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Second-line and Third-line Chemotherapy for Lung Cancer: Use and Cost

The American Journal of Managed CareMay 2008 - Theme Issue
Volume 14
Issue 5

Using health insurance claims, we identified common first-, second-, and third-line chemotherapy regimens for patients with lung cancer and associated utilization and costs of care.

Objectives: To identify commonly prescribed first-, second-, and third-line chemotherapy regimens for persons with lung cancer and to evaluate the utilization patterns and costs of care associated with receiving these regimens.

Study Design: Retrospective data analysis.

Methods: Using health insurance claims from January 1, 2002, through December 31, 2006, patients with lung cancer were identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. An algorithm was developed to identify first-, second-, and third-line chemotherapy. Patients were stratified by the number of discrete regimens received or by their specific chemotherapy agent or combination of agents. Data were analyzed for up to 2 years from the date of the initial first-line regimen and for 1 year from the second and third lines. Patient costs were based on total reimbursements for each group during the observation period.

Results: Of patients receiving first-line chemotherapy, 25% and 10% received second-line and third-line chemotherapy, respectively. Docetaxel, gefitinib, and erlotinib hydrochloride were the most commonly prescribed second-line regimens; gefitinib and docetaxel were the most commonly prescribed third-line regimens. The most commonly prescribed second- and third-line agents changed substantially over time. Total costs and costs per patient per month increased as the number of lines of chemotherapy prescribed increased.

Conclusions: Second- and third-line chemotherapy is prescribed infrequently, and patterns of prescribing are changing over time. Direct medical care costs increase substantially with additional lines of therapy.

(Am J Manag Care. 2008;14(5):297-306)

There is disagreement about the best strategy for second-line and third-line chemotherapy regimens. Little is known regarding patterns of chemotherapy use and costs of care for persons who receive such treatment.

  • Persons who received second-line chemotherapy that was not approved by the Food and Drug Administration had higher costs than persons who used approved therapies.

Lung cancer is the second most common cancer in the United States and is the most common cause of cancer-related death. The American Cancer Society1 estimated that there would be 213,380 new cases of lung cancer diagnosed in the United States and 160,390 deaths from this disease in 2007. Most of these individuals have regional or advanced disease at diagnosis and are eligible for chemotherapy. Many who begin chemotherapy show signs of disease progression or must discontinue first-line therapy because of intolerable adverse effects and are eligible for subsequent chemotherapy with different agents. Second-line chemotherapy can produce symptomatic improvement, objective responses, and modest improvements in survival for patients with advanced disease.2-5 Despite the availability of second and third-line therapies, there is disagreement about the best treatment strategy.6 Little is known regarding patterns of chemotherapy use and cost of care for persons who receive such treatment.

Using data from a large nationwide health insurer, we sought to determine the most common forms of second- and third-line chemotherapy use for persons with lung cancer. We also evaluated key services utilization (hospital days, ambulatory visits, and emergency department visits), and lifetime costs of care following initiation of the second-line chemotherapy regimen to determine if 1 or more regimens had a significant effect on costs of care relative to others (data not shown).


We identified patients with lung cancer from a health insurance database (i3, Ingenix, UnitedHealthcare) representing privately insured patients and individuals enrolled in Medicare + Choice and Medicaid across all 50 states, the District of Columbia, and the US Virgin Islands.7 We searched administrative records for patients diagnosed as having lung cancer between January 1, 2002, and December 31, 2006, who had received at least 1 chemotherapy agent since diagnosis, using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for malignant neoplasm of trachea, bronchus, and lung; malignant neoplasm of pleura; or carcinoma in situ of respiratory system (codes 162.xx, 163.xx, and 231.xx). To eliminate “false positives,” patients with ICD-9-CM lung cancer codes for whom lung cancer was being ruled out or patients being treated for other cancers, we required claims records with ICD-9-CM lung cancer codes on at least 5 separate dates of service and no more than 10 dates of service with diagnoses of other common malignant neoplasms that are treated with chemotherapy recorded between 30 days before and 6 months after the initial lung cancer diagnosis (Figure 1).

