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Post Hoc Economic Analysis of Temozolomide Versus Dacarbazine in the Treatment of Advanced Metastatic Melanoma

From the Department of Internal Medicine and the Massey Cancer Center, Medical College of Virginia Campus at Virginia Commonwealth University, Richmond, VA; University of Pittsburgh Cancer Institute, Pittsburgh, PA; Department of Medical Oncology, Christie Hospital National Health Services Trust, Manchester, United Kingdom.

Address reprint requests to Bruce E. Hillner, MD, Virginia Commonwealth University, Box 980170, Richmond, VA 23298-0170; email hillner{at}hsc.vcu.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the potential economic implications resulting from oral temozolomide (TEM) compared with intravenous (IV) dacarbazine (DTIC) for metastatic melanoma.

PATIENTS AND METHODS: We performed a cost-effectiveness (CE) analysis using hazard ratios (HRs) from the phase III (Schering I95–018) trial comparing TEM 200 mg/m²/d orally for 5 days every 28 days with DTIC 250 mg/m²/d IV for 5 days every 21 days. Sensitivity analyses assessed a range of TEM’s efficacy and costs, direct nonmedical costs, and the DTIC schedule.

RESULTS: The trial found an overall survival trend favoring TEM; median survival times of patients treated with DTIC and TEM were 6.4 and 7.7 months, respectively (HR = 1.18; 95% confidence interval [CI], 0.92 to 1.52; intention to treat, P = .20). The mean increase in survival of TEM over DTIC was 1.1 months. The projected average costs per patient were greater with TEM than DTIC ($6,902 v $3,697, respectively). The incremental CE ratio using TEM was $36,990 per life-year or $101 per day of life gained. The CE ratio’s 95% CI ranged from -$65,180 (DTIC is more effective) to $18,670 per year of life gained. The CE ratios decreased 50% if direct nonmedical costs were included and increased 50% if DTIC’s efficacy was unchanged if given as a single daily dosage. Sixty percent of simulations found TEM with a CE threshold of less than $50,000 per life-year gained.

CONCLUSION: Although the base-case efficacy of TEM compared with DTIC was not statistically significant, its associated incremental CE would be comparable with many interventions. TEM for metastatic melanoma illustrates the tension confronting providers choosing between similar agents that markedly differ in convenience and costs.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE POTENTIAL VALUE of oral versus intravenous (IV) chemotherapy, especially when given with palliative intent, is receiving increased attention. Liu et al¹ recently interviewed cancer patients and found that 90% of patients preferred oral chemotherapy if no compromise in the frequency or duration of treatment response was associated with oral therapy. Drug development efforts are increasingly focusing on creating orally active compounds of previously identified agents.² The general use of these new agents will likely create a new tension to cancer care providers. The oral agents probably will have greater direct costs (necessary to recover development costs) but lower delivery costs (no personnel or devices) and direct nonmedical costs (lower transportation needs). Although total costs may or may not be increased, the cost burden will clearly shift dependent on whose perspective or budget is considered. If the efficacy of the new treatments is equivalent, then these financial and patient preference trade-offs will need to be confronted.

For metastatic melanoma, this situation has arisen. The prognosis of patients with metastatic melanoma is unfortunately uniformly poor. Despite numerous encouraging phase II studies, phase III comparisons have not found any chemotherapy or biologic therapy that is consistently superior to single-agent dacarbazine (DTIC).^3,4 DTIC is associated with a response rate of approximately 20%, with rare long-term complete responses and a median survival of 4 to 6 months. DTIC requires IV delivery with subsequent liver metabolism to the active metabolite, monomethyl trazenoimidazole carboxamide. Temozolomide (TEM) is a new agent that is rapidly and completely orally absorbed with predictable pharmacokinetics. TEM does not require hepatic p450 or other liver metabolism but is converted to the same active metabolite, monomethyl trazenoimidazole carboxamide, at physiologic pH and is not known to interact with other drugs.

