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Economic Analysis of NCIC CTG JBR.10: A Randomized Trial of Adjuvant Vinorelbine Plus Cisplatin Compared With Observation in Early Stage Non–Small-Cell Lung Cancer—A Report of the Working Group on Economic Analysis, and the Lung Disease Site Group, National Cancer Institute of Canada Clinical Trials Group

Raymond Ng, Baktiar Hasan, Nicole Mittmann, Marie Florescu, Frances A. Shepherd, Keyue Ding, Charles Andrew Butts, Yvon Cormier, Gail Darling, Glenwood D. Goss, Richard Inculet, Lesley Seymour, Timothy L. Winton, William K. Evans, Natasha B. Leighl

From the Department of Hematology and Medical Oncology, Princess Margaret Hospital; Health Outcomes and Pharmacoeconomic Evaluation Research Centre, Sunnybrook Health Sciences Centre; Division of Thoracic Surgery, Toronto General Hospital, Toronto; National Cancer Institute of Canada Clinical Trials Group, Kingston; Division of Medical Oncology, Cross Cancer Institute, Edmonton, Alberta; Département de pneumologie, Hôpital Laval, Québec City, Québec; Ottawa Hospital Regional Cancer Centre, Ottawa; Division of Thoracic Surgery, London Health Sciences Centre, London; and the Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, Ontario, Canada

Address reprint requests to Natasha Leighl, MD, MMSc, FRCPC, Princess Margaret Hospital, Suite 5-105, 610 University Ave, Toronto, Ontario, Canada M5G 2M9; e-mail: Natasha.Leighl{at}uhn.on.ca

	ABSTRACT

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Purpose National Cancer Institute of Canada Clinical Trials Group JBR.10 study is among the landmark trials that have established third generation platinum-based adjuvant chemotherapy as the standard of care after resection of stages IB-II NSCLC, improving absolute 5-year survival by 15% and median survival by 21 months. This cost-effectiveness analysis of adjuvant chemotherapy from the perspective of Canada's public health care system was undertaken based on the JBR.10 study population.

Patients and Methods The primary outcome of the study was the incremental cost effectiveness ratio (ICER) expressed in dollars per life-year gained (LYG). Direct medical resource utilization data were collected retrospectively from trial data and medical records of patients enrolled in the JBR.10 study at the five largest accruing Canadian centers, from the time of random assignment until death or study closure (April 2004). Survival and available costs (2005 Canadian dollars [$CAD]) are presented both with and without discounting at 5% per year.

Results Utilization data were collected from 172 Canadian patients (36% of the trial population), 85 randomly assigned to observation and 87 randomly assigned to chemotherapy. The mean costs of treatment per patient in the observation and adjuvant chemotherapy arms were $23,878 and $31,319, respectively, with an ICER of CAD$7,175/LYG discounted (95% CI, –$3,463 to $41,565), and $10,096/LYG undiscounted (95% CI, –$819 to $55,651).

Conclusion Adjuvant vinorelbine plus cisplatin is a highly cost effective treatment that compares very favorably with other standard health care interventions.

	INTRODUCTION

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Lung cancer is the world's leading cause of cancer mortality¹ and causes 29% of all cancer deaths in the United States.² Surgery remains the treatment of choice for early stage non–small-cell lung cancer (NSCLC), but the outcome after resection alone remains relatively poor, with a 5-year survival rate of 22% to 67%.³ A meta-analysis in 1995 showed a statistically nonsignificant absolute 5-year survival benefit of 5% for cisplatin-based chemotherapy,⁴ but several subsequent trials had negative results.^5-7 In 2004, the International Adjuvant Lung Cancer Trialists study reported a 5-year absolute survival benefit of 4.1% with the use of cisplatin-based chemotherapy, but despite this, adjuvant chemotherapy still was not widely accepted due to the perception that its toxicity was not sufficiently offset by the modest survival benefit.⁸

