Survival and Prognostic Factors of Anaplastic Gliomas
Nuño, Miriam PhD; Birch, Kurtis MD; Mukherjee, Debraj MD, MPH; Sarmiento, J. Manuel BA; Black, Keith L. MD; Patil, Chirag G. MD, MS
Center for Neurosurgical Outcomes Research, Maxine Dunitz Neurosurgical Institute, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California
Correspondence: Chirag G. Patil, MD, MS, Center for Neurosurgical Outcomes Research, Maxine Dunitz Neurosurgical Institute, Department of Neurosurgery, Cedars-Sinai Medical Center, 8631 W. Third Street, Ste 800E, Los Angeles, CA 90048. E-mail: email@example.com
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.neurosurgery-online.com)
Received December 19, 2012
Accepted May 16, 2013
BACKGROUND: The prognosis of patients with anaplastic glioma tumors is relatively favorable compared with patients with glioblastoma multiforme.
OBJECTIVE: To estimate survival differences between anaplastic astrocytoma (AA) and anaplastic oligodendroglioma (AO) patients and factors associated with survival prognosis.
METHODS: A nationwide cohort of grade III glioma patients diagnosed between 1990 and 2008 was studied using the Surveillance, Epidemiology, and End Results registry. Multivariate Cox proportional hazard models evaluated the role of patient and clinical characteristics on overall survival.
RESULTS: A total of 1766 patients with AA and 570 patients with AO were studied. The median overall survival was 15 and 42 months among AA and AO patients, respectively. Age increments of 10 years implicated a 50% increase in mortality hazards among AA (hazard ratio [HR], 1.49; P < .001) and AO (HR, 1.51; P < .001) patients. Among AA patients, radiation (HR, 0.62; P < .001), surgery (vs biopsy; HR, 0.73; P < .001), female sex (HR, 0.87; P = .02), and married status (HR, 0.87; P = .02) were associated with a reduction in the hazard of mortality. Longer survival if diagnosed in 2000 relative to 1990 was observed (HR, 0.84; P = .004) in AA patients. Although surgery did not significantly improve survival among AO patients, gross total resection increased the median survival from 40 to 61 months (P = .001) in this cohort.
CONCLUSION: First-course radiation, younger age, female sex, treatment in recent years, and surgery were associated with improved survival in AA patients. In contrast, age was the most prominent predictor of survival in AO patients. Surgery alone did not seem to benefit AO patients, and gross total resection improved survival by 21 months.
ABBREVIATIONS: AA, anaplastic astrocytoma
AO, anaplastic oligodendroglioma
GTR, gross total resection
KSP, Karnofsky Performance Score
OS, overall survival
RT, radiation therapy
SEER, Surveillance, Epidemiology, and End Results
Gliomas account for 80% of primary malignant brain tumors.1 Grade III astrocyte and oligodendrocyte glial cell--derived tumors are categorized as anaplastic astrocytoma (AA) and anaplastic oligodendroglioma (AO), respectively, according to the World Health Organization classification.2 AA and AO tumors make up 10% to 15%3 and 4% to 7%4 of all gliomas, respectively.
Survival estimates for AA and AO tumors vary widely and seem to be associated with age,5-7 Karnofsky Performance Score (KPS) status,6,8,9 extent of surgical resection,10 use of adjuvant radiotherapy,11 ki-67 immunohistochemical markers,12-14 and sensitivity to chemotherapy as determined by genetic mutations such as IDH1,15 PTEN,16 EGFR amplification,16 and 1p19q codeletion.17 Codeletion of 1p19q among AO patients has been validated as an independent and significant predictor of improved survival.17,18 Estimates of median overall survival (OS) vary widely and range from 4.45 to 65.55 months for AA and 14.4 to 184.418 months for AO tumors, with some AO patients (1p/19q codeleted tumors) demonstrating median survival > 10 years.17,18
Given the limited data available regarding the prognosis of patients with grade III anaplastic gliomas, this study aimed to estimate the survival of AA and AO patients in a large, longitudinal, population-based cohort. Furthermore, we investigated patient and clinical factors associated with improved prognosis among these patients.
