13 minute read
Melanoma-related costs by disease stage and phase of management in Ireland
Written by Grainne E Crealey1, Caitriona Hackett2, Katharine Harkin3, Patricia Heckmann3, Fergal Kelleher4, Áine Lyng3, Triona McCarthy3, Maria McEnery3, Clare Meaney3, Darren Roche5, Anne-Marie Tobin2
1Clinical Costing Solutions, Belfast 2Tallaght University Hospital, Tallaght 3HSE National Cancer Control Programme (NCCP) 4St. James and Tallaght University Hospitals, Department of Medicine, Trinity College Dublin 5Sligo General Hospital, Sligo
Melanoma is the fifth most commonly diagnosed cancer in both men and women in Europe1 and has one of the fastest growing incidence rates globally.2 If 2020 rates continue, the global burden from melanoma is estimated to increase by ~50% by 2040 presenting an important challenge to cancer control and public health globally.2
In Ireland, over 1000 people are diagnosed with melanoma annually, a number which is predicted to triple between 2015 and 2045.3 Harmful exposure to UV radiation (mostly solar radiation) is the most avoidable cause of melanoma risk and mortality, with many economic evaluations reporting favourable benefits from preventative intervention.4 Although most cases are caught early, 10% of melanomas in Ireland are still diagnosed at Stage III or IV where 5-year survival rates for distant disease are much lower than for local disease (94.60 versus 32.68%).5
Recent advances in treatment have transformed the care of melanoma patients, delivering meaningful improvements in survival; however, the extremely high cost of such treatments presents a challenge for funders.6 The impact of early detection on extended survival and subsequent treatment costs has increased the interest in estimating the financial costs associated with melanoma and the associated cost-effectiveness of melanoma screening strategies.4 7 8
Numerous studies have explored the cost burden of melanoma;4,9–36 however, many of these findings are now obsolete as they were undertaken before the introduction of high-cost systemic drugs used for adjuvant and advanced melanoma treatment.
The aim of this study was to provide robust estimates of the stage-specific costs of melanoma over a 5-year time frame from the perspective of the Irish healthcare system to inform budgetary planning and underpin future economic evaluation of primary prevention to enable efficient allocation of public funds.
Methods
A model of cumulative cost depending on the initial stage at diagnosis (Stage 0/1A, Stage IB, Stages IIA–IIC, Stages IIIA–IIIC and Stage IV) was constructed, following the newly diagnosed patient for 5 years, when lymph node, in-transit or distant metastases are most likely to occur resulting in diagnostic procedures, surveillance and additional treatment. Tromme et al 9 developed a model to estimate the stage-specific economic burden of melanoma in Belgium (Fig. 1), which has subsequently been used to estimate costs in Brazil.33 We adopted a similar approach, modifying the model to reflect local data availability. In brief, during each annual cycle, and for each stage of disease, patients have a probability of transitioning to another stage. The model incorporated ‘timedependence’ such that the risk of progression, recurrence or death was dependent on duration in each stage. Our approach differed from Tromme et al 9 as we had access to disaggregated data for Stage IIIB/C (which was unavailable from the Belgian registry) hence intransit metastases were included as Stage IIIB; death was not disaggregated into ‘deaths from melanoma’ and ‘other causes’. In the interests of parsimony, we did not explicitly account for costs associated with false positives in the diagnostic phase of treatment or for multiple lesions. Transition probabilities were assumed the same for both genders and all ages and strictly local recurrences were not included because of their rarity.
A melanoma care pathway was developed for each stage of disease based on populationlevel data supplied by the National Cancer Registry Ireland (NCRI), where completeness of registration is estimated to be in excess of 96% of all diagnosed cancers.37 Once developed, the care pathway was reviewed by a multidisciplinary team comprising dermatologists (3), a medical oncologist, a health economist, public health medicine consultants (2), oncology pharmacists (2) and representatives from the National Cancer Control Programme (NCCP) (4) who were convened to oversee the construction, population and validation of the model. Additional expertise was supplied by the NCRI, the Healthcare Pricing Office (HPO) and the Primary Care Reimbursement Service (PCRS) of the Health Service Executive (HSE) in Ireland.
All patients entering the melanoma care pathway were referred by their GP (via the e-referral system) to the skin cancer clinic. Here they were diagnosed, staged (including imaging, dependent on initial preliminary or succeeding clinicpathological staging), discussed at a melanoma multidisciplinary team meeting (MDTM) and given a definitive diagnosis based on a surgical excision of the melanoma.
Patients with Stage 0 or IA disease underwent no further treatment. A proportion of Stage IB and IIA patients underwent sentinel lymph node biopsy (SLNB) and (where appropriate) were discussed at an Oncology MDTM (on at least one occasion). Patients with a positive SLNB underwent follow-up completion lymphadenectomy. Patients with Stage IV disease underwent surgery or stereotactic radiation for removal or treatment of oligometastatic melanoma. A proportion of patients with Stage IV BRAF mutant melanoma were treated with combination BRAF_ MEK inhibitors (it should be noted that the reporting period partly precedes national reimbursement approval of adjuvant Dabrafenib and Trametinib for public patients with Stage III melanoma). Reimbursement approval of these drugs will have financial implications arising from increased prescribing.
