;107:I-4 –I-8.)

VariableVariable FindingFinding

Seasonal VariationSeasonal Variation Possibly more common in winter and less Possibly more common in winter and less common in summercommon in summer

Risk FactorsRisk Factors25% to 50% “idiopathic”25% to 50% “idiopathic”

15%-25% associated with cancer15%-25% associated with cancer20% following surgery (3 months)20% following surgery (3 months)

Recurrent VTERecurrent VTE

6-month incidence, 7%;6-month incidence, 7%;Higher rate in patients with cancerHigher rate in patients with cancer

Recurrent PE more likely after PE than Recurrent PE more likely after PE than after DVTafter DVT

Death After Treated VTEDeath After Treated VTE

30-day incidence 6% after incident DVT30-day incidence 6% after incident DVT30-day incidence 12% after PE30-day incidence 12% after PE

Death strongly associated with Death strongly associated with cancercancer, , age, and cardiovascular diseaseage, and cardiovascular disease

Epidemiology of VTEEpidemiology of VTE

White R. White R. CirculationCirculation. 2003;107:I-4 –I-8.). 2003;107:I-4 –I-8.)

► One major risk factor for VTE is ethnicity, with a One major risk factor for VTE is ethnicity, with a significantly higher incidence among Caucasians significantly higher incidence among Caucasians and African Americans than among Hispanic and African Americans than among Hispanic persons and Asian-Pacific Islanders. persons and Asian-Pacific Islanders.

► Overall, about 25% to 50% of patient with first-time Overall, about 25% to 50% of patient with first-time VTE have an idiopathic condition, without a readily VTE have an idiopathic condition, without a readily identifiable risk factor. identifiable risk factor.

► Early mortality after VTE is strongly associated with Early mortality after VTE is strongly associated with presentation as PE, advanced age, presentation as PE, advanced age, cancer,cancer, and and underlying cardiovascular disease. underlying cardiovascular disease.

Comorbidity ConnectionComorbidity Connection

ComorbidityComorbidityConnectionConnection

Overview Overview

Acute Medical Illness and VTEAcute Medical Illness and VTE

Multivariate Logistic Regression ModelMultivariate Logistic Regression Modelfor Definite Venous Thromboembolism (VTE)for Definite Venous Thromboembolism (VTE)

Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968

Risk FactorRisk Factor Odds RatioOdds Ratio(95% CI)(95% CI)

XX22

Age > 75 yearsAge > 75 yearsCancerCancer

Previous VTEPrevious VTE

1.03 (1.00-1.06)1.03 (1.00-1.06)1.62 (0.93-2.75)1.62 (0.93-2.75)2.06 (1.10-3.69)2.06 (1.10-3.69)

0.00010.00010.080.080.020.02

Acute infectious Acute infectious diseasedisease

1.74 (1.12-2.75)1.74 (1.12-2.75) 0.020.02

Comorbid Condition and DVT Risk Comorbid Condition and DVT Risk

► Hospitalization for surgery (24%) and for medical illness Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while (22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%.nursing home residence accounted for 13%.

► The individual attributable risk estimates for The individual attributable risk estimates for malignant malignant neoplasmneoplasm, trauma, congestive heart failure, central venous , trauma, congestive heart failure, central venous catheter or pacemaker placement, neurological disease with catheter or pacemaker placement, neurological disease with extremity paresis, and superficial vein thrombosis were extremity paresis, and superficial vein thrombosis were 18%,18%, 12%, 10%, 9%, 7%, and 5%, respectively.12%, 10%, 9%, 7%, and 5%, respectively.

► Together, the 8 risk factors accounted for 74% of disease Together, the 8 risk factors accounted for 74% of disease occurrenceoccurrence

Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern MedArch Intern Med. . 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study embolism: a population-based study

VTE RecurrenceVTE Recurrence

Predictors of First Overall VTE RecurrencePredictors of First Overall VTE Recurrence

Heit J, Mohr D, et al. Heit J, Mohr D, et al. Arch Intern MedArch Intern Med. 2000;160:761-768. 2000;160:761-768

Baseline CharacteristicBaseline Characteristic Hazard RatioHazard Ratio(95% CI)(95% CI)

AgeAge 1.17 (1.11-1.24)1.17 (1.11-1.24)

Body Mass IndexBody Mass Index 1.24 (1.04-1.7)1.24 (1.04-1.7)

Neurologic disease with extremity Neurologic disease with extremity paresisparesis

1.87 (1.28-2.73)1.87 (1.28-2.73)

Malignant neoplasmMalignant neoplasmWith chemotherapyWith chemotherapy

Without chemotherapyWithout chemotherapy4.24 (2.58-6.95)4.24 (2.58-6.95)2.21 (1.60-3.06)2.21 (1.60-3.06)

ICOPER Cumulative MortalityICOPER Cumulative MortalityM

orta

lity

(%)

Mor

talit

y (%

)

Days From DiagnosisDays From Diagnosis

17.5%17.5%

00

55

1010

1515

2020

2525

Lancet 1999;353:1386-1389Lancet 1999;353:1386-1389

77 1414 3030 6060 9090

Stages of Chronic Venous InsufficiencyStages of Chronic Venous Insufficiency

1.1. Varicose veinsVaricose veins

2.2. Ankle/ leg edemaAnkle/ leg edema

3.3. Stasis dermatitisStasis dermatitis

4.4. LipodermatosclerosisLipodermatosclerosis

5.5. Venous stasis ulcerVenous stasis ulcer

Progression of Chronic Venous InsufficiencyProgression of Chronic Venous Insufficiency

From UpToDate 2006From UpToDate 2006

Rising VTE Incidence in Rising VTE Incidence in Hospitalized PatientsHospitalized Patients

Stein PD et al. Am J Cardiol 2005; 95: 1525-1526Stein PD et al. Am J Cardiol 2005; 95: 1525-1526

DVT Registry (N=5,451):DVT Registry (N=5,451):Top 5 Medical ComorbiditiesTop 5 Medical Comorbidities

1.1. HypertensionHypertension

2.2. ImmobilityImmobility

3.3. CancerCancer

4.4. Obesity (BMI > 30)Obesity (BMI > 30)

5.5. Cigarette SmokingCigarette Smoking

Am J Cardiol 2004; 93: 259-262Am J Cardiol 2004; 93: 259-262

Implementation of VTE prophylaxis Implementation of VTE prophylaxis continues to be problematic, despite continues to be problematic, despite

detailed North American and European detailed North American and European Consensus guidelines.Consensus guidelines.

ImplementationImplementation

SURGEON SURGEON GENERAL:GENERAL:CALL TO CALL TO

ACTION TO ACTION TO PREVENT PREVENT

DVT AND PEDVT AND PE

September 15, 2008September 15, 2008

http://www.surgeongeneral.gov/topics/deepvein/calltoaction/call-to-action-on-dvt-2008.pdf

Surgeon General’s Call to Action Surgeon General’s Call to Action 42-Page Document42-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 Foreword by Acting Surgeon General, Steven K. Galson, MD, MPH (RADM, U.S. Public K. Galson, MD, MPH (RADM, U.S. Public Health Service)Health Service)

Call to Action for VTECall to Action for VTE

► Dr. Galson’s 1Dr. Galson’s 1stst Call To Action Call To Action

► >> 350,000-600,000 Americans suffer VTE 350,000-600,000 Americans suffer VTE annuallyannually

► > 100,000 U.S. deaths per year > 100,000 U.S. deaths per year

► Negative impact on QOL of survivorsNegative impact on QOL of survivors

► ““Must disseminate info widely” to “address gap” Must disseminate info widely” to “address gap” because we’re not applying knowledge because we’re not applying knowledge systematicallysystematically

ForewordForeword

I. I. Major Public Health ProblemMajor Public Health Problem

II. II. Reducing VTE RiskReducing VTE Risk

III. Gaps in Application, Awareness of III. Gaps in Application, Awareness of EvidenceEvidence

IV. Public Health ResponseIV. Public Health Response

V. V. Catalyst for Action Catalyst for Action

Call to Action for VTECall to Action for VTE

Symposium Themes—Cancer/DVTSymposium Themes—Cancer/DVT

1.1. Cancer rates are increasing as heart disease Cancer rates are increasing as heart disease Rx improves and as cancer Rx improves.Rx improves and as cancer Rx improves.

2.2. Cancer increases VTE risk.Cancer increases VTE risk.

3.3. VTE is preventable (immunize!)VTE is preventable (immunize!)

4.4. VTE prophylaxis may slow cancerVTE prophylaxis may slow cancer

5.5. Increased emphasis on prophylaxis: OSG, Increased emphasis on prophylaxis: OSG, NCCN, ASCO, ACCP, NATFNCCN, ASCO, ACCP, NATF

6.6. Facilitate Facilitate prophylaxis with alertsprophylaxis with alerts..

Chemotherapy-Induced Chemotherapy-Induced Nausea and VomitingNausea and Vomiting

Causes, Challenges, Causes, Challenges, and Optimal Treatmentand Optimal Treatment


Professor of MedicineProfessor of MedicineUniversity of VermontUniversity of VermontBurlington, VermontBurlington, Vermont


Perception of Chemotherapy (1983)Perception of Chemotherapy (1983)

Nausea and vomiting are the two Nausea and vomiting are the two most feared toxicities of most feared toxicities of

chemotherapy.chemotherapy.

Coates, Eur J Cancer Clin Oncol 19:203, 1983Coates, Eur J Cancer Clin Oncol 19:203, 1983

Sun, Gynecol Oncol 87:118, 2002

Median Time-Trade-Off ScoresMedian Time-Trade-Off Scores

Medical Costs of EmesisMedical Costs of Emesis

► Why were we able to move most chemotherapy Why were we able to move most chemotherapy from an inpatient to an outpatient procedure?from an inpatient to an outpatient procedure?● Indwelling venous catheter/InfusaportIndwelling venous catheter/Infusaport● Effective antiemeticsEffective antiemetics

► What are the direct costs of emesis?What are the direct costs of emesis?● Few patients discontinue chemotherapy due to Few patients discontinue chemotherapy due to

toxicitytoxicity● Antiemetic control decreases duration of Antiemetic control decreases duration of

hospitalization and frequency of rehospitalizationhospitalization and frequency of rehospitalization

Grunberg, Eur J Cancer 36 Suppl:S28, 2000

Functional Living Index – Emesis (FLIE)Functional Living Index – Emesis (FLIE)

► FLIE is an 18-question questionnaire that evaluates the FLIE is an 18-question questionnaire that evaluates the effect of vomiting (9 questions) and nausea (9 questions) effect of vomiting (9 questions) and nausea (9 questions) on the ability to carry out Activities of Daily Livingon the ability to carry out Activities of Daily Living

► Each question is scored from 0 (inability to function) to 7 Each question is scored from 0 (inability to function) to 7 (normal function)(normal function)

► A value of 6 or above is considered to indicate No Impact A value of 6 or above is considered to indicate No Impact on Daily Livingon Daily Living

► Does Complete Protection from emesis improve quality Does Complete Protection from emesis improve quality of life by increasing the percentage of patients for whom of life by increasing the percentage of patients for whom emesis has No Impact on Daily Living?emesis has No Impact on Daily Living?