A phase III comparison of TEM versus single-agent IV DTIC has just been completed (Schering I95–018), demonstrating TEM was associated with an increased survival. However, the benefit did not reach statistical significance (intent-to-treat hazard ratio [HR] = 1.18; 95% confidence interval [CI], 0.92 to 1.52). The study was of sufficient size that it had a 90% power to show that TEM was equal to DTIC. Therefore, clinicians may conclude that a more convenient, possibly more effective, and at least equally effective therapy to DTIC is now available. Alternately, clinicians may choose to continue to use DTIC because TEM was not shown to be superior and is more expensive. For these reasons, we performed an economic analysis projection of the future use of TEM from a United States societal perspective to illustrate the trade-offs.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Design of Schering I95–018
The trial studied patients with advanced, metastatic malignant melanoma with at least one measurable site who were previously untreated for their metastatic disease. The trial’s primary objective was to compare the overall survival in these patients, who were treated with either TEM or DTIC. TEM was administered orally once a day for 5 days at a starting dose of 200 mg/m²/d repeated every 28 days, and DTIC was administered IV once a day for 5 days at a starting dose of 250 mg/m²/d repeated every 21 days.⁵ The open-label study was conducted at 34 European and Australian centers. Patients had to have a World Health Organization performance status of 0, 1, or 2 and no evidence of CNS involvement.

The trial’s target accrual was a total sample of 260 patients, with a planned final analysis after 210 deaths. This sample size could detect a minimum median survival increase of 3 months (6 months for DTIC v 9 months for TEM, HR = 1.5) with an 80% power and an overall 5% level of significance (two-sided). Treatment was given until disease progression or occurrence of unacceptable toxicity for a maximum of 1 year. Routine hematology and serum chemistries were monitored before each course of treatment for potential dose adjustment. All patients had a physician assessment less than 72 hours before each dose of therapy. Dosage for each drug after the initial cycle was adjusted based on the absolute neutrophil count and platelet count by a predefined algorithm. Prophylactic antiemetics were administered at the discretion of the treating physician. Other chemotherapy, radiation, or biologic therapy was not allowed. Additional details are available elsewhere.⁵

The patient characteristics are listed in Table 1. The groups were well-balanced, with no statistical differences in all pretreatment categories including disease site. Approximately 90% of patients had a performance status of 0 or 1. Table 2 lists the primary results of the overall survival based on Kaplan-Meier estimates. The probability distribution of the HRs found with 90% power that the HR of DTIC was at least 1.0. In other words, TEM was at least as effective as DTIC at power of 90%. At all points beyond the first 30 days, TEM-treated patients had a superior survival.

Economic Evaluation
The primary viewpoint of this analysis is from a United States societal prospective and its cancer care providers. The primary assessment was an incremental cost-effectiveness (CE) analysis.⁶ The assessment attempts to make an effectiveness projection using the trial efficacy results. The assessment makes a small set of assumptions in addition to the trial entry criteria.

These assumptions are as follows: (1) Physician and evaluation costs incurred in the initial staging to determine whether this form of therapy was appropriate were excluded. (2) All patients are assumed to receive oral antiemetics before each daily treatment. Oral therapy has been shown to be as equally effective as IV therapy for mildly emetogenic chemotherapy.⁷ (3) Patient survival and costs of palliative therapy after the development of progressive disease were assumed to be the same independent of initial therapy and, therefore, not considered. (4) Protocol-specific costs, primarily radiologic imaging, were excluded. (5) Because maximum treatment was 1 year and less than 10% of patients were treated for 9 months, costs were not discounted. (6) The observed progression-free survivals may be biased because of more frequent and earlier assessments in the DTIC (every 21 days) versus TEM groups (every 28 days). Therefore, the assessment used the median survival HR, 1.18, for the progressive-free survival hazard for determining the fraction of patients that were treated per cycle.⁸ (7) Efficacy of treatment was estimated from the observed mean survival. (8) Although most patients with metastatic cancer have measurable out-of-pocket and lost wages because of their disease, it seems unlikely that these will substantially differ between oral or IV chemotherapy. Therefore, these costs were excluded.

