Abstract
Objective:
Brain metastases (BM) are highly prevalent among anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) patients; yet little is known about their real-world treatment patterns and clinical and economic burdens. This study aimed to describe these patients’ treatment patterns, symptoms, and costs.
Research design and methods:
Retrospective study pooling data from three large administrative databases in the US (08/2011–06/2013). ALK+ NSCLC patients with BM and continuous enrollment for ≥ 60 days before and ≥30 days after the first observed BM diagnosis were identified by pharmacy records for crizotinib among patients with lung cancer and BM diagnostic codes.
Main outcome measures:
Treatment patterns, symptoms, healthcare resource utilization, and costs, before and after BM diagnosis.
Results:
Of the 213 crizotinib patients with BM diagnoses meeting the selection criteria, 23.0% had BM prior to NSCLC diagnosis; 47.4% had BM prior to crizotinib initiation; 19.2% during crizotinib treatment; and 10.3% post-crizotinib treatment. For those diagnosed with BM after NSCLC diagnosis, the median time between the NSCLC and BM diagnoses was 88 days. Following the first observed BM diagnosis, 88.7% used chemotherapy, 63.4% had radiotherapy, and 31.9% had stereotactic radiosurgery. The prevalence of BM-related symptoms substantially increased post-BM-diagnosis: fatigue (from 15% to 39%), headaches (from 5% to 24%), and depression (from 5% to 15%). Monthly costs per patient averaged $5983 before the BM diagnosis and $22,645 after diagnosis. Patients’ resource utilization increased significantly post-BM-diagnosis, with a 3-fold increase in OP visits and a 6-fold increase in IP stays. Post-BM-diagnosis costs were driven by pharmacy (42.0%), inpatient (29.6%), and outpatient costs (26.0%).
Limitations:
The study sample was limited to crizotinib-treated patients.
Conclusions:
Post-BM-diagnosis, patients experience high symptom burden. Post-BM-diagnosis, treatment is highly variable and costly: average monthly costs per patient almost quadrupled post-BM-diagnosis.
Introduction
Non-small-cell lung cancer (NSCLC) accounts for more than 85% of all lung cancers in the USCitation1. A large majority of NSCLC patients are diagnosed at an advanced stage of the disease and, as a result, experience limited success with treatment. Only a small fraction of patients (i.e., 4% of metastatic and 18% of all NSCLC) survive more than 5 years post-diagnosisCitation2. Growing understanding of the molecular pathogenesis of lung cancer has led to the development of targeted therapies in an effort to improve patient survivalCitation3,Citation4. In particular, tumors with activating mutations of select oncogenes, such as the fusion of the kinase domain of the anaplastic lymphoma kinase (ALK) to the amino-terminal section of the echinoderm microtubule-associated protein-like 4 (EML4) gene product, have been found to be susceptible to targeted therapiesCitation5. The EML4-ALK fusion results in the constitutive activation of a crucial cell-division-cascadeCitation6,Citation7; thus, these tumors tend to have an aggressive outlookCitation8,Citation9 with a high chance of early relapseCitation10. Patients with ALK+ NSCLC, which represent ∼2–8% of all patients diagnosed with NSCLCCitation11–19, tend to have a more advanced stage of the disease and multiple metastatic sites at diagnosis compared to other NSCLC typesCitation20.
The treatment of ALK+ NSCLC is often complex due to the frequent occurrence of brain metastases: initial occurrence of brain metastasis has been reported in 15–35% of casesCitation20–22, and, over the course of first-line therapy either with crizotinib or chemotherapyCitation10 the frequency of brain metastases can increase to 60%Citation23. Brain metastases are associated with many complications: some of these are neurocognitive, psychological, physical impairmentsCitation24,Citation25, severe comorbidity, and a decreased life expectancyCitation26,Citation27. Treatment of brain metastases usually involves radiotherapy (either whole-brain radiotherapy [WBRT] or stereotactic radiosurgery [SRS]) and may involve surgical resection (for isolated metastases or cases with a good prognosis) and/or chemotherapy (for salvage or experimental cases)Citation28–30. In addition, post-treatment, rehabilitation therapy may be neededCitation31, as well as help with daily living tasks for recovering patientsCitation32,Citation33. Thus, disease management and treatment planning for patients with brain metastases typically requires a multi-disciplinary approach and highly specialized careCitation34–36, and involves a substantial caregiverCitation32 and economicCitation27 burden.
Few studies have characterized the clinical and economic burden experienced by patients with brain metastasesCitation27,Citation37,Citation38, and none has specifically analyzed the (ALK+) NSCLC population. The objective of this study is to evaluate the impact of developing brain metastases on patients with ALK+ NSCLC in terms of economic and clinical outcomes.
Methods
Data sources
This study combined data from three large retrospective administrative-claims databases (Source Healthcare Analytics’ Source Lx database for June 2011–June 2013, IMS LifeLink Health Plan Claims database for January 2001–March 2013, and Truven Health Analytics MarketScan database for January 2002–September 2012) to extract patient data. The databases contain enrollment records, medical claims (physician and facility), and pharmacy claims. All census regions are represented in all three databases.
The Source Lx database contains linked healthcare data for more than 156 million annually covered lives, derived from three basic sources: pharmacy point-of-service; switch/network transactions; and additional direct prescription, medical, and hospital claims data.
The IMS LifeLink Health Plan Claims database contains combined claims for over 100 healthcare plans, representing ∼42 million annually covered lives.
The Truven Health Analytics MarketScan database contains combined claims for more than 130 employers that sponsor private health insurance, representing ∼40 million annually covered lives. In addition, the MarketScan Medicare Supplemental and Coordination of Benefits (Medicare Supplemental) database profiles the healthcare experience of retirees and their dependents with Medicare supplemental insurance paid for by employers.
All data used in this study had been de-identified according to the patient confidentiality requirements of the Health Insurance Portability and Accountability Act (HIPAA) and did not require approval from the Institutional Review Board or a waiver of authorization for use.
Study design
For this retrospective cross-sectional cohort study, patients who met the following selection criteria were selected: (1) ≥18 years of age; (2) ≥1 diagnosis for lung cancer (ICD-9 CM: 162.xx); (3) ≥1 prescription fill for crizotinib (this criterion is used as a proxy to identify patients with ALK+ NSCLC since there is no ICD-9 CM diagnosis code to identify ALK+ patients directly and crizotinib was restricted to the treatment of this population only); (4) no medical claims associated with a clinical trial (identified using ICD-9 CM code for V70.7); (5) ≥1 diagnosis of brain metastasis (ICD-9 CM codes 198.3 and 198.4); and (6) continuous eligibility ≥2 months before and ≥1 month after the date of the first observed diagnosis of brain metastasis. Patients selected for this study were referred to as ‘crizotinib patients’.
Patient characteristics
The reported patient characteristics included demographics (age, gender, geographical region), the year of the first observed brain metastasis diagnosis, the Charlson Comorbidity Index (CCI; a higher score indicates a greater comorbidity burden)Citation39, an indicator of the patient’s overall comorbidity profile, and the CCI components reported individually. Age was measured as of the date of the first observed brain metastasis diagnosis, while the comorbidities were measured during the pre-brain-metastasis-diagnosis period. The pre-brain-metastasis-diagnosis period was defined as a maximum 1-year period starting during the period of continuous eligibility and ending 30 days before the first observed brain metastasis diagnosis.
The timing (measured in days) of the development of brain metastases relative to NSCLC diagnosis and crizotinib treatment was captured for all eligible patients. This included the proportion of patients who developed brain metastases (a) on or prior to the date of the first observed NSCLC diagnosis, (b) after the first observed NSCLC diagnosis but prior to the date of the first observed prescription for crizotinib, (c) during crizotinib monotherapy-treatment, and (d) after crizotinib monotherapy-treatment. The average time between the first observed diagnosis of NSCLC and the first observed diagnosis of brain metastases recorded in the database were also reported among patients diagnosed with brain metastases after their first observed diagnosis for NSCLC.
Symptoms of brain metastases
For the analysis of symptoms frequently observed in patients with brain metastasis, the observation period was divided into two periods: the pre- and post-brain-metastasis-diagnosis periods. The pre-brain-metastasis-diagnosis period was defined as a maximum 1-year period starting during the period of continuous eligibility and ending 30 days before the first observed brain metastasis diagnosis, while the post-brain metastasis-diagnosis period spanned between 30 days before the first observed brain metastasis diagnosis and the end of data availability or of continuous eligibility (). The pre-metastasis-diagnosis period was truncated since some patients had very long observation periods, and truncation was done at 1 year since the median length of this period was ∼1 year. The following symptoms that required medical attention and the proportion of patients with these symptoms that are the most commonly reported in the literature were analyzed during these two observation periods: weakness or fatigue, shortness of breath, nausea or vomiting, headaches, pain or numbness, altered mental state, depression, seizure, stroke/transient ischemic attack, anxiety, vision disorder, drowsiness, loss of appetite, cognitive impairment, speech problems, problems with memory, focal neurologic deficits (motor or sensory), and changes in mood or personalityCitation24.
Figure 1. Study design.
Treatment patterns related to brain metastases
For the analysis of treatment patterns, the observation period started on the day of the first observed brain metastasis diagnosis and ended with the end of data availability or of continuous eligibility (). During the observation period, the following treatments were analyzed: chemotherapy, crizotinib, other targeted therapies (e.g., bevacizumab, erlotinib), corticosteroids, radiation therapy (including WBRT), SRS, brain surgery, and brachytherapy. The number of patients with at least one of the above treatments was reported. In addition, the list of all types of treatments received after brain metastasis diagnosis and the treatment patterns of the above treatments before, during, and after crizotinib treatment, regardless of the sequence and the course of the treatment, was summarized. Since at the time of the study, crizotinib was the only treatment available for patients with ALK+ NSCLC, the treatment patterns were expected to be influenced by the timing of the crizotinib course of treatment.
Healthcare resource utilization and costs
Healthcare resource utilization and costs were each assessed during the pre- and the post-brain-metastasis-diagnosis periods described above. Specifically, the number of inpatient (IP) stays, number of IP days, number of emergency room (ER) visits, number of outpatient (OP) visits, and number of other medical services (e.g., laboratory, radiology, patient’s home, hospice, or other ancillary services) were captured for each patient and reported as per-patient-per-month (PPPM) values.
Healthcare costs, measured from the payer’s perspective (i.e., including all charges reimbursed by payers—excluding the Medicare portion for patients 65 years and older from the IMS LifeLink Health Plan Claims database), were adjusted for inflation and expressed in 2013 US dollars using the Consumer Price Index medical care component. Total healthcare costs were comprised of pharmacy costs and medical service costs. Pharmacy costs included NSCLC-specific therapy costs (chemotherapy, targeted therapy, corticosteroids, or crizotinib) as well as costs for other therapies used for symptom management, and other pharmacy costs. Medical service costs included costs associated with IP stays, ER visits, OP visits, and other medical services. Healthcare costs associated with radiotherapy were also reported separately for each component of the medical costs. Only descriptive statistics were reported in all analyses. All statistical analyses were conducted using SAS 9.3 (SAS Institute Inc., Cary, NC).
Results
Patient characteristics
A total of 753 crizotinib patients were identified from a pool of 1,352,449 lung cancer patients; of these, 213 were diagnosed with brain metastases and satisfied all other selection criteria (). The mean patient age for the study sample was 54.8 years old and 55.9% of patients were female (). The study sample had an average CCI score of 2.7 (SD = 3.0). The most common comorbidities—other than cancer—in the patient sample were chronic pulmonary disease (16.9%), diabetes (8.0%), and mild liver disease (4.2%).
Figure 2. Sample selection.
Table 1. Patient characteristics.
In total, 70.4% of patients (n = 150) were diagnosed with brain metastasis prior to receiving targeted therapy for ALK + NSCLC. About 23.0% (n = 49) of patients were diagnosed with brain metastasis at the time of the initial NSCLC diagnosis and 47.4% (n = 101) were reported to have their first observed brain metastasis diagnosis following NSCLC diagnosis but prior to crizotinib initiation. Similarly, 19.2% (n = 41) had their first observed brain metastasis diagnosis observed during crizotinib monotherapy, and 10.3% (n = 22) after crizotinib monotherapy. The median time from the first observed NSCLC diagnosis to the first observed brain metastasis diagnosis among patients diagnosed with brain metastases was 88 days.
Frequent symptoms in patients with brain metastases
Overall, the symptom burden was high both before and after the diagnosis of brain metastasis in crizotinib patients, but patients experienced a substantially higher number of symptoms after brain metastasis diagnosis than before: the most frequent symptoms were fatigue (15.0% pre-diagnosis and 39.0% post-diagnosis), shortness of breath (14.1% and 38.0%, respectively), nausea or vomiting (10.8% and 33.3%, respectively), and headaches (4.7% and 23.9%, respectively) ().
Figure 3. Symptoms during the pre- and post-brain-metastasis-diagnosis periods.
Treatment patterns among brain metastases patients
After the diagnosis of brain metastases, 88.7% received chemotherapy, 84.0% received crizotinib, 63.4% received radiation therapy, and 31.9% had SRS at some point during the observation period. In addition to these anti-cancer therapies, 77.5% of the study sample received corticosteroids (). A good portion (69%) of patients received multiple treatments after the diagnosis of brain metastases, regardless if they were already treated with crizotinib (). Although treatment combinations varied, the most frequently used treatment combination consisted of crizotinib + radiotherapy (18.3%). Among patients who developed brain metastases before initiating crizotinib (n = 150), 16.7% received crizotinib only and 21.3% received crizotinib and radiotherapy after the diagnosis of brain metastases. Among patients who developed brain metastases while on crizotinib (n = 41), 31.7% continued on crizotinib monotherapy while 17.1% added or switched to radiotherapy. Finally, among patients who developed brain metastases after discontinuing crizotinib (n = 22), 63.6% of them remained untreated and 13.6% received radiotherapy only. Detailed treatment patterns are summarized in .
Table 2. Treatments received after brain metastasis diagnosis.
Table 3. All treatments received after brain metastasis diagnosisa.
Healthcare resource utilization and cost
Crizotinib patients’ resource utilization increased after the diagnosis of brain metastasis, with OP visits increasing from 1.37 visits PPPM pre-diagnosis to 3.25 visits PPPM post-diagnosis, IP stays increasing from 0.04 stays PPPM pre-diagnosis to 0.25 stays PPPM post-diagnosis, and patients having more IP days post-diagnosis (increasing from 0.25 days PPPM pre-diagnosis to 1.17 days PPPM post-diagnosis) (). Patients also had an almost 6-fold increase in the utilization of other medical services post-diagnosis, increasing from 0.19 PPPM pre-diagnosis to 1.09 visits PPPM in the post-diagnosis period.
Table 4. Treatment patterns after brain metastasis diagnosis relative to crizotinib treatmenta.
Table 5. Healthcare resource utilization pre- and post-brain-metastasis-diagnosis period.
Higher resource utilization resulted in higher healthcare costs, as costs rose in the post-brain metastasis-diagnosis period compared to the pre-brain-metastasis-diagnosis period: patients had an average total monthly cost of $5983 in the pre-brain-metastasis-diagnosis period vs $22,645 in the post-brain-metastasis-diagnosis period (). Furthermore, in the pre-brain-metastasis-diagnosis period, 79% of patients had total healthcare costs between $0–$10,000, compared to 26% of patients in the post-brain-metastasis-diagnosis period (). Post-diagnosis, medical costs increased 4-fold and represented a higher portion of the total healthcare costs (58%), with the cost of hospitalization and associated procedures dominating this cost category (IP costs were 51% of the medical care costs). Pharmacy costs increased more than 3-fold in the post-diagnosis period. In the pre-brain-metastasis-diagnosis period, crizotinib cost accounted for 52.7% of the total pharmacy costs ($2924), while in the post-brain-metastasis-diagnosis period, crizotinib costs accounted for 68.3% of the total pharmacy costs ($9520). Radiotherapy was mainly performed on an OP basis, and was responsible for 43% of the OP costs. Pre-diagnosis, 51% of total costs were due to medical care costs (with OP costs representing the majority—59%—of these costs), and the remainder was due to the cost of pharmacological treatment.
Figure 4. Healthcare costs during the pre- and post-brain-metastasis-diagnosis periods.
Figure 5. Distribution of total healthcare costs PPPM.
Discussion
The ALK+ translocation confers special clinicopathologic features to the NSCLC cancer sub-type: ALK + NSCLC patients tend to be diagnosed with lung cancer at a younger ageCitation14,Citation15,Citation19,Citation21,Citation40, and have a higher risk of developing brain (and other) metastases than patients with other NSCLC sub-typesCitation20,Citation21,Citation41,Citation42. Brain metastases are known to severely impact a patient’s quality-of-life (physical, cognitive, and functional impairments)Citation24,Citation31,Citation33, as well as to result in high healthcare resource utilizationCitation37 and substantial clinicalCitation43, economicCitation27, and caregiverCitation32 burden.
In this study, we found that the development of brain metastases is associated with a substantial treatment burden, resource use, and costs in ALK+ NSCLC patients (identified by the use of crizotinib). Patients with brain metastases experienced a high symptom burden, particularly post-diagnosis of these metastases: more than a third suffered from fatigue, shortness of breath, nausea/vomiting, and almost a quarter suffered from headaches post-diagnosis. Prior studies also report that neurological symptomsCitation44,Citation45 are frequently encountered (in 36–82%Citation44–46 of cases) in lung patients with brain metastases. Temporary relief from symptoms can be achieved with treatmentCitation22,Citation45,Citation47–49, but not all patients will respond to treatmentCitation49, and resistance to treatment eventually occursCitation48.
In this study, we observed that, after being diagnosed with brain metastases, most patients received several treatments—chemotherapy, crizotinib, corticosteroids, and radiation therapy—but treatment combinations and patterns remained highly variable among the sample studied. According to the NCCN guidelines, radiation therapy for brain metastasesCitation28–30 and crizotinib for advanced ALK+ NSCLCCitation50 are the de facto treatment options for most ALK+ patients with or without brain metastases, but, for intolerant or resistant patients, there are several recommended treatment options, with no clear hierarchical path (for all steps subsequent to crizotinib treatment, the NCCN recommendations are based upon lower-level evidence; there is NCCN consensus that the intervention is appropriateCitation50). Thus, the observed treatment variability is not unexpected, and a similar use of systemic therapy (65%), radiation therapy (47%), and corticosteroids (79%) has been noted previously in a retrospective study of lung cancer patients with brain metastasesCitation27.
With the increase in symptoms and the variety of treatments post-diagnosis of brain metastases, the current study found that the already high economic burden of treatment pre-diagnosis of brain metastases drastically increased after diagnosis. The average monthly costs per patient almost quadrupled after the diagnosis of brain metastases, with monthly costs per patient averaging $5983 (interquartile range: $118–$8667) vs $22,645 (interquartile range: $9452–$26,693) for the pre- and post-brain metastasis periods, respectively. The estimate reported by Ray et al.Citation27 of post-diagnosis monthly costs was similar to the mean total of $17,007 for all-cause healthcare costs (PPPM) reported for lung cancer patients, of all types, with newly diagnosed brain metastases. However, there are several differences in how costs are distributed for brain-metastasis diagnosed in crizotinib patients vs in lung cancer patients: crizotinib patients had much higher pharmacy costs post-diagnosis of brain metastases ($9520 vs $809 PPPM), but lower medical costs ($13,125 vs $16,198 PPPM, respectively), with similar IP stays, but fewer ER visits (0.04 visits vs 0.21 visits PPPM, respectively) and more OP visits (3.25 visits vs 2.8 visits PPPM, respectively). It must be noted that crizotinib was granted accelerated regulatory approval in the US in August 2011, and erlotinib was approved for NSCLC treatment in April 2010, hence these agents were not available at the time Ray et al.Citation27 conducted their study. In addition, since ALK+ NSCLC has a relatively rare rate of occurrence (2–8%) among all NSCLC lung cancersCitation11–19, the treatment patterns reported by Ray et al.Citation27 are likely not indicative of this type of cancer. A probable explanation for the differences in cost distribution is that using targeted agents for the treatment of (brain) metastatic ALK+ NSCLC increases pharmacy costs, but reduces the use of inpatient services, possibly indicating that the disease has been managed (for a period of time). Another study evaluating the costs of treating brain-metastatic cancer patients (of which 55% were lung cancer patients) also found that brain metastases are associated with a significant economic burden, concluding that the total costs per year of life amounted to $62,130 (where less than 25% of the patients survived the first year of treatment)Citation37.
This study has demonstrated that the development of brain metastases, common in ALK+ NSCLC, can be costly and can present a substantial clinical burden. Further analyses are warranted to explore how treatment patterns and the burden are impacted post-crizotinib, now that a new therapy is available for patients who do not respond to crizotinib.
Limitations
The current study was subject to some limitations. First, patients were selected based on several proxy indicators of the type of the disease, as there was no ICD-9 CM code to identify ALK+ and/or NSCLC patients. A prescription fill for crizotinib was used as a proxy to identify patients with ALK+ NSCLC among patients with a diagnosis of lung cancer. Thus, the findings of the study may not be representative of ALK+ NSCLC patients who did not receive crizotinib. Second, patients were not required to have more than one diagnosis of brain metastases. Thus, their brain metastases were not confirmed with at least two independent diagnoses. Third, information needed to identify ER visits in the Source Healthcare Analytics Source Lx database was not available, thus the use of ER services, as well as associated costs, may be under-estimated in this study. A similar limitation arises in the estimation of costs experienced by patients covered by Medicare: only the MarketScan database had linked information on previous employees now covered by Medicare, thus this study had very limited information on the Medicare-covered population, and its findings may not be immediately generalizable to non-privately-insured populations. Moreover, since information on different cost components (e.g., co-ordination of benefits, out of pocket costs) was not available in the Source Lx database, a common measure of costs was used for all three databases. Fourth, only symptoms that required medical attention were captured in the study. Fifth, this study examined only direct medical costs, evaluated from the payers’ perspective. Information to determine indirect costs, such as lost productivity and burden to caregivers, was not available. Given the high comorbidity burden of the study’s patients (general poor health) and frequent hospitalizations, we expect these undetermined indirect costs to be substantial. Further studies are warranted to investigate this aspect of the economic burden of the ALK+ NSCLC. Sixth, the treatment choices analyzed in this study do not include ceritinib, the newly-approved second generation tyrosine kinase inhibitor for the treatment of ALK+ NSCLC after progression on crizotinib, as at the time the study was conducted ceritinib was not yet available. Finally, further studies are warranted to study the healthcare resource utilization and costs associated with the development of brain metastases in ALK+ NSCLC patients using more recent data, other data sources, or different study designs.
Conclusions
In this study we found that brain metastases present a substantial burden in the ALK+ NSCLC patient population (crizotinib patients) and significant variability in the treatment options was observed after the patient was diagnosed with brain metastasis. Healthcare utilization and costs after brain metastasis diagnosis were substantially greater than before diagnosis. Given the large percentage of ALK+ NSCLC patients who will eventually develop brain metastases, this study may highlight an important unmet need.
Transparency
Declaration of funding
This study was funded by Novartis. M. Sasane, J. Zhang, and K. Culver are employees of Novartis and own stock/stock options. A. Guérin, K. Dea, R. Nitulescu, and E. Q. Wu are employees of Analysis Group Inc., which has received consultancy fees from Novartis.
Acknowledgments
The authors thank Ana Bozas, PhD, an employee of Analysis Group, for writing and editorial support. A synopsis of this study’s results has been recently accepted as a poster presentation at the 19th annual meeting of the Society of Neuro-Oncologists (SNO) in Miami, Florida from November 13th to 16th (Poster BM-19).
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