Online Resource A: Study Methods
1.
Study Design and Data Sources
This study employed a retrospective cohort design and data from two large integrated US healthcare
claims repositories spanning the period from January 1, 2006 through December 31, 2013. The two
repositories—the Truven Health Analytics MarketScan® Commercial Claims and Encounters and
Medicare Supplemental and Coordination of Benefits Databases, and the IMS’ LifeLink™ PharMetrics
Health Plan Claims Database—both comprise medical (i.e., facility and professional service) and
outpatient pharmacy claims from a large number of participating health plans.
The MarketScan Database primarily includes information from employer-sponsored plans throughout
the US that provide health benefits to over 15 million persons annually, including employees, their
spouses, and their dependents, 10% of whom are aged 65 years or older. The LifeLink Database includes
information from over 75 US private health plans providing healthcare coverage to a geographicallydiverse population of over 15 million persons annually; 4% of plan members are aged65 years or older.
The data available from each facility and professional-service claim include dates and places of service,
diagnoses, procedures performed/services rendered, and quantity of services (professional-service
claims). The data available for each outpatient pharmacy claim include the drug dispensed, dispensing
date, quantity dispensed, and number of days supplied. Medical and pharmacy claims also include
amounts paid (i.e., reimbursed) by health plans and patients to healthcare providers for services
rendered. Selected demographic and eligibility information—including age, sex, geographic region of
residence, and dates of plan eligibility—also is available. All data in each database can be arrayed to
provide a detailed chronology of medical and pharmacy services used by each plan member over time.
The study databases were de-identified prior to their release to study investigators, as set forth in the
Data Use Agreements. The study databases have been evaluated and certified by independent third
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parties to be in compliance with the Health Insurance Portability and Accountability Act (HIPAA) of 1996
statistical de-identification standards and to satisfy the conditions set forth in Sections 164.514 (a)-(b)1ii
of the HIPAA Privacy Rule regarding the determination and documentation of statistically de-identified
data. Use of the study databases for health services research is therefore fully compliant with the HIPAA
Privacy Rule and federal guidance on Public Welfare and the Protection of Human Subjects.
2.
Patient Eligibility
The source population comprised all patients aged 18 years or older who, between July 1, 2006 and June
30, 2013, received a course of myelosuppressive chemotherapy of at least two cycles duration for a solid
tumor of interest or non-Hodgkin’s lymphoma (NHL). For each patient in the source population, the first
observed qualifying course of chemotherapy was identified, as was the first two cycles of chemotherapy
within that course. Only patients who received pegfilgrastim prophylaxis in the first cycle of their first
qualifying chemotherapy course were retained in the source population. Prophylactic use of
pegfilgrastim was defined as receipt 1-3 days following completion of myelosuppressive chemotherapy
administration in a given chemotherapy cycle, and was identified based on medical claims with
corresponding HCPCS Level II codes (C9119, S0135, J2505).
From the source population, all patients who did not receive pegfilgrastim prophylaxis in their second
cycle of chemotherapy (“comparison patients”) were matched to those who received it (“pegfilgrastim
patients”). Each matched set meeting the additional selection criteria (as set forth below) were included
in the study population.
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2.1.
Inclusion Criteria
Patients who satisfied the following criteria were eligible for inclusion in the source population:

Age ≥18 years;

Presence of a single primary solid tumor or NHL;

Initiation of a new course of chemotherapy with a regimen containing ≥1
myelosuppressive agent;

Chemotherapy course spanned at least two cycles and the same chemotherapy regimen
was administered in cycle 1 and cycle 2;

Receipt of prophylactic pegfilgrastim in the first cycle of their chemotherapy course; and

Continuous health benefits for ≥6 months prior to chemotherapy initiation.
2.1.1. Cancer Chemotherapy Patients
Evidence of primary solid tumors or NHL was identified by the presence of ≥1 inpatient claims or ≥2
outpatient claims (at least 7 days apart) with a qualifying 3-digit International Classification of Diseases
9th Edition Clinical Modification (ICD-9-CM) diagnosis code (see below). The claims had to occur during
the period beginning 30 days prior to the date of chemotherapy initiation and ending 30 days thereafter.
Receipt of chemotherapy was ascertained based on the presence of one or more encounters for a
chemotherapy drug or administration thereof, which was identified using Healthcare Procedural Coding
System (HCPCS), ICD-9-CM, and Uniform Bill-92 (UB-92) codes. Evidence of initiation of a new course of
chemotherapy was based on the earliest encounter for chemotherapy during the study period that was
preceded by a 60-day or longer period without any other encounter for chemotherapy.
