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Effect of Gross Total Resection in World Health Organization Grade II Astrocytomas: SEER-Based Survival Analysis
Original Article
Effect of Gross Total Resection in World Health Organization Grade II Astrocytomas: SEER-Based Survival Analysis Alexander J. Schupper, Brian R. Hirshman, Kate T. Carroll, Mir Amaan Ali, Bob S. Carter, Clark C. Chen
INTRODUCTION: We sought to compare the survival benefit associated with gross total resection (GTR) in World Health Organization grade II astrocytomas (A2) with those of grade III (A3) and grade IV (glioblastoma) astrocytomas.
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METHODS: Using the Surveillance, Epidemiology, and End Results program database (1999e2010), we identified 4113 A2 patients. Surgical resection was defined as GTR, subtotal resection (STR), or no resection. Kaplan-Meier and multivariate Cox proportional hazards analyses were used to assess survival with respect to extent of resection. Results were compared with the benefit of GTR over STR in 2755 A3 and 21,962 glioblastoma patients from the same database.
that observed in glioblastoma, while GTR in A2 patients <50 years old was associated with a distinctly more favorable survival profile.
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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. However, because of differences in the natural history of these cohorts, the relative hazard reduction translated into distinct overall survival profiles. For A2 patients ‡50 years old, the GTR-associated survival benefit was approximately 6 months, resembling that observed in glioblastoma patients. In contrast, GTR in A2 patients <50 years old was associated with survival profiles superior to those observed in A3 patients.
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CONCLUSIONS: In the Surveillance, Epidemiology, and End Results (SEER) program database, GTR-associated survival benefit in A2 patients ‡50 years old resembled
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Key words Diffuse astrocytoma - WHO grade II astrocytoma - Gross total resection -
Abbreviations and Acronyms A2: Grade II astrocytoma diffuse astrocytoma A3: Grade III astrocytoma CBTRUS: Central Brain Tumor Registry of the United States EOR: Extent of resection GTR: Gross total resection HR: Hazard ratio IDH: Isocitrate dehydrogenase NOS: Not otherwise specified
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INTRODUCTION
A
strocytoma 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.1 Astrocytic tumors are classified histologically on the basis of World Health Organization (WHO) criteria into 4 distinct grades. WHO grade I astrocytomas typically exhibit well-defined boundaries between the tumor and normal brain.2 In contrast, grade IIeIV astrocytomas are characterized by tumor infiltration into the normal brain. The primary challenge in surgical management of these diseases is balancing the benefit of tumor debulking and the risks of neurologic injury related to surgical intervention.3 For patients afflicted with grade IIeIV astrocytomas, expected survival remains a complex function of the location of the tumor, extent of surgical resection obtainable in a given location, sensitivity of the tumor to radiation therapy and to chemotherapy, as well as overall clinical condition of the patient.4 Optimization of treatment 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 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
SEER: Surveillance, Epidemiology, and End Results STR: Subtotal resection WHO: World Health Organization Division of Neurosurgery, University of California, La Jolla, California, USA To whom correspondence should be addressed: Clark C. Chen, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2017) 103:741-747. http://dx.doi.org/10.1016/j.wneu.2017.03.140 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.
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GTR IN WHO GRADE II ASTROCYTOMAS: SURVIVAL ANALYSIS
Table 1. Demographics and Clinical Characteristics of Diffuse Astrocytoma, SEER 1999e2010
Table 1. Continued Overlapping lesion of brain
579 (14.08)
Number of patients
4113
Cerebrum
330 (8.02)
Age, mean
43.58
Brain, NOS
262 (6.37)
Surgery, number
4113
Ventricle, NOS
No surgery
1487 (36.15)
Cerebellum, NOS
74 (1.80) 142 (3.45)
Biopsy
806 (19.60)
STR
904 (21.98)
1999
163 (3.96)
GTR
916 (22.27)
2000
391 (9.51)
4003
2001
341 (8.29)
No
1894 (47.31)
2002
366 (8.9)
Yes
2109 (52.69)
2003
361 (8.78)
4113
2004
367 (8.92)
528 (12.84)
2005
343 (8.34)
18e44
1591 (38.68)
2006
355 (8.63)
45e60
974 (23.68)
2007
359 (8.73)
60e74
673 (16.36)
2008
384 (9.34)
75 and older
347 (8.44)
2009
355 (8.63)
4113
2010
328 (7.97)
Radiotherapy
Age category, years, number <18
Race, number
Year of diagnosis, number
4113
White
3008 (73.13)
Black
287 (6.98)
Living
2008 (48.82)
Asian/Pacific Islander
189 (4.60)
Diseased
2105 (51.18)
Hispanic
576 (14.00)
American Indian/Alaskan Native
28 (0.68)
Other/Unknown, Non-Hispanic
25 (0.61)
Marital status, number
4000
Single
1379 (34.48)
Married
2094 (52.35)
Separated, divorced, widowed Sex, number
527 (13.18) 4113
Male
2354 (57.23)
Female
1759 (42.77)
Tumor size, cm, number
1568 (64.37)
5e7
620 (25.45)
>7
248 (10.18)
Frontal lobe
4113 1179 (28.67)
Temporal lobe
821 (19.96)
Parietal lobe
450 (10.94)
Occipital lobe
79 (1.92)
Brain stem
197 (4.79) Continues
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4113
SEER, Surveillance, Epidemiology, and End Results; STR, subtotal resection; GTR, gross total resection; NOS, not otherwise specified.
