J Neurooncol (2008) 89:271–286 DOI 10.1007/s11060-008-9614-5

INVITED MANUSCRIPT

Surgical management of newly diagnosed glioblastoma in adults: role of cytoreductive surgery Timothy C. Ryken Æ Bruce Frankel Æ Terrance Julien Æ Jeffrey J. Olson

Received: 9 January 2008 / Accepted: 19 May 2008 Ó Springer Science+Business Media, LLC. 2008

Keywords Guideline

Glioblastoma  Surgery  Cytoreduction 

Level III recommendation

Level I recommendation

It is recommended that biopsy, partial resection or gross total resection may all be considered in the initial management of malignant glioma depending on the condition of the patient, the size and the location of the malignant glial tumor.

There is insufficient evidence to support a Level I Recommendation.

Rationale

Recommendations

Level II recommendation Based on the prospective data available and a general consensus in the retrospective data it is recommended that for newly diagnosed supratentorial malignant glioma in adults that the ‘‘maximal safe resection’’ be undertaken (i.e. the maximal cytoreductive procedure provided that postoperative neurological deficit can be minimized).

T. C. Ryken Department of Neurosurgery, University of Iowa College of Medicine, Iowa City, IA, USA B. Frankel Department of Neurosurgery, University of South Carolina, Charleston, SC, USA T. Julien Department of Neurosurgery, University of West Virginia, Morgantown, WV, USA J. J. Olson (&) Department of Neurosurgery, Emory University School of Medicine, 1365B Clifton Rd., NE, Ste. 6200, Atlanta, GA 30322, USA e-mail: [email protected]

Though over 125 years have passed since the historic report of Bennett and Godlee in 1888 describing their initial surgical approach to a patient with a primary brain tumor, the surgical aspects of malignant glioma remain an area of discussion and controversy [1]. Primary malignant brain tumors are among the most challenging human malignancies to treat. Even small malignant primary tumors often progress rapidly despite multi-modality therapy. The possibility of long-term survival is remote and much of the focus and treatment decisions are based on neuro-cognitive and quality of life issues. In many instances, the main bulk of the tumor is managed differently than the remaining rim of infiltrating malignant cells that are invariably present. A significant challenge remains in developing therapies targeted at this infiltrative component. This residual area is usually outside the zone of enhancement and is often less appreciated, but may represent the more challenging issue when considering the possibility of long term control. The role of surgical intervention is evolving as new techniques become available and continued study has outlined the effectiveness and contribution of surgical procedures to survival and quality of life in patients with malignant glioma. Controversy remains partly due to the

123

272

lack of consistent effective therapeutic intervention of any type. The relative role of cytoreductive surgery as opposed to biopsy, partial or subtotal resection has been the subject of numerous studies and publications and remains an area of investigation and debate. The balance of the extent of resection with the development of new neurological and neuro-cognitive deficit appears central to the decision making process. In this chapter the role of cytoreductive surgery is considered and the relevant literature is compiled and reviewed in an attempt to consolidate the current available data and formulate guidelines for cytoreductive surgery in addressing the initial management of the patient with a malignant glial tumor. In addition key areas for future study will be identified. This chapter is not written as a definitive text but as a dynamic work to be periodically updated as new information becomes available. This summary should serve as an example of the methodology one can use to investigate clinical issues of relevance in the on-going surgical management of newly diagnosed patients with malignant glioma. By utilizing an evidence-based approach we have reviewed the relevant literature and have addressed the question ‘‘What is the role of cytoreductive surgery in the initial management of the adult patient with malignant glioma?’’

J Neurooncol (2008) 89:271–286

No randomized clinical trials specifically addressing extent of resection in the initial management of adult patients with newly diagnosed suspected malignant glioma in the general adult population were identified. A small randomized trial was identified focusing only on patients over 65. A larger randomized trial compared two techniques of resection but did not specifically address extent of resection. One meta-analysis and two critical reviews were identified and included in the scientific foundation, although they provided no new data and were not graded or included in the Evidentiary Table 1. Overall, 10 studies were identified providing prospective data collection, and one retrospective study provided data using a ‘‘matched pair analysis’’. Three of the prospective studies were retrospective reviews of randomized prospective trials addressing treatment with radiation and chemotherapy in which the extent of resection data was collected as a covariable. The remaining studies represent prospective efforts to analyze the effect of extent of resection on patient outcome. In addition, 19 retrospective articles addressing extent of resection in newly diagnosed malignant glioma were included. These 30 references are summarized in the Evidentiary Table 1 and form the basis for this review. A written summary of the information extracted and a summation of the information provided will form the basis of our scientific foundation.

Search criteria A National Library of Medicine computerized literature search from 1966 through 2004 was undertaken using the Mesh Subject Heading of ‘‘astrocytoma’’ in combination with human yielding over 12,000 abstracts for review. The titles and abstracts were reviewed to eliminate clearly erroneous titles and irrelevant papers and allow selection of articles focusing on the surgical management of malignant glioma for further review. Secondary searches were performed crossing ‘‘astrocytoma’’ with ‘‘surgery’’ to crosscheck the initial hand search. In addition the bibliographies of the selected papers were reviewed to provide additional references. The search was updated through 2006 to review additional references added to the National Library of Medicine. The Cochrane database was also reviewed and one appropriate manuscript was included for review and is listed below. Articles were selected for additional review if they provided information on the relationship of surgical resection, survival and quality of life in patients with newly diagnosed malignant glioma. Papers were preferentially selected if they contained prospective data collection, provided detailed statistical analysis, indicated that neuro-imaging was used to assist in the determination of extent of resection or provided a major review of the topic and were often quoted in the papers under review.

123

Scientific foundation The neurosurgical literature remains unclear as to whether the extent of surgical resection statistically correlates with survival. The fact that such a fundamental question among surgeons remains unanswered for well over a hundred years of glioma surgery is remarkable. A number of authors have attempted to identify the reasons behind the ongoing controversy [2–4]. Some of the issues described include: differing classification criteria, differing distributions of co-variants, patient selection bias and numerous methodological inconsistencies. The majority of studies available for review are retrospective and subject to design variation and bias. The prospective data available has generally been poorly designed to address cytoreductive surgery. Proponents of aggressive surgery have continued to champion aggressive surgery based on the available data generally favoring cytoreduction despite the difficulty in obtaining randomized data. The intermittent reports of patients being ‘‘cured’’ with aggressive surgery and radiotherapy continue to encourage efforts to push the limits of resection [5, 6]. To provide an overview of the pertinent literature, the articles included in the Evidentiary Table 1 will be summarized in the following sections (see Table 1 provided at conclusion of this article).

J Neurooncol (2008) 89:271–286

273

Evidentiary Table 1 Cytoreductive surgery Author/Reference

Study description

Stummer et al. [12] Randomized trial comparing cytoreductive surgery using an fluorescent marker (5-aminoleuvulinice acid) versus conventional white light 322 patients with radiographically suspected malignant glioma amenable to cytoreductive surgery were randomized. Interim analysis performed on 270 Fluorescence group (n = 139) versus Control group (n = 131)

Data class

Conclusion

II (Effect of extent of resection on progression-free survival)

Complete resection of enhancement

I (Comparison of two surgical techniques)

Fluorescence group 65% (90/139) Control group 29% (47/131) P \ 0.0001 Progression-free survival (6 months) Fluorescence group 41.0% (32.8–49.2) Control group 21.1% (14.0–28.2) P = 0.0003 The authors concluded that surgery using tumor fluorescence enabled more complete resections of contrast-enhancing tumor that was associated with a significant improvement in progression-free survival in patients with newly diagnosed malignant glioma undergoing cytoreductive surgery

Median follow-up 35.4 months

Vuorinen et al. [10] Randomized trial of patients over age 65 with II radiographically suspected malignant glioma randomized to either biopsy or resective surgery followed by radiotherapy GBM—19 AA—4