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ICD-9-CM codes for primary cancers
Code
Description
140
Malignant neoplasm of of lip
141
Malignant neoplasm of of tongue
142
Malignant neoplasm of of major salivary glands
143
Malignant neoplasm of of gum
144
Malignant neoplasm of of floor of mouth
145
Malignant neoplasm of of other and unspecified parts of mouth
146
Malignant neoplasm of of oropharynx
147
Malignant neoplasm of of nasopharynx
148
Malignant neoplasm of hypopharynx
149
Malignant neoplasm of other and ill-defined sites within the lip, oral cavity, and pharynx
140-149
Lip, Oral Cavity, and Pharnyx
150
Malignant neoplasm of esophagus
151
Malignant neoplasm of stomach
152
Malignant neoplasm of small intestine, including duodenum
155
Malignant neoplasm of liver and intrahepatic bile ducts
156
Malignant neoplasm of gallbladder and extrahepatic bile ducts
157
Malignant neoplasm of pancreas
158
Malignant neoplasm of retroperitoneum and peritoneum
159
Malignant neoplasm of in the digestive organs and peritoneum
150-152, 155-159
Other Digestive Organs and Peritoneum (excluding colon and rectum)
153
Malignant neoplasm of colon
154
Malignant neoplasm of rectum, rectosigmoid junction, and anus
153-154
Colon and Rectum
160
Malignant neoplasm of nasal cavities, middle ear, and accessory sinuses
161
Malignant neoplasm of larynx
163
Malignant neoplasm of pleura
164
Malignant neoplasm of thymus, heart, and mediastinum
165
Malignant neoplasm of other and ill-defined sites within the respiratory system and intrathoracic organs
160-161, 163-165
Other Respiratory and Intrathoracic Organs (excluding trachea, bronchus, lung)
162
Trachea, Bronchus, and Lung
170
Malignant neoplasm of bone and articular cartilage
171
Malignant neoplasm of connective and other soft tissue
172
Malignant melanoma of skin
173
Other malignant neoplasm of skin
175
Malignant neoplasm of male breast
176
Kaposi's sarcoma
170-173, 175-176
Other Bone, Connective Tissue, Skin, Breast (excluding female breast)
174
Female Breast
179
Malignant neoplasm of uterus, part unspecified
180
Malignant neoplasm of cervix uteri
181
Malignant neoplasm of placenta
182
Malignant neoplasm of body of uterus
183
Malignant neoplasm of ovary and other uterine adnexa
184
Malignant neoplasm of other and unspecified female genital organs
186
Malignant neoplasm of testis
187
Malignant neoplasm of penis and other male genital organs
188
Malignant neoplasm of bladder
189
Malignant neoplasm of kidney and other and unspecified urinary organs
179-184, 186-189
Other Genitourinary Organs (excluding prostate)
185
Prostate
190
Malignant neoplasm of eye
191
Malignant neoplasm of brain
192
Malignant neoplasm of other and unspecified parts of the nervous system
193
Malignant neoplasm of thyroid gland
194
Malignant neoplasm of other endocrine glands and related structures
195
Other and ill-defined sites
190-195
Miscellaneous Other Sites
200
Lymphosarcoma and reticulosarcoma
202
Other malignant neoplasms of lymphoid and histiocytic tissue
200, 202
NHL
201
Hodgkin's Disease
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2.1.2. Chemotherapy Courses, Cycles, and Regimens
For each cancer chemotherapy patient, the first chemotherapy cycle (of the first course) was defined as
beginning with the date of initiation of chemotherapy and ending with the first service date for the next
administration of chemotherapy (as evidenced by an encounter with a corresponding HCPCS or ICD-9CM) occurring at least 7 days—but no more than 35 days—after the date of initiation of chemotherapy.
If a second chemotherapy cycle did not commence by day 35 the patient was excluded from
consideration. The second cycle of chemotherapy was similarly defined, except that the maximum cycle
duration was 60 days (to allow for full characterization of the consequence of FN). The chemotherapy
course, and the two cycles therein, were characterized based on observed patterns of administration
using information captured in claims—including corresponding procedure codes and dates of service—
as well as reference standards for the regimens and their patterns of use in clinical practice. Only
myelosuppressive chemotherapy agents were considered in characterizing courses and cycles therein.
Chemotherapy regimens were ascertained based on a review of all HCPCS Level II codes for parenterally
administered antineoplastic agents (myelosuppressive and non-myelosuppressive) on claims with
service dates within 6 days of the start of each cycle of chemotherapy. Regimens were categorized
based on the specific combination of agents received in the first cycle during the course as well the
duration of the first cycle (e.g., weekly [QW], once every two weeks [Q2W], once every three weeks
[Q3W], monthly [Q4W]).
2.1.3. Pegfilgrastim Prophylaxis
Prophylactic use of pegfilgrastim was defined as receipt 1-3 days following completion of
myelosuppressive chemotherapy administration in a given chemotherapy cycle, and was identified
based on medical claims with corresponding HCPCS Level II codes (C9119, S0135, J2505).
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*Schema is an exemplar of the characterization of chemotherapy courses/cycles/regimens, use of supportive care, and incidence of FN; study
subjects, including those who received pegfilgrastim prophylaxis in cycle 1, were stratified based on whether or not they received prophylaxis in
cycle 2, and outcomes (i.e., FN episodes) were identified from 4 days after completion of myelosuppressive chemotherapy to end of cycle 2
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2.2.
Exclusion Criteria
Patients were excluded from the source population if there was evidence of two or more primary
cancers (solid or blood) within (i.e., +/-) 30 days of their chemotherapy initiation date. However,
patients who had evidence of two (or more) primary cancers (e.g., breast cancer and lung cancer) and
evidence of metastatic disease to one (or more) of these sites (e.g., lung cancer) were classified as
having a single primary tumor, and were retained in the study population (the assumption in such cases
is that metastatic disease was mis-coded as a primary malignancy) (see below). Presence of metastasis
was identified on the basis of one or more ICD-9-CM 197-198 diagnosis codes on inpatient claims, or
two or more diagnosis codes on outpatient claims (excluding those for laboratory services), on different
days ≥7 days apart during the 12-month period prior to or within 30-days after chemotherapy initiation.
