Rates of Guideline Adherence Among US Community Oncologists Treating NSCLC

March 12, 2013
Zhaohui Wang, MD, PhD
Zhaohui Wang, MD, PhD

,
Inga Aksamit, RN, MBA
Inga Aksamit, RN, MBA

,
Lisa Tuscher, BA
Lisa Tuscher, BA

,
Kim Bergstrom, PharmD
Kim Bergstrom, PharmD

Volume 19, Issue 3

US community oncologists treating NSCLC were significantly more likely to be guideline adherent when providing first-line rather than adjuvant treatment.

Objectives:

To evaluate chemotherapy regimen utilization in patients with non—small cell lung cancer (NSCLC) treated in US community oncology practices, to examine the relationship between evidence-based guideline adherence and the follow-up monitoring period (FUMP) over 1.5 years, and to understand the relative costs of commonly administered chemotherapy regimens.

Study Design:

Retrospective data analysis.

Methods:

Using a large US medical oncology clinical database derived from a proprietary web-based drug dispensing technology, we identified adult patients with NSCLC who started adjuvant therapy for early-stage disease or first-line therapy for advanced and metastatic disease from July 1, 2009, through June 30, 2010. Adjuvant or first-line regimen utilization and the FUMP within 1.5 years were analyzed with respect to national evidence-based guideline adherence. Costs for commonly administered regimens based on 2010 Medicare reimbursement were compared.

Results:

A total of 3505 patient treatment regimens were included in this study. Rates of guideline adherence were 75.0% and 61.3% for the first-line and the adjuvant treatment groups, respectively (P <.0001). Treatment with guidelinebased regimens correlated with a significantly longer FUMP in the first-line treatment groupcompared with non—guideline-based regimens (P = .005). Regimen costs for the top 11 regimens in the adjuvant and first-line treatment settings varied greatly. Low-cost regimens were prescribed more commonly.

Conclusions: Rates of guideline adherence were significantly higher in the first-line than in the adjuvant NSCLC treatment group. First-line treatment with guideline-based regimens correlated with an extended FUMP for advanced NSCLC patients.

Am J Manag Care. 2013;19(3):185-192Retrospective analysis of a large US medical oncology clinical database indicated that rates of guideline adherence for community oncology practices in adjuvant and first-line treatment of non—small cell lung cancer (NSCLC) were 61.3% and 75.0% (P <.0001), respectively.

  • First-line treatment with guideline-adherent regimens correlated with a longer followup monitoring period in advanced NSCLC.

  • Regimen standardization would increase rates of guideline adherence and lower treatment costs.

  • Onmark Regimen Profiler is a financial tool to help clinicians to compare costs of treatments at the regimen level.

With the exception of skin cancer, lung cancer is the most common malignancy and is the leading cause of cancerrelated mortality worldwide.1 An estimated 222,520 Americans were diagnosed with lung cancer in 2010, while an estimated 157,300 died of the disease.2,3 There are 2 major subtypes of lung cancer: non—small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The majority (85%-90%) of lung cancers fall into the NSCLC subtype; a smaller percentage (10%-15%) are classified as SCLC or other cell types (up to 5%).2 For NSCLC, the 5-year survival rate is 46.9%, 26.1%, 8.4%, and 1.6% for stages I, II, III, and IV, respectively.4

National treatment guidelines (NTGs) provide evidence-based recommendations for treatment, and are available from a number of organizations, including the National Comprehensive Cancer Network,5 the American Society of Clinical Oncology,6,7 and McKesson Specialty Health.8

Treatment for NSCLC has evolved over the past 20 years to include chemotherapy, surgery, and radiation therapy. Chemotherapy plays an important role in both early and advanced disease. The treatment for early-stage NSCLC has evolved to include multimodality therapy utilizing chemotherapy and/or radiation therapy in addition to surgery, if the tumor is operable, in an effort to improve survival. Advanced NSCLC is often managed with chemotherapy or chemoradiation, which has been shown to prolong survival.9