First-line Chemotherapy Use

Second-line therapy is administered for disease progression, recurrence, or intolerable adverse effects following administration of initial chemotherapy. We defined a second-line chemotherapy agent in 1 of 2 ways. First, a second-line agent could be injectable; if so, then the agent was one with an initial injectable administration date that was at least 28 days following the last delivery date of a different first-line chemotherapy agent or widely recognized combination of agents. Second, oral agents such as erlotinib hydrochloride and gefitinib, which are used after failure of first-line chemotherapy, were counted as second-line agents if the initial date on which the prescription was filled occurred on or after the last date of administration of first-line chemotherapy.

For inclusion, second-line regimens had to meet the same criteria as the first line, as well as having no more than 3 uncoded chemotherapy visits between the last recorded date of the first-line treatment and the initiation of the second. If the patient received chemotherapy beyond his or her first-line treatment and the pattern of second-line administration did not meet the criteria, the patient was excluded from the analysis. We looked specifically for US Food and Drug Administration (FDA)-approved second-line therapies, including docetaxel, pemetrexed disodium, erlotinib, and gefitinib.

We defined third-line chemotherapy as any third chemotherapy agent with an initial administration date following 2 separate courses of treatment. Because of heterogeneity in prescribing and difficulty in identifying regimens as defined by the PDQ or as labeled by the FDA, agents identified as third-line therapy represent only the first drug given in the third-line setting.

Evaluating Resource Use and Cost of Care

The initial search yielded 30,798 individuals older than 20 years with at least 1 diagnosis code for lung cancer enrolled between January 1, 2002, and December 31, 2006. Applying exclusion criteria ruled out diagnoses of other cancers and reduced the sample to 11,953 patients; of those, 6289 had at least 1 claim record indicating that they had received chemotherapy. After applying restrictions for having a minimum number of agents specified along with an administration code as already outlined, 2523 patients were included in the analysis. Eighty-one percent of these individuals were covered by commercial insurance, 17% through Medicare contracts, and 2% through Medicaid contracts.

The mean interval between the last date of administration of the first-line agent and the initiation of the second-line treatment was 114 days for injectable agents. Almost half (46%) of the patients received second-line therapy within 60 days of the last date of administration of first-line therapy. An additional 24% received second-line therapy within 120 days of first-line therapy. Among the remaining 30%, the period between first and second treatments ranged from 121 to 844 days.

Among patients who had second-line therapy, patients receiving docetaxel had recorded claims for the greatest number of months (mean, 8.8 months) after the initiation of therapy, while those receiving erlotinib had the fewest number of claims months (mean, 5.4 months). Because erlotinib did not become available until December 2004, a higher relative percentage of patients began therapy toward the end of the observation period, resulting in a shorter observation time. For second-line therapy, an additional 385 agents or chemotherapy combinations were observed in the data; the most common regimens are given in Table 1.

Chemotherapy Prescribing PatternsOf 2523 persons included in the analysis, the most commonly prescribed first-line regimen was carboplatin and paclitaxel. Carboplatin in combination with etoposide phosphate, gemcitabine hydrochloride, and docetaxel was also commonly prescribed (Table 2).

Only 10% of first-line patients received third-line chemotherapy. Gefitinib was most commonly prescribed overall, but over time erlotinib replaced gefitinib as the most commonly prescribed third-line agent after the labeling of gefitinib was modified in June of 2005 to severely reduce its access (Figure 2).