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Patients also were excluded from the source population if:

They had evidence of bone marrow or stem cell transplantation at anytime

They received radiation therapy during cycle 1 or cycle 2

They received filgrastim/tbo-filgrastim/sargramostim/pegfilgrastim as treatment, or
they experienced FN, in cycle 1

They had evidence of pegfilgrastim prophylaxis in cycle 1 or cycle 2 based on codes from
the NDC system (pharmacy claims include dispense date only and thus actual date of
administration is unknown)

They received pegfilgrastim on or before the last day of myelosuppressive
chemotherapy administration in cycle 2

They received filgrastim/tbo-filgrastim/sargramostim or antibiotic agents as prophylaxis
in either the first or second cycle (this exclusion criterion was used to avoid confounding
of study results from receipt of prophylactic agents other than pegfilgrastim)

The duration of the first cycle of chemotherapy was defined as weekly (i.e., QW)

There were any gaps in their eligibility for comprehensive medical and drug benefits
during the 6-month (“pretreatment”) period prior to initiation of chemotherapy.
Prophylactic use of filgrastim/tbo-filgrastim/sargramostim and antibiotic agents was defined as receipt
on or before the 3rd day following completion of myelosuppressive chemotherapy in a given
chemotherapy cycle. Treatment with filgrastim/tbo-filgrastim/sargramostim was defined as first receipt
(in a given cycle) anytime on or after the 4th day following completion of myelosuppressive
chemotherapy in a given cycle, or receipt following the end of prophylaxis (defined as a gap of >3 days in
administration of the daily CSF agents [filgrastim, tbo-filgrastim, and sargramostim] or from receipt of
pegfilgrastim). Use of oral antibiotic agents (i.e., as prophylaxis) was identified based on corresponding
drug codes from the NDC system that are present on pharmacy claims with dispense dates and precede
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evidence of infection (based on corresponding diagnosis codes) by at least two calendar days. Receipt of
filgrastim, tbo-filgrastim, and sargramostim was identified based on medical claims with appropriate
HCPCS codes (J1440/J1441, J1446, and J2820, respectively) and outpatient pharmacy claims with
corresponding NDC codes.
2.3.
Matching
Matching was implemented for each patient in the source population who did not receive second-cycle
pegfilgrastim prophylaxis by first identifying all “candidate” patients who received second-cycle
pegfilgrastim prophylaxis and had the same cancer type and chemotherapy regimen. From all such
candidates for each patient, the candidate with the closest propensity score to the comparison patient
was selected as the matched patient using a fixed 1:1 ratio and nearest neighbor approach.
Propensity scores for receipt of second-cycle pegfilgrastim prophylaxis were estimated using
multivariate logistic regression; independent variables included all patient, cancer, and treatment
characteristics described below. The study population was limited to patients who received selected
intermediate/high-risk regimens for certain tumor types and for which the number of patients who
discontinued pegfilgrastim prophylaxis in cycle 2 was ≥100.
2.4.
Qualifying Cancer and Chemotherapy Regimen Combinations
The study population was limited to patients who received selected intermediate/high-risk regimens for
certain tumor types and for which the number of patients who discontinued pegfilgrastim prophylaxis in
cycle 2 was ≥100 (see below). Patients with the selected cancer/regimen combination who may have
experienced a dose delay (based on first cycle duration > standard dosing periodicity) were excluded
from the study population.
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Intermediate/high-risk regimens for non-metastatic breast cancer, non-metastatic colorectal cancer, non-metastatic lung cancer, or NHL
Chemotherapy
Standard Dosing
Exclusion Criterion for
Regimen
Periodicity
First Cycle Duration
TC
Q3W
Q4W
TAC
Q3W
Q4W
TCH
Q3W
Q4W
AC and AC-T (Dose Dense)
Q2W
Q3W/Q4W
Non-Metastatic Colorectal Cancer
FOLFOX
Q2W
Q3W/Q4W
Non-Hodgkin's Lymphoma
CHOP
Q2W/Q3W
Q4W
CHOP-R
Q2W/Q3W
Q4W
Non-Metastatic Lung Cancer
CAR+PAC
Q3W
Q4W
TC: docetaxel + cyclophosphamide; TAC: docetaxel + doxorubicin + cyclophosphamide; TCH: docetaxel + cyclophosphamide + trastuzumab;
AC and AC-T: doxorubicin + cyclophosphamide, with or without subsequent docetaxel or paclitaxel; FOLFOX: folinic acid + fluorouracil +
oxaliplatin; CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone with rituximab (R); CAR+PAC: carboplatin + paclitaxel; PEG:
pegfilgrastim; Q2W: once every two weeks; Q3W: once every three weeks; Q4W: once every four weeks
Primary Cancer
Non-Metastatic Breast Cancer
3.
FN Episodes
FN episodes were ascertained beginning four days after completion of myelosuppressive chemotherapy
administration in the second cycle of chemotherapy and ending on the last day of that cycle. FN
episodes requiring inpatient care were identified based on a hospital admission with a diagnosis—
principal or secondary—of neutropenia (ICD-9-CM 288.0), or fever (780.6), or infection (see below). FN
episodes requiring outpatient care only were identified based on an ambulatory encounter (e.g.,
physician’s office, emergency department, home) with a diagnosis of neutropenia, or fever, or infection
and—on the same date—a HCPCS Level I (i.e., CPT) code for IV administration of antimicrobial therapy.
Such encounters that preceded or followed an FN-related hospitalization during the same cycle of
chemotherapy were not considered as a separate outpatient episode (i.e., they were classified as part of
the episode of FN requiring inpatient care). An alternative (“narrow”) definition for FN comprising
inpatient encounters with a diagnosis (principal or secondary) of neutropenia, and outpatient
encounters with a diagnosis of neutropenia and evidence of IV antimicrobial therapy, also was
evaluated.
