Decision Framework for Chemotherapeutic Interventions for Metastatic Non-Small-Cell Lung Cancer

Jean-Marie Berthelot, B. Phyllis Will, William K. Evans, Douglas Coyle, Craig C. Earle, Louise Bordeleau

Affiliations of authors: J.-M. Berthelot, B. P. Will, Statistics Canada, Ottawa; W. K. Evans, C. C. Earle, L. Bordeleau, Ottawa Regional Cancer Centre, ON, Canada, and University of Ottawa; D. Coyle, Clinical Epidemiology Unit, Loeb Health Research Institute, Civic Campus, Ottawa Hospital.

Correspondence to: William K. Evans, M.D., F.R.C.P.C., Cancer Care Ontario, 620 University Ave., Toronto, ON M5G 2L7, Canada (e-mail: bill.evans{at}cancercare.on.ca).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Background: Best supportive care has long been considered to be the standard therapy for metastatic non-small-cell lung cancer (NSCLC). There is now evidence from randomized trials that a number of chemotherapy regimens can palliate cancer-related symptoms and modestly improve survival. We show how cost-effectiveness 1analyses can be used to make choices between different (ambulatory) chemotherapy regimens. Methods: Clinical algorithms describing the diagnosis, staging, and treatment of metastatic NSCLC were incorporated into Statistics Canada's Population Health Model. Using consistent methodology, we assessed the cost-effectiveness of several chemotherapeutic interventions: a combination of vindesine (VDS) plus cisplatin, etoposide (VP-16) plus cisplatin, vinblastine (VLB) plus cisplatin, vinorelbine (Navelbine; NVB) plus cisplatin, paclitaxel (Taxol) plus cisplatin, and gemcitabine (GEM) and NVB alone. We calculated the total chemotherapy costs in 1995 Canadian dollars, the cost per case, the average life-years saved, and the cost per life-year saved. Using the Population Health Model, we then constructed an advanced decision framework that rank-ordered the various treatment regimens so as to optimize benefit below various cost-effectiveness thresholds. Results: One regimen (VLB plus cisplatin) appears to result in better survival and lower health care expenditures than best supportive care. By use of cost-effectiveness thresholds of $25 000 and $50 000 per life-year gained, NVB plus cisplatin is the preferred regimen. When quality of life is considered, however, GEM is preferred to NVB plus cisplatin at a threshold value of $50 000. At thresholds of $75 000 and $100 000, paclitaxel plus cisplatin at a dose of 135 mg/m2 is the preferred regimen. At thresholds of $50 000 and above, best supportive care is the least preferred regimen. Conclusions: This decision framework allows the comparison of different treatment regimens based on various cost-effectiveness thresholds. Our analysis also supports the use of chemotherapy regimens and the abandonment of best supportive care as the standard of care for patients with advanced NSCLC. [J Natl Cancer Inst 2000;92:1321–9].



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Lung cancer is the leading cause of cancer death in North America (1). Non-small-cell lung cancer (NSCLC) is the most commonly seen histologic cell type, and its incidence is increasing yearly. Unfortunately, it usually presents in an advanced stage. Although metastatic NSCLC is incurable, many trials have shown that systemic chemotherapy can palliate cancer-related symptoms and modestly improve survival for this patient population (212). Economic evaluations have generally shown chemotherapy for lung cancer patients to be as cost-effective as commonly used treatments for other diseases (1316). In fact, active treatment with some chemotherapy regimens can even result in a lower cost of care compared with best supportive care (17), which, until recently, was the standard of care in Canada. Best supportive care is the management of cancer-related symptoms, including the use of palliative radiotherapy to relieve pain, antibiotics for infections, nutritional support, and other supportive care measures, as appropriate.

Given the increasing fiscal constraints on health care delivery in most countries, health care decision makers want to use interventions that provide the best "value for money." However, an array of economic evaluations, each showing a different treatment to be cost-effective for the same disease, gives little guidance as to which of the available treatments is preferred. Studies are often not comparable because of different methodologies, perspectives, or settings. In this analysis, we use a consistent methodology to estimate the cost-effectiveness associated with most of the chemotherapy regimens currently available for the treatment of metastatic NSCLC. Costs have been calculated assuming that chemotherapy is delivered on an ambulatory basis. Using these data, we developed a decision framework that ranks treatments on the basis of different thresholds of cost-effectiveness.


