Innovation ● Investigation ● Application

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

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

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

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

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

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

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

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

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

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

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

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

Comorbidity Connection
CAP UTI Cancer Heart Failure ABE/COPD Respiratory Failure Myeloproliferative Disorder Thrombophilia Surgery History of DVT Other SUBSPECIALIST STAKEHOLDERS Infectious diseases Oncology PHARMACISTS Cardiology Pulmonary medicine Hematology Oncology/hematology Interventional Radiology Hospitalist Surgeons EM PCP

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

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

Comorbidity Connection
Overview Comorbidity Connection

Acute Medical Illness and VTE
Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Risk Factor Odds Ratio (95% CI) X2 Age > 75 years Cancer Previous VTE 1.03 ( ) 1.62 ( ) 2.06 ( ) 0.0001 0.08 0.02 Acute infectious disease 1.74 ( ) Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:

Comorbid Condition and DVT Risk
Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%. The individual attributable risk estimates for malignant neoplasm, trauma, congestive heart failure, central venous catheter or pacemaker placement, neurological disease with extremity paresis, and superficial vein thrombosis were 18%, 12%, 10%, 9%, 7%, and 5%, respectively. Together, the 8 risk factors accounted for 74% of disease occurrence Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern Med. 2002 Jun 10;162(11): Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study

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

ICOPER Cumulative Mortality
5 10 15 20 25 17.5% Mortality (%) 7 14 30 60 90 Days From Diagnosis Lancet 1999;353:

Stages of Chronic Venous Insufficiency
Varicose veins Ankle/ leg edema Stasis dermatitis Lipodermatosclerosis Venous stasis ulcer

Progression of Chronic Venous Insufficiency
From UpToDate 2006

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

High Dose Metoclopramide – The First Highly Effective Antiemetic
Placebo (n=10) P Metoclopramide (n=11) Prochlorperazine (n=10) Emetic Episodes 1 0.9 10.5 5-25 0.001 1.5 0-6 12 5-16 0.005 Hours of Vomiting 0.2 0-16.8 3.6 2-17 0.028 0.5 0-16.5 4.5 NS Hours of Nausea 0-16.2 3.7 0-19.2 0.042 0.1 0-17.2 5 0-20 Gralla, NEJM 305:905, 1981

Phase I Study of Ondansetron
43 Patients Receiving Cisplatin > 60 mg/m2 Dose Level Complete Major Failure 0.01 mg/kg 1 2 0.06 mg/kg 3 0.18 mg/kg 0.30 mg/kg 4 0.48 mg/kg Total 44% 37% 19% Grunberg, J Clin Oncol 7:1137, 1989

Increase in Complete Protection with Dexamethasone
89 Patients Receiving Cisplatin > 50 mg/m2 Ondansteron Ondansteron/ Dexamethasone p Vomiting 64% 91% 0.0005 Nausea 66% 89% 0.0025 Nausea/Vomiting 56% 81% 0.0008 Preference 14% 39% 0.003 Roila, J Clin Oncol 9:675, 1991

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

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

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

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

Half-Life and Binding Affinities of 5-HT3 Receptor Antagonists
5-HT3 Antagonist Half-Life (h) Binding Affinity (pKi)*† Palonosetron 40.01 10.455 Ondansetron 4.02 8.395 Dolasetron 7.33 7.606 Granisetron 9.04 8.915 Tropisetron 8.05 8.75 Palonosetron demonstrates key pharmacologic differences compared with previously approved 5-HT3 receptor antagonists, including an extended plasma elimination half-life (approximately 40 hours) compared with other agents.1-4,5 Another pharmacologic difference between palonosetron and other 5-HT3 receptor antagonists is the 30-fold+ higher binding affinity for the 5-HT3 receptor of palonosetron compared with other agents in the class.5,6 The extended plasma half-life of palonosetron, combined with its high binding affinity, may contribute to its prolonged effect. 1. Aloxi (palonosetron HCl) prescribing information. Lugano, Switzerland: Helsinn Birex Pharmaceuticals, 2005; 2. Zofran® [package insert]. Research Triangle Park, NC, USA: GlaxoSmithKline; 2001. 3. Anzemet® [package insert]. Bridgewater, NJ, USA: Aventis Pharmaceuticals; 2000. 4. Kytril® [package insert]. Nutley, NJ, USA: Roche Laboratories Inc.; 2000. 5. Wong EHF, Clark R, Leung E et al. The interaction of RS , a potent and selective antagonist, with 5-HT3 receptors in vitro. Br J Pharmacol. 1995;114: 6. Miller RC, Galvan M, Gittos MW et al. Pharmacological properties of dolasetron, a potent and selective antagonist at 5-HT3 receptors. Drug Dev Res. 1993;28:87-93. *Log-scale †In vitro data; clinical significance has not been established 1. Aloxi® package insert, Zofran® package insert, Anzemet® package insert, Kytril® package insert, Wong EHF et al. Br J Pharmacol. 1995;114: Miller RC et al. Drug Dev Res. 1993;28:87-93.