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Selected ICD-9-CM codes for bacterial and fungal infections
ICD-9-CM
ICD-9-CM
Code
Description
Code
Description
002
Typhoid/paratyphoid fever
562.13
Diverticulitis of colon with hemorrhage
003
Other salmonella infection
566
Abscess of the anal and rectal regions
004
Shigellosis
567
Peritonitis
008.0
Intestinal infections due to E. coli
569.5
Intestinal abscess
008.1
Intestinal infections due to Arizona group of paracolon bacilli
569.61
Infection of colostomy or enterostomy
008.2
Intestinal infections due to Aerobacter aerogenes
572.0
Abscess of liver
008.3
Intestinal infections due to Proteus (mirabilis) (morganii)
575.0
Acute cholecystitis
008.4
Intestinal infections due to unspecified bacteria
590
Kidney infection
008.5
Bacterial enteritis, unspecified
599.0
Urinary tract infection not otherwise specified
034
Streptococcal throat/scarlet fever
601
Prostatic inflammation
035
Erysipelas
675.1
Abscess of breast
036
Meningococcal infection
680
Carbuncle and Furuncle
038
039
Septicemia
Actinomycotic infections
681
Cellulitis, finger/toe
682
Other cellulitis or abscess
040
Other bacterial diseases
683
Acute lymphadenitis
041
Bacterial infection in other diseases not specified
685.0
Pilonidal cyst, with abscess
101
Vincent's angina
686
Other local skin infection
112.0
Candidiasis, of mouth
711.0
Pyogenic arthritis
112.4
Candidiasis, of lung
728.86
Necrotizing fasciitis
112.5
Candidiasis, disseminated
730
Osteomyelitis
112.8
Candidiasis, of other specified sites
785.4
Gangrene
114
Coccidioidomycosis
785.52
Septic shock
115
Histoplasmosis
790.7
Bacteremia
116
Blastomycotic infection
958.3
Posttraumatic wound infection, not elsewhere classified
117
Other mycoses
995.91
Sepsis
118
Opportunistic mycoses
995.92
Severe Sepsis
320
Bacterial meningitis
996.6
Infection or inflammation of device/graft
321.0
Cryptococcal meningitis
998.5
Postoperative infection
321.1
Meningitis in other fungal diseases
999.3
Infectious complication of medical care not otherwise classified
324
CNS abcess
360.0
Purulent endophthalmitis
376.0
Acute inflammation of orbit
380.14
Malignant otitis externa
383.0
Acute mastoiditis
420.99
Acute pericarditis due to other specified organisms
421
Acute or subacute endocarditis
461
Acute sinusitis
462
Acute pharyngitis
463
Acute tonsillitis
475
Peritonsillar abscess
481
Pneumococcal pneumonia
482
485
Other bacterial pneumonia
Bronchopneumonia with organism not otherwise specified
486
Pneumonia, organism not otherwise specified
491.21
Acute exacerbation of obstructive chronic bronchitis
494
Bronchiectasis
510
Empyema
513
Absess of lung and mediastinum
522.5
Periapical abscess without sinus
522.7
Periapical abscess with sinus
526.4
Inflammatory conditions of the jaw
527.3
Abscess of the salivary glands
528.3
Cellulitis and abscess of oral soft tissue
540
Acute appendicitis
541
Appendicitis not otherwise specified
542
Other appendicitis
562.01
Diverticulitis of the small intestine without hemorrhage
562.03
Diverticulitis of the small intestine with hemorrhage
562.11
Diverticulitis of colon without hemorrhage
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4.
Characterization of Other Variables
Characteristics described below represent many of those listed by NCCN as important risk factors for FN.
Demographic characteristics were available for nearly all study subjects. All other characteristics were
defined based on the presence of specific data (e.g., diagnosis codes, procedure codes); the absence of
such data was assumed to indicate the absence of the characteristic captured by the variable.
Patient, cancer, and treatment characteristics included: age; sex; presence of selected chronic
comorbidities (cardiovascular disease, diabetes, liver disease, lung disease, renal disease, osteoarthritis,
rheumatoid disease, thyroid disorder); body weight/nutritional status (obesity, underweight,
malnutrition); proxies for health status (hospice/skilled nursing facility [SNF] care) and physical function
(use of hospital bed, supplemental oxygen, walking aid, wheelchair); use of immunosuppressive therapy;
history of blood disorders (anemia, neutropenia, other), infection, recent surgery, hospitalization (allcause and FN-related, respectively), chemotherapy, and radiation therapy; total healthcare expenditures
in the baseline period; presence of metastatic disease; and calendar year of chemotherapy initiation.
Age was assessed as of the first day of the first cycle of chemotherapy in the course. All of other risk
factors (except for recent surgery) were assessed during the 12-month period prior to the first day of
the chemotherapy course; recent surgery was assessed during the 90-day prechemotherapy period.
Chronic comorbidities were identified on the basis of ≥1 diagnosis codes on inpatient claims, ≥2
diagnosis codes on outpatient claims (excluding those for laboratory services) on different days, ≥1
procedure codes, and ≥1 drug codes, as appropriate. Blood disorders and infections were identified on
the basis of ≥1 diagnosis codes (on inpatient and/or outpatient claims) and ≥1 drug codes, as
appropriate. Hospitalizations were identified using acute-care facility inpatient claims; FN-related
hospitalizations were identified using diagnosis codes—principal or secondary—for neutropenia (ICD-9CM 288.0), or fever (780.6), or infection. Diagnosis and procedure codes that were used to identify
selected patient, cancer, and treatment characteristics are available from the authors upon request.