    METHODS
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Model for Assessment of Lung Cancer-Related Costs

The cost-effectiveness ratios of currently used chemotherapy regimens in metastatic NSCLC were derived from a model developed by Statistics Canada (Ottawa) as part of a larger project to simulate the health of Canadians (18). The Population Health Model (POHEM) integrates data on risk factors for major diseases affecting Canadians, disease onset and outcomes, health care utilization, and direct health care costs. In this model, a hypothetical cohort of people with demographic and labor force characteristics, risk factor exposures, and health histories typical of Canadians is generated. The POHEM model (18) and the lung cancer submodel have been reported previously in detail (19).

The lung cancer submodel assigns individuals to a particular histologic cell type and stage based on data collected from the Canadian Cancer Registry and from provincial databases (the Alberta Cancer Board and the Ontario Cancer Registry). It then assigns treatments, disease progression, and survival based on data from provincial cancer registries and clinical trials, supplemented by information from national physician surveys and expert opinion. Finally, it allocates costs to the various components of care appropriate for cell type and stage of disease, from the time of initial diagnosis to terminal care. For the purposes of this study, the costs associated with treating patients with metastatic NSCLC with different chemotherapeutic agents were assessed from the perspective of a provincial government payer in a universal health care system. Cost data in the model are in 1995 Canadian dollars. We did not discount financial costs or health benefits, since most patients with metastatic NSCLC die within 2 years of diagnosis (see Appendix for definition of "discounting"). In addition, we did not include the indirect costs incurred by patients or their families.

Costs of Care

Data from the Ontario Case Cost Project (1994/1995 and 1995/1996) were used to determine three different per diem rates—one for initial diagnostic work-up ($945.00), one for hospitalization for complications of treatment ($521.00), and a per diem for terminal care of $487.00 (20). Hospital length of stay was calculated from Statistics Canada's person-oriented database of hospital discharges (21). The average length of stay for those receiving best supportive care was 23 days. We used the results of a record linkage study in the province of Manitoba, which determined that patients receiving chemotherapy in 1990 were observed to spend an average of 6 fewer days (total, 17) in the hospital for terminal care than those receiving only best supportive care. This difference was eliminated in sensitivity analyses (see Appendix for definition).

The cost for each individual treatment (fraction) of palliative radiotherapy was estimated to be $138.00, based on a study by Earle et al. (22). This study included the costs of salaries and benefits, supplies, equipment, support services, and facilities overhead in the cost per fraction. The methodology used to calculate the total cost of palliative radiotherapy administration in 1995 was similar to that used in the National Cancer Institute of Canada BR5 study of NSCLC (7). That study determined that, on average, five fractions of palliative radiotherapy were given for symptom control during the terminal care of patients receiving only best supportive care, whereas only three fractions were required for patients who received palliative chemotherapy.

The cost of clinic visits for chemotherapy and radiotherapy ($68.60 per visit) was derived from local data at the Ottawa Regional Cancer Centre (ORCC). These costs included the following: personnel time for physicians, nurses, and clerks; general administration; and overhead.

Chemotherapy-Specific Costs

The chemotherapy regimens that we evaluated are summarized in Table 1Go. The cost of the chemotherapy drugs and their administration has been reported previously for vinorelbine (Navelbine; NVB) and gemcitabine (GEM) alone and a combination of NVB plus cisplatin, vindesine (VDS) plus cisplatin, etoposide (VP-16) plus cisplatin, vinblastine (VLB) plus cisplatin, and paclitaxel (Taxol) plus cisplatin (1416). Because of restricted access to hospital beds for chemotherapy, the cost of NVB plus cisplatin was estimated only as an ambulatory regimen, with the cisplatin administered on days 1 and 8 of the chemotherapy schedule (14). For similar reasons, cost estimates of paclitaxel plus cisplatin were determined for a 3-hour infusion of paclitaxel at dose levels of 135, 200, and 250 mg/m2 (31). At these same dose levels, it is assumed that 3- and 24-hour infusions are of equivalent efficacy (16). Chemotherapy-specific costs were based on the given doses of drugs and the average of the actual number of treatment cycles given.