Median survival: Resection 5.7 months versus biopsy alone 2.83 months (P = 0.035) No significant difference in the time of deterioration between these two treatments (P = 0.057) Radiotherapy had a significant effect on survival (P = 0.001)

Other—7 Stereotactic biopsy (n = 13)

The authors concluded that in this population survival time was improved by craniotomy and resection of tumor

Resection (n = 10)

Despite randomized design the small sample size and inclusion of only patients over 65 limit interpretation Lacroix et al. [2]

Retrospective single institution review of 416 patients (100% GBM)

III

Mean age 53 Preop KPS 75% were greater than 70

Although retrospective, most thorough analysis of the effect of volume of resection on outcome published to date

Extent of resection evaluated by MRI

197 patients (47%) with C98% resection 219 (53%) with \98% resection

Treated postop with XRT and or CTX

Median survival: Significantly increased survival comparing 13 months (56 weeks) if greater than 98% resection versus 8.8 months (38 weeks) if less than 98% resection using multivariate analysis (P = 0.02)

Shinoda et al. [24]

Retrospective review of 82 patients (100% GBM) Mean age 57 Extent of resection evaluated by MRI

III

Median survival: Cases stratified by size, location and eloquence using Stage 1–3 (best surgical candidates to worst). Best outcome group resulted in survival of 60 weeks with GTR (Stage 1) and declined to 48 weeks \ GTR (Stage 2) and 32 weeks (Stage 3) biopsy group (P = 0.0002). They found neurological deficit to also increase with increasing surgery and increasing size and eloquence as expected Both extent of resection and Karnofsky Performance Status were significant prognostic factors by multivariate analysis The authors use their data to support gross total resection when feasible consistent with the concept of maximal debulking without neurological deficit but clearly contains a bias toward selecting the best surgical candidates

123

274

J Neurooncol (2008) 89:271–286

Evidentiary Table 1 continued Author/Reference

Study description

Stummer et al. [11] Prospective study on extent of resection on 52 patients with glioblastoma

Data class III

Retrospective review of 92 patients with GBM

Median survival: 79.7 weeks Age, KPS and extent of residual enhancement were all significantly correlated with survival in multivariate analysis. Despite prospective design for extent of resection analysis no control data provided so is compared against historical controls

Utilized fluorescence guided resection (5aminolevulinic acid induced porphyrins)

Keles et al. [25]

Conclusion

III

Despite prospective design, no comparison group was described Median survival: 32 weeks 0–25% resection

Median age 51

57 weeks 25–49% resection

Extent of resection evaluated by CT or MRI

63 weeks 50–74% resection 88 weeks 75–99% resection 93 weeks 100% resection P \ 0.0005 The authors feel that the extent of resection of hemispheric GBM significantly affects overall outcome with respect to postoperative KPS, time to tumor progression and overall survival

Kreth et al. [26]

Retrospective review of 225 patients with GBM III in two institutions

37 weeks with resection

37 underwent gross total resection (18%)

33 weeks with biopsy

85 underwent partial resection (38%)

P = 0.09

99 had biopsy only (44%) both with 60 Gy postoperative radiation

Multivariate analysis was used

Volume determined by post resection CT

Mohan et al. [27]

III Retrospective review of 102 patients elderly patients with GBM (age greater than 70 years)

69 weeks with gross total resection and radiation 29 weeks with partial resection and radiation

42 underwent partial resection (41%)

20 weeks with biopsy and radiation

28 patients had biopsy and radiation only (28%) and 25 patients had biopsy only (24%)

5 weeks with biopsy only

Retrospective review of 75 patients

P \ 0.0001 Significant effect found on extent of resection III

Median survival:

29 underwent gross total resection

27 months (116 weeks) with gross total resection

33 underwent partial resection STR

33 months (143 weeks) with partial resection

13 with biopsy alone

13 months (56 weeks) with biopsy alone Extent of resection not significant in multivariate analysis. Significant factors for survival by multivariate analysis included tumor grade, age, KPS, radiation dose and postoperative complications

(52 GBM, 23 AA)

Volume determined by CT/MRI

123

No significant effect of resection on survival. Tumor resection deemed beneficial for patients with preoperative midline shift. Thirty patients in the biopsy only group with midline shift did significantly worse with a median survival of 23 weeks (P \ 0.001) Median survival:

7 patients underwent gross total resection (7%)

Postoperative volume CT or MRI Kowalczuk et al. [28]

Median survival:

J Neurooncol (2008) 89:271–286

275

Evidentiary Table 1 continued Author/Reference

Study description

Data class

Conclusion

Kiwit et al. [14]

Retrospective review of 274 patients with 80 patients analyzed in matched groups (54 GBM and 26 AA)

II

Median survival:

Matched pair analysis

292 days (42 weeks) with resective surgery

40 patients had resective surgery

P \ 0.05

40 had biopsy only

Resection had a significant effect on survival. Postoperative tumor volume significantly correlated with increased survival. Authors feel their data support the maximal debulking possible while sparing functional tissue

Postoperative volume determined by CT/MRI

Slotman et al. [13]

Prospective non-randomized study of 30 patients III with GBM

42 weeks if greater than 75% resection 31 weeks if less than 75% resection

(range 27–75)

P \ 0.05

12 (40%) [ 90% resection

Identified best outcome group as that with age less than 50, KPS [ 80 and extent of tumor resection greater than 75% suggesting that these three factors are highly interrelated Despite prospective design, no comparison group was described

8 (27%) \ 75% resection 2 (6%) biopsy Postoperative volume determined by CT/MRI Retrospective review of 101 patients with malignant glioma (68 with GBM, 32 with AA)

III

STR 48 weeks PR 44 weeks Multivariate analysis showed that

36 (36%) STR

GTR versus STR and GTR versus PR P \ 0.01,

39(38%) PR

For STR vs. PR P = 0.428

Postoperative volume determined by CT

Retrospective case review of 151 patients with GBM

Median survival: GTR 80 weeks

Mean age 55 (range 16–79) 26 (26%) GTR

Obwegeser et al. [30]

Median survival:

Mean age 56

8 (27%) 75–90% resection

Nitta et al. [29]

184 days (26 weeks) with biopsy alone

III

Extent of resection was significant in the patients with GBM but not in patients with AA. Overall supports maximal possible extent of resection as prolonging survival because they were unable to demonstrate a significant difference between subtotal and partial groups. Suggests that the maximal amount of removal may improve response to adjuvant therapy Median survival: GTR 58 weeks

Mean age 57.5 years

STR 31 weeks

GTR in 111 patients STR in 40 patients

P = 0.005

Postoperative imaging by CT

The authors conclude that they found a significant increase in survival for ‘‘macroscopic radical surgery’’ Other factors favoring survival in multivariate analysis included younger age (P \ 0.05), KPS of 60 or greater (P \ 0.001), and the use of post-op radiotherapy and chemotherapy (P \ 0.01)

123

276

J Neurooncol (2008) 89:271–286

Evidentiary Table 1 continued Author/Reference Quigley et al. [31]

Study description

Data class

Retrospective review of 63 patients

III

Conclusion Median survival:

44 (70%) with GBM, 19 (30%) with AA

GTR 108 weeks (27 months)

9 (14%) GTR

STR 44 weeks (11 months)

31 (49%) STR

Biopsy 40 weeks (10 months)

23 (37%) biopsy

GTR versus biopsy P \ 0.001

Postoperative volume determined by CT/MRI

STR versus biopsy P = 0.35 Authors conclude that age and gross total resection were correlated with survival by multivariate analysis but no difference identified between subtotal resection and biopsy

Albert et al. [15]

Prospective study of 60 patients with malignant III glioma 57(95%) with GBM, 3 (5%) with AA

GTR—64 weeks (16 months)

Resection assessed with CT and or MRI

STR—36 weeks (9 months)

