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Survival patterns of oligoastrocytoma patients: A surveillance, epidemiology and end results (SEER) based analysis
INAT-00237; No of Pages 6 Interdisciplinary Neurosurgery: Advanced Techniques and Case Management xxx (2017) xxx–xxx
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Neuroanatomical Studies
Survival patterns of oligoastrocytoma patients: A surveillance, epidemiology and end results (SEER) based analysis☆,☆☆ Tyler A. Lanman, BS a, Jason N. Compton, BS a, Kate T. Carroll, BA a, Brian R. Hirshman, MD b, Mir A. Ali, BS a, Bryson Lochte, BA a, Bob Carter, MD PhD b, Clark C. Chen, MD PhD c,⁎ a b c
School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States Division of Neurological Surgery, University of California, San Diego, 200 West Arbor Drive #8893, San Diego, CA 92103, United States Department of Neurosurgery, University of Minnesota, Minneapolis, D429 Mayo Memorial Building, 420 Delaware Street S.E., MMC 96MN 55455, United States
a r t i c l e
i n f o
Article history: Received 25 April 2017 Revised 24 June 2017 Accepted 30 July 2017 Available online xxxx
a b s t r a c t Objective: The 2016 update to the World Health Organization (WHO) states that oligoastrocytoma (OA) should be classified as either oligodendroglioma or astrocytoma based on molecular biomarkers. We examined the survival patterns of patients diagnosed with OA in the Surveillance, Epidemiology and End Results (SEER) registry in the context of this revised scheme. Methods: We used data from the SEER database (1999–2010) to identify patients diagnosed with WHO grade II astrocytoma (A2, n = 4113), WHO grade II oligodendroglioma (O2, n = 2378), and oligoastrocytoma (OA, n = 1505). Survival comparison was performed using Kaplan-Meier analysis and multivariate Cox proportional hazards analysis. Results: Similar to O2 patients, gross total resection (GTR) was not associated with improved survival in OA patients. In contrast, GTR is associated with improved survival in A2 patients. For OA patients who did not undergo surgery or radiation therapy (RT), those with tumors b 5 cm in maximal diameter exhibited survival patterns similar to O2 patients, while those with tumors ≥5 cm exhibited survival patterns similar to A2 patients. Conclusions: Distinct survival patterns were observed in SEER OA patients with tumors b or ≥5 cm in maximal diameter. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Certain pathologic diagnoses are adopted to overcome challenges associated with histologic ambiguity. A case-in-point involves oligoastrocytoma (OA), a diagnosis historically used when glioma specimens contain histological features of both oligodendroglioma and astrocytoma [1]. The 2016 update to the World Health Organization (WHO) states that now OA should be classified as oligodendroglioma or astrocytoma based on their molecular profiles [2]. Oligodendrogliomas are characterized by mutations in the Isocitrate Dehydrogenase (IDH) gene and 1p/19q deletion [3–6]. In contrast, astrocytomas are characterized by mutations in the a-thalassemia/mental retardation syndrome X-linked (ATRX) gene, over-expression of p53, and the lack of 1p/19q deletion [7–11]. When reclassified based on these molecular criteria, most
oligoastrocytoma (approximately 75%) are diagnosed as WHO grade II oligodendrogliomas (O2) [12]. WHO grade II astrocytomas (A2) and O2 exhibit distinct clinical survival patterns. For instance, A2 tend to be more chemo-resistant and derive survival benefit from gross total resection (GTR) [13–16]. In contrast, O2, like primary central nervous system lymphomas (PCNSL), are more chemo-sensitive [17–19], and improved survival is associated with chemotherapy more than extent of surgical resection [20–22]. The 2016 WHO classification revision is based on the observation that patients previously diagnosed with OA with molecular features of O2 (e.g. 1p/19q deletion and IDH mutation) exhibit survival patterns that resemble O2. Similarly, patients previously diagnosed with OA with molecular features of A2 (e.g. ATRX and p53 mutations) exhibit survival patterns resembling A2. Here we determined whether similar
Abbreviations: A2, WHO grade II astrocytoma; ATRX, a-thalassemia/mental retardation syndrome X-linked; GTR, gross total resection; ICD-O-3, International Classification of Disease for Oncology, 3rd Edition; IDH, isocitrate dehydrogenase; O2, WHO grade II oligodendroglioma; OA, oligoastrocytoma; NCI, National Cancer Institute; PCNSL, central nervous system lymphomas; RT, radiation therapy; SEER, Surveillance, Epidemiology and End Results; STR, subtotal resection; WHO, World Health Organization. ☆ Funding: None declared. ☆☆ Conflict of interest: None declared. ⁎ Corresponding author at: Department of Neurosurgery, University of California, San Diego, 3855 Health Sciences Drive #0987, La Jolla, CA 92093, United States. E-mail address: [email protected] (C.C. Chen).