Lindley, Qual Life Res 1:331, 1992Lindley, Qual Life Res 1:331, 1992

Correlation of Emesis Protection Correlation of Emesis Protection and Quality of Lifeand Quality of Life

Martin, Eur J Cancer 39:1395, 2003

Levels of EmetogenicityLevels of Emetogenicity

► Highly Emetogenic Chemotherapy (HEC) (> 90%)Highly Emetogenic Chemotherapy (HEC) (> 90%)● CisplatinCisplatin● MechlorethamineMechlorethamine

► Moderately Emetogenic Chemotherapy (MEC) (30-90%)Moderately Emetogenic Chemotherapy (MEC) (30-90%)● CyclophosphamideCyclophosphamide● DoxorubicinDoxorubicin

► Low Emetogenic Chemotherapy (10-30%)Low Emetogenic Chemotherapy (10-30%)● PaclitaxelPaclitaxel● 5-Fluorouracil5-Fluorouracil

► Minimally Emetogenic Chemotherapy (< 10%)Minimally Emetogenic Chemotherapy (< 10%)● VincristineVincristine● BleomycinBleomycin

Levels of Emetogenicity Levels of Emetogenicity Modifying FactorsModifying Factors

► AgeAge● Younger patients vomit more than older patientsYounger patients vomit more than older patients

► GenderGender● Women vomit more than menWomen vomit more than men

► Alcohol historyAlcohol history● Patients with a history of heavy alcohol use vomit Patients with a history of heavy alcohol use vomit

less than those without such a historyless than those without such a history

► Nausea/vomiting historyNausea/vomiting history● Patients with a history of morning sickness or motion Patients with a history of morning sickness or motion

sickness are more likely to vomitsickness are more likely to vomit

DefinitionsDefinitions

► Vomiting – expulsion of stomach contentsVomiting – expulsion of stomach contents

► Nausea – subjective feeling of imminent vomitingNausea – subjective feeling of imminent vomiting

► Complete Response – no vomiting or rescue Complete Response – no vomiting or rescue medicationmedication

► Complete Control – no vomiting, rescue medication Complete Control – no vomiting, rescue medication or significant nauseaor significant nausea

► Total Control – no vomiting, rescue medication or Total Control – no vomiting, rescue medication or nauseanausea

Role of Emesis in Natural SelectionRole of Emesis in Natural Selection

Vomiting is a physiologic process,Vomiting is a physiologic process,not a pathologic process.not a pathologic process.

It is the body’s natural defenseIt is the body’s natural defenseagainst ingestion of toxic substances.against ingestion of toxic substances.

Neurotransmitters Involved in EmesisNeurotransmitters Involved in Emesis

Emetic Emetic centercenter

GABAGABA

HistamineHistamine

EndorphinsEndorphins

CannabinoidCannabinoid

DopamineDopamine

Substance PSubstance P

SerotoninSerotonin

High Dose Metoclopramide – High Dose Metoclopramide – The First Highly Effective AntiemeticThe First Highly Effective Antiemetic

Gralla, NEJM 305:905, 1981Gralla, NEJM 305:905, 1981

Metoclopramide Metoclopramide (n=11)(n=11)

Placebo Placebo (n=10)(n=10)

PP Metoclopramide Metoclopramide (n=11)(n=11)

Prochlorperazine Prochlorperazine (n=10)(n=10)

PP

Emetic Emetic EpisodesEpisodes

110.90.9

10.510.55-255-25 0.0010.001 1.51.5

0-60-61212

5-165-16 0.0050.005

Hours of Hours of VomitingVomiting

0.20.20-16.80-16.8

3.63.62-172-17 0.0280.028 0.50.5

0-16.50-16.54.54.5

1.5-17.61.5-17.6 NSNS

Hours of Hours of NauseaNausea

000-16.20-16.2

3.73.70-19.20-19.2 0.0420.042 0.10.1

0-17.20-17.255

0-200-20 NSNS

Phase I Study of OndansetronPhase I Study of Ondansetron

43 Patients Receiving Cisplatin 43 Patients Receiving Cisplatin >> 60 mg/m 60 mg/m22

Grunberg, J Clin Oncol 7:1137, 1989Grunberg, J Clin Oncol 7:1137, 1989

Dose LevelDose Level CompleteComplete MajorMajor FailureFailure

0.01 mg/kg0.01 mg/kg 00 11 22

0.06 mg/kg0.06 mg/kg 22 33 00

0.18 mg/kg0.18 mg/kg 22 22 11

0.30 mg/kg0.30 mg/kg 44 11 00

0.48 mg/kg0.48 mg/kg 11 22 22

TotalTotal 44%44% 37%37% 19%19%

Increase in Complete Protection with Increase in Complete Protection with DexamethasoneDexamethasone

89 Patients Receiving Cisplatin 89 Patients Receiving Cisplatin >> 50 mg/m 50 mg/m22

Roila, J Clin Oncol 9:675, 1991

OndansteronOndansteron Ondansteron/Ondansteron/DexamethasoneDexamethasone pp

VomitingVomiting 64%64% 91%91% 0.00050.0005

NauseaNausea 66%66% 89%89% 0.00250.0025

Nausea/Nausea/VomitingVomiting 56%56% 81%81% 0.00080.0008

PreferencePreference 14%14% 39%39% 0.0030.003

Serotonin Antagonist Serotonin Antagonist Dose-Response CurveDose-Response Curve

Grunberg, in Tonato, ESMO Monographs, 1996Grunberg, in Tonato, ESMO Monographs, 1996

Natural History of Delayed Natural History of Delayed Nausea and VomitingNausea and Vomiting

Kris, J Clin Oncol 3:1379, 1985

Hours after cisplatinHours after cisplatin

Percent with Percent with nausea or nausea or vomitingvomiting

Perception vs Reality Perception vs Reality Highly Emetogenic ChemotherapyHighly Emetogenic Chemotherapy

Grunberg, Cancer 100:2261, 2004

Per

cent

of

Per

cent

of

patie

nts

patie

nts

Perception vs Reality Perception vs Reality Moderately Emetogenic ChemotherapyModerately Emetogenic Chemotherapy

Grunberg, Cancer 100:2261, 2004Grunberg, Cancer 100:2261, 2004

Per

cent

of

Per

cent

of

patie

nts

patie

nts

*Log-scale†In vitro data; clinical significance has not been established

Half-Life and Binding Affinities of Half-Life and Binding Affinities of 5-HT5-HT33 Receptor Antagonists Receptor Antagonists

1. Aloxi® package insert, 2005. 2. Zofran® package insert, 2001. 3. Anzemet® package insert, 2000. 4. Kytril® package insert, 2000. 5. Wong EHF et al. Br J Pharmacol. 1995;114:851-859. 6. Miller RC et al. Drug Dev Res. 1993;28:87-93.

5-HT5-HT33 Antagonist Antagonist Half-Life (h)Half-Life (h) Binding Affinity Binding Affinity (pKi)*(pKi)*††

PalonosetronPalonosetron 40.040.011 10.4510.4555

OndansetronOndansetron 4.04.022 8.398.3955

DolasetronDolasetron 7.37.333 7.607.6066

GranisetronGranisetron 9.09.044 8.918.9155

TropisetronTropisetron 8.08.055 8.78.755

Palonosetron for Highly Emetogenic ChemotherapyPalonosetron for Highly Emetogenic ChemotherapyEfficacy Results by 24 Hour PeriodEfficacy Results by 24 Hour Period

Palonosetron for Moderately Emetogenic ChemotherapyPalonosetron for Moderately Emetogenic ChemotherapyEfficacy Results by 24 Hour PeriodEfficacy Results by 24 Hour Period

Poli-Bigelli, Ann Oncol 14:1570, 2003Poli-Bigelli, Ann Oncol 14:1570, 2003

Palonosetron for Moderately Emetogenic Palonosetron for Moderately Emetogenic ChemotherapyChemotherapy

Efficacy Results by 24 Hour PeriodEfficacy Results by 24 Hour Period

Eisenberg, Cancer 98:2473, 2003Eisenberg, Cancer 98:2473, 2003

Inhibition of Serotonin-Induced Inhibition of Serotonin-Induced Calcium Ion FluxCalcium Ion Flux

Rojas, Anesth Analg 107:469, 2008Rojas, Anesth Analg 107:469, 2008

Neurotransmitters Involved in EmesisNeurotransmitters Involved in Emesis

Emetic Emetic centercenter

GABAGABA

HistamineHistamine

EndorphinsEndorphins

CannabinoidCannabinoid

DopamineDopamine

Substance PSubstance P

SerotoninSerotonin

L-758,298 vs OndansetronL-758,298 vs Ondansetron for Cisplatin-Induced Emesis for Cisplatin-Induced Emesis

Cocquyt, Eur J Cancer 37:835, 2001Cocquyt, Eur J Cancer 37:835, 2001

Ondansetron/Dexamethasone Ondansetron/Dexamethasone ++ Aprepitant Aprepitant for Cisplatin-Induced Emesisfor Cisplatin-Induced Emesis

Hesketh, J Clin Oncol 21:4112, 2003Hesketh, J Clin Oncol 21:4112, 2003

Time course of emesis following cisplatin with Time course of emesis following cisplatin with a 5-HTa 5-HT33 antagonist or aprepitant antagonist or aprepitant

Patients with no emesis (%)Patients with no emesis (%)

Time since cisplatin (hours)Time since cisplatin (hours)00 88 2424 4040 6060 8080 100100 120120

00

2020

4040

6060

8080

100100 Gran + dex d1 / placebo d2–5Gran + dex d1 / placebo d2–5Gran + dex + aprepitant d1 / aprepitant d2–5Gran + dex + aprepitant d1 / aprepitant d2–5Aprepitant d0 / aprepitant + dex d1 / aprepitant d2–5Aprepitant d0 / aprepitant + dex d1 / aprepitant d2–5Aprepitant + dex d1 / aprepitant d2–5Aprepitant + dex d1 / aprepitant d2–5

Hesketh, Support Care Cancer 10:365, 2002Hesketh, Support Care Cancer 10:365, 2002

Palonosetron/Dexamethasone/Aprepitant for Palonosetron/Dexamethasone/Aprepitant for MEC-Induced Emesis (n=58)MEC-Induced Emesis (n=58)

Grote, J Support Oncol 4:403, 2006

Palonosetron/Dexamethasone/Aprepitant for Palonosetron/Dexamethasone/Aprepitant for MEC-Induced Emesis – Single Day (n=41)MEC-Induced Emesis – Single Day (n=41)

Grunberg, Support Care Cancer (In Press) 2009

Palonosetron/Dexamethasone Palonosetron/Dexamethasone + + Aprepitant Aprepitant (3-day vs single day) (n=70)(3-day vs single day) (n=70)