as anaplastic astrocytomas) and grade IV astrocytomas (also known as glioblastoma).5,6 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.
METHODS
2436
<5
Tumor site, number
Overall mortality, number
Study Population We used the SEER database, which was established by the National Cancer Institute and compiles data from 18 comprehensive cancer institutes, encompassing approximately 28% of the U.S. population (SEER Research Data 1973e2010). This study included patients who were diagnosed with A2 between 1999 and 2010, with a follow-up period of 120 months. Patients with 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 grade II). These codes were described in Table 1 of the Central Brain Tumor Registry of the United States (CBTRUS) Statistical Report.7 In total, we identified 4113 A2 patients in SEER. The A3 and glioblastoma cohorts were described in our previous publications5,6
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Covariates and Extent of Resection Demographic covariates for this study are identical to our previous studies that focused on A36 and glioblastoma.5 They include age (<18, 18e45, 45e60, 60e75); marital status (single, married, previously married); race/ethnicity (white, black, 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,5,6 extent of resection was classified on the basis of SEER surgical codes. The most recent definitions for surgical resection 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.8 Previous definitions can be found on the SEER website.9 Extent of resection was classified into 3 groups: no surgery (code 00),
Figure 1. Kaplan-Meier plot of 10-year survival for patients with WHO grade II (A), III (B) and grade IV (C) glioma, by extent of resection. STR, subtotal
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subtotal resection (STR; codes 20, 21, and 40), or GTR (codes 30 and 55). On the basis of communication with SEER, determination of GTR was based on radiographic reports of the postoperative magnetic resonance imaging that were entered into the formal medical record. For patients who underwent “no surgery,” the tissue diagnosis was ascertained through autopsy. Statistical Analysis Analyses were performed using Stata version 11.2, with a significance level of P < 0.05. Kaplan-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 (75STs).10-12 We used multivariate Cox proportional hazards analyses to adjust for demographic and clinical covariates. Wald tests were performed to compare the GTR-to-STR benefit between glioma types.
resection; GTR, gross total resection.
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Table 2. Multivariate-Adjusted Hazard Ratio (HR)* of Death by Extent of Resection in Diffuse Astrocytoma Patients 50 or <50 Years of Age Adjusted HR
P Value
1
Reference
Gross total resection
0.740 (0.566e0.969)
0.028
No surgery
1.384 (1.087e1.763)
0.008
<50 years Subtotal resection
50 years Subtotal resection
1
Reference
Gross total resection
0.663 (0.529e0.831)
<0.0001
No surgery
1.229 (1.023e1.476)
0.027
1
Reference
Gross total resection
0.717 (0.603e0.852)
<0.0001
No surgery
1.323 (1.144e1.528)
<0.0001
Overall Subtotal resection
*Adjusted for race/ethnicity, marital status, sex, year of diagnosis, tumor size, tumor site, and radiotherapy.
RESULTS Patient and Clinical Characteristics Characteristics of patients included in this study are shown in Table 1. We identified 4113 A2 patients. The median age of diagnosis was 44 years (interquartile range: 29e59 years). There is a slight predominance of men (57% male and 43% female). The most common sites for A2 were frontal and temporal lobes. Most A2s presented with a tumor size of <5 cm (64.4%). The annual incidence of A2 remained approximately constant. Pertaining to the extent of resection, 1487 (36.15%) underwent
Figure 2. Kaplan-Meier plot of 10-year survival for patients with diffuse astrocytoma for age <50 (A) and age >50 (B). STR, subtotal resection;
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no surgery, 1710 (41.58%) underwent STR, and 916 (22.27%) underwent GTR.