http://dx.doi.org/10.1016/j.inat.2017.07.017 2214-7519/Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: T.A. Lanman, et al., Survival patterns of oligoastrocytoma patients: A surveillance, epidemiology..., Interdisciplinary Neurosurgery: Advanced Techniques and Case Management (2017), http://dx.doi.org/10.1016/j.inat.2017.07.017
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T.A. Lanman et al. / Interdisciplinary Neurosurgery: Advanced Techniques and Case Management xxx (2017) xxx–xxx
stratification can be made using clinical variables. Using the Surveillance, Epidemiology, and End Results (SEER) registry, we showed that for OA patients who did not undergo surgery or radiation therapy (RT), patients with OA b 5 cm in maximal diameter exhibit survival patterns similar to O2 patients, while those with tumors ≥5 cm exhibit survival patterns similar to A2 patients. 2. Materials & methods 2.1. Data source and population The SEER Program was established by the National Cancer Institute (NCI) to collect cancer incidence and survival data from 18 population-based cancer registries that cover about 28% of the total U.S. population (SEER Research Data 1973–2010). This study employed data released in April 2013 that was based on November 2012 submissions. Data was downloaded as an ASCII text file [23]. We chose to examine the oligoastrocytoma tumor type in relation to WHO grade II astrocytoma and oligodendroglioma [24]. This study included patients who were diagnosed between 1999 and 2010 with OA, A2, or O2 as the only cancer diagnosis. The following International Classification of Disease for Oncology, 3rd Edition (ICD-O-3) histology codes were used: 9382 (oligoastrocytoma, WHO grade II), 9400, 9410, 9411, 9420 (diffuse astrocytoma, WHO grade II), and 9450 (oligodendroglioma, WHO grade II). Brain tumors were selected with ICD-O-3 topologic site codes C71.0–C71.9. These codes were cross-referenced and validated with Table 1 of the Central Brain Tumor Registry of the United States Statistical Report [25]. Patients were excluded from the study if the surgical status was coded as unknown or if the histology did not have microscopic confirmation. Using these criteria, patients were grouped into three diagnostic categories: OA (n = 1505), A2 (n = 4113), and O2 (n = 2378). 2.2. Extent of resection and covariates The following surgery codes from SEER were used to define extent of surgical resection: no surgery (code 00), excisional biopsy (code 20), subtotal resection (codes 21, 40), or GTR (codes 30, 55). Despite minor modifications of codes in each edition of SEER Program Coding and Staging Manual, the general definition has remained constant during the time period we have selected [26,27]. Historical definitions can be found on the SEER website [28]. Survival time was defined as the number of months from diagnosis to the date of death due to any cause or the date of last known followup. The following demographic variables were used in the analysis: age (b 18, 18–44, 45–49, 50–54, 55–59, 60–74, or N75 years), race/ethnicity (white, black, Asian/Pacific Islander, Hispanic, American Indian/ Alaskan Native, or other/unknown), marital status (single, married, or [separated, divorced or widowed]), and sex (male or female). The following clinical variables were also included in the analysis: tumor size (b5 cm or ≥ 5 cm), tumor location (based on ICD-O-3 topologic site codes C71.0–C71.9), RT status (radiation or no radiation), and surgical treatment (no surgery, biopsy, STR, or GTR). 2.3. Statistical analysis All analyses were conducted using Stata version 11.2 [29], and the level of statistical significance was set at p b 0.05. We performed comparisons of overall survival between OA, A2, and O2 patients. Analyses were performed to determine the impact on survival of GTR relative to biopsy only. This GTR/biopsy hazard ratio was then compared in each tumor type relative to OA. Similarly, we analyzed the effect of RT on survival relative to no RT and further compared hazard ratios in each tumor type to OA. We performed post-hoc analyses in a subset of patients with no surgery and no radiation to explore the effect of tumor size (segregated into tumors b5 cm and ≥ 5 cm) on survival.
Table 1 Demographic and clinical characteristic of OA cases, SEER 1999–2010. Number of patients, n Age, median (IQR)
1505 40 (31–52)
Surgery, n (%) Gross total resection Partial resection Local excision/biopsy No surgery
555 (36.88) 452 (30.03) 280 (18.60) 218 (14.49)
Radiotherapy, n (%) No Yes
608 (41.36) 862 (58.64)
Age category, years, n (%) b18 18–45 45–60 60–75 N75
72 (4.78) 831 (55.22) 399 (26.51) 160 (10.63) 43 (2.86)
Race, n (%) White Black Asian/Pacific Islander Hispanic American Indian/Alaskan Native Other/Unknown, Non-Hispanic
1049 (69.70) 90 (5.98) 107 (7.11) 243 (16.15) 11 (0.73) 5 (0.33)
Marital status, n (%) Single Married Separated, divorced, widowed
456 (31.08) 836 (56.99) 175 (11.93)
Sex, n (%) Male Female
853 (56.68) 652 (43.32)
Tumor size, cm, n (%) b5 ≥5
554 (52.41) 503 (47.59)
Tumor site, n (%) Cerebrum Frontal lobe Temporal lobe Parietal lobe Occipital lobe Ventricle, NOS Cerebellum, NOS Brain stem Overlapping lesion of brain Brain, NOS
43 (2.86) 725 (48.17) 317 (21.06) 165 (10.96) 20 (1.33) 7 (0.47) 11 (0.73) 10 (0.66) 168 (11.16) 39 (2.59)
Year of diagnosis, n (%) 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
56 (3.72) 80 (5.32) 112 (7.44) 112 (7.44) 137 (9.10) 126 (8.37) 141 (9.37) 166 (11.03) 151 (10.03) 132 (8.77) 139 (9.24) 153 (10.17)
Overall mortality, n (%) Living Deceased
969 (64.39) 536 (35.61)
We used the Kaplan-Meier method to generate unadjusted survival curves for the overall population and specific subsets. Statistical significance was determined using log-rank tests across survival functions. To calculate the multivariate adjusted hazard ratios of death, we performed Cox proportional hazard analysis adjusting for all aforementioned demographic and clinical covariates. To compare the effect of treatment by tumor type, we used the Wald test.
