Colony-Stimulating Factor Prescribing Patterns in Patients Receiving Chemotherapy for Cancer

Objective: To examine variables influencing colony-stimulating factor (CSF) prescription as primary prophylaxis versus other use during patients' initial chemotherapy course among a large sample of health insurance records.

Study Design: Retrospective cohort study.

Methods: Adults 25 years or older with a diagnosis of breast, colorectal, or non-small cell lung cancer (NSCLC) between January 1, 2002, and December 31, 2005, were identified from the western Washington State Surveillance, Epidemiology, and End Results Seattle Puget Sound registry. We linked these records to health insurance claims. Chemotherapy regimens identified from insurance claims were categorized as carrying high, intermediate, or low risk of myelosuppression according to the National Comprehensive Cancer Network guidelines and the literature. Colony-stimulating factor use was described as primary prophylaxis, other use, or no use, and logistic regression analysis identified factors associated with CSF use.

Results: For patients with breast cancer, colorectal cancer, and NSCLC, respectively, 58%, 0%, and 28% received CSFs as primary prophylaxis in conjunction with high-risk chemotherapy regimens, whereas 10%, 7%, and 21% did so in conjunction with low-risk chemotherapy regimens. Prophylactic CSF use increased from 2002 to 2005 for breast cancer but remained constant for colorectal cancer and for NSCLC.

Conclusions: As primary prophylaxis, CSF use is underutilized based on recommendations for patients having cancer who receive chemotherapy regimens carrying high febrile neutropenia risk and may be overutilized for patients who receive chemotherapy regimens carrying low febrile neutropenia risk. Further research is needed to understand the barriers to implementing guidelines in clinical practice.

(Am J Manag Care. 2010;16(9):678-686)Based on practice guidelines, colony-stimulating factors (CSFs) are underutilized for primary prophylaxis and are overprescribed in settings where they offer little or no clinical benefit.

• Prophylactic CSF use has increased among patients with breast cancer but has remained constant among patients with colorectal and lung cancer.

• On average, less than 50% of patients with breast, colorectal, or non-small cell lung cancer received CSFs as primary prophylaxis in conjunction with chemotherapy regimens carrying high risk for febrile neutropenia.

• Up to 21% of patients received CSFs alongside chemotherapy regimens that pose little or no risk for febrile neutropenia.

Febrile neutropenia (FN) is a common and serious complication of cytotoxic chemotherapy. Clinical practice guidelines¹ recommend the use of colony-stimulating factors (CSFs) in the first chemotherapy cycle as primary prophylaxis to lessen chemotherapy- induced FN incidence when the expected risk of FN is approximately 20% or higher.^2,3 Individuals who experience FN are at risk for hospitalization^4-6 and death due to infection.⁷

In clinical trials, prophylactic treatment of patients with CSFs at the start of the initial chemotherapy cycle can reduce FN incidence by as much as 50%.^2,3,8-12 American Society for Clinical Oncology,¹ National Comprehensive Cancer Network (NCCN),¹³ and European Organisation for Research and Treatment of Cancer¹⁴ guidelines recommend the use of CSFs as primary prophylaxis when the anticipated incidence of FN associated with a chemotherapy regimen is approximately 20% or higher (high risk) or 10% to 20% (intermediate risk) if patient risk factors could contribute to greater risk of FN. Routine CSF use is not recommended when the risk of FN associated with chemotherapy is less than 10%, nor is it recommended to treat FN or severe neutropenia.^1,13,14

Although these guidelines have existed for years, surveys suggest that physicians commonly prescribe CSFs for indications that are not supported by evidence or guidelines.^15,16 No study to date has characterized the spectrum of CSF use among large populations of patients with cancer treated in community practice settings.

Using claims data from 4 large health insurance plans linked to cancer registry data, we evaluated patterns of CSF use among patients with breast cancer, colorectal cancer, or non—small cell lung cancer (NSCLC) who received myelosuppressive chemotherapy. We examined variables influencing use proximal to the initiation of chemotherapy to identify predictors of CSF prescription as primary prophylaxis versus other use.

METHODS

Databases Used

Patient-level data obtained from the western Washington State Surveillance, Epidemiology, and End Results (SEER) Seattle—Puget Sound registry were merged with healthcare claims data from 4 major insurers. These included Medicare, Medicaid, Premera Blue Cross, and Regence Blue Shield.