PATIENTS AND METHODS
Study Design and Setting
Patients were extracted retrospectively from the Surveillance, Epidemiology, and End Results (SEER) registry database. The SEER registry is maintained by the National Cancer Institute, which has collected incidence and survival data from up to 17 population-based cancer registries covering approximately 26% of the US population since 1973. The database contains information on patient demographics, primary tumor site, histology, stage at diagnosis, treatment regimens including surgery, extent of surgical resection, and radiation therapy (RT) as a first course of treatment, as well as date of death. Our cohort included patients in all 17 registries from the SEER database between 1990 and 200819 who met our inclusion criteria. To reduce bias involved in the diagnostic classification of AA vs AO tumors, this study included only patients who were diagnosed after 1990. Because the agreement in the histological classification of mixed grade III glioma (anaplastic oligoastrocytoma) is low (13%) compared with AA (76%) and AO (69%) tumors, we further excluded patients with anaplastic oligoastrocytoma tumors in this study.20
Participants and Study Size
We identified adult patients (> 18 years of age) diagnosed with AA and AO according to the International Classification of Disease for Oncology, Third Edition histology codes (9401 for AA and 9451 for AO); associated primary site codes included C710 through C714, C717 through C719, and C720 through C725 (brain and cranial nerves); C716 (cerebellum); C715 (ventricle); and C753 (pineal gland). Only patients with microscopic confirmation of disease were included. A total of 2336 grade III glioma patients met the inclusion criteria; among these, 1766 had AA and 570 had AO.
Patient demographics included a patient age (categorized in decade increments), sex (male or female), race (white, black, or other), and marital status (single, married, divorced, and other, which includes separated, widowed, or unknown). Clinical variables included the number of tumor primaries (single vs multiple), tumor location (cerebrum, cerebellum, ventricle, pineal gland), postoperative RT, extent of surgical resection (biopsy, partial resection, gross total resection [GTR], or surgery not otherwise specified), and year of diagnosis (categorized into decades, 1990 and 2000s). A biopsy involved the incisional, needle, or aspiration biopsy of the primary tumor site; partial resection denoted local tumor destruction, subtotal/partial resection, or excision of primary tumor; GTR denoted total/radical resection of primary site. Data regarding the use of adjuvant chemotherapy were not available in the SEER database.
The primary outcome of interest was survival. Survival was calculated as the time from diagnosis to the date of death or last follow-up. Observations were censored when a patient was alive at the time of last follow-up.
Univariate and multivariate analyses of survival were conducted for AA and AO patients independently. The χ2 and 2-sided t tests evaluated associations for binary and continuous outcome variables, respectively. OS distributions were compared by Kaplan-Meir estimates (log-rank test). Multivariate survival analysis evaluated predictors of survival using a Cox proportional hazards model. Adjusted hazard ratios (HRs), 95% confidence intervals, and corresponding P values were reported. A value of P ≤ .05 was considered to be statistically significant. All analyses were conducted with SAS software (version 9.2; SAS Inc, Cary, North Carolina). Race was missing in 0.3% of patients.
Participants and Descriptive Data
A total of 2336 patients with grade III anaplastic gliomas were identified between 1990 and 2008 (AA, 1766; AO, 570). Age (mean, 52.6 vs 49.5 years; P = .001), sex (male, 56.5% vs 57.4%; P = .70), and race (white, 88.9% vs 88.6%; P = .80) were similar in AA and AO patients, respectively (Table 1). A total of 1370 (77.5%) and 336 (59.0%) AA and AO patients, respectively, died during the study period. The median age for AA and AO patients was 52 and 48 years, respectively. Most patients were married (approximately 65%), had cerebral tumors (> 95%), and received RT (> 65%). Significantly fewer patients underwent GTR in the AA cohort compared with the AO cohort (18.5% vs 36.1%; P < .001).
Outcome Data: OS
The median OS was significantly longer in AO patients than in AA patients (42 vs 15 months; P < .001; Figure 1). Survival rates at 1 year were 74.4% in AO and 55.0% in AA patients. Three- and 5-year survival rates for AO patients were 54.1% and 43.1%, respectively. In contrast, 3- and 5-year survival rates for AA patients were 30.7% and 22.8% (P < .001; Table 2).