Herrington, Cancer 112:2080, 2008Herrington, Cancer 112:2080, 2008

Guideline OrganizationsGuideline Organizations

► MASCCMASCC

► ASCOASCO

► ASHPASHP

► NCCNNCCN

► EONSEONS

► Consensus of ConsensusConsensus of Consensus

Why do Guidelines Vary?Why do Guidelines Vary?Charge to the CommitteeCharge to the Committee

► Make the guidelines evidence-basedMake the guidelines evidence-based

Pro: high level of evidencePro: high level of evidence

Con: incomplete with variable complianceCon: incomplete with variable compliance

► Make the guidelines comprehensiveMake the guidelines comprehensive

Pro: advice for all situationsPro: advice for all situations

Con: variable level of evidence and complianceCon: variable level of evidence and compliance

► Make the guidelines acceptableMake the guidelines acceptable

Pro: advice for all situations and good compliancePro: advice for all situations and good compliance

Con: highly variable level of evidenceCon: highly variable level of evidence

Antiemetic Consensus Guidelines - 2008Antiemetic Consensus Guidelines - 2008

Adapted from Koeller, Support Care Cancer 10:519, 2002Adapted from Koeller, Support Care Cancer 10:519, 2002

RiskRisk AcuteAcute DelayedDelayed

HighHigh 5-HT3+DXM5-HT3+DXM+NK1+NK1 DXMDXM+NK1+NK1

ModerateModerate 5-HT3+DXM5-HT3+DXM+NK1+NK1 NK1NK1

LowLow Single AgentSingle Agent NoneNone

MinimalMinimal NoneNone NoneNone

Effect of Physician Education on Effect of Physician Education on Antiemetic Guideline ComplianceAntiemetic Guideline Compliance

► Distribution of written guidelinesDistribution of written guidelines

Improved compliance x 2 monthsImproved compliance x 2 months

► Lecture by visiting expertLecture by visiting expert

No change in behaviorNo change in behavior

► Direct feedback of patient experiencesDirect feedback of patient experiences

Improved compliance x 4+ monthsImproved compliance x 4+ months

Mertens, J Clin Oncol 21:1373, 2003Mertens, J Clin Oncol 21:1373, 2003

It’s not really a It’s not really a CodeCode

It’s actually It’s actually more of a more of a GuidelineGuideline- Pirates of the Caribbean, 2003

Remaining ChallengesRemaining Challenges

► Pharmacodynamics of antiemeticsPharmacodynamics of antiemetics

► Convenient schedule/extended efficacyConvenient schedule/extended efficacy

► Control of nauseaControl of nausea

► Control of anorexiaControl of anorexia

A Systematic Analysis of VTE A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Prophylaxis in the Setting of Cancer

Linking Science and Evidence to Clinical Practice—Linking Science and Evidence to Clinical Practice—What Do Trials Teach?What Do Trials Teach?

A Systematic Analysis of VTE A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Prophylaxis in the Setting of Cancer

Linking Science and Evidence to Clinical Practice—Linking Science and Evidence to Clinical Practice—What Do Trials Teach?What Do Trials Teach?








VTE and Cancer: EpidemiologyVTE and Cancer: Epidemiology

► Of all cases of VTE:Of all cases of VTE:● About 20% occur in cancer patientsAbout 20% occur in cancer patients● Annual incidence of VTE in cancer Annual incidence of VTE in cancer

patients ≈ 1/250patients ≈ 1/250

► Of all cancer patients:Of all cancer patients:● 15% will have symptomatic VTE15% will have symptomatic VTE● As many as 50% have VTE at autopsyAs many as 50% have VTE at autopsy

► Compared to patients without cancer:Compared to patients without cancer:● Higher risk of first and recurrent VTEHigher risk of first and recurrent VTE● Higher risk of bleeding on anticoagulantsHigher risk of bleeding on anticoagulants● Higher risk of dyingHigher risk of dying

Lee AY, Levine MN. Lee AY, Levine MN. CirculationCirculation. 2003;107:23 Suppl 1:I17-I21. 2003;107:23 Suppl 1:I17-I21

1.1. Ambrus JL et al. Ambrus JL et al. J MedJ Med. 1975;6:61-64. 1975;6:61-642.2. Donati MB. Donati MB. HaemostasisHaemostasis. 1994;24:128-131. 1994;24:128-1313.3. Johnson MJ et al. Johnson MJ et al. Clin Lab HaemClin Lab Haem. 1999;21:51-54. 1999;21:51-544.4. Prandoni P et al. Prandoni P et al. Ann Intern MedAnn Intern Med. 1996;125:1-7. 1996;125:1-7

DVT and PE in CancerDVT and PE in Cancer Facts, Findings, and Natural HistoryFacts, Findings, and Natural History

► VTE is the second leading cause of death VTE is the second leading cause of death in hospitalized in hospitalized cancer patientscancer patients1,21,2

► The risk of VTE in cancer patients undergoing surgery is The risk of VTE in cancer patients undergoing surgery is 3- 3- to 5-fold higher to 5-fold higher than those without cancerthan those without cancer22

► Up to Up to 50% of cancer patients 50% of cancer patients may have evidence of may have evidence of asymptomatic DVT/PEasymptomatic DVT/PE33

► Cancer patients with symptomatic DVT exhibit a Cancer patients with symptomatic DVT exhibit a high risk high risk for recurrent DVT/PE that persists for many yearsfor recurrent DVT/PE that persists for many years44

Clinical Features of VTE in CancerClinical Features of VTE in Cancer

► VTE has significant negative impact on quality VTE has significant negative impact on quality of lifeof life

► VTE may be the presenting sign of occult VTE may be the presenting sign of occult malignancymalignancy• 10% with idiopathic VTE develop cancer within 10% with idiopathic VTE develop cancer within

2 years2 years• 20% have recurrent idiopathic VTE20% have recurrent idiopathic VTE• 25% have bilateral DVT25% have bilateral DVT

Bura Bura et. al.,et. al., J Thromb HaemostJ Thromb Haemost 2004;2:445-51 2004;2:445-51

Thrombosis and SurvivalThrombosis and SurvivalLikelihood of Death After HospitalizationLikelihood of Death After Hospitalization

00 20 20 40 40 60 60 80 80 100 100 120 120140 160 180140 160 1800.000.00

0.200.20

0.400.40

1.001.00

0.800.80

0.600.60

DVT/PE and Malignant DiseaseDVT/PE and Malignant Disease

Malignant DiseaseMalignant Disease

DVT/PE OnlyDVT/PE Only

Nonmalignant DiseaseNonmalignant Disease

Number of DaysNumber of Days

Pro

bab

ility

of D

ea

thP

roba

bili

ty o

f De

ath

Levitan N, et al. Medicine 1999;78:285Levitan N, et al. Medicine 1999;78:285

Hospital Mortality With or Without VTEHospital Mortality With or Without VTE

Khorana, JCO, 2006Khorana, JCO, 2006

Mor

talit

y (%

)M

orta

lity

(%)

Mor

talit

y (%

)M

orta

lity

(%)

N=66,016N=66,016 N=20,591N=20,591 N=17,360N=17,360

Trends in VTE in Hospitalized Cancer PatientsTrends in VTE in Hospitalized Cancer Patients

VTE- patients on chemotherapyVTE- patients on chemotherapy VTE-all patientsVTE-all patients DVT-all patientsDVT-all patients

PE-all patientsPE-all patients

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.0

19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003

Rat

e of

VT

E (

%)

Rat

e of

VT

E (

%)

P<0.0001P<0.0001

Khorana AA et al. Khorana AA et al. Cancer. Cancer. 2007.2007.

Thrombosis Risk In Cancer Thrombosis Risk In Cancer

Primary ProphylaxisPrimary Prophylaxis► Medical InpatientsMedical Inpatients

► SurgerySurgery

► RadiotherapyRadiotherapy

► Central Venous CathetersCentral Venous Catheters

Risk Factors for Cancer-Associated VTERisk Factors for Cancer-Associated VTE

► CancerCancer● Type Type

• Men: prostate, colon, brain, lungMen: prostate, colon, brain, lung• Women: breast, ovary, lungWomen: breast, ovary, lung

● StageStage► TreatmentsTreatments

● SurgerySurgery• 10-20% proximal DVT10-20% proximal DVT• 4-10% clinically evident PE4-10% clinically evident PE• 0.2-5% fatal PE0.2-5% fatal PE

● ChemotherapyChemotherapy● Central venous cathetersCentral venous catheters (~4% generate clinically relevant (~4% generate clinically relevant

VTE)VTE)► PatientPatient

● Prior VTEPrior VTE● ComorbiditiesComorbidities● Genetic backgroundGenetic background

VTE Risk And Cancer TypeVTE Risk And Cancer Type“Solid And Liquid Malignancies”“Solid And Liquid Malignancies”

Stein PD, et al. Am J Med 2006; 119: 60-68Stein PD, et al. Am J Med 2006; 119: 60-68

Rel

ativ

e R

isk

of V

TE

inR

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ive

Ris

k of

VT

E in

Can

cer

Pat

ient

sC

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Pan

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ancr

eas

Bra

inB

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Mye

lopr

olM

yelo

prol

Sto

mac

hS

tom

ach

Lym

phom

aLy

mph

oma

Ute

rus

Ute

rus

Lung

Lung

Eso

phag

usE

soph

agus

Pro

stat

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rost

ate

Rec

tal

Rec

tal

Kid

ney

Kid

ney

Col

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olon

Ova

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vary

Live

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Leuk

emia

Leuk

emia

Bre

ast

Bre

ast

Cer

vix

Cer

vix

Bla

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Bla

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4.54.5443.53.5332.52.5221.51.5110.50.5

Relative Risk of VTE Ranged From 1.02 to 4.34Relative Risk of VTE Ranged From 1.02 to 4.34

Medical InpatientsMedical Inpatients

Cancer and ThrombosisCancer and Thrombosis

Thromboembolism in Hospitalized Thromboembolism in Hospitalized Neutropenic Cancer PatientsNeutropenic Cancer Patients

► Retrospective cohort study of Retrospective cohort study of discharges using the University Health discharges using the University Health System ConsortiumSystem Consortium

► 66,106 adult neutropenic cancer 66,106 adult neutropenic cancer patients between 1995 and 2002 at patients between 1995 and 2002 at 115 centers115 centers


Neutropenic Patients: ResultsNeutropenic Patients: Results

► 8% had thrombosis8% had thrombosis

► 5.4% venous and 1.5% arterial in 15.4% venous and 1.5% arterial in 1stst hospitalization hospitalization

► Predictors of thrombosisPredictors of thrombosis● Age over 55Age over 55● Site (lung, GI, gynecologic, brain)Site (lung, GI, gynecologic, brain)● Comorbidities (infection, pulmonary and renal Comorbidities (infection, pulmonary and renal

disease, obesity)disease, obesity)


Predictors of VTE in Predictors of VTE in Hospitalized Cancer PatientsHospitalized Cancer Patients

CharacteristicCharacteristic OROR PP ValueValue

Site of CancerSite of Cancer

LungLung

StomachStomach

PancreasPancreas

Endometrium/cervixEndometrium/cervix

BrainBrain

1.31.3

1.61.6

2.82.8

22

2.22.2

<0.001<0.001

0.00350.0035

<0.001<0.001

<0.001<0.001

<0.001<0.001

Age Age 65 y65 y 1.11.1 0.0050.005

Arterial thromboembolismArterial thromboembolism 1.41.4 0.0080.008

Comorbidities (lung/renal disease, Comorbidities (lung/renal disease, infection, obesity)infection, obesity) 1.3-1.61.3-1.6 <0.001<0.001

Khorana AA et al. Khorana AA et al. J Clin Oncol. J Clin Oncol. 2006;24:484-490.2006;24:484-490.