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Online Resource B: Additional Study Results
Numbers of patients qualifying for inclusion in the source and study populations
Total Population
n (%)
Source Population
Inclusion Criteria:
Aged >=18 years with >=1 claims for chemotherapy from 07/2006 - 06/2013
1,427,976 (100.0)
plus no chemotherapy claims during 60-day period before initial chemotherapy claim from 07/2006 - 06/2013
1,352,964 (94.7)
plus health benefits during 6-month period prior to chemotherapy
1,039,141 (72.8)
plus >=2 claims with a diagnosis of >1 solid/blood cancer
822,391 (57.6)
plus >=2 claims with a diagnosis of >=1 primary solid or blood cancer
669,409 (46.9)
plus >=1 medical claims for myelosuppressive chemotherapy agents in cycle 1
414,732 (29.0)
plus chemotherapy course spanned >=2 cycles
366,593 (25.7)
plus receipt of pegfilgrastim prophylaxis based on HCPCS Level II codes in cycle 1
87,898 (6.2)
Exclusion Criteria:
Evidence of bone marrow or stem cell transplant prior to or during chemotherapy
87,898 (6.2)
Evidence of radiation therapy in cycle 1 or cycle 2
84,466 (5.9)
Evidence of CSF reactive treatment or febrile neutropenia in cycle 1
79,900 (5.6)
Evidence of pegfilgrastim prophylaxis based on NDC codes in cycles 1 or 2
78,696 (5.5)
Evidence of pegfilgrastim on or before the last day of myelosuppressive chemotherapy in cycle 2
77,420 (5.4)
Evidence of filgrastim/sargramostim/antimicrobial prophylaxis in cycle 1 or cycle 2
69,633 (4.9)
Evidence of Chemotherapy in cycle 1 spanned > 35 days
69,180 (4.8)
Periodicity of cycle 1 = QW
68,442 (4.8)
Study Population
All Patients with Cancer/Regimen Combinations of Interest
42,314
Receipt of pegfilgrastim prophylaxis in cycle 1 only
2,245
% of patients who received pegfilgrastim prophylaxis in cycle 1 only
5.3%
Receipt of pegfilgrastim prophylaxis in cycles 1 and 2
All patients
40,069
Matched patients
2,245
Non-Metastatic Breast Cancer / TC
10,842
Receipt of pegfilgrastim prophylaxis in cycle 1 only
870
% of patients who received pegfilgrastim prophylaxis in cycle 1 only
8.0%
Receipt of pegfilgrastim prophylaxis in cycles 1 and 2
All patients
9,972
Matched patients
870
Non-Metastatic Breast Cancer / TAC
3,911
Receipt of pegfilgrastim prophylaxis in cycle 1 only
110
% of patients who received pegfilgrastim prophylaxis in cycle 1 only
2.8%
Receipt of pegfilgrastim prophylaxis in cycles 1 and 2
All patients
3,801
Matched patients
110
Non-Metastatic Breast Cancer / TCH
4,147
Receipt of pegfilgrastim prophylaxis in cycle 1 only
243
% of patients who received pegfilgrastim prophylaxis in cycle 1 only
5.9%
Receipt of pegfilgrastim prophylaxis in cycles 1 and 2
All patients
3,904
Matched patients
243
Non-Metastatic Breast Cancer / AC and AC-T (Dose Dense)
15,539
Receipt of pegfilgrastim prophylaxis in cycle 1 only
534
% of patients who received pegfilgrastim prophylaxis in cycle 1 only
3.4%
Receipt of pegfilgrastim prophylaxis in cycles 1 and 2
All patients
15,005
Matched patients
534
Non-Metastatic Colorectal Cancer / FOLFOX
1,472
Receipt of pegfilgrastim prophylaxis in cycle 1 only
175
% of patients who received pegfilgrastim prophylaxis in cycle 1 only
11.9%
Receipt of pegfilgrastim prophylaxis in cycles 1 and 2
All patients
1,297
Matched patients
175
Non-Hodgkin's Lymphoma / CHOP and CHOP-R
4,891
Receipt of pegfilgrastim prophylaxis in cycle 1 only
169
% of patients who received pegfilgrastim prophylaxis in cycle 1 only
3.5%
Receipt of pegfilgrastim prophylaxis in cycles 1 and 2
All patients
4,722