Outcome Data: The Impact of Radiation on OS
AA patients were more likely to receive RT than AO (77.6% vs 65.1%). Patients who were treated most aggressively (GTR and radiation) had by far the best survival benefit, particularly in the AA cohort. The median OS for AA patients undergoing GTR and radiation was 48 months compared with 18 and 4 months for RT and non-RT patients, respectively, independently of surgery (log-rank P < .001; Figure 2, top). Smaller differences in survival across all treatment cohorts (GTR + RT, RT, and no RT) were observed among AO patients (log-rank P = .02; Figure 2, bottom). Specific cohort comparisons showed that GTR + RT vs no RT (P = .01) and GTR + RT vs RT alone (P = .02) were the only significant comparisons in AO patients. RT alone, independently of extent of resection, increased survival in AA and AO patients by 14 months (log-rank P < .001) and 3 months (log-rank P = .1), respectively.
Confounder-adjusted analysis for AA patients showed that older age, male sex, lack of postoperative radiation, surgical biopsy vs resection, and older decade of treatment were significantly associated with shorter survival (Table 3). A decade increment in age increased the hazard of death by 49% (HR, 1.49; P < .001). Female patients (HR, 0.87; P = .02), married patients (HR, 0.87; P = .02), patients undergoing postoperative RT (HR, 0.62; P < .001), and those having surgical resection (HR, 0.73; P < .001) had lower risk of mortality than male, unmarried, nonirradiated, and biopsy patients, respectively. Patients treated during 2000 to 2008 compared with 1990 to 1999 had a 16% reduction in the hazard of mortality (HR, 0.84; P = .05).
In confounder-adjusted analysis of AO patients, we found that a 10-year age increment significantly increased the hazards of death (HR, 1.51; P < .001; Table 3). Although surgical resection among AO patients did not seem to confer a survival benefit (HR, 1.03; P = .79), undergoing GTR vs biopsy/partial resection improved the median survival from 40 to 61 months (P = .001).
We used the SEER database to analyze a large cohort of 2336 adult patients diagnosed with AA or AO between 1990 and 2008. The median OS of AO patients (42 months) was significantly longer than that for AA patients (15 months). The 5-year survival rate for AO patients was 43% compared with only 23% for AA patients. Younger age, female sex, married status, postoperative radiation, surgical resection (vs biopsy), and later decade of treatment were associated with improved survival in AA patients. Among AO patients, younger age and GTR rather than surgery (biopsy, partial resection) were the only factors significantly associated with survival. Although RT improved survival in AA patients, this finding was not significant among AO patients.
Key Results and Interpretation
Predictors of Survival Among Patients With Anaplastic Astrocytoma
Numerous retrospective and prospective studies over the past 20 years have helped to define factors associated with OS among patients with anaplastic gliomas (see Table 1, Supplemental Digital Content 1, http://links.lww.com/NEU/A555). These single- and multi-institution studies have shown that age, extent of surgical resection, KPS, tumor enhancement, and in some cases chromosome-7 deletions are among some of the factors associated with survival. The most common positive predictor of survival for AAs5,6,10,21-24 and AOs6,18,23,25 among these studies is young age. A large case series reported by Prados et al10 included 357 patients with AAs treated according to several protocols over 12 years in northern California. This study reported a median OS of 39.3 months and that only young age and high KPS score had a positive influence on survival and on time to first tumor progression.10 Of note, extent of surgical resection was analyzed in this study but did not hold a statistically significant relationship with survival. Our study substantiated previously reported prognostic factors pertaining to patients with anaplastic gliomas but also evaluated less known factors such as sex, marital status, and improvements in the modern management of malignant gliomas over the last 2 decades.
Predictors of Survival Among Patients With AO
Over the past 10 years, particularly after the identification of the loss of heterozygosity on chromosome arms 1p and 19q,18 a significant predictive and prognostic marker among oligodendrogliomas, myriad studies have been analyzed to further assess the influence of patient- and treatment-centered factors on survival of AO patients (see Table 1, Supplemental Digital Content 1, http://links.lww.com/NEU/A555). Patient age, extent of surgical resection, KPS, RT, chemotherapy, and tumor enhancement are some of the factors previously studied in association with survival.6,18,23,25-29 Younger patients (< 50 years of age) were found to have a 56-month survival compared with 15 months among older patients (≥ 50 years of age)25; in our study, younger (< 50 years of age) and older (≥ 50 years of age) patients achieved a median OS of 82 and 17 months, respectively. GTR vs biopsy (independently of RT) increased median survival from 40 to 61 months. Improvements in median OS were observed in the Nagy et al30 cohort in patients with GTR (vs biopsy); however, direct comparison with our estimates cannot be made because their cohort includes AA and AO tumors.
