Transcript J Clin Oncol - ClinicalWebcasts.com

Investigations • Innovation • Clinical Application
New Frontiers and Paradigm Changes in
Optimizing Supportive
Care in Cancer
Focus on Thrombosis Prevention, CINV, and
Hematologic Complications of Malignancy
Program Chairman
Gary H. Lyman, MD, MPH, FRCP (Edin)
Editor-In-Chief, Cancer Investigation
Professor of Medicine and Director
Health Services, Effectiveness and Outcomes Research
Division of Medical Oncology, Department of Medicine
Duke University School of Medicine and the Duke Comprehensive Cancer Center
Senior Fellow, Duke Center for Clinical Health Policy Research
Program Faculty
PROGRAM CHAIRMAN
GARY H. LYMAN, MD, MPH, FRCP (Edin)
Editor-In-Chief, Cancer Investigation
Professor of Medicine and Director
Health Services, Effectiveness and Outcomes
Research
Division of Medical Oncology, Department of
Medicine
Duke University School of Medicine and the Duke
Comprehensive Cancer Center
Senior Fellow, Duke Center for Clinical Health
Policy Research
Lee S. Schwartzberg, MD, FACP
Supportive Oncology Services, Memphis
Accelerated Community Oncology Research
Network
Clinical Professor of Medicine
University of Tennessee Medical Center
Memphis, Tennessee
Jeffrey Crawford, MD
George Barth Geller Professor for
Research In Cancer
Chief of Division of Medical Oncology
Department of Medicine
Duke University Medical Center
Editor-in-Chief, Supportive Care
Oncology
Durham, North Carolina
Alok A. Khorana, MD, FACP
Vice-Chief, Division of
Hematology/Oncology
Associate Professor of Medicine and
Oncology
James P. Wilmot Cancer Center
University of Rochester
Rochester, New York
Investigations • Innovation • Clinical Application
An Evidence-Based Overview to Critical
Issues in Supportive Care
Overview
Program Chairman
Gary H. Lyman, MD, MPH, FRCP (Edin)
Editor-In-Chief, Cancer Investigation
Professor of Medicine and Director
Health Services, Effectiveness and Outcomes Research
Division of Medical Oncology, Department of Medicine
Duke University School of Medicine and the Duke Comprehensive Cancer Center
Senior Fellow, Duke Center for Clinical Health Policy Research
Complications of Cancer Chemotherapy
Myelosuppressive chemotherapy
Neutropenia
Febrile neutropenia (FN)
Chemotherapy dose delays
and dose reductions
Complicated lifethreatening infection and
prolonged hospitalization
Decreased relative dose
intensity (RDI)
Reduced survival
Kuderer NM et al. Cancer 2006;106:2258–2266
Chirivella I et al. J Clin Oncol 2006;24;abstract 668
Bosly A et al. Ann Hematol 2007, advance access published 20 October 2007; doi:10.1007/s00277-007-0399-y
Meta-analysis of Randomized Controlled Trials
Relative risk of FN
Febrile Neutropeonia
(n = 3182)
RR
95% CI
p
0.61
0.53–0.72
<.001
Combined filgrastim (n=9)
0.62
0.44–0.88
0.007
Combined lenograstim (n=5)
0.08
0.03–0.18
<.001
Combined pegfilgrastim (n=1)
0.54
0.43–0.67
<.001
All G-CSF (n=15)
0.1 0.2 0.5 1.0 2.0 5.0 10
Favours
G-CSF
Kuderer et al. J Clin Oncol 2007;25:3158–3167
Favours
no G-CSF
Primary Prophylactic CSF
Administration
►
Required and recommended for “dose dense”
regimens
►
Recommended for the prevention of FN in
patients who have a high risk of FN based on:
• Age
• Medical history
• Disease characteristics
• Myelotoxicity of the chemotherapy regimen
►
Clinical trial data support the use of CSF when
the risk of FN is in the range of 20% or higher
Primary Prophylactic CSF Administration:
Special Circumstances
►
When the following clinical factors are present, primary
prophylaxis with CSF is often appropriate even with regimens
with FN rates of <20% :
●
●
●
●
●
●
●
●
●
●
Age >65 years
Poor performance status
Previous FN
Poor nutritional status
Open wounds or active infections
More advanced cancer
Extensive prior treatment, including large XRT ports
Administration of combined chemoradiotherapy
Cytopenias due to bone marrow involvement by tumor
Other serious comorbidities
Evidence-based G-CSF Guidelines
Key Recommendations
EORTC1
Summary of Recommendations
ASCO2 NCCN3
G-CSF primary prophylaxis with ≥20% overall FN risk