Please cite this article as: T.A. Lanman, et al., Survival patterns of oligoastrocytoma patients: A surveillance, epidemiology..., Interdisciplinary Neurosurgery: Advanced Techniques and Case Management (2017), http://dx.doi.org/10.1016/j.inat.2017.07.017
T.A. Lanman et al. / Interdisciplinary Neurosurgery: Advanced Techniques and Case Management xxx (2017) xxx–xxx
3. Results 3.1. Patient characteristics We identified 1505 OA patients in the SEER database. Patient characteristics are shown in Table 1. The median age of diagnosis was 40 (interquartile range: 33–52). The male to female ratio was approximately 1:1. The most common sites were frontal and temporal lobes. Of the OA patients, 218 (14%) did not undergo surgery, 280 (19%) underwent biopsy, 452 (30%) underwent STR, and 555 (37%) underwent GTR. Eight hundred and sixty-two (57%) patients were treated with RT. Ninety-
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nine (6.6%) patients did not undergo RT or surgery. The number of newly diagnosed OA remained essentially unchanged throughout the study period. 3.2. Analysis of survival after gross total resection (GTR) The median survivals for OA patients who underwent biopsy only versus GTR were comparable (124 months and 125 months, respectively, p = 0.957 Fig. 1). We performed a multivariate Cox proportional hazards analysis to determine how GTR impacts survival in OA patients after controlling for pertinent demographic and clinical variables. The
Fig. 1. Survival patterns of patients with OA, A2, and O2, comparing those who received GTR to those who received biopsy and those who received radiation therapy to those who did not. (A) Kaplan-Meier curves for OA, A2, and O2 patients who underwent biopsy (blue) or GTR (red). A2 patients who underwent GTR exhibited improved survival relative to those who underwent biopsy only. For OA and O2 patients, those who underwent GTR and those who received biopsy exhibit similar survival patterns. OA, oligoastrocytoma; A2, WHO grade II astrocytoma; O2, WHO grade II oligodendroglioma; GTR, gross total resection. (B) Kaplan-Meier curves for OA, A2, and O2 patients who underwent radiation therapy (red) or no radiation therapy (blue). Survival for patients who were selected for and received RT exhibited shortened survival relative to those who were not selected for RT for OA, A2, and O2 patients. OA, oligoastrocytoma; A2, WHO grade II astrocytoma; O2, WHO grade II oligodendroglioma; GTR, gross total resection; RT, radiation therapy. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Please cite this article as: T.A. Lanman, et al., Survival patterns of oligoastrocytoma patients: A surveillance, epidemiology..., Interdisciplinary Neurosurgery: Advanced Techniques and Case Management (2017), http://dx.doi.org/10.1016/j.inat.2017.07.017
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T.A. Lanman et al. / Interdisciplinary Neurosurgery: Advanced Techniques and Case Management xxx (2017) xxx–xxx
hazard ratio (HR) of death was comparable between the biopsy and the GTR group (Table 2). The HR of death for A2 was 0.67 for patients who underwent GTR relative to those who underwent biopsy only (95% CI 0.54–0.82, p b 0.001), and for O2 patients, it was 0.95 (95% CI 0.67– 1.35, p = 0.757). The pattern of survival after GTR in OA was more similar to that in O2 than in A2. 3.3. Analysis of survival after radiation therapy (RT) The median survival for OA patients who underwent RT was shorter than for those who were not treated with RT (68 months and median not reached, respectively, p b 0.0001, Fig. 1). In multivariate Cox proportional hazards analysis, the HR for death was higher for patients who underwent RT relative to those who did not (Table 2). Similar results were observed for A2 and O2 patients (HRs of 1.51 [95% CI 1.31–1.74, p b 0.001] and 1.69 [95% CI 1.33–2.15, p b 0.001], respectively). 3.4. Overall survival analysis Kaplan-Meier curves demonstrated that the overall survival of OA patients (median survival 68 months) was more favorable than that of A2 patients (median survival 52 months), but not as favorable as O2 patients (median survival not reached, Fig. 2). Multivariate Cox proportional hazards analysis was consistent with the Kaplan-Meier analysis, and showed that the HR for death was lowest for O2 (0.53, 95% CI 0.45–0.62, p b 0.001), highest for A2 (1.32, 95% CI 1.16–1.50, p b 0.001), and intermediate for OA (reference group) (Table 3). Next, we characterized the survival of patients who did not receive surgery or RT. We performed Kaplan Meier analysis after stratifying for the size of the tumor (b5 cm or ≥ 5 cm maximal diameter), since there were approximately equal number of OAs in these size categories. OA patients with tumors b 5 cm exhibited overall survival similar to O2 patients. In contrast, patients with tumors ≥5 cm exhibited overall survival similar to A2 patients (Fig. 3, Table 3). 4. Discussion Disease classification is an evolving process, requiring constant synthesis of emerging data due to advances in technological platforms and insights into pathogenesis. The 2016 update to the World Health Organization (WHO) suggests that oligoastrocytoma (OA) should be classified as O2 or A2 based on molecular features [18]. The natural corollary to this revised scheme is that subsets of patients with tumors previously classified as OA should exhibit survival patterns similar to A2 or O2. Our analysis of the SEER OA registry suggests that such
Table 2 Multivariate HR of death in OA, A2, and O2 for patients with GTR compared to biopsy and for patients with RT compared to no RT. HR, hazard ratio; RT, radiation therapy; OA, oligoastrocytoma; A2, WHO grade II astrocytoma; O2, WHO grade II oligodendroglioma; GTR, gross total resection. Tumor type
GTR/biopsy
GTR/biopsy relative to OA
HR (95% CI)a
p Value
HR
p Value
OA A2 O2
1.30 (0.91–1.94) 0.67 (0.54–0.82) 0.95 (0.67–1.35)
0.150 b0.001 0.757
1 (referent) 0.52 0.73
0.0014 0.2120
Tumor type
RT/No RT
OA A2 O2
RT/No RT relative to OA
HR (95% CI)b
p Value
HR
p Value
1.54 (1.21–1.97) 1.51 (1.31–1.74) 1.69 (1.33–2.15)
0.001 b0.001 b0.001
1 (referent) 0.98 1.1
0.8732 0.6012
a Adjusted for age, race/ethnicity, marital status, sex, tumor size, tumor location, and radiotherapy status. b Adjusted for age, race/ethnicity, marital status, sex, tumor size, tumor location, and surgical treatment received.
