Transcript Supportive Care in the Cancer Patient

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
Program Co-Chairman
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
Professor of Medicine
University of Vermont
Burlington, Vermont
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
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
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 endof-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 treatmentrelated 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
●
●
Nausea/vomiting
Constipation/diarrhea
Mucositis
Cardiovascular
●
●
Thrombosis
Cardiac
Neurologic
●
Gastrointestinal
●
►
►
●
Peripheral
neuropathy
Cognitive
►
Pulmonary
►
Renal
►
Cutaneous
●
●
Alopecia
Rash
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
COMORBIDITY
CONNECTION
SUBSPECIALIST
STAKEHOLDERS
CAP
UTI
Cancer
Heart Failure
ABE/COPD
Respiratory Failure
Myeloproliferative Disorder
Thrombophilia
Surgery
History of DVT
Other
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 (1.00-1.06)
1.62 (0.93-2.75)
2.06 (1.10-3.69)
0.0001
0.08
0.02
Acute infectious
disease
1.74 (1.12-2.75)
0.02
Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968
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):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary
embolism: a population-based study
VTE Recurrence
Predictors of First Overall VTE Recurrence
Baseline Characteristic
Hazard Ratio
(95% CI)
Age
1.17 (1.11-1.24)
Body Mass Index
1.24 (1.04-1.7)
Neurologic disease with extremity
paresis
1.87 (1.28-2.73)
Malignant neoplasm
With chemotherapy
Without chemotherapy
Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768
4.24 (2.58-6.95)
2.21 (1.60-3.06)
ICOPER Cumulative Mortality
25
17.5%
Mortality (%)
20
15
10
5
0
7
14
30
60
Days From Diagnosis
Lancet 1999;353:1386-1389
90
Stages of Chronic Venous Insufficiency
1.
Varicose veins
2.
Ankle/ leg edema
3.
Stasis dermatitis
4.
Lipodermatosclerosis
5.
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: 1525-1526
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: 259-262
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
►
> 350,000-600,000 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
1.
Cancer rates are increasing as heart disease
Rx improves and as cancer Rx improves.
2.
Cancer increases VTE risk.
3.
VTE is preventable (immunize!)
4.
VTE prophylaxis may slow cancer
5.
Increased emphasis on prophylaxis: OSG,
NCCN, ASCO, ACCP, NATF
6.
Facilitate prophylaxis with alerts.
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%)
●
●
►
Moderately Emetogenic Chemotherapy (MEC) (30-90%)
●
●
►
Cyclophosphamide
Doxorubicin
Low Emetogenic Chemotherapy (10-30%)
●
●
►
Cisplatin
Mechlorethamine
Paclitaxel
5-Fluorouracil
Minimally Emetogenic Chemotherapy (< 10%)
●
●
Vincristine
Bleomycin
Levels of Emetogenicity
Modifying Factors
►
Age
●
►
Gender
●
►
Women vomit more than men
Alcohol history
●
►
Younger patients vomit more than older patients
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
Histamine
Dopamine
Endorphins
Serotonin
Emetic center
Substance P
Cannabinoid
GABA
High Dose Metoclopramide –
The First Highly Effective Antiemetic
Metoclopramide Placebo
P
Metoclopramide
Prochlorperazine
(n=11)
(n=10)
P
(n=11)
(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
1.5-17.6
NS
Hours of
Nausea
0
0-16.2
3.7
0-19.2
0.042
0.1
0-17.2
5
0-20
NS
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
0
1
2
0.06 mg/kg
2
3
0
0.18 mg/kg
2
2
1
0.30 mg/kg
4
1
0
0.48 mg/kg
1
2
2
44%
37%
19%
Total
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
Percent of
patients
Perception vs Reality
Highly Emetogenic Chemotherapy
Grunberg, Cancer 100:2261, 2004
Percent of
patients
Perception vs Reality
Moderately Emetogenic Chemotherapy
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
*Log-scale
†In vitro data; clinical significance has not been established
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.