Extent of Surgical Resection
Although some studies such as that by Prados et al10 did not find a relationship between extent of surgical resection and survival, several other retrospective studies have linked aggressive surgical resection with improved survival in patients with anaplastic gliomas.21,23,24,30,31 Nomiya et al21 analyzed survival outcomes and prognostic factors for 170 patients with AA and found that patients who underwent total or subtotal resection had a significantly more favorable prognosis than did patients who underwent partial resection or biopsy. Two other studies reported incremental improvements in overall median survival with increased extent of surgical resection among patients with histologically different anaplastic gliomas (pure AA vs anaplastic oligoastrocytoma vs AO).23,30 Nagy et al30 reported a median OS of 32 months after GTR, 36 months after subtotal resection, and 12 months after biopsy.
Although our multivariable analysis showed that surgical resection significantly reduced the risk of mortality compared with biopsy for AA patients (HR, 0.33; P < .001), this effect was not observed in the AO cohort (HR 1.03; P = .79). However, a survival benefit among AO patients was observed after achieving GTR compared with biopsy. The median OS for biopsy, partial resection, and GTR in this cohort was 40, 42, and 61 months, respectively. In AA patients, a consistent improvement in the median survival was observed of 10, 21, and 47 months with biopsy, partial resection, and GTR, respectively. The small survival benefit observed among AO patients undergoing partial resection compared with biopsy may be due to the general treatment responsiveness previously documented in this cohort.
Impact of RT
RT has been shown to provide significant improvement in survival for AA patients in prior retrospective studies32,33; however, the benefits associated with this treatment modality for AO patients have been inconclusive.27,28,30,34 Some studies have shown a moderately favorable median OS for patients with AA (7 months, inclusive of biopsies and partial resections) and AO (47 months, inclusive of biopsies and partial resections) after postoperative RT,30 whereas others seem to suggest that AO tumors harboring the 1p/19q deletion may be exclusively treated with chemotherapy.34 Although the Iwadate et al34 cohort of 25 AO patients showed longer progression-free survival among 1p/19q codeletion patients and a 62.2% 5-year OS rate for all patients, this study had a median follow-up period of 3 years and fails to provides definite evidence for the role of chemotherapy as exclusive treatment for AO patients. A more likely treatment scenario would be to consider upfront chemotherapy to delay RT, particularly among patients with 1p19p codeleted tumors. Two prominent randomized controlled trials, one by the Radiation Therapy Oncology Group and the other by the European Organization for Research and Treatment of Cancer, showed that adjuvant RT plus procarbazine, lomustine, and vincristine chemotherapy does not improve OS compared with RT alone among AO patients without 1p/19q codeletion.27,28 However, this aggressive treatment strategy did improve progression-free survival, albeit at the expense of significant toxicities. In a 1p19q codeletion--specific analysis of AO and anaplastic oligoastrocytoma patients, Cairncross et al17 recently showed that survival increased in patients treated with RT alone vs procarbazine, lomustine, and vincristine + RT (from 2.6 to 14.7 years). The unavailability of details on possible allelic losses on chromosomes arms 1p and 19q in our patient population prevents us from fully assessing this observed survival disparity after RT. Our study results are consistent with reports in the literature showing a survival advantage in AA patients who undergo RT compared with those who are not irradiated. Moreover, our results indicate that postoperative RT trended toward conferring a survival benefit in AO patients. This survival benefit, however, was not statistically significant. A possible explanation for this result may be the inability to adjust for important prognostic factors that determine treatment response as previously described (1p/19q deletion status). Lastly, the lower rate of RT among AO patients compared with AA patients may be explained by the large variability in practice patterns and the lack of uniform guidelines in treating AOs.
Multiple studies have recently shown marital status to be an independent predictor of survival for patients with cancer.35-37 Interestingly, married patients treated for testicular cancer,36 pancreatic cancer,37 and non--small-cell lung cancer35 had longer survival times than their unmarried counterparts. A possible explanation for these findings is that marriage may be a surrogate for better supportive care and compliance with treatment. Our study found that AA patients who were married may have a reduced risk of death compared with those who were unmarried. AO patients showed a nonsignificant trend toward the same outcome (HR, 0.83; P = .11). This finding emphasizes the importance of social support in the treatment and management of cancer patients and suggests that marital status may influence the survival of patients with more indolent forms of anaplastic gliomas.