Palonosetron for Highly Emetogenic Chemotherapy Efficacy Results by 24 Hour Period

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

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

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

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

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

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

Time course of emesis following cisplatin with a 5-HT3 antagonist or aprepitant
Patients with no emesis (%) Gran + dex d1 / placebo d2–5 Gran + dex + aprepitant d1 / aprepitant d2–5 Aprepitant d0 / aprepitant + dex d1 / aprepitant d2–5 Aprepitant + dex d1 / aprepitant d2–5 100 80 60 40 20 8 24 40 60 80 100 120 Time since cisplatin (hours) Hesketh, Support Care Cancer 10:365, 2002

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

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

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

Guideline Organizations
MASCC ASCO ASHP NCCN EONS Consensus of Consensus

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

Antiemetic Consensus Guidelines - 2008
Risk Acute Delayed High 5-HT3+DXM+NK1 DXM+NK1 Moderate NK1 Low Single Agent None Minimal Adapted from Koeller, Support Care Cancer 10:519, 2002

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

It’s actually more of a Guideline
It’s not really a Code It’s actually more of a Guideline - Pirates of the Caribbean, 2003

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

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

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

DVT and PE in Cancer Facts, Findings, and Natural History
VTE is the second leading cause of death in hospitalized cancer patients1,2 The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer2 Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE3 Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years4 Let’s continue examining the association between DVT/PE and cancer. Consider these statistics. DVT/PE is the second leading cause of death in hospitalized cancer patients. Up to twenty percent of all DVT/PE cases occur in cancer patients and up to fifty percent of cancer patients may have evidence of asymptomatic DVT/PE. As I previously mentioned, surgery is a well-known risk factor; however cancer patients undergoing surgery compound that risk to 3 to 5-times greater than surgery patients without cancer. Finally, cancer patients are at higher risk of developing a recurrent DVT or PE following a primary experience than patients without cancer. Ambrus JL et al. J Med. 1975;6:61-64 Donati MB. Haemostasis. 1994;24: Johnson MJ et al. Clin Lab Haem. 1999;21:51-54 Prandoni P et al. Ann Intern Med. 1996;125:1-7

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

Thrombosis and Survival Likelihood of Death After Hospitalization
0.00 0.20 0.40 1.00 0.80 0.60 DVT/PE and Malignant Disease Malignant Disease DVT/PE Only Nonmalignant Disease Number of Days Probability of Death Levitan N, et al. Medicine 1999;78:285

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

Trends in VTE in Hospitalized Cancer Patients
7.0 6.5 6.0 5.5 5.0 4.5 4.0 Rate of VTE (%) 3.5 3.0 2.5 2.0 1.5 1.0 P<0.0001 0.5 0.0 1995 1996 1997 1998 1999 2000 2001 2002 2003 VTE- patients on chemotherapy VTE-all patients DVT-all patients PE-all patients Khorana AA et al. Cancer

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

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

VTE Risk And Cancer Type “Solid And Liquid Malignancies”
Relative Risk of VTE Ranged From 1.02 to 4.34 4.5 4 3.5 3 2.5 2 1.5 1 0.5 Pancreas Brain Myeloprol Stomach Lymphoma Uterus Lung Esophagus Prostate Rectal Kidney Colon Ovary Liver Leukemia Breast Cervix Bladder Relative Risk of VTE in Cancer Patients Stein PD, et al. Am J Med 2006; 119: 60-68