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Table 1. Summary of chemotherapy treatment regimens for advanced non-small-cell lung cancer*
 
Drug acquisition costs, as well as the cost of nursing and pharmacy/chemotherapy preparation time, were provided by staff of the Chemotherapy Treatment Unit of the ORCC. We estimated the number of laboratory and imaging studies from their reported frequency in the methods sections of the study protocols and determined their costs based on the fee schedule of the Ontario Health Insurance Plan. The number of physician assessments and associated fees were based on the number of chemotherapy treatments given and the expected number of physician encounters during these treatments. The rates and costs of treatment-associated complications were estimated on the basis of trial data, where available (2331).

The length of the hospital stay for any treatment-related complications was extracted from the reports of the chemotherapy studies or, if not reported, estimated on the basis of clinical experience using the same or similar chemotherapy regimens at the ORCC.

Survival

We obtained raw survival data for each regimen from the original trials. Having the raw data permitted recalculation of survival for only those patients with metastatic disease. We incorporated lung cancer-specific survival into POHEM by use of a piecewise Weibull survival function for each regimen. Mortality from causes other than lung cancer was obtained from Canadian vital statistics and built into POHEM as an annual hazards rate by age and sex. POHEM implements mortality with the use of a competing hazards approach. That is, patients are simultaneously at risk of dying of lung cancer and other causes. The hazards are used to calculate a waiting time until death. The event that has the shortest duration is deemed to have happened. POHEM was used to calculate the total survival gain between chemotherapeutic regimens, as well as between chemotherapy and best supportive care. Incremental survival differences were calculated as the area between survival curves, not the differences in median survival.

Utility Estimates

The effect of the various regimens on quality of life was incorporated into the analysis by estimating the quality-adjusted life-years (QALYs) gained through treatment (see Appendix for definition). QALYs are measured by weighting life expectancy by utility values, which represent preferences for the health states associated with each treatment.

We estimated the utilities of patients (see Appendix for definition) undergoing treatment with each of these regimens by surveying the members of the Lung Cancer Disease Site Group for the Ontario Practice Guidelines Initiative. Twenty-four oncologists with expertise in the medical, surgical, or radiation treatment of lung cancer were provided with clinical scenarios describing the toxic effects, inconveniences, and potential benefits of the chemotherapy regimens and new agents, as well as of best supportive care. The oncologists then estimated utilities on an anchored visual analog scale. On this scale, 0 represents death and 1 represents perfect health. The mean utility estimate (as evaluated by the oncologists) for each chemotherapy regimen was used in the cost-utility analysis.

Decision Framework

After determining the cost and survival associated with each regimen, we were able to create a league table of cost-effectiveness (see Appendix for definitions of league table, dominance, extended dominance, and threshold value) comparing the treatments with each other and with best supportive care. We ranked therapies according to the concept of extended dominance (32), whereby a more effective therapy is ranked above another therapy if the additional cost per additional benefit obtained is less than the pre-established threshold value. Therapies were ranked according to life-years saved and QALYs gained. Ranking was conducted according to a variety of threshold values (up to $100 000 per life-year or QALY gained) representing alternative maximum values that society might be willing to spend for a given benefit, such as a year of life. In Canada, $50 000 is a generally recognized threshold for a cost-effectiveness intervention (33).

Sensitivity Analysis

Survival and the numbers of days of terminal care hospitalization were varied to assess the robustness of our conclusions. In our base case, we assumed that the days of hospitalization for terminal care were equivalent in all of the chemotherapy arms and equal to that observed in a national database. In the sensitivity analysis, the duration of terminal care was increased to 23 days, which is equal to that of best supportive care. We also calculated the cost-effectiveness of the therapies, assuming survival gains, before the adjustment for QALY, of 25% and 50% less than those reported in the clinical trials.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Fig. 1Go provides an overview of the costs of the various chemotherapy interventions compared with those of best supportive care. Table 2Go summarizes the cost estimates for patients with metastatic NSCLC treated with various chemotherapy regimens. These costs include the costs of diagnosis, treatment, follow-up, relapse, and terminal care. Total average costs of care were derived from POHEM and take into account the fact that some patients die within the first year after diagnosis or die of other causes without incurring terminal care costs. The total average cost of best supportive care was estimated to be $25 904 Canadian dollars per case. It should be noted that this total cost is slightly different from the total cost for best supportive care shown in Table 1Go. The lower total costs shown in Fig. 1Go result from the simulation within POHEM, which assigns mortality from other causes, such as cardiac disease, to the simulated population. As a result, some "individuals" may not survive long enough to accrue the total cost of lung cancer care.