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) JBR.10 study was a randomized trial which compared four cycles of cisplatin plus vinorelbine chemotherapy to observation after resection for patients with stage IB and II NSCLC.⁹ With a median follow-up of 5.2 years, the median survival after chemotherapy was significantly prolonged at 94 months, compared with 73 months in the observation arm, (hazard ratio [HR], 0.69; 95% CI, 0.52 to 0.91; P = .009). There was an absolute 5-year survival advantage of 15%, with 69% survival (95% CI, 62% to 75%) in the chemotherapy group, and 54% (95% CI, 48% to 61%) in the observation group (P = .002). Similar findings were also reported by the Adjuvant Navelbine International Trialist Association study,¹⁰ in which adjuvant chemotherapy resulted in an absolute 5-year survival gain of 8% over observation alone. These studies have now unequivocally established third generation platinum-based adjuvant chemotherapy as the standard of care after resection for early stage NSCLC.^11,12

Significant cost burden is associated with the diagnosis and treatment of lung cancer,¹³ and there is an urgent need to evaluate costs in relation to the benefits of new emerging costly therapies. Phase III trials are recognized as an important source of information for economic analysis.¹⁴ They provide an excellent opportunity to qualify resources in the context of a trial in which comprehensive follow-up is available. The Working Group in Economic Analysis of the NCIC CTG has established criteria on which economic analyses are undertaken alongside prospective clinical trials.¹⁵ However, prospective economic analyses cannot be conducted alongside all trials for reasons of resource constraints¹⁶ and retrospective analyses are valid alternatives. The objective of this study was to conduct a cost-effective analysis (CEA) of the NCIC CTG JBR.10 trial to determine the incremental cost-effectiveness ratio (ICER) of direct medical costs of adjuvant chemotherapy compared with observation from the perspective of Canada's public health care system, and to determine the incremental cost per life-year gained (LYG).

	PATIENTS AND METHODS

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A retrospective economic evaluation of the JBR.10 study was performed using the CEA technique. Treatment benefit was defined as the mean survival gain after random assignment. This was used in preference to median survival because mean survival is a parametric estimate of interval data, and permits the required arithmetic manipulation of incremental survival duration in the derivation of the ICER. Resources and costs were considered from random assignment until death or April 28, 2004, the date the JBR.10 study closed. Direct medical resource utilization data were identified from medical records of patients enrolled at the five largest accruing Canadian centers: University Health Network (UHN) and Mount Sinai Hospital, (Toronto, Ontario), Cross Cancer Centre, (Edmonton, Alberta), London Health Sciences Centre, (London, Ontario), Ottawa Hospital, (Ottawa, Ontario) and L'Hôpital Laval, (Quebec City, Quebec). These data were collected by two trained data abstracters (R.N., M.F.), and merged with the central study database. Costs are presented in 2005 Canadian dollars (CAD$). Nonmedical direct and indirect costs and costs related to subsequent clinical trial participation were not included. Costs were determined at Princess Margaret Hospital (PMH) and applied to all the resource utilization data. Available costs and survival were calculated both with and without discounting at 5% per year, according to conventional practice.¹⁷ Mean overall survival was calculated based on the restricted mean survival method,¹⁸ while discounted mean survival was derived based on the method of Zhao and Tian.¹⁹ The study protocol was approved by the ethics committee of each participating institution.

JBR.10 patients generated costs related to chemotherapy, investigations, medications, hospitalizations, radiotherapy, surgery/procedures, outpatient visits, and emergency room (ER) visits. Method for determination of these costs is described in the following sections.

Cost of Chemotherapy
The cost of chemotherapy included adjuvant chemotherapy for the JBR.10 study, as well as palliative chemotherapy administered at relapse. The doses and cycles of chemotherapy were obtained directly from JBR.10 trial data and medical records. Costs related to chemotherapy include the cost of the drugs, as well as their preparation and administration. The cost of outpatient chemotherapy unit visits was derived from the attributable hotel costs (including facilities costs, overhead, medical and surgical supplies and calculated at $17.64 per visit). This was added to the cost of pharmacist and pharmacy technician salaries, direct nursing care, and physician's fees based on the 2005 Ontario Health Insurance Plan (OHIP) fee schedule.²⁰ A time-in-motion study was carried out at PMH to obtain the nursing, pharmacist, and pharmacy technician times and costs involved for each individual chemotherapy drug regimen.

