Effect of Gross Total Resection in World Health Organization Grade II Astrocytomas: SEER-Based Survival Analysis

Accepted Manuscript Effect of gross total resection (GTR) in WHO grade II astrocytomas: A SEER based survival analysis Alexander J. Schupper, B.A., Brian R. Hirshman, M.D. Ph.D., Kate T. Carroll, B.A., Mir Amaan Ali, B.S., Bob S. Carter, M.D., Ph.D., Clark C. Chen, M.D. Ph.D. PII:

S1878-8750(17)30463-1

DOI:

10.1016/j.wneu.2017.03.140

Reference:

WNEU 5509

To appear in:

World Neurosurgery

Received Date: 5 January 2017 Revised Date:

28 March 2017

Accepted Date: 29 March 2017

Please cite this article as: Schupper AJ, Hirshman BR, Carroll KT, Ali MA, Carter BS, Chen CC, Effect of gross total resection (GTR) in WHO grade II astrocytomas: A SEER based survival analysis, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.03.140. 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.

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Effect of gross total resection (GTR) in WHO grade II astrocytomas: A SEER based survival analysis

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Alexander J Schupper, B.A., Brian R Hirshman, M.D. Ph.D., Kate T. Carroll, B.A., Mir Amaan Ali, B.S., Bob S. Carter, M.D., Ph.D., Clark C Chen, M.D. Ph.D.

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ABSTRACT Introduction: We wished to compare the survival benefit associated with gross total resection

(A3) and grade IV (glioblastoma) astrocytomas.

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(GTR) in World Health Organization (WHO) grade II astrocytomas (A2) to those of grade III

Methods: Using the Surveillance, Epidemiology, and End Results (SEER) Program (1999-2010)

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database, we identified 4,113 A2 patients. Surgical resection was defined as GTR, subtotal resection (STR), or no resection. Kaplan-Meier and multivariate Cox proportional hazards

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analyses were used to assess survival with respect to extent of resection (EOR). Results were compared to the benefit of GTR over STR in 2,755 A3 and 21,962 glioblastoma patients from the same database.

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Results: A multivariate Cox proportional hazards analysis indicated that A2 patients who underwent a GTR had a 28.3% reduction in the hazard of death relative to A2 patients who underwent STR. Similar risk reductions were observed in A2 patients age < 50 and ≥ 50.

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However, because of differences in the natural history of these cohorts, the relative hazard reduction translated into distinct overall survival profiles. For A2 patients age ≥ 50, the GTR

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associated survival benefit was approximately 6 months, resembling that observed in glioblastoma patients. In contrast, GTR in A2 patients age < 50 was associated with survival profiles superior to those observed in A3 patients.

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Conclusions: In the SEER database, GTR associated survival benefit in A2 patients age ≥ 50 resembled that observed in glioblastoma, while GTR in A2 patients age < 50 was associated with

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a distinctly more favorable survival profile.

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INTRODUCTION Astrocytoma is a form of brain cancer derived from progenitor cells that give rise to astrocytes, the star-shaped cells instrumental in modulating homeostasis within the central nervous system

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(Markiewicz & Lukomska, 2006). Astrocytic tumors are classified histologically based on World Health Organization (WHO) criteria into four distinct grades. WHO grade I astrocytomas

typically exhibit well-defined boundaries between the tumor and the normal brain (Schiff &

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O’Neill, 2005). In contrast, grade II to IV astrocytomas are characterized by tumor infiltration into the normal brain. The primary challenge in surgical management of these diseases is

intervention (Burks et al., 2016).

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balancing the benefit of tumor debulking and the risks of neurologic injury related to surgical

For patients afflicted with grade II to IV astrocytomas, expected survival remains a complex

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function of the location of the tumor, the extent of surgical resection obtainable in a given location, the sensitivity of the tumor to radiation therapy and to chemotherapy, as well as the overall clinical condition of the patient (Duffau & Taillandier, 2015). Optimization of treatment

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decisions for these patients requires an understanding of how each treatment modality impacts survival, so therapy can be tailored to the needs of the individual patient. We previously used the

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Surveillance, Epidemiology, and End Results (SEER) database to characterize the impact of gross total resection (GTR) on the survival of patients with grade III astrocytomas (also known as anaplastic astrocytomas) and grade IV astrocytomas (also known as glioblastoma) (Noorbakhsh et al., 2014; Padwal et al., 2016). Here, we examine the impact of GTR on the survival of grade II astrocytoma (abbreviated in this manuscript as A2) patients and compare this benefit to that observed in anaplastic astrocytoma (A3) and glioblastoma patients.

