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Lisa E. Davis, PharmD, FCCP, BCPS, BCOP
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Cost-Effectiveness of New and Emerging Treatment Options for the Treatment of Metastatic Colorectal Cancer

Jennifer Zadlo, PharmD, BCOP
There are many variables evaluated within a cost-effectiveness study that can be analyzed in multiple ways, depending on the viewpoint taken, and may be related to individual drugs or lines of therapy. The variables may be confined to certain therapeutic time periods or may assess lifetime treatment costs. For example, Shankaran et al investigated the clinical effectiveness and incremental lifetime costs associated with the use of bevacizumab in older patients with mCRC. A total of 4414 patients were stratified by the type of treatment used, specifically no chemotherapy, chemotherapy alone, or chemotherapy plus bevacizumab. Mean lifetime costs were derived from Medicare claims for all services provided between diagnosis and the end of follow-up. Of patients studied, 15% received bevacizumab for first-line management. This agent was associated with improved survival but only for those patients who received treatment for more than 1 month. Both median and mean survival were longest in the chemotherapy plus bevacizumab cohort, with a median survival of 19.4 months and a mean survival of 28.0 months compared with patients who solely received chemotherapy (median survival of 15.1 months and mean survival of 22.9 months). The mean lifetime per-patient costs were $143,284 with combination chemotherapy and bevacizumab compared with $111,280 for chemotherapy alone. Overall, treatment with bevacizumab and chemotherapy was associated with a 5.1-month increase in mean survival along with a $32,004 increase in mean lifetime treatment costs. This calculated to an incremental cost of $75,303 per LYG. These results suggested that bevacizumab was clinically effective in this older population with costs that fell into an acceptable level in the United States of between $50,000 and $150,000 per QALY.17

More recently, another study led by Shankaran used data from the phase 3 FIRE-3 clinical trial to assess clinical and economic trade-offs associated with first-line treatment of patients with KRAS-WT mCRC.18 The FIRE-3 trial was an open-label, randomized, multicenter trial conducted in Germany and Austria of patients with mCRC receiving folinic acid and leucovorin plus 5-FU plus ironotecan (FOLFIRI) plus bevacizumab versus FOLFIRI plus cetuximab.19 A cost-effectiveness model was used to project survival and lifetime costs of chemotherapy with those regimens. Incremental cost-effectiveness ratios (ICERs) were assessed in terms of LYG. It is important to note that patients with extended RAS mutations were included in this trial. Results demonstrated that patients who received first-line cetuximab achieved 5.7 months LYG costing $46,266, for an ICER of $97,223 per life-year or $122,610 per QALY compared with patients in the bevacizumab cohort. For extended RAS-WT patients, the ICER was $77,339 per life-year ($99,584/QALY). Cetuximab treatment was determined to be cost-effective approximately 80.3% of the time. However, it must be noted that this was based on a “willingness-to-pay” threshold of $150,000 per LYG and that actual numbers surrounding value of care in this respect have varied over the years, with $50,000 per QALY being an original benchmark and others suggested between $110,00 and $160,000 per QALY based on more current US per-capita income.18,20 Overall, based on FIRE-3 data, cetuximab has an ICER of $86,487 per LYG when compared with bevacizumab, which is potentially important when considering first-line therapy in patients with mCRC.18

Graham et al performed another economic analysis of cetuximab, this time comparing cetuximab and panitumumab, both anti-EGFR therapies used for the treatment of mCRC in RAS-WT patients. Graham and colleagues compared costs and cost-effectiveness of subsequent-line therapy using cetuximab versus panitumumab in patients with KRAS-WT mCRC following failure of prior chemotherapy.21 The ASPECCT trial was a phase 3, randomized, multicenter study conducted in North America, South America, Europe, Asia, Africa, and Australia of patients who received either cetuximab or panitumumab for chemotherapy-refractory mCRC.22 Data from the ASPECCT trial were used in this economic analysis; Graham et al performed a cost-minimization analysis and developed a model to assess cost-effectiveness of each of the mAbs used as monotherapy, assuming equivalent efficacy based on progression-free survival from the trial.21 The cost-effectiveness model also included physician visits, monitoring for disease progression, best supportive care, and end-of-life costs. Results showed lower projected costs for patients treated with panitumumab compared with cetuximab, with a projected overall savings of 16.5% ($9468) per each patient who received panitumumab. The incremental cost per QALY gained also showed panitumumab therapy to be less expensive, although the outcomes with this drug were only slightly better than those seen with cetuximab per the clinical trial data.21