Cost of ER Visits and Acute Care Hospitalization
The frequency of ER visits and hospitalizations was derived from medical records. ER visit costs were based on the UHN sites and estimated at $244/visit exclusive of physician costs and medications (S. Tsui, UHN Accounting, personal communication, March 2006). Additional costs such as medications, surgery, and physician fees were added to this cost.

For acute hospitalizations, costs were derived by review of inpatient records as well as the current Ontario Case Costing Acute Inpatient Database (OCCAID). OCCAID provided information on cost of an International Classification of Diseases 10 coded admission with the mean length of stay and breakdown of these costs into nursing, pharmacy, laboratory, and diagnostic imaging costs. Where specific information for an admission was available from medical records, the corresponding pharmacy, laboratory, and diagnostic imaging costs were subtracted from this total cost to avoid double counting. The total admission cost for each corresponding International Classification of Diseases code was divided by the OCCAID mean length of stay to provide an estimated per diem cost. This per diem cost was then multiplied by the actual patient's length of admission, to arrive at an individualized admission cost. In instances where data for a particular admission were unavailable, the OCCAID total cost was used instead. Finally, physician fees based on the 2005 OHIP fee schedule²⁰ were added to this cost.

Costs of Outpatient Visits
The frequency of clinic visits was derived from outpatient record review. The cost of outpatient visits was determined by the hotel approximation method and included costs for the institution that could be attributed to the lung cancer clinic at PMH, and averaged over the number of visits. These included overhead, administration, facilities costs (including maintenance, housekeeping, and porter services), equipment central supply, and medical records. The average cost of nursing and supportive care staff was derived from 2005 salary levels, including benefits, educational leave, and hours attributed to the lung cancer clinic and workload. Physician fees were based on the 2005 OHIP fee schedule.²⁰ The salary costs were added to hotel costs to arrive at the clinic visit cost.

Cost of Surgery
The number and type of surgery were derived from medical record review. Costs were based on procedures undertaken at UHN (T. Marincic, UHN Accounting, personal communication, March 2006). Hotel cost was determined by the hotel approximation method and included the portion of hotel costs for the entire institution that could be attributed to the operating theaters. These included overhead, administration, and facilities costs. Anesthesiologist and surgeons' fees for the procedures were based on the 2005 OHIP fee schedule²⁰ and added to the hotel cost.

Cost of Radiation Treatment
Adjuvant radiotherapy was prohibited in the JBR.10 study and only used in the palliative setting at disease relapse. The dose and fractions of treatment were obtained from medical records. The cost per fraction was updated from an earlier economic analysis by Leighl et al²¹ and reflects attributed hotel costs and direct costs of radiation treatment at PMH. In 1999, the estimated cost per fraction was CAD$109.18. Allowing for inflation based on the Canadian Consumer Price Index, the 2005 cost was CAD$125.78/fraction. As these treatments were administered with palliative intent, computed tomography planning was not considered standard practice in Ontario and this was reflected in the costing methodology.

Other Costs
Inpatient and outpatient drug costs were determined by medical record review. Drug costs were based on hospital costs without adjustment for dispensing or mark-up. The number and type of laboratory and radiologic investigations were determined by medical record review with costs based on 2005 OHIP fee schedule (including professional and technical components).²⁰ Blood transfusion cost was provided by Canadian Blood Services and estimated at $322 per unit of red cell concentrate (L. Parry, personal communication, December 2005). For transfusions administered in outpatient setting, additional hotel costs were also included. The cost of visiting the outpatient transfusion unit was derived from staff salaries, attributable hotel costs including facilities costs, medical and surgical supply, and calculated at $44.76 per visit (of two units of blood transfusion).