Doublet chemotherapy regimens, particularly platinum-containing regimens, have emerged as standard treatment and are recommended by NTGs for neoadjuvant, adjuvant, initial, or first-line metastatic treatment for NSCLC.5,7,8 Cisplatin-containing regimens are morecommonly recommended in NTGs in the adjuvant setting than carboplatin-containing or other chemotherapy combinations.5,7,8 A meta-analysis demonstrated that, compared with surgery alone, cisplatin-based regimens are superior to non—cisplatin-containing regimens, based on a 13% reduction in the risk of death and a 5% absolute improvement in 5-year survival for patients receiving cisplatin-based regimens and a 15% increase in the risk of death for patients receiving non–cisplatin-containing regimens.10,11 However, no specific platinumbased cytotoxic combination is clearly superior.5 Use of chemotherapy varies greatly across the United States.12 Many different regimens are available, with varying efficacy, side effect profiles, and costs.13

There is increasing interest in better understanding the value obtained from specific cancer treatments. Value can be determined by examining quality (using physician adherence to evidence-based NTGs as a surrogate), treatment outcome (eg, survival), and cost of different cancer treatment options.14 Previous studies have demonstrated significant variability in adherence to guideline-driven care in oncology.15 When attempting to define the benefits of clinical practice guidelines, evidence for improvement in 1 of the 3 major outcomes is used as a primary determinant for the recommendations: (1) survival, (2) qualify of life, and 3) cost-effectiveness.16 The purpose of this retrospective study was to compare adjuvant and first-line NSCLC treatments prescribed by US community oncologists with the NTGs for this condition. Treatment regimen cost and the follow-up monitoring period (FUMP) as a surrogate for survival were examined too. Quality-of-life measurements, which have been shown to benefit little from chemotherapy in this population, were beyond the scope of this study.17,18

METHODS

Data Sources and Patient Population

Data were collected from Lynx Mobile, McKesson Specialty Health’s web-based drug inventory management technology. The Lynx Mobile data warehouse contains data from oncology patients treated in more than 750 US community oncology practice sites since 2001. The data warehouse contains patient clinical and demographic data as well as drug transactional data.

Eligible study patients were 18 to 80 years old with a diagnosis of NSCLC (utilizing International Classification of Diseases, Ninth Revision, Clinical Modification billing codes of 162.0-162.9 and NSCLC as a clinical diagnosis supplied by the clinician in the Lynx Mobile system) and with treatment for NSCLC started between July 1, 2009, and June 30, 2010. Patients were included if they started neoadjuvant/adjuvant treatment (defined as the adjuvant treatment group) for stage I-IIIa disease, or if they started first-line treatment including initial treatment of locally advanced disease and first-line metastatic treatment (defined as the first-line treatment group) for stage IIIb-IV disease. Patient data, including diagnosis, tumor stage, height, weight, and drug-related transactional data (doses and days of administration), were collected. Additional inferred information was added to the data set by a team of clinicians at McKesson, including the patients’ treatment regimen (utilizing a regimen library matched to drug dose and dosing patterns) and treatment line of therapy (LOT) (eg, neoadjuvant, adjuvant, initial/induction, firstline metastatic) using LOT rules and staging information.

Treatment was analyzed based on treatment intent. Patients were excluded from the study if their sex was unknown or if they received only 1 cycle of chemotherapy. Patients were excluded from the FUMP analysis if the FUMP was shorter than 21 days. If patients were given more than 1 regimen for the same treatment (eg, 2 regimens given in the adjuvant setting), only the first regimen was eligible for data analysis.

Treatment regimen cost information was derived from Onmark Regimen Profiler, a web-based tool developed by McKesson Specialty Health that evaluates, on a pro forma basis, regimen-associated costs for different payers including Medicare. Regimen costs were based on the first quarter 2010 Medicare Drug Fee Schedule and the 2010 National Average Procedure Fee Schedule. The regimen cost was the Medicare-allowable cost for a regimen in this study. Only adjuvant and first-line regimens were analyzed. First-line regimen costs assumed 4 cycles of therapy. Typical Evaluation & Management, administration procedures (such as injection method and infusion time), and basic lab tests were included. Dose calculations were based on an average patient body surface area of 1.7 m2 and weight of 70 kg. Pegfilgrastim (6-mg injection) and an antiemetic regimen (palonosetron 0.25 mg [intravenous infusion] and dexamethasone 20 mg) were included in the costs for all regimens associated with a high risk of febrile neutropenia or a high to moderate risk of emesis, respectively.