Incidence of postoperative enhancement was 70% (42 patients with STR), in 7 patients (12%) the enhancement was equivocal leaving 11 patients (18%) with GTR (no residual enhancement)

This is an underestimate as four of the 11 patients in the GTR group survived 18 months or longer and are not included in the above calculation

Median survival:

The authors conclude that resection had a positive impact on survival. Patients with residual tumor had 6.6 times higher risk of death Paper provides detailed support for postoperative MRI within 72 h of resection This paper also demonstrates the inaccuracy of surgical estimates on extent of resection. The correlation between surgical estimate and radiographic confirmation is only about 30%. The surgeon overestimated the extent of resection by 3-fold Eighty percent of tumor recurrence emerged from areas of postoperative enhancement. Residual tumor enhancement was the most prognostic predictive factor for survival in these patients with glioblastoma

Jeremic et al. [32]

Retrospective analysis of 86 patients with glioblastoma

III

Median survival: Biopsy only—29 weeks

Biopsy only in 25(29%)

STR/GTR—56 weeks (P \ 0.05)

STR or GTR in 61 (71%) Post op radiation plus chemotherapy given

One year and two year survival also significant (P \ 0.05) 62% versus 23% and 16% versus 0% Frontal location also significantly correlated with increased median survival 101 weeks versus 47 weeks (P = 0.00001) Multivariate analysis indicated that both extent of resection and frontal location were significantly associated with an increased survival

123

J Neurooncol (2008) 89:271–286

277

Evidentiary Table 1 continued Author/Reference

Study description

Kelly and Hunt [33] Retrospective review of 128 elderly patients (older than 65 years)with GBM

Devaux et al. [34]

Data class III

Conclusion Median survival: 27 weeks resection

Average age 72 years

15.4 weeks biopsy

Resection (40 patients) versus Biopsy (88 patients)

P = 0.008

Retrospective review of 218 resections for newly III diagnosed malignant glioma

Multivariate analysis performed on cortical and subcortical tumor location cases only.(196 cases excluding 22 cases of brain stem and midline tumors)

The strength of this study lies in the consistency of the technique applied to the surgical procedure resulting in ‘‘volumetric’’ stereotactic resection

164 patients with GBM (61 resection and 103 biopsy) and 54 patients with AA (14 resection and 40 biopsy)

Median survival in combined Grade III and IV: GTR 51.1 weeks Biopsy 29 weeks (log rank—not significant but P = 0.0008 Smirnov test) Comparing the Grade III tumors only GTR 135.4 weeks Biopsy 98.2 (not significant) Comparing the Grade IV tumors only GTR 44 weeks Biopsy 19 weeks (P = 0.0036 log rank and P \ 0.0001 Smirnov test) Authors conclude that resection had a positive impact on survival in Grade IV tumors even after correction for the effects of clinical prognostic factors.

Iacoangeli et al. [35] Rerospective review of 197 patients treated with III malignant glioma attempting to categorize by tumor extent, malignancy and extent of surgical resection

Median survival for subgroup of patients with glioblastoma undergoing surgical resection GTR—80 weeks (20 months) STR—48 weeks (12 months) PR—36 months (9 months)—statistical analysis on these groups is not stated individually Multivariate analysis performed to assess the relative importance of the grading factors indicated that the grade of malignancy was the only factor to maintain significance

Lai et al. J Formos Med Assoc 1993 [36]

Retrospective review of 116 patients with malignant glioma undergoing surgical management 71 patients with GBM 45 patients with AA GTR in 36 pts STR in 40 pts Biopsy in 40 pts

III

Median survival: GBM and AA groups combined GTR and STR 64 weeks (16 months) Biopsy 32 weeks (8 months) P = 0.0001 Overall survival for GBM group 10 months and for AA group 22 months Multivariate analysis indicated that duration of symptoms, extent of resection, postoperative radiation and pathology were all significant Overall the authors argue in support of extent of resection as significant factor in prolonging survival. Their analysis suggests that both gross total and subtotal resection are more beneficial than biopsy

123

278

J Neurooncol (2008) 89:271–286

Evidentiary Table 1 continued Author/Reference

Study description

Data class

Kreth et al. [37]

Retrospective comparison of 115 patients with GBM treated with either resection and radiation or biopsy plus radiation over a similar time period

III

Median survival: Resection group—39 weeks Biopsy—32 weeks (P = 0.8) The authors question the role of cytoreductive surgery as no impact on survival could be demonstrated Criteria for patient selection is not clear. Amount of resection is poorly quantified

Resection—57 pts Biopsy—58 pts

Simpson et al. [16]

Conclusion

Prospective data collection but retrospective II review of the three randomized RTOG trials combined to analyze the influence of location and extent of surgical resection on survival in patients with GBM GTR 125 pts (19%)

645 patients prospectively randomized RTOG trials offering surgical resection with radiotherapy in combination with chemotherapy regimens Median survival: GTR 45.2 weeks (11.3 months) versus Biopsy 26.4 weeks (6.6 months) P \ 0.0001

STR 413 pts (64%) Biopsy 107 pts (17%)

STR 41.6 weeks (10.4 months) versus Biopsy 26.4 weeks (6.6 months) P \ 0.001 Multivariate analysis confirmed age, KPS, extent of surgery, and primary site (frontal 11.4 months versus temporal (9.1 months) and parietal (9.4 months) P \ 0.02) were all associated with an improved survival No difference noted for tumor size The best survival was noted in patients less than 40 years of age, with a high KPS, a frontal location and a total resection giving a median survival of 17 months Despite the randomized data, extent of resection was not a factor for randomization

Curran et al. [17]

III Prospective data collection but retrospective review of three RTOG trials to address the role of surgery 103 pts with anaplastic foci treated on trial with radiotherapy and chemotherapy

Extent of resection did not reach significance with multivariate analysis. Only age, frontal location and smaller tumor size correlated with survival in this study Despite the review of randomized data, extent of resection was not a factor for randomization and not clear that all patients in the three studies were equivalent

STR 58 pts Biopsy 31 pts

123

Rerospective review of 357 patients with anaplastic astrocytoma treated on various protocols but reanalyzed. No patients with glioblastoma are included

Biopsy only—62 weeks (18 months) P = 0.02 Patients with frontal did better than other locations

GTR 14 pts

Prados et al. Int J Radiation Oncology Biol Phys 1992 [38]

Median survival: STR/GTR—196 weeks (49 months)

III

Multivariate analysis indicated that only age and performance status had a significant impact on survival Extent of surgery and use of brachytherapy as an initial therapy did not have a significant impact on survival

J Neurooncol (2008) 89:271–286

279

Evidentiary Table 1 continued Author/Reference

Study description

Data class

Bricola et al. [18]

Prospective study of 107 patients with planned aggressive surgical debulking

III

Conclusion One year survival: GTR 60%

GBM 86 pts (80%)

PR 24%

AA 21 pts (20%)

No statistical analysis was performed

GTR 66 (62%) STR in 41 (38%) All treated with postoperative radiation Postop volume evaluated by CT Vecht et al. [39]

Retrospective review of 243 patients with supratentorial malignant glioma

III

GBM 177 pts AA 66 pts

For GBM patients 24 underwent aggressive surgical debulking with a median survival of 4 months compared with the partial debulking group with a median survival of only 3 months (P \ 0.01). Radiation therapy improved survival in the GBM group to 9 months Multivariate analysis supported extent of resection as a prognostic variable with a 23% risk reduction of dying during the study period with aggressive surgery versus partial debulking Main criticisms of the paper are that the extent of resection was not verified by imaging and the statistical analysis is difficult to interpret

Ammirati et al. [19] Prospective but non-randomized goal to evaluate II the effect of extent of resection on length and quality of survival 31 patients (68% GBM, 32% AA)

