Abstract
Objectives. Most guidelines consider FDG PET-CT to detect occult extra-pulmonary disease prior to lung metastasectomy. A cost-effectiveness analysis, using a Markov model over a 10 year period, was performed to compare two different surveillance programs, either PET-CT or whole-body CT, in patients with suspected pulmonary metastasised melanoma. Methods. Data from published studies provided probabilities for the model. Complication and care costs were obtained from standardised administrative databases from 19 hospitals identified by DRG codes (reported in 2009 Euros). For the cost calculation of PET-CT we performed a microcosting analysis. All costs and benefits were yearly discounted at respectively 3% and 1.5%. Outcomes included life-months gained (LMG) and the number of futile surgeries avoided. Cost-effectiveness ratios were in Euros per LMG. Univariate and probabilistic sensitivity analyses addressed uncertainty in all model parameters. Results. The PET-CT strategy provided 86.29 LMG (95% CI: 81.50–90.88 LMG) at a discounted cost of €3 974 (95% CI: €1 339–12 303), while the conventional strategy provided 86.08 LMG (95% CI: 81.37–90.68 LMG) at a discounted cost of €5 022 (95% CI: €1 378–16 018). This PET-CT strategy resulted in a net saving of €1 048 with a gain of 0.2 LMG. Based on PET-CT findings, 20% of futile surgeries could be avoided. Conclusion. Integrating PET-CT in the management of patients with high risk MM appears to be less costly and more accurate by avoiding futile thoracotomies in one of five patients as well as by providing a small survival benefit at 10 years.
After primary treatment of cutaneous malignant melanoma (MM) about one third of patients will develop metastatic disease in almost any major organ of the body [Citation1,Citation2]. In 7–21% of melanoma patients the lung is the initial site of recurrence [Citation3–7]. They are usually asymptomatic and typically detected by follow-up chest x-ray or more recently thoracic CT-scan [Citation8–10]. Suspicious nodules noted on a screening chest radiograph should be further investigated to better characterise the lesions as well as the presence of distant metastases [Citation11].
Most patients are not candidates for curative resection and are often treated with bio-chemotherapy. Although these systemic treatments generally produce high response rates (50–60%), long-term survival benefits appear to occur in less than 5% of patients. The benefit must also be balanced by the significant toxicity and monetary expense of these therapies [Citation12].
Complete pulmonary metastasectomy is the only factor affecting the overall survival associated with a 5-year survival ranging from 21 to 39%, as opposed to 3 to 5% for patients undergoing incomplete resection or non-operative management. Most patients recover fully from the procedure within six weeks, compared to several months of toxicity for people undergoing systemic treatments. In the absence of more active agents, surgery should be reconsidered in the treatment paradigm at least for some highly selected patients [Citation13,Citation14].
Improved survival is dependent on careful patient selection, with only 10–35% of all patients being candidates for complete resection [Citation4,Citation15,Citation16]. As half of the economic burden of MM is due to the care for metastatic disease, with surgery as the main cost driver, it is essential to perform a thorough preoperative imaging evaluation [Citation17].
Hybrid imaging, using the combination of a Positron Emission Tomography and a CT scanner (PET-CT), with fluorine-18 fluoro-2-deoxyglucose (FDG) has been shown to have higher sensitivity and specificity for the detection of distant metastases from MM than other modalities, with impact on disease management [Citation18–21]. Most guidelines consider PET-CT to rule out occult extra-thoracic disease [Citation22–24].
Given the rising incidence of MM and the increasing emphasis on cost-containment, the aim of this study is to compare the health benefits and costs associated of CONVENTIONAL versus a PET-CT strategy in the management of pulmonary metastases.
Material and methods
Baseline analysis
We evaluated the cost-effectiveness of a surveillance program in which a hypothetical cohort of patients with resected high risk MM (stage IIc and III) underwent a PET-CT for suspicious lung metastatic disease. Their survival was compared with a similar group of patients where the lung lesions were conventionally staged with whole-body CT scans (from the head and neck region to the pelvis) [Citation25].
The primary objective is to determine whether the surveillance directed by FDG PET imaging improves the life expectancy, measured in life-months gained, the number of accurate diagnoses and the number of futile surgeries avoided. The incremental cost-effectiveness of each strategy was determined by dividing the incremental cost by the incremental effectiveness, also known as the Incremental Cost-Effectiveness Ratio (ICER). Secondary objectives are to determine whether FDG PET-guided surveillance is cost-effective.
The analysis was based on a Markov model that can be used to predict outcomes for patients as they progress through different health states over time and undergo diagnostic tests and/or therapeutic interventions [Citation26].