Survival Analysis as a Function of Surgical Resection We constructed Kaplan-Meier survival curves for the A2 cohort, stratified by patients who underwent GTR, STR, and no surgery. For all A2 patients, the median survival was 52 months (confidence interval [CI]: 46e58 months). The median survival was >120 months (CI: 103 to >120 months) for A2 patients who underwent GTR, 56 months (CI: 47e63 months) for A2 patients who underwent STR, and 23 months (CI: 20e27 months; Figure 1A) for A2 patients who did not undergo 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 with GTR and STR was 13 and 9 months, respectively (Figure 1C).
Cox Proportional Hazard Analysis of Survival 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 0.603e0.852; 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 A36 and glioblastoma.5 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 the GTR-to-STR benefit between glioma grades, we conducted Wald tests, which showed a significant difference between A2, A3, and glioblastoma (P < 0.001).
GTR, gross total resection.
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GTR IN WHO GRADE II ASTROCYTOMAS: SURVIVAL ANALYSIS
Table 3. Multivariate-Adjusted Hazard Ratio (HR)* of Death by Extent of Resection in Diffuse Astrocytoma Patients in Pre- and Post-Temozolomide (TMZ) Eras Adjusted HR
P Value
1
Reference
GTR
0.771 (0.613e0.971)
0.027
No surgery
1.405 (1.151e1.714)
0.001
Pre-TMZ (1999e2004) STR
Post-TMZ (2005e2010) STR
1
Reference
GTR
0.638 (0.488e0.835)
0.001
No surgery
1.219 (0.984e1.509)
0.069
STR, subtotal resection; GTR, gross total resection. *Adjusted for age, race/ethnicity, marital status, sex, year of diagnosis, tumor size, tumor site, and radiotherapy.
Age-Stratified Survival Analysis We previously demonstrated that the reduction in hazard of death associated with GTR differed in patients aged <50 and 50 with A3 tumors.6 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 2 age groups, we performed stratified multivariate Cox proportional hazards analyses. We observed that the HR of dying from A2 was significantly smaller with GTR compared with STR in both age cohorts (HR 0.740, 95% CI 0.566e0.969 for patients <50 years old; HR 0.663, 95% CI: 0.529e0.831 for 50 years old; Table 2). 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 median
Figure 3. Kaplan-Meier plot of 10-year survival for patients with diffuse astrocytoma patients in pre- (A) and post-temozolomide (TMZ) (B) eras.
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survival was not reached in the study period. We therefore used 75STs, or the time in months at which 25% of the original patient population had died. The 75STs 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 50 years old, the median survival was 18 months for those who underwent GTR and 12 months for those who underwent STR (Figure 2B). These survival patterns are highly reminiscent of those reported for glioblastoma patients. 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 of death for A2 patients was lower in the post-TMZ era (2005e2010) relative to the pre-TMZ era (1999e2004) irrespective of the extent of resection, corroborating the published efficacy of TMZ treatment for A2 (HR 0.816, P ¼ 0.002). When stratified by pre- and post-TMZ era, the survival benefits from GTR relative to STR were comparable (1999e2004: HR 0.771, 95% CI 0.613e0.971; 2005e2010: HR 0.638, 95% CI 0.488e0.835, Table 3). We also plotted Kaplan-Meier survival curves by extent of resection in both eras (Figure 3). 75STs for A2 patients who underwent GTR were comparable between the pre- and post-TMZ eras (33 and 37 months, respectively, see Figure 3A and B). DISCUSSION Here we used the SEER database to examine the survival benefit from GTR relative to STR in A2 patients and compared this benefit with those previously reported for A3 and glioblastoma patients.5,6 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 experiences13-16 and epidemiologic studies17 in support of maximal surgical resection for A2
STR, subtotal resection; GTR, gross total resection.
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patients. We further observed that the survival patterns for A2 patients age <50 or 50 differ significantly, independent 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 2 patient cohorts differs. The GTR-associated survival improvement for patients age >50 was 6 months, 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 favorable than that in A3 patients. Recent molecular analysis of A2 indicates 2 distinct patterns of survival. The subset of A2 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 does not harbor the IDH mutation exhibits survival profiles comparable with those observed in glioblastoma.18 Our SEER analysis provides evidence from an 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,19 the survival profiles are notably improved relative to A2 patients age 50. For patients age 50, a cohort in which IDH mutation is rare,19 the survival patterns are reminiscent of those afflicted with glioblastoma. These findings, however, should not be misconstrued as suggesting that age serves 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 in these age cohorts differ. However, it is a truism that as patients age, they generally become less resilient in tolerating oncology treatment.20 Moreover, age plays a major role in a patient’s desire to seek aggressive care or comfort care.21 The 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 <50 and 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 preference. The number of A2s analyzed in this study is notable, given the rarity of the disease.7 That said, the results of this study need to be interpreted with the following caveats. First, 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 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 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,4 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 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 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 relative to STR. Overall survival profiles of A2 patients age <50 and 50 significantly differ independently of the extent of resection. For A2 patients 50 years old, the GTR-associated survival benefit was approximately 6 months, resembling that observed in glioblastoma patients. In contrast, GTR in A2 patients <50 years old was associated with a distinctly more favorable survival profile.