FN risk associated with chemotherapy



Consider patient risk factors for overall FN risk



G-CSF primary prophylaxis to maintain
chemotherapy RDI



Dose-dense chemotherapy regimens



G-CSF for ongoing FN episode



G-CSF formulation and dosing



Secondary prophylaxis with G-CSF



1. Aapro et al. Eur J Cancer 2006;42:2433–2453;
2. Smith et al. J Clin Oncol 2006;24:3187–3205;
3. NCCN. Myeloid growth factors V.1.2009
Chemotherapy-Induced Acute Emesis
Classes of Antiemetic
►
Highest therapeutic index antiemetic agents
• 5-HT3 Serotonin Receptor Antagonists
• Corticosteroids (Dexamethasone)
• NK1 Receptor Antagonists (Aprepitant)
►
These classes of antiemetic agents
• Highly effective
• Few significant side effects (when used appropriately)
• Safe in combination
Emetic Risk of IV Administered Antineoplastic Agents
High (>90%)
Carmustine
Cisplatin
Cyclophosphamide >1500 mg/m 2
Dacarbazine
Dactinomycin
Mechlorethamine
Streptozotocin
Moderate (30% to 90%)
Carboplatin
Cyclophosphamide<1500 mg/m
Cytarabine >1 gm/m 2
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Ifosfamide
Irinotecan
Oxaliplatin
Low (10% to 30%)
2
5-Fluorouracil
Bortezomib
Cetuximab
Cytarabine <1000 mg/m 2
Docetaxel
Etoposide
Gemcitabine
Methotrexate
Mitomycin
Mitoxantrone
Paclitaxel
Pemetrexed
Topotecan
Trastuzumab
Minimal (<10%)
2-Chlorodeoxyadenosine
Bevacizumab
Bleomycin
Busulfan
Fludarabine
Rituximab
Vinblastine
Vincristine
Vinorelbine
Chemotherapy-Induced Acute Emesis
Antiemetic Agents
Combinations of Antiemetics
5-HT3 Serotonin
Receptor Antagonists
Dexamethasone
Aprepitant
5-HT3 Serotonin
Receptor Antagonists
Dexamethasone
Kris M et al, JCO 2006:24: 2932-2947
Yields greatest antiemetic protection in randomizedmulticenter studies
Chemotherapy of high emetic risk
Anthracycline + Cyclophosphamide
Indicated for patients receiving agents of moderate
emetic risk other than anthracycline +
cyclophosphamide
Antiemetic Regimens Based on Emetic Risk
ASCO Guidelines
High (> 90%)
Moderate (30-90%)
►
5-HT3 SRA: day 1
►
Dexamethasone: days 1-4
►
Aprepitant: days 1-3
►
5HT3 SRA: day 1
►
Dexamethasone: day 1 (2,3)*
(may omit days 2,3 s/p aprepitant)
►
(Aprepitant: days 1-3 for AC) (ACanthracycline + cyclophosphamide)
Low (10-30%)
Kris M et al, JCO 2006:24: 2932-2947
►
Dexamethasone: day 1
Investigations • Innovation • Clinical Application
Optimizing Management of Cancer
Patients at Risk for Venous
Thromboembolism
Program Chairman
Gary H. Lyman, MD, MPH, FRCP (Edin)
Editor-In-Chief, Cancer Investigation
Professor of Medicine and Director
Health Services, Effectiveness and Outcomes Research
Division of Medical Oncology, Department of Medicine
Duke University School of Medicine and the Duke Comprehensive Cancer Center
Senior Fellow, Duke Center for Clinical Health Policy Research
Growth
Invasion
Metastases
Angiogenesis
Tumor
Cells
Hemostatic
System
Procoagulant Activity
Cytokines
Growth Factors
Fibrinolytic Activity
Kuderer NM et al J Clin Oncol 2009; 27: 4902-4911
VTE Inpatient Risk and Mortality
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
20
VTE- patients on chemo
VTE-all patients
DVT-all patients
P<0.0001
PE-all patients
1995 1996 1997 1998 1999 2000 2001 2002 2003
* n = 1,015,598
Khorana et al. Cancer 2007; 110: 2339-2346
Inpatient Mortality (%)
Rate of VTE (%)
133 U.S. academic medical centers, 1995 – 2003
18
16
14
12
10
8
6
4
2
0
VTE
No VTE
P<0.0001
1995 1996 1997 1998 1999 2000 2001 2002 2003
Cancer and Venous Thromboembolism
Risk of VTE Varies Over Natural History of Cancer
8
7
Hospitalization
Chemotherapy
Relative Risk
6
5
End of life
Metastasis
Diagnosis
4
Risk in cancer population
3
2
Remission
1
Risk in general population
0
Time
Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007
Risk Factors for VTE in Patients with Cancer
Patient-related factors
Older age
► Race
● Higher in AA
● Lower in Asians
► Major comorbidities
► History of VTE
►
Treatment-related factors
►
►
►
►
►
►
►
Cancer-related factors
►
Major surgery
Hospitalization
Chemotherapy
Central venous catheters
Hormonal therapy
Antiangiogenic agents
ESAs
?Transfusions
• Site of cancer
• Advanced stage
Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007
Important Consequences of
VTE in Cancer Patients
► Increased morbidity
●
●
●
Hospitalization
Anticoagulation
Postphlebitic syndrome
► Increased mortality
► Increased risk of recurrent VTE
► Bleeding complications
► Cancer treatment delays
► Increased healthcare costs
Ambulatory Cancer Patients
Receiving Chemotherapy
Proportion with VTE
Prospective Study at 115 Randomly
Selected US Practice Sites
March 2002 – February 2006
[N = 4,458]
Cumulative Incidence of VTE
.04
.03
.02
.01
0.00
0
10
20
30
40
50
60
70
80
90
100
110 120
130 140
150
Time (Days)
1.00
HR = 4.90 [2.27-10.60], P<.0001
.99
Cumlative Survival
.98
All Cause Early Mortality
.97
.96
.95
.94
.93
.92
.91
.90
0
Kuderer NM et al; J Clin Oncol 2008
10
20
30
40
50
60
70
80
90
Time (Days)
100
110 120
130 140
150
Recommendations for Venous
Thromboembolism Prophylaxis and
Treatment in Patients with Cancer
ASCO Clinical Practice Guidelines
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
Clinical Questions
1. Should patients with cancer receive anticoagulation for
VTE prophylaxis while hospitalized? √
2. Should ambulatory patients with cancer receive
anticoagulation for VTE prophylaxis during systemic
chemotherapy? √
3. Should patients with cancer undergoing surgery receive
perioperative VTE prophylaxis?
4. What is the best method for treatment of patients with
cancer with established VTE to prevent recurrence? √
5. Should patients with cancer receive anticoagulants in
the absence of established VTE to improve survival? √
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
ASCO Recommendations for VTE
Prophylaxis in Patients with Cancer
►
Hospitalized patients with cancer should be
considered candidates for VTE prophylaxis in the
absence of bleeding or other contraindications to
anticoagulation.
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
Anticoagulant Prophylaxis to Prevent
Screen-Detected VTE
High Risk Hospitalized Medical Patients
►
3 large, randomized, placebo-controlled, double-blind
trials in medical patients at high risk including cancer
● MEDENOX (enoxaparin)1 ~ 15%
● PREVENT (dalteparin)2 ~5%
● ARTEMIS (fondaparinux)3 ~15%
►
Screening for asymptomatic DVT with venography
or ultrasound
1Samama
MM, et al. N Engl J Med. 1999;341:793-800
Leizorovicz A, et al. Circulation. 2004;110:874-9
3Cohen AT, et al. BMJ 2006; 332: 325-329
2
Anticoagulant Prophylaxis to Prevent ScreenDetected VTE
High Risk Hospitalized Medical Patients: VTE
Study
RRRRRR
MEDENOX1
P < 0.001
63%
PREVENT2
P = 0.0015
45%
Thromboprophylaxis Patients with VTE (%)
Placebo
Enoxaparin 40 mg
5.5
Placebo
5.0
Dalteparin 5,000
units
47%
Fondaparinux 2.5 mg
MM, et al. N Engl J Med. 1999;341:793-800
A, et al. Circulation. 2004;110:874-9
3Cohen AT, et al. BMJ 2006; 332: 325-329
2 Leizorovicz
2.8
10.5
Placebo
ARTEMIS3
1Samama
14.9
5.6
Incidence of Major Bleeding (%)
Anticoagulant Prophylaxis to Prevent
Screen-Detected VTE
High Risk Hospitalized Medical Patients:
Major Bleeding
1.7%
1.1%
0.49%
0.16%
Study
Samama MM, et al. N Engl J Med. 1999;341:793-800
Leizorovicz A, et al. Circulation. 2004;110:874-9
Cohen AT, et al. BMJ 2006; 332: 325-329
0.2%
ASCO Recommendations for VTE
Prophylaxis in Patients with Cancer
Ambulatory Cancer Patients
Routine prophylaxis with an antithrombotic
agent in the ambulatory setting is not
recommended.
NOTE: Patients receiving thalidomide or lenalidomide with chemotherapy
or dexamethasone are at high risk for thrombosis and warrant prophylaxis.
LMWH or adjusted dose warfarin (INR~1.5) is recommended.*
* This recommendation is based on extrapolation from studies of prophylaxis in other
high risk cancer settings.
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
Characteristics of Prophylaxis Studies
VTE – Prophylaxis with LMWH
Trial
FAMOUS
Solid Tumors
TOPIC-I
Breast Cancer
TOPIC-2
NSCLC
PRODIGE
Glioma
SIDERAS
Solid Tumors
PROTECHT
Solid Tumors
CONKO-04
Pancreatic Cancer
FRAGEM
Pancreatic Cancer
Year
Stage
N
LMWH /
Dose
Control
Arm
Duration
Type of
Pub
Specific
Chemo
2004
III/IV
385
Dalteparin
Placebo
12 months
Manuscript
No
2005
III/IV
353
Certoparin
Placebo
6 months
Abstract+
No
2005
III/IV
547
Certoparin
Placebo
6 months
Abstract+
No
2007
Any
186
Dalteparin
Placebo
6-12
months
Abstract
No
2006
IV
141
Dalteparin
NonPlacebo
Indefinitely
Manuscript
No
2008
III/IV
1166
Nadroparin
2:1
Placebo
< 4 months
with chemo
Manuscript
No
2009
Advanced
312
Enoxaparin
NonPlacebo
3 months
(to prog)
Abstract
2009
Advanced
123
Dalteparin#
NonPlacebo
3 months
Abstract
*Gemcitabine-based chemotherapy (1000 mg/m2)
Yes*
Yes*
# Higher dose than standard
prophylactic dose
Systematic Review of LMWH Prophylaxis
in Cancer Patients
VTE Versus Major Bleeding: Absolute Risk
Cancer Type
Benefit
Harm
Venous Thromboembolism
Major Bleeding
3.1% 
0.9% 
13.0% 
0.8% 
1.4% 
0.8% 
Overall
Pancreatic
Non-Pancreatic
Kuderer NM et al. ASH Oral Presentation 2009
Clinical Risk Model for Chemotherapy-associated VTE
Risk Score Based on Pretreatment Risk Factors
Risk Factors
Risk
score
1. Site of cancer
a) Very high risk cancer (stomach, pancreas)
2
b) High risk (lung, lymphoma, gynecologic, bladder, testicular)
1
2. Platelet count >350,000/mm3
1
3. Hemoglobin level < 10 g/dL or use of
Red cell growth factors
1
4. Leukocyte count >11,000 /mm3
1
5. BMI > 35 kg/m2
1
Khorana AA et al. Blood. 2008; 111: 4902-4907
VTE Prediction Risk Score
Chemotherapy – Associated Thrombosis
