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

Prior to first dose of pegfilgrastim

• Consent

• Questionnaires

• Randomize to naproxen/placebo

[Baseline]

Prior to first dose of pegfilgrastim

• Consent

• Questionnaires

• Randomize to naproxen/placebo

[Baseline]

Study participation ends

• Complete and mail outcome questionnaires

[Outcome]

Study participation ends

• Complete and mail outcome questionnaires

[Outcome]

Day 2, 3 or 4 of chemotherapy cycle

• pegfilgrastim administered SC

• Begin Study Medication

• Return Baseline questionnaires

• Outcome questionnaires

Day 2, 3 or 4 of chemotherapy cycle

• pegfilgrastim administered SC

• Begin Study Medication

• Return Baseline questionnaires

• Outcome questionnaires

Phone Call 3-5 days after pegfilgrastim administration

Phone Call 3-5 days after pegfilgrastim administration

5 to 8 days of naproxen sodium or placebo

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

AUC=13.5

Area Under Curve (AUC)

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=510; 257(Drug), 253 (Placebo).

No significant difference in arms for any characteristic.

Accrual from 7/08-12/09

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)

Patient Population• URCC CCOP

Research Base Study at 17 CCOP’s throughout the U.S.

• Accrual ranged from 1 to 110 at the sites

Central Illinois CCOP Gulf Coast MBCCOP North Shore University Hospital CCOP

Columbia River CCOP Hawaii MBCCOP Northwest CCOP

Columbus CCOP Hematology-Oncology of CNY CCOP Southeast Cancer Control Consortium

Dayton Clinical Oncology Program Kalamazoo CCOP University of Illinois at Chicago MBCCOP

Evanston CCOP Kansas City CCOP Upstate Carolina CCOP

Grand Rapids CCOP Marshfield Clinic Research Foundation CCOP Virginia Mason Research Center CCOP

Greenville CCOP Metro-Minnesota CCOP Wichita CCOP

Nevada Cancer Research Foundation CCOP

CCOPs

URCC

University of Rochester Cancer CenterCommunity Clinical Oncology Research Base

Map of Affiliates (2009)

Participant Flow

257 Randomized to Drug

253 Randomized to Control

N = 232 Analyzed N = 229 Analyzed

1 Ineligible

24 Did Not Complete Outcome Measures

510 Participants

24 Did Not Complete Outcome Measures

ResultsAUC for Pain was reduced from 7.7 (placebo group) to 6.0 (naproxen group)

p=0.037

Drug Placebo PPain 65.6% 76.3% 0.01Severe Pain 17.6% 24.5% 0.06

Incidence of Pain

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 African-Americans (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