5-aminolevulinic-acid guided resection

5-aminolevulinic-acid guided resection

In addition to stereotactic localization as well as intraoperative brain mapping, techniques to enhance visual identification of tumor intraoperatively may be used and include 5-aminolevulinic-acid (5-ALA). 5-ALA is metabolized into fluorescent porphyrins, which accumulate in malignant glioma cells. These property permits use of ultraviolet illumination during surgery as an adjunct to map out the tumor. This has been proven with RCT where the use of 5-ALA leads to more complete resection (65% vs. 36%, p < 0.0001), which translates into a higher 6-month progression-free survival (41% vs. 21.1%, p = 0.0003) but no effect on OS 1).


Fluorescein can be used as a viable alternative to 5-ALA for intraoperative fluorescent guidance in brain tumor surgery. Comparative, prospective, and randomized studies are much needed 2)

Indications

Doses

The highest visible and measurable fluorescence was yielded by 20 mg/kg. No fluorescence was elicited at 0.2 mg/kg. Increasing 5-ALA doses did not result in proportional increases in tissue fluorescence or PPIX accumulation in plasma, indicating that doses higher than 20 mg/kg will not elicit useful increases in fluorescence 3).


Application of 5mg/kg ALA was evaluated as equally reliable as the higher dose regarding the diagnostic performance when guidance was performed using a spectroscopic system. Moreover, no PpIX was detected in the skin of the patients 4).

Over time, several other tumour entities have been identified to metabolize 5-ALA and show a similar fluorescence pattern during surgical resection.

Further research is warranted to determine the role of 5-ALA accumulation in post-ischaemic and inflammatory brain tissue 5).

The positive predictive values (PPVs), of utilizing the most robust ALA fluorescence intensity (lava-like orange) as a predictor of tumor presence is high. However, the negative predictive values (NPVs), of utilizing the absence of fluorescence as an indicator of no tumor is poor. ALA intensity is a strong predictor for degree of tumor cellularity for the most fluorescent areas but less so for lower ALA intensities. Even in the absence of tumor cells, reactive changes may lead to ALA fluorescence 6).

Reviews

Senders et al., systematically review all clinically tested fluorescent agents for application in fluorescence guided surgery (FGS) for glioma and all preclinically tested agents with the potential for FGS for glioma.

They searched the PubMed and Embase databases for all potentially relevant studies through March 2016.

They assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.

The search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5 aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.

5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives. 7).

Complications

Despite its benefits, 5-ALA has not reached widespread popularity in the United States, primarily because of lack of Food and Drug Administration (FDA) approval. Even if it were approved, 5-ALA does have specific limitations including low depth of penetration, autofluorescence of background parenchyma


Findings suggest that the administration of 5-ALA or the combined effect of 5-ALA, anaesthesia and tumour resection can cause a mild and reversible elevation in liver enzymes. It therefore appears safe to change the regime of monitoring. Routine blood samples are thus abolished, though caution remains necessary in patients with known liver impairment 8).

For near infrared imaging, additional investigators have explored fluorescein as well as novel near-infrared (NIR) agents 9) 10) 11)

Stummer et al. showed that 5–ALA guided resections carry a higher risk of post-operative neurological deterioration than conventional resections (26% vs 15%, respectively), even though the difference vanished within weeks 12).

Just as tumour tissue is often indiscernible from normal brain tissue, functionally critical tissues are indistinguishable from tissues with less clinically relevant functions.

Thus, knowing when to stop a resection due to proximity to areas of crucial neurological functions is of obvious and utmost importance. Detailed knowledge of the normal brain anatomy and distribution of function is not sufficient during glioma resection. Interindividual variability and functional relocation (i.e., plasticity) induced by the presence of an infiltrating tumour 13) requires an exact functional brain map at the site of surgery in order to spare areas involved in crucial (so-called eloquent) functions. Preoperative localisation of function, either with functional MRI (fMRI) or navigated transcranial magnetic stimulation (nTMS), provides an approximate map 14) 15).