8%
7.1%
7%
Development cohort
Validation cohort
6%
Rate of VTE (%)
6.7%
5%
4%
3%
1.8%
2%
1%
2.0%
0.8%
0.3%
0%
n=734 n=374
RISK SCORE:
Low (0)
Khorana AA et al. Blood. 2008; 111:4902-4907
n=1,627 n=842
Intermediate (1-2)
n=340 n=149
High (>3)
Mortality and Progression-Free Survival
By VTE Risk Score
Low
Risk
Intermediate
Risk
High
Risk
All
N=1,206
N=2,709
N=543
N=4,458
1.2%
5.9%
12.7%
5.6%
Outcomes
Mortality
Risk (%)
HR [+/- CI]
1.0
3.6 [1.9-6.7] 6.9 [3.5-13.6]
-
Progression-free survival
Risk (%)
HR [+/- CI]
Kuderer NM et al. ASH 2008
93%
82%
72%
84%
1.0
2.8 [2-3.9]
4.3 [2.9-6.3]
-
ASCO Recommendations for VTE
Prophylaxis in Patients with Cancer
Preventing Recurrence in Cancer Patients
with Established VTE
► LMWH is the preferred approach for the initial 5 to 10 days
of anticoagulant treatment of the patient with cancer with
established VTE.
► LMWH for at least 6 months is also preferred for long-term
anticoagulant therapy.
► After 6 months, indefinite anticoagulant therapy should be
considered for patients with active cancer.
NOTE: Vena cava filters are only indicated for patients with contraindications
to anticoagulant therapy and in those with recurrent VTE despite adequate
long-term therapy with LMWH.
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
Recurrent VTE and Bleeding During
Anticoagulant Treatment
Patients with cancer and venous thrombosis
30
30
Cancer 21%
20
10
No Cancer 7%
Hazard ratio 2.2 [1.2-4.1]
Major Bleeding, %
Recurrent VTE, %
Hazard ratio 3.2 [1.9-5.4]
20
Cancer 12%
10
No Cancer 5%
0
0
0 1 2 3 4 5 6 7 8 9 101112
Time (months)
Prandoni P et al. Blood 2002; 100: 3484-3488
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (months)
RCTs of Long-term Treatment in Cancer
Patients with VTE
RCTs of LMWH vs. Vitamin K Antagonists in Cancer
Recurrent
VTE, %
Major
Bleed, %
Death,
%
Study
No.
Long-Term Treatment
Meyer1
2002
71
Warfarin
21.1*
22.7
67
Enoxaparin 1.5 mg/kg
10.5*
11.3
Lee2
2003
336
Warfarin
17*
4
41
336
Dalteparin 200/150 IU/kg
9*
6
39
30
Warfarin
10
2.9
8.8
29
Enoxaparin 1.0 mg/kg
6.9
6.5
6.5
32
Enoxaparin 1.5 mg/kg
6.3
11.1
19.4
100
Warfarin
10*
7
19
100
Tinzaparin 175 IU/kg
6*
7
20
Deitcher3
2006
Hull4
2006
* P < .05
1. Meyer G, et al. Arch Intern Med. 2002;162:1729-1735. 2. Lee AY, et al. N Engl J Med. 2003;349:146-153.
3. Deitcher SR, et al. Clin Appl Thromb Hemost. 2006;12:389-396. 4. Hull RD, et al. Am J Med.
2006;119:1062-1072.
The CLOT Trial
Study Schema
Control Group
Dalteparin 200
IU/kg OD
Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo
Experimental Group
Dalteparin 200 IU/kg OD x 1 mo
5 to 7 days
Lee AY, et al. N Engl J Med. 2003;349:146-153.
then ~150 IU/kg OD x 5 mo
1 month
6 months
The CLOT Trial:
Results: Symptomatic Recurrent VTE
risk reduction = 52%
HR 0.48 (95% CI 0.30, 0.77)
log-rank p = 0.002
Probability of Recurrent VTE, %
25
20
VKA, 17%
15
10
dalteparin, 9%
5
0
0
30
60
90
120
150
Days Post Randomization
Lee AY, et al. N Engl J Med. 2003;349:146-153.
180
210
ASCO Recommendations for VTE
Prophylaxis in Patients with Cancer
Improving survival in absence of established VTE
► Anticoagulants are not recommended at this
time as treatment to improve survival in patients
with cancer without VTE.
► Participation in clinical trials designed to evaluate
anticoagulant therapy as an adjunct to standard
anticancer therapies is encouraged.
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
Systematic Review of Anticoagulants
as Cancer Treatment
Impact on All Cause Mortality
Kuderer, N. M. et al. J Clin Oncol; 27:4902-4911 2009
Kuderer NM, et al. Cancer. 2007;110:1149-1161
Systematic Review of Anticoagulants
as Cancer Treatment
Impact on Major Bleeding
Kuderer, N. M. et al. J Clin Oncol; 27:4902-4911 2009
Kuderer NM, et al. Cancer. 2007;110:1149-1161
ASCO Recommendations for VTE
Prophylaxis in Patients with Cancer
Summary
Patient Group
Recommended
Not Recommended
Hospitalized
VTE prophylaxis with anticoagulants
patients with cancer
If bleeding or
contraindication to
anticoagulation
Ambulatory patients
Myeloma patients receiving thalidomide or
with cancer
Otherwise, no routine
lenalidomide + chemotherapy/ dexamethasone.
receiving
prophylaxis
LMWH or adjusted dose warfarin.
chemotherapy
Patients with
cancer undergoing
surgery
Prophylaxis with low-dose UFH or LMWH
Prophylaxis with mechanical methods for
patients with contraindications to
pharmacologic methods
Patients with
cancer with
established VTE
Anticoagulation for at least 6 months. Consider
continued anticoagulation beyond 6 months in
those with active cancer.
To improve survival
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
-
Consider mechanical
methods when
contraindications to
anticoagulation.
Not recommended
Recommendations for Primary Prevention
of VTE in Patients With Cancer
Comparisons of Guideline Panels
Parameter
ASCO
NCCN
AIOM/ESMO
FNCLCC
Prevention of VTE in the hospitalized cancer patient
Recommendation
All hospitalized cancer All hospitalized cancer Immobilized hospitalized
patients without
patients in the
cancer patients with acute
contraindications
absence of
medical illness
contraindications
NA
Prevention of VTE in the surgical cancer patient
Recommendation
Initial: major cancer
surgery
Prolonged : up to 4
weeks for major
surgery with high-risk
features
Initial: cancer surgery
Prolonged : up to 4
weeks for high risk
surgery
Initial: major cancer
surgery;
Prolonged; up to 35 days
after surgery
NA
Not recommended
Exception of thalid/
lenalid for MM
NA
Prevention of VTE in the ambulatory cancer patient
Recommendation
Not recommended
Exception of thalid/
lenalid for MM
Not recommended
Exception thalid/
Lenalid for MM
Prevention of VTE in cancer patients with central venous catheters
Recommendation
NA
Not recommended
Modified from Khorana AA et al J Clin Oncol 2009; 27: 4919-4926
Not recommended
Not
recommended
Unanswered Questions
A Call to Action for Future Research
►
Prevention of VTE in the ambulatory patient with
cancer: A role for targeted prophylaxis?
►
Prevention of VTE in the hospitalized patient with
cancer: a need for cancer-specific studies?
►
Optimal treatment of recurrent VTE
►
Management of incidental or screen-detected VTE
►
Impact of anticoagulation on survival of patients
with cancer
Khorana AA et al J Clin Oncol 2009; 27: 4919-4926
Cancer and Venous Thromboembolism
Conclusions
►
VTE is a common complication of cancer and cancer
treatment and is associated with considerable
morbidity, mortality and costs.
►
Hospitalized medical and surgical cancer patients are
at increased risk for VTE and should be considered for
pharmacologic prophylaxis if no contraindication to
anticoagulation exists.
►
Cancer patients treated for documented VTE should be
considered for continued anticoagulation, preferably
with LMWH, for up to 6 months or longer in patients
with active malignancy.
►
Routine thromboprophylaxis of ambulatory cancer
patients is not currently recommended.
Cancer and Venous Thromboembolism
Conclusions
►
Prophylaxis may be considered in selective high risk
settings such as multiple myeloma patients
receiving thalidomide/lenalidomide .
►
Consideration of prophylactic anticoagulation in
cancer patients must always balance the risk of VTE
with the increased risk of bleeding and other
complications.
►
Improved methods for the identification of cancer
patients at high risk for VTE and candidates for
targeted thromboprophylaxis are needed and under
active investigation.
Investigations • Innovation • Clinical Application
Chemotherapy-Induced Nausea
and Vomiting (CINV)
Optimizing Clinical Management
Lee S. Schwartzberg, MD, FACP
Supportive Oncology Services, Memphis
Accelerated Community Oncology Research Network
Clinical Professor of Medicine
University of Tennessee Medical Center
Memphis, Tennessee
Chemotherapy Experienced Patients
Rank Severe CINV Near Death
1.00
0.90
Moderate Delayed Nausea
Poorly Controlled
Acute & Delayed CINV
Median VAS Scores
0.80
0.70
0.60
0.50
0.40
Complete
Control
0.30
Death
0.20
0.10
0.00
Sun C et al. Support Care Cancer. 2005
Mucositis
Types of CINV: Definitions
►
Acute (posttreatment)
●
►
Delayed
●
●
►
CINV that begins after first 24 hours
May last for 120 hours
Anticipatory
●
►
Occurs within first 24 hours after administration of cancer
chemotherapy
Learned or conditioned response from poorly controlled
nausea and vomiting associated with previous
chemotherapy
Breakthrough
●
CINV that occurs despite prophylaxis and requires rescue
Emetogenic Potential of Single
Antineoplastic Agents
HIGH
Risk in nearly all patients (> 90%)
MODERATE
Risk in 30% to 90% of patients
LOW
Risk in 10% to 30% of patients
MINIMAL
Fewer than 10% at risk
Patient-Specific Risk Factors for CINV
►
Age <50 years
►
Women > men
►
History of light alcohol use
►
History of vomiting with prior exposure
to chemotherapeutic agents
►
Other risks
●
●
●
History of motion sickness
History of nausea or vomiting during pregnancy
History of anxiety
ASHP. Am J Health Syst Pharm. 1999:56:729-764; Balfour and Goa. Drugs. 1997:54:273-298
Other Causes of Nausea and
Vomiting in Cancer patients
►
Brain metastases
►
Electrolyte disturbances
►
Gastoparesis
►
Concurrent medications
►
Bowel obstruction
►
Vestibular dysfunction
Pathophysiology of
Chemotherapy-Induced Emesis
Pharmacologic Agents for
Prevention of CINV
► Corticosteroids
► Dopamine
► Serotonin
► NK-1
antagonists
(5-HT3) antagonists
receptor antagonists
Key Milestones in Antiemetic Treatment
1960
Phenothiazines: first agents to
demonstrate antiemetic effect
1970
1980
1990
2000 2002 2004