PharmacologicPharmacologic(Prophylaxis & Treatment)(Prophylaxis & Treatment)

NonpharmacologicNonpharmacologic(Prophylaxis)(Prophylaxis)

Antithrombotic Therapy: ChoicesAntithrombotic Therapy: Choices

IntermittentPneumaticCompression

Elastic Stockings

InferiorVena CavaFilter

OralAnticoagulants

UnfractionatedHeparin (UH)

Low Molecular Weight Heparin (LMWH)

New Agents: e.g. Fondaparinux,Direct anti-Xa inhibitors,Direct anti-IIa, etc.?

Prophylaxis Studies in Medical PatientsProphylaxis Studies in Medical Patients

Francis, NEJM, 2007Francis, NEJM, 2007

Placebo EnoxaparinPlacebo EnoxaparinMEDENOX TrialMEDENOX Trial

Placebo DalteparinPlacebo DalteparinPREVENTPREVENT

Placebo FondaparinuxPlacebo FondaparinuxARTEMISARTEMIS

Rat

e of

VT

E (

%)

Rat

e of

VT

E (

%)

Relative Relative risk risk reduction reduction 63%63%



ASCO GuidelinesASCO Guidelines

1. SHOULD HOSPITALIZED PATIENTS WITH1. SHOULD HOSPITALIZED PATIENTS WITHCANCER RECEIVE ANTICOAGULATION FORCANCER RECEIVE ANTICOAGULATION FORVTE PROPHYLAXISVTE PROPHYLAXIS??

RecommendationRecommendation. . Hospitalized patients with Hospitalized patients with cancer should be considered candidates for cancer should be considered candidates for VTE prophylaxis with anticoagulants in the VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications absence of bleeding or other contraindications to anticoagulation.to anticoagulation.

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

Surgical PatientsSurgical Patients


► Cancer patients have Cancer patients have 2-fold risk of post-operative DVT/PE 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxisand >3-fold risk of fatal PE despite prophylaxis::

Kakkar AK, et al. Kakkar AK, et al. Thromb HaemostThromb Haemost 2001; 86 (suppl 1): OC1732 2001; 86 (suppl 1): OC1732

Incidence of VTE in Surgical PatientsIncidence of VTE in Surgical Patients

No CancerNo CancerN=16,954N=16,954

CancerCancerN=6124N=6124

P-valueP-value

Post-op VTEPost-op VTE 0.61%0.61% 1.26%1.26% <0.0001<0.0001

Non-fatal PENon-fatal PE 0.27%0.27% 0.54%0.54% <0.0003<0.0003

Autopsy PEAutopsy PE 0.11%0.11% 0.41%0.41% <0.0001<0.0001

DeathDeath 0.71%0.71% 3.14%3.14% <0.0001<0.0001

Natural History of VTE in Cancer Surgery: Natural History of VTE in Cancer Surgery: The @RISTOS RegistryThe @RISTOS Registry

► Web-Based Registry of Cancer SurgeryWeb-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patientsTracked 30-day incidence of VTE in 2373 patients

Type of surgeryType of surgery • • 52% General 52% General • • 29% Urological29% Urological • • 19% Gynecologic19% Gynecologic

82% received in-hospital thromboprophylaxis82% received in-hospital thromboprophylaxis

31% received post-discharge thromboprophylaxis31% received post-discharge thromboprophylaxis

FindingsFindings

► 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 deathMost common cause of 30-day post-op death

Agnelli, Ann Surg 2006; 243: 89-95Agnelli, Ann Surg 2006; 243: 89-95

LMWH vs. UFHLMWH 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-opLMWH once daily vs. UFH tid for 7–10 days post-op

► DVT on venography at day 7–10 and symptomatic VTEDVT on venography at day 7–10 and symptomatic VTE

1. ENOXACAN Study Group. 1. ENOXACAN Study Group. Br J SurgBr J Surg 1997;84:1099–103 1997;84:1099–1032. McLeod R, et al. 2. McLeod R, et al. Ann SurgAnn Surg 2001;233:438-444 2001;233:438-444

Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients

StudyStudy NN DesignDesign RegimensRegimens

ENOXACAN ENOXACAN 11 631631 double-blinddouble-blind enoxaparin vs. UFHenoxaparin vs. UFH

Canadian Colorectal Canadian Colorectal DVT Prophylaxis DVT Prophylaxis 22 475475 double-blinddouble-blind enoxaparin vs. UFHenoxaparin vs. UFH

Canadian Canadian Colorectal DVT Colorectal DVT Prophylaxis TrialProphylaxis Trial13.9%13.9%

1.5% 2.7%1.5% 2.7%

16.9%16.9%

N=234N=234

N=241N=241

McLeod R, et al. McLeod R, et al. Ann SurgAnn Surg 2001;233:438-444 2001;233:438-444

P=0.052P=0.052

In

cide

nce

of O

utco

me

Eve

ntIn

cide

nce

of O

utco

me

Eve

nt

VTEVTE Major BleedingMajor Bleeding(Cancer) (All)(Cancer) (All)

Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients

VTE Prox Any MajorVTE Prox Any Major DVT Bleeding BleedingDVT Bleeding Bleeding

P=0.02

5.1%

1.8%

Bergqvist D, et al. (for the ENOXACAN II investigators) Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J MedN Engl J Med 2002;346:975-980 2002;346:975-980

ENOXACAN IIENOXACAN II

In

cide

nce

of O

utco

me

Eve

ntIn

cide

nce

of O

utco

me

Eve

nt

N=167

N=165

0% 0.4%

12.0%

4.8%

NNT = 140.6%

3.6%

Extended Prophylaxis inExtended Prophylaxis inSurgical PatientsSurgical Patients

► A multicenter, prospective, assessor-blinded, open-label, A multicenter, prospective, assessor-blinded, open-label, randomized trial: randomized trial: Dalteparin administered for 28 days Dalteparin administered for 28 days after major abdominal surgeryafter major abdominal surgery compared to 7 days of compared to 7 days of treatmenttreatment

► RESULTS:RESULTS: Cumulative Cumulative incidence of VTE was reduced incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3%patients) to 7.3% after prolonged thromboprophylaxis after prolonged thromboprophylaxis (12/165) ((12/165) (relative risk reduction 55%;relative risk reduction 55%; 95% confidence 95% confidence interval 15-76; P=0.012).interval 15-76; P=0.012).

► CONCLUSIONS:CONCLUSIONS: 4-week administration of dalteparin, 4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTEsignificantly reduces the rate of VTE, without increasing , without increasing the risk of bleeding, compared with 1 week of the risk of bleeding, compared with 1 week of thromboprophylaxis.thromboprophylaxis.

Major Abdominal Surgery: FAME InvestigatorsMajor Abdominal Surgery: FAME Investigators—Dalteparin Extended —Dalteparin Extended

Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.

ASCO Guidelines: VTE ProphylaxisASCO Guidelines: VTE Prophylaxis

► All patients undergoing major surgical intervention All patients undergoing major surgical intervention for malignant disease should be considered for for malignant disease should be considered for prophylaxis.prophylaxis.

► Patients undergoing laparotomy, laparoscopy, or Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receive thoracotomy lasting > 30 min should receive pharmacologic prophylaxis.pharmacologic prophylaxis.

► Prophylaxis should be continued at least 7 – 10 Prophylaxis should be continued at least 7 – 10 days post-op. Prolonged prophylaxis for up to 4 days post-op. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing weeks may be considered in patients undergoing major surgery for cancer with high-risk features.major surgery for cancer with high-risk features.

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

Thrombosis is a potential complication of central Thrombosis is a potential complication of central venous catheters, including these events:venous catheters, including these events:

–Fibrin sheath formationFibrin sheath formation

–Superficial phlebitisSuperficial phlebitis

–Ball-valve clotBall-valve clot

–Deep vein thrombosis (DVT)Deep vein thrombosis (DVT)

Central Venous CathetersCentral Venous Catheters

Geerts W, et al. Geerts W, et al. ChestChest Jun 2008: 381S–453S Jun 2008: 381S–453S

Placebo-Controlled TrialsPlacebo-Controlled Trials

StudyStudy RegimenRegimen NN CRT (%)CRT (%)

Reichardt* Reichardt* 20022002

Dalteparin 5000 U dailyDalteparin 5000 U dailyplaceboplacebo

285285140140

11 (3.7)11 (3.7) 5 (3.4)5 (3.4)

Couban*Couban*20022002

Warfarin 1mg dailyWarfarin 1mg dailyplaceboplacebo

130130125125

6 (4.6)6 (4.6) 5 (4.0)5 (4.0)

ETHICSETHICS††

20042004Enoxaparin 40 mg dailyEnoxaparin 40 mg daily

placeboplacebo155155155155

22 (14.2)22 (14.2)28 (18.1)28 (18.1)

**symptomatic outcomessymptomatic outcomes;; ††routine venography at 6 weeksroutine venography at 6 weeks

Prophylaxis for Venous CathetersProphylaxis for Venous Catheters

Reichardt P, et al. Reichardt P, et al. Proc ASCOProc ASCO 2002;21:369a; Couban S, et al, 2002;21:369a; Couban S, et al, BloodBlood 2002;100:703a; Agnelli G, et 2002;100:703a; Agnelli G, et al. al. Proc ASCOProc ASCO 2004;23:730 2004;23:730

Tolerability of Low-Dose WarfarinTolerability of Low-Dose Warfarin

► 95 cancer patients receiving FU-based infusion 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin dailychemotherapy and 1 mg warfarin daily

► INR measured at baseline and four time pointsINR measured at baseline and four time points

► 10% of all recorded INRs >1.510% of all recorded INRs >1.5

► Patients with elevated INRPatients with elevated INR2.0–2.92.0–2.9 6% 6%

3.0–4.93.0–4.9 19%19%

>5.0>5.0 7% 7%

Central Venous Catheters: WarfarinCentral Venous Catheters: Warfarin

Masci et al. J Clin Oncol. 2003;21:736-739

SummarySummary► Recent studies demonstrate a low Recent studies demonstrate a low

incidence of symptomatic catheter-related incidence of symptomatic catheter-related thrombosis (~4%)thrombosis (~4%)

► Routine prophylaxis is Routine prophylaxis is not warrantednot warranted to to prevent catheter-related thrombosis, but prevent catheter-related thrombosis, but catheter patency rates/infections have not catheter patency rates/infections have not been studiedbeen studied

► Low-dose LMWH and fixed-dose warfarin Low-dose LMWH and fixed-dose warfarin have not been shown to be effective for have not been shown to be effective for preventing symptomatic and asymptomatic preventing symptomatic and asymptomatic thrombosisthrombosis

Prophylaxis for Central Venous Prophylaxis for Central Venous Access DevicesAccess Devices

88thth ACCP Consensus Guidelines ACCP Consensus Guidelines

No routine prophylaxis to prevent No routine prophylaxis to prevent thrombosis secondary to central thrombosis secondary to central venous catheters, including LMWH venous catheters, including LMWH (2B) and fixed-dose warfarin (1B)(2B) and fixed-dose warfarin (1B)

ChestChest Jun 2008: 454S–545S Jun 2008: 454S–545S

Primary Prophylaxis in Cancer RadiotherapyPrimary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient The Ambulatory Patient

► No recommendations from ACCPNo recommendations from ACCP

► No data from randomized trials (RCTs)No data from randomized trials (RCTs)

► Weak data from observational studies in Weak data from observational studies in high risk tumors (e.g. brain tumors; high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas: mucin-secreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, Colorectal, pancreatic, lung, renal cell, ovarian)ovarian)

► Recommendations extrapolated from Recommendations extrapolated from other groups of patients if additional risk other groups of patients if additional risk factors present (e.g., hemiparesis in brain factors present (e.g., hemiparesis in brain tumors, etc.)tumors, etc.)