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Fig. 1. Metastatic non-small-cell lung cancer: chemotherapy interventions (solid boxes) versus standard therapy or best supportive care (open boxes) (1995 Canadian $) . * = Chemotherapy costs include the cost of drugs, their preparation and administration, inpatient and outpatient facility costs, and the costs of managing treatment-related toxic effects. The cost for best supportive care includes the cost incurred by palliative radiotherapy to relieve pain, the cost for antibiotics used in treating infections, and the costs for nutritional support as well as for other supportive care measures as appropriate. ** = Totals differ slightly from the numbers (given in the tables) generated by the Population Health Model because the Population Health Model simulates mortality from other causes as well.

 

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Table 2. Cost-effectiveness of chemotherapy treatments versus best supportive care for metastatic non-small-cell lung cancer (1995 Canadian $)*
 
Treatment with chemotherapy has been shown to reduce the cost of terminal care hospitalization by diminishing the number of days in the hospital (17 hospital days with chemotherapy versus 23 days with best supportive care) (7,13). Because we assumed this to be true for all chemotherapy regimens in this analysis, we found that, when compared with best supportive care, the use of VLB plus cisplatin in metastatic NSCLC decreased the cost of care per treated patient, while increasing survival. Therefore, compared with best supportive care, VLB plus cisplatin is a dominant treatment strategy.

Table 2Go also shows the cost-effectiveness and utility estimates of the different regimens as compared with best supportive care. The estimated mean utilities generated by oncologists for patients with metastatic NSCLC treated with different chemotherapy regimens ranged from a low of 0.52 for VLB plus cisplatin to a high of 0.65 for GEM. The utility for best supportive care was estimated to be 0.53. On this scale, 0 represents death and 1 represents perfect health. With the use of GEM as an example, the average cost per case was $28 463; the average survival was 0.9 years, which was 0.41 years longer than the average survival for best supportive care. The cost per life-year saved was $6800, the utility estimate for GEM was 0.65, and the cost per QALY gained over best supportive care was $8600. The total impact of treating all patients with metastatic lung cancer with GEM was calculated to be $142 million.

Table 3Go is composed of two tables that show a matrix comparing each intervention, including best supportive care, in terms of cost per life-year saved and cost per QALY gained. The tables show the incremental cost per life-year saved and cost per QALY gained of each regimen in the first column compared with the regimen in the top row. The regimen VDS plus cisplatin was not included in the comparison of cost per QALY gained, since Canadian oncologists rarely use this regimen and, therefore, did not calculate a utility for it. Table 3Go allows for the selective comparison of interventions.


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Table 3. Incremental cost per life-year saved and incremental cost per quality-adjusted life-year (QALY) gained: comparison between individual therapies for metastatic non-small-cell lung cancer*
 
As indicated earlier, "D" is used to indicate a "dominant strategy" (the therapy in the top row is both less expensive and more effective than the comparator regimen in the column). In such cases, it is not appropriate to show an actual cost number. For example, in the first table, there are four regimens that are dominant over VDS plus cisplatin and one that is weakly dominant because they have a lower average cost per case and greater or equal average survival of patients compared with VDS plus cisplatin.