A schedule of follow-up visits specific to each disease stage was detailed in the care pathway. Patients with Stage 0/1A disease had two appointments over the following 12 months. The frequency of clinic visits increased with stage of disease (e.g. patients in Stage IIIB/C had four appointments per year in Years 1–3 and twice annually in Years 4–5). In addition, a schedule of investigations accompanied such visits (biannual CT PET + MRI, Years 1–3; annually thereafter until Year 5). Patients suitable for systemic therapy followed a separate schedule of clinic visits, blood tests and imaging.
Data used to populate the model
Data on the distribution of patients across disease stages and resource use estimates (by stage) were supplied by the NCRI for all patients with an ICD-10 principal code for malignant melanoma of the skin (C43). At the time of this study, the most recent available data were for 2016 (n = 1140 patients). The probability of a patient receiving a treatment, alone or in combination, was tabulated by stage and site. Additional data (based on ICD-10 principal code) were obtained from the Hospital Inpatient Enquiry team. Supplementary data relating to diagnostic work-up and adherence to surveillance protocols were obtained by undertaking a retrospective chart review of melanoma patients from a large teaching hospital (n = 70, followup from 12 to 40 months).
In Ireland, data on medication use are captured by the PCRS database; however, it was not possible to isolate resource use by ICD-10 principal code. Data on treatment regimens (by stage) are collected by NCRI; however, this does not extend to the dose and duration of radiotherapy, chemotherapy, immunotherapy and targeted drugs. Hence conservative estimates based on NCCP approved treatment regimens for melanoma and validated by expert opinion within the group (Oncology Consultant and Senior NCCP pharmacists) were employed.
Following treatment, individuals have a stage-specific risk of remaining in remission, having a recurrence, distant metastases or death. In the absence of data on disease free progression for this patient population, data on the probability of dying in a 12-month period (using interval specific observed survival by stage for Years 1–5) were supplied by the NCRI. The probability of recurrence was based on recurrence-free survival rates presented in Leiter et al 38 and further assumed that 77% of initial recurrences were locoregional with the remainder classified as distant metastases.
Valuation of resources
Direct healthcare costs were collected from the perspective of the publicly funded Irish health and social care system (HSE) for 2020 (¤). Costs associated with diagnosis, in-patient and out-patient procedures, systemic therapy, relapse and supportive care were included. All costs were adjusted to 2020 (¤) using the Consumer Price Index for Health (Central Statistics Office www.cso.ie) and discounted at a rate of 4% per annum as per best practice guidelines for performing Health Technology Assessment in Ireland.39
Nationally produced unit costs for individual procedures are not produced in Ireland, hence procedures captured by NCRI were mapped across to Diagnosis Related Groups codes (DRGs) compiled by the Health Pricing Office (HPO) using the ICD-10 Principal code for Melanoma (C43). This work package involved assessing the frequency with which procedures were performed in conjunction with expert opinion from HPO senior analysts and clinical expert opinion to construct frequency weighted mean costs (reflecting level of complexity and whether it was performed as an inpatient or day case procedure). Analysts in HPO were consulted to ensure the ‘DRG cost bundle’ avoided double counting (specifically with respect to blood tests and imaging).
The cost of immunotherapy regimens approved for use by the HSE for treatment of melanoma was provided by the NCCP https:// www.hse.ie/eng/services/list/5/ cancer/profinfo/chemoprotocols/ melanoma/. Costs were based on list price including VAT (23%) plus an administration cost (DRG code R63Z from the Admitted Patient Price List 2020 for chemotherapy day case). The monitoring and management of adverse events (AEs) (which is not included in the administration cost DRG) were calculated separately based on reported AE frequency from clinical trials and using a list of costs from the ABF Admitted Patient Price List 2020. In the base-case analysis, costs associated with 12 months of therapy were applied to all patients residing in that state. The cost of supportive care was derived from estimates of the cost of palliative care in the Irish healthcare system utilizing only that portion of cost attributable to specialist palliative and hospital care costs (¤11,685).40
Sensitivity analysis
One-way and probabilistic sensitivity analyses (PSA) were undertaken to explore the impact of parameter uncertainty on the total cost estimates. Parameters associated with most uncertainty were subjected to one-way sensitivity analysis. PSA were conducted by running the model with a hypothetical cohort of 10,000 patients calculating cost estimates for each simulation. In each simulation, the value for each parameter was varied across a probability distribution reflective of the properties of the parameter under consideration and data informing them. Probabilities were modelled using beta distributions and parameterized with the sample size from the relevant published literature or data from NCRI. Costs were specified as gamma distributions as they are constrained to be positive, continuous and highly skewed.