Furthermore, intra-operative direct cortical and subcortical electrical stimulation (DCS) for functional analysis of the tissue in the tumour’s infiltration zone is required for accurate identification of areas that need to be spared in order to retain the patient’s functional integrity 16) 17). Motor evoked potentials (MEP) provide real-time information on the integrity of the primary motor cortex and the corticospinal tract 18). Direct cortical mapping and phase reversal identify the primary motor and sensory cortices. Subcortical mapping can estimate the distance to the pyramidal tract, acting as guidance close to functionally critical areas 19). When integrated into the existing surgical tools, continuous and dynamic mapping enables more extensive resection while simultaneously protecting motor function 20). Using these techniques and a detailed electrophysiological “Bern-concept”, a group achieved complete motor function protection in 96% of patients with high-risk motor eloquent tumours 21). Furthermore, localisation of cortical and subcortical regions relevant to language function is essential for speech preservation during resection of gliomas in proximity to presumed speech areas 22) and requires the patient to be awake during the brain mapping part of surgery. Similarly, intra-operative mapping of visual functions may contribute to increased resections while avoiding tissue essential for vision within the temporal and occipital lobes 23).

References

1)

Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ; ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006 May;7(5):392-401. PubMed PMID: 16648043.
2)

Hansen RW, Pedersen CB, Halle B, Korshoej AR, Schulz MK, Kristensen BW, Poulsen FR. Comparison of 5-aminolevulinic acid and sodium fluorescein for intraoperative tumor visualization in patients with high-grade gliomas: a single-center retrospective study. J Neurosurg. 2019 Oct 4:1-8. doi: 10.3171/2019.6.JNS191531. [Epub ahead of print] PubMed PMID: 31585425.
3)

Stummer W, Stepp H, Wiestler OD, Pichlmeier U. Randomized, Prospective Double-Blinded Study Comparing 3 Different Doses of 5-Aminolevulinic Acid for Fluorescence-Guided Resections of Malignant Gliomas. Neurosurgery. 2017 Apr 1. doi: 10.1093/neuros/nyx074. [Epub ahead of print] PubMed PMID: 28379547.
4)

Haj-Hosseini N, Richter J, Hallbeck M, Wårdell K. Low dose 5-aminolevulinic acid: Implications in spectroscopic measurements during brain tumor surgery. Photodiagnosis Photodyn Ther. 2015 Mar 25. pii: S1572-1000(15)00031-9. doi: 10.1016/j.pdpdt.2015.03.004. [Epub ahead of print] PubMed PMID: 25818546.
5)

Behling F, Hennersdorf F, Bornemann A, Tatagiba M, Skardelly M. 5-Aminolevulinic acid accumulation in a cerebral infarction mimicking high-grade glioma, a case report. World Neurosurg. 2016 May 10. pii: S1878-8750(16)30271-6. doi: 10.1016/j.wneu.2016.05.009. [Epub ahead of print] PubMed PMID: 27178236.
6)

Lau D, Hervey-Jumper SL, Chang S, Molinaro AM, McDermott MW, Phillips JJ, Berger MS. A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas. J Neurosurg. 2015 Nov 6:1-10. [Epub ahead of print] PubMed PMID: 26544781.
7)

Senders JT, Muskens IS, Schnoor R, Karhade AV, Cote DJ, Smith TR, Broekman ML. Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results. Acta Neurochir (Wien). 2017 Jan;159(1):151-167. doi: 10.1007/s00701-016-3028-5. Review. PubMed PMID: 27878374; PubMed Central PMCID: PMC5177668.
8)

Offersen CM, Skjoeth-Rasmussen J. Evaluation of the risk of liver damage from the use of 5-aminolevulinic acid for intra-operative identification and resection in patients with malignant gliomas. Acta Neurochir (Wien). 2016 Nov 10. [Epub ahead of print] PubMed PMID: 27832337.
9)

Shinoda J, Yano H, Yoshimura SI, et al. Fluorescence-guided resection of glioblastoma multiforme by using high-dose fluorescein sodium. Technical note. J Neurosurg. 2003;99(3):597–603.
10)

Rey-Dios R, Cohen-Gadol AA. Technical principles and neurosurgical applications of fluorescein fluorescence using a microscope-integrated fluorescence module. Acta Neurochir (Wien). 2013;155(4):701–706.
11)