Rules to Define Regimen Category, Line of Therapy, Guideline Adherence, and Follow-up Monitoring Period

Regimen Category. Regimens containing either carboplatin or cisplatin were categorized as carboplatin- or cisplatincontaining regimens, respectively.

Line of Therapy. Adjuvant patients were new to the practice, had stage I-IIIA disease, received therapy consistent with neoadjuvant or adjuvant treatment, and did not receive chemotherapy again within 90 days. First-line patients were either new to the practice, had stage IIIB or IV disease, had no previous chemotherapy, and received a regimen consistent with initial or first-line treatment, or were patients who had been previously treated with an adjuvant regimen and then received new therapy with a gap of >90 days.

Current staging, when available, was one of the factors used to determine appropriate LOT.

Maintenance treatment and second-line or higher metastatic treatment were not included in this study.

Guideline Adherence. Guideline adherence refers to regimens referenced in evidence-based NTG sources during the time of the study.5,8

Follow-up Monitoring Period. The FUMP was examined for the first-line patients only and was measured from the first date of first-line treatment to last clinical contact recorded in our database by the end of 1.5 years of monitoring. These data were accessed on January 13, 2012.

Statistical Analysis

The rates of guideline adherence for adjuvant and firstline treatments, the percentages of carboplatin- and cisplatin-containing regimens, and the regimen drug counts were evaluated statistically by x2 test without correction.19 The FUMP was evaluated by 1-way analysis of variance (ANOVA) test with MedCalc software.20 A 2-tailed P value of <.05 was considered significant.

RESULTSPatient and Practice Demographics

Between July 1, 2009, and June 30, 2010, a total of 3505 NSCLC patient regimens met the inclusion criteria. Median patient age was 68 years (SD 8.7 years). These patients were treated by 336 community oncology practices across 41 states in the United States.

Table 1

A total of 661 patients received adjuvant treatment. Of this group, 24.5% (n = 162) had valid staging information in the database. The proportions of patients with stage IIIA, II, and I disease were 46.9%, 31.5%, and 21.6%, respectively. More than 80% (n = 2844) of the patients in the sample received first-line treatment for advanced/metastatic disease. Among the patients in the first-line treatment group,37.1% (n = 1056) had valid staging information. Two cases in the adjuvant group and 3 in the first-line group had invalid staging information and were eliminated from valid staging analysis. shows the demographic characteristics of the patients.

Rates of Guideline Adherence

In this study, about 70% of patients had their body surface area, body weight, and height data recorded. When these data were absent, assumptions about drug dose and regimen selection were based on default values.

Figure

National treatment guidelines recommended 22 possible regimens for adjuvant treatment and 72 possible regimens for first-line treatment of advanced/metastatic NSCLC.5,8 Patients in the adjuvant and first-line treatment groups received 41 and 126 different regimens, respectively. In the adjuvant group, 13 regimens given to 405 patients (61.3%) were guideline adherent (Figure). In the first-line treatment group, 46 regimens given to 2133 patients (75%) were guideline adherent (). The rate of guideline adherence in the first-line treatment group was significantly higher than that in the adjuvant group (P <.0001 by the x2 test).

Impact of Guideline Adherence on Follow-up Monitoring Period

In the first-line treatment group, 23 and 35 cases in the guideline-adherent and nonadherent groups were removed from the FUMP analysis because their FUMP was fewer than 21 days. The mean (SE) FUMPs in the guideline-adherent and non—guideline-adherent treatment groups were 276.1 (3.9) days and 253.5 (7.0) days, respectively; P = .005 (F-ratio 7.922 by the ANOVA test). In addition, the FUMP rates at the 6th, 12th, and 18th month improved from 54.7%, 30.2%, and 14.8% to 59.4%, 34.0%, and 16.8%, respectively.

