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Journal of Clinical Oncology, Vol 25, No 17 (June 10), 2007: pp. 2442-2448 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.7284 Cost Effectiveness of Adjuvant Interferon in Node-Positive Melanoma
From the Departments of Surgical Oncology and Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Amgen Inc, Thousand Oaks, CA Address reprint requests to Janice N. Cormier, MD, MPH, Department of Surgical Oncology, Unit 444, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, PO Box 301402, Houston, TX 77230-1402; e-mail: jcormier{at}mdanderson.org
Purpose To assess the benefits of adjuvant high-dose interferon alfa (HDI) treatment for patients with high-risk melanoma. Methods We designed a decision-analytic probabilistic Markov model to simulate the natural history of patients with stage IIIA, IIIB, and IIIC melanoma and evaluate the outcomes with and without HDI treatment. Outcomes were in quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). Probability estimates and costs were derived from primary patient level data, while the efficacy of HDI and associated utilities were determined from published reports. The base-case analysis was a cohort of 50-year-old patients. Results HDI increased the median life expectancy in patients with stage III melanoma from 3.75 years in the observation cohort to 4.42 years in the HDI cohort. The difference in QALYs ranged from 0.31 years for stage IIIA patients to 0.60 years for stage IIIC patients treated with HDI. HDI was cost effective in patients with stage IIIB and IIIC melanoma, with ICERs of $95,304 and $76,068 per QALY gained, respectively. Using a threshold of $100,000 per QALY gained, HDI was cost effective for all stage III patients younger than 52 years. HDI was not cost effective for patients with stage IIIA disease and for subsets of patients older than 63 years with stage IIIB disease. Conclusion Our model demonstrates that the probability of HDI being cost effective varies substantially by melanoma substage. HDI showed the greatest benefit in terms of QALYs and was most cost effective in patients younger than 60 years with stage IIIC disease.
Surgical treatment alone has proven to be inadequate for patients with node-positive melanoma, with reported 5-year disease-specific survival rates ranging from 40% to 65% for such patients.1 The only agent that has shown any benefit as postoperative adjuvant treatment for these patients is the immunotherapy agent interferon alfa (  ), administered at a dosage of 20 million units/m2/d intravenously for 4 weeks followed by 10 million units/m2 given three times per week subcutaneously for 48 weeks. There have been five randomized trials2-6 as well as a pooled analysis of these studies7 comparing adjuvant high-dose interferon (HDI) treatment to observation alone or to the ganglioside BM2/keyhole limpet hemocyanin vaccine.2-5 However, all of these studies have indicated that there is only a modest increase in recurrence-free survival (three of five trials)2-6 and overall survival (one of five trials)6 associated with HDI. Despite these results and the fact that HDI has been approved for the treatment of high-risk melanoma by the US Food and Drug Administration and regulatory agencies worldwide, current treatment recommendations continue to vary widely.8 This is in part because of the significant toxicity associated with HDI.9 In particular, clinical trials of HDI have shown that grade 3 and 4 toxicity events occur in up to 78% of patients.2,3,10-12 A recent report noted that delays in HDI treatment or dose reductions were required in 28% to 44% of patients during the induction phase (month 1) and in 36% to 52% of patients during the maintenance phase.13 In addition, some clinicians have been skeptical that the findings from the clinical trials of HDI, which included heterogeneous populations of melanoma patients, may not apply to patients with micrometastatic nodal disease, designated as stage IIIA in the revised American Joint Committee on Cancer (AJCC) staging system.14,15 To provide guidance to clinicians in making recommendations for patients who are considered candidates for HDI, we used a model based on contemporary cohorts of patients, published utilities to assess the effects of treatment toxicity, and data on treatment efficacy from existing clinical trials, to determine the effectiveness and cost effectiveness of HDI in selected subsets of patients with node-positive melanoma.
Model Design We developed a probabilistic Markov model16 representing the natural history of node-positive (stage III) melanoma patients after completion of nodal dissection17 with seven health states (Fig 1). Death was programmed as two separate health states: death from metastatic disease and death from other causes that occur in the general population (extracted from the 2001 US life-tables)18 at a rate determined by age. Separate models were developed for patients with stage IIIA, IIIB, and IIIC disease, with transition probabilities calculated from actual patient level data. The model was designed to compare the outcomes after postoperative treatment with adjuvant HDI versus observation for a lifetime horizon. A 1-month cycle length was selected for the cohorts in order to reflect the differences in HDI dosing between month 1 versus months 2 to 12, as well as to account for dropouts during the 12-month treatment period. The model was designed and analyzed using TreeAge Pro 2006 (TreeAge Software, Williamstown, MA).
Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results in response to variations in model parameters. Variables to which our model was sensitive in a one-way sensitivity analysis were also examined in two-way sensitivity analyses. In addition, a probabilistic sensitivity analysis was constructed to control for all of the inherent uncertainties of the model. Beta distributions were used for all variables related to transition probabilities and utilities, while log normal distributions were applied for all variables related to costs. Following this, a Monte Carlo simulation with 50,000 draws was performed and used to estimate 95% CIs for the incremental cost-effectiveness ratio (ICER).19
Assumptions
Data
Transition Probabilities
Quality of Life Quality of life was incorporated into the model by using published utility weights for melanoma patients receiving HDI reported by Kilbridge et al.24 These utilities incorporate the impact of adverse effects associated with HDI. In a sensitivity analysis, we tested a range of utility weights from an overview of melanoma cost-utility studies.25,26 Direct melanoma-related costs were also incorporated into the model from the cost-accounting system of The University of Texas M.D. Anderson Cancer Center (Table 1). Unit costs were derived from actual institutional patient costs for eight patients for 18 months after surgical treatment. Costs were adjusted for inflation using the medical care component of the consumer price index29 and are expressed in 2005 US dollars. The cost figures obtained were compared with those reported in the literature,30,31 and the defined ranges in costs were used for the sensitivity analyses. For the base-case analysis, quality-adjusted life years (QALYs) and costs were discounted at a real annual rate of 3% to adjust for the relative value of a present year of life (or present dollars).
Model End Points
Among 50-year-old patients with stage III melanoma, the median life expectancy was 3.75 years in the observation arm and 4.42 years in the HDI arm, with a difference of 0.67 years in favor of HDI. When cohorts of patients were stratified according to melanoma substage, we found that the median life expectancy in stage IIIA patients was 8.33 years for patients in the observation arm and 9.50 years for patients in the HDI arm, with a difference of 1.17 years in favor of HDI. For the patients with stage IIIC disease, the median life expectancy shortened to 2.67 and 3.25 years for patients in the observation and HDI arms, respectively. The 5-year overall survival in patients treated with HDI compared with observation were 67% and 64% for patients with stage IIIA disease, 47% and 43% for patients with stage IIIB disease, and 37% and 32% for patients with stage IIIC disease, respectively. The 5-year recurrence-free survival in patients treated with HDI compared with observation were 61% and 59% for patients with stage IIIA disease, 41% and 37% for patients with stage IIIB disease, and 30% and 26% for patients with stage IIIC disease, respectively. Similarly, when overall survival and recurrence-free survival were examined according to age at diagnosis, there was a 4.2% and 4.5% increase in recurrence-free survival and overall survival for patients treated with HDI compared with observation for 30-year-old patients compared with an increase of 2.9% and 3.2% in 80-year-old patients, respectively. The base-case analysis showed an incremental cost of $48,129 and 0.56 QALYs associated with HDI, with an ICER of $85,776 per QALY gained. As the risk for melanoma recurrence increased in patients with advanced stages of disease, the total mean costs and ICER for HDI decreased. Specifically, the implementation of the HDI strategy yielded a gain of 0.31 to 0.60 QALYs when compared with the observation strategy for patients with stage IIIA versus IIIC disease. The ICER of the HDI strategy was $169,548, $95,304, and $76,068 for patients with stage IIIA, IIIB, and IIIC disease, respectively (Table 2).
The results of the sensitivity analyses are summarized in Table 3. The ICER was noted to vary widely according to age; for example, there was an increase ranging from $67,248 per QALY gained in 30-year-old patients to $219,864 per QALY gained in 80-year-old patients. Using a threshold of $100,000 per QALY gained, HDI was not cost effective for patients with stage IIIA melanoma but was cost effective for patients younger than 52 years with stage IIIB disease and for patients younger than 63 years with stage IIIC disease. The model was also sensitive to changes in the effectiveness of HDI in the first year, the utility of HDI, the costs of HDI in the first month, and the discount rate. In additional analyses, we simultaneously altered the benefits of HDI in the first year and the rates of disease recurrence. Figure 2 shows the relationship between the incremental cost effectiveness and varying the risk reduction of recurrence during the first year of HDI in patients with stages IIIA, IIIB, and IIIC melanoma. This shows that HDI was cost effective when the first-year risk reduction of recurrence associated with HDI approached, 46%, 27%, and 22% for patients with stage IIIA, IIIB, and IIIC disease, respectively. Using a more traditional threshold of $50,000 per QALY gained to define cost effectiveness, the first-year risk reduction of recurrence associated with HDI would have to achieve 80% for stage IIIA, 50% for stage IIIB, and 40% for stage IIIC patients (Fig 2) in order to be considered cost effective. The cost associated with intramuscular injections of HDI (months 2 to 12), the type of first recurrence, and the dropout rates from HDI did not alter the results.