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METHODS Study Population We used the SEER database, which was established by the National Cancer Institute and

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compiles data from 18 comprehensive cancer institutes, encompassing approximately 28% of the U.S. population (SEER Research Data 1973-2010). This study included patients who were

diagnosed with A2 between 1999 and 2010, with a follow up period of 120 months. Patients with

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A2 were identified using the following International Classification of Disease for Oncology, 3rd Edition (ICD-O-3) histology codes: 9400, 9410, 9411, and 9420 (diffuse astrocytoma, WHO

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grade II). These codes were described in Table 1 of the Central Brain Tumor Registry of the United States (CBTRUS) Statistical Report (Ostrom et al., 2014). In total, we identified 4,113 A2 patients in SEER. The A3 and glioblastoma cohorts were described in our previous

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publications (Noorbakhsh et al., 2014; Padwal et al., 2016).

Covariates and Extent of Resection

Demographic covariates for this study are identical to our previous studies that focused on A3

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(Padwal et al., 2016) and glioblastoma (Noorbakhsh et al., 2014). They include: age (<18, 18-45, 45-60, 60-75), marital status (single, married, previously married), race/ethnicity (white, black,

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Asian/Pacific Islander, Hispanic, American Indian/Alaskan Native, or other/ unknown), sex (male or female), tumor size (<5 cm, 5 to < 7 cm, or ≥7 cm), tumor location (based on ICD-O-3 topologic site codes C71.0-C71.9), and radiotherapy status (treatment or no treatment).

As with our previous studies (Noorbakhsh et al., 2014; Padwal et al., 2016), extent of resection was classified based on SEER surgical codes. The most recent definitions for surgical resection

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extent can be found in the SEER Program Coding and Staging Manual 2013 released on February 28, 2013 under Appendix C: Surgical Codes for Brain (“SEER Appendix C: Site Specific Coding Modules,” n.d.). Previous definitions can be found on the SEER website

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(“SEER Historical Staging and Coding Manuals.,” n.d.). Extent of resection was classified into three groups: no surgery (code 00), subtotal resection (code 20, 21 and 40), or gross total

resection (code 30, 55). Based on our communication with SEER, determination of GTR was

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based on radiographic reports of the postoperative MRI that were entered into the formal medical record. For patients who underwent “no surgery”, the tissue diagnosis was ascertained through

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autopsy.

Statistical Analysis

Analyses were performed using Stata version 11.2, with a significance level of P < 0.05. Kaplan-

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Meier unadjusted survival analyses were performed comparing patients < 50 years of age and patients ≥ 50 years of age to measure median and 75% survival times (75ST) (Hirsch FR, Varella-Garcia M, Bunn PA, Jr., 2003; Kantola S, Parikka M, Jokinen K, 2000; Kraay MJ,

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Figgie MP, Inglis AE, Wolfe SW, Ranawat CS, 1994). We used multivariate Cox proportional hazards analyses to adjust for demographic and clinical covariates. Wald tests were performed to

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compare the GTR to STR benefit between glioma types.

RESULTS

Patient and Clinical Characteristics Characteristics of patients included in this study are shown in Table 1. We identified 4,113 A2 patients. The median age of diagnosis was 44 years (interquartile range: 29-59 years). There is a

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slight predominance of men (57% male and 43% female). The most common sites for A2 were frontal and temporal lobes. Most A2 presented with a tumor size of < 5 cm (64.4%). The annual incidence of A2 remained approximately constant. Pertaining to the extent of resection, 1,487

Survival Analysis as a Function of Surgical Resection

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GTR.

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(36.15%) underwent no surgery, 1,710 (41.58%) underwent STR, and 916 (22.27%) underwent

We constructed Kaplan-Meier survival curves for the A2 cohort, stratified by patients who

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underwent GTR, STR, and no surgery. For all A2 patients, the median survival was 52 months (CI: 46-58 months). The median survival was >120 months (CI: 103 to >120 months) for A2 patients who underwent GTR, 56 months (CI: 47-63 months) for A2 patients who underwent STR, and 23 months (CI: 20-27 months; Figure 1A) for A2 patients who did not undergo

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surgery. For comparison, in A3 patients, median survival associated with GTR and STR was 64 months and 24 months, respectively (Figure 1B). For glioblastoma, median survival associated

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with GTR and STR was 13 and 9 months, respectively (Figure 1C).