Ambulatory Chemotherapy Ambulatory Chemotherapy PatientsPatients


Risk Factors for VTE inRisk Factors for VTE inMedical Oncology PatientsMedical Oncology Patients

► Tumor typeTumor type● Ovary, brain, pancreas, lung, colonOvary, brain, pancreas, lung, colon

► Stage, grade, and extent of cancerStage, grade, and extent of cancer● Metastatic disease, venous stasis due to Metastatic disease, venous stasis due to

bulky diseasebulky disease

► Type of antineoplastic treatmentType of antineoplastic treatment● Multiagent regimens, hormones,Multiagent regimens, hormones,

anti-VEGF, radiationanti-VEGF, radiation

► Miscellaneous VTE risk factorsMiscellaneous VTE risk factors● Previous VTE, Previous VTE, hospitalization, immobility, hospitalization, immobility,

infection, thrombophiliainfection, thrombophilia

Independent Risk Factors for DVT/PEIndependent Risk Factors for DVT/PE

Risk Factor/CharacteristicRisk Factor/Characteristic O.R.O.R.

Recent surgery with institutionalizationRecent surgery with institutionalization 21.7221.72

TraumaTrauma 12.6912.69

Institutionalization without recent surgeryInstitutionalization without recent surgery 7.987.98

Malignancy with chemotherapyMalignancy with chemotherapy 6.536.53

Prior CVAD or pacemakerPrior CVAD or pacemaker 5.555.55

Prior superficial vein thrombosisPrior superficial vein thrombosis 4.324.32

Malignancy without chemotherapyMalignancy without chemotherapy 4.054.05

Neurologic disease w/ extremity paresisNeurologic disease w/ extremity paresis 3.043.04

Serious liver diseaseSerious liver disease 0.100.10

Heit JA et al. Heit JA et al. Thromb HaemostThromb Haemost. 2001;86:452-463. 2001;86:452-463

VTE Incidence In Various TumorsVTE Incidence In Various Tumors

Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17

Oncology SettingOncology Setting VTE VTE IncidenceIncidence

Breast cancer (Stage I & II) w/o further treatmentBreast cancer (Stage I & II) w/o further treatment 0.2%0.2%

Breast cancer (Stage I & II) w/ chemoBreast cancer (Stage I & II) w/ chemo 2%2%

Breast cancer (Stage IV) w/ chemoBreast cancer (Stage IV) w/ chemo 8%8%

Non-Hodgkin’s lymphomas w/ chemoNon-Hodgkin’s lymphomas w/ chemo 3%3%

Hodgkin’s disease w/ chemoHodgkin’s disease w/ chemo 6%6%

Advanced cancer (1-year survival=12%)Advanced cancer (1-year survival=12%) 9%9%

High-grade gliomaHigh-grade glioma 26%26%

Multiple myeloma (thalidomide + chemo)Multiple myeloma (thalidomide + chemo) 28%28%

Renal cell carcinoma Renal cell carcinoma 43%43%

Solid tumors (anti-VEGF + chemo)Solid tumors (anti-VEGF + chemo) 47%47%

Wilms tumor (cavoatrial extension) Wilms tumor (cavoatrial extension) 4%4%

PrimaryPrimary VTE Prophylaxis VTE Prophylaxis

► Recommended for hospitalized Recommended for hospitalized cancer patientscancer patients

► Not recommended or generally used Not recommended or generally used for outpatientsfor outpatients● Very little dataVery little data● HeterogeneousHeterogeneous

Need for risk stratificationNeed for risk stratification

Ambulatory Cancer plus ChemotherapyAmbulatory Cancer plus Chemotherapy

Study MethodsStudy Methods

► Prospective observational study of Prospective observational study of ambulatory cancer patients initiating a new ambulatory cancer patients initiating a new chemotherapy regimen, and followed for a chemotherapy regimen, and followed for a maximum of 4 cyclesmaximum of 4 cycles

► 115 U.S. centers participated115 U.S. centers participated

► Patients enrolled between March, 2002 and Patients enrolled between March, 2002 and August, 2004 who had completed at least August, 2004 who had completed at least one cycle of chemotherapy were included in one cycle of chemotherapy were included in this analysisthis analysis

Khorana, Cancer, 2005 Khorana, Cancer, 2005

Ambulatory Cancer plus ChemotherapyAmbulatory Cancer plus Chemotherapy

► VTE events were recorded during mid-cycle or new-cycle VTE events were recorded during mid-cycle or new-cycle visitsvisits

► Symptomatic VTE was a clinical diagnosis made by the Symptomatic VTE was a clinical diagnosis made by the treating cliniciantreating clinician

► Statistical analysisStatistical analysis● Odds ratios to estimate relative riskOdds ratios to estimate relative risk● Multivariate logistic regression to adjust for other risk factorsMultivariate logistic regression to adjust for other risk factors

Khorana, Cancer, 2005Khorana, Cancer, 2005

Study MethodsStudy Methods

Incidence of VTEIncidence of VTE

VTE / 2.4 monthsVTE / 2.4 months VTE/monthVTE/month VTE /cycleVTE /cycle Cumulative rate Cumulative rate (95% CI)(95% CI)

1.93%1.93% 0.8%0.8% 0.7%0.7% 2.2% (1.7-2.8)2.2% (1.7-2.8)

0.0%0.0%

0.5%0.5%

1.0%1.0%

1.5%1.5%

2.0%2.0%

2.5%2.5%

3.0%3.0%

BaselineBaseline Cycle 1Cycle 1 Cycle 2Cycle 2 Cycle 3Cycle 3

Rat

e of

VT

E (

%)

Rat

e of

VT

E (

%)


Risk Factors: Site of CancerRisk Factors: Site of Cancer

00

22

44

66

88

1010

1212

All pat

ients

All pat

ients

Breas

t

Breas

t

Colon

Colon

Lung

Lung

Upper

GI

Upper

GI

Hodgk

in’s

Hodgk

in’s

NHLNHL

Other

s

Other

s


VT

E (

%)

/ 2.

4 m

onth

sV

TE

(%

) /

2.4

mon

ths


Incidence of Venous Thromboembolism By Incidence of Venous Thromboembolism By Quartiles of Pre-chemotherapy Platelet CountQuartiles of Pre-chemotherapy Platelet Count

p for trend=0.005p for trend=0.005

0.0%0.0%

0.5%0.5%

1.0%1.0%

1.5%1.5%

2.0%2.0%

2.5%2.5%

3.0%3.0%

3.5%3.5%

4.0%4.0%

4.5%4.5%

5.0%5.0%

<217 <217 217-270 217-270 270-337270-337 >337>337

Pre-chemotherapy Platelet Count/mmPre-chemotherapy Platelet Count/mm 33 (x1000)(x1000)

Inci

denc

e O

f V

TE

Ove

r 2.

4 In

cide

nce

Of

VT

E O

ver

2.4

Mon

ths(

%)

Mon

ths(

%)


Risk Factors: Multivariate AnalysisRisk Factors: Multivariate Analysis

CharacteristicCharacteristic OROR P valueP value


Upper GIUpper GI

LungLung

LymphomaLymphoma

3.883.88

1.861.86

1.51.5

0.030.03

0.00760.0076

0.050.05

0.320.32

Pre-chemotherapy platelet count Pre-chemotherapy platelet count >> 350,000/mm350,000/mm33 2.812.81 0.00020.0002

Hgb < 10g/dL or use of red cell Hgb < 10g/dL or use of red cell growth factorgrowth factor 1.831.83 0.030.03

Use of white cell growth factor in high-Use of white cell growth factor in high-risk sitesrisk sites 2.092.09 0.0080.008


Predictive ModelPredictive Model

Patient CharacteristicPatient Characteristic ScoreScore


Very high risk (stomach, pancreas)Very high risk (stomach, pancreas)

High risk (lung, lymphoma, gynecologic, GU High risk (lung, lymphoma, gynecologic, GU excluding prostate)excluding prostate)

22

11

Platelet count Platelet count >> 350,000/mm 350,000/mm33 11

Hgb < 10g/dL or use of ESAHgb < 10g/dL or use of ESA 11

Leukocyte count > 11,000/mmLeukocyte count > 11,000/mm33 11

BMI BMI >> 35 35 11

Khorana AA et al. Khorana AA et al. JTH JTH Suppl Abs O-T-002Suppl Abs O-T-002

Risk ScoreRisk Score 00 11 22 33 44

NN 1,3521,352 974974 476476 160160 3333

VTE(%) /2.4 mos.VTE(%) /2.4 mos. 0.80.8 1.81.8 2.72.7 6.36.3 13.213.2

Inci

denc

e of

VT

E O

ver

2.4

Mon

ths

Inci

denc

e of

VT

E O

ver

2.4

Mon

ths

0%0%

2%2%

4%4%

6%6%

8%8%

10%10%

12%12%

14%14%

16%16%

18%18%

00 11 22 33 44

Actual IncidenceActual IncidenceEstimated IncidenceEstimated Incidence95 % Confidence Limits95 % Confidence Limits

Predictive ModelPredictive Model

Predictive Model ValidationPredictive Model Validation

RiskRisk Low (0) Intermediate(1-2) High(Low (0) Intermediate(1-2) High(>>3)3)

0%0%

1%1%

2%2%

3%3%

4%4%

5%5%

6%6%

7%7%

8%8%

Rat

e of

VT

E o

ver

2.5

mos

(%

)R

ate

of V

TE

ove

r 2.