The SEER Seattle—Puget Sound registry was established in 1974 under contract with the federal SEER program. The registry provides data on the incidence, tumor characteristics, diagnosis stage, initial treatment, and survival of all newly diagnosed cancers (except nonmelanoma skin cancers) occurring in residents of 13 counties in western Washington State.¹⁷

Premera Blue Cross and Regence Blue Shield are 2 of the largest private health insurers in Washington State. Both are nonprofit, and Premera Blue Cross serves more than 1.4 million members in Washington State,¹⁸ while Regence Blue Shield provides coverage to more than 1 million Washington State residents.19

The Medicaid program provides health insurance for approximately 420,000 low-income residents in Washington State. The program operates under the auspices of the Washington State Department of Social and Health Services and the Health Recovery Services Administration.²⁰

The Medicare program,21 administered by the Centers for Medicare and Medicaid Services, provides coverage for persons 65 years or older, persons younger than 65 years with certain disabilities, and persons of all ages with end-stage renal disease. Medicare is composed of Part A (inpatient hospital care) and Part B (outpatient care and physician services).

The 4 health insurance databases used for this study include approximately 3.7 million Washington State residents. These residents represented more than 75% of the state’s population in 2005.

The study was approved by the appropriate institutional review boards. A waiver of consent was obtained for access to each database before linkage was performed.

Study Population

To identify subjects with incident cancers in the 4 health plans, we cross-linked person-level identifiers (ie, full name, sex, date of birth, zip code) from each plan’s enrollment files with cancer cases identified in the SEER Seattle—Puget Sound registry. Other inclusion criteria were age 25 years or older at the time of diagnosis, at least 1 health insurance claim for cancer chemotherapy, and diagnosis date between January 1, 2002, and December 31, 2005. Patients were excluded if they had any other malignant neoplasm previously recorded in SEER (including a diagnosis of breast cancer, colorectal cancer, or NSCLC before January 1, 2002) or had incomplete claims records over the period of interest. We excluded male patients with breast cancer from the study. Claims were collected until 12 months after diagnosis or until date of death.

Chemotherapy Use, CSF Use, and FN Event Identification

The study focus was to determine CSF use in primary prophylaxis versus other settings relative to the FN risk of each patient’s initial chemotherapy regimen. Colony-stimulating factors were defined as filgrastim or pegfilgrastim. Although sargramostim may be used in some settings for chemotherapyinduced neutropenia,²² it was excluded from analysis, as this use is not approved by the US Food and Drug Administration. We defined CSF administration as primary prophylaxis or as other use based on the date of CSF administration relative to the first date of chemotherapy administration.

When used as primary prophylaxis, CSFs should be administered 24 to 72 hours after chemotherapy administration.¹³ We extended this time range to account for potential coding misspecifications of administration date and to consider the common practice of giving patients CSFs to take home and self-administer following chemotherapy initiation. Therefore, we defined primary prophylaxis as CSF use at the first chemotherapy treatment, specifically 1 day before through 7 days after the first chemotherapy administration date. Other CSF use was defined as any use in other settings (eg, following an FN event).

Using insurance claims, we identified the initial chemotherapy agents administered, the dates each agent was started and stopped, the initial CSF use date, and FN events. Patients were grouped into categories based on the myelosuppressive risk of the chemotherapy regimen. We developed an algorithm to identify commonly used chemotherapy regimens. The algorithm, summarized in eAppendix A (available at www.ajmc.com), considers the chemotherapy regimen administered and the timing relative to the diagnosis dateand to other prescribed agents. The myelosuppressive risk of each chemotherapy regimen (the risk of developing FN in the absence of CSF administration) was assigned based on the high-, intermediate-, and low-risk categories published by the NCCN23 during the same period as the study population’s diagnoses (2001-2005). In cases where a regimen was not categorized by the NCCN, a board-certified oncology phar-macist (JSM) assigned the regimen to a risk category based on FN incidence descriptions from the published literature. The chemotherapy risk categorizations are listed in eAppendix B, available at www.ajmc.com.

Claims records were used to determine chemotherapy onset. To allow for lags in claims recording, records were searched from the initial administration date of the first chemotherapy agent to 14 days past the last date when a chemotherapy agent from the initial regimen appeared in the patient’s claims. If a different chemotherapy agent appeared during the 14-day window, then a new chemotherapy regimen was considered to have been initiated if at least 3 claims of the original chemotherapy agent had appeared or 2 expected cyclical time gaps had occurred since the first administration of the initial chemotherapy regimen (eAppendix A).

Data Analysis

We used logistic regression analysis to identify factors associated with CSF use, which was categorized as primary prophylaxis, other use, or no use. The cohort was stratified into groups of high, intermediate, and low risk of FN before running the regression analysis. Independent variables included age, sex (for colorectal cancer and NSCLC), race/ethnicity, health insurance plan, cancer site, stage at diagnosis, noncancer comorbidity in the 12 months before diagnosis, and receipt of surgery or radiation therapy within 30 days of initial chemotherapy administration. Health insurance plan was grouped as Medicare, Medicaid, or commercial (Regence Blue Shield and Premera Blue Cross combined). Persons enrolled in more than 1 health plan were assigned to the plan containing most claims over the period of observation. We included all claims from both plans for dually enrolled persons.