Our study has some limitations, including a lack of available data on KPS scores, molecular markers (eg, 1p/19q deletion status), adjuvant chemotherapeutic regimens, and total postoperative radiation. Another limitation of the study is the inaccuracy with which AA and AO were classified in the 1970s and 1980s, a system that has since evolved and improved over the years.38 To this end, the present study opted to include only cases diagnosed between 1990 and 2008, even though initial analysis involved a larger cohort (1973-2008); a preliminary analysis of all cases showed a ratio of AA vs AO tumor classification in 1970 and 1980 not consistent with recent years (1990-2008; Table 4). Although tumor classification is an inherent limitation of the database, we are confident that including cases diagnosed after 1990 and excluding mixed anaplastic glioma cases significantly reduced the uncertainty involved with coding without compromising the external validity of the present study. Mixed glioma cases were excluded because, as documented by Van den Bent,20 agreement across neuropathologists was 13% and agreement for AA and AO tumors was 76% and 69%, respectively. Additional confirmation of the agreement between AA and AO tumors rates documented in the present study (SEER database) with our institution cohort (2000-2011) of grade III glioma showed a 72.6% and 27.4% rate of AA and AO cases, respectively. These rates are comparable to the SEER cases documented in this study (AA, 75.6%; AO, 24.4%).
We have described in detail the overall prognosis of patients with AA and AO tumors in a large, national cohort using the SEER registry. In addition, we have validated previously described prognostic factors for AA patients such as younger age, surgical resection, and RT to be positively associated with survival. Furthermore, we found that female patients, married patients, and more recently treated patients with AA have better survival. Among AO patients, younger age and GTR were the most significant predictors of improved survival.
Survival estimates for patients with anaplastic glioma (AA, AO) vary widely and seem to be associated with patient demographics, clinical factors, and biomarkers, among others. This uniquely large study showed that predictors of survival vary significantly between the AA and AO cohorts. RT given as a first course of treatment, age, sex, decade of treatment, and surgery were significantly associated with OS among AA patients. Aside from age, AO patients were generally less responsive to surgical and RT benefits as observed in the AA cohort.
The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
1. Ricard D, Idbaih A, Ducray F, Lahutte M, Hoang-Xuan K, Delattre JY. Primary brain tumours in adults. Lancet. 2012;379(9830):1984–1996.
2. Louis DN, Ohgaki H, Wiestler OD, et al.. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97–109.
3. Chamberlain MC, Chowdhary SA, Glantz MJ. Anaplastic astrocytomas: biology and treatment. Expert Rev Neurother. 2008;8(4):575–586.
4. Chowdhary S, Chamberlain MC. Oligodendroglial tumors. Expert Rev Neurother. 2006;6(4):519–532.
5. Perry A, Jenkins RB, O'Fallon JR, et al.. Clinicopathologic study of 85 similarly treated patients with anaplastic astrocytic tumors: an analysis of DNA content (ploidy), cellular proliferation, and p53 expression. Cancer. 1999;86(4):672–683.
6. Tortosa A, Viñolas N, Villà S, et al.. Prognostic implication of clinical, radiologic, and pathologic features in patients with anaplastic gliomas. Cancer. 2003;97(4):1063–1071.
7. Keles GE, Chang EF, Lamborn KR, et al.. Volumetric extent of resection and residual contrast enhancement on initial surgery as predictors of outcome in adult patients with hemispheric anaplastic astrocytoma. J Neurosurg. 2006;105(1):34–40.
8. Compostella A, Tosoni A, Blatt V, Franceschi E, Brandes AA. Prognostic factors for anaplastic astrocytomas. J Neurooncol. 2007;81(3):295–303.
9. McGirt MJ, Chaichana KL, Gathinji M, et al.. Independent association of extent of resection with survival in patients with malignant brain astrocytoma. J Neurosurg. 2009;110(1):156–162.
10. Prados MD, Gutin PH, Phillips TL, et al.. Highly anaplastic astrocytoma: a review of 357 patients treated between 1977 and 1989. Int J Radiat Oncol Biol Phys. 1992;23(1):3–8.