5. Noorbakhsh A, Tang JA, Marcus LP, McCutcheon B, Gonda DD, Schallhorn CS, et al. Gross-total resection outcomes in an elderly population with glioblastoma: a SEER-based analysis. J Neurosurg. 2014;120:31-39.
9. SEER Historical Staging and Coding Manuals. (n.d.). Available at: http://seer.cancer.gov/tools/ codingmanuals/historical.html. Accessed October 20, 2016.
2. Schiff D, O’Neill BP. Cancer of the Nervous System: Principles and Practice of Neuro-Oncology. New York, NY: McGraw-Hill Medical; 2005.
6. Padwal JA, Dong X, Hirshman BR, Hoi-Sang U, Carter BS, Chen CC. Superior efficacy of gross total resection in anaplastic astrocytoma patients relative to glioblastoma patients. World Neurosurg. 2016;90:186-193.
10. Hirsch FR, Varella-Garcia M, Bunn PA Jr. Epidermal growth factor receptor in non-smallcell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 2003;21:3798-3807.
3. Burks JD, Bonney PA, Glenn CA, Conner AK, Briggs RG, Ebeling PA, et al. Symptom resolution in infiltrating WHO grade II-IV glioma patients undergoing surgical resection. J Clin Neurosci. 2016; 31:157-161.
7. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 20072011. Neuro-Oncol. 2014;16(suppl 4):iv1-iv63.
11. Kantola S, Parikka M, Jokinen K. Prognostic factors in tongue cancer—relative importance of demographic, clinical and histopathological factors. Br J Cancer. 2000;83:614-619.
4. Duffau H, Taillandier L. New concepts in the management of diffuse low-grade glioma: proposal of a multistage and individualized therapeutic approach. Neuro-Oncol. 2015;17:332-342.
8. SEER Appendix C. Site Specific Coding Modules. (n.d.). Available at: http://seer.cancer.gov/ manuals/2013/appendixc.html. Accessed October 20, 2016.
12. Kraay MJ, Figgie MP, Inglis AE, Wolfe SW, Ranawat CS. Primary semiconstrained total elbow arthroplasty. Survival analysis of 113 consecutive cases. J Bone Joint Surg Br. 1994;76:636-640.
REFERENCES 1. Markiewicz I, Lukomska B. The role of astrocytes in the physiology and pathology of the central nervous system. Acta Neurobiol Exp. 2006;66: 343-358.
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13. Hardesty DA, Sanai N. The value of glioma extent of resection in the modern neurosurgical era. Front Neurol. 2012;3:140. 14. Duffau H. A new philosophy in surgery for diffuse low-grade glioma (DLGG): oncological and functional outcomes. Neuro-Chirurgie. 2013;59:2-8. 15. McGirt MJ, Chaichana KL, Attenello FJ, Weingart JD, Than K, Burger PC, et al. Extent of surgical resection is independently associated with survival in patients with hemispheric infiltrating low-grade gliomas. Neurosurgery. 2008;63:700-707. 16. Smith JS, Chang EF, Lamborn KR, Chang SM, Prados MD, Cha S, et al. Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol. 2008;26: 1338-1345.
GTR IN WHO GRADE II ASTROCYTOMAS: SURVIVAL ANALYSIS
17. Jakola AS, Myrmel KS, Kloster R, Torp SH, Lindal S, Unsgård G, et al. Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA. 2012;308:1881-1888. 18. Cancer Genome Atlas Research Network, Brat DJ, Verhaak RGW, Aldape KD, Yung WKA, Salama SR, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372:2481-2498. 19. Wang PF, Liu N, Song HW, Yao K, Jiang T, Li SW, et al. IDH-1R132H mutation status in diffuse glioma patients: implications for classification. Oncotarget. 2016;7:31393-31400. 20. Wedding U, Honecker F, Bokemeyer C, Pientka L, Höffken K. Tolerance to chemotherapy in elderly patients with cancer. Cancer Control. 2007;14:44-56.
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21. Given B, Given CW. Older adults and cancer treatment. Cancer. 2008;113(suppl 12):3505-3511.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 5 January 2017; accepted 29 March 2017 Citation: World Neurosurg. (2017) 103:741-747. http://dx.doi.org/10.1016/j.wneu.2017.03.140 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.
