Improved Survival after Gross Total Resection of Malignant Gliomas in Pediatric Patients from the HIT-GBM Studies

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1 Improved Survival after Gross Total Resection of Malignant Gliomas in Pediatric Patients from the HIT-GBM Studies CHRISTOF M. KRAMM 1, SABINE WAGNER 2, STEFAN VAN GOOL 3, HANSJÖRG SCHMID 4, RONALD STRÄTER 5, ASTRID GNEKOW 6, STEFAN RUTKOWSKI 7 and JOHANNES E. A. WOLFF 8,9 1 Department of Pediatric Oncology, Hematology & Immunology, University Children s Hospital, Duesseldorf; 2 Department of Pediatric Hematology & Oncology, St. Hedwig Hospital, University of Regensburg, Regensburg, Germany; 3 Department of Pediatric Hematology & Oncology, University of Leuven, Belgium; 4 Department of Pediatric Hematology & Oncology, University Medical School of Hannover; 5 Department of Pediatric Hematology & Oncology, University of Münster; 6 Children s Hospital, Klinikum Augsburg, Augsburg; 7 Pediatric Oncology, University of Würzburg, Würzburg, Germany; 8 Department of Pediatric, MD Anderson Cancer Center, Houston, TX, U.S.A.; 9 Alberta Children s Hospital, University of Calgary, Calgary, AB, Canada Abstract. The present study was performed to investigate the prognostic impact of tumor resection on survival in children and adolescents with malignant gliomas. From the HIT-GBM data base of the Gesellschaft für Paediatrische Onkologie und Haematologie (GPOH), 85 pediatric patients with malignant non-pontine gliomas were analyzed. Histological diagnosis and extent of tumor resection had been confirmed by central neuropathological review and post-surgical imaging. The extent of tumor resection represented the most prominent prognostic factor for overall (OS) and event-free survival (EFS) in univariate and Cox regression analyses. Four-year survival after gross total tumor resection was 48.0±12.0% (OS) and 14.1±8.9% (EFS), after non-total resection 13.2±6.1% and 2.9±2.8%, respectively. From several clinical parameters, only histological grading displayed a similar statistical significance in Cox regression analysis. In conclusion, gross total tumor resection improves survival in pediatric patients with malignant gliomas and should always be attempted when possible. Malignant high grade gliomas, including glioblastoma multiform and anaplastic astrocytoma, account only for a small subgroup of brain tumors in pediatric patients, but Correspondence to: Johannes E. A. Wolff, Professor, MD Anderson Cancer Center, University of Texas, Department Pediatrics, Section Ped. Neurooncology, 1515 Holcombe Blvd, Unit 87, Houston, TX 77030, U.S.A. Tel: (+1) , Fax (+1) , jwolff@mdanderson.org Key Words: Neurosurgery, tumor resection, glioblastoma, anaplastic astrocytoma, malignant glioma, survival. have mostly proven resistant to a variety of multimodal oncological strategies. This unsatisfying therapeutic situation has initiated an ongoing discussion about the necessary extent of surgical intervention. Even for the population of adult patients with a much higher incidence of these tumors, conclusions from various studies remain controversial with different expert groups favoring either aggressive tumor resection or minimal invasive strategies (1-5). Pediatric patients with malignant gliomas appear to benefit significantly from gross total tumor resection with an improvement of survival (6-10). However, all these studies were performed within a quite similar North- American patient population and may also reflect some patient overlapping. Since the therapeutic impact of total tumor resection for malignant gliomas is still not generally accepted even among pediatric neuro-oncologists and neuro-surgeons, a re-evaluation of this very important question within the pediatric patient population of the German HIT-GBM studies was attempted (11). Patients and Methods Patients characteristics and inclusion/exclusion criteria. Patient data were obtained from the HIT-GBM data base of the Brain Tumor Study Group of the Society of Pediatric Oncology and Hematology in Germany, Austria and Switzerland (Gesellschaft fuer Paediatrische Onkologie und Haematologie, GPOH) (11). Informed consent from all patients and/or legal guardians had been given for statistical analyses at the time of their enrollment into the various GPOH brain tumor trials (12-16). Inclusion and exclusion criteria were defined for the present study, as follows: /2006 $