Resources and Cost Valuation
Table 3 lists the resources used, the number of units per cycle, and each unit’s baseline price and range. In sensitivity analysis, high- and low-end cost estimates for DTIC were evaluated, and a broad range of TEM pricing was provided because the price has not yet been established in the marketplace. For both forms of chemotherapy, no new capital or equipment costs would be incurred.

Adverse Events
No treatment-associated adverse events requiring hospitalization occurred. The frequency of grade 3 or 4 toxicity showed no statistical difference between treatments per cycle of treatment. Therefore, no additional costs were included.

Personal Costs
Patients were assumed to see their physician 72 hours or less before initiating or continuing each course of therapy. For DTIC, nursing time was estimated at 1 hour for preparing and completing the infusion. For DTIC, additional costs are incurred for preparing the solution because of the risk of photo-degradation, but many insurers do not cover these preparation costs. These cost estimates were based on current reimbursements and not actual time monitoring plus overhead. Sensitivity analyses considered including the pharmacist’s preparation fee.

Nonmedical Costs
Recent guidelines for CE analysis recommend including direct and indirect nonmedical costs.⁹ Patients with advanced cancer, even if they have a good performance status, commonly need transportation assistance and emotional support during their office visits. Because this data was not collected in the trial, these were excluded from the baseline analysis. A sensitivity analysis included these costs, with an assessment made based on a projection where all patients were assumed to require a family member or companion’s assistance for a half day per office visit for evaluation or IV therapy. The cost of $50 per half day was based on estimates from Hayman et al.¹⁰

Modeling Effectiveness of Therapy
The efficacy of treatment was defined as the change in the mean rather than median survival observed in the trial.¹¹ The mean increase was 1.04 months (95% CI, -0.43 to 2.52 months). In sensitivity analyses, the effects of using the median HRs for the efficacy of TEM were assessed.

Total Costs in Relation to Progression
Table 3 lists, on the left, the resources used per treatment cycle, the number of units per cycle, and the unit price and range. On the right of Table 3 are the aggregate base-case costs for the TEM strategy and the range of three different DTIC projections. Costs were incurred only if the patient was progression-free at the scheduled dosing interval (eg, days 1, 29, 57, 85, and so on for TEM and days 1, 22, 43, 74, and so on for DTIC). As stated in the assumptions, the recurrence hazard for DTIC was assumed to equal the survival HR. The median progression-free survival for TEM of 57 days was taken directly from the trial observation. This was converted to a daily recurrence risk of 1.2% per day. Multiplying this daily recurrence risk by the DTIC HR, 1.18, led to an estimated median progression-free survival of 48 days (95% CI, 38 to 63 days) for DTIC.

Utilities and Patient Preference Scores
The primary end point of the trial was overall survival. Health-related quality of life was assessed using the validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-30 from the patient’s perspective and focused on confirming an increase in quality of life if a clinical response occurred. No preference-based questions were used or attitudes explored comparing IV versus oral therapy. Unfortunately, only approximately two thirds of patients completed the initial evaluation questionnaire, and subsequent completion was poor. Although available data showed that TEM patients compared with DTIC patients were more likely to maintain or improve their quality-of-life score at 12 and 24 weeks, the number of patients responding was small, and this was not a primary end point.⁵ Therefore, a quality-adjusted survival analysis was not performed.

CE
The economic analysis was an incremental CE assessment: the additional cost of the TEM treatment for each added year of survival provided compared with the DTIC treatment. The baseline model was from a health system or centralized payer perspective because only direct medical cares were included. Direct nonmedical costs were included in the high-cost estimate of the DTIC treatment, and indirect costs were assumed not to differ between strategies. Sensitivity analyses of various factors were performed as outlined.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Baseline Analysis
Table 4 lists the results. Patients in each cohort received an average of slightly less than four treatment cycles (TEM, 3.71 cycles and DTIC, 3.92 cycles). The TEM treatment had an average per patient cost of $6,902 compared with $3,697 for the DTIC treatment, for an increase of $3,205 per patient. Using the mean increase survival time observed in the trial of 32 days, the incremental CE ratio, which is the additional cost to gain an additional 1 year of life, was $36,990; the additional cost to gain an additional day of survival was approximately $101.

