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�r�V	��	bbb����Z����Annual cost of bevacizumab in the primary adjuvant treatment of ovarian cancer in the United States

Adam C. Walter, M.D., Kelly J. Manahan, M.D, John P. Geisler, M.D.,
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology
University of Toledo College of Medicine and Life Sciences
Toledo, Ohio

Corresponding author:		John P. Geisler, MD
University of Toledo College of Medicine and Life Sciences
					Division of Gynecologic Oncology
					3120 Transverse Drive
					Mail Stop 1194
					Toledo, OH 43614
Email: john.geisler@utoledo.edu
Running head: Cost of bevacizumab
Key words: ovarian cancer, chemotherapy, bevacizumab
Synopsis: The U.S. will have difficulty absorbing the cost of adding bevacizumab to improve progression-free survival by 3.8 months/per patient without improving overall survival.

Figures 2, Tables 3, Manuscript 2152 words, Abstract 199 words
Abstract
Objective: To determine costs of adding bevacizumab to the treatment of ovarian cancer on a societal scale.
Methods: A decision model was developed based on Gynecologic Oncology Group protocol 218. Arm 1 is 6 cycles of carboplatin/paclitaxel (CP). Arm 2 is carboplatin/paclitaxel with maintenance bevacizumab (CP+B). Actual and estimated costs of treatment plus complications were established for each regimen.  
Results: The direct cost was $3,138.72/person for Arm 1 and $190,630.47/person for Arm 2.  Annual cost to the U.S. economy for infusion of medications alone would be $58 million for Arm 1 versus >$3.5 billion dollars for Arm 2.  This equates to $14,656 per quality adjusted progression free life year versus $184,306 per quality adjusted progression free life year (QAPFLY) for Arm 1 and Arm 2, respectively. Thus, to increase 1 year of progression free survival (without influencing survival) for each woman with ovarian cancer, the U.S. healthcare expenditure would have to increase spending on ovarian cancer alone by >$3.5 billion.
Conclusion: Unless costs are significantly reduced, or overall survival is significantly increased, the U.S. would have difficulty absorbing the cost of adding bevacizumab to only improve progression-free survival by an average of 3.8 months/per patient without improving overall survival. 
Introduction
	Ovarian cancer is the second most common gynecologic malignancy to afflict women in the United States.  Currently, approximately 22,000 new cases are discovered annually.  The Gynecologic Oncology Group (GOG) has published multiple papers examining the best chemotherapy regimen for treatment of women with advanced ovarian cancer after primary surgical cytoreduction.  For many years a platin-based chemotherapy has been thought to be standard for first-line treatment of ovarian cancer. For the last decade and a half, a taxane in combination with either carboplatin or cisplatin has been the regimen of choice.  With GOG 172, Armstrong et al challenged the paradigm of intravenous platin/taxane and demonstrated improved survival with intraperitoneal platin/taxane.  Recently, focus has been placed upon targeted molecules as adjuvants to therapy.  Due to the research and other costs involved, these new therapies come associated with a higher price tag than chemotherapies that have been in use for many years.  In some countries, i.e., the United Kingdom, national task forces examine the costs of new therapies before allowing the use of them in a broad basis.  The National Institute for Health and Care Excellence (NICE) has recently found that bevacizumab is to expensive to use in the UK for relapsed platinum sensitive ovarian cancer.  Other countries like Deutschland have decided to allow bevacizumab maintenance as first line therapy for ovarian cancer.
	Health care costs in the United States have risen dramatically in the last decade to over $2,500,000,000,000 in 2009, totaling > 17% of the gross domestic product (GDP).  This is a profound increase considering the GDP fell 1.1% over the same period.  Of this total, public spending in the health care sector accounted for $1.2 trillion, an increase of nearly 8.7%.  The Medicare/Medicaid systems swelled to account for the increasing numbers of unemployed during the recent economic downturn.  Medicare alone accounted for $507 billion of the total and grew 8.1% in 2009.  