11. Liang BC, Thornton AF, Sandler HM, Greenberg HS. Malignant astrocytomas: focal tumor recurrence after focal external beam radiation therapy. J Neurosurg. 1991;75(4):559–563.
12. Korshunov A, Golanov A, Sycheva R. Immunohistochemical markers for prognosis of anaplastic astrocytomas. J Neurooncol. 2002;58(3):203–215.
13. Li S, Yan C, Huang L, Qiu X, Wang Z, Jiang T. Molecular prognostic factors of anaplastic oligodendroglial tumors and its relationship: a single institutional review of 77 patients from China. Neuro Oncol. 2012;14(1):109–116.
14. Sallinen PK, Haapasalo HK, Visakorpi T, et al.. Prognostication of astrocytoma patient survival by Ki-67 (MIB-1), PCNA, and S-phase fraction using archival paraffin-embedded samples. J Pathol. 1994;174(4):275–282.
15. Hartmann C, Hentschel B, Wick W, et al.. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol. 2010;120(6):707–718.
16. Smith JS, Tachibana I, Passe SM, et al.. PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst. 2001;93(16):1246–1256.
17. Cairncross G, Wang M, Shaw E, et al.. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31(3):337–343.
18. Parkinson JF, Afaghi V, Payne CA, et al.. The impact of molecular and clinical factors on patient outcome in oligodendroglioma from 20 years’ experience at a single centre. J Clin Neurosci. 2011;18(3):329–333.
19. Surveillance, Epidemiology, and End Results (SEER) Program. http://www.seer.cancer.gov
. SEER*Stat Database: Incidence—SEER 17 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2010 Sub (1973–2008 varying)—Linked to County Attributes—Total U.S., 1969–2009 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, Released April 2011; updated October 28, 2011; based on the November 2010 submission. Accessed April 20, 2013.
20. van den Bent MJ. Interobserver variation of the histopathological diagnosis in clinical trials on glioma: a clinician’s perspective. Acta Neuropathol. 2010;120(3):297–304.
21. Nomiya T, Nemoto K, Kumabe T, Takai Y, Yamada S. Prognostic significance of surgery and radiation therapy in cases of anaplastic astrocytoma: retrospective analysis of 170 cases. J Neurosurg. 2007;106(4):575–581.
22. Chaichana KL, Kosztowski T, Niranjan A, et al.. Prognostic significance of contrast-enhancing anaplastic astrocytomas in adults. J Neurosurg. 2010;113(2):286–292.
23. Shirai K, Suzuki Y, Okamoto M, et al.. Influence of histological subtype on survival after combined therapy of surgery and radiation in WHO grade 3 glioma. J Radiat Res. 2010;51(5):589–594.
24. Scoccianti S, Magrini SM, Ricardi U, et al.. Radiotherapy and temozolomide in anaplastic astrocytoma: a retrospective multicenter study by the Central Nervous System Study Group of AIRO (Italian Association of Radiation Oncology). Neuro Oncol. 2012;14(6):798–807.
25. Yang LS, Huang FP, Zheng K, et al.. Factors affecting prognosis of patients with intracranial anaplastic oligodendrogliomas: a single institutional review of 70 patients. J Neurooncol. 2010;100(1):113–120.
26. Cairncross JG, Ueki K, Zlatescu MC, et al.. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst. 1998;90(19):1473–1479.
27. Intergroup Radiation Therapy Oncology Group Trial 9402; Cairncross G, Berkey B, Shaw E, et al.. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006;24(18):2707–2714.
28. van den Bent MJ, Carpentier AF, Brandes AA, et al.. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006;24(18):2715–2722.
29. Lassman AB, Iwamoto FM, Cloughesy TF, et al.. International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro Oncol. 2011;13(6):649–659.
30. Nagy M, Schulz-Ertner D, Bischof M, et al.. Long-term outcome of postoperative irradiation in patients with newly diagnosed WHO grade III anaplastic gliomas. Tumori. 2009;95(3):317–324.
31. Tanaka Y, Nobusawa S, Yagi S, Ikota H, Yokoo H, Nakazato Y. Anaplastic oligodendroglioma with ganglioglioma-like maturation. Brain Tumor Pathol. 2012;29(4):221–228.