5 m

os (

%)

n=734n=734 n=1627n=1627 n=340n=340

0.8%0.8%

1.8%1.8%

7.1%7.1%Development cohortDevelopment cohort

0.3%0.3%

2.0%2.0%

6.7%6.7%

Validation cohortValidation cohort

n=374n=374 n=842n=842 n=149n=149

Khorana AA et al. Khorana AA et al. JTH JTH Suppl Abs O-T-002Suppl Abs O-T-002

Oral Anticoagulant TherapyOral Anticoagulant Therapyin Cancer Patients: Problematicin Cancer Patients: Problematic

► Warfarin therapy is complicated by:Warfarin therapy is complicated by:

● Difficulty maintaining tight therapeutic control, due Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. to anorexia, vomiting, drug interactions, etc.

● Frequent interruptions for thrombocytopenia and Frequent interruptions for thrombocytopenia and proceduresprocedures

● Difficulty in venous access for monitoringDifficulty in venous access for monitoring● Increased risk of both recurrence and bleedingIncreased risk of both recurrence and bleeding

► Is it reasonable to substitute long-term LMWH Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?for warfarin ? When? How? Why?

CLOT: Landmark Cancer/VTE TrialCLOT: Landmark Cancer/VTE Trial

CANCER PATIENTS WITH CANCER PATIENTS WITH ACUTE DVT or PEACUTE DVT or PE RandomizationRandomization

[N = 677] [N = 677]

► Primary Endpoints:Primary Endpoints: Recurrent VTE and Bleeding Recurrent VTE and Bleeding► Secondary EndpointSecondary Endpoint:: Survival Survival

Lee, Levine, Kakkar, Rickles et.al. Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, N Engl J Med, 2003;349:1462003;349:146

Dalteparin Dalteparin

Dalteparin Oral Anticoagulant

Landmark CLOT Cancer TrialLandmark CLOT Cancer TrialReduction in Recurrent VTEReduction in Recurrent VTE

00

55

1010

1515

2020

2525

Days Post RandomizationDays Post Randomization

00 3030 6060 9090 120120 150150 180180 210210

Pro

bab

ility

of R

ecu

rre

nt V

TE

, %P

roba

bili

ty o

f Re

curr

en

t VT

E, % Risk reduction = 52%Risk reduction = 52%

pp-value = 0.0017-value = 0.0017

DalteparinDalteparin

OACOAC

Recurrent VTERecurrent VTE


DalteparinDalteparin N=338N=338

OACOACN=335N=335

P-value*P-value*

Major bleedMajor bleed 19 ( 5.6%) 19 ( 5.6%) 12 ( 3.6%)12 ( 3.6%) 0.270.27

Any bleedAny bleed 46 (13.6%)46 (13.6%) 62 (18.5%)62 (18.5%) 0.0930.093

* Fisher’s exact test* Fisher’s exact test

Bleeding Events in CLOTBleeding Events in CLOT


Treatment of Cancer-Associated VTETreatment of Cancer-Associated VTE

StudyStudy DesignDesignLength of Length of TherapyTherapy(Months)(Months)

NNRecurrent Recurrent

VTE VTE (%)(%)

Major Major BleedingBleeding

(%)(%)

DeathDeath(%)(%)

CLOT TrialCLOT Trial(Lee 2003)(Lee 2003)

DalteparinDalteparinOACOAC

6 6 336336336336

991717

6644

39394141

CANTHENOXCANTHENOX(Meyer 2002)(Meyer 2002)

EnoxaparinEnoxaparinOACOAC

3367677171

11112121

771616

11112323

LITELITE(Hull ISTH 2003)(Hull ISTH 2003)

TinzaparinTinzaparinOACOAC

3380808787

661111

6688

23232222

ONCENOXONCENOX(Deitcher ISTH (Deitcher ISTH 2003)2003)

Enox (Low)Enox (Low)Enox (High)Enox (High)OACOAC

66323236363434

3.43.43.13.16.76.7

NS

NS0.03

NS

NS0.002

NS

NS

NR

0.09 0.030.09

Treatment and 2Treatment and 2° Prevention of VTE ° Prevention of VTE in Cancer – Bottom Linein Cancer – Bottom Line

► New standard of care is LMWH at therapeutic New standard of care is LMWH at therapeutic doses for a doses for a minimum of 3-6 monthsminimum of 3-6 months (Grade 1A (Grade 1A recommendation—ACCP)recommendation—ACCP)

► NOTENOTE:: Dalteparin is only LMWH approved (May, Dalteparin is only LMWH approved (May, 2007) for both the 2007) for both the treatment and secondary treatment and secondary preventionprevention of VTE in cancer of VTE in cancer

► Oral anticoagulant therapy to follow for as long as Oral anticoagulant therapy to follow for as long as cancer is cancer is active (Grade 1C recommendation—active (Grade 1C recommendation—ACCP)ACCP)

ChestChest Jun 2008: 454S–545S Jun 2008: 454S–545S

New DevelopmentNew Development

CLOT 12-month MortalityCLOT 12-month MortalityAll PatientsAll Patients

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

00 3030 6060 9090 120120 180180 240240 300300 360360


OACOAC

HR 0.94 P-value = 0.40HR 0.94 P-value = 0.40


Pro

bab

ility

of S

urv

iva

l, %

Pro

bab

ility

of S

urv

iva

l, %

Lee AY et al. Lee AY et al. J Clin Oncol. J Clin Oncol. 2005; 23:2123-9.2005; 23:2123-9.

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100


00 3030 6060 9090 120120 150150 180180 240240 300300 360360

Pro

bab

ility

of S

urv

iva

l, %

Pro

bab

ility

of S

urv

iva

l, %

OACOAC


HR = 0.50 P-value = 0.03HR = 0.50 P-value = 0.03

Anti-Tumor Effects of LMWHAnti-Tumor Effects of LMWH CLOT 12-month MortalityCLOT 12-month Mortality

Patients Without Metastases (N=150)Patients Without Metastases (N=150)

Lee AY et al. Lee AY et al. J Clin Oncol. J Clin Oncol. 2005; 23:2123-9.2005; 23:2123-9.

► 84 patients randomized: Chemo +/- LMWH (18 weeks)84 patients randomized: Chemo +/- LMWH (18 weeks)

► Patients balanced for age, gender, stage, smoking Patients balanced for age, gender, stage, smoking history, ECOG performance statushistory, ECOG performance status

LMWH for Small Cell Lung CancerLMWH for Small Cell Lung CancerTurkish StudyTurkish Study

Altinbas et al. J Thromb Haemost 2004;2:1266.Altinbas et al. J Thromb Haemost 2004;2:1266.

Chemotherapy Chemotherapy plus Dalteparinplus Dalteparin

Chemo Chemo alonealone P-valueP-value

1-y overall survival, %1-y overall survival, % 51.351.3 29.529.5 0.010.01

2-y overall survival, %2-y overall survival, % 17.217.2 0.00.0 0.010.01

Median survival, mMedian survival, m 13.013.0 8.08.0 0.010.01

CEV = cyclophosphamide, epirubicin, vincristine; CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units dailyLMWH = Dalteparin, 5000 units daily

VTE Prophylaxis Is Underused VTE Prophylaxis Is Underused in Patients With Cancer in Patients With Cancer

1.Kakkar AK et al. Oncologist. 2003;8:381-3882.Stratton MA et al. Arch Intern Med. 2000;160:334-3403.Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912

Cancer:Cancer:FRONTLINE SurveyFRONTLINE Survey11— — 3891 Clinician 3891 Clinician RespondentsRespondents

Rat

e of

App

ropr

iate

Pro

phyl

axis

, %R

ate

of A

ppro

pria

te P

roph

ylax

is, %

Major Surgery2

Major Abdominothoracic Surgery (Elderly)3 Medical

Inpatients4

Confirmed DVT (Inpatients)5

Cancer: Surgical

Cancer: Medical

4.Rahim SA et al. Thromb Res. 2003;111:215-2195.Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262

Conclusions and SummaryConclusions and Summary

► Risk factors for VTE in the setting of cancer have Risk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, been well characterized: solid tumors, chemotherapy, surgery, thrombocytopeniasurgery, thrombocytopenia

► Long-term secondary prevention with LMWH has Long-term secondary prevention with LMWH has been shown to produce better outcomes than warfarinbeen shown to produce better outcomes than warfarin

► Guidelines and landmark trials support administration Guidelines and landmark trials support administration of LMWH in at risk patientsof 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 Health system pharmacists can play a pivotal role in improving clinical outcomes in this patient populationimproving clinical outcomes in this patient population

Mayo/NCCTG Mayo/NCCTG Symptom-Control Trials: Symptom-Control Trials:


Charles Loprinzi, MDCharles Loprinzi, MDProfessor of OncologyProfessor of Oncology

Director, NCCTG Cancer Control ProgramDirector, NCCTG Cancer Control ProgramCo-Director Mayo Cancer Center Cancer Co-Director Mayo Cancer Center Cancer

Prevention and Control ProgramPrevention and Control ProgramMayo ClinicMayo Clinic

Rochester, MNRochester, MN

Chemotherapy-induced Neuropathy Chemotherapy-induced Neuropathy and Hot Flashesand Hot Flashes

TopicsTopics

► Overview: Sx control studies can be Overview: Sx control studies can be accomplishedaccomplished

► Chemotherapy induced peripheral neuropathyChemotherapy induced peripheral neuropathy

► Hot flashesHot flashes

0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

30

198

5

198

6

198

7

198

8

198

9

199

0

199

1

199

2

199

3

199

4

199

5

199

6

199

7

199

8

199

9

200

0

200

1

200

2

200

3

200

4

200

5

200

6

200

7

200

8

200

9

Symptom Control TrialsSymptom Control Trials

Anorexia/cachexiaAnorexia/cachexia

Hot flashHot flash

AnemiaAnemia

Skin toxicitySkin toxicity

Sexual healthSexual health

FatigueFatiguePainPain

AntiemeticAntiemetic

Mucosal toxicityMucosal toxicity NeuropathyNeuropathy

Bone health Bone health

TopicsTopics




Mayo/NCCTG CIPN ProgramMayo/NCCTG CIPN Program

► Treatment of established CIPNTreatment of established CIPN

► Prevention of CIPNPrevention of CIPN

► Paclitaxel acute pain syndromePaclitaxel acute pain syndrome

Treatment of Established CIPNTreatment of Established CIPN

► NortriptylineNortriptyline

► GabapentinGabapentin

► LamotrigeneLamotrigene

► Baclofen/amitriptyline/ketamineBaclofen/amitriptyline/ketamine

Audience PollAudience Poll

How many practices areHow many practices are

commonly using gabapentincommonly using gabapentin

(Neurontin) or pregabalin (Lyrica) (Neurontin) or pregabalin (Lyrica)

for pts with CIPN?for pts with CIPN?