Matched patients
169
Non-Metastatic Lung Cancer / CAR+PAC
1,512
Receipt of pegfilgrastim prophylaxis in cycle 1 only
144
% of patients who received pegfilgrastim prophylaxis in cycle 1 only
9.5%
Receipt of pegfilgrastim prophylaxis in cycles 1 and 2
All patients
1,368
Matched patients
144
TC: docetaxel + cyclophosphamide; TAC: docetaxel + doxorubicin + cyclophosphamide; TCH: docetaxel + cyclophosphamide + trastuzumab; AC and AC-T: doxorubicin + cyclophosphamide, with or without
subsequent docetaxel or paclitaxel; FOLFOX: folinic acid + fluorouracil + oxaliplatin; CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone with rituximab (R); CAR+PAC: carboplatin + paclitaxel;
QW: once every week; Q2W: once every two weeks; Q3W: once every three weeks; Q4W: once every four weeks
Inclusion/Exclusion Criteria
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Characteristics of patients who received pegfilgrastim prophylaxis in cycle 1 only and patients who received pegfilgrastim prophylaxis in cycle 1 and cycle 2 (matched and all patients) within each cancer/regimen-specific subgroup
Non-Met. Breast Cancer /
TC
PEG in Cycles 1 and 2
Matched
All
(n=870)
(n=9,972)
PEG in
Cycle 1 Only
(n=870)
Patient
Age (years)
Mean (SD)
Male, %
Chronic Comorbidities, %
Cardiovascular Disease
Liver Disease
Lung Disease
Renal Disease
Osteoarthritis
Rheumatoid Disease
Thyroid Disorder
Body Weight and Nutritional Status, %
Obese
Underweight
Malnutrition
Proxies for Health Status, %
Hospice Care
SNF
Hospice or SNF
Proxies for Physical Function, %
Use of Hospital Bed
Use of Supplemental Oxygen
Use of Walking Aid
Use of Wheel Chair
Any of Above
Use of Immunosuppressive Drugs, %
History of Other Conditions/Events, %
Anemia
Neutropenia
Other Blood Disorders
Infection
Recent Surgery (prior 90 days)
History of Hospitalization for Any Reason
History of Chemotherapy
History of Radiation Therapy
Pre-Chemotherapy Expenditures ($), mean±SD
Non-Met. Breast Cancer /
TAC
PEG in Cycles 1 and 2
Matched
All
(n=110)
(n=3,801)
PEG in
Cycle 1 Only
(n=110)
Non-Met. Breast Cancer /
TCH
PEG in Cycles 1 and 2
Matched
All
(n=243)
(n=3,904)
PEG in
Cycle 1 Only
(n=243)
Non-Met. Breast Cancer /
AC and AC-T (Dose Dense)
PEG in
PEG in Cycles 1 and 2
Cycle 1 Only
Matched
All
(n=534)
(n=534)
(n=15,005)
Non-Met. Colorectal Cancer /
FOLFOX
PEG in Cycles 1 and 2
Matched
All
(n=175)
(n=1,297)
PEG in
Cycle 1 Only
(n=175)
59.1 (10.5) 58.4 (10.8)
59.4
54.2
Non-Hodgkin's Lymphoma /
CHOP and CHOP-R
PEG in
PEG in Cycles 1 and 2
Cycle 1 Only
Matched
All
(n=169)
(n=169)
(n=4,722)
55.1 (10.0)
0.0
55.4 (9.8)
0.0
56.1 (9.7)*
0.0
50.9 (9.5)
0.0
50.0 (9.1)
0.0
51.2 (9.2)
0.0
53.2 (9.7)
0.0
53.2 (9.9)
0.0
54.1 (10.1)
0.0
51.3 (9.4)
0.0
50.8 (9.4)
0.0
51.7 (9.4)
0.0
59.3 (11.7)
56.0
60.5 (12.1)
54.4
59.4 (12.2) 60.2 (13.0)
59.8
56.7
40.6
1.7
2.3
1.7
6.3
0.7
14.0
37.9
2.3
2.3
1.6
6.2
0.6
14.5
40.2
2.0
2.3
1.2
7.4
1.1
13.3
45.5
3.6
1.8
0.9
0.9
0.0
11.8
51.8*
7.3*
2.7
1.8
0.9
0.0
16.4*
58.6*
2.0
1.0
0.6
4.4
0.7
10.7
53.5
0.8
1.6
1.6
5.8
0.8
17.7
53.9
0.8
1.2
2.5
5.8
1.2
17.7
57.3
2.6
1.7
0.9
6.5
1.0
12.0*
47.9
3.2
0.7
0.7
6.7
0.7
9.4
47.9
3.7
0.4
0.7
6.6
0.6
10.9
53.7*
2.1
1.2
0.7
5.2
0.8
11.0
77.1
8.6
7.4
5.7
6.9
2.9
9.7
76.6
8.0
7.4
2.9*
8.6
2.3
10.3
79.3
8.6
5.5
3.3
6.1
0.4*
8.6
49.7
8.3
5.3
4.7
8.9
3.6
10.1
42.0*
7.7
8.9*
2.4*
9.5
5.3
12.4
5.1
0.2
0.3
4.4
0.2
0.1
5.0
0.1*
0.2
4.5
0.0
0.9
2.7
0.0
0.9
4.8
0.0
0.1*
2.9
0.0
0.0
3.3
0.0
0.0
4.0
0.0
0.1
3.6
0.0
0.0
3.0
0.0
0.0
3.8
0.0
0.1
8.0
0.0
2.9
5.7
0.0
1.7
7.3
0.0
3.5
4.7
0.0
0.6
0.3
0.5
0.8