Fig. 2. Overall survival of patients with OA, A2, and O2 who had no surgery and no radiation. Kaplan-Meier curves for overall survival of patients with OA, A2, and O2. Patients with OA had worse overall survival than patients with O2, but better overall survival than patients with A2. OA, oligoastrocytoma; A2, WHO grade II astrocytoma; O2, WHO grade II oligodendroglioma.
survival stratification may be made based on tumor size. In SEER, OA patients who did not undergo surgery or RT and had tumors b5 cm exhibited survival patterns similar to O2 patients with tumors b5 cm. In contrast, OA patients with tumors ≥ 5 cm exhibited survival patterns similar to A2 patients with ≥5 cm tumors. The finding that the survival pattern in OA patients after GTR, as a whole, more closely resembles that observed in O2 relative to A2 is also consistent with the reported finding that ~75% of gliomas previously classified as OA have been reclassified as O2 based on molecular profiling [12]. Overall, our findings support the premise of the 2016 WHO classification for OA. One explanation of the distinct survival patterns of OA as a function of tumor size involves the distinct biologic behavior of O2 and A2. It is well appreciated that O2 exhibits more indolent growth kinetics and clinical course relative to A2 [30]. In part, this difference can be accounted for by the observation that tumors with IDH mutations (such as O2) tend to exhibit slow growth kinetics [31]. In contrast, mutations of p53 (in A2) confer accelerated proliferation [32–34]. Because of these differential growth kinetics, A2 may be expected to achieve a Table 3 Multivariate HR of death in OA, A2, and O2 for patients with no surgery, no radiation, in overall cohorts and stratified by tumor size. HR, hazard ratio; OA, oligoastrocytoma; A2, WHO grade II astrocytoma; O2, WHO grade II oligodendroglioma. Overall cohorts Tumor type
HR (95% CI)a
p Value
OA A2 O2
1 (referent) 1.32 (1.16–1.50) 0.53 (0.45–0.62)
b0.001 b0.001
HR (95% CI)b
p Value
1 (referent) 3.96 (1.59–9.87) 1.9 (0.7–5.16)
0.003 0.210
1 (referent) 1.04 (0.47–2.33) 0.32 (0.12–0.87)
0.916 0.026
Stratified by tumor size Tumor Type b5 cm OA A2 O2 ≥5 cm OA A2 O2
a Adjusted for age, race/ethnicity, marital status, sex, tumor size, tumor location, radiotherapy status, and surgical treatment received. b Adjusted for age, race/ethnicity, marital status, sex, tumor location, radiotherapy status, and surgical treatment received.
Please cite this article as: T.A. Lanman, et al., Survival patterns of oligoastrocytoma patients: A surveillance, epidemiology..., Interdisciplinary Neurosurgery: Advanced Techniques and Case Management (2017), http://dx.doi.org/10.1016/j.inat.2017.07.017
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Fig. 3. Survival of patients with OA, A2, and O2 who had no surgery and no radiation stratified by tumor size. Kaplan-Meier analysis was performed after stratifying the tumor size by b5 cm and tumors ≥5 cm. For patients with tumors b5 cm, OA exhibited overall survival similar to O2 patients, which was greater compared to the overall survival of A2 patients. In contrast, for patients with tumors N5 cm, OA exhibited overall survival similar to A2 patients, which was shortened relative to the overall survival of O2 patients. OA, oligoastrocytoma; A2, WHO grade II astrocytoma; O2, WHO grade II oligodendroglioma.
greater size (e.g. ≥ 5 cm) on average relative to O2 (e.g. b5 cm). The implication of this interpretation is that OA patients with tumors b5 cm are more likely O2 patients, while OA patients with tumors N 5 cm are more likely A2 patients. However, we cannot exclude the possibility that differential survival patterns of OA b or ≥5 cm reflect an underlying biology that is completely distinct from those of O2 or A2. To the extent that the biology underlying our clinical observation remains unclear, classification of O2 and A2 in patients with histologic ambiguity should be made based on molecular features rather than tumor size. The increased hazard of death for O2, A2, and OA patients who underwent RT should be interpreted with caution. In general, O2, A2, and OA are treated similarly when it comes to RT. In our institution, patients at low risk for tumor progression (e.g. patients who underwent gross total resection) are not recommended to undergo RT in order to mitigate the risk of neuro-cognitive decline [35]. RT is typically reserved for patients at high risk for disease progression (e.g. age N 40 with significant tumor burden in regions that are not surgically accessible) or consequent to disease progression [36]. This pattern of clinical practice may account for the increased hazard of death in patients who underwent RT. As OA, O2, and A2 represent rare forms of brain cancer, the type of subset analysis performed here cannot be achieved with sufficient sample size using single institutional or single surgeon experiences. That said, our study is subject to the many limitations inherent to a population-based study. The most pertinent of these limitations is that no information on chemotherapeutic regimens is available in SEER. As such, it is conceivable that the improved survival of OA tumors b 5 cm may be secondary to more intense chemotherapeutic intervention or a distinct set of chemotherapeutic agents. However, these scenarios are unlikely since the typical clinical practice is to intensify chemotherapy in patients presenting with a larger tumor [37]. Moreover, because there is a limited set of chemotherapeutic agents available for glioma treatment, similar agents are used to treat OA, O2, and A2. We therefore believe that our findings remain robust despite the inherent limitations of the SEER dataset. Finally, the absence of GTR associated survival benefit in the OA population should not be interpreted as a blanket statement against extended surgical resection. Factors such as radiographic findings of mass effect, clinical symptoms of seizure or neurologic deficit, and patient preference need to be carefully weighed in the context of survival expectation during surgical planning. 5. Conclusion Analysis of the SEER OA dataset revealed distinct survival patterns in patients with tumors b or ≥5 cm in maximal diameter.