In Table 4Go, the data from Table 3Go are used to rank chemotherapy interventions by both cost per life-year saved and cost per QALY gained on the basis of several alternative threshold values. The ranking of each regimen varies according to the alternative threshold values chosen. With the use of the common threshold of $50 000 per life-year gained, NVB plus cisplatin followed by paclitaxel plus cisplatin at a dose of 135 mg/m2 are the preferred regimens, with best supportive care ranking last. NVB plus cisplatin is also the preferred option, based on a threshold of $25 000. For thresholds of $10 000 and lower, VLB plus cisplatin is the preferred option. With the use of $75 000 and $100 000 as thresholds, paclitaxel plus cisplatin at a dose of 135 mg/m2 is the preferred therapy, with best supportive care again ranked last.


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Table 4. Ranking of chemotherapy regimens by cost per life-year saved and per quality-adjusted life-year (QALY), based on alternative threshold values*
 
Rankings in terms of cost per QALY gained are slightly different, reflecting the effect of incorporating quality-of-life effects. The major difference observed is the improved ranking of GEM at threshold values of $25 000 or above. This reflects the higher utility values assigned to GEM by oncologists.

Table 5Go provides the results of the sensitivity analyses that were performed. The duration of terminal care for chemotherapy-treated patients was increased to 23 days, which is equal to that of best supportive care. We also calculated the cost-effectiveness of the chemotherapy treatments, assuming survival gains of 25% and 50% less than those reported in the clinical trials.


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Table 5. Sensitivity analysis for cost per life-year saved as a function of terminal care hospitalization and survival*

 
By plotting both the incremental cost and life-years or QALYs of each regimen compared with best supportive care, the above results can be illustrated graphically (Fig. 2Go, A and B). With the use of these graphs, one can appreciate the relative contribution of these variables to the cost-effectiveness of each intervention. When considering cost per life-year gained, combinations of VLB plus cisplatin, NVB plus cisplatin, paclitaxel plus cisplatin at a dose of 135 mg/m2 have extended dominance over all other regimens. When considering cost per QALY gained, combinations of VLB plus cisplatin, NVB plus cisplatin, paclitaxel plus cisplatin at a dose of 135 mg/m2, and GEM alone have extended dominance over all other regimens.




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Fig. 2. Incremental cost (in Canadian $) of various chemotherapy regimens compared with best supportive care plotted against life-years saved (panel A) and against quality-adjusted life-years (QALYs) gained (panel B). BSC = best supportive care; NVB = vinorelbine (Navelbine); P = cisplatin; VP-16 = etoposide; Gem = gemcitabine; VDS = vindesine; VLB = vinblastine; T = paclitaxel (Taxol). The combinations of VLB plus cisplatin, NVB plus cisplatin, cisplatin plus paclitaxel at a dose of 135 mg/m2 have extended dominance over all other regimens (see Appendix for definition of extended dominance) for life-years saved. The combinations of VLB plus cisplatin, NVB plus cisplatin, cisplatin plus paclitaxel at a dose of 135 mg/m2, and Gem alone have extended dominance over all other regimens for QALYs gained.

 

    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
The management of advanced NSCLC has been evolving rapidly, with the introduction of many new active agents and regimens (34). Best supportive care had been considered the standard therapy in Canada until quite recently (35). Improved supportive care measures have facilitated the adoption of the newer treatment approaches. However, many physicians remain concerned about the cost associated with these treatments in the face of modest survival gains (17). In this study, we reviewed ambulatory chemotherapy administration in patients with metastatic NSCLC in terms of its impact on survival and cost, and we applied a unique decision framework methodology to compare the cost-effectiveness and cost utility of common chemotherapy regimens. This study is the first to incorporate extended dominance theory into an economic analysis of different lung cancer interventions to allow comparisons that are rational from a policy maker's perspective.

Comparisons of cost-effectiveness are usually made with "league tables" by which interventions are ranked solely on the basis of their cost-effectiveness ratios (32). However, these must be interpreted with caution because they often group together studies carried out with different methodologies (36). The assumptions made and the range and sources of costs included may affect the ranking of various technologies within a league table, leading to erroneous conclusions. We have used the same methodology, year of analysis, discount rate, utility assessment, method of costing, and setting of study (i.e., country of origin) for each analysis, allowing comparison of available interventions for the treatment of metastatic NSCLC (see Appendix for definitions). The rank ordering of the regimens is, therefore, relevant for the point in time of the analysis. However, changes in drug pricing and other factors might change the rank ordering in the future.