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
Histamine
Dopamine
Endorphins
Serotonin
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 (%)
100
80
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
60
40
20
0
0
8
24
40
60
80
Time since cisplatin (hours)
Hesketh, Support Care Cancer 10:365, 2002
100
120
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
5-HT3+DXM+NK1
NK1
Low
Single Agent
None
Minimal
None
None
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 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
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:
●
●
►
Of all cancer patients:
●
●
►
About 20% occur in cancer patients
Annual incidence of VTE in cancer
patients ≈ 1/250
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 3to 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
1. Ambrus JL et al. J Med. 1975;6:61-64
2. Donati MB. Haemostasis. 1994;24:128-131
3. Johnson MJ et al. Clin Lab Haem. 1999;21:51-54
4. 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
1.00
Probability of Death
DVT/PE and Malignant Disease
0.80
0.60
Malignant Disease
0.40
DVT/PE Only
0.20
Nonmalignant Disease
0.00
0
20 40
60
80 100 120140 160 180
Number of Days
Levitan N, et al. Medicine 1999;78:285
Mortality (%)
Hospital Mortality With or Without VTE
N=66,016
Khorana, JCO, 2006
N=20,591
N=17,360
Rate of VTE (%)
Trends in VTE in Hospitalized Cancer Patients
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
P<0.0001
1995
1996
1997
VTE- patients on chemotherapy
Khorana AA et al. Cancer. 2007.
1998
1999
2000
2001
VTE-all patients
PE-all patients
2002
2003
DVT-all patients
Thrombosis Risk In Cancer
Primary Prophylaxis
►
Medical Inpatients
►
Surgery
►
Radiotherapy
►
Central Venous Catheters
Risk Factors for Cancer-Associated VTE
►
Cancer
● 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”
Stein PD, et al. Am J Med 2006; 119: 60-68
Bladder
Cervix
Breast
Leukemia
Liver
Ovary
Colon
Kidney
Rectal
Prostate
Esophagus
Lung
Uterus
Lymphoma
Stomach
Myeloprol
Brain
4.5
4
3.5
3
2.5
2
1.5
1
0.5
Pancreas
Relative Risk of VTE in
Cancer Patients
Relative Risk of VTE Ranged From 1.02 to 4.34
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
<0.001
<0.001
<0.001
Age 65 y
1.1
0.005
Arterial thromboembolism
1.4
0.008
Comorbidities (lung/renal disease,
infection, obesity)
1.3-1.6
<0.001
Khorana AA et al. J Clin Oncol. 2006;24:484-490.
Antithrombotic Therapy: Choices
Nonpharmacologic
(Prophylaxis)
Intermittent
Pneumatic
Compression
Elastic
Stockings
Inferior
Vena Cava
Filter
Pharmacologic
(Prophylaxis & Treatment)
Unfractionated
Heparin (UH)
Low Molecular
Weight
Heparin
(LMWH)
Oral
Anticoagulants
New Agents: e.g.
Fondaparinux,
Direct anti-Xa inhibitors,
Direct anti-IIa, etc.?
Rate of VTE (%)
Prophylaxis Studies in Medical Patients
Relative
risk
reduction
63%
Relative
risk
reduction
44%
Placebo Enoxaparin Placebo Dalteparin
MEDENOX Trial
PREVENT
Francis, NEJM, 2007
Relative
risk
reduction
47%
Placebo Fondaparinux
ARTEMIS
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: 5490-5505.
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
Cancer
N=16,954
N=6124
Post-op VTE
0.61%
1.26%
<0.0001
Non-fatal PE
0.27%
0.54%
<0.0003
Autopsy PE
0.11%
0.41%
<0.0001
Death
0.71%
3.14%
<0.0001
Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
P-value
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
double-blind
enoxaparin vs. UFH
1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103
2. McLeod R, et al. Ann Surg 2001;233:438-444
Prophylaxis in Surgical Patients
Incidence of Outcome Event
16.9%
P=0.052
13.9%
Canadian
Colorectal DVT
Prophylaxis Trial
N=234
N=241
1.5% 2.7%
VTE
(Cancer)
McLeod R, et al. Ann Surg 2001;233:438-444
Major Bleeding
(All)
Incidence of Outcome Event
Extended Prophylaxis in
Surgical Patients
12.0%
ENOXACAN II
P=0.02
N=167
5.1%
4.8%
N=165
3.6%
1.8%
0.6%
VTE
Prox
DVT
0% 0.4%
NNT = 14
Any
Major
Bleeding Bleeding
Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
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. 2006 Nov;4(11):2384-90. 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: 5490-5505.
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
placebo
130
125
6 (4.6)
5 (4.0)
ETHICS†
2004
Enoxaparin 40 mg daily
placebo
155
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
2.0–2.9
6%
3.0–4.9
19%
>5.0
7%
Masci et al. J Clin Oncol. 2003;21:736-739
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.)