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Neuroanatomical Studies
Survival patterns of oligoastrocytoma patients: A surveillance, epidemiology and end results (SEER) based analysis☆,☆☆ Tyler A. Lanman, BS a, Jason N. Compton, BS a, Kate T. Carroll, BA a, Brian R. Hirshman, MD b, Mir A. Ali, BS a, Bryson Lochte, BA a, Bob Carter, MD PhD b, Clark C. Chen, MD PhD c,⁎ a b c
School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States Division of Neurological Surgery, University of California, San Diego, 200 West Arbor Drive #8893, San Diego, CA 92103, United States Department of Neurosurgery, University of Minnesota, Minneapolis, D429 Mayo Memorial Building, 420 Delaware Street S.E., MMC 96MN 55455, United States
a r t i c l e
i n f o
Article history: Received 25 April 2017 Revised 24 June 2017 Accepted 30 July 2017 Available online xxxx
a b s t r a c t Objective: The 2016 update to the World Health Organization (WHO) states that oligoastrocytoma (OA) should be classified as either oligodendroglioma or astrocytoma based on molecular biomarkers. We examined the survival patterns of patients diagnosed with OA in the Surveillance, Epidemiology and End Results (SEER) registry in the context of this revised scheme. Methods: We used data from the SEER database (1999–2010) to identify patients diagnosed with WHO grade II astrocytoma (A2, n = 4113), WHO grade II oligodendroglioma (O2, n = 2378), and oligoastrocytoma (OA, n = 1505). Survival comparison was performed using Kaplan-Meier analysis and multivariate Cox proportional hazards analysis. Results: Similar to O2 patients, gross total resection (GTR) was not associated with improved survival in OA patients. In contrast, GTR is associated with improved survival in A2 patients. For OA patients who did not undergo surgery or radiation therapy (RT), those with tumors b 5 cm in maximal diameter exhibited survival patterns similar to O2 patients, while those with tumors ≥5 cm exhibited survival patterns similar to A2 patients. Conclusions: Distinct survival patterns were observed in SEER OA patients with tumors b or ≥5 cm in maximal diameter. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Certain pathologic diagnoses are adopted to overcome challenges associated with histologic ambiguity. A case-in-point involves oligoastrocytoma (OA), a diagnosis historically used when glioma specimens contain histological features of both oligodendroglioma and astrocytoma [1]. The 2016 update to the World Health Organization (WHO) states that now OA should be classified as oligodendroglioma or astrocytoma based on their molecular profiles [2]. Oligodendrogliomas are characterized by mutations in the Isocitrate Dehydrogenase (IDH) gene and 1p/19q deletion [3–6]. In contrast, astrocytomas are characterized by mutations in the a-thalassemia/mental retardation syndrome X-linked (ATRX) gene, over-expression of p53, and the lack of 1p/19q deletion [7–11]. When reclassified based on these molecular criteria, most
oligoastrocytoma (approximately 75%) are diagnosed as WHO grade II oligodendrogliomas (O2) [12]. WHO grade II astrocytomas (A2) and O2 exhibit distinct clinical survival patterns. For instance, A2 tend to be more chemo-resistant and derive survival benefit from gross total resection (GTR) [13–16]. In contrast, O2, like primary central nervous system lymphomas (PCNSL), are more chemo-sensitive [17–19], and improved survival is associated with chemotherapy more than extent of surgical resection [20–22]. The 2016 WHO classification revision is based on the observation that patients previously diagnosed with OA with molecular features of O2 (e.g. 1p/19q deletion and IDH mutation) exhibit survival patterns that resemble O2. Similarly, patients previously diagnosed with OA with molecular features of A2 (e.g. ATRX and p53 mutations) exhibit survival patterns resembling A2. Here we determined whether similar
Abbreviations: A2, WHO grade II astrocytoma; ATRX, a-thalassemia/mental retardation syndrome X-linked; GTR, gross total resection; ICD-O-3, International Classification of Disease for Oncology, 3rd Edition; IDH, isocitrate dehydrogenase; O2, WHO grade II oligodendroglioma; OA, oligoastrocytoma; NCI, National Cancer Institute; PCNSL, central nervous system lymphomas; RT, radiation therapy; SEER, Surveillance, Epidemiology and End Results; STR, subtotal resection; WHO, World Health Organization. ☆ Funding: None declared. ☆☆ Conflict of interest: None declared. ⁎ Corresponding author at: Department of Neurosurgery, University of California, San Diego, 3855 Health Sciences Drive #0987, La Jolla, CA 92093, United States. E-mail address: [email protected] (C.C. Chen).