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Effect of Gross Total Resection in World Health Organization Grade II Astrocytomas: SEER-Based Survival Analysis Alexander J. Schupper, Brian R. Hirshman, Kate T. Carroll, Mir Amaan Ali, Bob S. Carter, Clark C. Chen
INTRODUCTION: We sought to compare the survival benefit associated with gross total resection (GTR) in World Health Organization grade II astrocytomas (A2) with those of grade III (A3) and grade IV (glioblastoma) astrocytomas.
-
METHODS: Using the Surveillance, Epidemiology, and End Results program database (1999e2010), we identified 4113 A2 patients. Surgical resection was defined as GTR, subtotal resection (STR), or no resection. Kaplan-Meier and multivariate Cox proportional hazards analyses were used to assess survival with respect to extent of resection. Results were compared with the benefit of GTR over STR in 2755 A3 and 21,962 glioblastoma patients from the same database.
that observed in glioblastoma, while GTR in A2 patients <50 years old was associated with a distinctly more favorable survival profile.
-
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. However, because of differences in the natural history of these cohorts, the relative hazard reduction translated into distinct overall survival profiles. For A2 patients ‡50 years old, the GTR-associated survival benefit was approximately 6 months, resembling that observed in glioblastoma patients. In contrast, GTR in A2 patients <50 years old was associated with survival profiles superior to those observed in A3 patients.
-
CONCLUSIONS: In the Surveillance, Epidemiology, and End Results (SEER) program database, GTR-associated survival benefit in A2 patients ‡50 years old resembled
-
Key words Diffuse astrocytoma - WHO grade II astrocytoma - Gross total resection -
Abbreviations and Acronyms A2: Grade II astrocytoma diffuse astrocytoma A3: Grade III astrocytoma CBTRUS: Central Brain Tumor Registry of the United States EOR: Extent of resection GTR: Gross total resection HR: Hazard ratio IDH: Isocitrate dehydrogenase NOS: Not otherwise specified
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INTRODUCTION
A
strocytoma 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.1 Astrocytic tumors are classified histologically on the basis of World Health Organization (WHO) criteria into 4 distinct grades. WHO grade I astrocytomas typically exhibit well-defined boundaries between the tumor and normal brain.2 In contrast, grade IIeIV astrocytomas are characterized by tumor infiltration into the normal brain. The primary challenge in surgical management of these diseases is balancing the benefit of tumor debulking and the risks of neurologic injury related to surgical intervention.3 For patients afflicted with grade IIeIV astrocytomas, expected survival remains a complex function of the location of the tumor, extent of surgical resection obtainable in a given location, sensitivity of the tumor to radiation therapy and to chemotherapy, as well as overall clinical condition of the patient.4 Optimization of treatment 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 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
SEER: Surveillance, Epidemiology, and End Results STR: Subtotal resection WHO: World Health Organization Division of Neurosurgery, University of California, La Jolla, California, USA To whom correspondence should be addressed: Clark C. Chen, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2017) 103:741-747. http://dx.doi.org/10.1016/j.wneu.2017.03.140 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.
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Table 1. Demographics and Clinical Characteristics of Diffuse Astrocytoma, SEER 1999e2010
Table 1. Continued Overlapping lesion of brain
579 (14.08)
Number of patients
4113
Cerebrum
330 (8.02)
Age, mean
43.58
Brain, NOS
262 (6.37)
Surgery, number
4113
Ventricle, NOS
No surgery
1487 (36.15)
Cerebellum, NOS
74 (1.80) 142 (3.45)
Biopsy
806 (19.60)
STR
904 (21.98)
1999
163 (3.96)
GTR
916 (22.27)
2000
391 (9.51)
4003
2001
341 (8.29)
No
1894 (47.31)
2002
366 (8.9)
Yes
2109 (52.69)
2003
361 (8.78)
4113
2004
367 (8.92)
528 (12.84)
2005
343 (8.34)
18e44
1591 (38.68)
2006
355 (8.63)
45e60
974 (23.68)
2007
359 (8.73)
60e74
673 (16.36)
2008
384 (9.34)
75 and older
347 (8.44)
2009
355 (8.63)
4113
2010
328 (7.97)
Radiotherapy
Age category, years, number <18
Race, number
Year of diagnosis, number
4113
White
3008 (73.13)
Black
287 (6.98)
Living
2008 (48.82)
Asian/Pacific Islander
189 (4.60)
Diseased
2105 (51.18)
Hispanic
576 (14.00)
American Indian/Alaskan Native
28 (0.68)
Other/Unknown, Non-Hispanic
25 (0.61)
Marital status, number
4000
Single
1379 (34.48)
Married
2094 (52.35)
Separated, divorced, widowed Sex, number
527 (13.18) 4113
Male
2354 (57.23)
Female
1759 (42.77)
Tumor size, cm, number
1568 (64.37)
5e7
620 (25.45)
>7
248 (10.18)
Frontal lobe
4113 1179 (28.67)
Temporal lobe
821 (19.96)
Parietal lobe
450 (10.94)
Occipital lobe
79 (1.92)
Brain stem
197 (4.79) Continues
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4113
SEER, Surveillance, Epidemiology, and End Results; STR, subtotal resection; GTR, gross total resection; NOS, not otherwise specified.