Efficacy of Gabapentin in the Efficacy of Gabapentin in the Management of Chemotherapy-Induced Management of Chemotherapy-Induced

Peripheral Neuropathy: A Phase 3 Peripheral Neuropathy: A Phase 3 Randomized, Double-Blind, Placebo-Randomized, Double-Blind, Placebo-Controlled, Crossover Trial (N00C3)Controlled, Crossover Trial (N00C3)

Rao R, Michalak J, Sloan J, Loprinzi C, Soori G, Rao R, Michalak J, Sloan J, Loprinzi C, Soori G, Nikcevich D, Warner D, Novotny P, Kutteh L, Nikcevich D, Warner D, Novotny P, Kutteh L,

Wong GWong G

Cancer 110(9):2110, 2007Cancer 110(9):2110, 2007Cancer 110(9):2110, 2007Cancer 110(9):2110, 2007

Study SchemaStudy Schema

RR

6 wk6 wkGabapentinGabapentin

2700 mg/day2700 mg/dayPlaceboPlacebo

6 wk6 wk PlaceboPlaceboGabapentinGabapentin

2700 mg/day2700 mg/day

2 wk2 wk WashoutWashout

Chemotherapy-induced neuropathyChemotherapy-induced neuropathy

0

2

4

6

8

10

0 2 4 6 8 10 12 14

PlaceboPlacebo

GabapentinGabapentin

Meanpain

intensity

Meanpain

intensity

WeekWeek

P=0.21P=0.21 P=0.37P=0.37

First periodFirst periodWash-

outWash-

out Second periodSecond period

Mean Pain IntensityMean Pain Intensity

PlaceboPlacebo

GabapentinGabapentin

Cancer 110(9):2110, 2007Cancer 110(9):2110, 2007

Mean value at the end of the first 6-week phase (expressed as a percentage of baseline score)

Mean value at the end of the first 6-week phase (expressed as a percentage of baseline score)

POMSPOMS

UniscaleUniscale

SDSSDS

WHOWHO

ECOGECOG

Average pain (NRS)Average pain (NRS)

Worst pain (NRS)Worst pain (NRS)

PlaceboPlacebo GabapentinGabapentin

Gabapentin for CIPNGabapentin for CIPN

Conclusions Regarding Treatment of CIPN Conclusions Regarding Treatment of CIPN from this Experiencefrom this Experience

► 2 small tricyclic antidepressant studies – 2 small tricyclic antidepressant studies – but can’t rule out a small benefitbut can’t rule out a small benefit

► Gabapentin doesn’t appear to work – but Gabapentin doesn’t appear to work – but what about pregabalin?what about pregabalin?

► Lamotrigine doesn’t appear to workLamotrigine doesn’t appear to work

► Topical BAK looks like it is worth Topical BAK looks like it is worth pursuing furtherpursuing further

Prevention of CIPNPrevention of CIPN

► Calcium/magnesium Calcium/magnesium

OxaliplatinOxaliplatin

► Vitamin EVitamin E


How many are routinely using How many are routinely using

Ca/Mg for pts receiving FULFOX?Ca/Mg for pts receiving FULFOX?

DA Nikcevich, DA Nikcevich, A GrotheyA Grothey, JA Sloan, JW Kugler, , JA Sloan, JW Kugler, PT Silberstein, T Dentchev, DB Wender, PJ PT Silberstein, T Dentchev, DB Wender, PJ

Novotny, HE Windschitl, CL LoprinziNovotny, HE Windschitl, CL Loprinzi

J Clin Oncol 2008; May 20 suppl (abstract 4009)J Clin Oncol 2008; May 20 suppl (abstract 4009)

Intravenous Calcium and Magnesium Intravenous Calcium and Magnesium for Oxaliplatin-Induced Sensory for Oxaliplatin-Induced Sensory

Neurotoxicity (N04C7)Neurotoxicity (N04C7)

For the North Central Cancer Treatment GroupFor the North Central Cancer Treatment Group For the North Central Cancer Treatment GroupFor the North Central Cancer Treatment Group

DA Nikcevich, DA Nikcevich, A GrotheyA Grothey, JA Sloan, JW Kugler, PT , JA Sloan, JW Kugler, PT Silberstein, T Dentchev, DB Wender, PJ Novotny, HE Silberstein, T Dentchev, DB Wender, PJ Novotny, HE

Windschitl, CL LoprinziWindschitl, CL Loprinzi

► Cumulative peripheral sensory neurotoxicity is Cumulative peripheral sensory neurotoxicity is the dose-limiting toxicity of oxaliplatin the dose-limiting toxicity of oxaliplatin

► In a retrospective, non-randomized study, In a retrospective, non-randomized study, intravenous administration of calcium and intravenous administration of calcium and magnesium salts (CaMg) was associated with magnesium salts (CaMg) was associated with reduced oxaliplatin-induced PSN reduced oxaliplatin-induced PSN (Gamelin: (Gamelin: Clin Cancer Res, 2004) Clin Cancer Res, 2004)

BackgroundBackground

N04C7 Cancer Control Phase III Trial – N04C7 Cancer Control Phase III Trial – Study DesignStudy Design

N04C7 Cancer Control Phase III Trial – N04C7 Cancer Control Phase III Trial – Study DesignStudy Design

Patients to receive adj FOLFOXPatients to receive adj FOLFOX

RR

IV CaMgIV CaMg IV placeboIV placebo

% of grade 2+ sNT% of grade 2+ sNT

Primary Endpoint Grade 2+ sNT Primary Endpoint Grade 2+ sNT (CTCAE Scale)(CTCAE Scale)

Primary Endpoint Grade 2+ sNT Primary Endpoint Grade 2+ sNT (CTCAE Scale)(CTCAE Scale)

Neurotoxicity CaMg Placebograde n=50 n=52 P

Grade 2+ 22% 41% 0.038


Grade 2+ 22% 41% 0.038

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20

PlaceboPlacebo

Ca/MgCa/Mg

Time to Grade 2+ sNT (CTC scale)Time to Grade 2+ sNT (CTC scale)

% Free2+ sNT% Free2+ sNT

WeeksWeeks

P=0.05P=0.05

Endpoint: Grade 2+ sNT Endpoint: Grade 2+ sNT (Oxaliplatin Scale)(Oxaliplatin Scale)

Endpoint: Grade 2+ sNT Endpoint: Grade 2+ sNT (Oxaliplatin Scale)(Oxaliplatin Scale)


Grade 2+ 28% 51% 0.018


Grade 2+ 28% 51% 0.018

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20

PlaceboPlacebo

Ca/MgCa/Mg

Time to Grade 2+ sNT Time to Grade 2+ sNT (Oxaliplatin scale)(Oxaliplatin scale)

WeeksWeeks

P=0.03P=0.03

% Free2+ sNT% Free2+ sNT

Concept Trial StoryConcept Trial Story

Hochster HS, Grothey A, Childs BH. Use of Hochster HS, Grothey A, Childs BH. Use of calcium and magnesium salts to reduce calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. Journal of oxaliplatin-related neurotoxicity. Journal of Clinical Oncology 2007;25(25):4028-4029Clinical Oncology 2007;25(25):4028-4029

French NEUROXA Study French NEUROXA Study

► 144 patients with colorectal cancer in the 144 patients with colorectal cancer in the adjuvant and palliative settingadjuvant and palliative setting

► Randomized, in a double-blind manner, to Randomized, in a double-blind manner, to get CaMg versus a placeboget CaMg versus a placebo

► Early analyses of data from this trial have Early analyses of data from this trial have become availablebecome available

Gamelin L et al: J Clin Oncol 26(7):1188, 2008Gamelin L et al: J Clin Oncol 26(7):1188, 2008

French NEUROXA Study French NEUROXA Study

► Objective response rates and survivals Objective response rates and survivals were equivalent in the two armswere equivalent in the two arms

► Substantially less neurotoxicity in one Substantially less neurotoxicity in one group vs the other (5% vs 24% of grade 3 group vs the other (5% vs 24% of grade 3 NCI Common Toxicity Criteria, P<0.001)NCI Common Toxicity Criteria, P<0.001)

► The blind for this trial has not yet been The blind for this trial has not yet been brokenbroken

Gamelin L et al: J Clin Oncol 26(7):1188, 2008Gamelin L et al: J Clin Oncol 26(7):1188, 2008Gamelin L et al: J Clin Oncol 26(7):1188, 2008Gamelin L et al: J Clin Oncol 26(7):1188, 2008

The Use of Calcium and Magnesium The Use of Calcium and Magnesium for Prevention of Chemotherapy- for Prevention of Chemotherapy- Induced Peripheral Neuropathy Induced Peripheral Neuropathy

A Phase III Double-Blind Placebo- A Phase III Double-Blind Placebo- Controlled Study N08CBControlled Study N08CB

Placebo – 2 dosesPlacebo – 2 dosesPlacebo – 2 dosesPlacebo – 2 doses

FOLFOXFOLFOX R*R*

CaMg – 2 dosesCaMg – 2 dosesCaMg – 2 dosesCaMg – 2 doses

CaMg – 1 doseCaMg – 1 doseCaMg – 1 doseCaMg – 1 dose

Conclusions Regarding Prevention of Conclusions Regarding Prevention of CIPN from this ExperienceCIPN from this Experience

► CaMg looks like it works for oxaliplatin, CaMg looks like it works for oxaliplatin, but confirmation needed to convince but confirmation needed to convince the troops the troops

► Vitamin E does not appear to work for Vitamin E does not appear to work for CIPN, across different drugsCIPN, across different drugs


What is the etiology of the transient acute pain that What is the etiology of the transient acute pain that

commonly occurs a couple days after paclitaxel?commonly occurs a couple days after paclitaxel?• MyalgiaMyalgia• ArthralgiaArthralgia• Something elseSomething else

Paclitaxel Acute Pain SyndromePaclitaxel Acute Pain Syndrome

► Nerve injury hypothesisNerve injury hypothesis

► GlutamineGlutamine

(aka arthralgia/myalgia)(aka arthralgia/myalgia) (aka arthralgia/myalgia)(aka arthralgia/myalgia)

Animal Data Animal Data

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

The Paclitaxel Acute Pain Syndrome: The Paclitaxel Acute Pain Syndrome: Sensitization of Nociceptors as the Sensitization of Nociceptors as the

Putative Mechanism Putative Mechanism

Loprinzi et al: J Cancer Loprinzi et al: J Cancer 13(6):39913(6):399, , 2007 2007

MethodsMethods

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

GoalGoal

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

Patient CharacteristicsPatient Characteristics

Age 42-77Age 42-77

Tumor type

Breast 10

Gyn 5

Lung 2

Tonsil 1

Tumor type

Breast 10

Gyn 5

Lung 2

Tonsil 1

M/F 2/16M/F 2/16

Dose (mg/m2)

80 1

140 1

175 13

200 3

Dose (mg/m2)

80 1

140 1

175 13

200 3

Patient DescriptionsPatient 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


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

LocationLocation

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

LocationLocation

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


Severity

Mild 3

Mild-moderate 2

Moderate 3

Severe 9

Not stated 1

Severity

Mild 3

Mild-moderate 2

Moderate 3

Severe 9

Not stated 1

Aggrevating factors

None noted12

Walking 3

Sitting 1

Worse as day 1went on

Worse at night 1

Aggrevating factors

None noted12

Walking 3

Sitting 1

Worse as day 1went on

Worse at night 1

Deep vs 100%surface deep


Onset afterdrugs (days) Pt

1 1

2-4 15

5-7 2

Onset afterdrugs (days) Pt

1 1

2-4 15

5-7 2

Duration (days) Pt

1

1

2-3

6

4-5

6

7-11

5

Duration (days) Pt

1

1

2-3

6

4-5

6

7-11

5

ConclusionConclusion

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

Paclitaxel-Associated Acute Pain SyndromePaclitaxel-Associated Acute Pain SyndromeNatural History StudyNatural History Study