Analysis of Costs
ICER was calculated by determining the ratio of the difference in the mean costs and difference in mean survival between the chemotherapy and observation arms. However, given that some patients were alive and continued to incur medical costs beyond study closure, the medical costs of the two arms were estimated using the censored medical costs method described by Lin,²² which utilizes a weighted complete case estimator. This method avoids the potential for biased estimates of the mean costs²³ in the presence of censoring as commonly observed with survival as the end point, when using simple case estimators. It takes censored patients into account by incorporating the censoring proportion at each death time in the weight of the estimator of the mean cost. Confidence intervals of ICER were estimated based on nonparametric bootstrapping method.²⁴

Sensitivity Analysis
The ICER calculation was based on survival difference of this economic subset rather than the JBR.10 population as costing was based on this subset. It is likely that costs of the JBR.10 population are different from the subset, and as such, possible bias may be introduced if the survival outcomes for JBR.10 were used. A sensitivity analysis was undertaken using survival differences of the JBR.10 population to examine the impact on ICER. Seven participants in the economic subset were also involved in subsequent clinical trials at the time of relapse. Whenever possible, clinical trial costs were excluded. However, because the impact of trial participation on survival is unknown, a sensitivity analysis was undertaken by removing these participants. In addition, major drivers of medical care costs, namely hospitalization, chemotherapy, and survival, were varied ± 20%, to examine the impact on ICER.

	RESULTS

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Patient Demographics
Data were collected from all 172 patients (36% of the JBR.10 trial) from the five Canadian sites, 85 were randomly assigned to observation and 87 were randomly assigned to chemotherapy. Baseline demographics (Table 1) showed that there were more patients with stage IB disease in the economic subset compared with the overall study population for both observation and treatment arms (55.3% and 52.9% v 45.0% and 45.9%; P = .015). All other factors were comparable between the economic subset and the JBR.10 population. Mean survival of patients in the observation and chemotherapy arms in the economic subset were 5.65 and 7.00 years, respectively, compared with the corresponding JBR.10 population of 5.57 and 6.37 years. Cox regression modeling between the subset and overall trial population found these minor differences to be insignificant (test of treatment interaction not significant, P = .2).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Histogram of bootstrap replicates for the incremental cost-effectiveness ratio (ICER; discounted).

Sensitivity Analysis
Seven participants received subsequent treatment on clinical trial protocols, all of whom were in the observation arm. Removing these participants from the analysis led to a decrease in incremental survival and increase in incremental cost, resulting in an increase in the discounted ICER to $10,202/LYG (90% CI, –$2,050 to $83,876). One way deterministic sensitivity analyses showed that ICER was most sensitive to changes in survival and that by varying its value by ± 20% resulted in change in the discounted ICER from $6,289 to $8,513. Changes in hospitalization cost resulted in an ICER range of $6,102 to $8,247 while varying chemotherapy cost led to an ICER range of $7,100 to $7,249 (Fig 2). When survival difference of the JBR.10 population was used instead of the economic subset, the discounted ICER increased to $12,197 (95% CI, –$3,426 to $17,563). Overall, the sensitivity analyses confirm the robustness of the ICER.

View larger version (7K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Tornado plot of sensitivity analysis of incremental cost-effectiveness ratio (ICER) based on 20% addition/discount.

	DISCUSSION

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This analysis shows that adjuvant vinorelbine and cisplatin chemotherapy results in a discounted ICER of $7,175/LYG compared with observation. The result was robust to sensitivity analyses. The highest contributors to cost expenditure in both groups were hospitalization, followed by outpatient visits, surgery, chemotherapy, and radiology, with higher direct medical costs in the adjuvant chemotherapy arm. This is an expected finding, as adjuvant chemotherapy required closer monitoring for toxicity and greater utilization of laboratory tests, outpatient visits, and antibiotics. Conversely, the increased disease relapse rate in the observation arm resulted in greater palliative treatment costs, such as palliative chemotherapy, hospitalization, and blood transfusions.

Although decisions on health interventions should not be based on economic factors alone, health care costs are increasing exponentially and no health care system is without resource constraints. This is particularly true with the advent of targeted therapies that have seen cancer treatment costs spiral beyond the means of many countries. Ethical and political issues aside, most health providers generally consider $20,000 to $100,000/LYG to be an economically reasonable value for the provision of a health intervention.²⁵ The ICER of $7,175/LYG in this analysis therefore compares very favorably. Indeed it is at least comparable, if not superior to other adjuvant oncology treatments commonly accepted by society as worthwhile, such as the addition of paclitaxel to doxorubicin and cyclophosphamide in breast cancer (7,715 Euros/LYG, 2000),²⁶ high-dose interferon alfa for melanoma compared with observation (US$32,600/LYG at 7 years, 1996),²⁷ or docetaxel versus best supportive care in advanced NSCLC (CAD$31,776/LYG, 1999).²¹ Economic evaluations of vinorelbine-containing chemotherapy in advanced NSCLC have also shown favorable findings.^28,29 While these comparisons provide alternative therapies for one to benchmark the CEA against, we do recognize that implicit in these comparisons is the flawed assumption that health resources are infinite. Nevertheless, it remains pertinent to note the cost effectiveness of implementation of smoking cessation program (US$2,587/LYG, 1997).³⁰

