Transcript Patient Survivor Care.Kirshner.9014

Prevention of Pegfilgrastim-induced Bone
Pain (PIP): A URCC CCOP Randomized,
Double-blind, Placebo-controlled Trial of 510
Cancer Patients
Jeffrey J. Kirshner, Charles E. Heckler, Shaker R. Dakhil, Judith O. Hopkins,
Cynthia Coles, Gary R. Morrow.
Hematology-Oncology Associates of Central NY CCOP, East Syracuse, NY,
U. of Rochester Cancer Center, Rochester, NY, Wichita CCOP, Wichita, KS,
SECCC, Winston-Salem, NC, Metro-Minnesota CCOP, Minneapolis, MN
Disclosures
• None to report for any of the investigators
Background
• The development of G-CSF, particularly
pegfilgrastim, has enabled oncologists to
maintain dose intensity and to utilize
“dose-dense” chemotherapy ( by limiting
the severity and duration of neutropenia)
• This may lead to an improvement in
patient survival
• The toxicity of pegfilgrastim is minimal and
usually limited to bone pain
Background
• The incidence of pegfilgrastim-induced
bone pain ranges from 26-59 % and can
be “severe” in up to 24 % of patients
• Discontinuation of pegfilgrastim could lead
to less effective chemotherapy dosing and
a decrease in patient survival
Community Based Survey of 100 Patients
(Kirshner, et al: Community Oncology 2007)
• 59% incidence of pegfilgrastim-induced pain
• 24% incidence of severe pain (>5/10)
• NSAIDs seemed to be the most effective
analgesic for relief of pain, particularly naproxen
“An Ounce of Prevention Is
Worth a Pound of Cure”
• It is better to prevent pain than to treat it
once it occurs
• This could improve QOL and possibly
keep more patients on their chemotherapy
schedule
• NSAIDs seem to be somewhat effective in
relieving pegfilgrastim-induced pain
• NSAIDs have few side-effects and are
relatively inexpensive
Study Objectives
• To determine if naproxen can reduce the
incidence, severity and duration of
pegfilgrastim-induced pain
• To better assess the true incidence of this pain
in a large cross-section of patients treated by
community oncologists
• To determine if there are risk factors which
predict the development of such pain
• To determine if there are factors which predict
efficacy of naproxen
Study Design
Phone Call 3-5 days
after pegfilgrastim
administration
Prior to first dose
of pegfilgrastim
• Consent
• Questionnaires
• Randomize to
naproxen/placebo
[Baseline]
Day 2, 3 or 4 of
chemotherapy cycle
Study participation
ends
• pegfilgrastim
administered SC
• Complete and mail
outcome
questionnaires
• Begin Study
Medication
• Return Baseline
questionnaires
[Outcome]
• Outcome
questionnaires
5 to 8 days of
naproxen sodium or
placebo
Study Drug
• Naproxen 500 mg or matching placebo
was begun at BID dosing on the morning
of pegfilgrastim administration
• Drug was continued for a minimum of 5
days and up to 8 days if pain continued
Questionnaires
• Patient rated their pain on a daily basis,
using a scale of 0-10 (Brief Pain
Inventory)
• Quality of Life (QOL) assessments before
and after treatment, utilizing “Symptom
Inventory”
• Any additional medications to control pain
were documented (additional NSAIDs
were excluded)
Statistical Measures
• Primary outcome was measurement of the
AUC from baseline to Day 5 (Day 1= Day
of pegfilgrastim administration)
• Incidence of any pain and severe pain
(>5/10) was measured as well as
duration of pain
Area Under Curve (AUC)
10
9
8
7
Pain
6
5
4
AUC=13.5
3
2
1
0
1
2
3
Day
4
5
Eligibility
• Diagnosis of non-myeloid malignancy,
scheduled to receive chemotherapy and
receive a first dose of pegfilgrastim (6mg
sq) on Day 2, 3 or 4 of chemotherapy
cycle
• No history of active or past
gastrointestinal bleeding
• No heart surgery within the past 6 months
• No allergies to NSAIDs
Eligibility
• Not currently taking any NSAID or steroid
medication
• Not taking any medication for pre-existing
chronic pain
• Not taking therapeutic doses of warfarin
• Normal renal function (creatinine < 1.5 X
ULN)
Eligibility
•
•
•
•
Not pregnant or nursing
Able to understand English
18 years of age or older
Must give written informed consent
Demographics at Randomization
N
%
Female: 437
86%
African American:
33
6%
Asian:
14
3%
Caucasian: 455
89%
Other:
8
2%
Breast: 341
67%
Gynecological:
29
6%
Hematological:
35
7%
Lung:
53
10%
Other:
50
10%
Married: 360
71%
Some College: 344
68%
High school or less: 160
32%
Mean (Min-Max)
Age: 56.2 (22-89)
N=510; 257(Drug), 253
(Placebo).