Patients scheduled to receive Patients scheduled to receive IV paclitaxel at 1 of 2 IV paclitaxel at 1 of 2 dose/schedulesdose/schedules

175+ mg/m175+ mg/m22 q 2-4 wk q 2-4 wk70-90 70-90 mg/mmg/m22 weekly weekly

Patients scheduled to receive Patients scheduled to receive IV paclitaxel at 1 of 2 IV paclitaxel at 1 of 2 dose/schedulesdose/schedules

175+ mg/m175+ mg/m22 q 2-4 wk q 2-4 wk70-90 70-90 mg/mmg/m22 weekly weekly

Patient questionnaires looking Patient questionnaires looking at the incidence and severity of at the incidence and severity of paclitaxel-associated acute pain paclitaxel-associated acute pain and sensory neuropathyand sensory neuropathy

Patient questionnaires looking Patient questionnaires looking at the incidence and severity of at the incidence and severity of paclitaxel-associated acute pain paclitaxel-associated acute pain and sensory neuropathyand sensory neuropathy

GoalsGoals

► Detail the incidence, timing, severity, and Detail the incidence, timing, severity, and characteristics of the P-APS in patients characteristics of the P-APS in patients receiving paclitaxelreceiving paclitaxel

► Describe differences between patients getting Describe differences between patients getting weekly versus less frequent, higher dose weekly versus less frequent, higher dose treatmenttreatment

► Study whether individuals with more Study whether individuals with more prominent P-APS have more prominent later prominent P-APS have more prominent later term distal neuropathy problemsterm distal neuropathy problems

TopicsTopics




Mean Hot Flash Score Reduction Randomized Studies

0

20

40

60

80

100

0 1 2 3 4 5 6

Week

% R

edu

ctio

n (

Mea

n)

Placebo (n=420)Soy (n=78)

Clonidine (n=75)

Megestrol (n=74)

Fluoxetine (n=36)

Venlafaxine (n=48)

Vitamin E (n=53)

Mean Hot Flash Score Reduction Randomized Studies

0

20

40

60

80

100

0 1 2 3 4 5 6

Week

% R

edu

ctio

n (

Mea

n)

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)

-70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70

Favors antidepressant Favors placebo

Loprinzi, Fluoxetine 20 mg/g

HR (fixed)95% CIStudy

Stearns, Paroxetine 10 mg/d


Stearns, Paroxetine 12.5 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

Favors gabapentin Favors placebo

-70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70

Pandya 300 mg/d

Pandya 900 mg/d

Guttuso 900 mg/d

Reddy 2400 mg/d

Total

HR (fixed)95% CIStudy

Hot Flash ConclusionsHot Flash Conclusions

► Newer antidepressants decrease hot flashesNewer antidepressants decrease hot flashes

► Gabapentin decreases hot flashesGabapentin decreases hot flashes

Case StudiesCase Studies

Case #1Case #1

► 48 year old woman with Stage II breast cancer 48 year old woman with Stage II breast cancer treated with lumpectomy and radiotherapy – now treated with lumpectomy and radiotherapy – now scheduled for adjuvant chemotherapy with scheduled for adjuvant chemotherapy with cyclophosphamide and doxorubicincyclophosphamide and doxorubicin

► Non-smoker, non-drinkerNon-smoker, non-drinker► Has 2 children and had severe morning sickness Has 2 children and had severe morning sickness

with each pregnancywith each pregnancy► Experiences motion sickness on ships but not on Experiences motion sickness on ships but not on

airplanesairplanes► Taking coumadin for DVT that developed during Taking coumadin for DVT that developed during

her hospitalization for lumpectomyher hospitalization for lumpectomy

Case #1 - ManagementCase #1 - Management

► What would the initial antiemetic management be?What would the initial antiemetic management be?

► What is her expected response to antiemetic What is her expected response to antiemetic therapy?therapy?

► What risk factors are pertinent in estimating her What risk factors are pertinent in estimating her response?response?

► Are there any other changes to be made in her Are there any other changes to be made in her medical management?medical management?

Case #2Case #2

► 24 year old man with metastatic testicular cancer24 year old man with metastatic testicular cancer

► Being treated with PVB (cisplatin, vinblastine, Being treated with PVB (cisplatin, vinblastine, bleomycin)bleomycin)

► Smokes 1 pack per day of cigarettes; drinks beer on Smokes 1 pack per day of cigarettes; drinks beer on weekendsweekends

► Used marijuana while in college but has since Used marijuana while in college but has since discontinued usediscontinued use

Case #2 - ManagementCase #2 - Management

► What would the initial antiemetic management What would the initial antiemetic management be?be?

► How would you approach emesis occurringHow would you approach emesis occurring● One day after chemotherapyOne day after chemotherapy● 3 days after chemotherapy3 days after chemotherapy● 10 days after chemotherapy10 days after chemotherapy● 20 days after chemotherapy20 days after chemotherapy

► How would you evaluate refractory emesis?How would you evaluate refractory emesis?

Case #3Case #3

► Active 50 year old Caucasian male with “charley Active 50 year old Caucasian male with “charley horse” of RLE for >6 dayshorse” of RLE for >6 days

► Pain, swelling, erythema spreads to thigh over this Pain, swelling, erythema spreads to thigh over this timetime

► 36 pack year history of cigarette smoking36 pack year history of cigarette smoking

► Developed superficial thrombophlebitis 6 months Developed superficial thrombophlebitis 6 months ago after IV placement for routine colonoscopy ago after IV placement for routine colonoscopy

► Hypercoagulability work up negative for:Hypercoagulability work up negative for:● Factor V LeidenFactor V Leiden● Prothrombin gene mutationProthrombin gene mutation● Antithrombin III activityAntithrombin III activity● Protein C and SProtein C and S● LACLAC

► Duplex doppler ultrasound was positive for bilateral Duplex doppler ultrasound was positive for bilateral DVT s extending from popliteal to superficial femoral DVT s extending from popliteal to superficial femoral veinsveins

► Patient hospitalized for UFH and coumadin transitionPatient hospitalized for UFH and coumadin transition

Case #3Case #3

► CBC-WNL except platelets=650KCBC-WNL except platelets=650K

► CMP-WNLCMP-WNL

► Coagulation studies-WNL except for fibrinogen=758 Coagulation studies-WNL except for fibrinogen=758 mg/dLmg/dL

► D-dimers >2800 ng/mL (<200)D-dimers >2800 ng/mL (<200)

Case #3Case #3

Case #3

► Coumadin discontinued after 6 monthsCoumadin discontinued after 6 months

► Follow up labs:Follow up labs:● D-dimers = 1000 ng/mlD-dimers = 1000 ng/ml● Fibrinogen = 570 mg/mLFibrinogen = 570 mg/mL● FVIII = 650%FVIII = 650%

► Repeat Duplex dopplers = residual DVTsRepeat Duplex dopplers = residual DVTs

Case #3 - ConclusionsCase #3 - Conclusions

► Unprovoked DVT in patient >50 years old with Unprovoked DVT in patient >50 years old with negative family history and particularly large clot negative family history and particularly large clot burden requires look for occult malignancyburden requires look for occult malignancy

► Development of superficial thrombophlebitis in past Development of superficial thrombophlebitis in past and bilateral proximal DVT are significantand bilateral proximal DVT are significant

► Elevated FVIII and D-dimers and residual DVT post Elevated FVIII and D-dimers and residual DVT post adequate anticoagulation are indicators of adequate anticoagulation are indicators of hypercoagulabilityhypercoagulability

► CT scan of chest (hx of smoking) reveals 3 cm mass CT scan of chest (hx of smoking) reveals 3 cm mass and bronchogenic washings confirm bronchogenic and bronchogenic washings confirm bronchogenic CaCa

► 45 yo F Stage IB Endometrial Carcinoma45 yo F Stage IB Endometrial Carcinoma

► TAH, BSO, LND TAH, BSO, LND

► Received prophylactic post op IV heparin x 4 daysReceived prophylactic post op IV heparin x 4 days

► Post-op Day 6 - chest pain and SOB, collapsed, cyanoticPost-op Day 6 - chest pain and SOB, collapsed, cyanotic

► VQ scan (+) for PE & 5mm thrombosis @ tip of CVCVQ scan (+) for PE & 5mm thrombosis @ tip of CVC

► IV Heparin re-initiated + urokinase given for thrombolysis with IV Heparin re-initiated + urokinase given for thrombolysis with initial improvement in signs and symptomsinitial improvement in signs and symptoms

► Post-op Day 9 - sudden PLT drop 238,000 to 39,000mcLPost-op Day 9 - sudden PLT drop 238,000 to 39,000mcL

► HIT suspected, heparin d/c'dHIT suspected, heparin d/c'd

Aida H, Aoki Y, Ohki I, & Tanaka K. Anticoagulation with a selective thrombin inhibitor in a woman with Aida H, Aoki Y, Ohki I, & Tanaka K. Anticoagulation with a selective thrombin inhibitor in a woman with heparin-induced thrombocytopenia. heparin-induced thrombocytopenia. Obstet GynecolObstet Gynecol. 2001;98:952-954.. 2001;98:952-954.

Case #4

► POD 10, CVC thrombus larger. Underwent successful POD 10, CVC thrombus larger. Underwent successful thrombectomythrombectomy

► Argatroban was administered intra- and postoperativelyArgatroban was administered intra- and postoperatively

► PLT post-op Day 1 - 104,000/mcL PLT post-op Day 1 - 104,000/mcL

► Oral warfarin and ASA initiatedOral warfarin and ASA initiated

► PLT post-op Day 4 - 236,000/mcL PLT post-op Day 4 - 236,000/mcL

► Patient was discharged home without further complications on Patient was discharged home without further complications on hospital Day 32hospital Day 32

Case based on an actual patient. Individual results may vary.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 Aida H, Aoki Y, Ohki I, & Tanaka K. Anticoagulation with a selective thrombin inhibitor in a woman with heparin-induced thrombocytopenia. heparin-induced thrombocytopenia. Obstet GynecolObstet Gynecol. 2000;98:952-954.. 2000;98:952-954.

Case #4

►Potential CausesPotential Causes

►Drug therapyDrug therapy● anesthesia, pain anesthesia, pain

meds, heparin, meds, heparin, urokinaseurokinase

►Patient FactorsPatient Factors● obese, carcinomaobese, carcinoma

►EventsEvents● surgerysurgery

►Timing of PLT dropTiming of PLT drop● re-exposure of heparinre-exposure of heparin● day 3day 3

►Degree of PLT fallDegree of PLT fall● 238,000 to 39,000mcL238,000 to 39,000mcL

►Concurrent eventsConcurrent events● CVC thrombosisCVC thrombosis● PEPE

►Lab findingsLab findings● elevated IgG antibody elevated IgG antibody

by immunoassayby 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;98:952-954.

Case #4

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