Regimen Administration

Table 2

Common Regimens Administered and Their Costs. Regimens containing carboplatin and paclitaxel were the most common regimens administered in the adjuvant and first-line treatment groups. The top 5 regimens utilized were given to 68.8% and 36.5% of patients in adjuvant and first-line groups, respectively, while the top 11 regimens were given to 84.7% (n = 560) and 61.1% (n = 1737) of patients in adjuvant and first-line treatment groups, respectively (). Of the top 11 regimens in the adjuvant and first-line treatment groups, 6 and 10, respectively, were guideline recommended.

Treatment regimen costs based on Medicare national reimbursement rates for the top 11 regimens in the adjuvant and first-line settings varied considerably (Table 2). A standard course of therapy in the adjuvant setting ranged from $2716 for carboplatin (AUC5) D1—etoposide (100 mg/m2) D1-3 every 28 days to $16,729 for carboplatin (AUC5) D1—gemcitabine (1200 mg/m2) D1,8 every 21 days (Table 2). Regimen costs in the first-line treatment setting ranged from $3395 for carboplatin (AUC6) D1—paclitaxel (200 mg/m2) D1 every 21 days to $46,228 for carboplatin (AUC6) D1—pemetrexed (500 mg/m2) D1—bevacizumab (15 mg/kg) D1 every 21 days based on 4 cycles of therapy (Table 2). The median treatment costs within the top 11 regimens utilized were $4666 and $16,729 for the adjuvant and first-line treatment groups, respectively. The high cost of treatment in the first-line group was caused by several expensive drugs (eg, pemetrexed, bevacizumab, docetaxel, gemcitabine). A total of 425 (75.9%) and 895 (51.5%) patients in the adjuvant and first-line treatment groups, respectively, received regimens with median treatment costs equal to or lower than those of the top 11 regimens utilized. These data showed that community oncologists prescribed lower-cost regimens for most of their patients.

Table 3

Regimen Drug Count. The number of antitumor drugs in a regimen was evaluated. The percentages of patients receiving a 2-drug regimen in the adjuvant and first-line treatment groups were 98.5% and 67.7%, respectively, which were significantly higher than the percentages of patients who received regimens containing 1, 3, or more drugs (P <.0001 by the x2 test; ).

Cisplatin-Containing Versus Carboplatin-Containing Regimens. In the adjuvant treatment group, 72.9% (n = 482) and 26.2% (n = 173) of patients received carboplatincontaining and cisplatin-containing regimens, respectively. In the first-line treatment group 65.2% (n = 1853) received carboplatin-containing regimens and 17.8% (n = 505) received cisplatin-containing regimens. Carboplatincontaining regimens were administered significantly more often than cisplatin-containing regimens in both groups (P <.0001 by the x2 test). The rate of utilization of carboplatin-containing versus cisplatin-containing regimens was similar between the guideline-adherent and non—guidelineadherent groups.

Table 4

Regimen Drug Combination. The adjuvant treatment group received 19 drug combinations, and the first-line treatment group received 71 drug combinations. The top 5 drug combinations utilized in the adjuvant group were given to 87.1% of patients, and the top 5 drug combinations utilized in the first-line treatment group were given to only 50.1% of patients. The most common drug combination utilized was carboplatin-paclitaxel in both adjuvant and first-line treatment ().