Cancer and Thrombosis
Ambulatory Chemotherapy
Patients
Risk Factors for VTE in
Medical Oncology Patients
► Tumor
●
Ovary, brain, pancreas, lung, colon
► Stage,
●
►
grade, and extent of cancer
Metastatic disease, venous stasis due to
bulky disease
Type of antineoplastic treatment
●
►
type
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
Heit JA et al. Thromb Haemost. 2001;86:452-463
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, 2004 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 newcycle 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
Khorana, Cancer, 2005
Incidence of VTE
Rate of VTE (%)
3.0%
2.5%
2.0%
1.5%
1.0%
0.5%
0.0%
Baseline
Cycle 1
Cycle 2
Cycle 3
VTE / 2.4 months
VTE/month
VTE /cycle
Cumulative rate
(95% CI)
1.93%
0.8%
0.7%
2.2% (1.7-2.8)
Khorana, Cancer, 2005
Risk Factors: Site of Cancer
VTE (%) / 2.4 months
12
10
8
6
4
2
0
Site of Cancer
Khorana, Cancer, 2005
Incidence of Venous Thromboembolism By
Quartiles of Pre-chemotherapy Platelet
Count
Incidence Of VTE Over 2.4
Months(%)
5.0%
p for trend=0.005
4.5%
4.0%
3.5%
3.0%
2.5%
2.0%
1.5%
1.0%
0.5%
0.0%
<217
217-270
270-337
Pre-chemotherapy Platelet Count/mm
Khorana, Cancer, 2005
>337
3 (x1000)
Risk Factors: Multivariate Analysis
Characteristic
OR
Site of Cancer
P value
0.03
Upper GI
3.88
0.0076
Lung
1.86
0.05
Lymphoma
Pre-chemotherapy platelet count >
350,000/mm3
Hgb < 10g/dL or use of red cell growth
factor
Use of white cell growth factor in highrisk sites
1.5
0.32
2.81
0.0002
1.83
0.03
2.09
0.008
Khorana, Cancer, 2005
Predictive Model
Patient Characteristic
Score
Site of Cancer
Very high risk (stomach, pancreas)
2
High risk (lung, lymphoma, gynecologic, GU
excluding prostate)
1
Platelet count > 350,000/mm3
1
Hgb < 10g/dL or use of ESA
1
Leukocyte count > 11,000/mm3
1
BMI > 35
1
Khorana AA et al. JTH Suppl Abs O-T-002
Incidence of VTE Over 2.4 Months
Predictive Model
Actual Incidence
Estimated Incidence
95 % Confidence Limits
18%
16%
14%
12%
10%
8%
6%
4%
2%
0%
0
1
2
3
4
Risk Score
0
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
Rate of VTE over 2.5 mos (%)
8%
7.1%
7%
Development cohort
6%
Validation cohort
6.7%
5%
4%
3%
1.8% 2.0%
2%
1%
0.8%
0.3%
0%
n=734 n=374
Risk
Low (0)
Khorana AA et al. JTH Suppl Abs O-T-002
n=1627 n=842
Intermediate(1-2)
n=340 n=149
High(>3)
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
CANCER PATIENTS WITH
ACUTE DVT or PE
[N = 677]
►
►
Dalteparin
Randomization
Dalteparin
Oral Anticoagulant
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
Probability of Recurrent VTE, %
Reduction in Recurrent VTE
25
Risk reduction = 52%
p-value = 0.0017
Recurrent VTE
20
OAC
15
10
Dalteparin
5
0
0
30
60
90
120
150
Days Post Randomization
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
180
210
Bleeding Events in CLOT
Dalteparin
OAC
N=338
N=335
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
P-value*
Treatment of Cancer-Associated VTE
Study
Design
Length of
Therapy
(Months)
N
Recurrent
Major
Death
VTE
Bleeding
(%)
(%)
(%)
6
4
NS
39 NS
41
0.09
7
16
0.09
11 0.03
23
0.03
6
8
NS
23 NS
22
CLOT Trial
(Lee 2003)
Dalteparin
OAC
6
336
336
9
17
0.002
CANTHENOX
(Meyer 2002)
Enoxaparin
OAC
3
67
71
11
21
LITE
(Hull ISTH 2003)
Tinzaparin
OAC
3
80
87
6
11
ONCENOX
(Deitcher ISTH
2003)
Enox (Low)
Enox (High)
OAC
6
32
36
34
3.4
3.1
6.7
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
Probability of Survival, %
100
90
80
70
Dalteparin
60
OAC
50
40
30
20
10
0
HR 0.94 P-value = 0.40
0
30 60 90 120
180
240
300
Days Post Randomization
Lee AY et al. J Clin Oncol. 2005; 23:2123-9.