In our probabilistic sensitivity analysis, we determined the median ICER of HDI to observation for all stage III patients to be $89,730 per QALY (95% CI, $48,764 to $234,475). The median ICER decreased with increasing burden of disease (Table 2). Using a threshold of $100,000 per QALY gained, the probability that HDI is cost effective for all stage III patients was 63%. The substage-specific results are depicted in Figure 3, which demonstrates that the probability that HDI is cost effective using a defined ceiling ratio of $100,000 per QALY gained varies substantially for patients with different substages of disease, from a probability of 0 for stage IIIA patients to 71% for stage IIIB patients to 100% for stage IIIC patients.
Our analysis showed that the absolute benefits of HDI treatment compared with observation decreased substantially with increasing age at diagnosis and varied with respect to the burden of disease. HDI showed the greatest benefit in terms of QALYs and was most cost effective in patients younger than 60 years of age with stage IIIC disease. This is in part because patients with stage IIIC disease are at the highest risk of disease recurrence (approximately 70% at 5 years), and therefore the benefits of HDI were reaped by a greater proportion of patients in this group. For the subgroups of patients with stage IIIA, IIIB, and IIIC melanoma, the differences in median life expectancy were 14 months, 7 months, and 7 months, respectively. By incorporating treatment-related utilities, we found that, despite the fact that the absolute benefits of HDI treatment in terms of median life expectancy were greatest for patients with stage IIIA disease, the gains in terms of QALYs were the least for this group. This can be explained by the fact that the benefits of HDI occur in the fewest patients with stage IIIA disease because there are fewer recurrences in this population. In terms of cost effectiveness, the ICER of HDI treatment for all stage III patients in this analysis was $85,776 per QALY gained, ranging from $169,548 per QALY gained for stage IIIA patients to $76,068 per QALY gained for patients with stage IIIC disease. Our sensitivity analysis demonstrated that for patients with stage IIIA melanoma, the first-year risk reduction of recurrence associated with HDI had to approach 46% to be considered a cost-effective treatment using a defining threshold of $100,000 per QALY. These ICER values are higher than those from previously published analyses of HDI treatment in high-risk patients with melanoma,27,28,32,33 which range from an estimated $13,487 per life year27 to $59,515 per QALY28 (costs adjusted to 2005 US dollars). Explanations for these discrepancies are related primarily to costing methods and outcomes reported. Only one study27 considered the costs associated with melanoma relapse, and although two studies included HDI administration and associated costs,27,29 they did not incorporate utilities to account for toxicity of treatment. There are several aspects of our analysis that distinguish it from previous studies. The most unique aspect is that the probabilities of melanoma recurrence were defined by a contemporary cohort of patients who had undergone precise pathologic staging and long-term follow-up. In addition, outcomes were defined in several subgroups on the basis of the current AJCC staging system. In the previously published cost-effectiveness studies, outcomes were determined exclusively from data from the Eastern Cooperative Oncology Group 1684 trial, with no differentiation made between patients with varying degrees of nodal tumor burden.27,28,32 Second, the effectiveness of the intervention (HDI) was determined by a pooled analysis of randomized control trials (level I evidence).7 Third, model utilities were based on published values obtained using the standard gamble methodology,24 a microcosting analysis was performed using patient-level data, and results were reported in terms of a defined threshold for ICER. Finally, extensive sensitivity analyses were performed to assess the robustness of the model, including transition probabilities, utilities, cost estimates, and discount rate. Except for changes in age and the effectiveness of HDI, reasonable variations in model parameters did not affect the results of the analysis. While the thresholds for cost-effectiveness analyses have not been well-defined, historically it has been accepted that $20,000 per QALY is cost effective, while values between $20,000 to $100,000 per QALY gained are potentially cost effective.19,34,35 More recently, however, decision makers have argued that these values are too low and that societal willingness to pay for health improvements is at least $100,000 per QALY gained, and probably even