http://dx.doi.org/10.1016/j.inat.2017.07.017 2214-7519/Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: T.A. Lanman, et al., Survival patterns of oligoastrocytoma patients: A surveillance, epidemiology..., Interdisciplinary Neurosurgery: Advanced Techniques and Case Management (2017), http://dx.doi.org/10.1016/j.inat.2017.07.017
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stratification can be made using clinical variables. Using the Surveillance, Epidemiology, and End Results (SEER) registry, we showed that for OA patients who did not undergo surgery or radiation therapy (RT), patients with OA b 5 cm in maximal diameter exhibit survival patterns similar to O2 patients, while those with tumors ≥5 cm exhibit survival patterns similar to A2 patients. 2. Materials & methods 2.1. Data source and population The SEER Program was established by the National Cancer Institute (NCI) to collect cancer incidence and survival data from 18 population-based cancer registries that cover about 28% of the total U.S. population (SEER Research Data 1973–2010). This study employed data released in April 2013 that was based on November 2012 submissions. Data was downloaded as an ASCII text file [23]. We chose to examine the oligoastrocytoma tumor type in relation to WHO grade II astrocytoma and oligodendroglioma [24]. This study included patients who were diagnosed between 1999 and 2010 with OA, A2, or O2 as the only cancer diagnosis. The following International Classification of Disease for Oncology, 3rd Edition (ICD-O-3) histology codes were used: 9382 (oligoastrocytoma, WHO grade II), 9400, 9410, 9411, 9420 (diffuse astrocytoma, WHO grade II), and 9450 (oligodendroglioma, WHO grade II). Brain tumors were selected with ICD-O-3 topologic site codes C71.0–C71.9. These codes were cross-referenced and validated with Table 1 of the Central Brain Tumor Registry of the United States Statistical Report [25]. Patients were excluded from the study if the surgical status was coded as unknown or if the histology did not have microscopic confirmation. Using these criteria, patients were grouped into three diagnostic categories: OA (n = 1505), A2 (n = 4113), and O2 (n = 2378). 2.2. Extent of resection and covariates The following surgery codes from SEER were used to define extent of surgical resection: no surgery (code 00), excisional biopsy (code 20), subtotal resection (codes 21, 40), or GTR (codes 30, 55). Despite minor modifications of codes in each edition of SEER Program Coding and Staging Manual, the general definition has remained constant during the time period we have selected [26,27]. Historical definitions can be found on the SEER website [28]. Survival time was defined as the number of months from diagnosis to the date of death due to any cause or the date of last known followup. The following demographic variables were used in the analysis: age (b 18, 18–44, 45–49, 50–54, 55–59, 60–74, or N75 years), race/ethnicity (white, black, Asian/Pacific Islander, Hispanic, American Indian/ Alaskan Native, or other/unknown), marital status (single, married, or [separated, divorced or widowed]), and sex (male or female). The following clinical variables were also included in the analysis: tumor size (b5 cm or ≥ 5 cm), tumor location (based on ICD-O-3 topologic site codes C71.0–C71.9), RT status (radiation or no radiation), and surgical treatment (no surgery, biopsy, STR, or GTR). 2.3. Statistical analysis All analyses were conducted using Stata version 11.2 [29], and the level of statistical significance was set at p b 0.05. We performed comparisons of overall survival between OA, A2, and O2 patients. Analyses were performed to determine the impact on survival of GTR relative to biopsy only. This GTR/biopsy hazard ratio was then compared in each tumor type relative to OA. Similarly, we analyzed the effect of RT on survival relative to no RT and further compared hazard ratios in each tumor type to OA. We performed post-hoc analyses in a subset of patients with no surgery and no radiation to explore the effect of tumor size (segregated into tumors b5 cm and ≥ 5 cm) on survival.
Table 1 Demographic and clinical characteristic of OA cases, SEER 1999–2010. Number of patients, n Age, median (IQR)
1505 40 (31–52)
Surgery, n (%) Gross total resection Partial resection Local excision/biopsy No surgery
555 (36.88) 452 (30.03) 280 (18.60) 218 (14.49)
Radiotherapy, n (%) No Yes
608 (41.36) 862 (58.64)
Age category, years, n (%) b18 18–45 45–60 60–75 N75
72 (4.78) 831 (55.22) 399 (26.51) 160 (10.63) 43 (2.86)
Race, n (%) White Black Asian/Pacific Islander Hispanic American Indian/Alaskan Native Other/Unknown, Non-Hispanic
1049 (69.70) 90 (5.98) 107 (7.11) 243 (16.15) 11 (0.73) 5 (0.33)
Marital status, n (%) Single Married Separated, divorced, widowed
456 (31.08) 836 (56.99) 175 (11.93)
Sex, n (%) Male Female
853 (56.68) 652 (43.32)
Tumor size, cm, n (%) b5 ≥5
554 (52.41) 503 (47.59)
Tumor site, n (%) Cerebrum Frontal lobe Temporal lobe Parietal lobe Occipital lobe Ventricle, NOS Cerebellum, NOS Brain stem Overlapping lesion of brain Brain, NOS
43 (2.86) 725 (48.17) 317 (21.06) 165 (10.96) 20 (1.33) 7 (0.47) 11 (0.73) 10 (0.66) 168 (11.16) 39 (2.59)
Year of diagnosis, n (%) 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
56 (3.72) 80 (5.32) 112 (7.44) 112 (7.44) 137 (9.10) 126 (8.37) 141 (9.37) 166 (11.03) 151 (10.03) 132 (8.77) 139 (9.24) 153 (10.17)
Overall mortality, n (%) Living Deceased
969 (64.39) 536 (35.61)
We used the Kaplan-Meier method to generate unadjusted survival curves for the overall population and specific subsets. Statistical significance was determined using log-rank tests across survival functions. To calculate the multivariate adjusted hazard ratios of death, we performed Cox proportional hazard analysis adjusting for all aforementioned demographic and clinical covariates. To compare the effect of treatment by tumor type, we used the Wald test.