DISCUSSION

National treatment guidelines provide evidence-based treatment recommendations for specific diseases. Adherence to NTGs is a key step in improving the quality of care and outcomes for cancer patients. It has been reported that adherence rates for chemotherapy guidelines can reach 60% to 80% based on various diseases and treatment settings, whereas the general goal is 80% to 90%.21 Bergstrom et al22 investigated 7444 breast cancer patients treated with chemotherapy in US community practices and reported chemotherapy guideline—adherent rates of 85.4% and 69.4% in adjuvant and first-line treatment groups, respectively. Moreover, after investigating 3976 patients with breast cancer in Germany, Wockel et al14 reported that only 71.4% of chemotherapeutic treatment was guideline adherent, although guideline-adherent chemotherapy improved the 5-year recurrence-free survival and overall survival. After investigating 2976 colon cancer patients treated with chemotherapy as adjuvant and first-line treatment in US community practices, Wang et al23 reported that chemotherapy guideline—adherent rates were 80.9% and 76.6% in the adjuvant and first-line treatment groups, respectively. Our study showed that prescribing guideline-adherent regimens was correlated with a significantly longer FUMP in the first-line treatment group even though our study’s rate of guideline adherence (75.0%) did not reach 80% in the firstline treatment setting.

Also, we found a large number of distinct regimens: 41 and 126 different regimens were prescribed in the adjuvant and in the first-line treatment groups, respectively. Regimen standardization could help to reduce the variety of regimens prescribed and improve the rate of guideline adherence. Regimen standardization would encourage the practice of best evidence-based medicine, offer better toxicity management and fewer chemotherapy administration errors, and improve operational efficiency.21 Regimen standardization also would provide measurable and predictable outcomes.

There is wide variation in the choice of chemotherapy regimens for NSCLC,11 but 2-drug regimens are commonly utilized in both the adjuvant/neoadjuvant and first-line treatment settings.5,8,10,24 Our data showed that 98.5% and 67.7% of patients received doublet-based regimens for adjuvant and first-line treatment, respectively. This finding was consistent with guideline recommendations and other reports.25

Additionally, cisplatin-based regimens have consistently shown better outcomes than carboplatin-based regimens in randomized controlled trials,7,11,24 and guidelines recommend cisplatin-based regimens over carboplatin-based regimens.5,7,8 Literature has shown that cisplatin-based regimens were associated with more gastrointestinal and renal adverse effects, while carboplatin-containing regimens were associated with more severe thrombocytopenia. According to published reports, cisplatin-containing regimens used in first-line treatment produce higher response rates, inconsistent survival benefit, and more toxicity than carboplatin-containing regimens.25 After reviewing various trials, Lilenbaum24 suggested that cisplatin-containing regimens were preferred when chemotherapy is intended to be curative (ie, the adjuvant treatment group in this study), whereas carboplatin-containing regimens were appropriate for the majority of patients with advanced disease, for whom quality of life is an important consideration. However, our study found that in the community setting, carboplatin-containing regimens were administered significantly more often than cisplatin-containing regimens in both the adjuvant and first-line groups.

Our analysis of the top 11 regimens utilized in this study suggests that US community oncologists might have considered treatment cost and prescribed regimens with low treatment costs for the majority of patients in both the adjuvant and first-line groups. Neubauer et al26 reported that the total 1-year treatment cost for NSCLC patients receiving on-guideline adjuvant or first-line treatment was significantly lower than the cost for off-guideline treatment.

As we move toward value-based care, it is important to consider the cost of care when the quality of care (balancing efficacy and toxicity) might be difficult to distinguish among regimens.25 In the advanced/metastatic disease setting, toxicity and costs become important factors when selecting a specific therapy for patients. Considerably less effort has been focused on the cost of cancer care than on the development of treatment options. Although tools like Onmark Regimen Profiler are widely available to community-based oncology clinics, they are often not tied to regimen utilization patterns to better understand how regimen choice and regimen cost together can drive value in cancer care. As can be seen in this study, the cost of guidelinebased therapy varies widely.

If healthcare reform is going to succeed by improving quality while lowering cost, these twin components of value-driven healthcare will need to be carefully examined.

Limitations

There are several limitations to this study. As noted, this study was performed using drug-dispensing and patient diagnosis information. Radiation therapy data were not available in this database. Chemoradiation regimens were determined through business rules based on drug dose and schedule. With this methodology, an underestimate of radiation use was likely. Both the LOT and the specific regimen needed to be inferred in this study. However, in a separate pilot study of similar patients, LOT and treatment regimen that were inferred were matched to related data in clinical records provided by the clinicians with 90% to 95% accuracy (unpublished data).