All analyses were undertaken in Tree-Age Pro 2021 (Tree-Age Software, Inc., Williamstown, MA) and reported in line with The Consolidated Health Economic Evaluation Reporting Standards 2022 statement.41
Results
Patients with the best prognosis (Stage IA) were the least costly to treat and manage compared with those with the worst prognosis (Stage IV). The cost of managing a case of melanoma diagnosed at Stage IV was over 25 times more expensive than managing a case diagnosed at Stage IA (Stage IV ¤122,985 versus Stage IA ¤4269).
Sensitivity analysis
The 95% confidence interval (CI) for the average (stage-weighted) cost per person for managing a case of melanoma over a 5-year period (base case ¤20,268) was estimated from the PSA and ranged from ¤16,126 to ¤25,071. To reflect changes in practice since data were obtained from NCRI (for 2016), we assumed that 70% of patients in Stage IIIA and 100% of patients in Stages IIIB and IIIC received immunotherapy or targeted drugs for a maximum of 12 months, and 100% of Stage IV patients for a maximum of 24 months. This assumption was based on expert opinion within the group. Under these assumptions the stage-weighted average cost per person almost doubled from ¤20,268 (CI: ¤16,126–¤25,071) to ¤37,715 (CI: ¤32,619–¤43,019). In the base-case analysis, we assumed that all patients consumed 100% of prescribed medication. When we assumed that 88% of doses were consumed (as per Pike et al 29) the stage-weighted average cost per person fell to ¤18,561 (¤14,915–¤22,793). A flat-rate of 88% was used; however, it is noteworthy that Pike et al 29 also adjusted the quantity of doses consumed downward on a monthly basis by drug type.
In the base-case analysis, we assumed that 77% of recurrences were locoregional, and the rest were distant. When we assumed a 20% reduction in locoregional progression, the stage-weighted average cost per person rose to ¤21,079 (¤16,681–¤26,180) and similarly fell to ¤19,461 (¤15,569— ¤23,988) when we assumed a 20% increase.
Interval-specific recurrence rates for each stage were employed in the model.38 When these recurrence rates were varied by 20% around the base case estimate, the stage-weighted average cost per patient changed from ¤19,217 (CI: ¤15,388–¤23,680) to ¤21,476 (¤13,365–¤26,658).
Discussion
Main findings of this study
Healthcare costs for those diagnosed with Stage IV disease (over a 5-year time horizon) were over 25 times higher than for those diagnosed at Stage IA. Given prognosis is also superior, it underscores the importance of early detection and intervention. The cost of managing melanoma was particularly sensitive to those factors that contribute to the cost of immunotherapeutic and targeted drugs (such as dose, duration and choice of agent).
Despite the use of sensitivity analysis to explore potential sources of uncertainty, it is clear that the collection of ‘real-world’ data relating to ‘key’ cost drivers is crucial if we are to understand the distribution of costs and accurately estimate the cost-effectiveness of early intervention and treatment strategies.
What is already known on this topic
Our study echoes findings in the literature regarding the relationship between disease stage and cost.10 20–22 27 32 33 However, the difference in costs between stages has changed dramatically with the introduction of immunotherapeutic and targeted drugs rendering findings from earlier papers less relevant.
Our findings support those found in other recent studies, which have differentiated cost by stage of disease. One-year costs within the Italian health service ranged from ¤1,837 to ¤66,950 producing a cost ratio of 31.27 (between Stages I and IV).32 In the Spanish health care system, costs estimated over a 10-year time frame ranged from ¤1689 (Stage I) to ¤88,268 (Stage IV) reporting a doubling in costs where there was lymph node involvement, and treatment costs that were 52-fold higher for those with the least as opposed to most favourable prognosis.31 Similarly, spending on advanced melanoma in Brazil (estimated over a 3-year time frame) was reported as being up to 34-fold higher in the public health system compared with lower-stage disease.33 In the Netherlands, the real-world healthcare costs of melanoma were explored, and since the introduction of immunotherapeutic and targeted drugs, systemic therapies now account for 84% of costs, with costs differing substantially between patients who receive systemic therapy (¤105,078) and those who do not (¤7988).6
What this study adds
This is the first study to estimate the healthcare costs for melanoma patients by disease stage in Ireland. A strength of this study is that real-world data were used to populate the model that contrasts with other studies that have estimated resource utilization using national guidelines, ‘best practice’ or expert opinion/elicitation. Our study will enable robust estimation of the cost-effectiveness of prevention strategies in the Irish healthcare setting, and provide a blue-print for estimating the stage-specific costs of other cancers in Ireland. It has also clarified where best to focus resources with respect to data collection and linkage efforts moving forward.
References available on request https://academic.oup.com/jpubhealth/ advance-article/doi/10.1093/pubmed/ fdac154/7160043