Cox Proportional Hazard Analysis of Survival

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To assess the survival benefit associated with GTR relative to STR when controlling for pertinent demographic and clinical variables, we performed a multivariate Cox proportional hazards analysis. In this analysis, we found that the hazard ratio (HR) for dying from A2 was 0.717 in patients who underwent GTR relative to those who underwent STR (CI 0.603-0.852; Table 2), indicating that GTR conveys a 28.3% reduction in the hazard of dying from A2. We had previously characterized this HR for patients afflicted with A3 (Padwal et al., 2016) and

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glioblastoma (Noorbakhsh et al., 2014). The magnitude of hazard reduction by GTR relative to STR in A2 patients was in between that observed in A3 (where GTR reduced hazard of death by 40%) and that in glioblastoma (where GTR reduced hazard of death by 24%). To compare GTR

difference between A2, A3 and glioblastoma (P < 0.001).

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Age-Stratified Survival Analysis

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to STR benefit between glioma grades, we conducted Wald tests, which showed a significant

We previously demonstrated that the reduction in hazard of death associated with GTR differed

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in patients age < and ≥ 50 with A3 tumors (Padwal et al., 2016). Here we examined whether this age-dependent survival effect of GTR is also observed in A2 patients. To quantitate the survival benefit of GTR relative to STR in these two age groups, we performed stratified multivariate Cox proportional hazards analyses. We observed that the HR of dying from A2 was significantly

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smaller with GTR compared to STR in both age cohorts (HR 0.740, 95% CI 0.566-0.969 for patients < age 50; HR 0.663, 95% CI: 0.529-0.831 for ≥ age 50; Table 2).

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We next constructed a series of Kaplan-Meier survival curves for A2 patients age < 50 and ≥ 50 as a function of GTR and STR. For A2 patients age < 50 who underwent GTR and STR, the

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median survival was not reached in the study period. We therefore used 75ST, or the time in months at which 25% of the original patient population had died. The 75ST in A2 age < 50 who underwent GTR and STR were 82 months and 40 months, respectively (Figure 2A). The difference in 75ST translates into a survival difference of 3.5 years. For A2 patients age ≥ 50, the median survival was 18 months for those who underwent GTR and 12 months for those who

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underwent STR (Figure 2B). These survival patterns are highly reminiscent of those reported for glioblastoma patients.

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Survival Analysis by Era of Diagnosis

To assess if the introduction of temozolomide (TMZ) influenced the survival pattern of A2

patients, we looked at whether diagnosis before or after 2005 impacted survival. The overall HR

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of death for A2 patients was lower in the post-TMZ era (2005-2010) relative to the pre-TMZ era (1999-2004) irrespective of the extent of resection, corroborating the published efficacy of TMZ

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treatment for A2 (HR 0.816, P = 0.002). When stratified by pre- and post-TMZ era, the survival benefits from GTR relative to STR were comparable (1999-2004: HR 0.771, 95% CI 0.6130.971; 2005-2010: HR 0.638, 95% CI 0.488-0.835, Table 3). We also plotted Kaplan-Meier survival curves by extent of resection in both eras (Figure 3). 75ST for A2 patients who

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underwent GTR were comparable between pre- and post-TMZ era (33 and 37 months,

DISCUSSION

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respectively, Figures 3A and 3B).

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Here we utilized the SEER database to examine the survival benefit from GTR relative to STR in A2 patients and compared this benefit to those previously reported for A3 and glioblastoma patients (Noorbakhsh et al., 2014; Padwal et al., 2016). Using multivariate Cox analysis, we estimate that GTR reduces the risk of dying from A2 by 28.3% (Table 2). These results add to an expanding literature of institutional experiences (Hardesty & Sanai, 2012) and epidemiological studies (Jakola et al., 2012) in support of maximal surgical resection for A2 patients. We further observed that the survival patterns for A2 patients age < or ≥ 50 differ significantly, independent

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of the extent of surgical resection. In general, A2 patients age < 50 exhibit a distinctly favorable profile relative to those age ≥ 50. Moreover, the survival benefit of GTR in these two patient cohorts differs. The GTR associated survival improvement for patients age > 50 was 6 months,

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an effect similar to that observed in glioblastoma patients. In contrast, the overall survival

improvement observed in A2 patients age < 50 who underwent GTR relative to STR was more

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favorable than that in A3 patients.