High-dose metoclopramide
shown to enhance antiemetic
effect
Combination therapy: addition of
a corticosteroid shown to
improve antiemetic response
First clinical studies of 5-HT3
antagonists
Introduction of 5-HT3 antagonists
into clinical practice for CINV
New class of drug: NK-1
antagonists in clinical
development for CINV
Aprepitant: March 2003
Palonosetron: July 2003
Viale PH. Clin J Onc Nurs. 2005;9(1):77-84
Hesketh PJ. Support Care Cancer. 2001;9:350-4
Grunberg SM, Hesketh PJ. New Engl J Med. 1993;329(24):1790-6
Hesketh PJ. Support Care Cancer. 2004;12:550-4







Controlling Cisplatin-induced Emesis:
Progress Over the Past 30 Years
Complete Response:
(24 hour control)
(120 hour control)
100% 70%
60%
75% 50%
50% 25% -
0%
1978
1988
No Useful Rx
HD-MCP/Dex
1998
5-HT3/Dex
2008
5-HT3/Dex/NK1
Patterns of Emesis
Cisplatin vs Cyclophosphamide and Carboplatin
Cisplatin
Intensity of Emesis
Cyclophosphamide/Carboplatin
0
1
2
3
Days
Martin M. Oncology. 1996;53(suppl 1): 26-31
4
5
1st Generation 5HT3 RAs
are Therapeutically Equivalent
►Highest Level Evidence
MASCC 2009
NCCN 2010
ASCO 2006
►1st Generation Agents
are therapeutically
equivalent
•
•
•
Dolasetron
Ondansetron
Granisetron
►1st Generation oral, IV
& patch forms equally
effective
Perez et al. J Clin Oncol 1998;16:754
Pts receiving MEC* (N=1,085)
Complete Control (%)
•
•
•
Oral granisetron 2 mg
IV ondansetron 32 mg
59.0 58.0
Total
71.0 72.0
60.0 58.0
Nausea
Emesis
80% of pts received prophylactic steroids
*Cyclophosphamide 500 - 1200 mg/m2, carboplatin
≥300 mg/m2
Palonosetron
►
Second generation 5-HT3 antagonist
►
Pharmacologic differences from older 5-HT3 antagonists
●
●
►
FDA approved
●
●
►
Prolonged half-life (~40 hours)
Enhanced receptor binding affinity (30-fold)
IV formulation July 25, 2003
Oral formulation August 22, 2008
Regimens
●
●
IV 0.25 mg pre chemotherapy
acute/delayed HEC/MEC
PO 0.50 mg pre chemotherapy
acute MEC
Palonosetron vs. 1st gen HT-3RA: Complete
Response on Day of Chemo & Beyond
Palonosetron 0.25 mg (n=378)
Ondansetron/Dolasetron 32/100 mg (n=376)
Complete Response (CR)
(% of Patients)
100
80
*
72.0
60.6
*
64.0
*
57.7
60
46.8
42.0
40
20
0
Acute: 0-24
(Day 1)
Delayed: 24-120
(Days 2-5)
Overall: 0-120
(Days 1-5)
Time (hr)
CR = no emetic episodes or use of rescue medications
*p<0.025 for pairwise difference (2-sided Fisher’s exact test) between palonosetron and ondansetron/dolasetron.
Gralla R et al. Ann Oncol. 2003; Eisenberg P et al. Cancer. 2003
Rubenstein EB et al. Proc Am Soc Clin Oncol. 2003. Abstract 2932
Palonosetron vs Ondansetron
High Emetic Risk Chemotherapy
Patients Also Receiving Dexamethasone
N=447
(67%)
*
Aapro M Support Care Cancer 2003:11:391
*
Phase III Trial of IV Palonosetron vs. IV Granisetron
with Cisplatin or AC-Based Chemotherapy
►
1114 patients
►
Cisplatin (57%) or anthracycline/cyclophosphamide (43%)
►
Single 0.75 mg dose of palo vs. single 40 μg/kg dose of
granisetron
►
Dexamethasone 16 mg d1; 4mg/d d 2-3 (AC/EC); 8mg/d
d 2-3 CDDP
►
Objective: demonstrate non-inferiority d1 and superiority
d 2-5 of palonosetron
►
Primary endpoint complete response (no emesis/no
rescue)
Saito M et al. Lancet Oncol. 2009;10(2):115-24
Phase III Trial Palonosetron vs. Granisetron
both with Dexamethasone in HEC
Palo+ Dex
(n=555)
%
Grani+ Dex
(n=558)
%
P
Complete Response,
Acute (0-24h)
73.7
72.1
ND
CR, Delayed (24-120h)
53.0
42.4
0.0003
CR, Overall (0-120h)
47.9
38.1
0.0007
No Nausea: 0-120 hours
32
25
0.01
No Emesis: 0-120 hours
58
49
0.006
Outcome
Saito M et al. Lancet Oncol. 2009;10(2):115-24
Palonosetron + Dexamethasone vs Granisetron +
Dexamethasone in Japanese Patients
Complete Response – AC/EC Subset
90
80
Complete Response
(% of patients)
70
Palonosetron 0.75 mg IV (n=239)
Granisetron 40 mcg/kg IV (n=236)
69.0
64.8
61.1
60
*
50.0
50
52.7
*
42.8
40
30
20
10
0
Acute (0-24 hrs)
Please note that the EU approved dose is 0.25 mg
Data on file, Taiho/Helsinn 2008
Saito M, et al. Lancet Oncol 2009;10:115-124
Delayed (24-120 hrs)
* p = 0.0165
Overall (0-120 hrs)
† p = 0.030
* Fisher’s exact test indicates a difference between PALO and GRAN
† Chi-square test indicates a difference between PALO and GRAN
5-HT3
Treatment-Related Adverse Reactions
Palonosetron
0.25 mg IV
(n=187)
Palonosetron
0.75 mg IV
(n=188)
n
%
n
%
n
%
Headache
9
4.8
10
5.3
10
5.3
Constipation
3
1.6
6
3.2
3
1.6
Dizziness
1
0.5
0
0.0
6
3.2
Adverse Reaction
Ondansetron
32 mg IV
(n=187)
Adverse reaction = adverse event judged by the investigator to have a definite, probable, possible or unknown
relationship to study medication
n = number of patients with the adverse reaction
*Reported in 2% of patients in any treatment group
Gralla R, et al. Ann Oncol. 2003;14:1570-1577
Palonosetron:
5-HT3 Antagonist of Choice?
►
Palonosetron is a 5-HT3 antagonist with strong receptor
binding affinity and an extended half-life
►
Comparable tolerability
►
Ease of use and trends towards superiority in delayed
CINV favor palonosetron as the preferred 5-HT3
antagonist
►
Definitive proof of superiority to first generation 5-HT3
antagonists would require trials with control arms utilizing
corticosteroids, NK1 antagonists and repetitive dosing of
the first generation agents
Aprepitant
►
Selective antagonist of the binding of Substance P to the
neurokinin 1 (NK1) receptor
►
FDA approved
● Oral formulation: March 26, 2003
● IV formulation (fosaprepitant): January 31, 2008
►
Regimen
● 125 mg PO day 1, 80 mg PO days 2-3
acute/delayed HEC/MEC
● 115 mg IV day 1, 80 mg PO days 2-3
acute/delayed HEC/MEC
Aprepitant in Anthracycline/
Cyclophosphamide Chemotherapy
Complete Response (CR)
(% of Patients)
Complete Response (N=857)
Aprepitant (n=433)
Standard (n=424)
100
80
*
76
69
55
60
49
*
51
42
40
20
0
Acute: 0-24
(Day 1)
*p<0.05
Delayed: 24-120
(Days 2-5)
Time (hr)
Complete response (CR): no emesis and no rescue medication.
Warr DG et al. J Clin Oncol 2005; 23:2822-2830
Overall: 0-120
(Days 1-5)
Aprepitant in Moderately
Emetogenic Chemotherapy
Percent of Patients with No Emesis
100
Emesis-Free
(% of Patients)
80
*
Aprepitant (n=433)
Standard (n=424)
*
88
*
81
77
76
69
59
60
40
20
0
Acute: 0-24
(Day 1)
*p<0.001
Delayed: 24-120
(Days 2-5)
Time (hr)
Warr DG et al. J Clin Oncol 2005; 23:2822-2830
Overall: 0-120
(Days 1-5)
Aprepitant in Moderately
Emetogenic Chemotherapy
Percent of Patients with No Nausea
100
Aprepitant (n=430)
Standard (n=424)
Nausea-Free
(% of Patients)
80
61
60
59
37
40
36
33
33
20
0
Acute: 0-24
(Day 1)
Delayed: 24-120
(Days 2-5)
Overall: 0-120
(Days 1-5)
Time (hr)
No nausea: score <5 mm on 0-100 mm VAS.
Warr DG et al. J Clin Oncol 2005; 23:2822-2830; Warr DG et al. Support Care Cancer. 2004. Abstract A027
Phase III Aprepitant Study (801):
Multiple-day Ondansetron
•Initial cycle cisplatin > 70 mg/m2
•445 patients
Group
Day 1
O D
Days 2-3
A
Aprepitant
32 12 125
Control
32 20
P
Day 4
O
D
A
O
D
P
8 80
P
8
16
16
16
16 P
O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo
Schmoll et al: Ann Oncol 17:1000-6, 2006
Phase III Aprepitant Study (801):
Multiple-day Ondansetron
►
Identical design to Protocols 052 and 054 except
ondansetron dosed days 1-4
►
Primary endpoint: complete response on days 1 5 after cisplatin
►
Aprepitant regimen superior to control regimen of
protracted ondansetron and dexamethasone
dosing, CR 72% vs. 61% respectively
Schmoll et al: Ann Oncol 17:1000-6, 2006
Perception vs Reality:
Emetogenic Chemotherapy
Highly Emetogenic Chemotherapy Moderately Emetogenic Chemotherapy
Grunberg S. Cancer. 2004;100:2261-2268
Optimizing Supportive
Care in Cancer
The best treatment of delayed
CINV is to prevent it!
Are Oral Followup 5-HT3 RAs Really
Effective for Delayed CINV?
►
671 pts receiving doxorubicin-based chemotherapy
●
►
Pts then randomized for days 2 and 3:
●
●
●
►
All treated w/ 1st generation 5HT3 + Dex on Day 1 of CT
Arm 1: Prochlorperazine 10 mg p.o. three times daily (q 8 h)
Arm 2: Any oral 5-HT3 antiemetic, using standard dosing
regimens
Arm 3: Prochlorperazine 10 mg p.o. as needed for nausea
Rescue medications for control of symptoms were
allowed
Hickock et al ASCO 2005 Final Results URCC-CCOP
Oral 5HT3 RAs:
Majority of Patients Experience Nausea
100
90
80
70
60
50
40
30
20
10
83
75
87
Prochlorperazine q 8h*
5HT3*
Prochlorperazine PRN*
* p = 0.002 (overall comparison); p = 0.06 (Prochlorperazine q 8 h vs 5-HT3 );
p = NS (Prochlorperazine prn vs 5-HT3 )
• Patients randomized for days 2 and 3; rescue medications allowed
Hickock et al ASCO 2005 Final Results URCC-CCOP
Oral 5HT3 RAs
Not Effective for Delayed CINV
►
Vomiting
●
►
Significantly more patients vomited at least once during the
delayed period (34%) than on the day of treatment (19%) p
<0.01
Nausea
●
●
Nausea severity was significantly greater during the delayed
period than on the day of treatment p < 0.01
More patients getting oral 5HT3 RAs required rescue
medications (45%) than patients getting Compazine® (2730%) p=0.002
Hickock et al ASCO 2005 Final Results URCC-CCOP
Meta-Analysis of Efficacy of 5-HT3RA in Prevention
of Delayed Emesis from Chemotherapy
►
►
Reviewed 5 studies, 1,716 pts comparing 5-HT3 RA to placebo,
5 studies, 2,240 pts comparing 5-HT3 RA + dexamethasone to
dexamethasone alone
5-HT3 RA as monotherapy
Absolute RR (95% CI)
8.2% (3.0-13.4)
NNT 12.2
Number of doses per protected pt: 74.4
5-HT3 RA as adjunct to dexamethasone
Absolute RR (95% CI)
2.6% (-0.6-5.8)
NNT 38.8
Number of doses per protected pt: 423
Geling and Eichler, JCO 2005; 23:1289-1294
Breakthrough Medications for CINV
Consider other classes, alone or in combination
►
Antipsychotics
►
Cannabinoids
►
Benzodiazepines
►
Phenothiazines
►
Dopamine Receptor Antagonists
NCCN Antiemesis Guidelines
v.2.2010: HEC Recommendations
Emetic
risk group
High and AC
combinations
Risk (% of
patients)
>90%
Acute prevention
Delayed prevention
5-HT3 RA
DEX + aprepitant
+ DEX + aprepitant
 lorazepam  H2 blocker or
proton pump inhibitor
 lorazepam  H2 blocker
or proton pump inhibitor
DEX, dexamethasone; AC, anthracycline-cyclophosphamide
For more information see: http://www.nccn.org
NCCN Antiemesis Guidelines v.2.2010:
MEC Recommendations
Emetic
risk group
Moderate
Risk (% of
patients)
30-90%
Acute prevention
Delayed prevention
5-HT3 RA + DEX
5-HT3 RA or DEX
 lorazepam  H2 blocker
or proton pump inhibitor
 lorazepam  H2 blocker or
proton pump inhibitor
DEX, prochlorperazine, or
metoclopramide
Low
Minimal
10-30%
<10%
 lorazepam  H2 blocker
or proton pump inhibitor
No routine prophylaxis
DEX, dexamethasone
For more information see: http://www.nccn.org
No preventive measures
No preventive measures
MASCC / ESMO Committees II-V
Combined Statement #3 – Moderate*
Prevention of nausea and vomiting following
chemotherapy of moderate emetic risk:
To prevent acute and delayed vomiting and nausea
following chemotherapy of moderate emetic risk, we
recommend a regimen of palonosetron and multiday
dexamethasone beginning before chemotherapy
* Does not include “AC” given its higher risk of nausea and
vomiting, in which an NK1 RA is added to Dex + 5HT3 RA
Multinational Association for Supportive Care in Cancer. www.mascc.org
June 2009
Summary
►
1st generation 5HT3 RA’s therapeutically equivalent & major
advance in supportive care for control of acute emesis
►
Newer agents include 2nd generation 5-HT3 RA
palonosetron and NK-1 antagonist aprepitant
►
Treatment guidelines have changed
●
●
►
Degree of nausea incurred has been refined for many agents
Delayed CINV recommendations are updated
Prevention of CINV has improved, but challenges remain
●
●
●
●
Improving detection of CINV, especially after 24 hours
Educating patients and oncology healthcare givers
The development and evaluation of clinically useful
assessment tools
Further development of regimens to treat delayed CINV
Investigations • Innovation • Clinical Application
Risk Stratification Tools to Identify Patients
for Primary and Secondary Prevention of
VTE in the Setting of Malignancy
Screening and VTE Risk Assessment Across the
Complex Spectrum of Malignant Disorders—What
Works? What Doesn’t?
Alok A. Khorana, MD, FACP
Vice-Chief, Division of Hematology/Oncology
Associate Professor of Medicine and Oncology
James P. Wilmot Cancer Center
University of Rochester
Rochester, New York
Optimizing Supportive Care in Cancer




Risk Assessment for VTE In Cancer
Patients
 Risk Factors for VTE
 Biomarkers
Risk Assessment Models
Implications for Study Design of
Prophylaxis Trials
Secondary Prophylaxis
Risk Factors for VTE
Patient-related factors
 Older age
 Race, gender
 Comorbidities
Cancer-related factors

Site of cancer

Advanced stage

Initial period after
diagnosis
Rao et al., in Cancer-Associated Thrombosis.
(Khorana and Francis, Eds) 2007
Treatment-related factors
 Hospitalization
 Chemotherapy
 Anti-angiogenics
 Major surgery
 Erythropoiesis-stimulating
agents
 Transfusions
VTE and Site of Cancer
Type of cancer
Hematologic
Lung
Adjusted OR
(95% CI)
28 (4-199.7)
22.2 (3.6-136.1)
GI
20.3 (4.9-83)
Breast
4.9 (2.3-10.5)
Prostate
2.2 (0.9-5.4)
Blom JW et al. JAMA 2005
VTE in the REAL-2 Study:
Oxaliplatin vs Cisplatin
P=0.0003
HR for cisplatin 0.51; 95% CI, 0.34 to 0.76; P = .001
Starling et al JCO 2009
VTE With Bevacizumab
RR=1.29 (95% CI, 1.03-1.63)
Rate of VTE (%)
13%
9.9%
RR=1.38 (95% CI, 1.12-1.70)
6.2%
4.2%
Bevacizumab
(n=1,196)
Control
(n=1,083)
All-Grade VTE
(6 studies)
Bevacizumab
(n=3,795)
Control
(n=3,167)
High-Grade VTE
(13 studies)
VTE in Myeloma
Cumulative Percentage
0.2
MPT
0.1
MPT and Enoxaparin
RMP and Aspirin
0
0
5
10
15
Months
Palumbo et al. JTH 2006: 4 1842-45
MP
20
25
Candidate Biomarkers
►Blood counts