Please cite this article as: T.A. Lanman, et al., Survival patterns of oligoastrocytoma patients: A surveillance, epidemiology..., Interdisciplinary Neurosurgery: Advanced Techniques and Case Management (2017), http://dx.doi.org/10.1016/j.inat.2017.07.017
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3. Results 3.1. Patient characteristics We identified 1505 OA patients in the SEER database. Patient characteristics are shown in Table 1. The median age of diagnosis was 40 (interquartile range: 33–52). The male to female ratio was approximately 1:1. The most common sites were frontal and temporal lobes. Of the OA patients, 218 (14%) did not undergo surgery, 280 (19%) underwent biopsy, 452 (30%) underwent STR, and 555 (37%) underwent GTR. Eight hundred and sixty-two (57%) patients were treated with RT. Ninety-
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nine (6.6%) patients did not undergo RT or surgery. The number of newly diagnosed OA remained essentially unchanged throughout the study period. 3.2. Analysis of survival after gross total resection (GTR) The median survivals for OA patients who underwent biopsy only versus GTR were comparable (124 months and 125 months, respectively, p = 0.957 Fig. 1). We performed a multivariate Cox proportional hazards analysis to determine how GTR impacts survival in OA patients after controlling for pertinent demographic and clinical variables. The
Fig. 1. Survival patterns of patients with OA, A2, and O2, comparing those who received GTR to those who received biopsy and those who received radiation therapy to those who did not. (A) Kaplan-Meier curves for OA, A2, and O2 patients who underwent biopsy (blue) or GTR (red). A2 patients who underwent GTR exhibited improved survival relative to those who underwent biopsy only. For OA and O2 patients, those who underwent GTR and those who received biopsy exhibit similar survival patterns. OA, oligoastrocytoma; A2, WHO grade II astrocytoma; O2, WHO grade II oligodendroglioma; GTR, gross total resection. (B) Kaplan-Meier curves for OA, A2, and O2 patients who underwent radiation therapy (red) or no radiation therapy (blue). Survival for patients who were selected for and received RT exhibited shortened survival relative to those who were not selected for RT for OA, A2, and O2 patients. OA, oligoastrocytoma; A2, WHO grade II astrocytoma; O2, WHO grade II oligodendroglioma; GTR, gross total resection; RT, radiation therapy. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Please cite this article as: T.A. Lanman, et al., Survival patterns of oligoastrocytoma patients: A surveillance, epidemiology..., Interdisciplinary Neurosurgery: Advanced Techniques and Case Management (2017), http://dx.doi.org/10.1016/j.inat.2017.07.017
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hazard ratio (HR) of death was comparable between the biopsy and the GTR group (Table 2). The HR of death for A2 was 0.67 for patients who underwent GTR relative to those who underwent biopsy only (95% CI 0.54–0.82, p b 0.001), and for O2 patients, it was 0.95 (95% CI 0.67– 1.35, p = 0.757). The pattern of survival after GTR in OA was more similar to that in O2 than in A2. 3.3. Analysis of survival after radiation therapy (RT) The median survival for OA patients who underwent RT was shorter than for those who were not treated with RT (68 months and median not reached, respectively, p b 0.0001, Fig. 1). In multivariate Cox proportional hazards analysis, the HR for death was higher for patients who underwent RT relative to those who did not (Table 2). Similar results were observed for A2 and O2 patients (HRs of 1.51 [95% CI 1.31–1.74, p b 0.001] and 1.69 [95% CI 1.33–2.15, p b 0.001], respectively). 3.4. Overall survival analysis Kaplan-Meier curves demonstrated that the overall survival of OA patients (median survival 68 months) was more favorable than that of A2 patients (median survival 52 months), but not as favorable as O2 patients (median survival not reached, Fig. 2). Multivariate Cox proportional hazards analysis was consistent with the Kaplan-Meier analysis, and showed that the HR for death was lowest for O2 (0.53, 95% CI 0.45–0.62, p b 0.001), highest for A2 (1.32, 95% CI 1.16–1.50, p b 0.001), and intermediate for OA (reference group) (Table 3). Next, we characterized the survival of patients who did not receive surgery or RT. We performed Kaplan Meier analysis after stratifying for the size of the tumor (b5 cm or ≥ 5 cm maximal diameter), since there were approximately equal number of OAs in these size categories. OA patients with tumors b 5 cm exhibited overall survival similar to O2 patients. In contrast, patients with tumors ≥5 cm exhibited overall survival similar to A2 patients (Fig. 3, Table 3). 4. Discussion Disease classification is an evolving process, requiring constant synthesis of emerging data due to advances in technological platforms and insights into pathogenesis. The 2016 update to the World Health Organization (WHO) suggests that oligoastrocytoma (OA) should be classified as O2 or A2 based on molecular features [18]. The natural corollary to this revised scheme is that subsets of patients with tumors previously classified as OA should exhibit survival patterns similar to A2 or O2. Our analysis of the SEER OA registry suggests that such
Table 2 Multivariate HR of death in OA, A2, and O2 for patients with GTR compared to biopsy and for patients with RT compared to no RT. HR, hazard ratio; RT, radiation therapy; OA, oligoastrocytoma; A2, WHO grade II astrocytoma; O2, WHO grade II oligodendroglioma; GTR, gross total resection. Tumor type
GTR/biopsy
GTR/biopsy relative to OA
HR (95% CI)a
p Value
HR
p Value
OA A2 O2
1.30 (0.91–1.94) 0.67 (0.54–0.82) 0.95 (0.67–1.35)
0.150 b0.001 0.757
1 (referent) 0.52 0.73
0.0014 0.2120
Tumor type
RT/No RT
OA A2 O2
RT/No RT relative to OA
HR (95% CI)b
p Value
HR
p Value
1.54 (1.21–1.97) 1.51 (1.31–1.74) 1.69 (1.33–2.15)
0.001 b0.001 b0.001
1 (referent) 0.98 1.1
0.8732 0.6012
a Adjusted for age, race/ethnicity, marital status, sex, tumor size, tumor location, and radiotherapy status. b Adjusted for age, race/ethnicity, marital status, sex, tumor size, tumor location, and surgical treatment received.
