Affiliations of authors: S. D. Ramsey, C. M. Moinpour, L. C. Lovato, J. J. Crowley, Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA; P. Grevstad, S. E. Rivkin, Swedish Medical Center, Tumor Institute, Seattle; C. A. Presant, St. Vincent Medical Center, Los Angeles Oncology Institute, CA; K. Kelly, University of Colorado Health Sciences Center, Denver; D. R. Gandara, University of California, Davis, Sacramento.
Correspondence to: Scott D. Ramsey, M.D., Ph.D., Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., MP-900, Box 19024, Seattle, WA 981091024 (e-mail: sramsey{at}fhcrc.org).
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We performed an economic analysis as part of a Southwest Oncology Group (SWOG) multicenter, randomized clinical trial of vinorelbine plus cisplatin versus paclitaxel plus carboplatin for the treatment of advanced non-small-cell lung cancer. The goal of the analysis was to estimate the cost-effectiveness of the new regimen (paclitaxel + carboplatin) versus the standard SWOG therapy (vinorelbine + cisplatin). Health care utilization and outcome data were collected prospectively along with clinical data over the period of observation. Because of the extended follow-up period, the results also estimate the lifetime cancer-attributable costs of care for persons with advanced lung cancer when treated with the most widely used combination therapies for this condition.
![]() |
PATIENTS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The clinical study was a prospective, randomized, controlled trial of vinorelbine plus cisplatin versus paclitaxel plus carboplatin for the treatment of advanced non-small-cell lung cancer. Patients with stage IV or selected stage IIIb disease by the International Staging System for Lung Cancer were eligible. Patients with stage IIIb disease had positive pleural effusions or multiple ipsilateral lung nodules. Those with brain metastases were ineligible. Patients could not have previous chemotherapy or biologic therapy, but prior surgery and radiotherapy were allowed. The trial was open to all SWOG member institutions. SWOG study sites include oncology clinics affiliated with community hospitals and academic medical centers.
Patients were enrolled during the period from April 1996 through January 1998. Eligible patients were randomly assigned to one of two study arms: 1) cisplatin at a dose of 100 mg/m2 every 4 weeks and vinorelbine at a dose of 25 mg/m2 weekly or 2) paclitaxel at a dose of 225 mg/m2 plus carboplatin AUC = 6 every 3 weeks. Patients remained on treatment for a minimum of six cycles (maximum of 10 cycles) unless there was progression of disease or intolerable toxicity. Drug doses were modified on the basis of toxicity and response to treatment. The entire protocol, including protocol-mandated visits and monitoring, is described in detail in an earlier publication (2). Patients were followed for 24 months from the time of randomization.
Salvage therapies for patients suffering relapses or disease progression were not protocol specified and included a variety of systemic chemotherapeutic agents and radiation therapy.
Tumor response rates and overall rates of survival were computed for each treatment arm. To assess cancer-related quality of life, the Functional Assessment of Cancer TherapyLung Questionnaire was administered at the time of randomization and at 3 months and 6 months after randomization (3).
Economic Analysis
Both the clinical and economic analyses were conducted as intent-to-treat analyses. The perspective of the economic study was that of the health insurer responsible for all cancer-related medical care costs. The economic analysis was originally planned as a cost-effectiveness analysis with survival as the primary measure of effectiveness (i.e., cost per year of life gained). Because the clinical study found no statistically significant differences in survival or quality of life, the economic analysis was modified from a cost-effectiveness analysis to a cost-minimization analysis. In this framework, the goal of the analysis is to identify the least costly approach to treatment.