higher.36,37 Several widely accepted cancer practices have ICERs similar to or higher34 than those found in this analysis, including palliative fluorouracil-based chemotherapy versus supportive care for pancreatic/biliary cancer ($120,000 per QALY),38 breast cancer screening beginning at 40 years rather than 50 years of age ($140,000 per QALY),39 and antiemetic therapy with odansetron versus metoclopramide for cisplatin-induced nausea ($190,000 per QALY).40 Our study has several potential limitations. First, the probabilities of recurrence and death from disease were held constant across gender, which may not be precisely accurate. Second, our patient level data represented a population of patients treated at a single tertiary cancer center. With a median follow-up of 4.5 years, limited information is available for rates of recurrence beyond 10 years. Another potential limitation is that the analysis was based on the perspective of the health care system, rather than the societal perspective.19 In addition to direct medical costs, the broader societal perspective includes indirect costs such as patients’ time and out-of-pocket costs (eg, wages lost and transportation) related to their illness or its treatment. In reality, these indirect costs are difficult to capture and estimate accurately. To address this issue, our sensitivity analysis included a wide range of up to 200% beyond the base estimates. In this study, we modeled the benefits of HDI in several cohorts of melanoma patients using different outcomes (median life expectancy and QALY) so that the outcomes most important to an individual patient could be used in making decisions. Our analysis demonstrated that the survival benefits must be assessed in the context of potential toxicity and its effect on quality of life. However, while these results should provide a basis for assessing the tradeoffs between the burdens and potential benefits of HDI for an individual patient, the gains in recurrence-free survival time and overall survival need to be interpreted carefully, as they apply to the average time gained across a cohort, not to individual patients. Clinicians may find these data valuable when they discuss adjuvant treatment choices and the adverse effects of HDI with patients.
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: Jeffrey E. Gershenwald, Schering Plough; Merrick I. Ross, Schering Plough Research Funds: Janice N. Cormier, ASCO Career Development Award, NIH, K12 Award administered by M.D. Anderson Cancer Center Testimony: N/A Other: N/A
Conception and design: Janice N. Cormier, Yan Xing, Meichun Ding, Scott B. Cantor, Jeffrey E. Gershenwald, Merrick I. Ross Financial support: Janice N. Cormier Administrative support: Janice N. Cormier, Kristi J. Salter Provision of study materials or patients: Kristi J. Salter, Jeffrey E. Lee, Paul F. Mansfield, Jeffrey E. Gershenwald, Merrick I. Ross Collection and assembly of data: Janice N. Cormier, Yan Xing, Kristi J. Salter Data analysis and interpretation: Janice N. Cormier, Yan Xing, Meichun Ding, Scott B. Cantor, Jeffrey E. Lee, Paul F. Mansfield, Jeffrey E. Gershenwald, Merrick I. Ross Manuscript writing: Janice N. Cormier, Yan Xing, Meichun Ding, Scott B. Cantor, Kristi J. Salter, Jeffrey E. Lee, Paul F. Mansfield, Jeffrey E. Gershenwald, Merrick I. Ross Final approval of manuscript: Janice N. Cormier, Yan Xing, Meichun Ding, Scott B. Cantor, Kristi J. Salter, Jeffrey E. Lee, Paul F. Mansfield, Jeffrey E. Gershenwald, Merrick I. Ross
Supported in part by an American Society of Clinical Oncology Career Development Award, and National Cancer Institute, Clinical Oncology Research Development Program, 5-K12-CA088084 [GenBank] . Presented in part in the Expert Review of Pharmacoeconomics Outcomes Research and at the Society of Medical Decision Making, October 18-22, 2003, Chicago, IL; and the International Society of Pharmacoeconomics and Outcomes Research, May 18-21, 2004, Arlington, VA. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Kirkwood JM, Ibrahim JG, Sosman JA, et al: High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: Results of intergroup trial E1694/S9512/C509801. J Clin Oncol 19:2370-2380, 2001 6. Kirkwood JM, Ibrahim J, Lawson DH, et al: High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: Results of the Multicenter Eastern Cooperative Oncology Group Phase II trial E2696. J Clin Oncol 19:1430-1436, 2001 7. Kirkwood JM, Manola J, Ibrahim J, et al: A pooled analysis of Eastern Cooperative Oncology Group and Intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 10:1670-1677, 2004 8. Schuchter LM: Adjuvant interferon therapy for melanoma: High-dose, low-dose, no dose, which dose? J Clin Oncol 22:7-10, 2004 9. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