Fig. 2. Overall survival of patients with OA, A2, and O2 who had no surgery and no radiation. Kaplan-Meier curves for overall survival of patients with OA, A2, and O2. Patients with OA had worse overall survival than patients with O2, but better overall survival than patients with A2. OA, oligoastrocytoma; A2, WHO grade II astrocytoma; O2, WHO grade II oligodendroglioma.
survival stratification may be made based on tumor size. In SEER, OA patients who did not undergo surgery or RT and had tumors b5 cm exhibited survival patterns similar to O2 patients with tumors b5 cm. In contrast, OA patients with tumors ≥ 5 cm exhibited survival patterns similar to A2 patients with ≥5 cm tumors. The finding that the survival pattern in OA patients after GTR, as a whole, more closely resembles that observed in O2 relative to A2 is also consistent with the reported finding that ~75% of gliomas previously classified as OA have been reclassified as O2 based on molecular profiling [12]. Overall, our findings support the premise of the 2016 WHO classification for OA. One explanation of the distinct survival patterns of OA as a function of tumor size involves the distinct biologic behavior of O2 and A2. It is well appreciated that O2 exhibits more indolent growth kinetics and clinical course relative to A2 [30]. In part, this difference can be accounted for by the observation that tumors with IDH mutations (such as O2) tend to exhibit slow growth kinetics [31]. In contrast, mutations of p53 (in A2) confer accelerated proliferation [32–34]. Because of these differential growth kinetics, A2 may be expected to achieve a Table 3 Multivariate HR of death in OA, A2, and O2 for patients with no surgery, no radiation, in overall cohorts and stratified by tumor size. HR, hazard ratio; OA, oligoastrocytoma; A2, WHO grade II astrocytoma; O2, WHO grade II oligodendroglioma. Overall cohorts Tumor type
HR (95% CI)a
p Value
OA A2 O2
1 (referent) 1.32 (1.16–1.50) 0.53 (0.45–0.62)
b0.001 b0.001
HR (95% CI)b
p Value
1 (referent) 3.96 (1.59–9.87) 1.9 (0.7–5.16)
0.003 0.210
1 (referent) 1.04 (0.47–2.33) 0.32 (0.12–0.87)
0.916 0.026
Stratified by tumor size Tumor Type b5 cm OA A2 O2 ≥5 cm OA A2 O2
a Adjusted for age, race/ethnicity, marital status, sex, tumor size, tumor location, radiotherapy status, and surgical treatment received. b Adjusted for age, race/ethnicity, marital status, sex, tumor location, radiotherapy status, and surgical treatment received.
Please cite this article as: T.A. Lanman, et al., Survival patterns of oligoastrocytoma patients: A surveillance, epidemiology..., Interdisciplinary Neurosurgery: Advanced Techniques and Case Management (2017), http://dx.doi.org/10.1016/j.inat.2017.07.017
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Fig. 3. Survival of patients with OA, A2, and O2 who had no surgery and no radiation stratified by tumor size. Kaplan-Meier analysis was performed after stratifying the tumor size by b5 cm and tumors ≥5 cm. For patients with tumors b5 cm, OA exhibited overall survival similar to O2 patients, which was greater compared to the overall survival of A2 patients. In contrast, for patients with tumors N5 cm, OA exhibited overall survival similar to A2 patients, which was shortened relative to the overall survival of O2 patients. OA, oligoastrocytoma; A2, WHO grade II astrocytoma; O2, WHO grade II oligodendroglioma.
greater size (e.g. ≥ 5 cm) on average relative to O2 (e.g. b5 cm). The implication of this interpretation is that OA patients with tumors b5 cm are more likely O2 patients, while OA patients with tumors N 5 cm are more likely A2 patients. However, we cannot exclude the possibility that differential survival patterns of OA b or ≥5 cm reflect an underlying biology that is completely distinct from those of O2 or A2. To the extent that the biology underlying our clinical observation remains unclear, classification of O2 and A2 in patients with histologic ambiguity should be made based on molecular features rather than tumor size. The increased hazard of death for O2, A2, and OA patients who underwent RT should be interpreted with caution. In general, O2, A2, and OA are treated similarly when it comes to RT. In our institution, patients at low risk for tumor progression (e.g. patients who underwent gross total resection) are not recommended to undergo RT in order to mitigate the risk of neuro-cognitive decline [35]. RT is typically reserved for patients at high risk for disease progression (e.g. age N 40 with significant tumor burden in regions that are not surgically accessible) or consequent to disease progression [36]. This pattern of clinical practice may account for the increased hazard of death in patients who underwent RT. As OA, O2, and A2 represent rare forms of brain cancer, the type of subset analysis performed here cannot be achieved with sufficient sample size using single institutional or single surgeon experiences. That said, our study is subject to the many limitations inherent to a population-based study. The most pertinent of these limitations is that no information on chemotherapeutic regimens is available in SEER. As such, it is conceivable that the improved survival of OA tumors b 5 cm may be secondary to more intense chemotherapeutic intervention or a distinct set of chemotherapeutic agents. However, these scenarios are unlikely since the typical clinical practice is to intensify chemotherapy in patients presenting with a larger tumor [37]. Moreover, because there is a limited set of chemotherapeutic agents available for glioma treatment, similar agents are used to treat OA, O2, and A2. We therefore believe that our findings remain robust despite the inherent limitations of the SEER dataset. Finally, the absence of GTR associated survival benefit in the OA population should not be interpreted as a blanket statement against extended surgical resection. Factors such as radiographic findings of mass effect, clinical symptoms of seizure or neurologic deficit, and patient preference need to be carefully weighed in the context of survival expectation during surgical planning. 5. Conclusion Analysis of the SEER OA dataset revealed distinct survival patterns in patients with tumors b or ≥5 cm in maximal diameter.
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Please cite this article as: T.A. Lanman, et al., Survival patterns of oligoastrocytoma patients: A surveillance, epidemiology..., Interdisciplinary Neurosurgery: Advanced Techniques and Case Management (2017), http://dx.doi.org/10.1016/j.inat.2017.07.017