Pediatric Pleomorphic Xanthoastrocytoma: A National Database Inquiry on Current Treatment Approaches in the United States

Abstract Background Pleomorphic xanthoastrocytomas (PXAs) account for <1% of primary brain tumors, occurring predominantly in children and young adults. Surgical resection serves as the primary treatment for PXAs, while radiotherapy (RT) and chemotherapy protocols remain poorly defined. Aim This study aims to determine current care patterns utilized for pediatric patients (≤ 18 years) diagnosed with PXAs and their effect on overall survival. Methods The United States National Cancer Database (NCDB) was queried between 2004 and 2015 for pediatric patients (≤18 years) diagnosed with PXAs. Results From the 224 qualifying patients, most patients proceeded with surgery only (78.1%), while 11.6% of patients received both adjuvant RT and chemotherapy. In the 2010‐2015 cohort, patients with subtotal resection were associated with poorer prognosis than those with gross‐total resection (hazard ratio = 17.44, 95% confidence interval = 2.10‐144.90, p < .001). RT and chemotherapy recipients were similarly associated with poorer survival than those treated with surgery only, with p‐values of <.001 and respective hazard ratios of 3.82 (95% confidence interval = 1.85‐7.90) and 6.68 (95% confidence interval = 3.21‐13.89). The key factors impacting the probability of RT delivery involved WHO grade (p < .001) and chemotherapy administration (p < .001). However, WHO grade alone did not significantly impact survival (p‐value = .088). Conclusion Maximally safe resection is the current treatment goal for patients with PXAs. RT and chemotherapy are poorly utilized but had a greater role in managing more aggressive cases of PXAs. Additional research focusing on the impact of adjuvant therapies on tumor progression is needed to better guide treatment decisions.


| INTRODUCTION
Pleomorphic xanthoastrocytomas (PXAs) are rare neuroglial tumors that occur predominantly in children and young adults. 1,2 They account for <1% of primary brain tumors and are considered World Health Organization (WHO) grade II tumors. 1,[3][4][5] They are associated with favorable prognosis with respective 5-year and 10-year overall survival (OS) rates of about 77.8% and 68.5%, 2,3,5 with an approximate 5-year progression-free survival (PFS) rate of 68.3%. 2,5 However, these tumors may transform into anaplastic PXAs (aPXAs) in 15%-20% of patients. 3,5,6 aPXAs are defined as a subset of PXAs in the revised 2016 WHO classification for central nervous system (CNS) tumors. These tumors are considered WHO grade III with their increased mitotic activity of ≥5 per high-powered fields. 1,2,5,7 They present with a higher likelihood for necrosis, proliferation, absent pericellular reticulin, and infiltration. 2,[7][8][9] Complete surgical resection presently serves as the primary treatment for PXAs, 3,10 while the role of adjuvant radiotherapy (RT) and chemotherapy in managing this disease remains undefined. To gain a better understanding of care patterns for pediatric PXAs, the current study aims to evaluate the effect of treatment, particularly RT, on OS using the United States National Cancer Database (NCDB).

| METHODS
The NCDB was established in 1988 by the American College of Surgeons Commission on Cancer (CoC) and the American Cancer Society. 11 It is a hospital-based cancer registry that collects information on patients receiving care from a CoC-accredited institution, which comprises 30% of 5000+ hospitals in the United States. Information reported in the NCDB include deidentified sociodemographic, treatment, tumor, and survival data of oncology patients.
Based on the International Classification of Diseases for Oncology, 3rd edition Histology code of 9424/3, a search through the NCDB brain dataset was conducted for pediatric patients (≤18 years) diagnosed with PXAs in 2004-2015. The data were exported on February 28, 2020, by authors Y.Y., C.B., and Y.C. These authors verified the data to ensure no problem occurred while data export.
Descriptive analysis was conducted summarizing patient demographic and clinical characteristics. To increase transparency concerning the impact of patients with missing values in the study analyses, footnotes referring to the inclusion or exclusion of these patients were provided for each table.
Patients were categorized in two treatment groups: "surgery only" and "surgery and RT." To assess for differences in patient characteristics between treatment groups, Kruskal-Wallis test was used for continuous variables (i.e., age and tumor size); Cochran-Armitage test was used for three-level ordinal variables (i.e., comorbidity score); and Fisher's exact test was used for other categorical variables. Analyses concerning extent of resection (EOR) were based on patients diagnosed between 2010 and 2015 as such information was made available in the database. Our variables were analyzed utilizing log rank testing and Kaplan-Meier modeling. OS was defined as the time in months from diagnosis to death or last follow-up, whichever occurs first. Univariate and multivariable Cox proportional hazard ratio models were fitted to the data. The final multivariable model was determined based on purposeful selection combined with Akaike's information criterion and Bayesian information criterion. All analyses were performed using R-version 3.6.2. p-values of <.05 were considered statistically significant. Data consisting of <20 patients were deidentified with asterisks (*) and reported only in percentages.

| RESULTS
For the 224 eligible, pediatric patients, an almost equal occurrence was found between males and females with a median diagnosis age of 14 years ( PXAs may be erroneously diagnosed as glioblastomas (GBMs). 8,[13][14][15] GBMs are commonly mistaken for aPXAs, as they appear similar in radiographic images and exhibit high mitotic activity and frequent necrosis. 16,17 The absence of appropriate nuclear pleomorphism, abundant reticulin sites, lymphocytic infiltration, and lipidfilled cytoplasms are also associated with aPXAs and a variety of GBMs. 16  Several studies have noted that EOR affects patient outcomes.  Furthermore, since the NCDB contains information on newly diagnosed cancer cases, the impact of demographic, clinical, and treatment factors on PFS could not be evaluated. 11 However, PFS remains a valuable outcome to evaluate in a condition that has a high tendency to recur. 4,20,23 Presently, maximally safe resection is the primary treatment recommendation for PXAs. 3,20,22 Observation for younger patients who undergo GTR is a reasonable approach, as EOR and young age are considered significant factors in improved PFS and OS. 20,22 Surveillance MRIs of the brain with contrast-enhancement is recommended at 3-month intervals during the first 3 years from diagnosis, biannually the following 2 years, and annually thereafter. 22 If the tumor recurs, patients should pursue aggressive treatment, such as secondary surgery and RT. 20 For tumors with atypical features, administrating postoperative therapy, such as RT and chemotherapy, may be beneficial considering these tumors are associated with reduced survival and a higher likelihood for recurrence than PXAs. 3,22

| CONCLUSION
Maximally safe resection is the mainstay treatment for patients with PXAs. The role of adjuvant therapies, such as RT and chemotherapy, remains poorly defined but is greatly utilized post surgery for patients with high-risk disease. Further investigation is warranted to determine the use of adjuvant therapies in managing and minimizing tumor progression in PXAs.