Cancer and Thrombosis Medical Inpatients

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

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

Predictors of VTE in Hospitalized Cancer Patients
Characteristic OR P Value Site of Cancer Lung Stomach Pancreas Endometrium/cervix Brain 1.3 1.6 2.8 2 2.2 <0.001 0.0035 Age 65 y 1.1 0.005 Arterial thromboembolism 1.4 0.008 Comorbidities (lung/renal disease, infection, obesity) [Khorana.JClinOncol. Jan.2006/p489/Table 4] Khorana AA et al. J Clin Oncol. 2006;24:

Antithrombotic Therapy: Choices
Pharmacologic (Prophylaxis & Treatment) Nonpharmacologic (Prophylaxis) Low Molecular Weight Heparin (LMWH) Intermittent Pneumatic Compression Elastic Stockings Unfractionated Heparin (UH) Inferior Vena Cava Filter Several classes of agents have been used for prophylaxis and treatment of VTE Nonpharmacologic approaches to prophylaxis include: intermittent pneumatic compression (IPC), elastic stockings, and inferior vena cava filter Most commonly used pharmacologic agents for thromboprophylaxis and treatment of VTE include: unfractionated heparin (UH) (standard, low-dose, or adjusted-dose), oral anticoagulants such as warfarin, and low molecular weight heparins (LMWHs) Oral Anticoagulants New Agents: e.g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.?

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

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

Cancer and Thrombosis Surgical Patients

Incidence of VTE in Surgical Patients
Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis: No Cancer N=16,954 Cancer N=6124 P-value Post-op VTE 0.61% 1.26% <0.0001 Non-fatal PE 0.27% 0.54% <0.0003 Autopsy PE 0.11% 0.41% Death 0.71% 3.14% Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732

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

Prophylaxis in Surgical Patients
LMWH vs. UFH Abdominal or pelvic surgery for cancer (mostly colorectal) LMWH once daily vs. UFH tid for 7–10 days post-op DVT on venography at day 7–10 and symptomatic VTE Study N Design Regimens ENOXACAN 1 631 double-blind enoxaparin vs. UFH Canadian Colorectal DVT Prophylaxis 2 475 1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103 2. McLeod R, et al. Ann Surg 2001;233:

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

Extended Prophylaxis in Surgical Patients
12.0% ENOXACAN II P=0.02 Incidence of Outcome Event N=167 4.8% 5.1% N=165 3.6% 1.8% NNT = 14 0.6% 0% 0.4% VTE Prox Any Major DVT Bleeding Bleeding Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:

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

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

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

Prophylaxis for Venous Catheters
Placebo-Controlled Trials Study Regimen N CRT (%) Reichardt* 2002 Dalteparin 5000 U daily placebo 285 140 11 (3.7) 5 (3.4) Couban* 2002 Warfarin 1mg daily 130 125 6 (4.6) 5 (4.0) ETHICS† 2004 Enoxaparin 40 mg daily 155 22 (14.2) 28 (18.1) *symptomatic outcomes; †routine venography at 6 weeks Reichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G, et al. Proc ASCO 2004;23:730

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

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

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

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

Ambulatory Chemotherapy Patients
Cancer and Thrombosis Ambulatory Chemotherapy Patients

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

Independent Risk Factors for DVT/PE
Risk Factor/Characteristic O.R. Recent surgery with institutionalization 21.72 Trauma 12.69 Institutionalization without recent surgery 7.98 Malignancy with chemotherapy 6.53 Prior CVAD or pacemaker 5.55 Prior superficial vein thrombosis 4.32 Malignancy without chemotherapy 4.05 Neurologic disease w/ extremity paresis 3.04 Serious liver disease 0.10 Dr. John Heit and colleagues have provided some interesting information regarding the risk factors associated with developing DVT/PE based on a very thorough epidemiological study. This study, part of the Rochester Epidemiology Project, looked at all residents in Olmsted County, 90 miles southeast of Minneapolis, Minnesota. The study collected information on every patient that underwent a diagnostic test looking for DVT/PE over a 25 year period. The investigators also looked at all death certificates and autopsy reports to gather further data. Obviously, this was a large study covering a considerable period of time. Over 9,000 patients were included. What you see here are the relative odds ratios of various risk factors or risk characteristics from this study for developing either DVT or PE. Notice that malignancy with chemotherapy carried an odds ratio of 6.53 and malignancy without chemotherapy, an odds ratio of In comparison to other well known risk factors, such as surgery alone, these data indicate malignancy with and without chemotherapy are frequently associated with the development of a DVT or PE. Heit JA et al. Thromb Haemost. 2001;86:

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

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

Ambulatory Cancer plus Chemotherapy
Study Methods Prospective observational study of ambulatory cancer patients initiating a new chemotherapy regimen, and followed for a maximum of 4 cycles 115 U.S. centers participated Patients enrolled between March, 2002 and August, who had completed at least one cycle of chemotherapy were included in this analysis METHODS: We analyzed data from a prospective observational study conducted by the Awareness of Neutropenia in Chemotherapy Study Group, funded by Amgen, Inc. Patients were enrolled on study at the start of a new chemotherapy regimen, and followed prospectively for a maximum of 4 cycles, at 115 participating US centers. Patients enrolled between March, 2002 and August, who had completed at least one cycle of chemotherapy were included in this analysis. Khorana, Cancer, 2005

Ambulatory Cancer plus Chemotherapy
Study Methods VTE events were recorded during mid-cycle or new-cycle visits Symptomatic VTE was a clinical diagnosis made by the treating clinician Statistical analysis Odds ratios to estimate relative risk Multivariate logistic regression to adjust for other risk factors VTE events were recorded during mid-cycle or new-cycle visits. Since this was an observational study, VTE was diagnosed by the treating physician by usual tests based on clinical suspicion. Statistical analysis included generation of odds ratios to estimate relative risk, and a logistic regression analysis to adjust for other risk factors. The predictive model was constructed based on the multivariate analysis. The risk score estimates for each variable were derived using beta-coefficients from the multivariate model. First order interactions were incorporated into the final score. Khorana, Cancer, 2005

Incidence of VTE 0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% Baseline Cycle 1
Rate of VTE (%) A total of 58 patients (1.93%) developed VTE during a median follow-up period of 2.4 months (0.8%/month). One patient developed VTE prior to starting chemotherapy. The rate of VTE did not differ significantly among chemotherapy cycles, occurring in 0.77% during cycle 1, 0.74% during cycle 2, and 0.7% during cycle 3. As shown in this figure, the cumulative rate of VTE was 2.2% (95% CI, ) during cycles 1 through 3. VTE / 2.4 months VTE/month VTE /cycle Cumulative rate (95% CI) 1.93% 0.8% 0.7% 2.2% ( ) Khorana, Cancer, 2005

Risk Factors: Site of Cancer
12 10 8 6 VTE (%) / 2.4 months 4 2 The primary site of cancer affected the risk of VTE (p=0.01), with the highest rates observed in patients with upper gastrointestinal cancers (particularly gastric and pancreatic) (2.3%/month), and lung cancer (1.2%/month). Among patients with hematologic malignancies, those with a diagnosis of Hodgkin’s or non-Hodgkin’s lymphoma had the highest rates of VTE (1.1%/month). Lung NHL Colon Breast Upper GI Others Hodgkin’s All patients Site of Cancer Khorana, Cancer, 2005

Incidence of Venous Thromboembolism By Quartiles of Pre-chemotherapy Platelet Count
p for trend=0.005 0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% 3.5% 4.0% 4.5% 5.0% <217 >337 Incidence Of VTE Over 2.4 Months(%) This figure depicts the incidence of venous thromboembolism by quartiles of pre-chemotherapy platelet count. As can be seen, elevated platelet counts were associated with an increased risk of venous thromboembolism. Patients in the highest quartile of pre-chemotherapy platelet count with a count of > 337,000/ cu mm, had a 3.6% risk of VTE, and this was significantly greater than the 1.1 % risk observed with patients in the lowest quartile, with a pre-chemotherapy platelet count of < 217,000/ cu mm. The p value for trend was highly significant at 0.005, and the difference between the highest and lowest quartile was also significant at 3 Pre-chemotherapy Platelet Count/mm (x1000) Khorana, Cancer, 2005