2 a) Inclusion criteria: WHO grade III or IV glioma proven by central neuropathological review (Institute of Neuropathology, University of Bonn, Bonn, Germany); patient age 0-18 years; diagnosis prior to 2003; known extent of tumor surgery. Gross total tumor resection was defined as 100% macroscopic removal of the tumor mass, no gross total resection as less than 100% tumor removal. No gross total tumor resection included subtotal (<100%, but 90%) and partial (<90%) resection, as well as an open or stereotactic biopsy without tumor debulking. The estimation of the extent of tumor removal was primarily the responsibility of the local neurosurgeons, but was also validated by post-surgical MRI scan review (first post-surgical imaging: median 2 months, range 0-4 months after surgery). Only patients in whom post-surgical imaging results (measurable vs. non-measurable disease) were in concordance with the reported extent of surgery (total vs. non-total tumor resection) were included in the present study. b) Exclusion criteria: tumor location within the brainstem. By applying these criteria, 85 patients were identified. The clinical characteristics of these patients are listed in Table I. Statistical analysis. The statistical analysis was performed using the statistical package for social studies (SPSS Inc, San Francisco, Ca, USA). Overall (OS) and event-free (EFS) survival were determined by Kaplan-Meier analysis and log-rank testing. Patient groups were defined by the following parameters: Gender (male/female), age (<7 years/ 7 years), tumor location (cortex and cerebellum/other and overlapping locations), extent of surgery (no gross total resection/gross total resection), histological grading (WHO grade III/WHO grade IV), chemotherapy (yes/no) and/or radiation therapy (yes/no). Univariate analysis of OS and EFS was performed for all groups. For evaluation of a survival advantage after gross total tumor resection, prognostic relevance of the extent of surgical tumor resection was compared in a subgroup analysis for the subgroups "age, gender, tumor location, histological grading, chemotherapy and radiation therapy" as defined above. Finally, a Cox regression analysis (stepwise entry: 0.05, removal: 0.1, maximal iterations: 20) was performed for resulting subgroups within the total patient population. Results Gross total tumor resection was achieved in 29.4% of all patients (n=25). Among patients with non-total tumor resection (70.6%; n=60), 43.5% (n=37) underwent a subtotal/partial resection, in 27.1% (n=23) only a biopsy was performed (Table I; Figure 1a, b). Interestingly, 39.2% of grade IV patients (n=20), but only 14.3% of grade III patients (n=5) underwent gross total tumor resection. Tumor location had obviously some impact on the extent of surgery. Tumors with a supposedly facilitated neurosurgical access like cortical (frontal, temporal, parietal, or occipital lobe) or cerebellar gliomas underwent more frequently total gross resection than tumors in other brain regions (Table I). In patients with thalamic tumors (n=19; 22.4%), no total tumor resection was performed (subtotal/partial resection: n=12; biopsy: n=7); data not shown). Surgical procedures were obviously not accompanied by an increased mortality risk since no patient died within 4 weeks after surgery (data not shown). Gross total tumor resection provided a significant better OS (p=0.0097; Table II) and EFS (p=0.0033; Table III) than non-total resection in univariate analysis. This was also mostly true when total resection is compared with subtotal/partial resection (EFS: p=0.0234, Figure 1b) or biopsy (OS: p=0.0012, Figure1a; EFS: p=0.0007, Figure 1b). However, the OS comparison between gross total and subtotal/partial resection revealed only a tendency towards better OS of patients with total resection, but did not reach statistical significance (p=0.0639; Figure 1a). Interestingly, patients who underwent subtotal/partial resection also showed a significantly better OS (p=0.0096, Figure 1a) and EFS (p=0.0425, Figure 1b) than biopsy patients emphasizing the impact of tumor debulking in general. Other clinical parameters (gender, age, tumor location, histological grading, radiotherapy and chemotherapy) were also analyzed in an univariate setting. Here, only OS differences between male and female patients (p=0.0360; Table II) and EFS differences between cortical/cerebellar and other/overlapping tumor locations (p=0.0035, Table III) were statistically significant. The impact of gross total tumor resection on OS and EFS was also separately analyzed in various clinical subgroups characterized by gender, age, tumor location, histological grading, radiotherapy and chemotherapy. Here, significant survival differences in comparison to non-total tumor resection were found for most subgroups (Table II: OS: female patients, children 7 years and older, cortical and cerebellar tumors, grade IV tumors, radiotherapy, and chemotherapy. Table III: EFS: female patients, children 7 years and older, grade IV tumors, radiotherapy and chemotherapy). Finally, Cox regression analyses were performed which confirmed the independent impact of gross total tumor resection on OS (p=0.016; Table II) and EFS (p=0.015; Table III). The extent of tumor resection was the most prominent prognostic factor followed by histological grading (OS: p=0.025, Table II; EFS: p=0.016, Table III) and age (EFS: p=0.048, Table III). Discussion The present study strongly confirms the high prognostic significance of gross total tumor resection for pediatric patients with malignant gliomas. Gross total tumor resection represents a prognostic factor, which remains independent from other clinical parameters like gender, age and tumor localization. All data analyses were performed in a population of 85 pediatric patients with malignant gliomas who were identified from the HIT-GBM database of the GPOH in Germany, Austria, and Switzerland. Only patients with central neuropathological review and post-surgical imaging 3774