Model structure
As shown in , 11 mutually exclusive health states could be isolated: no evidence of metastatic disease, pulmonary metastastic disease death and other metastases related death and death from other causes, the presence of other metastatic disease. As sometimes two subsequent metastasectomies may occur, we subdivided the following stages in two different episodes: resectable pulmonary metastatic disease, recurrence free survival after resection of the pulmonary metastastic disease and systemic treatment [Citation27,Citation28].
Figure 1. Health state diagram.
This model considers one cycle to be one month, accounting for each time a patient underwent surgery or chemotherapy. Note that resectable pulmonary metastatic disease, recurrence free survival after resection of the pulmonary metastastic disease and systemic treatment were subdivided in two different episodes as sometimes two subsequent metastasectomies may occur. The diamond represent the different absorbing states: death of other causes, lung metastatic disease related death and other metastases related death.
In each monthly cycle patients were at risk for developing pulmonary metastases. Depending on their health states, patients were also at risk of other recurrence or of dying from their disseminated disease, from other conditions associated with their disease or from non-melanoma related causes.
The life expectancies of the initial decision: either PET-CT or CONVENTIONAL strategy, were calculated by running the model over different periods of time and until the entire cohort died. Since a small body of literature exists on the quality of life following darcabazine treatment in metastatic melanoma patients, little research has considered the case of the surgical management of lung metastases [Citation29]. Therefore no formal utility measurement effort was undertaken to populate this model.
The endpoints are life-months gained (LMG) and the number of futile surgeries avoided. The latter was based on the number of patients who were classified as inoperable due to extra-thoracic disease revealed by a positive test.
Model inputs
Probabilities. The baseline estimates and their ranges were derived from published studies and confirmed by expert opinion (BJF). The probabilities used in the model and ranges explored in univariate sensitivity analyses are summarised in .
Table I. Clinical baseline model estimates.
The risk for the development of pulmonary metastasis was derived from largest and most recent data of the Duke Comprehensive Cancer Centre. The estimated cumulative risk varies over time from 13% at 5 years, to 17% at 10 years, and 23% at 20 years after initial diagnosis [Citation4].
The risk of relapse is highest in the first two years, and 90% of relapses occur by five years after primary treatment. Although the risk diminishes over time, melanoma patients could even recur 10–35 years after the initial diagnosis [Citation30]. To take in account this variation of risk over time we included this variable risk of relapse in the model.
The probability of dying from other causes was derived from Belgian age-specific mortality tables [Citation31].
Dacarbazine is generally considered to be the most active single chemotherapy agent in patients with metastatic melanoma. However, the vast majority of responses are only partial and the median response duration is only four to six months. [Citation29,Citation32–36].
Cost. The Belgian health care payer perspective was adopted. Costs were calculated by multiplying the unit costs by the volumes of use. We assigned costs to different health states or transitions among health states.
As proposed by the Belgian guidelines, the unit cost values of hospitalisation, drugs, surgery and diagnostic procedures were obtained from the current public prices published by the RIZIV/INAMI (Health Insurance Institution, Belgium) in January 2009, VAT included, but also the direct health care related out-of-pocket expenses of patients [Citation37]. We used a micro-costing approach to calculate the true actual costs spent in performing a PET-CT study [Citation38].
As video assisted thoracoscopy cannot be considered standard of care in Europe, the surgery cost is based on the stapled wedge resection, lobectomy, segmentectomy or pneumectomy. By taking in account the proportion of surgery used in the study of Petersen et al. [Citation4], we calculated a weighted mean surgery cost. As serious complications are rather rare for surgery and chemotherapy, we used a mean cost with their ranges at the health state level.
We included the resources used by a cohort of patients followed in standardised administrative databases (Public Health School, Université Catholique de Louvain) of 19 hospitals between 2005 and 2006 identified by the Diagnosis Related Groups (DRG) codes.
We did not formally include indirect time costs, such as lost income due to hospital stays. Costs of care and ranges explored in sensitivity analyses are shown in .
Table II. Economical baseline model estimates.
We calculated the cost of 850–1 000 mg/m2 dacarbazine given once every four weeks in an outpatient setting. Second-line systemic therapy is highly variable and only given in an experimental setting.
In order to include the temporal differences between the two strategies, future costs were discounted at a rate of 3% and future LMG were discounted at a rate of 1.5%, as recommended by Belgian guidelines for cost-effectiveness analysis [Citation37]. Number of futile surgeries was not discounted.
The DATA software package was used (version 9, TreeAge Software, Inc., Williamstown, MA) to construct the model and perform the analyses.
Key assumptions of the model
We assumed that in presence of extra-thoracic metastases the pulmonary metastatic disease was inoperable.
We did consider that after a second pulmonary metastasectomy the subsequent metastases were not resectable. In the experience of the International Registry of Lung Metastases (IRLM), only 5% of the patients had more than two sequential operations [Citation39].
Patients, who developed potential resectable extra-thoracic metastases during the natural course of the disease inside the model, were further excluded from analysis through a separate absorbing health state.