Platelet count
Leukocyte count
Hemoglobin
►Tissue factor
►Soluble P-selectin
►D-dimer
►C-reactive protein
►Factor VIII
Incidence Of VTE Over 2.5 Months(%)
Incidence of VTE By Quartiles Of
Pre-Chemotherapy Platelet Count
6%
5%
4%
3%
2%
•P =0.005
1%
0%
<250
250-300
300-350
Pre-chemotherapy Platelet Counts (x1000)
Khorana AA et al. Cancer 2005
>350
Incidence Of VTE Over 2.4 Months (%)
Incidence of VTE by Pre-Chemotherapy
Leukocyte Count
6%
5%
4%
3%
2%
•P =0.0008
1%
0%
<4.5 (n=342)
4.5-11 (n=3202)
>11 (n=513)
3
Pre-chemotherapy WBC Counts (x1000/mm)
Khorana AA et al. Blood 2008
Incidence of VTE by Type of Leukocyte
Absolute Neutrophil
Count
Absolute Monocyte
Count
Proportion with VTE
P=0.0001
P<0.0001
Connolly et al ISTH 2009 Abs 1573
Independent Effect of Platelet & Leukocyte
Counts In A Multivariate Analysis
Variable
Odds Ratio*
(95% CI)
P value
Platelet count
>350,000/mm3
1.8 (1.1-3.2)
0.03
Leukocyte count
>11,000/mm3
2.2 (1.2-4.0)
0.008
*Adjusted for site of cancer, stage, hemoglobin < 10g/dl or use of ESAs and obesity
Khorana AA et al. Blood 2008
Effect of Leukocyte and Platelet
Counts on VTE Risk

In the Vienna CATS registry, platelet count
>443,000 was associated with VTE (HR3.5)
 Simanek et al, J Thromb Hemost 2009

In the RIETE registry, patients with leukocytosis
had increased risk of recurrent VTE and death (OR
2.7)
 Trujillo-Santos et al, Thromb Hemost 2008

In the REAL-2 study of advanced GEJ/gastric
cancers, leukocytosis was associated with VTE
during chemotherapy (HR 2.0)
 Starling et al, J Clin Oncol 2009
Proportion Died
Mortality by Pre-chemotherapy
Leukocyte Count
0.20
0.18
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
WBC>11x109/L
WBC<11x109/L
0
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Time (Days)
MVA for early mortality: HR 2.0, p = 0.001
Kuderer et al ASH 2008
Connolly et al ISTH 2009
14.0% (8.9%-21.6%)
4.4% (3.2%-6.1%)
P <0.0001
Tissue Factor in Cancer:
Lack of Standardized Assays
►
Immunohistochemistry of tumor
specimens
►
TF ELISA
►
TF MP procoagulant activity assay
►
Impedance-based flow cytometry
Rate of VTE (%)
Tissue Factor Expression and VTE
P = 0.04
Khorana AA, et al. Clin Cancer Res. 2007;13:2870-2875.
Circulating Tissue Factor and VTE
Plasma TF (pg/mL)
DVT
Khorana AA, et al. J Thromb Haemost. 2008;6:1983-1985.
DVT Fatal PE
P = .04
Cumulative Incidence of VTE
Cumulative Incidence of VTE for Cancer Patients
According to TF–bearing Microparticles
0.6
Log Rank P=0.002
0.5
0.4
0.3
0.2
0.1
0.0
0
5
Zwicker J I et al. Clin Cancer Res 2009;15:6830-6840
10
15
Months
20
25
FRAGEM and TF Biomarker Data
Boxplot of the percentage change of tissue factor antigen in the sera of
pancreatic cancer patients in both the control and dalteparin groups
250
Control
200
150
100
50
0
-50
Maraveyas, et al. Blood Coagul Fibrinolysis 2010
Dalteparin
TF and Survival In Pancreatic Cancer
Proportion surviving
Median Survival in pts with TF MP-PCA >2.5 and </=2.5pg/ml.
10
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Median survival was
98.5 days for TF >2.5
pg/mL vs.
231 days for TF </=
2.5 pg/mL
p=< 0.0001
0
100 200
300
400 500 600
Days on study
TF (pg/mL)
Bharthuar et al ASCO GI 2010
<2.5
700
800
>=2.5
900
1000
N=117 patients with
pancreaticobiliary
cancers
Cumulative probability of VTE (%)
Soluble P-Selectin and VTE in Cancer
0.25
► 687 cancer patients
followed for median of 415
days
0.20
0.15
> 75th percentile
► sP-Selectin independent
predictor of VTE
0.10
< 75th percentile
0.05
0.00
0
100
200
300
400
500
600
► Cumulative 6-mo probability
of VTE was 12% vs 4% for
levels < 75th percentile
700
Observation time (days)
Originally published in Ay C, et al. Blood. 2008;112:2703-2708. Copyright © 2008 American Society
of Hematology.
D-dimer, F1/2 and VTE in Cancer
Cumulative Risk (probability)
0.25
Elevated D-d
0.20
0.15
Elevated D-d+F1/2
0.10
Elevated F1/2 alone
0.05
Nonelevated D-d and
F1/2
0
100
200
300
400
500
Observation Time (Days)
Ay, C. et al. J Clin Oncol; 27:4124-4129 2009
600
700
Optimizing Supportive Care in Cancer



Risk Assessment for VTE In Cancer
Patients
 Risk Factors
 Biomarkers
Risk Assessment Models
Implications for Study Design of
Prophylaxis Trials
VTE in Cancer Outpatients
►
►
►
The overwhelming majority of cancer patients
are treated in the outpatient/ambulatory setting
Which patients are most at risk?
Which patients will benefit most from
prophylaxis?
How do you define “high” risk?
►
Level of risk for which prophylaxis is considered
acceptable by both patients and oncologists
Risk Model
Patient Characteristic
Site of Cancer
Very high risk (stomach, pancreas)
High risk (lung, lymphoma, gynecologic, GU
excluding prostate)
Score
2
1
Platelet count > 350,000/mm3
1
Hb < 10g/dL or use of ESA
1
Leukocyte count > 11,000/mm3
1
BMI > 35 kg/m2
1
Khorana AA et al. Blood 2008
Rate of VTE over 2.5 mos (%)
Risk Model Validation
8%
7%
Development cohort
6%
7.1%
6.7%
Validation cohort
5%
4%
3%
1.8% 2.0%
2%
1%
0.8%
0%
0.3%
n=734 n=374
Risk
Low (0)
Khorana AA et al. Blood 2008
n=1627 n=842
Intermediate(1-2)
n=340 n=149
High(>3)
Vienna CATS Validation
►
►
Full data available in 839 patients
Median observation time/follow-up: 643 days
Number of
Events
Patients
n
n (%)
17.7%
Score ≥3
Score ≥3
96
16 (17%)
Score 2
Score 2
231
25 (11%)
Score 1
Score 1
233
14 (6%)
Score 0
Score 0
279
7 (3%)
9.4%
3.8%
1.5%
6 months
Ay et al ISTH 2009 Abs
Expanded Risk Score with
D-Dimer and sP-selectin
Score ≥5
Number of
Patients Events
n
n (%)
30.3%
Score 4
Score 3
1.0%
6 months
Ay et al ISTH 2009 Abs
Score 2
Score 1
Score 0
Score ≥5
31
9 (29%)
Score 4
52
10 (19%)
Score 3
137
15 (11%)
Score 2
226
11 (5%)
Score 1
192
13 (7%)
Score 0
201
4 (2%)
Risk Model Is Highly Predictive of ShortTerm Overall Survival
By VTE Risk Score Categories
1.00
Low
.95
Intermediate
Overall Survival
P < 0.0001
.90
High
.85
.80
.75
0
10
20
30
40
50
60
70
Time (Days)
Kuderer NM et al. ASH 2008
80
90
100
110
120
Progression-Free Survival and Overall
Survival by VTE Risk Category
Outcomes
Low
Risk
Intermediat
e Risk
High
Risk
All
Patients
(at 4 months)
N=1,206
N=2,709
N=543
N=4,458
1.2%
5.9%
12.7%
5.6%
1.0
3.56 [1.916.66]
6.89 [3.5013.57]
-
93%
82%
72%
84%
1.0
2.77 [1.973.87]
4.27 [2.90-6.27]
-
Mortality
Risk (%)
HR [+/- CI]
PFS
Risk (%)
HR [+/- CI]
Kuderer NM et al. ASH 2008
Optimizing Supportive Care in Cancer

Risk Assessment for VTE In Cancer
Patients


Risk Factors
Biomarkers

Risk Assessment Models

Implications for Study Design of
Prophylaxis Trials
Rates of VTE in Recent
Prophylaxis Studies
N=1165
Agnelli et al Lancet Onc 2009
Palumbo et al ASH 2009
Riess et al ISTH 2009
Maraveyas et al ESMO 2009
N=930
N=312
N=123
VTE in Lung Cancer:
PROTECHT and TOPIC studies
sVTE LMWH
sVTE
Placebo
All VTE
LMWH
All VTE
Placebo
3.5%
5%
4%
6.2%
3%
5.7%
4.5%
8.3%
3.2%
5.5%
4.3%
7.8%
PROTECHT
TOPIC-2
All
Major
Bleeding
LMWH
Major
Bleeding
Placebo
1%
0%
TOPIC-2
3.7%
2.2%
All
2.5%
1.7%
PROTECHT
Verso et al. JTH 2010 online
NNT=50 (sVTE)
NNT=28 (allVTE)
RRR=46%
NNH=125
International Myeloma Working Group
Thromboprophylaxis Recommendations
Individual risk factors: obesity (BMI ≥ 30), prior VTE, central venous catheter
Comorbid risk factors: cardiac disease, chronic renal disease, diabetes, acute
infection, immobilization
Surgery risk factors: trauma, general surgery or any anesthesia
Medications: erythropoietin
Myeloma-related risk factors: diagnosis, hyperviscosity
Myeloma therapy risk factors: multiagent chemotherapy, doxorubicin, high-dose
steroids

Patients with ≤ 1 VTE risk factor: Aspirin (81-325 mg daily)

Patients with ≥ 2 VTE risk factors: LMWH (enoxaparin 40 mg/d) or full-dose
warfarin, although less existing supporting data for the latter

Patients receiving thalidomide/lenalidomide concurrently with high-dose
dexamethasone or doxorubicin should receive LMWH thromboprophylaxis