	The projected Medicare budget by the year 2019, the year in which more than half of the baby boomer population is projected to be moving to Medicare, will be nearly double the current $ 507 billion.  At this projected rate, health care costs would be nearly 19.5% of the projected GDP.  This projection also includes a projected 21.3% cut in Medicare reimbursement.  
	Cancer care in the United States costs over $225 billion dollars annually.  Direct costs are just under half of this at $103 billion annually.  Clinically, this amount becomes very significant, as 27% of patients with a cancer diagnosis are uninsured, and either delay treatment or do not obtain care based on financial reasons.
A large portion of costs in the oncology sector are directly related to the cost of antineoplastic agents.  They accounted for 7 of the top 15 hospital drug expenditures in 2007, and 15% of total prescription drug costs.   The majority of these are targeted novel agents such as bevacizumab, cetuximab, and trastuzumab.  As previously mentioned bevacizumab has been of recent interest as adjuvant therapy for ovarian cancer.  
	Although GOG 218 has so far shown a significant increase in progression free survival (PFS), the addition of bevacizumab increases the cost of therapy and management of side effects.  The objective of this study is to perform a cost effectiveness analysis of these regimens to determine which regimen is most cost effective.  This study essentially expands upon the work of Cohn et al and applies it to yearly estimates for cost in the United States.  Even the non-medical press is now questioning the costs of new/novel treatments.  Therefore, this analysis would hopefully guide us to judicially use chemotherapy so that while decreasing costs, we can increase the quality of care. 
Materials and Methods
A decision analysis model was created to estimate the costs and outcomes of treating women with advanced ovarian cancer following initial cytoreduction with carboplatin/paclitaxel (arm 1: CP) versus carboplatin/paclitaxel/bevacizumab (arm 2: CPB) using a health system perspective. The authors had access to results from GOG 218 beyond what was published in the referenced articles.  In the model analysis, all patients were treated with all planned cycles of chemotherapy.
 	Fig. 1 represents half of the model and depicts the format used to model treatment with CP.  The remaining half of the model is identical with the exception that it models treatment with CPB. A 5-year time horizon was assumed. 
In arm 1, patients receive carboplatin (AUC 6)/ paclitaxel 175 mg/m2 q21 days for 6 cycles.  In arm 2, all patients received carboplatin (AUC 6)/ paclitaxel 175 mg/m2 q 21 days for 6 cycles with bevacizumab 15 mg/kg q 21 days for 21 cycles (cycle 2-22). Probabilities for complications, recurrence, and survival were derived from the results of the GOG 182 and GOG 218 randomized trials as detailed below.  We did not adjust complication, recurrence, or survival rates for age, and we assumed that experiencing a grade 3�4 complication did not affect recurrence or survival rates.
With the addition of bevacizumab, the risk of grade 3�4 complications increased but overall survival increased.  Per published studies, terminal care was estimated at $40,000.  These estimates were based on 2011 Medicare costs as well as published figures.  The values used in the base case, as well as the ranges used for sensitivity analysis, are shown in Table 1.  Overall survival statistics are not yet available so statistics were performed using progression free survival.  Thus, instead of examining quality adjusted life years (QALY), quality adjusted progress free life years (QAPFLY) were examined.
Because of the uncertainty surrounding all estimates, values were varied widely in sensitivity analysis to determine the effect on results.  One-way sensitivity analysis was performed on all variables.  Incremental cost-effectiveness was measured as cost per quality adjusted life year survival, calculated by dividing the difference in cost between the strategies by the difference in survival among the strategies.  A willingness to pay threshold of $50,000 per QALY saved was chosen as a marker for comparison among regimens.  
Results
According to currently available data, GOG 218 demonstrated an increase in PFS with the CP arm having a progression survival (PFS) of 10.3 months while the CPB arm had a PFS of 14.1 months.  These numbers made up the base case analysis. Table 1 gives the PFS and sensitivity data used in analysis.