Over the past 20 years, various follow-up strategies have been proposed with large variations in frequencies and the type of surveillance examinations. None of them reached international consensus [Citation22,Citation40]. The current model was based on a conventional surveillance visit including clinical examination, blood tests and chest x-ray, every six months for five years and annually thereafter [Citation9,Citation22,Citation41]. The type and frequencies of surveillance examinations are similar to that described by Petersen et al. to calculate the cumulative incidence of developing lung metastatic disease although in more recent years thoracic CT-scan has often replaced chest x-ray. When suspicious for metastasis, the patient underwent either whole body CT or PET-CT.
As the variety of conventional imaging included in the reference test is not standardised, the conventional strategy in the model is based on the test accuracy data of whole-body CT as shown in .
As second-line systemic therapy is quite variable without consensus on type of treatment, dosages and schemes, darcarbazine was included also as the second line chemotherapy.
Palliative care costs were assumed to be identical in the two arms, but were nevertheless included.
Sensitivity analysis
Model building requires assumptions that oversimplify the realities of clinical practice. Sensitivity analysis allows examination of alternate scenarios not represented by base-case assumptions. Therefore, we performed one-way sensitivity analyses over wide intervals to evaluate the stability of our results by varying the probabilities, utilities, costs and the discount rate in our model. Variations in costs were based on estimated minima and maxima derived from the cohort of patients included in the analysis. The most influential variables and their impact on the ICER are represented in the Tornado diagram (). This diagram shows the degree to which uncertainty in individual variables affects the ICER.
Figure 2. Tornado diagram of univariate analyses. This diagram shows the degree to which uncertainty in individual variables affects ICER. Other parameters also evaluated but without influence on the ICER were Sensitivity and Specificity of the WB-CT scan, cost of the WB-CT scan and the probability to die from other metastases.
Monte Carlo sensitivity analyses were run to simulate the “real world” distribution of costs and probabilities between individual patients. In this analysis, each parameter was simultaneously varied using set probability distributions as the model ran through multiple iterations. The Monte Carlo analyses describe the spectrum of cost-effectiveness ratios observed under the PET-CT versus CONVENTIONAL strategy. Normal distributions were calculated from the high and low ranges for the sensitivity and specificity of the PET-CT and WB-CT scan.
The ranges and the type of distributions are reported in . For the probabilities beta distributions were used with base case values serving as the mean and standard deviations. Costs were modelled with a gamma distribution due the positive nature and the positive skew of costs. The gamma distribution has a better fit with the data provided by the administrative database compared with the lognormal distribution. As for some costs no distributions were available, they were modelled with a triangular distribution based on expert input. Finally, the transition probabilities were modelled with a uniform distribution by varying the parameters with +/− 20%.
Results
In our deterministic base-line analysis, as shown in , the PET-CT strategy provided 90.61 LMG at a discounted cost 3 438 €, while the conventional strategy provided 90.42 LMG at a discounted cost of 4 384 € of 10 years of follow-up. This PET-CT strategy resulted in a net saving of 946 € per LMG which was accompanied by gain in life expectancy of 0.1929 LMG or six days and is therefore dominant. Without discounting, PET-CT provided 97.15 LMG at a cost of 3 438 € compared to 96.93 LMG for whole-body CT at a cost of 4 384 €.
Table III. Deterministic analysis Costs, life months gained, cost-effectiveness ratio, and incremental cost-effectiveness ratio of the screening regimens over a 10 years period.
The results of univariate sensitivity analyses are displayed in a Tornado diagram in which each bar represents the impact of uncertainty of the individual parameter on the ICER (). ICER is rather robust for the different parameters tested. Specificity of PET-CT, which has the greatest impact on ICER shows an uncertainty of less than 1%.
In the probabilistic sensitivity analysis, the PET-CT strategy provided 86.29 LMG (95% CI: 81.50–90.88 LMG) at a discounted cost of 3 974 € (95% CI: 1 339–12 303 €), while the conventional strategy provided 86.08 LMG (95% CI: 81.37–90.68 LMG) at a discounted cost of 5 022 € (95% CI: 1 378–16 018 €). This PET-CT strategy remained dominant with a net saving of 1 048 € and a gain of 0.2 LMG.
The results of the probabilistic sensitivity analysis were plotted as an incremental cost-effectiveness scatterplot () to show the distribution of 1 000 trials from the Monte Carlo simulation. Each trial point provides a comparison of the incremental costs and benefits of PET-CT screening to whole-body CT. For each comparison, parameters for both screening strategies were simultaneously and randomly sampled from the probability, cost, and outcome distributions to account for uncertainty in the base case parameter estimates. The points could fall in four quadrants. Quadrant NE, where the PET-CT screening strategy is both more costly and more effective than the standard regimen, contained 6.4% of the samples. Quadrant NW, where the PET-CT strategy is more costly but less effective (inferior), contained 22.6% of the samples.