Using the 97.5% CI of the survival difference is complex. The DTIC strategy would have decreased costs because the duration of response and number of patients treated was lower. The cost difference between the strategies increased to $3,920. However, because TEM would increase survival by 76 days, the incremental CE ratio would decrease to $18,670 per life-year gained.

Sensitivity Analyses
DTIC cost estimates. The analysis was quite sensitive to the extremes of the DTIC cost estimates. The high-cost scenario, where additional costs for pharmacy preparation of the IV infusion and direct nonmedical costs were included, found that the difference in costs decreased approximately 50%. Therefore, the baseline CE ratio decreased approximately 50% to $17,300 per life-year gained. In the low-cost scenario (1-day infusion of DTIC at 850 mg/m²), no pharmacy preparation or direct nonmedical costs leads to an approximate 50% increase in the CE ratio to approximately $60,000 per life-year gained.

TEM cost estimate. If the drug cost for TEM were decreased from $1,500 to $1,000 per treatment, then the CE ratio would decrease to $15,600 (95% CI, -$13,400 to $9,830). If the lower TEM drug cost of $1,000 per cycle was combined with the high-cost DTIC scenario estimate, then TEM would be the dominant treatment strategy, with lower costs and higher efficacy ($4,111 saved per life-year gained; 95% CI, $45,400 saved per life-year gained to $3,300 additional per life year gained). Using the common threshold of $50,000 per life-year gained and the base-case efficacy, the threshold price for TEM would be $1,805 per course.

Median Survivals
If the TEM survival advantage is more accurately projected by the median survival and not the mean survival, the CE ratios will change modestly ($29,590 using the intent-to-treat median survival and $21,370 using the treated eligible population median survival).

Threshold Analysis
An estimate of the relative chance of TEM compared with DTIC of having an incremental CE at or below the commonly used threshold of $50,000 per life-year found that 60% of the simulations meet this threshold.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Numerous cytotoxic, biologic, and immunotherapies have been evaluated in the hope of finding an effective agent or combination in metastatic melanoma. Unfortunately, no therapy has been found superior to single-agent IV DTIC.⁴ More often than not, DTIC is ineffective, with response rates of approximately only 20%. A new agent, TEM, has been developed that is metabolized to the same active agent as DTIC. For pharmacokinetic reasons associated with its longer serum half-life, TEM may actually be superior to DTIC. Because TEM is an oral agent, patient convenience would favor its use especially in light of the poor chances of any response to either agent.

The recent phase III comparison of TEM with DTIC found TEM to be at least as effective as DTIC and have a nonstatistically significant trend to greater survival. Therefore, an economic analysis projection of this comparison may provide important insights for cancer care providers and policy makers when confronting the decision to find additional financial resources to use a more expensive but more convenient agent with probably a modest survival advantage.

In this post hoc analysis, the survival data was taken directly from the phase III comparison of TEM and DTIC. The results showed that using the mean survival difference observed in the trial and the initial average wholesale price for TEM, the incremental CE is approximately $37,000 per life-year gained or approximately $100 per day of survival. Although league tables ranking the incremental CE of new medical interventions are fraught with limitations and controversy, these results for TEM of approximately $40,000 per life-year gained are less than the commonly used standard of hemodialysis for end-stage renal disease.¹² Using the Canadian guidelines, this level would receive a "C" recommendation because the new therapy is more effective, but the CE ratio is between $20,000 and $100,000 per year.¹³

The willingness of many oncologists, purchasers, and regulators to accept and use these results is uncertain. Many clinical trials in advanced cancers are designed to detect a minimal threshold improvement of a 3-month increase in survival or a minimal HR difference of 50%. Using such a threshold, the I95–018 trial would be interpreted as negative or at least under-powered. Whether CE analyses should be performed on statistically nonsuperior treatments is controversial.¹⁴ However, because the I95–018 trial showed a trend to an improved survival and no other more effective agent is available, the threshold simulation may be particularly helpful. The projected incremental CE ratio was less than $50,000 per life-year in approximately 60% of simulations. In addition, it is not likely that additional phase III comparisons between the two agents will be forthcoming.