360
Anti-Tumor Effects of LMWH
CLOT 12-month Mortality
Patients Without Metastases (N=150)
Probability of Survival, %
100
Dalteparin
90
80
70
OAC
60
50
40
30
20
10
HR = 0.50 P-value = 0.03
0
0
30 60 90 120 150 180
240
300
Days Post Randomization
Lee AY et al. J Clin Oncol. 2005; 23:2123-9.
360
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
0.01
Median survival, m
13.0
8.0
0.01
CEV = cyclophosphamide, epirubicin, vincristine;
LMWH = Dalteparin, 5000 units daily
Altinbas et al. J Thromb Haemost 2004;2:1266.
Rate of Appropriate Prophylaxis, %
VTE Prophylaxis Is Underused
in Patients With Cancer
Cancer:
FRONTLINE Survey1—
3891 Clinician
Respondents
Cancer:
Surgical
Major
Surgery2
Major
Abdominothoracic
Surgery (Elderly)3
Medical
Inpatients4
Confirmed DVT
(Inpatients)5
Cancer:
Medical
1. Kakkar AK et al. Oncologist. 2003;8:381-388
4. Rahim SA et al. Thromb Res. 2003;111:215-219
2. Stratton MA et al. Arch Intern Med. 2000;160:334-340
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
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
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
30
Mucosal toxicity
Anorexia/cachexia
Pain
Hot flash
Skin toxicity
Sexual health
28
26
24
22
20
18
Neuropathy
Anemia
Bone health
Fatigue
Antiemetic
16
14
12
10
8
6
4
2
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
1986
1985
0
Symptom Control Trials
30
Mucosal toxicity
Anorexia/cachexia
Pain
Hot flash
Skin toxicity
Sexual health
28
26
24
22
20
18
Neuropathy
Anemia
Bone health
Fatigue
Antiemetic
16
14
12
10
8
6
4
2
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
1986
1985
0
Topics
►
Overview: Sx control studies can be
accomplished
►
Chemotherapy induced peripheral neuropathy
►
Hot flashes
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
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, PlaceboControlled, 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
R
6 wk
Gabapentin
2700 mg/day
2 wk
6 wk
Placebo
Washout
Placebo
Gabapentin
2700 mg/day
Mean Pain Intensity
10
8
Mean
pain
intensity
P=0.21
6
P=0.37
Placebo
4
Gabapentin
Gabapentin
Placebo
2
Washout
First period
Second period
0
0
2
4
6
8
Week
10
12
14
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
small tricyclic antidepressant studies –
but can’t rule out a small benefit
►2
► Gabapentin
doesn’t appear to work – but
what about pregabalin?
► Lamotrigine
► Topical
doesn’t appear to work
BAK looks like it is worth
pursuing further
Mayo/NCCTG CIPN Program
►
Treatment of established CIPN
►
Prevention of CIPN
►
Paclitaxel acute pain syndrome
Prevention of CIPN
►
Calcium/magnesium
Oxaliplatin
►
Vitamin E
Audience Poll
How many are routinely using
Ca/Mg for pts receiving FULFOX?