32. Walker MD, Green SB, Byar DP, et al.. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980;303(23):1323–1329.
33. Walker MD, Alexander E, Hunt WE, et al.. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial. J Neurosurg. 1978;49(3):333–343.
34. Iwadate Y, Matsutani T, Shinozaki N, Saeki N. Anaplastic oligodendroglial tumors harboring 1p/19q deletion can be successfully treated without radiotherapy. Anticancer Res. 2011;31(12):4475–4479.
35. Nichols EM, Liriano M, Garofalo M, et al.. Marital status is an independent predictor of survival for patients undergoing definitive chemoradiation for stage III non-small cell lung cancer. In:Chicago Multidisciplinary Symposium in Thoracic Oncology 2012. 2012;84(3):S566–S567.
36. Abern MR, Dude AM, Coogan CL. Marital status independently predicts testis cancer survival: an analysis of the SEER database. Urol Oncol. 2012;30(4):487–493.
37. Baine M, Sahak F, Lin C, Chakraborty S, Lyden E, Batra SK. Marital status and survival in pancreatic cancer patients: a SEER based analysis. PLoS ONE. 2011;6(6):e21052.
38. Kleihues P, Burger PC, Scheithauer BW. The new WHO classification of brain tumours. Brain Pathol. 1993;3(3):255–268.
This interesting article evaluates survival and its association with clinical factors in patients with anaplastic gliomas between 1990 and 2008. This era witnessed extraordinary evolution in our understanding of and approach to anaplastic gliomas, including the recognition that anaplastic oligodendrogliomas were chemosensitive to procarbazine, lomustine, and vincristine; the development and approval of temozolomide for recurrent anaplastic glioma; and the appreciation that prognosis in anaplastic glioma was much more strongly associated with 1p/19q deletion status than to histological classification. The last observation has functionally transformed the oncologic approach to anaplastic gliomas. Anaplastic gliomas are now split into codeleted vs noncodeleted tumors in terms of clinical trials, regardless of whether the cell type is oligodendroglial or astrocytic.1 Similarly, it is now clear that codeleted anaplastic gliomas should receive chemotherapy along with radiation therapy, whereas this remains unproven for noncodeleted tumors.2,3
This reality highlights one of the major weaknesses of the Surveillance, Epidemiology, and End Results database on which this manuscript relies: the absence of molecular/cytogenetic data. The lack of any data regarding chemotherapy represents another substantial limitation; over the last decade of this study, some patients with anaplastic oligodendroglioma likely received chemotherapy before radiation. This may explain the observed lower rate of radiation in the anaplastic oligodendroglial population. For anaplastic astrocytoma, the better survival for diagnosis after 2000 relative to the 1990s may reflect the impact of temozolomide, approved for recurrent anaplastic gliomas in 1999. We are ready for incorporation of well-validated molecular markers into the next World Health Organization brain tumor classification.4
1. Schiff D. Temozolomide and radiation in low-grade and anaplastic gliomas: temoradiation. Cancer Invest. 2007;25(8):776–784. PubMed | CrossRef Cited Here... |
2. Cairncross G, Wang M, Shaw E, et al.. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31(3):337–43. PubMed | CrossRef Cited Here... |
3. van den Bent MJ, Brandes AA, Taphoorn MJ, et al.. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31(3):344–350. PubMed | CrossRef Cited Here... |
4. Louis DN. The next step in brain tumor classification: “Let us now praise famous men”? Or molecules? Acta Neuropathol. 2012;124(6):761–76. Cited Here...
The authors are to be commended for providing a well-organized, concise, and well-written retrospective multivariate analysis of the prospective Surveillance, Epidemiology, and End Results (SEER) database over an extended period of acquisition and patient follow-up. Although few of their conclusions are new or surprising, the study provides us with reliable, useful, baseline data for designing future studies and making historical comparisons.