An impetus for our interest in this project began with an earlier project that assessed the CE of adjuvant interferon for high-risk (node-positive) primary melanoma patients.¹⁵ As part of that assessment, a panel of melanoma specialists described a broad range of patterns of care at their institutions for patients with metastatic melanoma.⁴ Most patients with good performance status received hospital-based continuous infusion interleukin-2 potentially combined with other immunotherapy or chemotherapy, others received phase I or II vaccine or other immunotherapy, and still others received chemotherapy, including cisplatin, DTIC with vinblastine, or carmustine. Only rarely did patients receive DTIC alone. The cost consequences of these treatments range from approximately $10,000 to more than $150,000 per patient. Although only approximately 8,000 United States patients die annually from melanoma, the cost consequences could reach $1.2 billion per year for treating advanced melanoma.

How TEM will be viewed in the marketplace will be a function of its efficacy, safety, and price. Although TEM was not recommended for approval by the Oncologic Drugs Advisory Committee to the United States Federal Drug Administration in March 1999, TEM is approved for another condition, anaplastic astrocytoma. Therefore, it may potentially be used off-label.

Because of the lack of a benefit covering oral medications in some commercial insurance plans, a few patients may be forced to continue to get office-based IV therapies. Some plans may not consider TEM to be a superior agent but still choose to provide TEM because it may be viewed as an oral equivalent of an IV therapy. This justification may be affected by the payer’s attitude of where the costs go as well as the amount.

The analysis was particularly sensitive to different assumptions about direct nonmedical costs and the practice style of DTIC delivery. Lost wages and the time of companion’s to accommodate patients for office-based IV therapy are not relevant to a health plan but are important from a societal perspective. A 5-day DTIC schedule was the appropriate baseline because it mimics the trial and is the regimen approved by the Food and Drug Administration. Many oncologists believe that response rates and duration are not affected by the schedule or daily dose of DTIC and, therefore, advocate the 1-day schedule.¹⁶ The 1-day DTIC cost projection would increase TEM’s CE ratio, but the estimated CE ratio would be less than $60,000 per life-year.

TEM’s average wholesale price of $1,500 per course is consistent with the pricing of recently approved IV chemotherapies, such as vinorelbine and gemcitabine, and is less than the price of paclitaxel or docetaxel. However, TEM is more expensive than two recently approved oral therapies for advanced breast cancer, capecitabine, which has a typical acquisition price of $700 per 3 week course, and anastrazole, which can be acquired for $200 per month. Patient willingness to pay or cost-share for the convenience of taking a probably slightly more or at least equally effective therapy for advanced cancer is an unexplored area. In addition, among the patients who completed the quality-of-life questionnaire in the I95–018 trial, a clear trend for better maintenance of their initial functional status was seen with TEM.

Providers in United States capitated environments and Canada have quickly shifted to using newer, more expensive chemotherapy for advanced non–small-cell lung cancer based on numerous studies showing real but modest increases in response rates and survival. This analysis finds that the incremental costs per benefit of TEM are more than likely to be in the range of other new adopted therapies. Whether patient interest and/or demand for a more convenient, possibly slightly more effective, but more expensive therapy for advanced melanoma also leads to a shift to the new TEM therapy will only be learned with time.

	ACKNOWLEDGMENTS

 
Supported in part by a Faculty Research Award from the American Cancer Society and an unrestricted grant from Schering-Plough Corporation.

	REFERENCES

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Submitted July 9, 1999; accepted December 9, 1999.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hillner, B. E. Articles by Middleton, M. R. Search for Related Content PubMed PubMed Citation Articles by Hillner, B. E. Articles by Middleton, M. R. Social Bookmarking                            What's this?