0.5
0.3
0.8
0.3
0.6
0.9
0.9
0.9
1.8
0.9
0.0*
0.9
0.4
0.2
0.6
0.0
0.0
0.0
0.0
0.0
0.0
0.4
0.3
0.7
0.0
0.2
0.2
0.0
0.2
0.2
0.3
0.2
0.5
0.0
0.6
0.6
0.0
0.6
0.6
0.0
1.4
1.4
0.1
1.8
1.0
0.3
3.0
4.5
0.2
1.8
0.8
0.1
3.0
3.0
0.2
2.3
1.0
0.2
3.5
5.0
0.0
0.9
0.9
0.0
1.8
7.3
0.0
0.0*
0.0*
0.0
0.0*
11.8*
0.1
1.5
0.7
0.2
2.3
6.1
0.0
1.6
1.6
0.0
3.3
5.8
0.0
1.6
1.6
0.0
2.9
7.8
0.2
1.6
0.9
0.1
2.6
7.1
0.0
1.1
1.3
0.2
2.6
1.9
0.0
0.9
1.3
0.2
2.2
1.7
0.1
1.3
0.8
0.2
2.2
3.3
0.6
1.1
3.4
0.6
5.1
1.7
2.3*
1.7
4.6
0.6
7.4
1.7
11.3
4.0
4.1
32.5
86.7
32.4
0.0
5.9
34,126
(25,548)
12.5
3.7
3.9
31.5
85.5
29.7
0.0
6.4
33,948
(26,256)
12.1
5.5
3.5
31.2
88.3
31.7
0.0
8.0*
33,819
(25,471)
9.1
3.6
3.6
27.3
60.9
26.4
0.0
0.9
27,546
(20,535)
6.4*
5.5
4.5
26.4
63.6
23.6
0.0
0.0*
27,027
(18,024)
11.5
4.1
3.2
29.3
66.5
30.1
0.2
2.1
29,687
(20,037)
11.5
4.1
2.1
31.7
67.1
30.0
0.0
1.2
31,394
(20,999)
11.5
3.7
0.0*
31.3
67.1
27.6
0.0
1.6
31,333
(20,634)
11.4
5.1
3.9
29.8
71.1
29.0
0.1
4.6*
32,762
(22,813)
9.4
6.9
3.7
32.2
65.5
33.5
0.0
1.3
31,232
(21,371)
9.0
5.1
2.8
32.2
65.9
33.7
0.0
0.6
30,187
(18,225)
10.4
4.5*
3.9
28.8
69.2
31.4
0.0
2.1
31,177
(21,365)
46.9
7.4
6.3
40.0
89.1
91.4
0.6
5.1
44,724
(32,169)
42.9
7.4
6.3
44.6
91.4
93.7
0.0
4.6
47,860
(39,516)
Non-Met. Lung Cancer /
CAR+PAC
PEG in Cycles 1 and 2
Matched
All
(n=144)
(n=1,368)
PEG in
Cycle 1 Only
(n=144)
65.7 (9.7)
53.5
66.2 (9.7)
50.7
64.7 (9.3)
57.1
52.5
7.0
5.1
4.6
10.1
1.9
11.5
64.6
4.9
43.8
4.2
6.9
0.0
6.3
68.8
5.6
45.1
4.2
6.9
0.0
6.9
70.8
5.0
46.1
4.2
9.8
1.8
7.5
6.5
0.0
0.0*
4.0
0.0
2.2
2.8
0.0
0.0
2.8
0.0
0.0
2.9
0.2
0.8
0.6
1.8
2.4
0.0*
3.0
3.0
0.2
1.8
1.9
0.0
2.8
2.8
0.0
4.2
4.2
0.1
1.4
1.5
0.6
2.9
3.0
0.6
6.2
1.9
0.6
1.2
2.4
0.6
4.1
4.7
0.6
0.0*
3.6
1.2
4.7
0.6*
0.6
4.2
2.8
1.0
7.5
6.6
0.0
18.8
2.8
0.7
21.5
6.3
0.0
21.5
1.4
0.7
22.9
4.2
0.5
16.6
3.2
0.4
19.4
5.9
49.0
9.2
5.2
42.4
86.4
89.5
1.4
8.6
48,538
(42,667)
24.9
18.3
30.2
41.4
15.4
34.9
0.6
3.0
43,565
(74,707)
29.0
21.3
24.9*
40.8
16.0
36.7
0.0
1.8
41,613
(47,509)
30.1
18.2
21.9*
44.7
14.2
40.4
0.2
1.9
34,444
(31,329)*
22.2
6.3
4.9
58.3
25.0
52.8
0.0
6.9
28,806
(20,144)
26.4
8.3
1.4*
58.3
24.3
54.9
0.0
13.2*
30,247
(24,306)
18.2
7.7
5.5
56.4
32.7
56.9
1.0
6.9
36,891
(33,459)*
Chemotherapy and Supportive Care
Number of Myelosuppressive Drugs, %
1
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
2
100.0
100.0
100.0
0.0
0.0
0.0
0.0
0.0
0.0
100.0
100.0
100.0
100.0
100.0
100.0
0.0
0.0
0.0
100.0
100.0
100.0
>=3
0.0
0.0
0.0
100.0
100.0
100.0
100.0
100.0
100.0
0.0
0.0
0.0
0.0
0.0
0.0
100.0
100.0
100.0
0.0
0.0
0.0
Year of Chemotherapy, %
2006-2008
27.8
28.4
20.5*
46.4
36.4*
37.2
15.6
19.8*
13.9*
32.8
35.0
31.9
34.3
37.7
34.5
36.1
35.5
28.7*
38.9
43.1
45.0
2009-2010
36.9
35.7
33.9*
25.5
36.4*
31.9
39.5
32.9*
32.6*
31.6
30.0
28.1
28.0
25.7
29.8
34.9
35.5
31.5*
32.6
32.6
27.9
2011-2013
35.3
35.9
45.6*
28.2
27.3
30.9
44.9
47.3
53.5*
35.6
35.0
40.1
37.7
36.6
35.7
29.0
29.0
39.8*
28.5
24.3
27.0
Day of Pegfilgrastim Prophylaxis
Cycle 1
Day +1
84.1
87.4
88.0*
87.3
89.1
86.9
82.7
88.9*
86.7
86.9
90.8*
91.7*
6.3
8.6
4.6
76.9
85.2*
83.0
78.5
82.6*
82.5
Day +2
6.7
4.8
5.1*
5.5
2.7*
4.4
7.4
4.1*
5.9
7.5
3.7*
4.1*
66.9
66.9
68.4
11.8
6.5*
8.9
11.8
9.0
8.6
Day +3
9.2
7.8
7.0*
7.3
8.2
8.7
9.9
7.0*
7.3
5.6
5.4
4.3*
26.9
24.6
27.0
11.2
8.3
8.2
9.7
8.3
9.0
Cycle 2
Day +1
—
87.9*
88.4
—
88.2*
88.8
—
86.9*
87.9
—
90.0*
92.0
—
5.8*
4.4
—
88.6*
86.2
—
88.6*
87.4
Day +2
—
4.9*
5.5
—
5.5*
4.5
—
5.9*
5.8
—
5.3*
4.5
—
71.1*
69.5
—
6.0*
7.8
—
7.9*
6.9
Day +3
—
7.2*
6.1
—
6.4*
6.7
—
7.2*
6.3
—
4.7*
3.5
—
23.1*