Anticoagulant treatment can continue for 4 to 6 months or longer if additional
risk factors are present
Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide associated
thrombosis in myeloma. Leukemia. 2008 Feb;22(2): 414-23.
PHACS : Prophylaxis in High-risk
Ambulatory Cancer Patients Study
Patients deemed
high-risk for VTE
starting chemotherapy
Dalteparin prophylaxis x 12
weeks with 4-weekly
screening US and
start/end CT chest
R
Observe x 12 weeks
with 4-weekly screening US
and start/end CT chest
R01 HL095109-01, 9/2008
Ongoing Clinical Trials
Study (Agent)
Criteria for
inclusion*
N
Endpoints
PHACS
(dalteparin x 12 wks)
-Risk score >=3
404
Asymptomatic
and symptomatic
VTE
SAVE-ONCO
(semuloparin up
to 4 mos)
-Lung, bladder, GI, ovary
-Metastatic or locally
advanced
3200
DVT, PE, VTErelated death
227
VTE
-Lung, colon, pancreas
MicroTEC
-Metastatic or
(enoxaparin x 6 mos) unresectable
-Elevated TF MPs
* All studies enroll patients initiating a new chemotherapy regimen
Treatment of VTE in Cancer:
The CLOT Study
Lee, A. Y.Y. et al. N Engl J Med 2003;349:146-153
CLOT Study:
Probability of Recurrent VTE, %
Reduction in Recurrent VTE
25
Recurrent VTE
20
Risk reduction =
52%
p-value = 0.0017
OAC
15
10
Dalteparin
5
0
0
Lee et.al. N Engl J Med,
2003;349:146
30
60
90
120
150
Days Post Randomization
180
210
Summary of NCCN Guidelines Updates
Summary of Major Changes in the
1.2009 Version of the NCCN Venous
Thromboembolic Disease Guidelines
Changes in 2009 NCCN Guidelines
►
Stage 1 Immediate:
“Stage 1 Immediate: Concomitant with diagnosis or while diagnosis
and risk assessment (heparin phase)” changed to “Stage 1 Immediate:
At diagnosis or during diagnostic evaluation”
►
Low –molecular-weight-heparin: New footnote “6” was added that
states, “Although each of the low molecular weight heparins (LMWH),
have been studies in randomized control trials in cancer patients,
dalteparin’s efficacy in this population is supported by the highest
quality evidence and it is the only LMWH approved by the FDA for this
indication.”
►
Unfractionated heparin (IV): target aPTT range changed from “2.0-2.9
x control) to “2.0-2.5 x control…” (Also for VTE-H) in these patients.
Changes in 2009 NCCN Guidelines
Stage 3 Chronic:
► “Third bullet: “Consider indefinite anticoagulation….”
changed to “Recommend indefinite anticoagulation….”
► Fourth bullet: “For catheter associated thrombosis,
anticoagulate as long as catheter is in place and for at
least 3 months after catheter removal”.
Changes in 2009 NCCN Guidelines
►
6Although
each of the low molecular weight heparins
(LMWH) have been studied in randomized controlled
trials in cancer patients, dalteparin’s efficacy in this
population is supported by the highest quality evidence
and is the only LMWH approved by the FDA for this
indication.
Lee AYY, Levine MN, Baker RI, Bowden C, et al. Low-molecular-weight
heparin versus a coumarin for the prevention of recurrent venous
thromboembolism on patients with cancer. New Eng J Med 2003;349(2):
146-153.
(VTE-D): Therapeutic Anticoagulation
Treatment for VTE
► The NCCN panel recommends VTE thromboprophylaxis for all
hospitalized patients with cancer who do not have
contraindications to such therapy, and the panel also
emphasized that an increased level of clinical suspicion of VTE
should be maintained for cancer patients. Following hospital
discharge, it is recommended that patients at high-risk of VTE
(e.g. cancer surgery patients) continue to receive VTE
prophylaxis for up to 4 weeks post-operation. Careful
evaluation and follow-up of cancer patients in whom VTE is
suspected and prompt treatment and follow-up for patients
diagnosed with VTE is recommended after the cancer status of
the patient is assessed and the risks and benefits of treatment
are considered.
Therapeutic Anticoagulation Failure
Therapeutic
INR
Patient
on
warfarin
Switch to heparin
(LMWH preferred)
or fondaparinux
Check
INR
Subtherapeutic
INR
Increase warfarin
dose and treat with
parenteral agent until
INR target achieved
or consider switching
to heparin (LMWH
preferred) or
fondaparinux
Therapeutic Anticoagulation Failure
Therapeutic
aPTT
Patient
on
heparin
Increase dose of heparin
or Switch to LMWH
or Switch to fondaparinux
and Consider placement
of IVC filter
and Consider HIT
Check
aPTT
levels
Subtherapeutic
aPTT
Increase dose of
heparin to reach
therapeutic level
Conclusions


Cancer patients are clearly at increased risk
for VTE but risk is highly variable
TF is an emerging candidate biomarker
predictive of VTE and survival
 ?generalizability to all cancers
 Lack of standardized assay

