Quoc-Dien Trinh, MD

: Although tyrosine kinase inhibitor (TKI) agents have significantly changed clinical practice for metastatic renal cell carcinoma (RCC), the economic burden of targeted agents remains poorly described. Thus, we sought to investigate the economic burden from the total costs, private insurance reimbursement, and out-of-pocket costs for oral TKI agents among metastatic RCC patients.

: Using a large private health insurance database, we identified patients who were diagnosed with metastatic RCC and received sorafenib or sunitinib from 2005 to 2010 in the United States. The primary outcomes were total costs, amount reimbursed, and out-of-pocket costs for 6 months of treatment with a TKI agent.

Methods: General estimated equations were used to determine the adjusted costs and reimbursement adjusting for patient age, gender, Elixhauser comorbidity score, and geographic region.

: Among 506 patients in the study sample, 389 (76.9%) patients received sunitinib and 117 (23.1%) patients received sorafenib. On multivariable analysis, sunitinib and sorafenib had similar adjusted total costs ($19,233 vs $19,030; P = .11) and amount reimbursed ($18,443 vs $18,314; P = .21). Patients were also responsible for similar out-of-pocket costs for 6 months of sunitinib or sorafenib ($1129 vs $1142; P = .67), which accounted for 4% of the total costs for both TKIs. From 2005 to 2010, there were minimal changes to each cost outcome over time.

: Metastatic RCC patients experienced high out-of-pocket costs for oral targeted agents from 2005-2010. Our findings have important implications since patients are becoming increasingly responsible for higher co-payments. High out-of-pocket costs may make the accessibility of targeted agents challenging, or may introduce economic hardship to metastatic RCC patients.

It is estimated that prescription drug expenditures are responsible for more than approximately $260 billion annually, or almost 10% of the $2.8 trillion spent on US healthcare each year.

 To limit the rate of growth in US healthcare spending, the Affordable Care Act (ACA) has, in part, shifted some of the cost burden to patients by increasing deductibles or co-pays for hospital services and prescription drugs, respectively.

 With respect to prescription drugs, for example, private health insurances have begun to introduce tiered plans to encourage lower growth in spending by limiting access to or raising out-of-pocket costs for certain expensive medications.

Against this backdrop, in the United States, more than 60,000 patients are diagnosed with kidney cancer each year. Of these, many present with metastatic disease, or recur or progress following primary treatment.

 Therefore, it is not surprising that the economic burden from renal cell carcinoma (RCC) is significant, and estimated to cost as much as $5.2 billion annually.

 One contributor to the high costs in healthcare is the development and rapid dissemination of targeted agents for RCC. Tyrosine kinase inhibitors (TKIs), for example, are expensive oral drugs that have now become the standard of care as first-line agents for metastatic RCC, based on clinical practice guidelines and several clinical trials demonstrating modest gains in overall survival compared with traditional cytokine therapy.

 The total costs of sunitinib and sorafenib, both commonly used first-line oral TKI agents in the clinical setting of metastatic RCC, have been estimated to range from $6990 to $7945 for a 1-month supply.

It is essential to recognize that, among metastatic RCC patients, key knowledge gaps may exist about the economic burden presented by oral TKI agents. More specifically, many patients are largely unaware of the costs attributable to TKI agents prior to commencing treatment. However, the out-of-pocket costs for oral TKI agents must be accurately determined to properly assess potential economic burden and to ensure that these medications are financially accessible to patients diagnosed with metastatic RCC. Therefore, using a large private US health insurance claims database, we sought to investigate the economic burden from total costs, health insurance reimbursement, and out-of-pocket costs among patients treated for metastatic RCC

Data for all patients diagnosed with metastatic RCC were abstracted from the IMS LifeLink Health Plan Claims Database, which was provided by IMS Health. The database covers approximately 55 million privately insured patients and more than 80 health plans in the United States. It includes all claims and encounters from outpatient office visits, hospitalizations and operative procedures, ambulatory procedures, emergency department visits, and home health services. In addition, the IMS database accurately captures data on the total costs of each outpatient medication as well as payment from private insurance for each prescription.

In this study, patients diagnosed between 2005 and 2010 were identified from the IMS data. We adapted a validated methodology for case ascertainment of RCC patients with receipt of TKI agents, with or without cytoreductive nephrectomy, from a claims-based algorithm using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes and Current Procedural Terminology-4 (CPT-4) procedure codes.

To limit the patient sample to those presenting with metastatic RCC, we identified all patients with ICD-9-CM codes with 2 or more claims for a primary diagnosis of kidney cancer (189.0 and 189.9), and a concomitant claim for metastatic disease to the secondary malignant neoplasm of lymph nodes (196.x), respiratory system (197.0, 197.1, 197.2, 197.3), digestive system (197.4, 197.5, 197.8), retroperitoneum and peritoneum (197.6), liver (197.7), other urinary organs (198.1), skin (198.2), brain or spinal cord (198.3, 198.4), bone (198.5) and adrenal (198.7), or disseminated disease (199.x). In addition, we restricted inclusion to those patients with claims of kidney cancer and metastatic disease within 3 months of each other. Furthermore, we only included patients with at least 1 year of continuous enrollment prior to and 6 months after the initial ICD-9-CM claim of kidney cancer or metastatic disease.

Based on this claims-based methodology, we initially identified 7371 patients aged 18 to 46 years with metastatic RCC. After removing patients without at least 1 year of continuous enrollment prior to diagnosis and 6 months post, 3195 patients remained. We further restricted our analytic cohort to 506 patients with outpatient claims for sunitinib or sorafenib within the 6 months after diagnosis.

Clinical information included as covariates were patient age at the time of diagnosis, gender, comorbidities, receipt of surgery, geographic region of care (east, midwest, south, or west), and year of diagnosis. Secondary diagnosis codes enumerated an Elixhauser comorbidity score for each patient, using all claims 1 year prior to the diagnosis of metastatic kidney cancer.

To identify those patients who underwent surgery, hospitalization claims were used to identify patients who underwent open or laparoscopic radical nephrectomy by ICD-9-CM (55.5, 55.51, 55.52, 55.54) or CPT-4 (50220, 50230, 50236, 50546, 50548) codes, or partial nephrectomy by ICD-9-CM (55.4) or CPT-4 (50240) codes. For first-line systemic agents for metastatic RCC, National Drug Code or Healthcare Common Procedure Coding System identifiers from the outpatient and pharmacy claims were used to identify sunitinib or sorafenib. We also restricted the patient sample to those with outpatient pharmacy claims for sunitinib or sorafenib within 6 months of the diagnosis of metastatic kidney cancer.

The primary outcome of this study was patient out-of-pocket costs for sorafenib and sunitinib at 6 months following the diagnosis of metastatic kidney cancer. Evaluating each cost or reimbursement outcome was based on a 6-month period. This period represented, for sunitinib, 3 cycles of treatment, in which a single cycle was consistent with 4 weeks of therapy followed by 2 weeks off therapy, or, for sorafenib, 6 months of continuous treatment. Secondary outcomes were the total costs and the amount reimbursed by private health insurance plans for each TKI agent at the same time interval. To define out-of-pocket costs, we calculated the differences between the total costs of each TKI agent and the amount reimbursed across all private health insurance plans. The total costs, amount reimbursed, and out-of-pocket costs were adjusted to 2010 US dollars using the National Income and Product Accounts table of the Gross Domestic Product price index.

Bivariate associations of patient variables for all targeted agents were tested by Pearson’s χ2 test or Fisher's exact test, where appropriate. We then fit generalized estimating equation (GEE) models to ascertain the differences in unadjusted and adjusted total costs, amount reimbursed, and out-of-pocket costs at 6 months for each oral TKI agent of interest. For the multivariable analysis, the GEE model adjusted for patient age at the time of diagnosis, gender, comorbidities, and geographic region of care (east, midwest, south, or west). To account for the skewed distribution of costs, we specified a gamma distribution and log link in the GEE models and determined adjusted total costs, amount reimbursed, and out-of-pocket cost.

 Nonparametric bootstrapping was used to estimate the 95% CIs for each cost outcome.

 SAS version 9.3 (SAS Institute Inc, Cary, North Carolina) was used to perform all statistical analyses. A 2-sided P-value of ≤.05 was used to determine statistical significance.

Among the 506 patients diagnosed with metastatic RCC from 2005 to 2010, 389 (76.9%) patients received sunitinib and 117 (23.1%) patients received sorafenib. Table 1 provides the clinical and pathologic characteristics among our privately insured cohort. Overall, approximately a quarter of patients underwent nephrectomy (23.5%). Minimal differences existed between the sunitinib or sorafenib groups, with the exception of geographic region: sunitinib was used more commonly in the midwest and east, while sorafenib was more commonly used in the south and west. At 6 months, the unadjusted total costs were significantly higher for patients receiving sunitinib compared with sorafenib ($20,077 vs $16,153; P <.0001). While private health insurance reimbursed more for sunitinib compared with sorafenib ($19,332 vs $15,328; P <.0001), patients ultimately paid more out-of-pocket costs for sunitinib than sorafenib at 6 months ($1213 vs $1023; P <.0001).

After adjusting for patient characteristics and geographic region, our analysis demonstrated that the total costs, amount reimbursed, and out-of-pocket costs were substantial, but similar for sunitinib and sorafenib at 6 months on multivariable analysis (Table 2). For example, the adjusted total costs for sunitinib and sorafenib at 6 months were $19,233 and $19,030, respectively (P = .11). Although private health insurances covered an equally substantial amount for sunitinib and sorafenib at 6 months on multivariable analysis ($18,443 vs $18,314; P = .21), patients were responsible for covering 4% of out-of-pocket costs, amounting to $1129 and $1142, respectively (P = .67). In addition, the adjusted total costs and amount reimbursed changed minimally over time for sunitinib (Figure 1A) and sorafenib (Figure 1B). Likewise, the out-of-pocket costs remained unchanged for each agent over time, with patients responsible for approximately $900 to $1300 for 6 months of sunitinib or sorafenib, respectively (Figure 2).

In this study, we sought to comprehensively investigate the costs attributable to oral TKI agents among patients with metastatic RCC. The purpose of this study is salient considering their rapid adoption in the targeted therapy era, and that clinical practice guidelines now recommend many of these agents as first-line therapy.

Our study also has several key findings regarding the economic implications of targeted agents at a time when patients are likely to be increasingly responsible in sharing healthcare costs. First, to the best of our knowledge, our study is the first to demonstrate that patients likely face a significant economic burden regarding out-of-pocket costs for oral TKIs in the clinical setting of metastatic RCC.

We found that metastatic RCC patients pay, on average, $1100 out-of-pocket for a total of 3 cycles of either sunitinib or sorafenib. With previous studies reporting high and variable lifetime costs and cost-effectiveness associated with the use of TKI agents (ranging from $8537-$72,254 and $49,595-$272,419 per quality-adjusted life-year [QALY] gained), our study suggests, in combination with previous evidence, that these high out-of-pocket costs may affect the oncologic care patients receive.

 For instance, Dusetzina et al reviewed the costs of imatinib in treatment of chronic myeloid leukemia (CML) from 2002 to 2011, and demonstrated increasing monthly out-of-pocket costs per patient from $2798 to $4892 during this time frame.

Significantly, patients in the top quintile for co-payments for imatinib were associated with higher adjusted relative risk (RR) for nonadherence (RR, 1.42; 95% CI, 1.19-1.69), which was defined as a CML patient who was in possession of less than 80% of the oral TKI they should have had over a 180-day period. In addition, a recent survey of cancer patients demonstrated that more than two-thirds would like to discuss the out-of-pocket costs of medical care before starting treatment, and almost 40% reported paying for cancer care as difficult or that they faced financial hardship.24 Although the IMS Life-Link data do not capture the variables regarding adherence to oral TKI agents or patient attitudes about the associated costs, our results suggest that these high out-of-pocket costs for oral TKI agents among patients with metastatic RCC certainly raise the possibility of marked financial constraints or of harm by limiting access or adherence.

Second, our results illuminate the total costs and amount reimbursed attributable to commonly used oral TKI agents, and possible changes in these outcomes in relation to shifts in out-of-pocket costs over time from 2005 to 2010. In addition, a recent survey of cancer patients demonstrated that more than two-thirds would like to discuss the out-of-pocket costs of medical care before starting treatment, and almost 40% reported that paying for cancer care was difficult or induced financial hardship.

 The results suggest that while the total costs of 6 months for either oral TKI agent is substantial at approximately $19,000, private health insurance plans cover more than 90% of these costs. Another key finding is that there were minimal changes to the total and out-of-pocket costs and private health insurance reimbursement over time, which is contrary to the findings of Dusetzina et al on a near doubling of co-pays from 2002 to 2011.

In our study, the total costs remained stable over time, which likely contributed to minimal changes to the reimbursement and the out-of-pocket costs for both oral TKI agents. Third, we found minimal differences in the cost outcomes and private health insurance reimbursement for sunitinib versus sorafenib. Several studies have embarked on evaluating the cost-effectiveness of different targeted agents for metastatic RCC.

 Remak et al conducted a cost-effectiveness analysis using a Markov model and demonstrated that, compared with interferon-alpha, sunitinib correlated with significantly better progression-free year gained at $18,611 and life-year gained at $67,214.

However, Benedict and colleagues more recently reported that sunitinib conferred a 0.17 of QALY increase and savings of $13,576 per patient relative to sorafenib in the United States.

 Further study is needed also to elucidate and comprehensively evaluate the cost-effectiveness of different targeted agents by also focusing on out-of-pocket and other potential economic implications for these drugs.

Our study has several limitations. Since this national private insurance database did not include information regarding stage or other clinical variables, we could not reliably investigate the possible relationship of disease burden or other clinical aspects, such as performance status or physician/patient preference, on costs and reimbursement. It is also plausible that different private health insurance plans may vary in the amount they reimburse, thereby affecting the out-of-pocket costs for which patients are responsible. The IMS LifeLink Health Plan Claims Database, however, is limited by not supplying information about individual health insurance plans.

It is certainly possible that the economic burden of targeted agents may have varied substantially across different private health insurance plans. We also acknowledge that determining the out-of-pocket costs relied on estimating this outcome from calculating the difference between the total costs and private health insurance reimbursement of each agent, rather than directly inquiring about the direct and indirect healthcare costs from patients. Lastly, we recognize that the differing dosing schedules for each oral TKI may have impacted the out-of-pocket costs.

Our study on the economic burden of sunitinib and sorafenib among patients diagnosed with metastatic RCC has important policy implications in this targeted therapy era. For both oral TKI agents, patients appear to be responsible for approximately $1100 in out-of-pocket costs over a 6-month duration, or 3 cycles of treatment. Such high out-of-pocket costs may represent formidable barriers in equitable access to sunitinib or sorafenib, or pose economic hardship to metastatic RCC patients. Moreover, the economic costs to patients (even those who, like those studied, are covered by insurance) for these first-line agents for metastatic RCC may become increasingly problematic due to greater cost sharing on the part of patients as a result of the ACA.

 Patients and physicians should ensure that discussions about treatment alternatives for metastatic RCC include mention of potential out-of-pocket costs. Further research is needed to establish whether out-of-pocket costs may be a barrier to access to targeted agents and/or can adversely impact compliance regarding these beneficial drugs for metastatic RCC patients.

: University Hospitals Case Medical Center, Case Western Reserve University School of Medicine (SPK), Cleveland, OH; Cancer Outcomes and Public Policy Effectiveness Research Center (COPPER) (SPK, CPG) and Department of Internal Medicine, Yale School of Medicine (CPG), Yale University, New Haven, CT; Division of Urology, Brigham and Women’s Hospital, Harvard Medical School (Q-DT), Boston, MA; Department of Surgery, Fox Chase Cancer Center-Temple University Health System (MCS), Philadelphia, PA; Department of Urology (RHT, SPP), and Knowledge and Evaluation Research Unit (NDS), and Division of Health Care Policy and Research (HVH, LCH, NDS), Mayo Clinic, Rochester, MN; Department of Urology, Case Western University School of Medicine (RA), Cleveland, OH; Henry Ford Hospital’s Vattikuti Urology Institute (JDS), Detroit, MI; Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre (MS), QC, Canada.

: Dr Kim was supported by the career development award from the Conquer Cancer Foundation of the American Society of Clinical Oncology.

: Dr Gross is a member of the FAIR Health, Inc, Scientific Advisory Board, and has received grants from Medtronic, Inc (as principal investigator [PI]), Johnson & Johnson (co-PI), and 21st Century Oncology (co-PI); he has also received honoraria as a speaker at the American Society for Radiation Oncology annual meeting in September 2014. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

: Concept and design (SPK, CPG, Q-DT, SPP, JDS, MS); acquisition of data (SPK, HVH); analysis and interpretation of data (SPK, Q-DT, SPP, HVH, LCH, JDS); drafting of the manuscript (SPK, HVH, RA, JDS); critical revision of the manuscript for important intellectual content (SPK, CPG, Q-DT, MS, RHT, SPP, HVH, LCH, RA, JDS); statistical analysis (SPK, HVH); obtaining funding (SPK); administrative, technical, or logistic support (SPK, LCH); and supervision (SPK, RA).

: Simon P. Kim, MD, MPH, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Mailstop LKS5046, Cleveland, OH 44106. E-mail: simon.kim@UHhospitals.org.

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Articles

Study investigate the economic burden from the total costs, private insurance reimbursement, and out-of-pocket costs for oral TKI agents among metastatic RCC patients.