Median survival: 90 weeks GTR 43 weeks STR P \ 0.001

Median age 50

KPS increased with GTR and these patients remained independent longer

Median KPS 70 19 (61%) with GTR

Distribution of pathology may be a bias with 37% of GTR group was AA versus only 25% of the STR group

12 (39%) with STR Postoperative volume analyzed by CT

No multivariate analysis Ciric et al. Neurosurg 1987 [41]

Retrospective analysis of 42 patient

III

Malignant Glioma 33 (79%) Low-grade astrocytoma 4 (10%) Oligodendroglioma 5 (12%) GTR in 36 patients (86%) GT \/= 10% left PR [/= 10% left

35 of 36 patients (97%) with GTR were unchanged or had improved neurological status post-operatively and at the time of discharge Main focus of report is on role of CT imaging in making the assessment of resection and in demonstrating that resection can be accomplished with minimal morbidity

CT used for postoperative imaging Levin et al. [20]

Prospective randomized study of 76 patients II with GBM and 72 patients with AA evaluating two forms of chemotherapy and assessing extent of resection as a co-variable

Multivariate analysis indicated that age was of significance for survival in both AA and GBM patients Extent of resection was significant only in the AA group (P \ 0.06) Despite the randomized data, extent of resection was not a factor for randomization

123

280

J Neurooncol (2008) 89:271–286

Evidentiary Table 1 continued Author/Reference

Study description

Andreau et al. [40]

Retrospective analysis of previous study III population of 115 (100% AA) to define CT prognostic criteria for radical tumor resection

Postoperative residual tumor volume was inversely related to length of survival and postop KPS (P \ 0.01)

Mean age 55 years

Postoperative edema and increased enhancement were also of prognostic value and showed an inverse relation to survival (P \ 0.01)

All cases GTR was attempted Pre and postoperative volume determined by CT

Data class

Conclusion

Younger patients proved more likely than older patients to attain long-term survival Residual tumor burden of less than 45 mm diameter on postoperative CT scans was associated with 70% chance of long-term survival The authors feel that their findings support the aggressive surgical management of glioma

Meta-analysis and critical reviews One meta-analysis and two critical reviews were identified and are summarized in the following section In 2003, Metcalfe and Grant provided an update on the Cochrane report of 2000 on biopsy versus resection for malignant glioma [7]. After a search of over 2,100 documents the authors were unable to locate sufficient randomized data for analysis, no conclusion could be drawn. A recommendation was made calling for randomized prospective study of this important issue. Although unpublished at the time of this review, these authors indicate in an updated on-line abstract that a small randomized controlled trial had been reported to them consisting of 30 randomized patients of which 23 had primary brain tumors. The Cochrane reviewers did not indicate that this study was going to change their initial conclusions [8]. Quigley et al. provided a critical review of the previously published studies addressing extent of resection for malignant glioma in 1991. The authors included 20 papers in their review of over 5,000 patients and identified 16 papers in which some statistical analysis was performed. In four of these papers a beneficial effect of surgery was reported but in the remaining 12 the extent of resection was not deemed of statistical significance. Interestingly the papers that favored resection as a positive influence on prognosis were all published in the last several years of the study period and were the largest of the series described. Nonetheless this review provided little if any support for the concept of maximal cytoreductive surgery. Nazzaro and Neuwelt reviewed the available literature in 1990 and raised numerous concerns regarding the opinions and studies at the time regarding the role of cytoreductive surgery [9]. The authors concluded after an

123

exhaustive review of the papers published over the previous 30 years that there was little justification for dogmatic statements that maximal resective surgery was associated with improved survival in the management of the patient with malignant glioma, particularly with the use of radiation therapy. The authors point out a number of concerns with previous publications many of which remain relevant. Some of these include: poor control for age and KPS (known prognostic predictors), poor control for tumor location, variation in histological diagnosis, lack of appropriate statistical analysis, insufficient study population to justify conclusions and limited ability to accurately identify postoperative tumor burden (either from radiographic or biologic limitations). The authors suggest the need for high quality studies with thorough multivariate analysis will be required before this issue can be appropriately addressed. Randomized trials, prospective studies and matched pair analysis Vuorinen et al. reported a small randomized study specifically focusing on patients older than 65 [10]. In this study, 30 patients over 65 years old with radiographically suspected newly diagnosed malignant glioma were randomized to either stereotactic biopsy or resection. Only 23 patients ultimately were diagnosed with a malignant glioma (19 glioblastoma and 4 anaplastic astrocytoma). The other seven (23%) had a variety of diagnoses (three stroke, two metastasis, one lymphoma). The randomization resulted in assignment to stereotactic biopsy (n = 13) or resection (n = 10) followed by radiotherapy. Overall median survival was 4.86 months. Median survival following craniotomy was 5.7 months versus 2.83 months following biopsy alone (P = 0.035). There was no

J Neurooncol (2008) 89:271–286

significant difference in the time of deterioration between these two treatments (P = 0.057) and radiotherapy had a significant effect on survival (P = 0.001). The authors concluded that in this population survival time was improved by craniotomy and resection of tumor. Stummer et al. describe a prospective study evaluating the extent of resection and its influence on survival employing 5-aminolevulinic acid, a fluorescent marker [11]. The authors found a significant correlation of extent of resection with survival in multivariate analysis. Although prospective in nature the lack of a control group limits the broad interpretation of this study and its real strength lies in the novelty of the approach using a fluorescent marker to aid in the resection decisions. These authors followed this intriguing preliminary study with a randomized study assessing the effect of fluorescence-guidance on extent of resection, progression-free survival, overall survival and morbidity [12]. Three hundred and twenty-two adult patients with radiographically suspected malignant glioma were randomly assigned to either 5-aminolevulinic acid for fluorescence-guided resection (n = 161) or to conventional microsurgery with white light (n = 161). The primary endpoints were the number of patients without contrast-enhancing tumor on early MRI (i.e., that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumor on postoperative MRI, overall survival, neurological deficit, and toxic effects. The authors published an interim analysis of 270 patients in the full-analysis population (139 assigned 5aminolevulinic acid, 131 assigned white light), excluding patients with ineligible histological and radiological findings as assessed by blinded central reviewers. The study was terminated following the interim analysis due to the effectiveness of the therapy. Median follow-up was 35.4 months (95% CI 1.0–56.7) and there were no significant difference in the number of adverse events between the groups. The use of fluorescence-guidance resulted in a 65% rate of complete resection (90 of 139 patients with no contrast on early postoperative imaging). The control group had a 36% (47 of 131) chance of complete resection (P \ 0.0001). The fluorescence-guidance group also had a higher 6-month progression free survival (41% versus 21%, P = 0.0003). The authors concluded that the use of fluorescenceguided resection using 5-aminolevulinic acid resulted in an increase in the number of complete resections of contrastenhancing tumor, which was associated with a significant improvement in progression-free survival. Although this paper provides Level I evidence evaluating the use of the authors’ fluorescence-guided surgical technique, patients