No significant difference
in arms for any
characteristic.
Accrual from 7/08-12/09
Patient Population
• URCC CCOP
Research Base
Study at 17
CCOP’s
throughout the
U.S.
• Accrual ranged
from 1 to 110 at
the sites
Wichita
Metro Minnesota
Hem Onc CNY
SCCC
Greenville
Columbus
Marshfield
Evanston
Kansas City
Dayton
North Shore
Grand Rapids
Hawaii
Upstate Carolina
Northwest
Central Illinois
Nevada
Virginia Mason
0
20
40
60
80
100
120
University of Rochester Cancer Center
Community Clinical Oncology Research Base
Map of Affiliates (2009)
URCC
CCOPs
Central Illinois CCOP
Columbia River CCOP
Columbus CCOP
Dayton Clinical Oncology Program
Evanston CCOP
Grand Rapids CCOP
Greenville CCOP
Gulf Coast MBCCOP
Hawaii MBCCOP
Hematology-Oncology of CNY CCOP
Kalamazoo CCOP
Kansas City CCOP
Marshfield Clinic Research Foundation CCOP
Metro-Minnesota CCOP
Nevada Cancer Research Foundation CCOP
North Shore University Hospital CCOP
Northwest CCOP
Southeast Cancer Control Consortium
University of Illinois at Chicago MBCCOP
Upstate Carolina CCOP
Virginia Mason Research Center CCOP
Wichita CCOP
Participant Flow
510 Participants
257 Randomized to
Drug
253 Randomized to
Control
1 Ineligible
24 Did Not Complete
Outcome Measures
N = 232 Analyzed
24 Did Not Complete
Outcome Measures
N = 229 Analyzed
Results
8.0
6.0
AUC
AUC for Pain was
reduced from 7.7
(placebo group) to
6.0 (naproxen
group)
4.0
2.0
p=0.037
0.0
Mean
Placebo
7.7
Drug
6.0
Incidence of Pain
Pain
Severe Pain
Drug
65.6%
17.6%
Placebo
76.3%
24.5%
P
0.01
0.06
Average Pain across Days
Repeated Measures
Analysis:
P(Arm)=0.04
P(Arm*Day)=0.31
(Curves don’t have
significantly different
shapes.)
N=461
Duration of Pain
• 2.40 days (placebo) vs. 1.92 days
(naproxen)
• P= 0.005
Risk Factors for Pain
• No relationship to age, types of cancer nor
chemotherapy
• Suggestion that pegfilgrastim induced
pain may be more frequent in AfricanAmericans (but only 33 patients): AUC
12.88 vs 6.48
Relationship to Efficacy of
Naproxen
• No effect of age, race, type of cancer nor
chemotherapy regimen
Adverse Events
• None reported on either study arm
• Specifically, no reports of gastrointestinal
bleeding or GI distress
Conclusions
• Naproxen 500 mg BID is effective in reducing
the incidence, severity and duration of
pegfilgrastim induced bone pain
• It should be considered for patients beginning
pegfilgrastim, providing there are no
contraindications
• A significant percentage of patients still will
experience pegfilgrastim induced pain and there
is a need to develop more effective preventive
treatments
Acknowledgments
• NCI DCP- CCOP Program (PHS Grants:
1R25CA10618 and U10CA37420)
• CCOP Investigators and Staff
• Patients, Family and Friends