RESULTS

Among 8354 patients with breast cancer, colorectal cancer, or NSCLC, 2728 patients were identified as having received chemotherapy during the study period. Table 1 lists the characteristics of these individuals. Most initial chemotherapy regimens administered to patients with breast cancer were categorized as high FN risk (74% across health plans), whereas most chemotherapy regimens administered to patients with NSCLC and colorectal cancer were characterized as low FN risk (59% and 77%, respectively). Patients with NSCLC were older and had the highest proportion of individuals diagnosed at the most advanced stage (62% across health plans), whereas most patients with breast and colorectal cancer were diagnosed at the regional stage (56% and 59%, respectively). Patients with NSCLC had the highest mean comorbidity ratings among the 3 cancer groups.

Comparing health plans, a higher proportion of Medicaid patients were diagnosed as having distant-stage disease than those enrolled in Medicare or with the commercial insurers. The proportion of nonwhite patients with cancer enrolled in Medicaid was 21% to 24% vs 5% to 11% in the other health plans.

CSF Use Patterns

Across all tumor types, the proportions of all CSFs given as primary prophylaxis to persons with high-, intermediate-, and low-risk chemotherapy were 54%, 24%, and 15%, respectively. The proportions of CSFs given as primary prophylaxis in conjunction with high-risk chemotherapy were 58% for breast cancer and 28% for NSCLC. No patients with colorectal cancer received CSFs as primary prophylaxis in conjunction with high-risk chemotherapy. The proportions of patients with breast, NSCLC, and colorectal cancer receiving primary prophylactic CSFs and intermediate-risk chemotherapy were 46%, 24%, and 8%, respectively (Table 2). In the low-risk chemotherapy setting, 10%, 7%, and 21% of breast, colorectal, and NSCLC patients received CSF as primary prophylaxis. Among patients with breast cancer, NSCLC, and colorectal cancer, the proportions receiving CSFs in any setting were 34%, 33%, and 21%, respectively.

The proportion of all patients with breast cancer receiving CSFs as primary prophylaxis increased from 9% in 2002 to 46% in 2005. Primary prophylactic CSF use was highest among patients receiving high-risk chemotherapy regimens and was lowest among patients receiving low-risk chemotherapy regimens (Table 2 and the Figure). The proportion

receiving chemotherapy and any CSFs increased from 40% in 2002 to 74% in 2005. The increase was greatest among patients who were commercially insured (from 44% in 2002 to 80% in 2005) and was lower among patients who were enrolled in Medicaid (from 38% in 2002 to 61% in 2005) or in Medicare (from 34% in 2002 to 67% in 2005).

Among patients with NSCLC who received any CSFs, primary prophylactic use ranged between 20% and 26% from 2002 to 2005. The proportion of patients with NSCLC receiving chemotherapy and any CSFs increased from 32% in 2002 to 44% in 2005. The percentage increase was greatest among patients who were enrolled in Medicaid (from 27% in 2002 to 41% in 2005) or in Medicare (from 32% in 2002 to 45% in 2005) and was lowest among patients who were commercially insured (from 36% in 2002 to 39% in 2005).

Among patients with colorectal cancer who received any CSFs, 7% received primary prophylactic CSFs. Of those receiving high-risk chemotherapy regimens, 38% received any CSFs during chemotherapy, whereas 43% of patients receiving intermediate-risk chemotherapy regimens and 21% of patients receiving low-risk chemotherapy regimens received any CSFs. The proportion of patients with colorectal cancer undergoing chemotherapy who received any CSFs increased from 21% in 2002 to 25% in 2005. The increase was greatest among patients enrolled in Medicaid (from 13% in 2002 to 25% in 2005) or in Medicare (from 19% in 2002 to 25% in 2005). The percentage of commercially insured patients receiving CSFs decreased slightly (from 26% in 2002 to 24% in 2005).