Cancer-related costs include the direct costs of therapy (e.g., protocol chemotherapy and administration costs) and the costs associated with treating consequences of therapy, both intended and unintended (e.g., side effects). Special forms were designed to capture resource use related to therapy and the consequences of therapy (Table 1). Dollar costs drawn from nationally representative databases were assigned to each resource (Table 2
).
|
|
Because the trial was conducted at several SWOG-affiliated study sites, each with varying internal capacities to record resource use information, a specially designed resource use form was designed to track therapy-related resource use. The forms were designed to track resources used that were related to lung cancer care for all study participants over the 24-month period of observation. The findings of Jaakkimainen et al. (4) guided our decision to monitor medical resource use for a longer period. In the trial conducted by Jaakkimainen et al. (4), downstream resource use was greater for the supportive care arm compared with the chemotherapy arm, resulting in a larger incremental cost per year of life gained. Medical resource use forms distinguished between inpatient and outpatient care as well as care received at home and in nursing homes. Site staff were instructed to monitor resource use outside the study site by checking with potential providers of care in their community. In training sessions, study leaders met with site staff to address potential issues that might arise when tracking care outside the SWOG institution and to identify solutions. Related nonmedical resources (e.g., patient transportation to and from the clinics) and effects of treatment on workplace productivity (i.e., indirect costs) were not assessed for this study. Two resource forms were created: 1) a form tracking most protocol and nonprotocol resource use during the first 6 months of the study and 2) a less detailed second form tracking the most costly resources consumed from month 6 through the end of the observation period. Table 1 lists the goods and services tracked on each form.
Nurse-coordinators at each study site were given resource forms for each patient at the time they were enrolled. All on-site resource use data were based on chart audits conducted by site staff. The reviews typically involved multiple patient records (e.g., outpatient clinic, hospital, and nursing home). Cancer-related resource use that occurred outside the study sites was recorded on the basis of patient interviews at scheduled clinic visits.
The resource use forms identified the number of patient visits for nonprotocol salvage therapies (chemotherapy and radiation therapy) and whether the therapy was given in inpatient or outpatient settings, but they did not identify the specific agent or dose. Because an unexpectedly high proportion of patients received salvage chemotherapy in both arms of the study, we took additional steps to determine treatment costs for these services. During the analysis phase, we identified 190 patients who received salvage therapy. Of that group, we randomly selected 57 patients for a detailed chart audit (24 patients in the vinorelbine plus cisplatin arm and 33 patients in the carboplatin plus paclitaxel arm; budgetary limitations prevented full sampling). The study coordinator reviewed charts for that group of patients to identify the type of salvage therapy received, dosing schedules, and duration of therapy. In cases where the dose varied, we based cost estimates on the higher dose. We applied the proportions of patients receiving specific sequences of salvage therapy in the sample to the total number of patients in each treatment arm who had salvage therapy. Visits for radiation therapy were captured for all patients. Radiation therapy costs were based on Medicare-allowable reimbursements for doses and sites.
Analysis
Costs over the years of observation were totaled after adjustment to 1998 dollars with the use of the medical care component of the consumer price index. We present the results with costs in years beyond year 1 discounted at 3%, as is recommended for economic analyses of medical therapies where costs and benefits accrue beyond 1 year (5). Averages, standard errors, and 95% confidence intervals (CIs) for total costs were computed for each treatment arm with the use of a method developed to account for dependent patient censoring (6). Dependent censoring is a problem in most cost-to-event analyses in medicine (7,8). Applying traditional analytical methods to costs under dependent censoring can lead to substantial overestimation (9). The 95% CIs created from the standard errors are asymptotic and are derived by use of the counting-process formulation for the KaplanMeier estimator of survival. The estimate of variance used to construct the CIs is a function of empirical quantities, including the observed survival distribution and its associated hazard function, and is implemented through a FORTRAN subroutine. Costs for the treatment arms were then compared with the use of two-sided Student's t tests. In a secondary analysis, important cost components were compared (e.g., chemotherapy and hospitalizations), after adjustment for multiple comparisons with the use of the Bonferroni method.
