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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
Cancer of the colon and rectum is now the third most common form of cancer in the United States in both women and men. Approximately 21% of patients with colorectal cancer (CRC) are diagnosed with metastatic spread upon initial presentation, and 50% to 60% of all patients with earlier stage CRC will eventually develop metastases. Advances in systemic therapies have improved overall survival for patients with metastatic CRC (mCRC), but with an increasing cost burden on the healthcare system. Patterns of treatment choice and resulting medical care usage and costs can differ depending on patient-specific characteristics, impacting overall patient care and healthcare usage. The economic burden associated with CRC and its management is affected by several factors, including stage of disease at diagnosis, patient age, time period studied, oncologic therapy choice, and point of view. Available data assessing cost impact have recently been emerging; however, they are complex to interpret given the substantial heterogeneity among study population and the types and duration of analyses.
Am J Manag Care. 2018;24(7):-S0
The Impact of Metastatic Disease on CRC

In the United States, colon cancer and rectal cancer are the third most common form of cancer in both men and women. An estimated 140,250 new cases of colorectal cancer (CRC) are expected to be diagnosed in this country in 2018, including 75,610 cases in men and 64,640 in women. In addition, 50,630 deaths are expected from CRC in the same year, totaling 27,390 deaths among men and 23,240 deaths among women. Overall, CRC is expected to comprise 9% of the total new cancer cases in the male population in the United States and 7% of all cancers in women, along with 8% of all cancer deaths for both genders.1

While the overall number of cases of CRC and deaths from the disease have been steadily decreasing since the early 1990s, the actual incidence of CRC is increasing in people younger than 50 years. The number of expected deaths has risen likely because of the very poor prognosis for people who are diagnosed with metastatic CRC (mCRC) from initial presentation.2 Approximately 21% of patients with CRC are diagnosed with metastatic spread upon initial diagnosis, and another 50% to 60% of all patients who presented with earlier stage CRC will eventually develop metastases. A staggering 80% to 90% of these patients will have unresectable liver metastases.3 Advances in systemic therapies have improved overall survival for patients with mCRC. These may include combining multiple approaches and therapies, ranging from surgery to chemotherapy and targeted biologic treatments. That said, patterns of treatment choice and resulting medical care usage and costs can differ depending upon the phase of mCRC and other factors impacting patient care and healthcare usage.4,5

The Cost Implications of mCRC

The economic costs associated with CRC and its management generally vary by many factors, including stage of disease at diagnosis, patient age, the observation time included in an individual analysis (specified time period vs lifetime costs), types of medical services included, and the overall scope of the costs considered in an investigation. Data in general have been complex to assess and compare because there can be substantial heterogeneity across studies and in the factors and variables included in each of those individual analyses. However, comparisons of data within a health organization and between different systems can assist clinicians in better comprehending the potential significance of differences in cancer care policies and how they affect costs and clinical management. In addition, understanding the extent to which such data can be compared is crucial for economic evaluations of all aspects of cancer care, including therapeutic interventions.6

A MEDLINE literature search for cost-effectiveness of mCRC treatment in the United States was conducted. One early study by Paramore et al retrospectively studied use patterns and healthcare costs for patients with newly diagnosed mCRC, reviewing assessments of claims data from selected US health insurance plans. Details of this study are highlighted in the Table.4,5,7,8 This analysis showed that the incremental cost difference in the follow-up period averaged $97,031 more for mCRC cases than for those in the control arm. Notable cost drivers in this analysis were hospitalizations ($37,369) and specialist visits ($34,582), including chemotherapy administration. Approximately 40% of the 672 patients in the phase analysis experienced a fatal event during follow-up. Mean and median monthly costs increased during the study period, unrelated to any particular disease phase. The investigators concluded that the overall economic burden of mCRC is substantial for patients insured by commercial health plans in this country, and that costs of care have increased significantly in recent years.7 It is noteworthy that this study included claims data from 1998 through 2004, making the application of these results limited. Several therapies currently used in the treatment of mCRC were FDA approved late during this time, or after this study was conducted. Oxaliplatin was FDA approved in 2002, and both bevacizumab and cetuximab were FDA approved in February of 2004. Although this study demonstrated the substantially increasing economic impact of mCRC, most patients would likely not have received treatment with the newer, more costly agents that are currently considered standard of care. Caution should be exercised when extrapolating these results to current day.

Song et al also performed an analysis to assess patterns of medical care in patients with newly diagnosed mCRC. Patients in this study were selected from a sizeable US insurance claims database. These patients were observed from their initial diagnosis until death, disenrollment, or end of the study period, whichever occurred first. Patterns of medical care were analyzed via different (and mutually exclusive) service categories, including outpatient, inpatient, emergency department, outpatient pharmacy, chemotherapy, and biologic therapy. Data measured estimated aggregate and category costs monthly. Details of the study are summarized in the Table. While the treatment phase was the least expensive, it also had the longest duration, with a mean 16.4 months, compared with the diagnostic and death phases at 2.8 months and 2.4 months, respectively. Inpatient care was the highest cost component in both the diagnostic phase, accounting for 41.7% of costs, and the death phase at 71.4% of costs. However, inpatient care accounted for only 17.9% of total care costs for patients in the treatment phase. In contrast, outpatient care was the leading cost driver in the treatment phase, accounting for 45% of total costs. In terms of actual treatments, biologic agents contributed 7.7%, 17.6%, and 4.1% of costs for the diagnostic, treatment, and death phases, respectively, versus chemotherapy, which accounted for 11.5%, 15.6%, and 2.9% of costs in the diagnosis, treatment, and death phases, respectively. Overall, the study demonstrated notable differences in the patterns and costs related to healthcare usage in different phases of mCRC management.4

Additional variables also have an impact on healthcare costs and usage in patients with mCRC. A review by Chastek et al assessed costs and usage by initial CRC stage upon diagnosis and the number of treatment lines received by patients with mCRC. Details of this study are listed in the Table. Linked healthcare claims from a US health insurance database were incorporated into this analysis to delineate both healthcare costs and patient characteristics. A 4-year estimate of total healthcare costs stratified by disease stage and patient characteristics was the key endpoint, with follow-up terminated by patient death, insurance plan disenrollment, or study conclusion. Overall, estimated 4-year total costs showed that CRC stage at diagnosis and the number of lines of treatment a patient received after metastasis were substantial cost drivers. Variables associated with a statistically significant (P < .05) cost included gender, patient age group, and comorbidity index score following development of metastases. Total overall 4-year costs were greatest among patients who presented initially with mCRC and lowest among those with stage 3 disease who later developed metastatic spread.5

These studies demonstrate the substantial heterogeneity that exists across studies evaluating healthcare costs associated with the treatment of mCRC, making it difficult to draw meaningful comparisons and conclusions. These studies demonstrate the continually rising high costs associated with this disease, in addition to the need for structured studies evaluating costs across healthcare organizations. 

Cost-Effectiveness of Treatments: Delineating Differences in Therapies Used

Systemic therapy with chemotherapy plus biologic therapy or targeted therapy remains the backbone for treatment of mCRC. Chemotherapy usually consists of a fluoropyrimidine backbone with 5-fluorouracil (5-FU) or capecitabine, in combination with irinotecan or oxaliplatin. Over the course of several decades, these chemotherapy combinations have increased patient survival from a meager 1 month to 21 months.9,10 However, more recent advances in mCRC therapy have been driven by the introduction of monoclonal antibodies (mAbs) as additional first-line treatments in combination with chemotherapy or in second-line or later treatment lines. Two major classes of mAbs exist: those that inhibit tumor growth by interference with angiogenesis through blockade of vascular endothelial growth factor (VEGF) and those that inhibit tumor growth by interference with cell signaling, including blocking signal transduction through epidermal growth factor receptor (EGFR).11 Currently used mAbs for the treatment of mCRC include the anti-VEGF agents bevacizumab, ziv-aflibercept, and ramucirumab, and the anti–EGFR-targeted drugs cetuximab and panitumumab. The latter are specifically indicated for the subgroup of patients with mCRC and Kirsten ras oncogene (KRAS) wild-type (WT) tumors.3,11-13 Regorafenib is a small-molecule inhibitor that blocks several signaling pathways, including VEGF. According to current National Comprehensive Cancer Network (NCCN) guidelines, regorafenib may also be given as treatment for mCRC.3 In more recent years, trifluridine-tipiracil, pembrolizumab, and nivolumab have also been approved by the FDA for use in patients with mCRC.14 The immunotherapy agents nivolumab and pembrolizumab are currently used in a specific subset of patients with mCRC with microsatellite instability-high (MSI-high) or mismatch repair deficiency (dMMR).15 While these newer targeted therapies represent significant breakthroughs in the treatment of mCRC, their application can elevate treatment costs substantially. It is vital to assess the economic impact of these targeted treatments along with their clinical effectiveness. This is important not only for appropriate stratification of patients for therapy, but also to support price negotiations and reimbursement decisions.11 In general, study designs for cost-effectiveness include cost-effectiveness analysis and cost utility analysis. Life-years gained (LYG) and quality-adjusted life-years (QALYs), an index value combining gained additional lifetime along with quality of life during that gained lifetime, comprise the most commonly used benefit measures. The overriding purpose of these health economic evaluations is to compare differences in costs and benefits between alternative interventions and/or treatments.11,16

 
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