as anaplastic astrocytomas) and grade IV astrocytomas (also known as glioblastoma).5,6 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.
METHODS
2436
<5
Tumor site, number
Overall mortality, number
Study Population We used the SEER database, which was established by the National Cancer Institute and compiles data from 18 comprehensive cancer institutes, encompassing approximately 28% of the U.S. population (SEER Research Data 1973e2010). This study included patients who were diagnosed with A2 between 1999 and 2010, with a follow-up period of 120 months. Patients with 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 grade II). These codes were described in Table 1 of the Central Brain Tumor Registry of the United States (CBTRUS) Statistical Report.7 In total, we identified 4113 A2 patients in SEER. The A3 and glioblastoma cohorts were described in our previous publications5,6
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Covariates and Extent of Resection Demographic covariates for this study are identical to our previous studies that focused on A36 and glioblastoma.5 They include age (<18, 18e45, 45e60, 60e75); marital status (single, married, previously married); race/ethnicity (white, black, 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,5,6 extent of resection was classified on the basis of SEER surgical codes. The most recent definitions for surgical resection 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.8 Previous definitions can be found on the SEER website.9 Extent of resection was classified into 3 groups: no surgery (code 00),
Figure 1. Kaplan-Meier plot of 10-year survival for patients with WHO grade II (A), III (B) and grade IV (C) glioma, by extent of resection. STR, subtotal
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subtotal resection (STR; codes 20, 21, and 40), or GTR (codes 30 and 55). On the basis of communication with SEER, determination of GTR was based on radiographic reports of the postoperative magnetic resonance imaging that were entered into the formal medical record. For patients who underwent “no surgery,” the tissue diagnosis was ascertained through autopsy. Statistical Analysis Analyses were performed using Stata version 11.2, with a significance level of P < 0.05. Kaplan-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 (75STs).10-12 We used multivariate Cox proportional hazards analyses to adjust for demographic and clinical covariates. Wald tests were performed to compare the GTR-to-STR benefit between glioma types.
resection; GTR, gross total resection.
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Table 2. Multivariate-Adjusted Hazard Ratio (HR)* of Death by Extent of Resection in Diffuse Astrocytoma Patients 50 or <50 Years of Age Adjusted HR
P Value
1
Reference
Gross total resection
0.740 (0.566e0.969)
0.028
No surgery
1.384 (1.087e1.763)
0.008
<50 years Subtotal resection
50 years Subtotal resection
1
Reference
Gross total resection
0.663 (0.529e0.831)
<0.0001
No surgery
1.229 (1.023e1.476)
0.027
1
Reference
Gross total resection
0.717 (0.603e0.852)
<0.0001
No surgery
1.323 (1.144e1.528)
<0.0001
Overall Subtotal resection
*Adjusted for race/ethnicity, marital status, sex, year of diagnosis, tumor size, tumor site, and radiotherapy.
RESULTS Patient and Clinical Characteristics Characteristics of patients included in this study are shown in Table 1. We identified 4113 A2 patients. The median age of diagnosis was 44 years (interquartile range: 29e59 years). There is a slight predominance of men (57% male and 43% female). The most common sites for A2 were frontal and temporal lobes. Most A2s presented with a tumor size of <5 cm (64.4%). The annual incidence of A2 remained approximately constant. Pertaining to the extent of resection, 1487 (36.15%) underwent
Figure 2. Kaplan-Meier plot of 10-year survival for patients with diffuse astrocytoma for age <50 (A) and age >50 (B). STR, subtotal resection;
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no surgery, 1710 (41.58%) underwent STR, and 916 (22.27%) underwent GTR.