The logistic regression analysis showed that age, choice of first-line regimen, time to initial treatment, and diagnosis year were significantly associated with receiving second-line treatment. Older persons were significantly less likely to receive second-line chemotherapy, but the odds ratio (OR) was only marginally different from 1 (OR, 0.97; 95% confidence interval [CI], 0.96-0.98). Likewise, increasing time from initial diagnosis to treatment was associated with lower likelihood of receiving second-line therapy (OR, 0.83; 95% CI, 0.75-0.92). Using cisplatin plus etoposide as the reference regimen, we found that persons receiving carboplatin plus etoposide (OR, 0.56; 95% CI, 0.39-0.79) and carboplatin plus paclitaxel (OR, 0.73; 95% CI, 0.55-0.97) were significantly less likely to receive second-line chemotherapy. No other major first-line chemotherapy regimen was significantly associated with the likelihood of receiving second-line chemotherapy.

Utilization and Cost for Those Receiving Second-line and Third-line ChemotherapyWe compared overall costs for persons receiving only first-line chemotherapy vs additional chemotherapy regimens. Patients receiving first-line therapy only were observed for a mean of 8.1 months vs 11.8 months among those receiving first- vs second-line therapy and for a mean of 16 months among persons receiving third-line therapy. In the first 12 months following the administration of chemotherapy, the costs per patient per month (PPPM) were similar for the different regimens among persons receiving only first-line therapy (Table 3), ranging from approximately $3500 to $3900. The PPPM costs in the first 12 months for those receiving first- and second-line therapy were highest for those receiving carboplatin plus docetaxel as first-line therapy and were lowest for those receiving carboplatin plus etoposide. The PPPM costs were incrementally higher for those who received third-line vs second-line vs first-line chemotherapy regardless of initial first-line regimen, with PPPM costs ranging from $7200 to $9600 for those receiving 3 lines of chemotherapy.

DISCUSSIONWe conducted an analysis of patterns of utilization and costs of second- and third-line chemotherapy for patients with lung cancer from the perspective of a health insurer. We find that few patients receive second- and third-line therapy. In general, the lifetime costs of care for patients who receive chemotherapy do not vary substantially according to their initial regimen. Rather, what matters is whether they receive second- or third-line treatment.

Monthly costs of care were substantially higher for those receiving second-line treatment and were still higher for patients receiving third-line chemotherapy compared with costs for those receiving only first-line treatment. Expenditures for all services (such as inpatient stays, outpatient visits, and emergency department visits) increased for these individuals. Therefore, the total costs may reflect more intensive management at all levels. Observation times were significantly longer for persons who received second- and third-line treatments compared with those who received only first-line treatment.

Several factors were significantly associated with the likelihood of receiving second-line therapy. As has been found in other population-based analyses of lung cancer therapy,15,16 we find that older persons were somewhat less likely to receive second-line therapy. Increasing time between diagnosis and first-line therapy was associated with a lower likelihood of receiving second-line therapy. It is somewhat difficult to interpret this finding without clinical information, but delays in initiating first-line chemotherapy may be a marker of reduced physician or patient preference for chemotherapy in general or of clinical factors that delay the use of chemotherapy (eg, poorly controlled cardiovascular disease). Persons who received chemotherapy that included a platinum-containing agent (carboplatin or cisplatin) were less likely to receive second-line therapy than those who did not. Platinum-containing agents are recommended for first-line therapy17 but are poorly tolerated. Therefore, those who receive them in this setting may be less likely to seek second-line therapy.

During the study period, the use of the tyrosine kinase inhibitors gefitinib and erlotinib grew substantially as agents for second- and third-line therapies, replacing a proportion of injectable chemotherapy agents. Erlotinib seems to have made substantial gains in utilization as a second- and third-line treatment for patients with lung cancer. Following FDA restrictions on the use of gefitinib, this drug is now all but removed from general use in this setting. It is likely that most patients who were candidates for gefitinib are now being treated with erlotinib. It is unclear whether erlotinib is replacing other chemotherapy agents in order of treatment preference. It is clear that erlotinib is not being used substantially as a third-line agent for those who fail second-line therapy.

A modest proportion of patients who began chemotherapy received third-line chemotherapy. Most patients were given few administrations of third-line agents, and the intervals between administrations were irregular. This is understandable because survival is poor overall for patients with lung cancer, and it is likely that most patients who showed signs of progression after second-line treatment died before having the opportunity to receive third-line treatment or they or their physicians decided that the costs (monetary and treatment-related morbidity) of further treatment were not justified by the expected survival difference.