Examining the base case scenario, the cost of chemotherapy, chemotherapy associated medications, and infusion of them was $3,139/person for CP (6 cycles) and $190,640/person for CPB (6 cycles + 16 maintenance cycles).  If cost/QAPFLY is examined per person, it would be $14,656/QAPFLY versus $184,306/QAPFLY.  Comparing base case scenarios again, the incremental cost effectiveness ratio (ICER) was $760,918/QAPFLY.  This is compared to a typical willingness to pay threshold of $50,000/QALY (Table 2).
Siegel et al published that the annual incidence of newly diagnosed ovarian cancer was expected to be nearly 22,000 cases in 2011.  Eighty-five or more percent of women with ovarian cancer get chemotherapy (18,598 women).  Based on these numbers, annual cost to the U.S. economy for infusion of medications alone would be $58,379,122 for CP versus $3,545,336,740 for CPB, respectively. Since healthcare cannot increasingly spend money, one assumption to examine is how many women could be treated for the same current cost but with bevacizumab incorporated.  In accordance with that cap, only 306 women would be able to receive chemotherapy leaving 18,292 women without chemotherapy.  If all women receiving adjuvant chemotherapy for newly diagnosed ovarian cancer received bevacizumab, the annual expenditure would have to be increased 6,000% without increasing OS.  This would lead to the chemotherapy costs for newly diagnosed ovarian cancer (associated medications and infusions included) to be 3% of all direct cancer care expenditures while only helping a small percentage of patients. 
Sensitivity analysis was performed on multiple variables (Table 2 and Table 3).  To reach a threshold of < $50,000/QAPFLY saved, the PFS of CPB would have to increase to 62 months. Alternatively, the cost of bevacizumab 15 mg/kg for 21 cycles could be lowered to $0/person (direct costs) which still gives indirect costs of  $6,011/person. Giving the bevacizumab for free would make it cost effective with regards to progression-free survival with an ICER of <$50,000.
Discussion
In evaluating the costs of bevacizumab, two factors become prominent.  First, the lack of evidence to support any increase in OS makes it difficult to justify adding any additional costs to an already strained healthcare system,.  Without demonstrating an increase in survival, we are left with overwhelming costs for a 3.8 month increase in PFS.  In making the case for a modest increase in PFS of 3.8 months, the cost of the agent should be in proportion with its added benefit.  As bevacizumab would increase annual spending nearly 60 times the current regimen, the benefit is out of proportion to the cost.  
Secondly, the current US economy cannot support unrestrained growth in the health care sector.  Currently 54% of health care costs are paid through private funds, and as premiums increase to cover the rising costs, more Americans are unable to afford insurance.  A 1% increase in premiums will cause roughly 164,000 Americans to lose employer paid health insurance NOTEREF _Ref341768667 \h  \* MERGEFORMAT 7.  As the population ages, and a significantly higher percentage of the population depend on public programs, the problem worsens.  Medicare reimbursement is projected to decrease by 21.3% over the next 7 years, to accommodate the increasing patient volume.  As providers we will be pressed to provide excellent, relevant, evidence based therapies on a fixed budget.  
In Figure 2, a logarithmic graph is used to depict the relevant numbers from this study.  While the average total cost (direct and indirect) to treat one woman with ovrian cancer with CP is just over $3,000, to add bevacizumab would increase this cost to >$190,000/person.  To put this in relevant terms, treating each woman with CP+B would cost more than 3x the average household income in the United States.  Currently, the total cost of treating the approximately 18,500 women each year who require adjuvant chemotherapy for ovarian cancer is just over $58 million.  If the standard regimen was changed to CP+B, the cost would increase to $3.7 billion annually. This would be a significant portion of all the money spent on all cancer care in the US.  In fact, the treatment of newly diagnosed ovarian cancer would increase from 0.026% to 1.6% of the cost of all cancer treatments in the US.  Many other patients, men and women, would not be able to get care or the US would have to go further into debt.
Understanding and evaluating costs of our current and new therapies are vital to the success and sustainability of our public and private payers, as well as our patients.  We must understand that containing costs is not rationing care, it is providing the best care for the most patients.        
Conflicts of interest: The authors have no financial disclosures, conflicts of interest, acknowledgements, or funding sources for the manuscript.
References








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