The authors try to mitigate the temporal issue of “histological drift” towards the diagnosis of oligodendroglioma once the potential chemotherapeutic sensitivity of oligodendrogliomas relative to astrocytomas was recognized in a series of publications between 1988 and 1992 by restricting their analysis to post-1990 cases. However, this cannot account for the remaining marked institutional variability in calling an anaplastic glioma an anaplastic astrocytoma (AA) vs an anaplastic oligodendroglioma (AO). Just for fun, in 2000, we sent 6 of our anaplastic glioma specimens for second opinions to 2 of the top brain tumor neuropathology divisions in the country. One called 5 of 6 AOs and the other 5 of 6 AAs (they agreed on only 1 in 6). There is also no accounting for mixed AA/AO or AO/AA in this study, presumably because this is not accounted for in the SEER database. Thus, consistency of histological interpretation both over time and between institutions and inability of this study to say anything about mixed anaplastic gliomas remain issues.
The second histological bias that cannot be removed from the SEER database involves the major World Health Organization (WHO) diagnostic change in 2000 for astrocytomas. Before 2000, without necrosis present, a glioma would only qualify for grade III. After 2000, necrosis was no longer required by WHO, thus expanding the grade IV (glioblastoma multiforme) category to include many tumors that previously would have been called grade III. Thus, although their noted improvement in outcome statistics for AA after the year 2000 may reflect better and more consistent therapeutic intervention, it is impossible to sort out whether it might solely be accounted for by eliminating probable glioblastoma multiforme from the category after 2000 based on the WHO grading criteria change.
The authors correctly point out that the SEER database is unfortunately silent on potentially correlative molecular data such as EGFRviii, IDH1, 1p, 19q, and PTEN that would be of significant interest for response to therapy subset analysis.
Ultimately, age and histology remain the dominant risk factors correlating with patient malignant glioma outcome as confirmed in this study. As a retrospective study, it is less reliable for assessing the impact of surgical resection. At most of the 17 relatively large, academically advanced centers contributing to the SEER database, I suspect that most of the neurosurgeons approached their patients with an intent toward maximal safe resection. Thus, failure to achieve radical resection most likely selectively biased the subtotal resection residual component and biopsy groups to deep and eloquent brain locations or the very infirm and/or elderly. Deep and eloquent brain location, as well as functional status, which correlates with these other variables, not only confound one another but also have been independently identified as variables correlating with outcome in other studies. Age was shown to be the major correlating variable in this study.
The most surprising and potentially interesting correlations identified in this study include the absence of a significant therapeutic effect of radiotherapy for AO and the correlations of outcome with female and married patients. The former is hard to rationalize given the higher likelihood of 1p-19q defects in AO vs AA and the association of 1p-19q loss with response to either chemotherapy or radiotherapy. The last 2 findings suggest the need for further study of these issues, particularly as they affect quality of life, patient support systems throughout their illness, and compliance with prescribed therapy.
Mark E. Linskey
This is a large population-based patient cohort that attempts to describe overall survival of patients with grade III gliomas. Furthermore, the authors analyze patient characteristics and clinical factors associated with better prognosis. The strength of the article is the large number of patients studied. The major weakness is that the data are retrospective and do not take into consideration contemporary prognostic biomarkers such as 1p19 loss of heterozygosity or IDH-1 mutation that have proven so important for patients with anaplastic oligodendroglioma. Overall, this article is informative, especially for general survival data for these tumors. However, in the modern era of molecular biomarker analysis, the robustness of this data is less clear. An anaplastic oligodendroglioma with 1p19q deletion and IDH-1 mutation is a completely different tumor than an anaplastic oligodendroglioma with no loss of heterozygosity at 1p19q and intact IDH-1. The same holds true for making survival predictions when lumping together the very differently behaving anaplastic astrocytoma or mixed anaplastic oligoastrocytoma compared with anaplastic.
Salt Lake City, Utah
1. What genetic mutation has been shown to independently correlate with improved survival in anaplastic astrocytic tumors?
b. 1p19q co-deletion
2. In patients with anaplastic oligodendrogliomas, which of the following factors favors improved survival?
a. Gross-total resection
b. Biopsy/partial resection
c. Pre-operative seizures
d. Age > 50
3. What is the impact of postoperative radiotherapy on survival in anaplastic astrocytomas (AA) and anaplastic oligidendrogliomas (AO)?
a. Equally effective in AA and AO
b. More effective in AA
c. More effective in AO
d. Ineffective in both
Anaplastic astrocytoma; Anaplastic oligodendroglioma; Overall survival; Progression-free survival
Supplemental Digital Content
Copyright © by the Congress of Neurological Surgeons
Highlight selected keywords in the article text.