Role of the Funding Sources
The study was funded jointly by Glaxo Wellcome, Inc. (Research Triangle Park, NC) and Bristol-Myers Squibb, Inc. (New York, NY). The sponsors were allowed to review and comment on an earlier draft of this manuscript. We had complete independence in the design, conduct, and final reporting of the study.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
The clinical and quality-of-life results of SWOG S9509 are reported in detail elsewhere (2,10,11). We briefly review these results here. Post-randomization survival rates at years 1 and 2 were 36% and 16% for the vinorelbine plus cisplatin arm versus 38% and 15% for the carboplatin plus paclitaxel arm (P = .75 and P = .75, respectively) (2). Median survival was 8 months for patients in both the vinorelbine plus cisplatin arm and the carboplatin plus paclitaxel arm. Overall quality of life did not differ statistically significantly between study arms (11).
Among the 408 patients eligible for therapeutic analysis, rates of return of the resource use forms, stated as a proportion of surviving patients, were as follows: 13 weeks = 91.2%, 25 weeks = 87.7%, 13 months = 80.3%, 18 months = 76.3%, and 25 months = 68.4%. Therefore, 359 (180 in the vinorelbine plus cisplatin arm and 179 in the paclitaxel plus carboplatin arm) of the 408 eligible patients had resource use information for at least one time interval. Response rates were not statistically significantly different between study arms at each time period.
Table 4 lists the overall average costs and costs for each category of resource use in each arm over the period of observation. Average costs over the period of observation were $40 292 (95% CI = $36 226 to $44 359) for patients in the cisplatin plus vinorelbine arm and $48 940 (95% CI = $44 674 to $53 208) for patients in the carboplatin plus paclitaxel arm (P = .004). Most of the observed difference in overall costs was caused by higher drug costs in the carboplatin plus paclitaxel arm (difference of $11 863). Medical procedure costs were statistically significantly higher in the paclitaxel arm, whereas protocol chemotherapy delivery costs were significantly higher in the vinorelbine arm. Higher numbers of chest x-rays and computerized tomography scans of the chest and abdomen were the primary reason for higher procedure-related costs in the carboplatin plus paclitaxel arm. There was no difference in costs for growth factors, antiemetics (including 5-hydroxytryptamine-3 antagonists), or radiation therapy. Patients in the vinorelbine arm incurred, on average, twice the number of outpatient visits during the time of protocol therapy. Patients in the paclitaxel arm tended to use more ambulatory, hospital, and hospice services than did patients in the vinorelbine arm (Table 5
).
|
|
Average total costs by time interval are shown in Fig. 1. Average total costs for the first 6 months of care were $25 215 versus $34 819, and the costs for months 724 were $15 077 versus $14 121 for the vinorelbine and paclitaxel arms, respectively.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients who were initially treated with cisplatin plus vinorelbine received a lower proportion of the planned drug dose than those treated with carboplatin plus paclitaxel. These findings account in part for the greater costs associated with the paclitaxel plus carboplatin regimen. However, the higher delivered dose in the carboplatin plus paclitaxel arm did not translate into better survival or quality of life.
Second- and third-line therapy was common in both arms of the study. Because the cost of paclitaxel was a major component of the difference in total costs between arms, and a high proportion of patients in the cisplatin plus vinorelbine arm later received salvage therapy with paclitaxel, salvage therapy was a potentially important issue. Because the average administered dose of paclitaxel during second- and third-line therapy was substantially lower than that during primary therapy, and more patients in the carboplatin plus paclitaxel arm received gemcitabine (a comparatively expensive agent) than those in the cisplatin plus vinorelbine arm, salvage therapy costs ultimately did not differ between arms.
More than 71% of the 171 000 individuals diagnosed with lung cancer have regional or distant spread of the tumor at the time of diagnosis (12). Changes in treatment for these individuals, therefore, can have profound consequences for the national health economy. We estimate, using the mean and 95% CI of the difference in total cost between the two regimens (mean = $8648; 95% CI = $2634 to $14 662) and the assumption that 75% of individuals with advanced non-small-cell lung cancer receive therapy, that widespread use of carboplatin plus paclitaxel will increase national expenditures for treatment of advanced lung cancer by $787 million (95% CI = $514 million to $1.06 billion) compared with cisplatin plus vinorelbine. Currently, carboplatin plus paclitaxel is the predominant therapeutic regimen for advanced lung cancer in the United States. Given the large difference in lifetime costs between arms and the lack of difference in clinical outcomes, we believe that this economic analysis should compel interested parties (physicians, health plans, and patients) to discuss the merits and drawbacks of each regimen.