A recently validated risk model can predict
risk of VTE (and mortality) using 5 simple
clinical and laboratory variables
Conclusions
►Thromboprophylaxis is safe and effective in
certain high-risk settings
►LMWH-base prophylaxis is guideline-based
standard of care
●
●
Hospitalized and surgical patients
Highly selected cancer outpatients (myeloma,
?pancreas, ?? lung)
►Ongoing studies are adopting novel approaches
to selecting patients for prophylaxis
Investigations • Innovation • Clinical Application
Hematologic Complications of
Chemotherapy
Balancing Benefits and Risks of Intervention
Jeffrey Crawford, MD
George Barth Geller Professor for Research In Cancer
Chief of Division of Medical Oncology
Department of Medicine
Duke University Medical Center
Editor-in-Chief, Supportive Care Oncology
Durham, North Carolina
APPRISE – Assisting Providers and Cancer Patients
with Risk Information for the Safe Use of ESAs
►
Doctors will be required to register and
undergo training on risks and benefits of ESAs
in order to continue prescribing.
►
As part of the program, patients will be given a
medication guide that outlines the risks and
benefits of ESAs.
►
Enrollment of providers begins March 24,
2010.
Biological Characteristics of
Erythroid Stimulating Agents (ESAs)
► Epoetin alfa – FDA approval for chemotherapy induced anemia (CIA) 1993
●
In vivo half-life 8.5 h (IV) and 16-19 h (SC) in healthy subjects1
► Darbepoetin alfa – FDA approval for CIA -2002
●
Higher proportion of sialic acid-containing carbohydrate, resulting
in a 3-fold longer half-life and a 4-fold weaker binding affinity for
the EPO receptor2
► Epoetin beta – Approved for CIA in Europe
●
Less sialated than epoetin alfa and a slightly longer half-life when
given SC (~24 h in healthy subjects)3
► Despite pharmacodynamic differences, efficacy/safety of ESAs in CIA
patients appear similar
1Procrit
prescribing information 2002; 2Egrie JC et al. Oncology (Huntingt) 2002; 3Halstenson CE
et al. Clin Pharmacol Ther 1991
Rescue by Transfusion vs an Improvement/
Maintenance Strategy with ESAs: a Conceptual Model
Hb Level
Asymptomatic Zone
ESA
improvement/
maintenance
strategy
Transfusion
Rescue
Strategy
Individualized
patient trigger
Weeks of Chemotherapy
ODAC Meeting, 5/20/07
Modeled Probability of Receiving a Blood
Transfusion as a Function of Baseline Hb
Predicted Probability TFN
1
DA
Placebo
0.9
0.8
0.7
0.6
0.5
0.4
0.3
OR=0.41, 95%CI (0.33, 0.51)
0.2
0.1
0
15
14
13
12
11
10
9
8
7
6
Baseline Hb (g/dL)
4 Phase 3, placebo-controlled CIA Studies, n=1641 (980297, 20000161, 20010145, 20030232)
ODAC Meeting, 5/20/07
5
Summary of HRQoL Data from Systematic
Review of Randomized Placebo-controlled Trials
Source
Littlewood
Boogaerts
Iconomou
Witzig
Savonije
Fixed-effects model
Random-effects model
Difference in Standardized
Mean FACT-F Values
(95% CI)
0.23 (-0.02 to 0.48)
0.11 (-0.16 to 0.38)
0.44 (0.07 to 0.82)
0.11 (-0.12 to 0.33)
0.42 (0.12 to 0.71)
0.076
0.428
0.021
0.360
0.005
0.22 (0.10 to 0.34)
0.22 (0.10 to 0.36)
0.000
0.001
QOL Scale
(ESA vs control)
P
-1.00 -0.50 0.00
Mean
Change
P-value
FACT-F (5 studies, 1418 max pts)
3.6 vs -0.8
<0.001
LASA (4 studies, 1076 max pts)
4.8 vs -3.6
<0.001
1Cella
Difference in Standardized Means
(95% CI)
D et al, J Pain Symptom Manage. 2002;24(6):547-561
Ross, S et al. Clin Ther. 2006; 28(6): 1-31
Favors Control
0.50
1.00
Favors EPO/DARB
 3-point difference in FACT-F
defined as clinically important1
Higher Hb is Associated
with Higher HRQoL
LASA Overall QOL Score
65
60
55
50
45
0
7
8
1 study (n=1580)
Crawford J, et al. Cancer. 2002;95(4):888-895.
9
10
Hb level (g/dL)
11
12
13
14
When and Why do Physicians Transfuse?
Data from 5 Phase 3 CIA Darbepoetin alfa Studies
Across all studies, recommendation for transfusion was Hb <8 g/dL
(or signs & symptoms of anemia)
(n=2286)
Hb at Time of Transfusion
Reasons Given for Transfusion
(n=2185 transfusion episodes)
(n=2227 CRF responses )
10-12 g/dL
≥12 g/dL (0.7%)
9.2%
<8 g/dL
35.9%
8 – 10 g/dL
54.3%
Hb Trigger
34.7%
Therapeutic
46.0%
Other
13.7%
Prophylactic (1.2%)
Medically Indicated (4.4%)
Common Risks of Blood Product Infusions
Some of the Risks of Transfusion
► Febrile nonhemolytic
► Acute transfusion reaction from
mismatch
► Acute hemolytic
► Delayed hemolytic
► Allergic
 Anaphylactic
 Human leukocyte antigen
sensitization
 Red blood cell allosensitization
 Graft-versus-host disease
► Clotting disturbances
► Electrolyte disturbances
► Volume overload in the young and
elderly
► Transfusion-related acute lung injury
► Peri-operative infection susceptibility
► Blood borne infectoons – viral (HIV,
hepatitis), bacterial, prions, parasites
(malaria)
► Increased tumor recurrence from perioperative transfusion
► Worsensed cancer prognosis from
peri-operative transfusion
Upile, T, et al. Clinical Advances in Hematology & Oncology Volume 7, Issue 10 October 2009
Patterns of Use and Risks Associated with ErythropoiesisStimulating Agents Among Medicare Patients with Cancer
Background: Erythropoiesis-stimulating agents (erythropoietin and
darbepoietin) have been approved to reduce the number of blood
transfusions required during chemotherapy; however, concerns about
the risks of venous thromboembolism and mortality exist.
Methods: Study of patients aged 65 years or older in the
Surveillance, Epidemiology and End Results-Medicare database; with
colon, non-small cell lung or breast cancer or with diffuse large B-cell
lymphoma from 1991 through 2001; and who received
chemotherapy. The main outcome measures were claims for use of
an erythropoiesis-stimulating agent, blood transfusion, venous
thromboembolism (i.e., deep vein thrombosis or pulmonary
embolism), and overall survival.
Hershman, D. JNCI 101 (23):1-9, 2009
Patterns of Use and Risks of ESAs
Results
► 56,210 patients received chemotherapy
► 15,346 (27%) received an ESA
► 22% received transfusions
► 14.3% of ESA patients had VTE
► 9.8% of nonESA patients had VTE
ESA – erythroid stimulating agent
VTE – venous thromboembolism
Hershman, D. JNCI 101 (23):1-9, 2009
Trends in ESA and Transfusion
Use in All Patients
70
% of Patients Receiving ESA
% of Patients Receiving Blood Transfusion
60
% of Patients
50
40
30
20
10
0
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Hershman, D. JNCI 101 (23):1-9, 2009
Overall Survival
Proportion alive
1.00
0.75
0.50
EAS use
0.25
ESA non-use
0
2
4
6
Time to death (years)
Hershman, D. JNCI 101 (23):1-9, 2009
8
10
Blood Transfusions, Thrombosis and Mortality
in Hospitalized Patients with Cancer
Population
504,208 pts
with cancer
admitted
between 19952003 at 60
medical centers
Khorana, Francis, Blumberg, Culakova, Refaai, Lyman.
Arch Intern Med 2008;168:2377-2381.
Blood Transfusions, Thrombosis and Mortality in Hospitalized Patients with Cancer
Khorana, Francis, Blumberg, Culakova, Refaai, Lyman.
Community Oncology ESA Experience
Mean hemoglobin levels at different time points
Pre-NCD cohort
Timepoint
Post NCD cohort
P Value
Number
Hb level
(SD)
Number
Hb level
(SD)
Baseline
225
10.7 (0.9)
144
9.7 (0.8)
<0.0001
Week 4
206
11.0 (1.2)
138
10.2 (1.2)
<0.0001
Week 8
138
11.2 (1.3)
102
10.3 (1.1)
<0.0001
Feinberg, B. Community Oncology, June 2009, 257-261
Community Oncology ESA Experience
Feinberg, B. Community Oncology, June 2009, 257-261
Focused ESA Safety Data
Survival, Tumor Progression, TVE*
ENHANCE
BEST
EPO-CAN-20
PREPARE
2003‡
2005‡
2007‡
11/07†
20000161
4/05, 4/07†
20010103
GOG-191
1/07†
2007†
DAHANCA
12/06†
*8 trials selected by FDA for label inclusion out of 57 total, ‡ publication date, † = date data reported to FDA
Lancet 2003;632:1255-60. J Natl Cancer Inst 2006:98:708-14. J Clin Oncol
2005;23:5960-72. J Natl Cancer Inst 2005;97:489-98. J Clin Oncol 2007;25:102732. http://www.fda.gov (accessed 3/20/08). JAMA 2008;299:914-24
EPO CAN-20
►
300 patients not on active treatment
►
Primary endpoint: QOL at 12 weeks
►
Target hemoglobin 12-14 g/dL
►
Unplanned safety analysis 70 patients
►
Result : Survival decrement HR 1.84
Survival Probability
Wright et al
Overall Survival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Results of unplanned interim analysis (n = 70)
Placebo
Log-rank P = 0.04
4
8
12
16
Epoetin alfa
20
24
28
32
36
40
44
48
52
1
7
1
6
56
60
Post-random Assignment (weeks)
No. at risk:
Epoetin alfa 33
Placebo
37
28
34
20
30
Overall Survival
Eprex® is a registered trademark of Ortho Biotech
Wright JR., et al. J Clin Onc. 2007:25;1027-1032
15
26
13
22
12
17
12
15
9
15
5
12
3
11
1
9
HR
p value
1.84
0.04
1
5
1
5
1
3
EPO-CAN-20 (Advanced NSCLC)
Reported Causes of Death
Cause of Death
Placebo
(34 deaths)
Epoetin Alfa
(32 deaths)
No. of
Patients
%
No. of
Patients
%
Progressive lung cancer
31
91.2
28
87.5
Pneumonia
1
2.9
1
3.1
Myocardial infarction
1
2.9
1
Renal failure
1
2.9
-
Hyponatremia
-
1
3.1
Bowel perforation
-
1
3.1
Unknown cause
-
1
3.1
Wright J et al. JCO 2007 Mar 20;25(9):1027-32. Epub 2007 Feb 20
Meta-analysis: Lung Cancer Trials
Study Name
No. of
Deaths/Total
ESA
AoC NSCLC
Wright 2007 (EPO-CAN-20)
CIA NSCLC
EPO-GER-22
Vansteenkiste 2002 NSCLC
Milroy 2003 (INT-49)
Random Effects Model: NSCLC
CIA SCLC
Vansteenkiste 2002 SCLC
Pirker 2007 (AMG 20010145)
EPO-CAN-15
Thatcher 1999
Grote 2005 (N93-004)
Random Effects Model: SCLC
32/33
95% CI
Odds
Ratio Lower Upper
Control
Limit Limit
34/37
146/195 159/190
72/108
82/114
136/214 126/210
28/47
37/45
241/298 251/298
28/52
29/52
7/86
3/44
100/109 101/115
2.82
0.28
28.56
0.58
0.78
1.16
0.83
0.35
0.44
0.79
0.96
1.38
1.72
0.54
1.27
0.12
0.52
0.43
0.30
0.64
0.83
1.21
2.00
4.93
3.72
0.53
1.28
0.32
0.79
0.93
1.21
1.54
0.83
0.1
ODAC 2008 Supplement
0.2
0.5
Favors ESA
1
2
5
Favors Control
10
Cochrane Meta Analysis –
Summary of Results
Study
population
N
Hazard Ratio
(95% CI)
P-value
All cancer pts
13, 933
1.17 (1.06,
1.30)
0.002
Chemotherapy
trials
10, 441
1.10 (0.98,
1.24)
0.12
All cancer pts
13, 933
1.06 (1.00,
1.12)
0.05
Chemotherapy
trials
10, 441
1.04 (0.97,
1.11)
0.26
On-study mortality1
Overall survival2
Bohlius et al, (Lancet 2009)
1deaths
during active study phase; 2 deaths during
longest follow-up available
Meta Analysis of Disease Progression
Glaspy, Crawford, Vansteenkiste, Henry, Rao, Bowers,
Berlin, Tomita, Bridges, Ludwig British Journal of Cancer
102, 301-315 (5 January 2010)
Clinical Trials Identifier
NCT00858364
A Randomized, Double-Blind, PlaceboControlled Study to Evaluate the Long-Term
Safety and Efficacy of Darbepoetin Alfa
Administered at 500 µg Once-Every-3-Weeks in
Anemic Subjects With Advanced Stage NonSmall Cell Lung Cancer Receiving Multi-Cycle
Chemotherapy
Clinical Trials Identifier
NCT00858364
►
Sponsor
Amgen Inc.
►
General Design
Randomized, double-blind, placebo-controlled Phase 3, non-inferiority
study intended to evaluate the long term safety and efficacy of
darbepoetin alfa
►
Intervention
Aranesp or placebo administered Q3W (2:1 randomization)
►
Study population
Subjects with advanced stage non-small cell lung cancer and anemia
(Hb <=11 g/dL) receiving or about to receive first-line chemotherapy
►
Sample size
3000 subjects
Clinical Trials Identifier
NCT00858364
►
Primary outcome measure
●
►
Overall Survival (OS)
Secondary outcome measures
●
●
●
●
●
●
●
Progression-free survival (PFS)
Objective tumor response
Incidence of at least 1 RBC transfusion or hemoglobin less than or
equal to 8.0 g/dL from week 5 (day 29) to end of efficacy treatment
period
Incidence of at least 1 RBC transfusion or hemoglobin less than or
equal to 8.0 g/dL from study day 1 to end of treatment period
Incidence of neutralizing antibody formation to darbepoetin alfa
Change in hemoglobin from baseline to end of efficacy treatment
period
Incidence of adverse events (AEs) such as thrombovascular events
(TVE), venous thromboembolic events (VTE), and AEs associated with
RBC transfusions
Study Status as of June 2010
►
Study start date: June 2009
►
Currently recruiting subjects in North
America, Europe, Asia and Latin
America
●
Study sites planned for a total of
approximately 400 sites in over 30
countries
Chemotherapy-induced Neutropenia
and Its Complications
Myelosuppressive chemotherapy
Neutropenia
Febrile neutropenia (FN)
Chemotherapy dose delays
and dose reductions
Complicated life-threatening
infection and prolonged
hospitalization
Reduced survival
Kuderer NM et al. Cancer 2006;106:2258–2266
Chirivella I et al. J Clin Oncol 2006;24;abstract 668
