new dimensions and landmark advances in supportive care for the cancer patient optimizing prevention...
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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
Steven Grunberg, MDSteven Grunberg, MDProgram Co-ChairmanProgram Co-Chairman
Professor of MedicineProfessor of MedicineUniversity of VermontUniversity of VermontBurlington, VermontBurlington, Vermont
Innovation ● Investigation ● ApplicationInnovation ● Investigation ● Application
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
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
Innovation ● Investigation ● ApplicationInnovation ● Investigation ● Application
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
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
Steven Grunberg, MDSteven Grunberg, MDProgram Co-ChairmanProgram Co-Chairman
Professor of MedicineProfessor of MedicineUniversity of VermontUniversity of VermontBurlington, VermontBurlington, Vermont
Innovation ● Investigation ● ApplicationInnovation ● Investigation ● Application
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?
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
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
Innovation ● Investigation ● ApplicationInnovation ● Investigation ● Application
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
elat
ive
Ris
k of
VT
E in
Can
cer
Pat
ient
sC
ance
r P
atie
nts
Pan
crea
sP
ancr
eas
Bra
inB
rain
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
eP
rost
ate
Rec
tal
Rec
tal
Kid
ney
Kid
ney
Col
onC
olon
Ova
ryO
vary
Live
rLi
ver
Leuk
emia
Leuk
emia
Bre
ast
Bre
ast
Cer
vix
Cer
vix
Bla
dder
Bla
dder
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
Khorana, JCO, 2006Khorana, JCO, 2006
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)
Khorana, JCO, 2006Khorana, JCO, 2006
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%
Relative Relative risk risk reduction reduction 44%44%
Relative Relative risk risk reduction reduction 47%47%
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 and ThrombosisCancer and Thrombosis
► 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
Cancer and ThrombosisCancer and Thrombosis
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 (
%)
Khorana, Cancer, 2005Khorana, Cancer, 2005
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
Site of CancerSite of Cancer
VT
E (
%)
/ 2.
4 m
onth
sV
TE
(%
) /
2.4
mon
ths
Khorana, Cancer, 2005Khorana, Cancer, 2005
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(
%)
Khorana, Cancer, 2005Khorana, Cancer, 2005
Risk Factors: Multivariate AnalysisRisk Factors: Multivariate Analysis
CharacteristicCharacteristic OROR P valueP value
Site of CancerSite of Cancer
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
Khorana, Cancer, 2005Khorana, Cancer, 2005
Predictive ModelPredictive Model
Patient CharacteristicPatient Characteristic ScoreScore
Site of CancerSite of Cancer
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
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
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
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
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
DalteparinDalteparin
OACOAC
HR 0.94 P-value = 0.40HR 0.94 P-value = 0.40
Days Post RandomizationDays Post Randomization
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
Days Post RandomizationDays Post Randomization
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
DalteparinDalteparin
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:
Innovation ● Investigation ● ApplicationInnovation ● Investigation ● Application
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
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
► Overview: Sx control studies can be Overview: Sx control studies can be accomplishedaccomplished
► Chemotherapy induced peripheral neuropathyChemotherapy induced peripheral neuropathy
► Hot flashesHot flashes
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
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
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
Prevention of CIPNPrevention of CIPN
► Calcium/magnesium Calcium/magnesium
OxaliplatinOxaliplatin
► Vitamin EVitamin E
Audience PollAudience Poll
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
Neurotoxicity CaMg Placebograde n=50 n=52 P
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)
Neurotoxicity CaMg Placebograde n=50 n=52 P
Grade 2+ 28% 51% 0.018
Neurotoxicity CaMg Placebograde n=50 n=52 P
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
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
Audience PollAudience Poll
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
Patient DescriptionsPatient Descriptions
Real deep bone pain, not in the joints
Deep bone pain
Dull constant ache
Joint, aching, what I think arthritis would be like
Real deep bone pain, not in the joints
Deep bone pain
Dull constant ache
Joint, aching, what I think arthritis would be like
Shooting pain
Deep pain like the flu
Joint pain, muscle aches
Low level flu, body ache, muscle
Shooting pain
Deep pain like the flu
Joint pain, muscle aches
Low level flu, body ache, muscle
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
Patient DescriptionsPatient Descriptions
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
Patient DescriptionsPatient Descriptions
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
► Overview: Sx control studies can be Overview: Sx control studies can be accomplishedaccomplished
► Chemotherapy induced peripheral neuropathyChemotherapy induced peripheral neuropathy
► Hot flashesHot flashes
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)
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 20 mg/d
Stearns, Paroxetine 12.5 mg/d
Stearns, Paroxetine 25 mg/d
Paroxetine total
Gordon, Sertraline 50 mg/d
Kimmick, Sertraline 50 mg/d
Grady, Sertraline 100 mg/d
Sertraline total
Loprinzi, Venlafaxine 37.5 mg/d
Loprinzi, Venlafaxine 75 mg/d
Loprinzi, Venlafaxine 150 mg/d
Venlafaxine total
Antidepressants total
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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