281

were not assigned to groups to undergo a predetermined extent of resection. Level II evidence is provided because similar cohorts are studied prospectively and the impact of extent of resection on survival is significant. Slotman et al. report in 1996 describes a prospective non-randomized study of 30 patients with glioblastoma all treated with a hypo fractionated radiotherapy regimen [13]. Patients undergoing greater than 75% resection of their initial enhancing volume survived significantly longer than those with biopsy only (42 weeks versus 31 weeks, P \ 0.05). The authors indicate that age less than 50, KPS greater than 80 and extent of resection greater than 75%. The best survival was in this group and was 50 weeks. In 1996 Kiwit et al. published their analysis of prognostic factors for survival in malignant glioma [14]. Initially a 274 patients retrospective review was performed including a matched pair analysis of 40 biopsy and 40 resective surgery patients. The authors demonstrated a significant effect of cytoreductive surgery over biopsy only favoring survival, comparing 42 weeks with 26 weeks (P \ 0.05). The authors also found no significant improvement in KPS in the cytoreductive surgery group. Postoperative tumor volume significantly correlated with increased survival and the authors favor maximal debulking while minimizing neurological deficit. Albert et al. published a well-designed and often quoted study in 1994 [15]. Evaluating the surgical management and detailed assessment of postoperative tumor volume was the goal of this prospective analysis of 60 patients with malignant glioma (57 patients with GBM and three with anaplastic astrocytoma). A detailed analysis of the effect of residual enhancing tumor was performed demonstrating a striking impact on survival. Patients with residual tumor were 6.6 times as likely to die during the study period as the group with no residual tumor with 80% of recurrent/ progressive tumor growth being noted in the area of postresection enhancement. The median survival of the patients with a gross total resection was 64 weeks versus 36 weeks in the patients with residual enhancement. The authors also evaluated the accuracy of intra-operative surgical assessment to determine the extent of resection and found that surgeons overestimated their resection by up to 3-fold. This paper also strongly promotes early (within 72 h) postoperative enhanced MRI imaging to allow the most accurate assessment of residual enhancement following resection. The influence of extent of surgery, tumor size and site were the subject of a study published by Simpson et al. combining the data from three large Radiation Therapy Oncology Group (RTOG) prospective randomized trials [16]. Although the data was collected in randomized prospective fashion it was not randomized to directly assess the extent of resection but rather the role of combined radiation and chemotherapy following surgical resection or

123

282

biopsy for glioblastoma. Six hundred and forty-five patients with a diagnosis of glioblastoma on central pathologic review were included and analyzed for survival with respect to potential prognostic factors in multivariate fashion including age, KPS, extent of resection, size of tumor and location. One hundred and twenty-five patients had a gross total resection (19%), 413 had a subtotal resection (64%) and 107 had biopsy only (17%). Patients undergoing either total resection (11.3 months) or partial resection (10.4 months) had a significantly prolonged median survival when compared to the biopsy group (6.6 months, P \ 0.0001, P \ 0.001). Patients with frontal lobe tumors survived longer than temporal or parietal tumors. Multivariate analysis confirmed significant correlation with age, KPS, extent of surgery and primary site with survival. The best survival rates occurred in patients who had at least of the following features: age less than 40 years, high KPS, frontal location and underwent a total resection. This group had a median survival of 17 months. Curran et al. reviewed the patient data obtained in three randomized RTOG trials that were evaluating combination radiotherapy and chemotherapy in the treatment of a total of 103 patients with anaplastic astrocytoma [17]. The extent of resection was analyzed as a covariate. Gross total resection was reported in 14 patients, subtotal resection in 58 and biopsy only in 31. In univariate analysis both STR and GTR groups demonstrated prolonged survival versus biopsy alone (median survival 49 months versus 62 weeks, P = 0.02). However, in multivariate analysis only age, frontal location and smaller tumor size correlated with survival. Bricolo et al. published their preliminary report of a prospective data collection on patients with presumed malignant glioma subjected to an aggressive surgical strategy and assessed postoperatively with CT scanning to place them either in a gross total resection or subtotal resection (10–15% remaining enhancement) group [18]. While no statistical analysis is provided the authors report a 60% 1 year survival for their gross total resection group versus only 24% in the subtotal resection group. Thirty-one patients operated on for supratentorial glioblastoma or anaplastic astrocytoma were prospectively studied to evaluate the extent of resection on the length and quality of survival [19]. Twenty-one patients (68%) had glioblastoma and 10 patients (32%) had anaplastic astrocytoma. Early postoperative enhanced computed tomography was used to determine the extent of tumor resection. Gross total resection was accomplished in 19 patients (61%) and subtotal resection was performed in 12 patients (39%). The gross total resection group lived longer than the subtotal resection group (median survival of 90 versus 43 weeks, P \ 0.001). Postoperatively the KPS was significantly increased in the gross total resection group (P = 0.006) but not in the subtotal resection group

123

J Neurooncol (2008) 89:271–286

(P [ 0.05). The gross total resection group spent significantly more time after the operation in an independent status compared to the subtotal resection group. The authors conclude that gross total resection of supratentorial glioblastomas and anaplastic astrocytomas is feasible and is directly associated with longer and better quality survival when compared to subtotal resection. A randomized study conducted to compare two chemotherapy regimens (PCV vs. BCNU) in malignant glioma patients treated with surgery and radiation was reported by Levin et al. [20]. The study group consisted of 76 patients with GBM and 72 patients with anaplastic astrocytoma. The study while designed as a Class I study for chemotherapy provides prospective data on extent of resection as this was studied as a co-variable. In multivariate analysis age was determined to be the most important predictor of survival in both GBM and AA patients. Extent of resection was a significant predictor of survival in the patients with anaplastic astrocytoma but did not achieve significance in the glioblastoma patients. Retrospective studies Lacroix et al. study represents the most comprehensive attempt to correlate extent of resection with survival published to date [2]. A retrospective review of a large patient database was made incorporating 416 patients undergoing resection for glioblastoma over a 6 year time period in a single institution. The volume of the preoperative and postoperative enhancing tumor was performed using computer assisted image analysis. Other features of the images were also identified including proximity to functional cortex, mass effect, degree of enhancement and edema. The amount of tumor necrosis, the patient’s age and the Karnofsky Performance Score (KPS) were also included in the analysis. The authors identified five independent predictors of survival following multivariate statistical analysis including age, KPS, degree of necrosis, enhancement on preoperative magnetic resonance imaging studies and extent of surgical resection. The extent of resection became significant when a resection of 98% or greater of the preoperative enhancing volume was achieved. The median survival time was 13 months for those patients with 98% or greater resection compared with 8.8 months for those with less than 98% resections (P value = 0.02). The authors went on to propose a clinical outcome scale ranging from 0 to 5 based on age, KPS and radiographic evidence of necrosis. They observed significantly improved survivals in patients with scores from 1 to 3 who also had undergone aggressive surgical resection. Overall, this study supports the concept of aggressive cytoreductive surgery in the management of malignant

J Neurooncol (2008) 89:271–286

glioma patients and begins to analyze the subgroups that may experience more benefit than others. The computer assisted volumetric image analysis technique lays the groundwork for additional prospective data collection. Issues of concern regarding conclusions drawn from this study include the heterogeneity of treatments prior to the index procedure, the lack of separation of primary versus secondary tumors and the potential selection bias introduced by the reason for partial resections in some patients [21–23]. In response to these questions the authors indicated that a prospective trial of this issue is underway and will represent a valuable contribution to the current literature. Shinoda et al. retrospectively reviewed 82 patients stratifying them according to size location and eloquence of adjacent tissue [24]. The stratification into different Stages from 1 to 3 was used to build recommendations for the amount of resection to pursue in the various groups. The study is inherently biased to select out better surgical candidates but does support the value of resection. Keles et al. describe a retrospective experience with 92 patients with glioblastoma evaluating the extent of resection dividing the patients into categories based on the amount of postoperative enhancement [25]. The study clearly supports extent of resection as a significant factor in prolonging survival, increasing the time to tumor progression and maintaining KPS. Patients with a KPS under 70 were excluded and the determination of residual tumor volume, though made using volumetric technique, was made on a combination of CT and MRI scans potentially complicating interpretation. Kreth et al. reported a retrospective study of 225 patients undergoing operative therapy for glioblastoma in two institutions [26]. The authors found no difference between patients undergoing biopsy plus radiation when compared to resection plus radiation, comparing 33 weeks and 37 weeks, respectively (P = 0.09). The presence of midline shift in the thirty patients undergoing biopsy only resulted in a reduced survival of 23 weeks in this subgroup (P \ 0.001). The authors conclude that in their group resection offered no survival advantage over biopsy alone except in the presence of mass effect resulting in measurable midline shift. Mohan et al. evaluated 102 elderly patients based on the selected treatment regimen [27]. Seven patients underwent gross total resection followed by radiation therapy with a median survival of 69 weeks. Forty-two patients were treated with partial resection followed by radiation therapy with a median survival of 29 weeks. Twenty-eight patients had a biopsy followed by radiation therapy (median survival 20 weeks). Twenty-five patients had a biopsy only with no further treatment with a limited survival of only 5 weeks. Multivariate analysis supported extent of