Non–small cell lung cancer comprises approximately 80% of all lung cancer cases. During the period of this analysis, 4 agents (docetaxel, pemetrexed, gefitinib, and erlotinib) were approved for use as second-line therapy in patients with refractory non–small cell lung cancer. For small cell lung cancer that progresses after initial treatment, agents that have shown activity as second-line treatment include oral etoposide, etoposide-cisplatin, cyclophosphamide-doxorubicin–vincristine sulfate, lomustine-methotrexate, paclitaxel, and topotecan hydrochloride.19 Our data suggest that a substantial fraction of chemotherapy used in second-line settings is inconsistent with FDA labeling or is not supported by clinical studies. This determination, combined with the finding of wide variation in the use of agents, suggests a need for quality improvement. Of note, persons who received chemotherapy that is not FDA approved had higher costs than those who used approved therapies in the second-line setting, although the absolute difference (stated as PPPM cost) is modest overall.

Author Affiliations: From the Fred Hutchinson Cancer Research Center (SDR, LST), Seattle, WA; the Division of Oncology (RGM) and the Department of Pharmacy (DKB), University of Washington, Seattle; ICON Lifesciences Group (DL), San Francisco, CA; and Genentech, Incorporated (CMR), South San Francisco, CA.

Funding Source: This study was supported by an unrestricted grant from Genentech, Incorporated.

Author Disclosure: Dr Ramsey receives grant support from Genentech. Dr Martins receives grant support from Amgen, Eli Lilly, Genentech, Infinity, and Pfizer. He is also a paid consultant for Genentech and reports receiving honoraria from Eli Lilly and Genentech. Dr Lubeck and Dr Reyes own stock in Genentech and are past and present employees, respectively, of that company. Dr Blough and Dr Tock 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, RGM, LST, DL, CMR); acquisition of data (SDR); analysis and interpretation of data (SDR, RGM, DKB, LST, DL); drafting of the manuscript (SDR, LST, CMR); critical revision of the manuscript for important intellectual content (SDR, RGM, DKB); statistical analysis (SDR); provision of study materials or patients (SDR); obtaining funding (SDR, DL, CMR); administrative, technical, or logistic support (SDR); and supervision (SDR).

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.

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5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non–small-cell lung cancer. N Engl J Med. 2005;353(2):123-132.

7. Ingenix Web site. Ingenix TouchStone. http://www.ingenix.com/Products/Employers/EmpBrokerMktCat/EmployerBrokersConsultants/IngenixTouchStone/. Accessed December 31, 2007.

9.Warren JL, Harlan LC, Fahey A, et al. Utility of the SEER-Medicare data to identify chemotherapy use. Med Care. 2002;40(8)(suppl):IV-55-IV-61.

11. National Cancer InstituteWeb site. Non–small cell lung cancer treatment (PDQ): purpose of this PDQ summary. http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/HealthProfessional. Accessed February 22, 2008.

13. Lin DY. Regression analysis of incomplete medical cost data. Stat Med. 2003;22(7):1181-1200.

15. Ramsey SD, Howlader N, Etzioni RD, Donato B. Chemotherapy use, outcomes, and costs for older persons with advanced non–small-cell lung cancer: evidence from Surveillance, Epidemiology and End Results–Medicare. J Clin Oncol. 2004;22(24):4971-4978.

17. National Comprehensive Cancer Network Web site. NCCN clinical practice guidelines in oncology: non–small cell lung cancer: V.2.2008. http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. Accessed March 27, 2006.

19. National Cancer InstituteWeb site. Small cell lung cancer treatment (PDQ): extensive-stage small cell lung cancer. http://www.cancer.gov/cancertopics/pdq/treatment/small-cell-lung/HealthProfessional/page7. Accessed February 22, 2008.

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