Predictors of CSF Use

Colorectal cancer was removed from the multivariate analysis for high-risk chemotherapy regimens because there was no primary prophylactic CSF use in this category. In addition, because of low proportions of minority races/ethnicities,the racial/ethnic categories were collapsed to white versus nonwhite. Multivariate analysis revealed that factors predicting CSF use as primary prophylaxis differed across tumor types (eAppendices A, B, and C). Among patients receiving high-risk chemotherapy regimens, patients with breast cancer were significantly more likely to receive CSFs as primary prophylaxis than patients with NSCLC (odds ratio [OR], 2.43; 95% confidence interval [CI], 1.07-5.49) (eAppendix C). Among patients undergoing intermediate-risk chemotherapy regimens, patients with breast cancer were significantly more likely to receive CSFs as primary prophylaxis than patients with NSCLC (OR, 4.01; 95% CI, 1.06-15.15), and patients with colorectal cancer were significantly less likely to receive CSFs as primary prophylaxis than patients with NSCLC (OR, 0.24; 95% CI, 0.07-0.80) (eAppendix D). Among patients undergoing low-risk chemotherapy regimens, patients with breast cancer (OR, 0.32; 95% CI, 0.11-0.93) and colorectal cancer (OR, 0.26; 95% CI, 0.11-0.66) were less likely to receive CSFs as primary prophylaxis than patients with NSCLC (eAppendix E).

DISCUSSION

Using cancer registry and claims records, we examined patterns of CSF use among patients enrolled in 4 health insurance plans in Washington State receiving initial chemotherapy for breast cancer, colorectal cancer, or NSCLC. Although overall CSF use increased substantially over time, its use as primary prophylaxis was variable among cancer sites. Colony-stimulating factors were used as prophylaxis frequently for patients with breast cancer but in few patients with colorectal cancer or NSCLC.

Overall CSF use increased substantially from 2002 to 2005. The greatest increase occurred in women with breast cancer, such that in the last year of the observation period almost 75% received CSFs during their initial chemotherapy regimen. However, less than half of the CSF use was as primary prophylaxis. These results suggest that (with the possible exception of breast cancer) past and current guidelines addressing CSF use for patients receiving myelosuppressive chemotherapy have been ineffective in aligning actual practice patterns with use best supported by evidence and package labeling.^1,23,24

Multivariate analysis showed that for women with breast cancer the likelihood of primary prophylactic CSF use was predicted by administration of chemotherapy regimens with higher FN risk. Most clinical evidence supports CSF use in this setting, and guidelines have been in place for the longest time. Among patients with breast cancer administered high-risk chemotherapy herein, 28% received CSFs as primary prophylaxis, and 26% never received CSFs.

Among patients with NSCLC and colorectal cancer who received high- or intermediate-risk chemotherapy, prophylactic CSF use was low and did not change over time. Most of these patients were placed on regimens with an intermediate FN risk, in which guidelines recommend that consideration be given to CSF prophylaxis if other risk factors exist (eg, preexisting neutropenia or poor performance status).^23,24 Patients with NSCLC and colorectal cancer were older and had more noncancer comorbidities than patients with breast cancer, which may have motivated physicians to prescribe lower-intensity chemotherapy doses, thereby lowering the perceived need for prophylactic CSFs. Unfortunately, information for evaluating chemotherapy doses delivered was unavailable among the claims data used for this study.

One clinical trial evaluated the efficacy of CSFs among patients with small cell lung cancer⁴; there are no direct studies of CSF use among patients with NSCLC. Some controversy persists as to the relative effectiveness of CSFs among speciï¬ÂAuthor Affiliations: From the Fred Hutchinson Cancer Research Center (SDR, CLM), Seattle, WA; Department of Pharmacy (JSM, DKB, SDS), University of Washington, Seattle, WA; Cornerstone Systems (LC), Lynden, WA; and Amgen, Inc (JLM), Thousand Oaks, CA. Dr Malin is now with the Veterans Affairs Greater Los Angeles Health Care System, Los Angeles, CA.

Funding Source: This study was funded by Amgen, Inc.

Author Disclosures: Drs Ramsey and Sullivan report receiving a grant from Amgen, Inc for this research. Ms Clarke reports serving as a paid consultant to the Fred Hutchinson Cancer Research Center for her involvement in this study. Dr Malin was an employee of Amgen, Inc at the time this work was performed and now serves as a paid consultant to the company. The other authors (JSM, DKB, CLM) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (SDR, JSM, JLM, SDS); acquisition of data (SDR, CLM, LC); analysis and interpretation of data (SDR, JSM, DKB, LC, JLM, SDS); drafting of the manuscript (SDR, JSM, CLM, SDS); critical revision of the manuscript for important intellectual content (SDR, JSM, DKB, CLM, JLM, SDS); statistical analysis (SDR, DKB); provision of study materials or patients (SDR); obtaining funding (SDR, SDS); administrative, technical, or logistic support (SDR, JSM, CLM, LC); and supervision (SDR). Additional Information: References 31 through 54 are cited in eAppendix B.

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