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

, , , , , ,
The American Journal of Managed Care, September 2010, Volume 16, Issue 9

We linked health insurance records to cancer registry data to analyze colony-stimulating factor use, finding wide divergence from that recommended by practice guidelines.

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 hospitalization4-6 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.

Address correspondence to: Scott D. Ramsey, MD, PhD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M3-B232, Seattle, WA 98109-1024. E-mail: sramsey@fhcrc.org.1. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187-3205.

2. Fossa SD, Kaye SB, Mead GM, et al; European Organization for Research and Treatment of Cancer, Genito-Urinary Group, and the Medical Research Council Testicular Cancer Working Party, Cambridge, United Kingdom. Filgrastim during combination chemotherapy of patients with poor-prognosis metastatic germ cell malignancy. J Clin Oncol. 1998;16(2):716-724.

3. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol. 2005;23(6):1178-1184.

4. Crawford J, Ozer H, Stoller R, et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med. 1991;325(3):164-170.

5. Talcott JA, Finberg R, Mayer RJ, Goldman L. The medical course of cancer patients with fever and neutropenia: clinical identification of a low-risk subgroup at presentation. Arch Intern Med. 1988;148(12):2561-2568.

6. Riikonen P, Saarinen UM, Makipernaa A, et al. Recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of febrile neutropenia: a double blind placebo-controlled study in children. Pediatr Infect Dis J. 1994;13(3):197-202.

7. Caggiano V, Weiss RV, Rickert TS, Linde-Zwirble WT. Incidence, cost, and mortality of neutropenia hospitalization associated with chemotherapy. Cancer. 2005;103(9):1916-1924.

8. Lew MA, Kehoe K, Ritz J, et al. Prophylaxis of bacterial infections with ciprofloxacin in patients undergoing bone marrow transplantation. Transplantation. 1991;51(3):630-636.

9. Donnelly JP. Selective decontamination of the digestive tract and its role in antimicrobial prophylaxis. J Antimicrob Chemother. 1993;31(6):813-829.

10. Savarese DM, Hsieh C, Stewart FM. Clinical impact of chemotherapy dose escalation in patients with hematologic malignancies and solid tumors. J Clin Oncol. 1997;15(8):2981-2995.

11. Phillips KA, Tannock IF. Design and interpretation of clinical trials that evaluate agents that may offer protection from the toxic effects of cancer chemotherapy. J Clin Oncol. 1998;16(9):3179-3190.

12. Bokemeyer C, Kuczyk MA, Kohne H, Einsele H, Kynast B, Schmoll HJ. Hematopoietic growth factors and treatment of testicular cancer: biological interactions, routine use and dose-intensive chemotherapy. Ann Hematol. 1996;72(1):1-9.

13. Crawford J, Armitage J, Balducci L, et al; National Comprehensive Cancer Network. Myeloid growth factors: clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2009;7(1):65-84. http://www.jnccn.org/content/7/1/64.full.pdf. Accessed August 19, 2010.

14. Aapro MS, Cameron DA, Pettengell R, et al; European Organisation for Research and Treatment of Cancer (EORTC) Granulocyte Colony-Stimulating Factor (G-CSF) Guidelines Working Party. EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer. 2006;42(15):2433-2453.

15. Bennett CL, Weeks JA, Somerfield MR, Feinglass J, Smith TJ; Health Services Research Committee of the American Society of Clinical Oncology. Use of hematopoietic colony-stimulating factors: comparison of the 1994 and 1997 American Society of Clinical Oncology surveys regarding ASCO clinical practice guidelines. J Clin Oncol. 1999;17(11):3676-3681.

16. Bennett CL, Smith TJ, Weeks JC, et al; Health Services Research Committee of the American Society of Clinical Oncology. Use of hematopoietic colony-stimulating factors: the American Society of Clinical Oncology survey. J Clin Oncol. 1996;14(9):2511-2520.

17. About the Cancer Surveillance System. http://www.fhcrc.org/ science/phs/css/about.html. Accessed September 14, 2010.

18. Premera Blue Cross. Company fact sheet. https://www.premera. com/stellent/groups/public/documents/xcpproject/newsroom_ company_fact_sheet.asp. Accessed August 19, 2010.

19. Regence Group. 2006 annual report. http://www.regence.com/ about/annualReport/annual-report.jsp. Accessed August 19, 2010.

20. Washington State Department of Social and Health Services. Medicaid Purchasing Administration. http://www.dshs.wa.gov/. Accessed August 19, 2010.

21. Medicare.gov. The official U.S. government site for Medicare. http://www.medicare.gov/Default.aspx?AspxAutoDetectCookieSupport=1. Accessed August 19, 2010.

22. Heaney ML, Toy EL, Vekeman F, et al. Comparison of hospitalization risk and associated costs among patients receiving sargramostim, filgrastim, and pegfilgrastim for chemotherapy-induced neutropenia. Cancer. 2009;115(20):4839-4848.