3 Kramm et al: Improved Survival after Total Glioma Resection Table I. Characteristics of patients with gross total and no gross total tumor resection of high grade gliomas (except pons tumors). Variable Total no. of patients with No. of patients with no No. of patients with high grade glioma gross total resection gross total resection Total number (70.6%) 25 (29.4%) Gender male 50 (58.8%) 36 (60%) 14 (56.0%) female 35 (41.2%) 24 (40%) 11 (44.0%) Age median 11 years 11 years 10 years range 0-18 years 0-18 years 4-16 years HIT-GBM A trial (11, 12) 10 (11.8%) 6 (10%) 4 (16%) HIT-GBM B trial (11, 15) 20 (23.5%) 13 (21.7%) 7 (28%) HIT-GBM C trial (11) 52 (61.2%) 38 (63.3%) 14 (56%) HIT GBM D-Pilot trial (11) 3 (3.5%) 3 (5%) 0 Post-surgical imaging median 2 months 2 months 2 months range 0-4 months 0-4 months 0-4 months Follow-up median 12 months 11 months 16 months range 1-65 months 1-53 months 3-65 months Tumor location cortex/cerebellum 46 (52.4%) 21 (35%) 25 (100%) other and overlapping locations 39 (47.6%) 39 (65%) 0 Histological grading grade III 34 (0%) 29 (48.3%) 5 (20.0%) grade IV 51 (60%) 31 (51.7%) 20 (80.0%) Radiotherapy yes 80 (94.1%) 56 (93.3%) 24 (96.0%) no 3 (3.5%) 3 (5.0%) 0 unknown 2 (2.4%) 1 (1.7%) 1 (4.0%) Chemotherapy yes 79 (5.9%) 55 (91.7%) 24 (96.0%) no 1 (1.2%) 1 (1.7%) 0 unknown 5 (5.9%) 4 (6.7%) 1 (4.0%) confirming the extent of tumor resection were enrolled to increase the reliability and reproducibility of the resulting findings. Furthermore, pediatric patients with pontine gliomas had been explicitly excluded since gross total tumor resection cannot be achieved in these patients. Although earlier studies (7-9, 17) had already suggested a significant survival advantage for pediatric patients after gross total glioma resection, we felt obliged to perform the present study since there is still a quite common fatalistic attitude to treat malignant glioma patients with less aggressive surgery and adjuvant treatment modalities. Furthermore, the previous pediatric studies (7-9, 17) were all performed in a North- American patient population and suggest that there is some patient overlapping. Thus, an independent investigation in a completely different patient population with a representative number of pediatric patients is certainly advisable to further corroborate and distribute the concept of gross total tumor resection in patients with malignant gliomas. As mentioned above, the present study indeed confirmed the marked survival advantage of gross total tumor 3775

4 Figure 1. Kaplan-Meier analysis of overall (OS; 1a) and event-free (EFS; 1b) survival in relation to the extent of tumor surgery in pediatric patients with malignant gliomas. Statistical significances of differences in survival (p values) were determined by log-rank testing. 3776