Patient performance status and comorbidity were not known for the study population. Therefore, patient characteristics might not be balanced between the guideline-adherent and nonadherent treatment groups.

In addition, because no direct survival data were available in our database, FUMP was examined as a surrogate for survival in this study. According to Surveillance, Epidemiology, and End Results and other data, median survival for stage IIIB and IV NSCLC patients is 13 months and 7 to 8 months, respectively.3,9,27 For the first-line treatment group, we monitored each patient’s drug and other clinical activity through the Lynx Mobile system for at least 1.5 years and evaluated their FUMP for 1.5 years. Patients who had no activity for 90 days may have died, but due to limitations of the data set we could not confirm this. Therefore we could only report on the 1.5-year FUMP.

CONCLUSIONS

US community oncologists prescribed high rates of guideline-recommended regimens for first-line treatment more often than they did for adjuvant treatment for NSCLC patients. This study showed that the first-line treatment with guideline-adherent regimens may correlate with a significantly longer FUMP compared with treatment with nonadherent regimens in patients with advanced NSCLC. Community oncologists prescribed lower-cost regimens more often. Based on our findings, there is still room for US community oncology providers to improve rates of guideline adherence in terms of regimen selection. Regimen standardization can increase rates of guideline adherence and reduce treatment costs. Considering both guideline regimens and their associated treatment costs, as provided in the Onmark Regimen Profiler, would help oncologists select appropriate regimens to treat NSCLC patients.

Author Affiliations: From McKesson Specialty Health, McKesson, San Francisco, CA.

Funding Source: This study was not supported by any research funding and grant.

Author Disclosures: The authors (ZW, IA, LT, KB) 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 (ZW, IA, KB); acquisition of data (ZW, IA, LT); analysis and interpretation of data (ZW, IA, LT, KB); drafting of the manuscript (ZW, IA); critical revision of the manuscript for important intellectual content (ZW, IA, KB); statistical analysis (ZW); provision of study materials or patients (ZW, IA, LT, KB); administrative, technical, or logistic support (LT); and supervision (KB).

Address correspondence to: Zhaohui Wang, MD, PhD, McKesson Specialty Health, McKesson, 123 Mission St, San Francisco, CA 94105. E-mail: zhaohui.wang@mckesson.com.1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics [published correction appears in CA Cancer J Clin. 2011;61(2):134]. CA Cancer J Clin. 2011;61(2):69-90.

2. American Cancer Society. Non-small cell lung cancer. Learn About Cancer. http://www.cancer.org/Cancer/LungCancer-Non-SmallCell/index?ssSourceSiteId=null. Published 2011. Accessed July 3, 2011.

3. National Cancer Institute. SEER stat fact sheets: lung and bronchus. Surveillance Epidemiology and End Results (SEER). http://seer.cancer.gov/statfact/html/lungb.html. Published 2011. Accessed July 2, 2011.

4. Greene FL, Page DL, Fleming ID, et al, eds. Lung. In: AJCC Cancer Staging Manual. Vol 1. 6th ed. Chicago, IL: American Joint Commission on Cancer; 2002:167-177.

5. National Comprehensive Cancer Network. Non-small cell lung cancer. Version 2. Clinical Practice Guidelines in Oncology. http://www.nccn.org. Published 2010. Accessed January 6, 2010.

6. Azzoli CG, Baker S Jr, Temin S, et al; American Society of Clinical Oncology. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol. 2009;27(36):6251-6266.

7. Pisters KM, Evans WK, Azzoli CG, et al; Cancer Care Ontario; American Society of Clinical Oncology. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline. J Clin Oncol. 2007;25(34):5506-5518.

8. McKesson Specialty Health. Treatment guidelines—non small cell lung cancer. Version 1. McKesson Specialty Care Solutions Treatment Guidelines. http://www.onmarkservices.com. Published 2010. Accessed January 10, 2011.

