This study showed that the HCRU and costs of Medicaid-enrolled pediatric patients with NF1 and PN were substantial. Treatment patterns consisted primarily of supportive care with medications. Our data include many completely novel findings from a real-world population that highlight the burden of disease in pediatric NF1 patients with PN.
The last evaluation of HCRU and cost in NF1 was published in the year 2000; it was a prospective analysis of 201 adult NF1 patients receiving care at a hospital-based referral center in France (25). Inpatient and outpatient visits and procedures were retrieved from the hospital’s information system or by chart review. Over a 3-year period, 45% of patients had outpatient visits and 23% had inpatient admissions. Reconstructive surgery for PN was cited as the reason for hospitalization in 4% of patients. The mean (median) cost of management per patient per year was £810 (240). Both cost and hospitalization frequency increased with increasing severity of disease. Despite the intervening time and the differences between our study and theirs, a few comparisons are pertinent. The lower rate of outpatient visits in Wolkenstein et al. versus our study (45% versus ~100%) seems to confirm the stability of disease in adult versus pediatric populations. Also, the rate of surgery for PN was similarly low in the adult population of Wolkenstein et al. and our pediatric population (4% versus 7%), suggesting that the invasive nature of PN is a deterrent to surgical excision in all age groups and has remained so over time. The placement of these somewhat disparate studies side by side highlights the scarcity of information on the burden and cost of disease in NF1 patients and underscores the novelty of our findings.
One additional study published in the intervening time provides some insight into the burden of disease in children with NF1 and PN. Kim et al. assessed the pre-enrollment characteristics of 59 children (median age 8 years) enrolled in NF1/PN trials at the National Institutes of Health in 1996-2007 (26). Very few of these patients had had prior chemotherapy (5%), while 47% had had debulking surgery for their PN. These numbers vary widely from the proportions observed in the Medicaid population (25% had chemotherapy and 7% had surgery). The differences may be attributed to differences in age and severity between the study populations, with older patients (as in the Medicaid population) more likely to consider using chemotherapy, and patients with surgically intractable PNs (as in the NIH population) more likely to enroll in a trial.
The use of a Medicaid population as a data source offers a unique perspective on the burden of NF1 with PN. First, it includes race data that are not available in other Marketscan® databases. In comparison to previously published observational studies in the United States, which drew from sources such as the National NF Registry/Lurie Children’s Hospital in Chicago (27, 28), the National Cancer Institute’s natural history cohort (23, 29), and the Cincinnati Children’s Hospital (30), our study population had a lower proportion of White patients and a higher proportion of Black patients. Thus, our results provide insight into a different cross-section of NF1 patients than might be seen with other data sources. Second, in comparison to a similar analysis performed on a commercially insured population (31), several interesting differences were noted. Medicaid patients were most frequently diagnosed at a campus-based hospital (68%), versus a doctor’s office for the commercial population (58%). A higher proportion of Medicaid patients used pain medications (59%), and more of them were observed to use targeted therapies (1.6%), compared to the commercially insured patients (44% and 1.0%, respectively). ER visits were more frequent in the Medicaid population (45%) than the commercial population (25%), as were ‘other’ types of resource use (76% Medicaid, 51% commercial), and medical costs were driven by inpatient rather than outpatient services. These differences, though qualitative, suggest that resource use and costs are different in NF1 patients with different types of health insurance coverage, and this may inform future studies of treatment patterns, disease burden, and health outcomes in different populations.
The rate of use of pain relievers (59%) in the Medicaid population was higher than in some previous studies (23, 32). However, in a population drawn from the National Cancer Institute’s natural history cohort (N=41; median age 8 years), the rate of pain reliever use rose from 43% at baseline to 63% at the time point of maximum PN volume (a median time span of 6.5 years) (22). A high rate of pain reliever use may suggest that patients in the Medicaid population have larger tumors and/or experience more pain than some other cohorts.
The substantial resource use and cost burden described here, along with the findings of others regarding the burden of disease, highlight the need for new and more effective pharmacotherapies. Targeted agents like the recently approved selumetinib (21) represent the future of treatment for NF1 patients, especially those with inoperable PNs. Use of targeted agents will almost certainly lead to changes in treatment patterns, HCRU, and costs that can be the subject of future studies.
Limitations
Several limitations inherent to the use of administrative claims data apply to our study. First, since the IBM® MarketScan® Multistate Medicaid database contains information on individuals enrolled in Medicaid, the results may not be generalizable to other populations, e.g., the uninsured or those with employer-sponsored coverage. Second, the use of diagnosis codes and procedure codes to identify NF1 patients and PN-related procedures is imperfect because of variations in coding. Specifically, there is no single ICD code identifying PN; however, the diagnosis codes used in this study were reviewed for accuracy by a clinician specializing in NF1. Third, drugs administered during an inpatient stay do not appear in the database, so we were not able to capture individual drugs administered in hospital. Fourth, although dexamethasone and tretinoin are included as chemotherapy in the Cancer Research Network’s 2017 chemotherapy look-up tables (33), they may be used as non-chemotherapies in conditions other than cancer. Finally, NF1 is a chronic disease, and compared to a long-term horizon, the follow-up period in our study was relatively short (mean follow-up of 448 days, or 1.2 years). Study timing also affected the list of treatments observed, as many therapies were still undergoing investigation at the study end point in 2017.