Because the difference in drug costs is the primary component of the overall difference in costs between arms, one issue that may affect the interpretation of our results is the use of generic forms of paclitaxel. Generic forms of paclitaxel have recently been approved for marketing in the United States. We note, however, that the cost of the paclitaxel-based regimen is currently threefold greater than the vinorelbine-based regimen; thus, generic drug costs will have to fall substantially (along with widespread adoption of nonbranded paclitaxel) before the economic impact of treatment with carboplatin plus paclitaxel regimen is equivalent to cisplatin plus vinorelbine.
This economic study was unique in three ways. First, it was co-sponsored equally by the manufacturers of two of the competing chemotherapeutic agents (vinorelbine and paclitaxel) in the trial. This forward-thinking step by both manufacturers overcomes some of the traditional barriers to funding economic analyses alongside clinical trials, while also addressing potential conflicts of interest in study design and presentation (13). The latter issue is a commonly raised concern with regard to economic analyses (14,15). Second, the study was performed in a large, heterogeneous group of care settings (16). This heterogeneity enhances the external validity of the findings. Third, unlike most economic studies, medical resource use was tracked well beyond the initial protocol treatment period and, in fact, encompassed the entire survival history for most of the patients in the study. Historically, economic analyses performed alongside cooperative oncology group trials have not tracked costs or quality of life beyond the initial period of therapy (1719). Economists have expressed concern that economic analyses alongside clinical trials can be misleading if resource use is not monitored after the protocol period has ended (20,21). In our study, we continued monitoring resource use from 2 years after randomization on the basis of, as noted earlier, the experience of Jaakkimainen et al. (4). The American Society of Clinical Oncology and the National Cancer Institute encourage cancer cooperative groups to include economic analyses in selected phase III clinical trials (22). Practical issues related to conducting economic analyses alongside cooperative group clinical trials have also been published (23).
It is important to note the limitations of this study, particularly as they relate to health care payers. First, the economic analysis was performed alongside a clinical trial rather than as a study of typical clinical practice. The external validity concerns that apply to clinical trials also apply to economic studies performed alongside these trials. Clinical trials necessarily involve more intensive patient monitoring than typical clinical practice. Because the monitoring protocol was similar for both arms, our estimate of the difference in total costs effectively eliminates protocol costs. Others (2427) have noted that the total cancer-attributable costs of care for subjects enrolled in clinical trials are only modestly higher than the costs of cancer care in practice.
A second concern is that rates of return of the resource use forms fell in the final weeks of observation. However, the bulk of the missing resource use data occurred in the final reporting period. Because the great majority of total care-related expenses were incurred in the early part of the trial (when completion rates were highest) and response rates were similar in both arms at all points in the study, we do not believe that the missing data have biased the results.
A third concern is that we did not collect extensive information on agents and dosages used for second- and third-line chemotherapy. The chart audit suggests that 63% of patients initially treated with cisplatin plus vinorelbine and 20% of patients initially treated with carboplatin plus paclitaxel later received paclitaxel following protocol therapy, in all cases, at a substantially lower dose than initial therapy. We used these data to adjust the analysis to account for the costs of salvage therapy. If the audit differed substantially from the true rate of protocol use or doses for nonprotocol use of paclitaxel, the precision of our analysis would be affected.
Finally, our costs are based on Medicare reimbursements for services, procedures, and medications. Reimbursements for these items will vary from setting to setting. Costs for medications are based on the average wholesale price (the price usually paid by Medicare and Medicaid), but the prices paid by health care providers and private health insurers can be lower (28).