Risk Factors: Multivariate Analysis
Characteristic OR P value Site of Cancer Upper GI Lung Lymphoma 3.88 1.86 1.5 0.03 0.0076 0.05 0.32 Pre-chemotherapy platelet count > 350,000/mm3 2.81 0.0002 Hgb < 10g/dL or use of red cell growth factor 1.83 Use of white cell growth factor in high-risk sites 2.09 0.008 We included clinically and statistically significant variables in a multivariate logistic regression analysis. This slide demonstrates variables found to be significant in this analysis. Risk factors independently associated with VTE included primary site of cancer (upper gastrointestinal or lung), an elevated pre-chemotherapy platelet count, hemoglobin < 10g/dL or use of erythropoietin (a combined variable), and use of white cell growth factors. We found a significant first-order interaction between site of cancer and use of white cell growth factors (p=0.02). Patients with sites of cancer associated with higher risk of VTE (upper gastrointestinal, lung or lymphoma) had a significantly increased risk of VTE associated with white cell growth factor use (VTE rate of 5.9% versus 1.52% without growth factor use, p =0.0001; odds ratio 4.0, [95% CI, ]). In contrast, patients with other sites of cancer did not appear to have an increased risk of VTE with the use of white cell growth factors (VTE rate of 1.31% versus 1.42% without growth factor use, p =0.84). Khorana, Cancer, 2005

Patient Characteristic
Predictive Model Patient Characteristic Score Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate) 2 1 Platelet count > 350,000/mm3 Hgb < 10g/dL or use of ESA Leukocyte count > 11,000/mm3 BMI > 35 Khorana AA et al. JTH Suppl Abs O-T-002

Predictive Model Risk Score 1 2 3 4 N 1,352 974 476 160 33
0% 2% 4% 6% 8% 10% 12% 14% 16% 18% 1 2 3 4 Actual Incidence Estimated Incidence 95 % Confidence Limits Incidence of VTE Over 2.4 Months The performance of the predictive risk assessment model is illustrated in this figure, which shows the rate of VTE by risk score. As you can see, the predicted incidence of VTE, shown as a yellow line, correlates closely with the actual incidence of VTE, shown as red triangles. The goodness of the model fit was confirmed by Hosmer and Lemeshow test. The proposed predictive model discriminates well between subgroups of patients at low and high risk of VTE during chemotherapy. Patients with a risk score of 0 had a VTE rate of 0.8% over the median 2.4 month follow-up. In contrast, patients with a risk score of 2 had a 3-fold higher rate at 2.7%, and those with a risk score of 3 had a 6.3% rate of VTE. Risk Score 1 2 3 4 N 1,352 974 476 160 33 VTE(%) /2.4 mos. 0.8 1.8 2.7 6.3 13.2

Predictive Model Validation
8% n=734 n=1627 n=340 0.8% 1.8% 7.1% Development cohort 7% 0.3% 2.0% 6.7% Validation cohort n=374 n=842 n=149 6% 5% Rate of VTE over 2.5 mos (%) 4% 3% 2% 1% 0% Risk Low (0) Intermediate(1-2) High(>3) Khorana AA et al. JTH Suppl Abs O-T-002

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

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

Landmark CLOT Cancer Trial
Reduction in Recurrent VTE 5 10 15 20 25 Days Post Randomization 30 60 90 120 150 180 210 Probability of Recurrent VTE, % Risk reduction = 52% p-value = Dalteparin OAC Recurrent VTE Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

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

Treatment of Cancer-Associated VTE
Study Design Length of Therapy (Months) N Recurrent VTE (%) Major Bleeding Death CLOT Trial (Lee 2003) Dalteparin OAC 6 336 9 17 4 39 41 CANTHENOX (Meyer 2002) Enoxaparin 3 67 71 11 21 7 16 23 LITE (Hull ISTH 2003) Tinzaparin 80 87 8 22 ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) 32 36 34 3.4 3.1 6.7 NS 0.002 NS 0.09 0.09 0.03 0.03 NS NS NS NS NR

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

CLOT 12-month Mortality All Patients Dalteparin
10 20 30 40 50 60 70 80 90 100 120 180 240 300 360 Dalteparin OAC HR 0.94 P-value = 0.40 Days Post Randomization Probability of Survival, % Lee AY et al. J Clin Oncol. 2005; 23:

Anti-Tumor Effects of LMWH
CLOT 12-month Mortality Patients Without Metastases (N=150) 10 20 30 40 50 60 70 80 90 100 Dalteparin OAC Probability of Survival, % HR = P-value = 0.03 30 60 90 120 150 180 240 300 360 Lee AY et al. J Clin Oncol. 2005; 23: Days Post Randomization

LMWH for Small Cell Lung Cancer Turkish Study
84 patients randomized: Chemo +/- LMWH (18 weeks) Patients balanced for age, gender, stage, smoking history, ECOG performance status Chemotherapy plus Dalteparin Chemo alone P-value 1-y overall survival, % 51.3 29.5 0.01 2-y overall survival, % 17.2 0.0 Median survival, m 13.0 8.0 CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily Altinbas et al. J Thromb Haemost 2004;2:1266.

VTE Prophylaxis Is Underused in Patients With Cancer
[1/Kakkar. Oncologist.2003/ p381/c1/line A1-A24; p383/c1/line 44-46, c2/line 1-3] [2/Stratton. ArchInternMed. Feb.2000/ p336/c2/line 7-11] [3/Bratzler. ArchInternMed. Sept.1998/ p1909/c1/line A10-A15, c2/line A1-A3] [4/Rahim.ThrmbRes. 2003/p3/c2/line 1-5] [5/Goldhaber. AmJCardiol.Jan.2004/ p261/c2/line 6-8] Cancer: FRONTLINE Survey1— 3891 Clinician Respondents Major Surgery2 Cancer: Surgical Major Abdominothoracic Surgery (Elderly)3 Confirmed DVT (Inpatients)5 Rate of Appropriate Prophylaxis, % Medical Inpatients4 Cancer: Medical VTE prophylaxis is underused in patients with cancer The Fundamental Research in Oncology and Thrombosis (FRONTLINE) survey was a questionnaire distributed globally to clinicians involved in cancer care and accessible on a dedicated Web site1 Data from 3891 completed questionnaires were available for analysis1 The results indicated that 52% of respondents would routinely utilize thromboprophylaxis for surgical oncology patients, and that most respondents only considered thromboprophlyaxis in approximately 5% of their medical oncology patients1 These results can be compared with prophylaxis rates in other patient groups as determined by other recent studies A retrospective record review in 10 US teaching or community-based hospitals of patients undergoing major surgeries (major abdominal surgery, total hip replacement, hip fracture repair, or total knee replacement) showed VTE prophylaxis was used in 89% of patients2 A retrospective record review of patients aged 65 and older in 20 Oklahoma hospitals undergoing major abdominothoracic surgery indicated that prophylaxis was used in 38% of patients3 A retrospective record review at 2 Canadian hospitals of medical inpatients indicated that prophylaxis was used in 33% of patients4 In the DVT-FREE prospective registry of patients with ultrasound-confirmed DVT, among 5451 patients, 42% had received prophylaxis5 [1/Kakkar.Oncologist. 2003/p381/c1/ line A5-A22] [1/Kakkar/p381/c1/ line A23-A24] [1/Kakkar/p383/c1/ line 44-46, c2/line 1-3] [2/Stratton.ArchIntern Med.Feb.2000/ p334/c1/line A14-A19, c2/line A1-A2; p336/c2/line 7-11] [3/Bratzler.ArchIntern Med.Sept.1998/ p1909/c1/line A10-A15, c2/line A1-A3] [4/Rahim.ThrmbRes. 2003/p1/line A1-A12; p3/c2/line 1-5] [5/Goldhaber.AmJ Cardiol.Jan.2004/ p259/c1/line A1-A10; p261/c2/line 6-8] 1. Kakkar AK et al. Oncologist. 2003;8: 2. Stratton MA et al. Arch Intern Med. 2000;160: 3. Bratzler DW et al. Arch Intern Med. 1998;158: 4. Rahim SA et al. Thromb Res. 2003;111: 5. Goldhaber SZ et al. Am J Cardiol. 2004;93: 1. Kakkar AK, Levine M, Pinedo HM, Wolff R, Wong J. Venous thrombosis in cancer patients: insights from the FRONTLINE survey. Oncologist. 2003;8: 2. Stratton MA, Anderson FA, Bussey HI, et al. Prevention of venous thromboembolism: adherence to the 1995 American College of Chest Physicians consensus guidelines for surgical patients. Arch Intern Med. 2000;160: 3. Bratzler DW, Raskob GE, Murray CK, Bumpus LJ, Piatt DS. Underuse of venous thromboembolism prophylaxis for general surgery patients: physician practices in the community hospital setting. Arch Intern Med. 1998;158: 4. Rahim SA, Panju A, Pai M, Ginsberg J. Venous thromboembolism prophylaxis in medical inpatients: a retrospective chart review. Thromb Res. 2003;111: 5. Goldhaber SZ, Tapson VF, for the DVT FREE Steering Committee. A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol. 2004;93:

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

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

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

Symptom Control Trials
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Mucosal toxicity Neuropathy Anorexia/cachexia Anemia Pain Bone health Hot flash Fatigue Skin toxicity Antiemetic Sexual health

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

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

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

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

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

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

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

Conclusions Regarding Treatment of CIPN from this Experience
2 small tricyclic antidepressant studies – but can’t rule out a small benefit Gabapentin doesn’t appear to work – but what about pregabalin? Lamotrigine doesn’t appear to work Topical BAK looks like it is worth pursuing further

Prevention of CIPN Calcium/magnesium Oxaliplatin Vitamin E

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

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

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

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

Primary Endpoint Grade 2+ sNT
(CTCAE Scale) Neurotoxicity CaMg Placebo grade n=50 n=52 P Grade 2+ 22% 41% 0.038

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

Endpoint: Grade 2+ sNT (Oxaliplatin Scale)
Neurotoxicity CaMg Placebo grade n=50 n=52 P Grade 2+ 28% 51% 0.018

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

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

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

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

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

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

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

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

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

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

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

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

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

Patient Characteristics
Age 42-77 M/F 2/16 Dose (mg/m2) 80 1 175 13 Tumor type Breast 10 Gyn 5 Lung 2 Tonsil 1

Patient Descriptions 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

Patient Descriptions Real deep bone pain, not in the joints
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

Location Low back, then hips, legs, knees, whole body Knees
Started at top of legs, down to ankles All over From the top of the knees to front of shin and top of feet, bilaterally 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

Location 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

Patient Descriptions Severity Mild 3 Mild-moderate 2 Moderate 3
Severe 9 Not stated 1 Aggrevating factors None noted 12 Walking 3 Sitting 1 Worse as day 1 went on Worse at night 1 Deep vs % surface deep

Patient Descriptions Onset after drugs (days) Pt 1 1
1 1 2-4 15 Duration (days) Pt 1 1 2-3 6 4-5 6 7-11 5

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

Paclitaxel-Associated Acute Pain Syndrome Natural History Study
Patients scheduled to receive IV paclitaxel at 1 of 2 dose/schedules 175+ mg/m2 q 2-4 wk mg/m2 weekly Patient questionnaires looking at the incidence and severity of paclitaxel-associated acute pain and sensory neuropathy

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

Placebo (n=420) Soy (n=78) Vitamin E (n=53) Clonidine (n=75)
Fluoxetine (n=36) Venlafaxine (n=48) Megestrol (n=74) CP Loprinzi, CL KK

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

Favors antidepressant Favors placebo
HR (fixed) 95% CI Study Loprinzi, Fluoxetine 20 mg/g 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 antidepressant Favors placebo CP Loprinzi, CL KK

HR (fixed) 95% CI Study Favors gabapentin Favors placebo
Pandya 300 mg/d Pandya 900 mg/d Guttuso 900 mg/d Reddy 2400 mg/d Total Favors gabapentin Favors placebo CP Loprinzi, CL KK

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

Case Studies

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

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

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

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

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

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

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

Case #3 Coumadin discontinued after 6 months Follow up labs:
D-dimers = 1000 ng/ml Fibrinogen = 570 mg/mL FVIII = 650% Repeat Duplex dopplers = residual DVTs

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

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

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

Case #4 Potential Causes Drug therapy
anesthesia, pain meds, heparin, urokinase Patient Factors obese, carcinoma Events surgery Timing of PLT drop re-exposure of heparin day 3 Degree of PLT fall 238,000 to 39,000mcL Concurrent events CVC thrombosis PE Lab findings elevated IgG antibody by immunoassay PLT = platelet. CVC = central venous catheter. PE = pulmonary embolism. IgG = immunoglobulin G. 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:

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