Recent molecular analysis of A2 indicates two distinct patterns of survival. The subset of A2

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patients with the isocitrate dehydrogenase (IDH) mutation exhibits a more indolent clinical course and improved survival relative to A2 with wild type IDH status. A2 that do not harbor the IDH mutation exhibit survival profiles comparable to those observed in glioblastoma (Cancer Genome Atlas Research Network et al., 2015). Our SEER analysis provides evidence from an

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independent cohort that supports these findings. In A2 patients age < 50, where the prevalence of IDH mutations is reported to be significantly higher than in older patients (Wang et al., 2016), the survival profiles are notably improved relative to A2 patients ≥ age 50. For patients age ≥ 50,

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a cohort in which IDH mutation is rare (Wang et al., 2016), the survival patterns are reminiscent of those afflicted with glioblastoma. These findings, however, should not be misconstrued as

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suggesting that age serve as the sole proxy for IDH status. While there is general association between these variables, there are also complex interactions between them, especially pertaining to clinical prognostication and therapeutic predictions.

The observation that A2 patients age < 50 and ≥ 50 exhibit different survival patterns, independent of the extent of resection, suggests the possibility that the intrinsic disease processes

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in these age cohorts differ. However, it is a truism that as patients age, they generally become less resilient in tolerating oncology treatment (Wedding et al., 2007). Moreover, age plays a major role in a patient’s desire to seek aggressive care or comfort care (Given et al., 2008). The

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absence of molecular data (including IDH mutation status), patient neurologic/clinical status, and patient treatment preference in the SEER database renders it impossible to determine the relative contribution of these considerations to the observed survival difference in A2 patients age < and

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≥ 50. Meaningful insights into the matter will require detailed analysis of the tumor molecular landscape in the context of pertinent clinical variables, such as patient condition and treatment

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preference.

The number of A2 analyzed in this study is notable, given the rarity of the disease (Ostrom et al., 2014). That said, the results of this study need to be interpreted with the following caveats. First,

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the results need to be filtered through the lens of potential selection bias since the clinical criteria by which patients were selected to undergo GTR cannot be ascertained from SEER. Second, while we do use the SEER variable for location (describing the primary region of the brain where

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the tumor is located) in our model, we are unable to discern fully whether the observed benefit is due to the resection itself or a favorable location that permits a GTR. Third, there is a lack of

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information on chemotherapeutic regimens in SEER. As such, we cannot exclude the possibility that the differential survival was due to the use of distinct chemotherapies. To the extent that A2 patients are often treated with similar chemotherapeutic regimens (Duffau & Taillandier, 2015), we do not believe that this hypothesis is likely. Finally, in the SEER dataset, the extent of resection is subjectively assessed without objective volumetric assessment. Despite the inherent limitations of SEER, the results presented here are consistent with institutional experiences

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demonstrating resection related survival benefits in A2 patients. As such, our study adds to this literature as an independent data source to support the efficacy of surgical resection in A2

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patients, with a sample size that cannot be recapitulated by single-institution experiences.

CONCLUSION

For A2 patients in SEER, GTR was associated with a 28.3% reduction in the hazard of death

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relative to STR. Overall survival profiles of A2 patients age < 50 and ≥ 50 significantly differ independent of the extent of resection. For A2 patients age ≥ 50, the GTR associated survival

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benefit was approximately 6 months, resembling that observed in glioblastoma patients. In contrast, GTR in A2 patients age < 50 was associated with a distinctly more favorable survival

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2436 1568 (64.37) 620 (25.45) 248 (10.18) 4113 1179 (28.67) 821 (19.96) 450 (10.94) 79 (1.92) 197 (4.79) 579 (14.08) 330 (8.02) 262 (6.37) 74 (1.80) 142 (3.45) 4113 163 (3.96) 391 (9.51) 341 (8.29) 366 (8.9) 361 (8.78) 367 (8.92)