Survival Analysis as a Function of Surgical Resection We constructed Kaplan-Meier survival curves for the A2 cohort, stratified by patients who underwent GTR, STR, and no surgery. For all A2 patients, the median survival was 52 months (confidence interval [CI]: 46e58 months). The median survival was >120 months (CI: 103 to >120 months) for A2 patients who underwent GTR, 56 months (CI: 47e63 months) for A2 patients who underwent STR, and 23 months (CI: 20e27 months; Figure 1A) for A2 patients who did not undergo 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 with GTR and STR was 13 and 9 months, respectively (Figure 1C).
Cox Proportional Hazard Analysis of Survival 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 0.603e0.852; 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 A36 and glioblastoma.5 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 the GTR-to-STR benefit between glioma grades, we conducted Wald tests, which showed a significant difference between A2, A3, and glioblastoma (P < 0.001).
GTR, gross total resection.
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GTR IN WHO GRADE II ASTROCYTOMAS: SURVIVAL ANALYSIS
Table 3. Multivariate-Adjusted Hazard Ratio (HR)* of Death by Extent of Resection in Diffuse Astrocytoma Patients in Pre- and Post-Temozolomide (TMZ) Eras Adjusted HR
P Value
1
Reference
GTR
0.771 (0.613e0.971)
0.027
No surgery
1.405 (1.151e1.714)
0.001
Pre-TMZ (1999e2004) STR
Post-TMZ (2005e2010) STR
1
Reference
GTR
0.638 (0.488e0.835)
0.001
No surgery
1.219 (0.984e1.509)
0.069
STR, subtotal resection; GTR, gross total resection. *Adjusted for age, race/ethnicity, marital status, sex, year of diagnosis, tumor size, tumor site, and radiotherapy.
Age-Stratified Survival Analysis We previously demonstrated that the reduction in hazard of death associated with GTR differed in patients aged <50 and 50 with A3 tumors.6 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 2 age groups, we performed stratified multivariate Cox proportional hazards analyses. We observed that the HR of dying from A2 was significantly smaller with GTR compared with STR in both age cohorts (HR 0.740, 95% CI 0.566e0.969 for patients <50 years old; HR 0.663, 95% CI: 0.529e0.831 for 50 years old; Table 2). 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 median
Figure 3. Kaplan-Meier plot of 10-year survival for patients with diffuse astrocytoma patients in pre- (A) and post-temozolomide (TMZ) (B) eras.
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survival was not reached in the study period. We therefore used 75STs, or the time in months at which 25% of the original patient population had died. The 75STs 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 50 years old, the median survival was 18 months for those who underwent GTR and 12 months for those who underwent STR (Figure 2B). These survival patterns are highly reminiscent of those reported for glioblastoma patients. 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 of death for A2 patients was lower in the post-TMZ era (2005e2010) relative to the pre-TMZ era (1999e2004) irrespective of the extent of resection, corroborating the published efficacy of TMZ treatment for A2 (HR 0.816, P ¼ 0.002). When stratified by pre- and post-TMZ era, the survival benefits from GTR relative to STR were comparable (1999e2004: HR 0.771, 95% CI 0.613e0.971; 2005e2010: HR 0.638, 95% CI 0.488e0.835, Table 3). We also plotted Kaplan-Meier survival curves by extent of resection in both eras (Figure 3). 75STs for A2 patients who underwent GTR were comparable between the pre- and post-TMZ eras (33 and 37 months, respectively, see Figure 3A and B). DISCUSSION Here we used the SEER database to examine the survival benefit from GTR relative to STR in A2 patients and compared this benefit with those previously reported for A3 and glioblastoma patients.5,6 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 experiences13-16 and epidemiologic studies17 in support of maximal surgical resection for A2
STR, subtotal resection; GTR, gross total resection.
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patients. We further observed that the survival patterns for A2 patients age <50 or 50 differ significantly, independent 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 2 patient cohorts differs. The GTR-associated survival improvement for patients age >50 was 6 months, 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 favorable than that in A3 patients. Recent molecular analysis of A2 indicates 2 distinct patterns of survival. The subset of A2 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 does not harbor the IDH mutation exhibits survival profiles comparable with those observed in glioblastoma.18 Our SEER analysis provides evidence from an 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,19 the survival profiles are notably improved relative to A2 patients age 50. For patients age 50, a cohort in which IDH mutation is rare,19 the survival patterns are reminiscent of those afflicted with glioblastoma. These findings, however, should not be misconstrued as suggesting that age serves 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 in these age cohorts differ. However, it is a truism that as patients age, they generally become less resilient in tolerating oncology treatment.20 Moreover, age plays a major role in a patient’s desire to seek aggressive care or comfort care.21 The 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 <50 and 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 preference. The number of A2s analyzed in this study is notable, given the rarity of the disease.7 That said, the results of this study need to be interpreted with the following caveats. First, 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 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 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,4 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 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 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 relative to STR. Overall survival profiles of A2 patients age <50 and 50 significantly differ independently of the extent of resection. For A2 patients 50 years old, the GTR-associated survival benefit was approximately 6 months, resembling that observed in glioblastoma patients. In contrast, GTR in A2 patients <50 years old was associated with a distinctly more favorable survival profile.