9. Schrump DS, Altorki NK, Henschke CL, Carter D, Turrisi AT, Gutierrez ME. Lung cancer: non-small cell lung cancer. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Vol 1. 7th ed. Philadelphia, PA: Wolters Kluwer Health: Lippincott Williams & Wilkins; 2005:753-809.

10. Hanna N. Adjuvant systemic therapy in resectable non-small cell lung cancer. 19.2. UpToDate. http://www.uptodate.com. Published 2011. Accessed July 8, 2011.

11. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ. 1995;311(7010):899-909.

12. Cufer T, Ovcaricek T, O'Brien ME. Systemic therapy of advanced non-small cell lung cancer: major-developments of the last 5-years [published online December 19, 2012]. Eur J Cancer. pii: S0959-8049(12)00917-3. doi: 10.1016/j.ejca.2012.11.021.

13. Midthun D. Overview of the initial evaluation, treatment and prognosis of lung cancer. 19.2. UpToDate. http://www.uptodate.com. Published 2011. Accessed May 15, 2011.

14. Wöckel A, Kurzeder C, Geyer V, et al. Effects of guideline adherence in primary breast cancer—a 5-year multi-center cohort study of 3976 patients. Breast. 2010;19(2):120-127.

15. Malin JL, Schneider EC, Epstein AM, Adams J, Emanuel EJ, Kahn KL. Results of the National Initiative for Cancer Care Quality: how can we improve the quality of cancer care in the United States? J Clin Oncol. 2006;24(4):626-634.

16. Varga D, Wischnewsky M, Atassi Z, et al. Does guideline-adherent therapy improve the outcome for early-onset breast cancer patients? Oncology. 2010;78(3-4):189-195.

17. Ganguli A, Wiegand P, Gao X, Carter JA, Botteman MF, Ray S. The impact of second-line agents on patients’ health-related quality of life in the treatment for non-small cell lung cancer: a systematic review [published online July 18, 2012]. Qual Life Res.

18. Tanvetyanon T, Soares HP, Djulbegovic B, Jacobsen PB, Bepler G. A systematic review of quality of life associated with standard chemotherapy regimens for advanced non-small cell lung cancer. J Thorac Oncol. 2007;2(12):1091-1097.

19. GraphPad QuickCalcs [computer program]. La Jolla, CA: GraphPad Software; 2011. http://www.graphpad.com. Accessed April 10, 2011.

20. MedCalc [computer program]. Version 12.2.0.0. Mariakerke, Belgium: MedCalc Software; 2011.

21. Ellis PG. Challenge of reducing disease-specific variation in care. Presented at: 2010 ASCO Annual Meeting; June 4-8, 2010; Chicago, IL.

22. Bergstrom KA, Wang Z, Aksamit I, et al. Guideline adherence rates of chemotherapy treatment for breast cancer patients treated in U.S. community oncology practices. J Clin Oncol. 2010;28(15S):abstr 596. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=54593. Accessed January 30, 2013.

23. Wang Z, Bergstrom KA, Aksamit I, et al. Guideline adherence rates of chemotherapy treatment for colon cancer patients treated in U.S. community oncology practices. J Clin Oncol. 2010;28(15S):abstr 3620. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=54357. Accessed January 30, 2013.

24. Lilenbaum R. Initial systemic chemotherapy for advanced nonsmall cell lung cancer. 19.1. UpToDate. http://www.uptodate.com. Published 2011. Accessed April 4, 2011.

25. Bergstrom KA. Management of unresectable locoregionally advanced and metastatic nonsquamous NSCLC. Am J Pharm Benefits. 2011;3(2):89-93.

26. Neubauer MA, Hoverman JR, Kolodziej M, et al. Cost effectiveness of evidence-based treatment guidelines for the treatment of nonsmall- cell lung cancer in the community setting. J Oncol Pract. 2010;6(1):12-18.

27. Eldridge L. Lung cancer: lung cancer survival rates by type and stage. About.com. Lung Cancer. http://lungcancer.about.com/od/ whatislungcancer/a/lungcancersurvivalrates.htm?p=1. Published 2011. Accessed February 23, 2012.