Policy makers overseeing an entire health care budget must make decisions that will maximize health by getting the highest value for the resources consumed. Their decisions often reflect a "utilitarian" philosophy of doing the greatest good for the greatest number of people. To do this, a technology must be assessed for its efficiency relative to all other potential uses of the same resources. However, if applied strictly, as in a league table, this philosophy can lead to a recommendation for a less effective treatment if its cost-effectiveness ratio is more attractive. In NSCLC, there are many potential chemotherapy drug combinations available. A number of randomized trials have shown improved survival and quality of life with some of these regimens (23,24,30,31), but unfortunately, the chemotherapy costs of the newer regimens tend to be high.

The decision framework we have developed addresses this problem. It looks at maximizing health within the constraints set by the value society attaches to measures of effectiveness. Decision makers can select the threshold they are willing to pay for a life-year or a quality-adjusted life-year. The framework then provides a ranking of interventions that fall below that threshold, ordered in relation to the survival gains they afford. The basic concepts underlying the decision framework can be applied to a broad range of health care systems. However, the results obtained from this Canadian analysis, in terms of the ranking of the interventions, may be not directly transferable to health care systems in other countries. Specific differences between health care systems need to be taken into account in the evaluation and ranking of different cost-effectiveness studies.

Our study has several limitations. First, the results are based on hypothetical rather than on real cases and the proportion of cases receiving specific tests and treatments is based on the proportion of cases in various categories in the databases used. The costs are average values derived from clinical algorithms describing the diagnosis, staging, and treatment of advanced NSCLC. Our survival data were taken from the results of clinical trials, which are biased toward the inclusion of patients with better prognostic characteristics than are seen in the general population. Furthermore, the data provided for GEM were based on a large phase II clinical trial, which provides a lower level of confidence than data from phase III trials. However, sensitivity analyses showed our results to be robust to assumptions about survival gain (Table 5Go). The assumption that the use of hospital beds and palliative radiotherapy for terminal care were equivalent for each regimen could have affected our results. If anything, though, the utility estimates suggest that the newer regimens may avoid some of these expenditures, making the paclitaxel- and NVB-containing treatments even more cost-effective.

We performed both a cost-effectiveness and a cost-utility analysis. The main reason for performing the cost-utility analysis was to present a comprehensive framework for both types of analysis. To estimate the utility of the various chemotherapy regimens, we used a convenient sample of treating physicians involved in the development of practice guidelines in the province of Ontario, Canada. It can be argued that these academically oriented treating physicians may value the consequences of chemotherapy side effects differently than patients. However, we would expect that both treating physicians and patients would rank a chemotherapy regimen with severe side effects lower than one with moderate side effects. We would, therefore, expect that the ordering of the different interventions would not be significantly different.

Treatment of advanced NSCLC incurs a relatively small cost per treated case. However, the impact on overall health care expenditure is substantial, given the high incidence of lung cancer in the general population. In this era of economic rationalization, a decision framework, such as the one we have presented, could be very useful to decision makers. This approach permits health-care providers, patients, and policy makers to apply their own values to the results of economic studies to inform decisions.

Using the POHEM, we were able to obtain rankings for each treatment under various threshold values in the Canadian health care environment. Assuming a threshold of $25 000, NVB plus cisplatin is the preferred chemotherapy regimen. At higher threshold levels, other regimens would be preferred, because of either higher utility or greater survival. This decision framework allows the comparison of different treatment regimens on the basis of various thresholds for the value of a life-year saved and the selection of preferred regimens by physicians and policy makers. As new information becomes available from clinical trials, it can be introduced into POHEM and the decision framework to assist decisions concerning the adoption of new therapies. This economic analysis also provides additional support for the abandonment of best supportive care as a standard of care for metastatic NSCLC.


    Appendix
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 


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    NOTES
 
L. Bordeleau is a Cancer Care Ontario Fellow.

We thank Bill Flanagan (Statistics Canada) for revising the Population Health Model and Rolande Belanger and Christine Allen for their administrative assistance.


    REFERENCES
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 

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Manuscript received September 14, 1999; revised June 9, 2000; accepted June 20, 2000.


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