23. Crawford J, Althaus B, Armitage J, et al; National Comprehensive Cancer Network (NCCN). Myeloid growth factors: clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2007;5(2):188-202.

24. American Society of Clinical Oncology. Recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol. 1994;12(11):2471-2508.

25. Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol. 2007;25(21):3158-3167.

26. Du XL, Lairson DR, Begley CE, Fang S. Temporal and geographic variation in the use of hematopoietic growth factors in older women receiving breast cancer chemotherapy: findings from a large population-based cohort. J Clin Oncol. 2005;23(34):8620-8628.

27. Crawford J, Dale DC, Kuderer NM, et al. Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: the results of a prospective nationwide study of oncology practice. J Natl Compr Canc Netw. 2008;6(2):109-118.

28. Graham ID, Evans WK, Logan D, et al; Provincial Lung Disease Site Group of Cancer Care Ontario. Canadian oncologists and clinical practice guidelines: a national survey of attitudes and reported use. Oncology. 2000;59(4):283-290.

29. Institute of Medicine. Rewarding Provider Performance: Aligning Incentives in Medicare. Washington, DC: National Academies Press; 2006.

30. Crawford J, Althaus B, Armitage J, et al; National Comprehensive Cancer Network. Myeloid growth factors clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2005;3(4):540-555.

31. Laack E, Dickgreber N, Muller T, et al; German and Swiss Lung Cancer Study Group. Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group. J Clin Oncol. 2004;22(12):2348-2356.

32. Georgoulias V, Pallis AG, Kourousis C, et al. Docetaxel versus docetaxel/cisplatin in patients with advanced non-small-cell lung cancer: preliminary analysis of a multicenter, randomized phase III study. Clin Lung Cancer. 2003;4(5):288-293.

33. Schiller JH, Harrington D, Belani CP, et al; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92-98.

34. Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 2007;25(12):1545-1552.

35. Kosmidis PA, Kalofonos HP, Christodoulou C, et al. Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer: a phase III study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2008;19(1):115-122.

36. Fossella FV, DeVore R, Kerr RN, et al; TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol. 2000;18(12):2354-2362.

37. Stinchcombe TE, Harper HD, Hensing TA, et al. The feasibility of adjuvant carboplatin and docetaxel in patients with curatively resected non-small cell lung cancer. J Thorac Oncol. 2008;3(2):145-151.

38. Belani CP, Einzig A, Bonomi P, et al. Multicenter phase II trial of docetaxel and carboplatin in patients with stage IIIB and IV non-smallcell lung cancer. Ann Oncol. 2000;11(6):673-678.comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer. Ann Oncol. 2005;16(7):1069- 1075.

39. Belani CP, Lee JS, Socinski MA, et al. Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non—small cell lung cancer. Ann Oncol. 2005;16(7):1069-1075.

40. Kelly K, Crowley J, Bunn PA Jr, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001;19(13):3210-3218.

41. Georgoulias V, Ardavanis A, Tsiafaki X, et al. Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol. 2005;23(13):2937-2945.

42. Binder D, Schweisfurth H, Grah C, et al. Docetaxel/gemcitabine or cisplatin/gemcitabine followed by docetaxel in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC): results of a multicentre randomized phase II trial. Cancer Chemother Pharmacol. 2007;60(1):143-150.

43. Georgoulias V, Androulakis N, Kotsakis A, et al. Docetaxel versus docetaxel plus gemcitabine as front-line treatment of patients with advanced non-small cell lung cancer: a randomized, multicenter phase III trial. Lung Cancer. 2008;59(1):57-63.

44. Stathopoulos GP, Veslemes M, Georgatou N, et al. Front-line paclitaxel-vinorelbine versus paclitaxel-carboplatin in patients with advanced non-small-cell lung cancer: a randomized phase III trial. Ann Oncol. 2004;15(7):1048-1055.

45. Ejlertsen B, Mouridsen HT, Jensen MB, et al. Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer. Eur J Cancer. 2007;43(5):877-884.

46. Schmid P, Untch M, Kosse V, et al. Leuprorelin acetate every- 3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol. 2007;25(18):2509-2515.

47. Marti­n M, Lluch A, Segui­ MA, et al. Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen. Ann Oncol. 2006;17(8):1205-1212.

48. Jones SE, Savin MA, Holmes FA, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006;24(34):5381-5387.

49. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22(1):23-30.

50. Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007;25(23):3456-3461.

51. Andre T, Boni C, Mounedji-Boudiaf L, et al; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigator. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343-2351.

52. Van Cutsem E, Twelves C, Cassidy J, et al; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001;19(21):4097-4106.

53. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352(26):2696- 2704.

54. Rothenberg ML. Irinotecan (CPT-11): recent developments and future directions: colorectal cancer and beyond. Oncologist. 2001;6(1):66-80.