Figure 3. Incremental Cost and Effectiveness (LMG) of PET-CT over Conventional Strategy. This scatter plot shows the distribution of 1 000 trials from the Monte Carlo simulation.
Quadrant IV represents a situation where the PET-CT screening strategy is less costly and more effective (superior), while quadrant SW represents a situation where PET-CT screening is both less costly and less effective. They contained 71% and no points of the samples, respectively.
The acceptability curve shows that 71% of trials are dominant and 6.4% have a high cost-effectiveness with a low incremental cost for the PET-CT strategy ().
Figure 4. Net health benefit acceptability curves.
Moreover, the analysis confirmed that PET-CT avoided 20% futile surgeries and had 5% more accurate diagnoses. Despite the small survival benefit, the PET-CT strategy is more effective and less costly.
Discussion
Metastatic melanoma is a devastating illness, and treatment options are limited. Complete pulmonary metastasectomy is the only treatment with impact on patient outcome and minimal morbidity [Citation14,Citation35,Citation42,Citation43].
Despite the common perception that pre-operative assessment of pulmonary metastases is expensive, there has been little economic analysis in the field. Previous economical studies evaluated the impact of life-time follow-up strategies of melanoma patients [Citation30,Citation44–47]. As stressed by a recent systematic review, none of them evaluated the impact of PET-CT in the management of pulmonary metastases [Citation29].
The PET-CT strategy appears to be strictly dominant, with a small gain in survival benefit and a lower overall cost. Moreover our data suggests the integration of this strategy in the presurgical management of pulmonary metastases will reduce overall costs and patient morbidity by avoiding futile surgeries in patients with extra-thoracic disease. The univariate and the probabilistic sensitivity analyses confirmed the robustness of the findings in the base-case.
In colorectal cancer, other models showed a similar net savings of PET-CT for the screening of high risk patients for hepatic recurrences, thanks to avoidance of expensive surgery in patients with extra-hepatic disease [Citation48,Citation49].
Any conclusions from our study must be viewed in light of assumptions made in the model. First, we focused only on pulmonary recurrences and resect-ability. Various studies showed that the lungs are one the most common site for recurrence of cutaneous MM and resection is a beneficial intervention. Given the higher diagnostic performance of PET-CT in the detection of gastro-intestinal and deep soft tissue metastases, it is likely that we would have improved FDG PET cost-effectiveness in a more generalised model by incorporating these other metastatic sites [Citation50–52]. We did not address other sites of potential resectable recurrences due to the lack of specific data for these other regions and the difficulty in creating a decision model that would encompass each possible recurrence site.
Other limitations imposed by the assumptions of this decision analysis and tree structure deserve mention. Clinical practices vary considerably across hospitals and physicians, even if the patient populations are considered similar. Today the clinical algorithm for the diagnostic imaging work-up of these patients is not clearly defined. We derived the annual probability of developing pulmonary metastases from the largest retrospective study realised between 1970 and 2004 [Citation4]. Many of these patients, especially from the earlier years, were evaluated with chest x-ray. The a priori risk for developing lung metastatic disease was the same for both strategies based on this screening program. The usefulness of both strategies lies in their capability of excluding the presence of extra-thoracic disease. As a screening program with chest CT at surveillance visits will probably increase the absolute incidence of the pulmonary metastatic disease, it is likely to expect a better cost-effectiveness of PET-CT strategy. Moreover, improvement of the model could be increased by explicitly modelling the tumor growth process. However, we did not address these features mainly due to the lack of data on the incidence of pulmonary metastases based on thoracic CT performance on resected melanoma patients.
Another possible limitation might have arisen from the data of the primary studies. Most of the studies compare PET-CT with whole-body CT, sometimes with oral contrast medium agents. Moreover, the population is very heterogeneous with a mixed referral. Technical improvements of PET and CT (e.g. administration of contrast agents and respiratory gating), more organ-specific comparison and a more homogeneous population might increase the accuracy of both strategies.
The model exclusion of the second-line chemotherapy may have influenced our results. Following guidelines [Citation29,Citation32–36], the type, the dosages and the schemes are still trial-based. Modelling them would have induced the additional higher trial-based costs and biases due the choice of the therapy. Developing arbitrary probabilities and costs could have influenced the results inappropriately.
This analysis did not deal with the psychological issues which play a role in the patient's decision-making process. Our intent was to address policy issues for the cost-effective management of pulmonary metastases in MM using a population-based approach.
In conclusion, PET-CT strategy is cost-effective in the diagnostic imaging work-up of patients with suspected pulmonary metastasised melanoma. The strategy provides a minor increase in average overall life expectancy of six days, but mainly saves many patients from undergoing unnecessary surgical treatments and its associated complications.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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