5. Noorbakhsh A, Tang JA, Marcus LP, McCutcheon B, Gonda DD, Schallhorn CS, et al. Gross-total resection outcomes in an elderly population with glioblastoma: a SEER-based analysis. J Neurosurg. 2014;120:31-39.
9. SEER Historical Staging and Coding Manuals. (n.d.). Available at: http://seer.cancer.gov/tools/ codingmanuals/historical.html. Accessed October 20, 2016.
2. Schiff D, O’Neill BP. Cancer of the Nervous System: Principles and Practice of Neuro-Oncology. New York, NY: McGraw-Hill Medical; 2005.
6. Padwal JA, Dong X, Hirshman BR, Hoi-Sang U, Carter BS, Chen CC. Superior efficacy of gross total resection in anaplastic astrocytoma patients relative to glioblastoma patients. World Neurosurg. 2016;90:186-193.
10. Hirsch FR, Varella-Garcia M, Bunn PA Jr. Epidermal growth factor receptor in non-smallcell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 2003;21:3798-3807.
3. Burks JD, Bonney PA, Glenn CA, Conner AK, Briggs RG, Ebeling PA, et al. Symptom resolution in infiltrating WHO grade II-IV glioma patients undergoing surgical resection. J Clin Neurosci. 2016; 31:157-161.
7. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 20072011. Neuro-Oncol. 2014;16(suppl 4):iv1-iv63.
11. Kantola S, Parikka M, Jokinen K. Prognostic factors in tongue cancer—relative importance of demographic, clinical and histopathological factors. Br J Cancer. 2000;83:614-619.
4. Duffau H, Taillandier L. New concepts in the management of diffuse low-grade glioma: proposal of a multistage and individualized therapeutic approach. Neuro-Oncol. 2015;17:332-342.
8. SEER Appendix C. Site Specific Coding Modules. (n.d.). Available at: http://seer.cancer.gov/ manuals/2013/appendixc.html. Accessed October 20, 2016.
12. Kraay MJ, Figgie MP, Inglis AE, Wolfe SW, Ranawat CS. Primary semiconstrained total elbow arthroplasty. Survival analysis of 113 consecutive cases. J Bone Joint Surg Br. 1994;76:636-640.
REFERENCES 1. Markiewicz I, Lukomska B. The role of astrocytes in the physiology and pathology of the central nervous system. Acta Neurobiol Exp. 2006;66: 343-358.
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13. Hardesty DA, Sanai N. The value of glioma extent of resection in the modern neurosurgical era. Front Neurol. 2012;3:140. 14. Duffau H. A new philosophy in surgery for diffuse low-grade glioma (DLGG): oncological and functional outcomes. Neuro-Chirurgie. 2013;59:2-8. 15. McGirt MJ, Chaichana KL, Attenello FJ, Weingart JD, Than K, Burger PC, et al. Extent of surgical resection is independently associated with survival in patients with hemispheric infiltrating low-grade gliomas. Neurosurgery. 2008;63:700-707. 16. Smith JS, Chang EF, Lamborn KR, Chang SM, Prados MD, Cha S, et al. Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol. 2008;26: 1338-1345.
GTR IN WHO GRADE II ASTROCYTOMAS: SURVIVAL ANALYSIS
17. Jakola AS, Myrmel KS, Kloster R, Torp SH, Lindal S, Unsgård G, et al. Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA. 2012;308:1881-1888. 18. Cancer Genome Atlas Research Network, Brat DJ, Verhaak RGW, Aldape KD, Yung WKA, Salama SR, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372:2481-2498. 19. Wang PF, Liu N, Song HW, Yao K, Jiang T, Li SW, et al. IDH-1R132H mutation status in diffuse glioma patients: implications for classification. Oncotarget. 2016;7:31393-31400. 20. Wedding U, Honecker F, Bokemeyer C, Pientka L, Höffken K. Tolerance to chemotherapy in elderly patients with cancer. Cancer Control. 2007;14:44-56.
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21. Given B, Given CW. Older adults and cancer treatment. Cancer. 2008;113(suppl 12):3505-3511.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 5 January 2017; accepted 29 March 2017 Citation: World Neurosurg. (2017) 103:741-747. http://dx.doi.org/10.1016/j.wneu.2017.03.140 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.
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