283

resection significantly impacting overall survival. The authors also indicate that their data supports the aggressive treatment of elderly patients with glioblastoma providing their KPS is at least 70 and no coexisting major medical issues. Kowalczuk et al. describe a retrospective review of 75 patients with malignant glioma (52 GBM, 23 AA) [28]. In this group 29 underwent gross total resection (median survival 27 months), 33 underwent partial resection (median survival 33 months) and 13 underwent biopsy (median survival 13 months). In this study no statistical relationship could be made between extent of resection and survival. Nitta et al. describe their experience with 101 patients with malignant glioma including 68 patients with GBM and 32 with anaplastic astrocytoma who underwent operative procedures followed by a uniform radiotherapy and chemotherapy regimen [29]. The authors found that in the glioblastoma group that the patients undergoing gross total resection as judged by postoperative CT survived significantly longer than patients undergoing either a partial resection (less than 75%) or subtotal resection (75—less than 100%). They suggested that gross total excision might aid in the adjuvant therapy following surgical intervention. Obwegeser et al. published their retrospective experience with 151 glioblastoma patients dividing their operative cases into gross total excision (111 patients) and subtotal or partial excision (40 cases) with a significant difference in median survival comparing 58 weeks with 31 weeks (P = 0.05) [30]. Younger age, KPS of 60 or greater and the use of postoperative radiotherapy and chemotherapy were also significant predictors of survival. Quigley et al. reports 63 patients with malignant glioma (44 glioblastoma and 19 with anaplastic astrocytoma) undergoing surgical procedures (9 with gross total resection, 31 with subtotal resection and 23 with biopsy only) showing a significant improvement in survival in patients with a gross total resection comparing 108 weeks with 44 weeks and 40 weeks in the subtotal and biopsy groups, respectively [31]. Only age and the achievement of a gross total resection were significant in multivariate analysis in this series. There was no significant difference in survival when comparing biopsy versus subtotal resection. Jeremic et al. retrospectively reviewed 86 patients with glioblastoma stratifying them into biopsy only (25 patients) and subtotal or gross total resection (61 patients) [32]. The median survival was significantly increased in the combined STR/GTR group versus the biopsy group (56 weeks versus 29 week P \ 0.05). This survival advantage was maintained in the one and 2-year survival rates with 16% of the debulking group still alive after 2 years. Multivariate analysis confirmed that both extent of resection and frontal location were predictive of increased survival.

123

284

Kelly and Hunt reviewed 128 patients with glioblastoma over 65 years of age in which 40 underwent resection and 88 patients underwent a biopsy [33] The median survival in the resection group was 27 weeks, significantly longer than the biopsy group (15.4 weeks, P = 0.008). Devaux et al. retrospectively reviewed a series including 218 patients with newly diagnosed malignant glioma including 164 patients with Grade IV tumors and 54 patients with Grade III tumors [34]. Of the Grade IV tumors 61 underwent a stereotactic-guided volumetric resection and 103 underwent biopsy and of the Grade III tumors 14 underwent resection and 40 underwent biopsy. The subset of 196 cases in a cortical or sub-cortical location was analyzed separately (omitting brain stem and midline tumors from the resection analysis). The median survival of both Grade III and IV tumors was 51.1 weeks in the resection group compared with 29 weeks in the biopsy group. This was significant by the Smirnov test but not by log-rank. Analyzing the Grade IV group independently indicated that a median survival of 44 weeks for the resection group versus 19 weeks for the biopsy only group. This different was significant for both statistical parameters noted while the median survival for the Grade III group (135.4 weeks versus 98.2 weeks) did not achieve significance, possibly due to the fewer number of patients and the longer survival time in both groups. The authors conclude that using a detailed surgical approach designed to achieve volumetric resection was of benefit in prolonging survival in Grade IV patients even after adjusted for no clinical prognostic factors. A prospective study evaluating this finding in follow-up is mentioned by not to our knowledge been published to date. Iacongeli et al. attempted to define staging criteria for malignant glioma and included data on median survival based on extent of surgical resection [35]. The authors proposed a ‘‘TGS’’ classification based on tumor extent (T), grading of malignancy (G) and extent of surgical resection (S). Grade of malignancy was the only variable to maintain significance in multivariate analysis. Lai et al. published a retrospective review of 116 patients with malignant glioma including 71 patients with glioblastoma and 45 patients with anaplastic astrocytoma [36]. Surgery resulted in a gross total resection in 36 patients, a subtotal resection in 40 patients and biopsy in 40 patients. The median survival was significantly increased with a gross total (16 months) or subtotal resection (16 months) compared with biopsy (8 months, P = 0.0001). Multivariate analysis confirmed that extent of resection, postoperative radiotherapy, duration of symptoms and pathologic diagnoses were all predictive of median survival. The study published by Kreth et al. in 1993 was unable to demonstrate an advantage to surgical debulking and the authors favored biopsy plus radiotherapy, with the possible

123

J Neurooncol (2008) 89:271–286

exception of those patients demonstrating mass effect (midline shift) on preoperative imaging [37]. This study is lacking in detail about how patients were selected for the different groups and to how the assessment of postoperative residual tumor was made and affected the results of the analysis. Prados and co-workers reported a retrospective analysis of 357 patients treated on a variety of protocols addressing prognostic factors for increased survival [38]. The overall survival of the patient group was 171 weeks (3.5 years) and on multivariate analysis was only dependent on age and KPS. Extent of resection had no significant impact on survival. Vecht et al. described a retrospective review of 243 patients treated with supratentorial glioblastoma including 177 with GBM and 66 with AA [39]. Of the GBM patients 24 underwent surgical debulking resulting in a median survival of 4 months. This was significantly greater than the partial resection group (3 months, P \ 0.01). The patient numbers in this study are small and the statistical analysis described is difficult to follow. The extent of resection is not verified by imaging. Forty-two patients with supratentorial glioma not involving the basal ganglia (extraganglionic) were studied pre and postoperatively with computed tomographic scans to evaluate the effect of the extent of surgical resection on the immediate postoperative results [19]. Thirty-three patients (79%) had malignant astrocytic glioma (either GBM or AA). The remainder of the tumors was lower grade glial tumors. A gross total resection was defined as less than 10% residual enhancement for this study. A gross total resection was achieved in 36 patients (86%) and an improved or stable postoperative neurological status was present in 35 of these patients (97%). In contrast the rate of neurological morbidity after a partial resection was 2 in 5 (40%). No comparative survival analysis was performed between the groups. The authors conclude that gross total resection can be carried and generally results in an improved neurological status when achievable. Andreau et al. described a retrospective review of 115 patients with anaplastic astrocytoma undergoing maximal resective surgery evaluating postoperative tumor volume using enhanced computed tomography [40]. Both survival and postoperative KPS were significantly related to postoperative tumor volume. The presence of postoperative edema and enhancement were also predictive of a worsened survival. A residual tumor burden of less than 45 mm in diameter was associated with a 70% long-term survival and a burden of less than 30 mm was associated with a 78% chance of long-term survival (defined as more than 700 days). The authors conclude that aggressive surgical treatment improves survival and quality of life in the patient with anaplastic astrocytoma.