Previous studies have found that cisplatin-based therapy can be cost-effective as therapy for individuals with advanced non-small-cell lung cancer. Smith et al. (29) found that, compared with vinorelbine alone, cisplatin plus vinorelbine added 56 days at a cost of $2700, resulting in a cost-effectiveness ratio of $17 700 (1990 U.S. dollars) per year of life gained. Jaakkimainen et al. (4) compared vindesine and cisplatin with best supportive care and found that chemotherapy improved the mean survival by 12.8 weeks at a incremental cost of $14 778 (1990 Canadian dollars) per year of life gained.
This was the first large-scale economic analysis that the SWOG has conducted. Completing the resource use forms was burdensome for SWOG site staff, particularly for smaller clinical sites with few resources to allocate to this task. Independent research-oriented organizations have to carefully weigh benefits versus resource demands when selecting clinical trials. Conducting an economic analysis alongside a clinical trial substantially raises the demands on the coordinating center and study sites. Even with external funding support, it will not be possible to repeat analyses such as these for every oncology trial. This trial seemed particularly suited to an economic analysis, however, because of the burden of disease, costs of the agents involved, and expected differences in toxicity and survival. In addition, data gathered from this trial will allow researchers to refine the resource use forms so that data are collected more efficiently in the next study.
![]() |
NOTES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We appreciate the assistance provided by the following individuals: Kristie Beasley for chart review and management of resource use forms, Dorothy Giroux for analysis of dosing data, John Godwin for pilot testing of forms, and members of the Southwest Oncology Group Clinical Practices Committee for their input regarding forms design and cost study results. We also thank the clinical research associates and nurses who collected the health resource use data used to estimate costs in this trial.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1 Brown ML, Lipscomb J, Snyder C. The burden of illness of cancer: economic cost and quality of life. Annu Rev Public Health 2001;22:91113.[Medline]
2
Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, 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;19:32108.
3 Cella DF, Bonomi AE, Lloyd SR, Tulsky DS, Kaplan E, Bonomi P. Reliability and validity of the Functional Assessment of Cancer TherapyLung (FACT-L) quality of life instrument. Lung Cancer 1995;12:199220.[Medline]
4 Jaakkimainen L, Goodwin PJ, Pater J, Warde P, Murray N, Rapp E. Counting the costs of chemotherapy in a National Cancer Institute of Canada randomized trial in nonsmall-cell lung cancer. J Clin Oncol 1990;8:13019.[Abstract]
5 Gold MR, Siegal JE, Russell LB, Weinstein MC, editors. Cost-effectiveness in health and medicine. New York (NY): Oxford University Press; 1996.
6
Lin DY. Linear regression analysis of censored medical costs. Biostatistics 2000;1:3547.
7 Hallstrom AP, Sullivan SD. On estimating costs for economic evaluation in failure time studies. Med Care 1998;36:4336.[Medline]
8 Lin DY, Feuer EJ, Etzioni R, Wax Y. Estimating medical costs from incomplete follow-up data. Biometrics 1997;53:41934.[Medline]
9 Etzioni RD, Feuer EJ, Sullivan SD, Lin D, Hu C, Ramsey SD. On the use of survival analysis techniques to estimate medical care costs. J Health Econ 1999;18:36580.[Medline]
10 Moinpour CM, Lyons B, Lovato LC, Grevstad P, Kelly K, Crowley J, et al. Comparison of quality of life (QOL) outcomes for two chemotherapy regimens in non-small cell lung cancer (NSCLC). Lung Cancer 2000;29(Suppl 1):34.
11 Moinpour CM, Lyone B, Grevstad PK, Lovato LC, Crowley J, Czaplicki K, et al. Quality of life in advanced non-small cell lung cancer: Results of a Southwest Oncology Group randomized trial. Qual Life Res. [In press.]
12 Ries LA, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK, editors. SEER cancer statistics review, 19731996. NIH Publ. No. 992789. Bethesda (MD): National Cancer Institute; 1999.