Limitations in this analysis include its retrospective nature, with potential for missed costs. It is possible that not all resource information has been captured fully. There may have been some ascertainment bias in the chemotherapy arm, particularly with resource use related to toxicity and treatment complications. However, it is probable that any ascertainment bias would have skewed the outcome in favor of the observation arm, thereby reducing the cost effectiveness of chemotherapy. Lastly, this CEA estimated the ICER with no adjustment for quality of life. It has been shown that despite treatment toxicity, JBR.10 participants treated with adjuvant chemotherapy maintained and improved their quality of life within the first year after surgery.³¹ Therefore, it is doubtful that the ICER would have increased significantly with quality adjustment, particularly with evidence that in most economic analyses, quality adjustment rarely results in a significant alteration in cost-effectiveness estimates.³²

In conclusion, the NCIC CTG JBR.10 trial is a landmark study that established third generation adjuvant platinum-based chemotherapy as the standard of care in resected early stage NSCLC. Our analysis shows that adjuvant chemotherapy is a cost-effective treatment that compares favorably with other health interventions routinely accepted as worthwhile by society and validates this as a standard of care. Cost should not be regarded as a significant barrier when offering potentially curative adjuvant therapy to patients with resected NSCLC.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Frances A. Shepherd, Pierre Fabre, GlaxoSmithKline; Timothy L. Winton, Pierre Fabre Research Funds: Lesley Seymour, GlaxoSmithKline Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Raymond Ng, Baktiar Hasan, Nicole Mittmann, Marie Florescu, Frances A. Shepherd, Keyue Ding, William K. Evans, Natasha B. Leighl

Financial support: Lesley Seymour, Natasha B. Leighl

Administrative support: Frances A. Shepherd, Charles Andrew Butts, Yvon Cormier, Gail Darling, Glenwood D. Goss, Richard Inculet, Lesley Seymour, Timothy L. Winton, Natasha B. Leighl

Provision of study materials or patients: Frances A. Shepherd, Charles Andrew Butts, Yvon Cormier, Gail Darling, Glenwood D. Goss, Richard Inculet, Lesley Seymour, Timothy L. Winton

Collection and assembly of data: Raymond Ng, Nicole Mittmann, Marie Florescu, Natasha B. Leighl

Data analysis and interpretation: Raymond Ng, Baktiar Hasan, Nicole Mittmann, Keyue Ding, William K. Evans, Natasha B. Leighl

Manuscript writing: Raymond Ng, Baktiar Hasan, Nicole Mittmann, Frances A. Shepherd, Keyue Ding, Lesley Seymour, William K. Evans, Natasha B. Leighl

Final approval of manuscript: Raymond Ng, Baktiar Hasan, Nicole Mittmann, Marie Florescu, Frances A. Shepherd, Keyue Ding, Charles Andrew Butts, Yvon Cormier, Gail Darling, Glenwood D. Goss, Richard Inculet, Lesley Seymour, Timothy L. Winton, William K. Evans, Natasha B. Leighl

	ACKNOWLEDGMENTS

 
We thank all the clinical trial co-coordinators at the five Canadian sites for their support and assistance during the data extraction. We thank A. Salvarrey, MD, H. Selormey, and A. Lau at Princess Margaret Hospital for assistance with data management and M. Whitehead at National Cancer Institute of Canada Clinical Trials Group for data management.

	NOTES

 
Supported by the Department of Hematology and Medical Oncology, Princess Margaret Hospital, the University of Toronto, and the National Cancer Institute of Canada Clinical Trials Group.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted October 5, 2006; accepted March 5, 2007.

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