J Neurooncol (2008) 89:271–286

Summary Thirty papers are included in the attached Evidentiary Table 1. These include 10 prospective studies and twenty retrospective studies. Five of the prospective studies provided Class II data [10, 12, 16, 19, 20] and one of the 20 retrospective studies provided Class II data [14]. All but one of these better quality studies support extent of resection as a factor in improving survival in newly diagnosed adult patients with malignant glioma. Of these only the study of Levin published in 1985 failed to support extent of resection for glioblastoma, but did demonstrate a survival advantage in cases of anaplastic astrocytoma. Of the remaining retrospective papers reviewed, all provided Class III data. Fourteen of the nineteen provided data that supported the concept of cytoreductive surgery in the initial management of malignant glioma. As a result, it follows that the majority of the reviewed data supports maximal cytoreductive surgery. In addition it is clear that rigorous postoperative imaging and analysis of residual tumor burden is best done by an independent analyst and that it is indicative of increased survival. Quality of life continues is an important pre and postoperative consideration and appears to be maintained for longer periods of time in the setting of a maximal debulking operation.

Key issues for future investigation The need for better data either through randomized trial or prospective ‘‘case control’’ methodology is clear from reviewing the long list of studies that have attempted to address the issue of extent of resection and the resultant effect on survival and quality of life in patients with malignant glioma. Major advances can be identified since the studies in the late 1980s in terms of clarifying the histopathological diagnosis and in assessing the extent of resection using neuroimaging as opposed to intraoperative surgical judgment. It is clear from this review that studies designed to address the impact of extent of resection or postoperative tumor burden on clinical outcome must incorporate neuroimaging methodology that allows accurate and consistent analysis. The role of advanced neuro-imaging in effecting resections in these patients remains an area of investigation. The role of MRI and advanced ultrasound imaging need to be clarified and expanded to improve the extent and safety of surgery while balancing cost-effective technology development. Development of standardized methodologies for residual tumor assessment and investigation into techniques for assessing the residual ‘‘non-enhancing’’ tumor burden are

285

needed. The study of malignant primary neoplasms with evolving molecular imaging techniques will allow the impact of residual malignant cells on patient outcome to be evaluated and trigger the continued development of molecular based treatment paradigms. The continued development of intra-operative tumor markers or enhancing agents should greatly assist in surgical decision-making and may result in improved extent of resection without creating new neurological deficit. Acknowledgements We wish to acknowledge Stephen Haines, MD, Jack Rock, MD, and Tom Mikkelson, MD for their review and consultations regarding on this work. The authors also wish to express appreciation to the AANS/CNS Joint Guidelines Committee for their review, comments and suggestions. We also thank Linda Phillips for meeting organization and collection of materials and Emily Feinstein for her assistance in editing the material for publication.

References 1. Bennett H, Godlee R (1888) Excision of a tumour from the brain. Lancet 2:906 2. Lacroix M, Abi-Said D, Fourney DR et al (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95(2):190–198 3. Hess KR (1999) Extent of resection as a prognostic variable in the treatment of gliomas. J Neurooncol 42(3):227–231 4. Jackson RJ, Fuller GN, Abi-Said D et al (2001) Limitations of stereotactic biopsy in the initial management of gliomas. Neurooncology 3(3):193–200 5. Yoshida T, Kawano N, Oka H, Fujii K, Nakazato Y (2000) Clinical cure of glioblastoma—two case reports. Neurol Med Chir (Tokyo) 40(4):224–229 6. Bucy PC, Oberhill HR, Siqueira EB, Zimmerman HM, Jelsma RK (1985) Cerebral glioblastomas can be cured!. Neurosurgery 16(5):714–717 7. Metcalfe SE (2000) Biopsy versus resection for malignant glioma. Cochrane Database Syst Rev 2:CD002034 8. Metcalfe SE, Grant R (2003) Biopsy versus resection for malignant glioma (Cochrane Review). The Cochrane Library 9. Nazzaro JM, Neuwelt EA (1990) The role of surgery in the management of supratentorial intermediate and high-grade astrocytomas in adults. J Neurosurg 73(3):331–344 10. Vuorinen V, Hinkka S, Farkkila M, Jaaskelainen J (2003) Debulking or biopsy of malignant glioma in elderly people—a randomised study. Acta Neurochir (Wien) 145(1):5–10 11. Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ (2000) Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 93(6):1003–1013 12. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7(5):392–401 13. Slotman BJ, Kralendonk JH, van Alphen HA, Kamphorst W, Karim AB (1996) Hypofractionated radiation therapy in patients with glioblastoma multiforme: results of treatment and impact of prognostic factors. Int J Radiat Oncol Biol Phys 34(4):895–898 14. Kiwit JC, Floeth FW, Bock WJ (1996) Survival in malignant glioma: analysis of prognostic factors with special regard to cytoreductive surgery. Zentralbl Neurochir 57(2):76–88

123

286 15. Albert FK, Forsting M, Sartor K, Adams HP, Kunze S (1994) Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34(1):45– 60; discussion 60–41 16. Simpson JR, Horton J, Scott C et al (1993) Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: results of three consecutive Radiation Therapy Oncology Group (RTOG) clinical trials. Int J Radiat Oncol Biol Phys 26(2):239–244 17. Curran WJ Jr, Scott CB, Horton J et al (1992) Does extent of surgery influence outcome for astrocytoma with atypical or anaplastic foci (AAF)? A report from three Radiation Therapy Oncology Group (RTOG) trials. J Neurooncol 12(3):219–227 18. Bricolo A, Turazzi S, Cristofori L et al (1990) Experience in ‘‘radical’’ surgery of supratentorial gliomas in adults. J Neurosurg Sci 34(3–4):297–298 19. Ammirati M, Vick N, Liao YL, Ciric I, Mikhael M (1987) Effect of the extent of surgical resection on survival and quality of life in patients with supratentorial glioblastomas and anaplastic astrocytomas. Neurosurgery 21(2):201–206 20. Levin VA, Wara WM, Davis RL et al (1985) Phase III comparison of BCNU and the combination of procarbazine, CCNU, and vincristine administered after radiotherapy with hydroxyurea for malignant gliomas. J Neurosurg 63(2):218–223 21. Albert FK, Forsting M (2003) Resection and prognosis. J Neurosurg 98(1):225–226; author reply 226 22. Silbergeld DL, Rostomily RC (2002) Resection of glioblastoma. J Neurosurg 96(4):809; author reply 810 23. Stummer W, Steiger HJ (2002) Resection of glioblastoma. J Neurosurg 96(4):809–810; author reply 810 24. Shinoda J, Sakai N, Murase S, Yano H, Matsuhisa T, Funakoshi T (2001) Selection of eligible patients with supratentorial glioblastoma multiforme for gross total resection. J Neurooncol 52(2):161–171 25. Keles GE, Anderson B, Berger MS (1999) The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere. Surg Neurol 52(4):371–379 26. Kreth FW, Berlis A, Spiropoulou V et al (1999) The role of tumor resection in the treatment of glioblastoma multiforme in adults. Cancer 86(10):2117–2123 27. Mohan DS, Suh JH, Phan JL, Kupelian PA, Cohen BH, Barnett GH (1998) Outcome in elderly patients undergoing definitive surgery and radiation therapy for supratentorial glioblastoma multiforme at a tertiary care institution. Int J Radiat Oncol Biol Phys 42(5):981–987 28. Kowalczuk A, Macdonald RL, Amidei C et al (1997) Quantitative imaging study of extent of surgical resection and prognosis