Bosly A et al. Ann Hematol 2008;87:277-283
Decreased relative dose
intensity (RDI)
100
(temperature >38.2◦C and
ANC <0.5 x 109/L)
Predicted probability of FN (%)
Risk of FN Increases with Duration of
Severe Neutropenia*
80
60
40
20
0
0
*ANC <0.5 x 109/L
1
2
3
4
5
6
Days of severe neutropenia
Adapted from Blackwell S, Crawford J. In: Morstyn G, Dexter TM. Filgrastim;
(r-metHuG-CSF) in Clinical Practice. New York: Marcel Dekker; 1994 p 103–116
Crawford J et al. N Engl J Med 1991;325:164–170
7
8
9
Most Initial FN Events Occur During
the First Cycle of Chemotherapy
Events in cycle 1 (%)
Proportion of first FN events in cycle 1 by cancer type
• FN events documented in 287/2692 (10.7%) of adult cancer patients during
the 1st three cycles of chemotherapy
NSCLC – non-small cell lung cancer;
Adapted from Crawford J et al. JNCCN 2008;6:109–118
SCLC – small cell lung cancer;
NHL - non-Hodgkin’s lymphoma;
HD – Hodgkin’s disease
Death as a Result of FN Hospitalization
Inpatient mortality
(percent patients admitted for FN)
25
Mortality following hospital admission of adult
cancer patients with FN*
21.4
20
15
10
10.3
9.5
5
2.6
0
Overall
(n=41,779)
No major
comorbidity
(n=21,386)
*Data based on a single admission per patient
Kuderer NM et al. Cancer 2006;106:2258–2266
One major
comorbidity
(n=12,398)
>one major
comorbidity
(n=7,995)
Clinical Consequences of Neutropenia
and Febrile Neutropenia
1.0
1.0
+ +
0.8
+
RDI
0.6
+
+
< 85%
0.4
+++
 85%
+ < 85%, censored
0.2
+  85%, censored
0.0
0
2
4
6
8
10
Disease-Free Survival (years)
• Reduced RDI resulted in lower OS in
ESBC receiving anthracyclinecontaining chemotherapy1
Estimated Survival
Cum Proportion Survival
 Suboptimal chemotherapy reduces survival
0.8
0.6
ARDI
0.4
>90%
86–≤90%
≤85%
0.2
0.0
0
1
2
3
4
5
6
7
8
Years Post Chemotherapy
• Reduced RDI resulted in lower
OS in patients with DLBCL receiving
CHOP-21 chemotherapy2
OS, overall survival; ARDI, average relative dose intensity
1 Chirivella I, et al. Breast Cancer Res Treat 2009;114(3):479-484
2 Bosly A, et al. Ann Hematol 2008; 87:277–283
Myelosuppression Predicts for Survival Benefit of
Adjuvant Chemotherapy in Breast Cancer Patients
Mayers C, Tannock IF. Cancer 2001;91:2253
Lyman G. JNCCN 2009;7:99-108
Neutropenia as a Pharmacodynamic
Endpoint of Clinical Benefit
Analysis of 4626 Hodgkin’s Lymphoma patients on German HDSG
Trials 1988-1998
Results
Female
Male
P value
G3/4 leukopenia
69.90
52.20
p<0.0001
FFTF at 66 months
81%
74%
Hypothesis: The better outcome of female HL patients is due to
greater systemic chemotherapy exposure.
Klimm B. J Clin Oncol 2005;23:8003-8011
Overall Survival by Grade of Chemotherapy-Induced
Neutropenia for Advanced NSCLC Patients
Probability of Survival
1.0
0.8
No neutropenia
Mild neutropenia
Severe neutropenia
0.6
Log-rank P=0.0118
(stratified by treatment)
0.4
0.2
0
0
13
Patients at Risk
No neutropenia
208
Mild neutropenia
138
Severe neutropenia 90
Di Maio M et al. Lancet Oncol 2005;6:669
26
39
52
65
78
91
104
Time From Landmark Day (Weeks)
150
98
69
102
74
50
68
54
28
43
38
21
29
33
14
20
21
14
13
13
8
10
11
4
Strategies For Management of
Chemotherapy-Induced Neutropenia
►
Prevention
●
●
Chemotherapy Dose reduction/delay
Myeloid growth factors
• G-CSF (filgrastim, lenograstim)
• GM-CSF (sargramostim, molgramostim)
• Pegfilgrastim
- Antibiotics
►
Treatment
●
●
●
Observation if afebrile
Antibiotics
Myeloid growth factors (limited benefit)
Meta-Analysis: Antibiotic Prophylaxis
Reduces Mortality in Neutropenic Patients
►
95 randomized controlled trials, 1973-2004
(n=9283)
►
79 studies were on inpatients with hematologic
malignancies and/or PSCT
►
52 trials involved quinolone prophylaxis
►
7 trials included CSFs
Gafter-Gvili, A. Ann Intern Med. 2005:142(12):979-995
Meta-Analysis: Antibiotic Prophylaxis
Reduces Mortality in Neutropenic Patients
Results of Prophylaxis with Fluoroquinolones
Outcome
Relative Risk (CI)
Fever
.67 (.56-.81)
Documented Infection
.50 (.35-.70)
Infection Related Death
.38 (.21-.69)
All cause mortality
.52 (.35-.77)
Adverse Events
1.30 (.61-2.76)
Development of resistant bacteria
1.69 (.73-3.92)
Gafter-Gvili, A. Ann Intern Med. 2005:142(12):979-995
Meta-Analysis: Antibiotic Prophylaxis
Reduces Mortality in Neutropenic Patients
Limitations of Prophylactic Antibiotics
►
Insufficient number of outpatient solid
tumor/chemotherapy patients to be applicable
►
Not recommended by IDSA guidelines because of
concerns regarding antibiotic resistance
►
Routine application limited to high risk inpatients
with hematologic malignancies/stem cell transplants
Gafter-Gvili, A. Ann Intern Med. 2005:142(12):979-995
Role of Prophylactic Antibiotics in the
Prevention of Infection after Chemotherapy
SIGNIFICANT Trial
►Solid tumor/lymphoma patients (n-1565) receiving
standard dose multicycle chemotherapy
►Randomized to levofloxacin 500 mg qd x 7 day vs
placebo
►Primary endpoint – reduction in febrile episodes
attributed to infection
SIGNIFICANT Trial. Cullen, et al. NEJM 2005; 353:988-998
Role of Prophylactic Antibiotics in the
Prevention of Infection after Chemotherapy
SIGNIFICANT Trial
Outcome
In first cycle
Febrile episode
Probable infection
Hospitalization
In any Cycle
Febrile episode
Probable infection
Hospitalization
Severe Infection or
Death
RR Reduction
Levofloxacin Placebo
(95% CI)
Number
Needed to
Treat (CI)
3.5
14
6.7
7.9
19
10
56 (32-72)
28 (10-43)
36 (10-54)
23 (15-46)
19 (11-58)
28 (16-109)
11
34
16
15
41
22
29 (8.1-45)
18 (6.3-27)
27 (9.9-410)
23 (13-91)
14 (9-410
18 (11-52)
1
2
50 (-14 to 78)
Not significant
Values are percentages unless otherwise specified.
Moon, S. et al. Supportive Cancer Therapy, 2006 3(4):207-13
Primary Prophylaxis with MGFs
Reduces Febrile Neutropenia
RR = 0.538
95% CI (0.430-0.673)
46% reduction in
risk of febrile
neutropenia with
primary prophylaxis
Kuderer NM et al. J Clin Oncol. 2007;25:3158-3167
Primary Prophylaxis with MGFs
Reduces Infection-related Mortality
RR = 0.552
95% CI (0.338-0.902)
45% reduction in
risk of infectionrelated mortality with
primary prophylaxis
Kuderer NM et al. J Clin Oncol. 2007;25:3158-3167
Primary Prophylaxis with MGFs
Reduces Early Mortality
RR = 0.599
95% CI (0.4330.830)
40% reduction in
risk of early
mortality with
primary prophylaxis
Kuderer NM et al. J Clin Oncol. 2007;25:3158-3167
What impact does pegfilgrastim have on early, allcause mortality in patients receiving chemotherapy?
Design
Community-based, prospective observational study
Inclusion
criteria
Eligibility was not restricted on the basis of older age or major
co-morbidities; 3 month life expectancy and 4 cycles
chemotherapy planned
Patient
population
4,458 consecutive adult patients initiating chemotherapy at
115 U.S. practice sites
Endpoints
Time to febrile neutropenia, progression-free and overall
survival
Lyman GH, et al. J Clin Oncol 2008; May 20 suppl:6552
Pegfilgrastim Primary Prophylaxis Demonstrates Significant
Impact on Early Overall and Progression-free Survival
Pegfilgrastim
Primary Prophylaxis
Survival
0.95
No Pegfilgrastim
Prophylaxis
0.90
0.85
Hazard Ratio = 0.412 [0.210,0.211]
P = 0.010
0.80
Pegfilgrastim
Primary Prophylaxis
1.00
Progression Free Survival
1.00
0.75
0.95
0.90
No Pegfilgrastim
Prophylaxis
0.85
Hazard Ratio = 0.554 [0.453,0.923]
P = 0.015
0.80
0.75
0
10 20 30 40 50 60 70 80 90
Time (Days)
Lyman GH, et al. J Clin Oncol 2008; May 20 suppl:6552
0
10 20 30 40 50 60 70 80 90
Time (Days)
Impact of Pegfilgrastim on Overall and Disease Free
Survival was Apparent in Major Prognostic Subgroups
A 1.00
0.95
No Pegfilgrastim
Planned RDI ≥ 85%
N = 2,623
0.90
0.85
Hazard Ratio = 0.310 [0.133,0.723]
P = 0.007
0.80
Pegfilgrastim
0.95
Survival
Survival
B 1.00
Pegfilgrastim
Lung Cancer
N = 907
0.90
0.85
Hazard Ratio = 0.346 [0.125,0.954]
P = 0.040
0.80
0.75
No Pegfilgrastim
0.75
0
10
20
30
40
50
60
70
80
90
0
10
20
30
Time (Days)
40
50
70
80
90
Time (Days)
D 1.00
C 1.00
Pegfilgrastim
Pegfilgrastim
0.95
ECOG ≥ 1
N = 2,024
0.90
No Pegfilgrastim
0.85
Hazard Ratio = 0.383 [0.192,0.761]
P = 0.006
0.80
Survival
0.95
Survival
60
Liver Dysfunction
0.90 N = 1,045
No Pegfilgrastim
0.85
Hazard Ratio = 0.274 [0.110,0.684]
P = 0.006
0.80
0.75
0.75
0
10
20
30
40
50
60
70
80
90
Time (Days)
Lyman GH, et al. J Clin Oncol 2008; May 20 suppl:6552
0
10
20
30
40
50
60
Time (Days)
70
80
90
Risk of Mortality in Patients with Cancer
Experiencing Febrile Neutropenia
Kaplan-Meier Survival Curve for Early Mortality
1.00
Survival
0.99
0.98
0.97
0.96
Log rank test: Chi2(1)=4.79, p=0.0287
0.95
0
2
4
6
8
Length of Follow-up in Months
10
Non febrile neutropenia patients
Febrile neutropenia patients
Barron, R. Abstract 9561, ASCO 2009
12
Risk of Mortality in Patients with Cancer
Experiencing Febrile Neutropenia
Kaplan-Meier Survival Curve for Overall Mortality
1.00
Log rank test: Chi2(1)=23.15, p<0.0001
Survival
0.95
0.90
0.85
0.80
0.75
0
10
20
30
40
50
Length of Follow-up in Months
60
Non febrile neutropenia patients
Febrile neutropenia patients
Barron, R. Abstract 9561, ASCO 2009
70
Guidelines at a Glance:
Primary Prophylactic CSF Administration
Neutropenic
Event Risk
EORTC
2006
ASCO
2006
NCCN
2007
Moderate to
High
Use CSF ≥ 20%
Use CSF ~ 20%
Use CSF > 20%
Intermediate
Consider CSF
10 - 20%
with risk factors
Recommend
< 20%
(with risk factors)
Consider CSF
10 - 20%
with risk factors
Low
CSF is not
recommended
< 10%
Risk Factor
Assessment
+++
Not specified
+++
CSF is not
recommended for
most patients
< 10%
++
NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors. v.1.2007. Available at:
http://www.nccn.org, accessed May 23, 2007
Smith TJ, et al. J Clin Oncol. 2006;24(19):3187-3205
Aapro MS, et al. European J Cancer. 2006;42:2433-2453
NCCN Practice Guidelines in Oncology v.1.2010
Myeloid Growth Factors
Patient Risk Factors for Developing Febrile Neutropenia
In addition to the risk of the chemotherapy regimen and the specific
malignancy being treated, these factors need to be considered when
evaluating a patient’s overall risk for febrile neutropenia.
► Older patient, notably patients age 65 and older (see NCCN Senior Adult
Oncology Guidelines)
► Previous chemotherapy or radiation therapy
► Pre-existing neutropenia or bone marrow involvment with tumor
► Pre-existing conditions
 Neutropenia
 Infection/open wounds
 Recent surgery
► Poor performance status
► Poor renal function
► Liver dysfunction, most notably elevated bilirubin
Adverse Events Associated with
Myeloid Growth Factors
Filgrastim/Pegfilgrastim
Common
Bone/musculoskeletal pain (25-50%)
Less Common
Splenomegaly (3%)
Headache, nausea
Fever (1%)
Rare
Allergic reaction
Sweet’s syndrome
Controversial
Acute myeloid leukemia – epidemiologic association, but not
confirmed in randomized prospective trials
Myeloid Growth Factor Guidelines v.1.2008, www.NCCN.org
Acute Myeloid Leukemia or Myelodysplastic Syndrome
and Overall Mortality with Chemotherapy and
Granulocyte Colony-Stimulating Factor
Meta-Analysis of Randomized Controlled Trials
Relative Risk for AML/MDS by Cancer Type
Lyman, G. ASCO Abstract 9524, 2009
Acute Myeloid Leukemia or Myelodysplastic Syndrome
and Overall Mortality with Chemotherapy and
Granulocyte Colony-Stimulating Factor
Meta-Analysis of Randomized Controlled Trials
AML/MDS by Planned CT Regimen Category
Lyman, G. ASCO Abstract 9524, 2009
Acute Myeloid Leukemia or Myelodysplastic Syndrome
and Overall Mortality with Chemotherapy and
Granulocyte Colony-Stimulating Factor
Meta-Analysis of Randomized Controlled Trials
All-Cause Mortality by Tumor Type
Lyman, G. ASCO Abstract 9524, 2009
Acute Myeloid Leukemia or Myelodysplastic Syndrome
and Overall Mortality with Chemotherapy and
Granulocyte Colony-Stimulating Factor
Meta-Analysis of Randomized Controlled Trials
All-Cause Mortality by Regimen Category
Lyman, G. ASCO Abstract 9524, 2009
Neutropenia / Management Summary
►
Neutropenia is the major risk factor for fever and infection,
as well as reduced chemotherapy dose delivery; both of
which can be associated with reduced survival of the
cancer patient.
►
In patients at significant risk of febrile neutropenia (>20%)
prophylactic CSFs are warranted in the first and all
subsequent cycles of chemotherapy.
►
Prophylactic antibiotics may add to the benefit of CSFs in
selected settings, but cannot replace them.
►
Further prospective studies evaluating chemotherapy RDI
and outcomes in cancer patients are needed.