Previous lines of therapy may also impact the cost-effectiveness of subsequent lines. A study by Woldemichael et al examined how the cost-effectiveness of second-line chemotherapy varied by the first-line treatment regimens used in elderly patients with mCRC. In this review of 11,000 patients with mCRC in the Medicare population, mean incremental survival was 6.7 months for those who received second-line therapy. However, survival varied between 4 months and 9 months, depending on whether 5-FU with or without leucovorin, irinotecan, oxaliplatin, or other agents were used as part of first-line treatment. The incremental cost associated with second-line treatment was $60,231 but ranged between $55,368 and $71,211, depending on the first-line treatment course. ICERs per LYG associated with the receipt of second-line treatment were $97,368, $110,621, $130,689, and $247,951 when irinotecan, 5-FU/leucovorin, oxaliplatin, and all other combinations, respectively, were administered in first-line treatment. The investigators concluded that when therapies are administered in a sequential manner, cost-effectiveness of second-line therapy depended on what was actually administered during first-line treatment.10

Data surrounding newer therapies beyond bevacizumab, cetuximab, and panitumumab are sparser at this time, especially for treatments used for third-line therapies and beyond. One cost-effectiveness study used clinical data from the RECOURSE and CORRECT trials.23 The RECOURSE trial was a phase 3, randomized, placebo-controlled, double-blind, multicenter, international study conducted in Japan, the United States, Europe, and Australia of trifluridine/tipiracil versus placebo for refractory mCRC.24 CORRECT was a phase 3, randomized, placebo-controlled, double-bind, multicenter, international study conducted in 16 different countries in North America, Europe, Asia, and Australia of regorafenib plus placebo versus best supportive care plus placebo in patients with refractory mCRC.25 The cost-effectiveness study by Bullement et al, performed in the United Kingdom, demonstrated that the use of trifluridine/tipiracil was associated with a 0.27 incremental LYG compared with just best supportive care, which corresponds to a 0.17 QALY gain.23 The incremental cost of treatment with trifluridine/tipiracil was £8479 (approximately US $11,363 at the time of publication), resulting in an incremental cost-effectiveness ratio of £51,194 (US $68,605) per QALY gained.23

Of great importance in the use of these targeted therapies is considering the economic burden of common adverse events (AEs) associated with their use in treating mCRC. Fu et al performed an analysis to determine hospitalization costs of AEs associated with use of mAbs (bevacizumab, cetuximab, or panitumumab) for mCRC. The main outcomes in this study included the length of stay (LOS) and hospitalization costs based on 2010 US dollars for AEs identified upon patient discharge. Results demonstrated that gastrointestinal (GI) perforation incurred the longest median LOS, totaling 11.5 days in terms of hospitalizations. Other notable AEs included wound-healing complications (LOS 7 days), followed by arterial thromboembolism (5.5 days), venous thromboembolism (4 days), and heart failure (also 4 days). GI perforations resulted in the highest inpatient cost per event with a mean cost of $66,224 and median cost of $34,027, followed by arterial thromboembolism (mean $40,992 and median $18,587), wound-healing complications (mean $36,440 and median $21,163), interstitial lung disease (mean $26,705 and median $19,111), and acute myocardial infarction (mean $22,395 and median $15,223). Skin toxicity led to a cost of $6475 and median cost of $6110 with hypertension also creating lower costs overall at a mean cost of $14,108 and median cost of $6047. Overall, the study showed that costs associated with treatment-related AEs can vary substantially; however, cost data such as this could be applied to economic assessment of head-to-head comparisons of the agents used in treatment for mCRC.26

A more recent study by Latremouille-Viau and colleagues assessed patients with mCRC treated with chemotherapy or targeted therapies using data from administrative claims databases from 2009 to 2014. This study included 4158 patients with 1 or more mCRC treatment episodes. The adjusted monthly total cost difference delineated by categories of AE found that the costliest AEs per month, in descending order, were hematologic events ($1480 monthly costs), respiratory AEs ($1253 monthly), endocrine/metabolic events ($1213 monthly), central nervous system AEs ($1136 monthly), and cardiovascular events ($1036 monthly).27

Despite the amount of data related to cost-effectiveness of cancer therapy, it is still extremely difficult to actually assign a “value” to any type of cancer care.28,29 The definition of value itself is arbitrary and may vary due to type of healthcare system, patient population, or even by country.28,29 In response to this concern, the American Society of Clinical Oncology (ASCO) worked to develop a formula to determine the value of care based on the concept that the cost of a given intervention should relate to its benefit to the patient. ASCO created a value framework for those with advanced malignant disease, creating a clinical benefit score encompassing aspects related to survival, a therapy toxicity score, along with palliation and treatment-free intervals to calculate a net health benefit. A summary assessment of the cost of the therapy (drug acquisition cost and a calculated actual patient cost or co-pay based on healthcare coverage) was also taken into consideration. This framework is considered an iterative process and an ongoing effort, and ASCO welcomes comment on it from all interested parties.29

Of note, ASCO is just 1 example of an organization with the development of a formula to determine value-based cancer care. The NCCN has implemented evidence-based blocks into their treatment guidelines, the European Society for Medical Oncology has developed their Magnitude of Clinical Benefit Scale (ESMO-MCBS), and Memorial Sloan Kettering Cancer Center has developed the DrugAbacus tool to help guide clinicians in providing valuable cancer care.30

Patient Care and Shared Decision Making to Optimize Outcomes

 
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