123

J Neurooncol (2008) 89:271–286

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

of malignant astrocytomas. Neurosurgery 41(5):1028–1036; discussion 1036–1028 Nitta T, Sato K (1995) Prognostic implications of the extent of surgical resection in patients with intracranial malignant gliomas. Cancer 75(11):2727–2731 Obwegeser A, Ortler M, Seiwald M, Ulmer H, Kostron H (1995) Therapy of glioblastoma multiforme: a cumulative experience of 10 years. Acta Neurochir (Wien) 137(1–2):29–33 Quigley MR, Flores N, Maroon JC, Sargent B, Lang S, Elrifai A (1995) Value of surgical intervention in the treatment of glioma. Stereotact Funct Neurosurg 65(1–4):171–175 Jeremic B, Grujicic D, Antunovic V, Djuric L, Stojanovic M, Shibamoto Y (1994) Influence of extent of surgery and tumor location on treatment outcome of patients with glioblastoma multiforme treated with combined modality approach. J Neurooncol 21(2):177–185 Kelly PJ, Hunt C (1994) The limited value of cytoreductive surgery in elderly patients with malignant gliomas. Neurosurgery 34(1):62–66; discussion 66–67 Devaux BC, O’Fallon JR, Kelly PJ (1993) Resection, biopsy, and survival in malignant glial neoplasms. A retrospective study of clinical parameters, therapy, and outcome. J Neurosurg 78(5):767–775 Iacoangeli M, Roselli R, Prezioso A, Scerrati M, Rossi GF (1993) Staging of supratentorial hemispheric glioma using tumour extension, histopathological grade and extent of surgical resection. Br J Surg 80(9):1130–1133 Lai DM et al (1993) Therapy for supratentorial malignant astrocytomas: survival and possible prognostic factors. J Formos Med Assoc 92(3):220–226 Kreth FW, Warnke PC, Scheremet R, Ostertag CB (1993) Surgical resection and radiation therapy versus biopsy and radiation therapy in the treatment of glioblastoma multiforme. J Neurosurg 78(5):762–766 Prados MD et al (1992) Highly anaplastic astrocytoma: a review of 357 patients treated between 1977 and 1989. Int J Radiat Oncol Biol Phys 23(1):3–8 Vecht CJ, Avezaat CJ, van Putten WL, Eijkenboom WM, Stefanko SZ (1990) The influence of the extent of surgery on the neurological function and survival in malignant glioma. A retrospective analysis in 243 patients. J Neurol Neurosurg Psychiatry 53(6):466–471 Andreou J, George AE, Wise A et al (1983) CT prognostic criteria of survival after malignant glioma surgery. AJNR Am J Neuroradiol 4(3):488–490 Ciric I et al (1987) Supratentorial gliomas: surgical considerations and immediate postoperative results. Gross total resection versus partial resection. Neurosurgery 21(1):21–26

Ryken et al 2008

Springer Science+Business Media, LLC. 2008. Keywords ..... One year and two year survival also significant. (P \ 0.05) ..... enhancing tumor was performed using computer assisted ... ing age, KPS, degree of necrosis, enhancement on.

215KB Sizes 4 Downloads 293 Views

Recommend Documents

Micallef et al. 2008
National Oceanography Centre, University of Southampton, European Way, Southampton, SO14 3ZH, ... 8100±250 cal yrs BP (Haflidason et al., 2005), the ... veyed using state-of-the-art acoustic imaging techni- ...... Freeman, San Francisco.

Schulp et al. 2008
higher tooth count than other species of Prognathodon. The teeth, particularly the anterior ones, are relatively slender compared to most other species of. Prognathodon (with the exception of P. solvayi), and most other mosasaurs, for that matter, bu

Grimm et al. 2008
Feb 24, 2009 - related to this article. A list of selected additional articles on the Science Web sites ... With the advent 10 years ago of National Science ..... The best-documented example of ..... change and a host of global environmental.

2008 Saha et al Biophysical Journal.pdf
Peabody, MA) with a 352–377-nm bandpass filter. This resulted in an IPN. with a high density of pEG at the surface (35). Details regarding peptide grafting to the IPN can be found elsewhere. (29,30), and are described briefly below. After formation

Miller et al. 2008 - Black Croaker.pdf
Amigo que desilusión. No todo es blanco,. O negro: es gris. Todo depende del matiz,. Busca y aprende a distinguir. La luna puede calentar. Whoops! There was a problem loading this page. Retrying... Miller et al. 2008 - Black Croaker.pdf. Miller et a

Burt et al 2008 Marine Biology.pdf
Download. Connect more apps... Try one of the apps below to open or edit this item. Burt et al 2008 Marine Biology.pdf. Burt et al 2008 Marine Biology.pdf. Open.

2008 Saha et al Biophysical Journal.pdf
only recently were the mechanical properties of a stem cell's microenvironment shown to regulate its behavior. It would be. desirable to have independent ...

Claisse et al 2014Platform_Fish_Production_w_supporting_info.pdf ...
Claisse et al 2014Platform_Fish_Production_w_supporting_info.pdf. Claisse et al 2014Platform_Fish_Production_w_supporting_info.pdf. Open. Extract.

et al
Jul 31, 2008 - A new algorithm was developed to extract the biomarker from noisy in vivo data. .... Post Office Box 5800, 6202 AZ Maastricht, Netherlands.3Depart- ment of ... School of Medicine, Broadway Research Building, Room 779, 733.

Stierhoff et al
major influence on subsequent recruitment, particu- larly for ... hypoxia could affect survival rates and recruitment through subtle effects .... using SPSS software.

(Cornelius et al).
rainforest in Chile, IV- dry Chaco in Argentina, and V- tropical forests in Costa Rica (map modified from ..... Chaco is subject to logging and conversion to.

DHM2013_Vignais et al
Table 1: Mean normalized resultant joint force (JF) and joint moment ... the mean joint reaction force of the distal joint was ... OpenSim: open-source software to.

Schmidt et al, in press
At the beginning of the experimental session, participants were asked to read and familiarize themselves with ..... Feldman R., & Eidelman A. I. (2007). Maternal postpartum ... In G. E. Stelmach & J. Requin (Eds.), Tutorials in motor behavior (pp.

VanLavieren et al PolicyReport_LessonsFromTheGulf.pdf ...
VanLavieren et al PolicyReport_LessonsFromTheGulf.pdf. VanLavieren et al PolicyReport_LessonsFromTheGulf.pdf. Open. Extract. Open with. Sign In.

Altenburger et al
Jun 30, 2005 - email: [email protected]. JEL Classification: ... The Universities Act 2002 (official abbreviation: UG 2002), which is still in the stage of .... Thirdly, ICRs can serve marketing purposes by presenting interpretable and.

figovsky et al
biologically active nanochips for seed preparation before planting; enhance seed germination, enhance seed tolerance to pathogens, salinization, draught, frost, ...

Casas et al..pdf
Adoption of Agroforestry Farm Models in Bukidnon-Its Implication to Ecological Services (2013)-Casas et al..pdf. Adoption of Agroforestry Farm Models in ...

Maione et al., 2014 JEthnopharmacol.pdf
Western blot analysis ... (ECL) detection kit and Image Quant 400 GE Healthcare software ... displayed a similar effect compared to TIIA 50 μM (data not shown).

Levendal et al.
data management protocols for data collection to ensure consistency, ...... need to change to a culture of promptly and rigorously analysing data and using the.

Gray et al.
Sep 21, 2009 - related to this article. A list of selected additional articles on the Science Web sites ... 7 articles hosted by HighWire Press; see: cited by. This article has ..... Conference on Austronesian Linguistics, E. Zeitoun,. P. J. K. Li, E

(Cornelius et al).
also because of processes related to forest type and ... tropical and humid cloud forests of Mexico correlated ... forests provide a high variety of cavities ... What do we know about cavity availability for birds ... requirements for large cavities

(Guthery et al).
Peer edited. In My Opinion: .... (research hypothesis) that pre-incubation storage times are longer in ... Longer storage times might permit more eggs to be laid ...

Rius et al.
species settled preferentially in the dark with no geotactic preferences and another 2 showed an inter- action between ...... as larval movement and offspring retention (Petersen. & Svane ... Plessis (Zoology Department, University of Cape Town) for

Nunez et al.
based on simulations and analytic-statistical studies with a volume conductor model. ...... simulated correlations do not agree exactly because analytic solutions.