13 Bennett CL, Smith TJ, George SL, Hillner BE, Fleishman S, Niell HB. Free-riding and the prisoner's dilemma: problems in funding economic analyses of phase III cancer clinical trials. J Clin Oncol 1995;13:245763.[Abstract]
14
Kassirer JP, Angell M. The journal's policy on cost-effectiveness analyses. N Engl J Med 1994;331:66970.
15
Friedberg M, Saffran B, Stinson TJ, Nelson W, Bennett CL. Evaluation of conflict of interest in economic analyses of new drugs used in oncology. JAMA 1999;282:14537.
16 Gulati SC, Bennett CL. Granulocytemacrophage colony-stimulating factor (GM-CSF) as adjunct therapy in relapsed Hodgkin disease. Ann Intern Med 1992;116:17782.[Medline]
17 Bennett CL, Stinson TJ, Lane D, Amylon M, Land VJ, Laver JH. Cost analysis of filgrastim for the prevention of neutropenia in pediatric T-cell leukemia and advanced lymphoblastic lymphoma: a case for prospective economic analysis in cooperative group trials. Med Pediatr Oncol 2000;34:926.[Medline]
18 Bennett CL, Stinson TJ, Tallman MS, Stadtmauer EA, Marsh RW, Friedenberg W, et al. Economic analysis of a randomized placebo-controlled phase III study of granulocyte macrophage colony stimulating factor in adult patients (>55 to 70 years of age) with acute myelogenous leukemia. Eastern Cooperative Oncology Group (E1490). Ann Oncol 1999;10:17782.[Abstract]
19
Pui CH, Boyett JM, Hughes WT, Rivera GK, Hancock ML, Sandlund JT, et al. Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. N Engl J Med 1997;336:17817.
20 Dummond MF, Davies L. Economic analysis alongside clinical trials. Revisiting the methodological issues. Int J Technol Assess Health Care 1991;7:56173.[Medline]
21 Coyle D, Davies L, Drummond MF. Trials and tribulations. Emerging issues in designing economic evaluations alongside clinical trials. Int J Technol Assess Health Care 1998;14:13544.[Medline]
22 Integrating economic analysis into cancer clinical trials: the National Cancer InstituteAmerican Society of Clinical Oncology economics workbook. J Natl Cancer Inst Monogr 1998;24:128. [Medline]
23 Bennett CL, Waters TM. Economic analyses in clinical trials for cooperative groups: operational considerations. Cancer Invest 1997;15:44853.[Medline]
24
Wagner JL, Alberts SR, Sloan JA, Cha S, Killian J, O'Connell MJ, et al. Incremental costs of enrolling cancer patients in clinical trials: a population-based study. J Natl Cancer Inst 1999;91:84753.
25
Fireman BH, Fehrenbacher L, Gruskin EP, Ray GT. Cost of care for patients in cancer clinical trials. J Natl Cancer Inst 2000;92:13642.
26
Bennett CL, Stinson TJ, Vogel V, Robertson L, Leedy D, O'Brien P, et al. Evaluating the financial impact of clinical trials in oncology: results from a pilot study from the Association of American Cancer Institutes/Northwestern University clinical trials costs and charges project. J Clin Oncol 2000;18:280510.
27 Aaron HJ, Gellband H, editors. Extending Medicare reimbursement in clinical trials. Washington (DC): Institute of Medicine, National Academy Press; 2000.
28 Cloud DJ, McGinley L. How drug makers influence Medicare reimbursements to doctors. The Wall Street Journal, 2000 Sept 27; p. B1.
29 Smith TJ, Hillner BE, Neighbors DM, McSorley PA, Le Chevalier T. Economic evaluation of a randomized clinical trial comparing vinorelbine, vinorelbine plus cisplatin, and vindesine plus cisplatin for non-small-cell lung cancer. J Clin Oncol 1995;13:216673.[Abstract]
Manuscript received June 21, 2001; revised December 11, 2001; accepted December 28, 2001.
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |