- Email: [email protected]
Management and Survival of Adult Patients with Pilocytic Astrocytoma in the National Cancer Database
Accepted Manuscript Management and survival of adult patients with pilocytic astrocytoma in the National Cancer Database Kevin J. Lee, BS, Eduardo Marchan, MD, Jennifer Peterson, MD, Anna C. Harrell, MPH, CCRP, Alfredo Quinones-Hinojosa, MD, Paul D. Brown, MD, Daniel M. Trifiletti, MD PII:
S1878-8750(18)30251-1
DOI:
10.1016/j.wneu.2018.01.208
Reference:
WNEU 7406
To appear in:
World Neurosurgery
Received Date: 19 December 2017 Revised Date:
29 January 2018
Accepted Date: 30 January 2018
Please cite this article as: Lee KJ, Marchan E, Peterson J, Harrell AC, Quinones-Hinojosa A, Brown PD, Trifiletti DM, Management and survival of adult patients with pilocytic astrocytoma in the National Cancer Database, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.01.208. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. Management and survival of adult patients with pilocytic astrocytoma in the National Cancer Database Kevin J. Lee, BS1; Eduardo Marchan, MD1; Jennifer Peterson, MD1,2; Anna C. Harrell, MPH, CCRP1; Alfredo
Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, USA
2
Department of Neurological Surgery, Mayo Clinic, Jacksonville, FL, USA
3
Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
Running Title: Pilocytic astrocytoma NCDB
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1
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Quinones-Hinojosa, MD2; Paul D. Brown, MD3; Daniel M. Trifiletti, MD1,2
Keywords: radiation, radiosurgery, resection, grade I, brain Corresponding Author:
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Daniel M. Trifiletti, MD Department of Radiation Oncology Mayo Clinic
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4500 San Pablo Road South Jacksonville, FL, 32224
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Phone: (904) 953-2000 Fax: (904) 953-2898
Email: [email protected]
Acknowledgements: none Conflict of interest: none
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al.
Abstract Purpose/Objectives: Adult pilocytic astrocytomas (PA) are relatively rare central nervous system (CNS)
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tumors with a favorable prognosis. We sought to investigate existing clinical management
strategies and overall survival (OS) as a function of various clinical characteristics among adult patients with PA.
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Methods/Materials: All patients over age 18 years, diagnosed with CNS pilocytic astrocytomas from 2004-2014 in the National Cancer Database were included. Clinical and treatment-related
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characteristics were recorded and analyzed for an association with OS following diagnosis using univariate and multivariate analyses.
Results: 3,057 adult patients met the inclusion criteria with a median age of 32 years. At diagnosis, 1,138 patients (41%) had cerebral tumors, 832 patients (30%) had cerebellar tumors, 252 patients (9%)
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had tumors of the spinal cord, and 534 patients (19%) had tumors of unspecified location. 77% of patients received surgery alone as local therapy, while the remainder was split between surgery+radiation (11.9%), radiation alone (4.5%), and biopsy alone (6.9%). On multivariate
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analysis, factors associated with inferior OS included older age (HR=1.05, p<0.001), lower income (p<0.001), higher Charlson/Deyo Score (p=0.023), larger tumor size (p=0.023), and
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radiation technique (p<0.001, HR 3.37 for external beam, EBRT). Conclusions: The present data provide large-scale prognostic information from a contemporary cohort of patients with pilocytic astrocytoma. It confirms that age, median income, Charlson/Deyo Score, and tumor size had a significant effect on OS. While resection status, tumor size, and location likely bias against EBRT, it is clear that novel therapeutics are needed in patients with tumors not amenable to resection or radiosurgery.
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. Introduction Pilocytic astrocytomas (PA) are WHO grade I tumors, which commonly present as a wellcircumscribed cystic mass in the central nervous system (CNS) with an accompanying mural nodule.1
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Overall, they make up between 0.6-5.1% of all intracranial malignancies.2,3 It is well established that they exhibit a bimodal age presentation. Nonetheless, the vast majority of cases present before the age of 20.4
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The childhood subtype of pilocytic astrocytoma often possesses alterations in the MAPK
pathway including BRAF fusions and point mutations in genes including NF1, BRAF, KRAS, FGFR1, and
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PTPN11.5,6 It also occurs commonly in children with mutations in NF1, and these patients usually present with unilateral and bilateral optic nerve gliomas.5,7
In contrast, adult PA has been less studied given its decreased incidence, hence, much of what is known about adult PA has been extrapolated from the childhood PA literature.8 Diagnosis is usually obtained through radiopathologic methods, although the radiologic findings in this tumor type are
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widely variable and often not specific.9 Current national consensus guidelines recommend surgical resection as the initial modality of treatment, both for histopathologic confirmation, immediate
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decompression, and as a definitive therapy.10 Moreover, data from the prospective trial by Brown et al. has shown that close observation is reasonable for patients with a complete or subtotal resection.11 This
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landmark study in the field clearly showed good local control of disease with both gross total and subtotal resection, with only one patient requiring salvage radiotherapy.11 However, if patients develop symptomatic recurrence, then radiation therapy (or sometimes radiosurgery) is commonly recommended as salvage therapy.11-13 Recently, Johnson et al.14 showed that survival rates of PA declined significantly with age, from a 96.5% 5-year survival in patients 5-19 years to 52.9% 5-year survival in adult patients 60+ years of age, with a corresponding decrease in relative and cancer-specific survival rates. However, due to the relative
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. paucity of cases, large randomized controlled trials (RCTs) in adult PA are not feasible. We reviewed the National Cancer Database (NCDB) in order to assess the common modalities of clinical management and
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the overall prognosis for adult patients with PA.
Methods Data source in cohort selection
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This is a retrospective analysis utilizing data obtained from the NCDB. The NCDB is a nationwide facility-based comprehensive clinical surveillance resource that is managed jointly by the American
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College of Surgeons and the American Cancer Society. It comprises 70% of new cancer diagnoses in the United States annually15 It displays patient-level data including various clinical and pathologic characteristics of the initial treatment course as well as long term outcomes such as overall survival (OS) following diagnosis.16
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We evaluated patients in the NCDB, treated between 2004 and 2014, with pathologically diagnosed PA (among 448,453 total patients with CNS tumors). Clinical characteristics including year of diagnosis, patient age, gender, race, facility type, and Charlson/Deyo comorbidity index were analyzed.
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Moreover, we studied various tumor and treatment-related characteristics to identify factors that were associated with changes in OS. Extent of tumor resection was reported through the NCDB which does
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not specify the means of this assessment (intraoperative assessment, radiographic, etc.).
Statistical analysis
For the purposes of OS analyses, subtotal resection (STR) and gross total resection (GTR) were
analyzed independently, as were all radiation techniques [including fractionated external beam irradiation (EBRT), stereotactic radiosurgery (SRS), and radiation therapy not otherwise specified (RTNOS)]. Variables potentially associated with OS were selected after univariate Cox regression analysis.
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. Because of the small size of subgroups, tumor location was grouped for survival analysis (supratentorial, infratentorial, spinal cord, and other). Those independent variables with p-values of under 0.10 on univariable analysis were included in the final multivariable Cox regression analysis. This was conducted
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via a two-tailed test whereby p < 0.05 was deemed statistically significant. All statistical analyses were performed using the SPSS statistical software package (SPSS, version 24, SPSS Incorporated, Chicago, IL).
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Results Clinical characteristics
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Three thousand fifty-seven (3,057) patients met the inclusion criteria representing 0.68% of the total number of cases in the database. Table 1 describes the salient characteristics of the patient population divided by their clinical characteristics. The average age of the patients was 30-36 years across all of the local treatment modalities. More than 75% of all cases received surgery alone as local
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therapy, while the remainder was split between surgery + radiation (11.9%), radiation alone (4.5%), and biopsy alone (6.9%). Of note, the majority of patients (2,131 patients, 69.7%) had an extent of resection
Overall survival
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that was not reported.
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Table 2 provides the results of the univariable and multivariable survival analyses. After multivariable-adjustment for confounders, factors associated with inferior OS included older age (HR=1.05, p < 0.001), lower median income (p < 0.001), higher Charlson/Deyo Score (p = 0.023), and larger tumor size (p = 0.023). On multivariable analysis, extent of resection did not impact OS (p = 0.283). Figure 1 demonstrates the significant association between radiation technique and overall survival (p < 0.001, HR 3.37 for external beam). Specifically, patients undergoing external beam radiation
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. therapy (EBRT) had a 5-year overall survival under 60%, while those receiving other therapies had a 5year OS at least in excess of 75%, and this trend held with more than 10 years of follow up from diagnosis. Kaplan-Meier curves for overall survival as a function of type of radiation therapy
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demonstrated similar 10 year outcomes for ‘no radiation therapy’ compared to SRS (HR: 1.517, p = 0.161) and radiation-NOS (HR: 0.844, p = 0.618). Nonetheless, patients treated with EBRT were found to have a decreased OS (compared to “no radiation therapy”) (HR: 3.370, p < 0.001).
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Tumor location also impacted OS, with patients with PAs in the spinal cord demonstrating inferior OS than other tumor locations, as demonstrated in Figure 2. In contrast, individuals with
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supratentorial tumors appeared to have improved OS in the time frame of 2-8 years after diagnosis. Of note, while primary tumor site was statistically significant in univariable analysis, this association did not hold in the multivariable model (p = 0.01 and 0.11, respectively).
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Discussion
In this analysis, we have described the observed outcomes and treatment modalities in 3,057 adult patients with PA. We found a significant association between radiation technique and overall
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survival, namely, patients receiving fractionated EBRT had inferior survival when compared to patients receiving no radiation therapy. In contrast, those patients who underwent SRS had a 5-year overall
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survival in excess of 75% as opposed to those who had fractionated EBRT who had a five-year overall survival under 60%.
It is likely that the association between EBRT and inferior survival is confounded by other clinical
covariables that have a known impact on outcome like tumor size, extent of resection, a more aggressive clinical phenotype, and location. While we do not believe that the use of EBRT directly results in inferior survival, we do believe that patients who are recommended EBRT have very limited effective therapeutic options. In common practice, patients recommended for EBRT have large tumors in
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. eloquent locations, where neurosurgical resection and radiosurgery would be considered of excessive risk. These findings support the need to develop alternative therapies for PA, perhaps through advancements in radiosensitizing or stand-alone systemic therapies.
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Interestingly, tumor location demonstrated an unclear association with survival. This is in
contrast to a previous study by Johnson et al., evaluating the Surveillance, Epidemiology, and End
Results program (SEER) that found among 865 adults on univariate analysis cerebellar tumors carry a
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more favorable prognosis when compared to cerebral tumors.14 The current series, with considerably more patients and statistical controlling of known prognostic factors, provided alternative results.
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As anticipated, patient age, median income, Charlson-Deyo score, and tumor size all had a significant effect on OS. Increasing age is a known prognostic factor in adult PA.14 In the Johnson et al. series, survival rates declined significantly with age, from 96.5% 5 year survival in patients 5-19 years (95% CI 95.3-97.4) to a 52.9% 5-year survival in adult patients who were 60 years of age or older (95% CI
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38.4-65.5). There was also a corresponding decrease in relative and cancer-specific survival rates.14 The authors hypothesized that the increased mortality for older adults above and beyond that expected for normal aging could be explained by a qualitative difference in the intrinsic biology of adult PA tumors.
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With the widespread national adoption of SRS as a treatment modality in patients with brain tumors,17 we anticipate a decrease in treatment side effects with an ever-increasing rate of local disease
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control.18 Illustratively, a recently published case series including 28 patients with pilocytic astrocytoma showed that after mean clinical follow-up of 5.2 years, all patients who underwent SRS were alive and without evidence of active disease, a result which confirms the effectiveness of SRS in appropriately selected patients with PA.19
At the Mayo Clinic, the currently-accepted treatment paradigm for adult PA is surgical gross total resection.11,20 If gross total resection is not possible for technical considerations or medical comorbidities, radiotherapy is likely to improve local control. Stereotactic radiosurgery is utilized when
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. appropriate based on tumor volume and location.19 When tumors are not amenable to neurosurgical resection or SRS, the long term risks of EBRT should be weighed carefully against the risks of tumor location, and individualized to the patient and their goals. When patients opt for EBRT, we treat with
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advanced delivery techniques (arc-based intensity modulated radiotherapy or proton beam therapy) to 45-54 Gy in 1.8 Gy fractions.
As any retrospective analysis, there is the possibility of uncontrolled, confounding covariables
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that could impact the current results. As an example, tumor location within the cerebrum is unknown (eloquent or non-eloquent location). Moreover, tumor molecular status is unknown in this data set and
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could impact patient outcomes. Additionally, in this study extent of tumor resection was likely determined subjectively rather than by rigorous volumetric analysis, and no interpretation of the value of extent of resection in this setting should be done based on this study alone. Despite these limitations, we believe that these results provide accurate and meaningful information and can offer important
Conclusion
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information to clinicians caring for patients with this rare CNS neoplasm.
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Adult PA generally carries a slightly poorer prognosis than its childhood counterpart. Additional studies and advanced molecular diagnostic testing will more fully elucidate the underlying biology in
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adult PA, and perhaps expand treatment options. These advances are particular needed among patients with unresectable PA, currently recommended for EBRT.
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. References 1.
Kleihues P, Burger PC, Scheithauer BW. The new WHO classification of brain tumours. Brain pathology (Zurich, Switzerland). 1993;3(3):255-268. Dutton JJ. Gliomas of the anterior visual pathway. Survey of Ophthalmology. 1994;38(5):427-
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Sekula RF, Jr., Marchan EM, Quigley MR, Frederickson AM, Pu C. A case of an elderly adult
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presenting with obstructive hydrocephalus secondary to a rare hemorrhagic suprasellar pilocytic astrocytoma. Clinical neuropathology. 2008;27(6):396-399.
Koeller KK, Rushing EJ. From the archives of the AFIP: pilocytic astrocytoma: radiologic-
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pathologic correlation. Radiographics : a review publication of the Radiological Society of North America, Inc. 2004;24(6):1693-1708. 5.
Rodriguez FJ, Giannini C, Asmann YW, Sharma MK, Perry A, Tibbetts KM, et al. Gene expression
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profiling of NF-1-associated and sporadic pilocytic astrocytoma identifies aldehyde dehydrogenase 1 family member L1 (ALDH1L1) as an underexpressed candidate biomarker in aggressive subtypes. Journal of neuropathology and experimental neurology. 2008;67(12):1194-
6.
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Tomic TT, Olausson J, Wilzen A, Sabel M, Truve K, Sjogren H, et al. A new GTF2I-BRAF fusion
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mediating MAPK pathway activation in pilocytic astrocytoma. PLoS One. 2017;12(4):e0175638. Chen YH, Gutmann DH. The molecular and cell biology of pediatric low-grade gliomas. Oncogene. 2014;33(16):2019-2026.
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Garcia DM, Fulling KH. Juvenile pilocytic astrocytoma of the cerebrum in adults. A distinctive neoplasm with favorable prognosis. Journal of Neurosurgery. 1985;63(3):382-386.
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Theeler BJ, Ellezam B, Sadighi ZS, Mehta V, Tran MD, Adesina AM, et al. Adult pilocytic astrocytomas: clinical features and molecular analysis. Neuro-Oncology. 2014;16(6):841-847. 9
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Nabors LB, Portnow J, Ammirati M, Baehring J, Brem H, Butowski N, et al. NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017. J Natl Compr Canc Netw. 2017;15(11):1331-1345. Brown PD, Buckner JC, O'Fallon JR, Iturria NL, Brown CA, O'Neill BP, et al. Adult patients with
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supratentorial pilocytic astrocytomas: a prospective multicenter clinical trial. Int J Radiat Oncol Biol Phys. 2004;58(4):1153-1160.
van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K, et al. Long-term
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efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma
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in adults: the EORTC 22845 randomised trial. Lancet. 2005;366(9490):985-990. Kidd EA, Mansur DB, Leonard JR, Michalski JM, Simpson JR, Perry A. The efficacy of radiation therapy in the management of grade I astrocytomas. Journal of Neuro-Oncology. 2006;76(1):5558.
Johnson DR, Brown PD, Galanis E, Hammack JE. Pilocytic astrocytoma survival in adults: analysis
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of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Journal of Neuro-Oncology. 2012;108(1):187-193. American College of Surgeons, Quality Programs, National Cancer Database. 2016;
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https://www.facs.org/quality-programs/cancer/ncdb. Accessed December 1, 2016. American College of Surgeons, National Cancer Database: Patient User File Data Dictionary
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Items. 2011; http://ncdbpuf.facs.org/?q=node/259. Accessed December 1, 2016.
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Trifiletti DM, Sheehan JP, Grover S, Dutta S, Rusthoven CG, Kavanagh BD, et al. National trends in radiotherapy for brain metastases at time of diagnosis of non-small cell lung cancer. Under Review. 2017.
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Hallemeier CL, Pollock BE, Schomberg PJ, Link MJ, Brown PD, Stafford SL. Stereotactic radiosurgery for recurrent or unresectable pilocytic astrocytoma. Int J Radiat Oncol Biol Phys. 2012;83(1):107-112. Trifiletti DM, Peach MS, Xu Z, Kersh R, Showalter TN, Sheehan JP. Evaluation of outcomes after
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stereotactic radiosurgery for pilocytic astrocytoma. Journal of Neuro-Oncology. 2017;134(2):297-302.
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Bell D, Chitnavis BP, Al-Sarraj S, Connor S, Sharr MM, Gullan RW. Pilocytic astrocytoma of the adult--clinical features, radiological features and management. British journal of neurosurgery.
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2004;18(6):613-616.
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20.
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. Figure and Table Legend
Figure 1: Overall survival among patients with pilocytic astrocytoma in the National Cancer Database
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2004-2014 by radiation modality as a local treatment, with external beam radiation therapy demonstrating inferior survival.
Figure 2: Overall survival among patients with pilocytic astrocytoma in the National Cancer Database
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2004-2014 by primary site of the tumor, with supratentorial tumors demonstrating superior survival.
Table 1: Clinical characteristics of the 3057 adult patients with pilocytic astrocytoma in the National Cancer Database 2004-2014.
Table 2: Univariable and multivariable analysis of factors associated with overall survival among patients
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with pilocytic astrocytoma in the National Cancer Database 2004-2014.
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Table 1: Clinical characteristics of the 3057 adult patients with pilocytic astrocytoma in the National Cancer Database 2004-2014.
Charlson/Deyo Score
25-100 mi >100 mi Unknown 0 1 2 Frontal Lobe Temporal Lobe Parietal Lobe Occipital Lobe Cerebellum Brainstem Spinal Cord Cerebrum NOS Other Right Left Midline/bilateral 1-19mm 20-39mm 40-59mm 60-79mm 80-99mm 100+mm Unknown
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Primary Site
<25 mi
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Distance to Hospital
Laterality
Tumor Size
21
28.4%
18
46
62.2%
5
% 4.5%
Surgery only
n 2,344 2009 30 1,844 205 10 38 72 175 395 543 654 731 19
% 76.7%
Surgery + Radiation % 11.9%
78.7% 8.7% 0.4% 1.6% 3.1% 7.5% 17.0% 23.4% 28.2% 31.5% 2.5%
n 365 2009 36 273 41 1 6 13 31 54 103 86 117 3
29.0%
224
29.3%
46
28.2%
36
58.1%
432
56.5%
84
51.5%
6.8%
7
11.3%
90
11.8%
30
18.4%
0.0%
0
0.0%
0
0.0%
0
0.0%
76.8% 10.1% 0.0% 2.2% 1.4% 9.4% 12.5% 24.3% 32.4% 30.9% 1.6%
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71.0% 11.0% 0.5% 2.9% 3.8% 11.0% 21.6% 22.1% 24.0% 32.2% 2.7%
n 138 2009 36 106 14 0 3 2 13 17 33 44 42 1
0
% 6.9%
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Other specified types of cancer programs
n 210 2009 33 149 23 1 6 8 23 45 46 50 67 2
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N (of 3,057) Year of Diagnosis (median) Patient Age (median) Race White Black American Indian Asian/Pacific Islander Unknown Hispanic Median Income <$38,000 $38,000-$47,999 $48,000-$62,999 $63,000 + Facility Type Community Cancer Program Comprehensive Community Cancer Program Academic/Research Program Integrated Network Cancer Program
Radiation only
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Biopsy alone
74.8% 11.2% 0.3% 1.6% 3.6% 8.5% 15.0% 28.6% 23.9% 32.5% 1.8%
118
56.2%
84
60.9%
1,338
57.1%
226
61.9%
60 30 2 185 17 8 22 10 9 8 17 21 10 69 44 52 43 115 45 73 24 5 3 0 60
28.6% 14.3% 1.0% 88.1% 8.1% 3.8% 10.5% 4.8% 4.3% 3.8% 8.1% 10.0% 4.8% 32.9% 21.0% 24.8% 20.5% 54.8% 21.4% 34.8% 11.4% 2.4% 1.4% 0.0% 28.6%
38 14 2 125 9 4 7 5 5 2 8 29 18 30 34 19 26 93 22 42 24 2 0 1 47
27.5% 10.1% 1.4% 90.6% 6.5% 2.9% 5.1% 3.6% 3.6% 1.4% 5.8% 21.0% 13.0% 21.7% 24.6% 13.8% 18.8% 67.4% 15.9% 30.4% 17.4% 1.4% 0.0% 0.7% 34.1%
676 309 21 1,997 260 87 203 210 97 72 732 197 168 289 376 351 322 1,671 376 712 467 102 14 22 651
28.8% 13.2% 0.9% 85.2% 11.1% 3.7% 8.7% 9.0% 4.1% 3.1% 31.2% 8.4% 7.2% 12.3% 16.0% 15.0% 13.7% 71.3% 16.0% 30.4% 19.9% 4.4% 0.6% 0.9% 27.8%
95 39 5 287 54 24 27 13 5 8 75 54 56 47 80 47 30 288 40 125 68 11 6 2 113
26.0% 10.7% 1.4% 78.6% 14.8% 6.6% 7.4% 3.6% 1.4% 2.2% 20.5% 14.8% 15.3% 12.9% 21.9% 12.9% 8.2% 78.9% 11.0% 34.2% 18.6% 3.0% 1.6% 0.5% 31.0%
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Subtotal Gross total Unknown None External Beam Radiation Stereotactic Radiosurgery Radiation NOS
9
4.3%
8
5.8%
0
0.0%
0
0.0%
0 0 201 210 0 0 0
0.0% 0.0% 95.8% 100.0 % 0.0% 0.0% 0.0%
0 0 130 0 99 23 16
0.0% 0.0% 94.2% 0.0% 71.7% 16.7% 11.6%
276 535 1,533 2,344 0 0 0
11.8% 22.8% 65.4% 100.0 % 0.0% 0.0% 0.0%
64 34 267 0 246 39 80
17.5% 9.3% 73.2% 0.0% 67.4% 10.7% 21.9%
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Radiation Technique
Biopsy only
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Extent of Resection
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Table 2: Univariable and multivariable analysis of factors associated with overall survival among patients with pilocytic astrocytoma in the National Cancer Database 2004-2014.
p Year of Diagnosis
Multivariable p
Hazard Ratio
< 0.001
1.050
0.227
Patient Age
< 0.001
Race
0.531 <$38,000
0.01
0.001
0.621
$48,000-$62,999
< 0.001
0.543
< 0.001
0.600
$63,000 + Facility Type
0.259
Distance to Hospital
Primary Site
0.128 0
< 0.001
1
0.222
2
0.009
Supratentorial
0.01
Infratentorial Spinal Cord Other/Unknown Laterality Tumor Size
upper 95% 1.056
0.464
0.832
0.405
0.730
0.453
0.793
1.182
0.904
1.547
1.647
1.133
2.393
0.536
1.097
0.818
1.473
0.825
0.956
0.639
1.428
0.056
1.334
0.993
1.791
0.010
1.661
1.130
2.441
0.006
1.803
1.187
2.739
< 0.001
3.029
1.748
5.248
0.125
1.920
0.835
4.415
0.388
0.416
0.057
3.050
0.001
1.916
1.310
2.801
4.219
0.111
0.14 1-19mm
< 0.001
20-39mm 40-59mm
100+mm Unknown Extent of Resection
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60-79mm 80-99mm
0.002
0.283
None
< 0.001
< 0.001
External Beam Radiation
< 0.001
3.370
2.692
Stereotactic Radiosurgery
0.161
1.517
0.847
2.716
Radiation NOS
0.618
0.844
0.432
1.648
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Radiation Technique
0.023
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Charlson/Deyo Score
< 0.001
$38,000-$47,999
1.044
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Median Income
lower 95%
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Univariable
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Values bolded if p < 0.05.
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Radiation Technique
0.8
none EBRT SRS RT NOS none-censored EBRT-censored SRS-censored RT NOS-censored
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1.0
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Survival
0.6
0.4
0.2
0.0 24
48
72
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0
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p < 0.001
96
120
144
Months from Diagnosis
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Figure 1: Overall survival among patients with pilocytic astrocytoma in the National Cancer Database 2004-2014 by radiation modality as a local treatment, with external beam radiation therapy demonstrating inferior survival.
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Primary Site
1.0
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Supratentorial Infratentorial Spinal cord Other or unknown Supratentorial-censored Infratentorial-censored Spinal cord-censored Other or unknowncensored
0.8
Survival
0.6
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p = 0.010
0.2
0.0 24
48
72
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0
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96
120
144
Months from Diagnosis
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Figure 2: Overall survival among patients with pilocytic astrocytoma in the National Cancer Database 2004-2014 by primary site of the tumor, with supratentorial tumors demonstrating superior survival.
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A large database reports the management of patients with pilocytic astrocytoma Age, income, comorbidities, and tumor size had a significant effect on survival Novel therapeutics are needed in patients with tumors not amenable to surgery
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• • •
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Abbreviations PA: pilocytic astrocytoma OS: overall survival
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CNS: central nervous system EBRT: external beam radiation therapy
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NCDB: national cancer database
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The authors have declared no conflicts of interest as it pertains to this manuscript
S1878-8750(18)30251-1
DOI:
10.1016/j.wneu.2018.01.208
Reference:
WNEU 7406
To appear in:
World Neurosurgery
Received Date: 19 December 2017 Revised Date:
29 January 2018
Accepted Date: 30 January 2018
Please cite this article as: Lee KJ, Marchan E, Peterson J, Harrell AC, Quinones-Hinojosa A, Brown PD, Trifiletti DM, Management and survival of adult patients with pilocytic astrocytoma in the National Cancer Database, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.01.208. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. Management and survival of adult patients with pilocytic astrocytoma in the National Cancer Database Kevin J. Lee, BS1; Eduardo Marchan, MD1; Jennifer Peterson, MD1,2; Anna C. Harrell, MPH, CCRP1; Alfredo
Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, USA
2
Department of Neurological Surgery, Mayo Clinic, Jacksonville, FL, USA
3
Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
Running Title: Pilocytic astrocytoma NCDB
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1
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Quinones-Hinojosa, MD2; Paul D. Brown, MD3; Daniel M. Trifiletti, MD1,2
Keywords: radiation, radiosurgery, resection, grade I, brain Corresponding Author:
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Daniel M. Trifiletti, MD Department of Radiation Oncology Mayo Clinic
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4500 San Pablo Road South Jacksonville, FL, 32224
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Phone: (904) 953-2000 Fax: (904) 953-2898
Email: [email protected]
Acknowledgements: none Conflict of interest: none
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al.
Abstract Purpose/Objectives: Adult pilocytic astrocytomas (PA) are relatively rare central nervous system (CNS)
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tumors with a favorable prognosis. We sought to investigate existing clinical management
strategies and overall survival (OS) as a function of various clinical characteristics among adult patients with PA.
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Methods/Materials: All patients over age 18 years, diagnosed with CNS pilocytic astrocytomas from 2004-2014 in the National Cancer Database were included. Clinical and treatment-related
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characteristics were recorded and analyzed for an association with OS following diagnosis using univariate and multivariate analyses.
Results: 3,057 adult patients met the inclusion criteria with a median age of 32 years. At diagnosis, 1,138 patients (41%) had cerebral tumors, 832 patients (30%) had cerebellar tumors, 252 patients (9%)
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had tumors of the spinal cord, and 534 patients (19%) had tumors of unspecified location. 77% of patients received surgery alone as local therapy, while the remainder was split between surgery+radiation (11.9%), radiation alone (4.5%), and biopsy alone (6.9%). On multivariate
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analysis, factors associated with inferior OS included older age (HR=1.05, p<0.001), lower income (p<0.001), higher Charlson/Deyo Score (p=0.023), larger tumor size (p=0.023), and
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radiation technique (p<0.001, HR 3.37 for external beam, EBRT). Conclusions: The present data provide large-scale prognostic information from a contemporary cohort of patients with pilocytic astrocytoma. It confirms that age, median income, Charlson/Deyo Score, and tumor size had a significant effect on OS. While resection status, tumor size, and location likely bias against EBRT, it is clear that novel therapeutics are needed in patients with tumors not amenable to resection or radiosurgery.
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. Introduction Pilocytic astrocytomas (PA) are WHO grade I tumors, which commonly present as a wellcircumscribed cystic mass in the central nervous system (CNS) with an accompanying mural nodule.1
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Overall, they make up between 0.6-5.1% of all intracranial malignancies.2,3 It is well established that they exhibit a bimodal age presentation. Nonetheless, the vast majority of cases present before the age of 20.4
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The childhood subtype of pilocytic astrocytoma often possesses alterations in the MAPK
pathway including BRAF fusions and point mutations in genes including NF1, BRAF, KRAS, FGFR1, and
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PTPN11.5,6 It also occurs commonly in children with mutations in NF1, and these patients usually present with unilateral and bilateral optic nerve gliomas.5,7
In contrast, adult PA has been less studied given its decreased incidence, hence, much of what is known about adult PA has been extrapolated from the childhood PA literature.8 Diagnosis is usually obtained through radiopathologic methods, although the radiologic findings in this tumor type are
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widely variable and often not specific.9 Current national consensus guidelines recommend surgical resection as the initial modality of treatment, both for histopathologic confirmation, immediate
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decompression, and as a definitive therapy.10 Moreover, data from the prospective trial by Brown et al. has shown that close observation is reasonable for patients with a complete or subtotal resection.11 This
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landmark study in the field clearly showed good local control of disease with both gross total and subtotal resection, with only one patient requiring salvage radiotherapy.11 However, if patients develop symptomatic recurrence, then radiation therapy (or sometimes radiosurgery) is commonly recommended as salvage therapy.11-13 Recently, Johnson et al.14 showed that survival rates of PA declined significantly with age, from a 96.5% 5-year survival in patients 5-19 years to 52.9% 5-year survival in adult patients 60+ years of age, with a corresponding decrease in relative and cancer-specific survival rates. However, due to the relative
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. paucity of cases, large randomized controlled trials (RCTs) in adult PA are not feasible. We reviewed the National Cancer Database (NCDB) in order to assess the common modalities of clinical management and
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the overall prognosis for adult patients with PA.
Methods Data source in cohort selection
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This is a retrospective analysis utilizing data obtained from the NCDB. The NCDB is a nationwide facility-based comprehensive clinical surveillance resource that is managed jointly by the American
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College of Surgeons and the American Cancer Society. It comprises 70% of new cancer diagnoses in the United States annually15 It displays patient-level data including various clinical and pathologic characteristics of the initial treatment course as well as long term outcomes such as overall survival (OS) following diagnosis.16
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We evaluated patients in the NCDB, treated between 2004 and 2014, with pathologically diagnosed PA (among 448,453 total patients with CNS tumors). Clinical characteristics including year of diagnosis, patient age, gender, race, facility type, and Charlson/Deyo comorbidity index were analyzed.
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Moreover, we studied various tumor and treatment-related characteristics to identify factors that were associated with changes in OS. Extent of tumor resection was reported through the NCDB which does
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not specify the means of this assessment (intraoperative assessment, radiographic, etc.).
Statistical analysis
For the purposes of OS analyses, subtotal resection (STR) and gross total resection (GTR) were
analyzed independently, as were all radiation techniques [including fractionated external beam irradiation (EBRT), stereotactic radiosurgery (SRS), and radiation therapy not otherwise specified (RTNOS)]. Variables potentially associated with OS were selected after univariate Cox regression analysis.
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. Because of the small size of subgroups, tumor location was grouped for survival analysis (supratentorial, infratentorial, spinal cord, and other). Those independent variables with p-values of under 0.10 on univariable analysis were included in the final multivariable Cox regression analysis. This was conducted
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via a two-tailed test whereby p < 0.05 was deemed statistically significant. All statistical analyses were performed using the SPSS statistical software package (SPSS, version 24, SPSS Incorporated, Chicago, IL).
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Results Clinical characteristics
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Three thousand fifty-seven (3,057) patients met the inclusion criteria representing 0.68% of the total number of cases in the database. Table 1 describes the salient characteristics of the patient population divided by their clinical characteristics. The average age of the patients was 30-36 years across all of the local treatment modalities. More than 75% of all cases received surgery alone as local
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therapy, while the remainder was split between surgery + radiation (11.9%), radiation alone (4.5%), and biopsy alone (6.9%). Of note, the majority of patients (2,131 patients, 69.7%) had an extent of resection
Overall survival
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that was not reported.
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Table 2 provides the results of the univariable and multivariable survival analyses. After multivariable-adjustment for confounders, factors associated with inferior OS included older age (HR=1.05, p < 0.001), lower median income (p < 0.001), higher Charlson/Deyo Score (p = 0.023), and larger tumor size (p = 0.023). On multivariable analysis, extent of resection did not impact OS (p = 0.283). Figure 1 demonstrates the significant association between radiation technique and overall survival (p < 0.001, HR 3.37 for external beam). Specifically, patients undergoing external beam radiation
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. therapy (EBRT) had a 5-year overall survival under 60%, while those receiving other therapies had a 5year OS at least in excess of 75%, and this trend held with more than 10 years of follow up from diagnosis. Kaplan-Meier curves for overall survival as a function of type of radiation therapy
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demonstrated similar 10 year outcomes for ‘no radiation therapy’ compared to SRS (HR: 1.517, p = 0.161) and radiation-NOS (HR: 0.844, p = 0.618). Nonetheless, patients treated with EBRT were found to have a decreased OS (compared to “no radiation therapy”) (HR: 3.370, p < 0.001).
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Tumor location also impacted OS, with patients with PAs in the spinal cord demonstrating inferior OS than other tumor locations, as demonstrated in Figure 2. In contrast, individuals with
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supratentorial tumors appeared to have improved OS in the time frame of 2-8 years after diagnosis. Of note, while primary tumor site was statistically significant in univariable analysis, this association did not hold in the multivariable model (p = 0.01 and 0.11, respectively).
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Discussion
In this analysis, we have described the observed outcomes and treatment modalities in 3,057 adult patients with PA. We found a significant association between radiation technique and overall
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survival, namely, patients receiving fractionated EBRT had inferior survival when compared to patients receiving no radiation therapy. In contrast, those patients who underwent SRS had a 5-year overall
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survival in excess of 75% as opposed to those who had fractionated EBRT who had a five-year overall survival under 60%.
It is likely that the association between EBRT and inferior survival is confounded by other clinical
covariables that have a known impact on outcome like tumor size, extent of resection, a more aggressive clinical phenotype, and location. While we do not believe that the use of EBRT directly results in inferior survival, we do believe that patients who are recommended EBRT have very limited effective therapeutic options. In common practice, patients recommended for EBRT have large tumors in
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. eloquent locations, where neurosurgical resection and radiosurgery would be considered of excessive risk. These findings support the need to develop alternative therapies for PA, perhaps through advancements in radiosensitizing or stand-alone systemic therapies.
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Interestingly, tumor location demonstrated an unclear association with survival. This is in
contrast to a previous study by Johnson et al., evaluating the Surveillance, Epidemiology, and End
Results program (SEER) that found among 865 adults on univariate analysis cerebellar tumors carry a
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more favorable prognosis when compared to cerebral tumors.14 The current series, with considerably more patients and statistical controlling of known prognostic factors, provided alternative results.
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As anticipated, patient age, median income, Charlson-Deyo score, and tumor size all had a significant effect on OS. Increasing age is a known prognostic factor in adult PA.14 In the Johnson et al. series, survival rates declined significantly with age, from 96.5% 5 year survival in patients 5-19 years (95% CI 95.3-97.4) to a 52.9% 5-year survival in adult patients who were 60 years of age or older (95% CI
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38.4-65.5). There was also a corresponding decrease in relative and cancer-specific survival rates.14 The authors hypothesized that the increased mortality for older adults above and beyond that expected for normal aging could be explained by a qualitative difference in the intrinsic biology of adult PA tumors.
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With the widespread national adoption of SRS as a treatment modality in patients with brain tumors,17 we anticipate a decrease in treatment side effects with an ever-increasing rate of local disease
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control.18 Illustratively, a recently published case series including 28 patients with pilocytic astrocytoma showed that after mean clinical follow-up of 5.2 years, all patients who underwent SRS were alive and without evidence of active disease, a result which confirms the effectiveness of SRS in appropriately selected patients with PA.19
At the Mayo Clinic, the currently-accepted treatment paradigm for adult PA is surgical gross total resection.11,20 If gross total resection is not possible for technical considerations or medical comorbidities, radiotherapy is likely to improve local control. Stereotactic radiosurgery is utilized when
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. appropriate based on tumor volume and location.19 When tumors are not amenable to neurosurgical resection or SRS, the long term risks of EBRT should be weighed carefully against the risks of tumor location, and individualized to the patient and their goals. When patients opt for EBRT, we treat with
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advanced delivery techniques (arc-based intensity modulated radiotherapy or proton beam therapy) to 45-54 Gy in 1.8 Gy fractions.
As any retrospective analysis, there is the possibility of uncontrolled, confounding covariables
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that could impact the current results. As an example, tumor location within the cerebrum is unknown (eloquent or non-eloquent location). Moreover, tumor molecular status is unknown in this data set and
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could impact patient outcomes. Additionally, in this study extent of tumor resection was likely determined subjectively rather than by rigorous volumetric analysis, and no interpretation of the value of extent of resection in this setting should be done based on this study alone. Despite these limitations, we believe that these results provide accurate and meaningful information and can offer important
Conclusion
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information to clinicians caring for patients with this rare CNS neoplasm.
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Adult PA generally carries a slightly poorer prognosis than its childhood counterpart. Additional studies and advanced molecular diagnostic testing will more fully elucidate the underlying biology in
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adult PA, and perhaps expand treatment options. These advances are particular needed among patients with unresectable PA, currently recommended for EBRT.
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. References 1.
Kleihues P, Burger PC, Scheithauer BW. The new WHO classification of brain tumours. Brain pathology (Zurich, Switzerland). 1993;3(3):255-268. Dutton JJ. Gliomas of the anterior visual pathway. Survey of Ophthalmology. 1994;38(5):427-
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452. 3.
Sekula RF, Jr., Marchan EM, Quigley MR, Frederickson AM, Pu C. A case of an elderly adult
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presenting with obstructive hydrocephalus secondary to a rare hemorrhagic suprasellar pilocytic astrocytoma. Clinical neuropathology. 2008;27(6):396-399.
Koeller KK, Rushing EJ. From the archives of the AFIP: pilocytic astrocytoma: radiologic-
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pathologic correlation. Radiographics : a review publication of the Radiological Society of North America, Inc. 2004;24(6):1693-1708. 5.
Rodriguez FJ, Giannini C, Asmann YW, Sharma MK, Perry A, Tibbetts KM, et al. Gene expression
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profiling of NF-1-associated and sporadic pilocytic astrocytoma identifies aldehyde dehydrogenase 1 family member L1 (ALDH1L1) as an underexpressed candidate biomarker in aggressive subtypes. Journal of neuropathology and experimental neurology. 2008;67(12):1194-
6.
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1204.
Tomic TT, Olausson J, Wilzen A, Sabel M, Truve K, Sjogren H, et al. A new GTF2I-BRAF fusion
7.
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mediating MAPK pathway activation in pilocytic astrocytoma. PLoS One. 2017;12(4):e0175638. Chen YH, Gutmann DH. The molecular and cell biology of pediatric low-grade gliomas. Oncogene. 2014;33(16):2019-2026.
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Garcia DM, Fulling KH. Juvenile pilocytic astrocytoma of the cerebrum in adults. A distinctive neoplasm with favorable prognosis. Journal of Neurosurgery. 1985;63(3):382-386.
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Theeler BJ, Ellezam B, Sadighi ZS, Mehta V, Tran MD, Adesina AM, et al. Adult pilocytic astrocytomas: clinical features and molecular analysis. Neuro-Oncology. 2014;16(6):841-847. 9
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Nabors LB, Portnow J, Ammirati M, Baehring J, Brem H, Butowski N, et al. NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017. J Natl Compr Canc Netw. 2017;15(11):1331-1345. Brown PD, Buckner JC, O'Fallon JR, Iturria NL, Brown CA, O'Neill BP, et al. Adult patients with
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supratentorial pilocytic astrocytomas: a prospective multicenter clinical trial. Int J Radiat Oncol Biol Phys. 2004;58(4):1153-1160.
van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K, et al. Long-term
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efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma
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in adults: the EORTC 22845 randomised trial. Lancet. 2005;366(9490):985-990. Kidd EA, Mansur DB, Leonard JR, Michalski JM, Simpson JR, Perry A. The efficacy of radiation therapy in the management of grade I astrocytomas. Journal of Neuro-Oncology. 2006;76(1):5558.
Johnson DR, Brown PD, Galanis E, Hammack JE. Pilocytic astrocytoma survival in adults: analysis
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of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Journal of Neuro-Oncology. 2012;108(1):187-193. American College of Surgeons, Quality Programs, National Cancer Database. 2016;
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https://www.facs.org/quality-programs/cancer/ncdb. Accessed December 1, 2016. American College of Surgeons, National Cancer Database: Patient User File Data Dictionary
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16.
Items. 2011; http://ncdbpuf.facs.org/?q=node/259. Accessed December 1, 2016.
17.
Trifiletti DM, Sheehan JP, Grover S, Dutta S, Rusthoven CG, Kavanagh BD, et al. National trends in radiotherapy for brain metastases at time of diagnosis of non-small cell lung cancer. Under Review. 2017.
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Hallemeier CL, Pollock BE, Schomberg PJ, Link MJ, Brown PD, Stafford SL. Stereotactic radiosurgery for recurrent or unresectable pilocytic astrocytoma. Int J Radiat Oncol Biol Phys. 2012;83(1):107-112. Trifiletti DM, Peach MS, Xu Z, Kersh R, Showalter TN, Sheehan JP. Evaluation of outcomes after
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stereotactic radiosurgery for pilocytic astrocytoma. Journal of Neuro-Oncology. 2017;134(2):297-302.
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Bell D, Chitnavis BP, Al-Sarraj S, Connor S, Sharr MM, Gullan RW. Pilocytic astrocytoma of the adult--clinical features, radiological features and management. British journal of neurosurgery.
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2004;18(6):613-616.
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20.
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ACCEPTED MANUSCRIPT Pilocytic astrocytoma NCDB Lee et al. Figure and Table Legend
Figure 1: Overall survival among patients with pilocytic astrocytoma in the National Cancer Database
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2004-2014 by radiation modality as a local treatment, with external beam radiation therapy demonstrating inferior survival.
Figure 2: Overall survival among patients with pilocytic astrocytoma in the National Cancer Database
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2004-2014 by primary site of the tumor, with supratentorial tumors demonstrating superior survival.
Table 1: Clinical characteristics of the 3057 adult patients with pilocytic astrocytoma in the National Cancer Database 2004-2014.
Table 2: Univariable and multivariable analysis of factors associated with overall survival among patients
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with pilocytic astrocytoma in the National Cancer Database 2004-2014.
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Table 1: Clinical characteristics of the 3057 adult patients with pilocytic astrocytoma in the National Cancer Database 2004-2014.
Charlson/Deyo Score
25-100 mi >100 mi Unknown 0 1 2 Frontal Lobe Temporal Lobe Parietal Lobe Occipital Lobe Cerebellum Brainstem Spinal Cord Cerebrum NOS Other Right Left Midline/bilateral 1-19mm 20-39mm 40-59mm 60-79mm 80-99mm 100+mm Unknown
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Primary Site
<25 mi
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Distance to Hospital
Laterality
Tumor Size
21
28.4%
18
46
62.2%
5
% 4.5%
Surgery only
n 2,344 2009 30 1,844 205 10 38 72 175 395 543 654 731 19
% 76.7%
Surgery + Radiation % 11.9%
78.7% 8.7% 0.4% 1.6% 3.1% 7.5% 17.0% 23.4% 28.2% 31.5% 2.5%
n 365 2009 36 273 41 1 6 13 31 54 103 86 117 3
29.0%
224
29.3%
46
28.2%
36
58.1%
432
56.5%
84
51.5%
6.8%
7
11.3%
90
11.8%
30
18.4%
0.0%
0
0.0%
0
0.0%
0
0.0%
76.8% 10.1% 0.0% 2.2% 1.4% 9.4% 12.5% 24.3% 32.4% 30.9% 1.6%
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71.0% 11.0% 0.5% 2.9% 3.8% 11.0% 21.6% 22.1% 24.0% 32.2% 2.7%
n 138 2009 36 106 14 0 3 2 13 17 33 44 42 1
0
% 6.9%
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Other specified types of cancer programs
n 210 2009 33 149 23 1 6 8 23 45 46 50 67 2
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N (of 3,057) Year of Diagnosis (median) Patient Age (median) Race White Black American Indian Asian/Pacific Islander Unknown Hispanic Median Income <$38,000 $38,000-$47,999 $48,000-$62,999 $63,000 + Facility Type Community Cancer Program Comprehensive Community Cancer Program Academic/Research Program Integrated Network Cancer Program
Radiation only
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Biopsy alone
74.8% 11.2% 0.3% 1.6% 3.6% 8.5% 15.0% 28.6% 23.9% 32.5% 1.8%
118
56.2%
84
60.9%
1,338
57.1%
226
61.9%
60 30 2 185 17 8 22 10 9 8 17 21 10 69 44 52 43 115 45 73 24 5 3 0 60
28.6% 14.3% 1.0% 88.1% 8.1% 3.8% 10.5% 4.8% 4.3% 3.8% 8.1% 10.0% 4.8% 32.9% 21.0% 24.8% 20.5% 54.8% 21.4% 34.8% 11.4% 2.4% 1.4% 0.0% 28.6%
38 14 2 125 9 4 7 5 5 2 8 29 18 30 34 19 26 93 22 42 24 2 0 1 47
27.5% 10.1% 1.4% 90.6% 6.5% 2.9% 5.1% 3.6% 3.6% 1.4% 5.8% 21.0% 13.0% 21.7% 24.6% 13.8% 18.8% 67.4% 15.9% 30.4% 17.4% 1.4% 0.0% 0.7% 34.1%
676 309 21 1,997 260 87 203 210 97 72 732 197 168 289 376 351 322 1,671 376 712 467 102 14 22 651
28.8% 13.2% 0.9% 85.2% 11.1% 3.7% 8.7% 9.0% 4.1% 3.1% 31.2% 8.4% 7.2% 12.3% 16.0% 15.0% 13.7% 71.3% 16.0% 30.4% 19.9% 4.4% 0.6% 0.9% 27.8%
95 39 5 287 54 24 27 13 5 8 75 54 56 47 80 47 30 288 40 125 68 11 6 2 113
26.0% 10.7% 1.4% 78.6% 14.8% 6.6% 7.4% 3.6% 1.4% 2.2% 20.5% 14.8% 15.3% 12.9% 21.9% 12.9% 8.2% 78.9% 11.0% 34.2% 18.6% 3.0% 1.6% 0.5% 31.0%
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Subtotal Gross total Unknown None External Beam Radiation Stereotactic Radiosurgery Radiation NOS
9
4.3%
8
5.8%
0
0.0%
0
0.0%
0 0 201 210 0 0 0
0.0% 0.0% 95.8% 100.0 % 0.0% 0.0% 0.0%
0 0 130 0 99 23 16
0.0% 0.0% 94.2% 0.0% 71.7% 16.7% 11.6%
276 535 1,533 2,344 0 0 0
11.8% 22.8% 65.4% 100.0 % 0.0% 0.0% 0.0%
64 34 267 0 246 39 80
17.5% 9.3% 73.2% 0.0% 67.4% 10.7% 21.9%
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Radiation Technique
Biopsy only
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Extent of Resection
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Table 2: Univariable and multivariable analysis of factors associated with overall survival among patients with pilocytic astrocytoma in the National Cancer Database 2004-2014.
p Year of Diagnosis
Multivariable p
Hazard Ratio
< 0.001
1.050
0.227
Patient Age
< 0.001
Race
0.531 <$38,000
0.01
0.001
0.621
$48,000-$62,999
< 0.001
0.543
< 0.001
0.600
$63,000 + Facility Type
0.259
Distance to Hospital
Primary Site
0.128 0
< 0.001
1
0.222
2
0.009
Supratentorial
0.01
Infratentorial Spinal Cord Other/Unknown Laterality Tumor Size
upper 95% 1.056
0.464
0.832
0.405
0.730
0.453
0.793
1.182
0.904
1.547
1.647
1.133
2.393
0.536
1.097
0.818
1.473
0.825
0.956
0.639
1.428
0.056
1.334
0.993
1.791
0.010
1.661
1.130
2.441
0.006
1.803
1.187
2.739
< 0.001
3.029
1.748
5.248
0.125
1.920
0.835
4.415
0.388
0.416
0.057
3.050
0.001
1.916
1.310
2.801
4.219
0.111
0.14 1-19mm
< 0.001
20-39mm 40-59mm
100+mm Unknown Extent of Resection
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60-79mm 80-99mm
0.002
0.283
None
< 0.001
< 0.001
External Beam Radiation
< 0.001
3.370
2.692
Stereotactic Radiosurgery
0.161
1.517
0.847
2.716
Radiation NOS
0.618
0.844
0.432
1.648
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Radiation Technique
0.023
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Charlson/Deyo Score
< 0.001
$38,000-$47,999
1.044
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Median Income
lower 95%
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Univariable
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Values bolded if p < 0.05.
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Radiation Technique
0.8
none EBRT SRS RT NOS none-censored EBRT-censored SRS-censored RT NOS-censored
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1.0
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Survival
0.6
0.4
0.2
0.0 24
48
72
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0
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p < 0.001
96
120
144
Months from Diagnosis
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Figure 1: Overall survival among patients with pilocytic astrocytoma in the National Cancer Database 2004-2014 by radiation modality as a local treatment, with external beam radiation therapy demonstrating inferior survival.
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Primary Site
1.0
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Supratentorial Infratentorial Spinal cord Other or unknown Supratentorial-censored Infratentorial-censored Spinal cord-censored Other or unknowncensored
0.8
Survival
0.6
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p = 0.010
0.2
0.0 24
48
72
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0
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0.4
96
120
144
Months from Diagnosis
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Figure 2: Overall survival among patients with pilocytic astrocytoma in the National Cancer Database 2004-2014 by primary site of the tumor, with supratentorial tumors demonstrating superior survival.
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Highlights
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A large database reports the management of patients with pilocytic astrocytoma Age, income, comorbidities, and tumor size had a significant effect on survival Novel therapeutics are needed in patients with tumors not amenable to surgery
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Abbreviations PA: pilocytic astrocytoma OS: overall survival
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CNS: central nervous system EBRT: external beam radiation therapy
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NCDB: national cancer database
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The authors have declared no conflicts of interest as it pertains to this manuscript