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Table 1. Demographics and clinical characteristics of diffuse astrocytoma, SEER 1999-2010 Number of patients 4113 Tumor size, cm, n <5 Age, mean 43.58 5 to 7 Surgery, n 4113 >7 No surgery 1487 (36.15) Tumor site, n Biopsy 806 (19.60) Frontal lobe STR 904 (21.98) Temporal lobe GTR 916 (22.27) Parietal lobe Radiotherapy 4003 Occipital lobe No 1894 (47.31) Brain stem Yes 2109 (52.69) Overlapping lesion of brain Age category, years, n 4113 Cerebrum <18 528 (12.84) Brain, NOS 18-44 1591 (38.68) Ventricle, NOS 45-60 974 (23.68) Cerebellum, NOS 60-74 673 (16.36) Year of diagnosis, n 75 and older 347 (8.44) 1999 Race, n 4113 2000 White 3008 (73.13) 2001 Black 287 (6.98) 2002 Asian/Pacific Islander 189 (4.60) 2003 Hispanic 576 (14.00) 2004 American Indian/Alaskan Native 28 (0.68) 2005 Other/Unknown, NonHispanic 25 (0.61) 2006 Marital status, n 4000 2007 Single 1379 (34.48) 2008 Married 2094 (52.35) 2009 Separated, divorced, widowed 527 (13.18) 2010 Sex, n 4113 Overall mortality, n Male 2354 (57.23) Living Female 1759 (42.77) Diseased

343 (8.34) 355 (8.63) 359 (8.73) 384 (9.34) 355 (8.63) 328 (7.97) 4113 2008 (48.82) 2105 (51.18)

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A2, diffuse astrocytoma (WHO grade II); SEER, Surveillance, Epidemiology, and End Results; NOS, not otherwise specified.

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Table 2. Multivariate-adjusted HR* of death by EOR in diffuse astrocytoma patients ≥ or < 50 years of age Adjusted HR P value < 50 years Subtotal Resection 1 Reference Gross Total Resection 0.740 (0.566-0.969) 0.028 No surgery 1.384 (1.087-1.763) 0.008 > 50 years Subtotal Resection 1 Reference Gross Total Resection 0.663 (0.529-0.831) <0.0001 No surgery 1.229 (1.023-1.476) 0.027 Overall Subtotal Resection 1 Reference Gross Total Resection 0.717 (0.603-0.852) <0.0001 No surgery 1.323 (1.144-1.528) <0.0001

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HR, hazard ratio; EOR, extent of resection *Adjusted for race/ethnicity, marital status, sex, year of diagnosis, tumor size, tumor site, and radiotherapy

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1 0.638 (0.488-0.835) 1.219 (0.984-1.509)

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Post-TMZ (2005-2010) STR GTR No surgery

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Table 3. Multivariate-adjusted HR* of death by EOR in diffuse astrocytoma patients in pre- and post-temozolomide (TMZ) eras Adjusted HR P Value Pre-TMZ (1999-2004) STR 1 Reference GTR 0.771 (0.613-0.971) 0.027 No surgery 1.405 (1.151-1.714) 0.001

Reference 0.001 0.069

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HR, hazard ratio; EOR, extent of resection. *Adjusted for age, race/ethnicity, marital status, sex, year of diagnosis, tumor size, tumor site, and radiotherapy

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Figure 1. Kaplan-Meier plot of 10-year survival for patients with WHO grade II, III and grade IV glioma, by extent of resection. STR, subtotal resection; GTR, gross total resection.

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Figure 1a

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Figure 1. Kaplan-Meier plot of 10-year survival for patients with WHO grade II, III and grade IV glioma, by extent of resection. STR, subtotal resection; GTR, gross total resection.

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Figure 1B

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Figure 2. Kaplan-Meier plot of 10-year survival for patients with diffuse astrocytoma for age < 50 and age > 50. STR, subtotal resection; GTR, gross total resection.

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Figure 2A

Figure 2B

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Figure 3. Kaplan-Meier plot of 10-year survival for patients with diffuse astrocytoma patients in pre- and posttemozolomide (TMZ) eras. STR, subtotal resection; GTR, gross total resection.

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Figure 3A

Figure 3B

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The survival benefit of gross total resection for grade II astrocytomas was assessed. Gross total resection survival benefit was dependent upon the age of the patient. Grade II survival benefit in older patients resembled grade IV astrocytoma. Grade II survival benefit in younger patients resembled grade III astrocytoma.

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Gross total resection; GTR Subtotal resection; STR Diffuse astrocytoma; A2 World Health Organization; WHO Grade II astrocytoma; A2 Grade III astrocytoma; A3 Grade IV astrocytoma; glioblastoma Surveillance, Epidemiology, and End Results; SEER Extent of resection; EOR Not otherwise specified; NOS Central Brain Tumor Registry of the United States; CBTRUS Hazard ratio; HR Isocitrate dehydrogenase; IDH

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Conflicts of interest: none