Intravenous Calcium and Magnesium
for Oxaliplatin-Induced Sensory
Neurotoxicity (N04C7)
Nikcevich, A
A Grothey,
Grothey, JA
JWJW
Kugler,
PT
DADA
Nikcevich,
JASloan,
Sloan,
Kugler,
Silberstein, T Dentchev, DB Wender, PJ Novotny, HE
PT Silberstein,
T Dentchev, DB Wender, PJ
Windschitl, CL Loprinzi
Novotny, HE Windschitl, CL Loprinzi
For the North Central Cancer Treatment Group
J Clin Oncol 2008; May 20 suppl (abstract 4009)
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
Primary Endpoint Grade 2+ sNT
(CTCAE Scale)
Neurotoxicity
grade
Grade 2+
CaMg
n=50
Placebo
n=52
P
22%
41%
0.038
Time to Grade 2+ sNT (CTC scale)
100
Ca/Mg
80
60
% Free
2+ sNT 40
Placebo
20
P=0.05
0
0
2
4
6
8
10
Weeks
12
14
16
18
20
Endpoint: Grade 2+ sNT
(Oxaliplatin Scale)
Neurotoxicity
grade
Grade 2+
CaMg
n=50
Placebo
n=52
P
28%
51%
0.018
Time to Grade 2+ sNT
(Oxaliplatin scale)
100
Ca/Mg
80
% Free
2+ sNT
60
40
Placebo
20
P=0.03
0
0
2
4
6
8
10
Weeks
12
14
16
18
20
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):4028-4029
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
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
The Use of Calcium and Magnesium
for Prevention of ChemotherapyInduced Peripheral Neuropathy
A Phase III Double-Blind PlaceboControlled 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
Mayo/NCCTG CIPN Program
►
Treatment of established CIPN
►
Prevention of CIPN
►
Paclitaxel acute pain syndrome
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)
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Nerve injury hypothesis
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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)
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
M/F
42-77
2/16
Dose (mg/m2)
Tumor type
80
1
Breast
10
140
1
Gyn
5
175
13
Lung
2
200
3
Tonsil
1
Patient Descriptions
Aching
Sharp deep pain
Aching, pain, bad
ache
Aching
Joint pain, growing
pains
Pain, achiness
Pulsating, electricity,
discomfort
Shooting pain
Aching, tired pain
Dull ache progressing
to shooting pains
Patient Descriptions
Real deep bone pain,
not in the joints
Shooting pain
Deep bone pain
Deep pain like the flu
Dull constant ache
Joint pain, muscle
aches
Joint, aching, what I
think arthritis would be
like
Low level flu, body
ache, muscle
Location
Low back, then hips, legs,
knees, whole body
Front of legs (shins);
ankles/feet
Knees
Hips, butt, thighs,
knees, ankles, and
feet
Started at top of legs,
down to ankles
All over
Radiating from the
legs down to ankle
From the top of the knees
to front of shin and top of
feet, bilaterally
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
Aggrevating factors
Mild
3
None noted
Mild-moderate
2
Walking
3
Moderate
3
Sitting
1
Severe
9
1
Not stated
1
Worse as day
went on
Worse at night
1
Deep vs
surface
100%
deep
12
Patient Descriptions
Onset after
drugs (days)
1
Pt
1
Duration (days)
Pt
1
1
2-4
15
2-3
6
5-7
2
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 wk70-90
mg/m2 weekly
Patient questionnaires looking
at the incidence and severity of
paclitaxel-associated acute pain
and sensory neuropathy
Goals
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Detail the incidence, timing, severity, and
characteristics of the P-APS in patients
receiving paclitaxel
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Describe differences between patients getting
weekly versus less frequent, higher dose
treatment
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Study whether individuals with more
prominent P-APS have more prominent later
term distal neuropathy problems
Topics
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Overview: Sx control studies can be
accomplished
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Chemotherapy induced peripheral neuropathy
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Hot flashes
Mean Hot Flash Score Reduction
Randomized Studies
% Reduction (Mean)
100
Placebo (n=420)
Soy (n=78)
Vitamin E (n=53)
Clonidine (n=75)
Fluoxetine (n=36)
80
60
40
Venlafaxine (n=48)
20
Megestrol (n=74)
0
0
1
2
3
Week
4
5
6
Mean Hot Flash Score Reduction
Randomized Studies
100
% Reduction (Mean)
Black Cohosh (n=58)
Placebo (n=420)
Soy (n=78)
Vitamin E (n=53)
Clonidine (n=75)
Fluoxetine (n=36)
80
60
Ven (vs MPA) (n=94)
Venlafaxine (n=48)
40
MPA 400 mg (n=94)
20
Megestrol (n=74)
0
0
1
2
3
Week
4
5
6
Mean Hot Flash Score Reduction
Randomized Studies
100
% Reduction (Mean)
Black Cohosh (n=58)
Placebo (n=420)
Soy (n=78)
Vitamin E (n=53)
Clonidine (n=75)
Fluoxetine (n=36)
80
60
Ven (vs MPA) (n=94)
Venlafaxine (n=48)
40
MPA 400 mg (n=94)
20
Megestrol (n=74)
0
0
1
2
3
Week
4
5
6
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
-70 -60 -50 -40 -30 -20 -10 0
Favors antidepressant
10 20 30 40 50 60 70
Favors placebo
Study
HR (fixed)
95% CI
Pandya 300 mg/d
Pandya 900 mg/d
Guttuso 900 mg/d
Reddy 2400 mg/d
Total
-70 -60 -50 -40 -30 -20 -10 0
Favors gabapentin
10 20 30 40 50 60 70
Favors placebo
Hot Flash Conclusions
► Newer
antidepressants decrease hot flashes
► Gabapentin
decreases hot flashes
Case Studies
Case #1
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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
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What would the initial antiemetic management be?