26.1
—
5.4*
6.1
—
3.6*
5.7
Met: metastatic; TC: docetaxel + cyclophosphamide; TAC: docetaxel + doxorubicin + cyclophosphamide; TCH: docetaxel + cyclophosphamide + trastuzumab; AC and AC-T: doxorubicin + cyclophosphamide, with or without subsequent docetaxel or paclitaxel; FOLFOX: folinic acid + fluorouracil + oxaliplatin; CHOP: cyclophosphamide + doxorubicin +
vincristine + prednisone with rituximab (R); CAR+PAC: carboplatin + paclitaxel; PEG: pegfilgrastim
*Standard difference >=0.1 (matched comparison), assumed to represent non-negligible difference; p-value <0.05 (unmatched comparison)
-15-
Odds ratios for febrile neutropenia during second cycle of chemotherapy among patients who received pegfilgrastim prophylaxis in cycle 1 only versus patients who received pegfilgrastim prophylaxis in cycle 1 and cycle 2, for
cancer/regimen-specific subgroups of interest (alternative propensity-score matching using 1:3 ratio, sequential approach)
FN — Broad Definition*, Inpatient+Outpatient
FN — Broad Definition*, Inpatient Only
FN — Narrow Definition**, Inpatient+Outpatient
n (%)
OR (95% CI)
p-value
n (%)
OR (95% CI)
p-value
n (%)
OR (95% CI)
p-value
All Cancer Types
PEG in Cycle 1 Only (n=2,245)
86 (3.8)
2.0 (1.5-2.7)
72 (3.2)
2.1 (1.5-2.9)
58 (2.6)
3.7 (2.5-5.5)
<0.001
<0.001
<0.001
PEG in Cycles 1 and 2 -- Matched (n=6,735)
132 (2.0)
104 (1.5)
48 (0.7)
Non-Metastatic Breast Cancer
TC
PEG in Cycle 1 Only (n=870)
33 (3.8)
2.4 (1.5-3.9)
27 (3.1)
3.1 (1.8-5.3)
27 (3.1)
8.3 (4.0-17.3)
<0.001
<0.001
<0.001
PEG in Cycles 1 and 2 -- Matched (n=2,610)
42 (1.6)
27 (1.0)
10 (0.4)
TAC
PEG in Cycle 1 Only (n=110)
5 (4.5)
7.8 (1.5-41.1)
4 (3.6)
--5 (4.5)
--0.015
PEG in Cycles 1 and 2 -- Matched (n=330)
2 (0.6)
0 (0.0)
0 (0.0)
TCH
PEG in Cycle 1 Only (n=243)
10 (4.1)
3.4 (1.3-9.1)
7 (2.9)
2.7 (0.9-7.5)
6 (2.5)
18.4 (2.2-154.7)
0.013
0.063
0.007
PEG in Cycles 1 and 2 -- Matched (n=729)
9 (1.2)
8 (1.1)
1 (0.1)
AC and AC-T (Dose Dense)
PEG in Cycle 1 Only (n=534)
17 (3.2)
1.4 (0.8-2.5)
14 (2.6)
1.3 (0.7-2.5)
12 (2.2)
1.5 (0.7-3.1)
0.254
0.385
0.252
PEG in Cycles 1 and 2 -- Matched (n=1,602)
37 (2.3)
32 (2.0)
24 (1.5)
Non-Metastatic Colorectal Cancer - FOLFOX
PEG in Cycle 1 Only (n=175)
4 (2.3)
2.4 (0.6-9.1)
3 (1.7)
1.8 (0.4-7.6)
1 (0.6)
3.0 (0.2-48.4)
0.187
0.417
0.436
PEG in Cycles 1 and 2 -- Matched (n=525)
5 (1.0)
5 (1.0)
1 (0.2)
Non-Hodgkin's Lymphoma- CHOP and CHOP-R
PEG in Cycle 1 Only (n=169)
11 (6.5)
1.6 (0.8-3.3)
11 (6.5)
2.0 (1.0-4.2)
5 (3.0)
1.4 (0.5-4.1)
0.198
0.062
0.565
PEG in Cycles 1 and 2 -- Matched (n=507)
21 (4.1)
17 (3.4)
11 (2.2)
Non-Metastatic Lung Cancer - CAR+PAC
PEG in Cycle 1 Only (n=144)
6 (4.2)
1.1 (0.4-2.9)
6 (4.2)
1.2 (0.5-3.1)
2 (1.4)
6.1 (0.5-68.1)
0.798
0.689
0.144
PEG in Cycles 1 and 2 -- Matched (n=432)
16 (3.7)
15 (3.5)
1 (0.2)
OR: odds ratio; CI: confidence interval; PEG: pegfilgrastim; TC: docetaxel + cyclophosphamide; TAC: docetaxel + doxorubicin + cyclophosphamide; TCH: docetaxel + cyclophosphamide + trastuzumab; AC and AC-T: doxorubicin +
cyclophosphamide, with or without subsequent docetaxel or paclitaxel; FOLFOX: folinic acid + fluorouracil + oxaliplatin; CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone with rituximab (R); CAR+PAC: carboplatin +
paclitaxel
*Admission to hospital with a diagnosis of neutropenia, infection, or fever, or outpatient encounter with such a diagnosis and IV antimicrobial therapy;
**Admission to hospital with a diagnosis of neutropenia, or outpatient encounter with such a diagnosis and IV antimicrobial therapy
-16-