5 Kramm et al: Improved Survival after Total Glioma Resection Table II. Statistical analysis of overall survival (OS) with regards to total tumor resection. Group definition 1-year OS (%) 4-year OS (%) Univariate Statistical subgroup Cox regression ±SD (%) ±SD (%) analysis analysis in relation analysis to tumor resection (non-total vs. total) Total (n=85) 60.7± ±5.9 Gender p= Not significant male (n=50) 55.5± ±6.7 Not significant female (n=35) 67.7± ±9.7 p= Age Not significant Not significant <7 years (n=17) 55.6±13.6 n.a.* Not significant 7 years (n=67) 63.1± ±6.5 p= Tumor location Not significant p= Not significant cortex and cerebellum (n=46) 69.9± ±8.5 p= other and overlapping locations (n=39) 53.3± ±7.3 n.a.** Histological grading Not significant p=0.025 grade III (n=34) 71.2± ±10.2 n.a.** grade IV (n=51) 54.5± ±7.0 p= Radiotherapy n.a.** n.a.** yes (n=80) 60.1± ±5.8 p= no (n=3) n.a.** n.a.** n.a. ** Chemotherapy n.a.** n.a.** yes (n=79) 60.4± ±6.0 p= no (n=1) n.a.** n.a.** n.a. ** Extent of tumor resection p= p=0.016 no gross total resection (n=60) 55.4± ±6.1 gross total resection (n=25) 73.1± ±12.0 n.a. not applicable. *follow-up of all surviving patients less than 4 years. **no sufficient patient numbers in one or all subgroups. resection for pediatric patients with malignant gliomas. Patients with subtotal or partial tumor resection showed a reduced therapeutic outcome, but still displayed an improved survival in comparison to patients who had only received a biopsy without tumor debulking. There was no mortality observed within 4 weeks after surgery illustrating the safety of the performed surgical procedures. The relatively good therapeutic outcome of children and adolescents with malignant gliomas after gross total tumor resection (4-year OS 48.0±12.0%) indicates that the diagnosis of malignant glioma does not necessarily imply a hopeless prognosis for pediatric patients. Similar survival data are not usually reported for the adult population. Thus, these differences in survival may support the hypothesis that pediatric and adult high grade gliomas represent different biological tumor entities with divergent molecular characteristics (18, 19). However, in a multivariate analysis of 416 adult patients with glioblastoma multiforme (4), a subgroup of patients with young age and good physical performance, showed a similar good overall survival after gross total tumor resection. This finding may indicate that at least some adult malignant gliomas may share certain features with their pediatric counterparts. In the present study, histological tumor grading was also proven to represent a strong independent prognostic factor of EFS and OS, in concordance with Wisoff et al. (8). Interestingly, gender as the third independent prognostic parameter for progression-free survival in that (8) did not reach statistical significance in our own Cox regression analyses for OS and EFS. However, we identified age as an additional independent prognostic factor for EFS. This finding supports the clinical experience that younger children with malignant gliomas may show a different 3777

6 Table III. Statistical analysis of event-free survival (EFS) with regards to total tumor resection. Group definition 1-year EFS (%) 4-year EFS (%) Univariate Statistical subgroup Cox regression ±SD (%) ±SD (%) analysis analysis in relation analysis to tumor resection (non-total vs. total) Total (n=85) 33.8± ±3.5 Gender Not significant Not significant male (n=50) 31.7±7.3 n.a.* Not significant 3 year EFS:5.6±5.1 female (n=35) 36.1± ±5.0 p= Age Not significant p=0.048 <7 years (n=17) 24.2±11.7 n.a.* Not significant 7 years (n=67) 38.3± ±3.9 p= Tumor location p= Not significant cortex and cerebellum (n=46) 44.8± ±5.9 Not significant other and overlapping locations (n=39) 19.4±7.4 0 n.a.** Histological grading Not significant p=0.016 grade III (n=34) 36.8±9.4 n.a.** n.a.** 3 year EFS:11.1±7.0 grade IV (n=51) 31.7± ±4.5 p= Radiotherapy n.a.** n.a.** yes (n=80) 34.6± ±3.6 p= no (n=3) n.a.** n.a.** n.a.** Chemotherapy n.a.** n.a.** yes (n=79) 32.3± ±3.8 p= no (n=1) n.a.** n.a.** n.a.** Extent of tumor resection p= p=0.015 no gross total resection (n=60) 22.3±6.0 n.a.* 3 year EFS:2.9±2.8 gross total resection (n=25) 57.9± ±8.9 n.a. not applicable. *follow-up of all patients without event less than 4 years. **no sufficient patient numbers in one or all subgroups. treatment response than older children. It is interesting in this context that there is an attempt in several European countries to establish a separate treatment protocol for infants with malignant gliomas. The independent therapeutic impact of radiotherapy and chemotherapy could not be established in the present study since numbers of patients without radiotherapy or chemotherapy were too small for conclusive statistical analyses. In conclusion, the present study strongly supports the hypothesis that pediatric patients with malignant (nonpontine) gliomas show a significantly prolonged survival after tumor debulking. Gross total tumor resection should be attempted as often as possible. Acknowledgements We thank all colleagues who contributed patients and their data from the HIT studies cited. The present study is dedicated to Joachim Kühl. Supported by research funding from Deutsche Kinderkrebsstiftung, Bonn, Germany, and from Chugai-Pharma, Frankfurt a. M., Germany. References 1 Devaux BC, O'Fallon JR and Kelly PJ: Resection, biopsy, and survival in malignant glial neoplasms. A retrospective study of clinical parameters, therapy, and outcome. J Neurosurg 78: ,

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