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What is her expected response to antiemetic
therapy?
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What risk factors are pertinent in estimating her
response?
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Are there any other changes to be made in her
medical management?
Case #2
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24 year old man with metastatic testicular cancer
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Being treated with PVB (cisplatin, vinblastine,
bleomycin)
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Smokes 1 pack per day of cigarettes; drinks beer on
weekends
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Used marijuana while in college but has since
discontinued use
Case #2 - Management
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What would the initial antiemetic management
be?
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How would you approach emesis occurring
●
●
●
●
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One day after chemotherapy
3 days after chemotherapy
10 days after chemotherapy
20 days after chemotherapy
How would you evaluate refractory emesis?
Case #3
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Active 50 year old Caucasian male with “charley
horse” of RLE for >6 days
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Pain, swelling, erythema spreads to thigh over this
time
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36 pack year history of cigarette smoking
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Developed superficial thrombophlebitis 6 months
ago after IV placement for routine colonoscopy
Case #3
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Hypercoagulability work up negative for:
●
●
●
●
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Factor V Leiden
Prothrombin gene mutation
Antithrombin III activity
Protein C and S
LAC
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Duplex doppler ultrasound was positive for bilateral
DVT s extending from popliteal to superficial femoral
veins
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Patient hospitalized for UFH and coumadin transition
Case #3
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CBC-WNL except platelets=650K
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CMP-WNL
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Coagulation studies-WNL except for fibrinogen=758
mg/dL
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D-dimers >2800 ng/mL (<200)
Case #3
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Coumadin discontinued after 6 months
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Follow up labs:
● D-dimers = 1000 ng/ml
● Fibrinogen = 570 mg/mL
● FVIII = 650%
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Repeat Duplex dopplers = residual DVTs
Case #3 - Conclusions
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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
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Elevated FVIII and D-dimers and residual DVT post
adequate anticoagulation are indicators of
hypercoagulability
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CT scan of chest (hx of smoking) reveals 3 cm mass
and bronchogenic washings confirm bronchogenic
Ca
Case #4
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45 yo F Stage IB Endometrial Carcinoma
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TAH, BSO, LND
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Received prophylactic post op IV heparin x 4 days
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Post-op Day 6 - chest pain and SOB, collapsed, cyanotic
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VQ scan (+) for PE & 5mm thrombosis @ tip of CVC
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IV Heparin re-initiated + urokinase given for thrombolysis with
initial improvement in signs and symptoms
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Post-op Day 9 - sudden PLT drop 238,000 to 39,000mcL
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HIT suspected, heparin d/c'd
Aida H, Aoki Y, Ohki I, & Tanaka K. Anticoagulation with a selective thrombin inhibitor in a woman with
heparin-induced thrombocytopenia. Obstet Gynecol. 2001;98:952-954.
Case #4
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POD 10, CVC thrombus larger. Underwent successful
thrombectomy
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Argatroban was administered intra- and postoperatively
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PLT post-op Day 1 - 104,000/mcL
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Oral warfarin and ASA initiated
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PLT post-op Day 4 - 236,000/mcL
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Patient was discharged home without further complications on
hospital Day 32
Case based on an actual patient. Individual results may vary.
Aida H, Aoki Y, Ohki I, & Tanaka K. Anticoagulation with a selective thrombin inhibitor in a woman with
heparin-induced thrombocytopenia. Obstet Gynecol. 2000;98:952-954.
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
●
●
►Lab
●
events
CVC thrombosis
PE
findings
elevated IgG antibody
by immunoassay
Aida H, Aoki Y, Ohki I, & Tanaka K. (2001). Anticoagulation with a selective thrombin inhibitor in a woman with
heparin-induced thrombocytopenia. Obstet Gynecol. 2001;98:952-954.