Swanson KI, Clark PA, Zhang RR, et al. Fluorescent cancer-selective alkylphosphocholine analogs for intraoperative glioma detection. Neurosurgery. 2015;76(2):115–123.
12)

Stummer W1, Tonn JC, Mehdorn HM, Nestler U, Franz K, Goetz C, et al. ALA-Glioma Study Group. Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5–aminolevulinic acid glioma resection study. J Neurosurg. 2011;114(3):613–23. doi: 10.3171/2010.3
13)

Ojemann G, Ojemann J, Lettich E, Berger M. Cortical language localization in left, dominant hemisphere. An electrical stimulation mapping investigation in 117 patients. J Neurosurg. 1989;71(3):316–26.
14)

Seghier ML, Lazeyras F, Pegna AJ, Annoni JM, Zimine I, Mayer E, et al. Variability of fMRI activation during a phonological and semantic language task in healthy subjects. Hum Brain Mapp. 2004;23(3):140–55.
15)

Krieg SM, Shiban E, Buchmann N, Gempt J, Foerschler A, Meyer B, et al. Utility of presurgical navigated transcranial magnetic brain stimulation for the resection of tumors in eloquent motor areas. J Neurosurg. 2012;116(5):994–1001. doi: 10.3171/2011.12.JNS111524
16) , 22)

Duffau H, Capelle L, Sichez N, Denvil D, Lopes M, Sichez JP, et al. Intraoperative mapping of the subcortical language pathways using direct stimulations. An anatomo-functional study. Brain. 2002;125(1):199–214.
17)

Duffau H, Capelle L, Denvil D, Sichez N, Gatignol P, Taillandier L, et al. Usefulness of intraoperative electrical subcortical mapping during surgery for low-grade gliomas located within eloquent brain regions: functional results in a consecutive series of 103 patients. J Neurosurg. 2003;98(4):764–78.
18)

Seidel K, Beck J, Stieglitz L, Schucht P, Raabe A. The warning-sign hierarchy between quantitative subcortical motor mapping and continuous motor evoked potential monitoring during resection of supratentorial brain tumors. J Neurosurg. 2013;118(2):287–96.
19)

Seidel K, Beck J, Stieglitz L, Schucht P, Raabe A. Low Threshold Monopolar Motor Mapping for Resection of Primary Motor Cortex Tumors. Neurosurgery. 2012;71(1):104–14.
20)

Raabe A, Beck J, Schucht P, Seidel K. Continuous dynamic mapping of the corticospinal tract during surgery of motor eloquent brain tumors: evaluation of a new method. J Neurosurg. 2014;120(5)1015–24. doi: 10.3171/2014.1.JNS13909.
21)

Schucht P, Seidel K. Beck J, Murek M, Jilch A, Wiest R, et al. Intraoperative monopolar mapping during 5-ALA-guided resections of glioblastomas adjacent to motor eloquent areas: evaluation of resection rates and neurological outcome. Neurosurg Focus. 2014;27(6):E16.
23)

Gras-Combe G, Moritz-Gasser S, Herbet G, Duffau H. Intraoperative subcortical electrical mapping of optic radiations in awake surgery for glioma involving visual pathways. J Neurosurg. 2012;117(3):466–73.

Diffusion tensor imaging for brain tumor resection

Diffusion tensor imaging for brain tumor resection

Preserving subcortical connectivity is crucial in optimizing functional outcomes of patients undergoing surgery for intraaxial tumors.

Diffusion tensor imaging (DTI) attempts to aid in the preservation of these subcortical networks by providing a framework for localizing these tracts in relation to the surgical target. DTI takes advantage of the anisotropic diffusion of water along white matter fiber bundles, which can be assessed with magnetic resonance imaging (MRI). Postprocessing platforms are used to map the tracts, which can then be integrated into neuronavigation. This permits the neurosurgeon to ascertain the location and orientation of major white matter tracts for preoperative and intraoperative decision making.


Diffusion tensor imaging (DTI) based on echo planar imaging (EPI) can suffer from geometric image distortions in comparison to conventional anatomical magnetic resonance imaging (MRI). Therefore, DTI-derived information, such as fiber tractography (FT) used for treatment planning of brain tumors, might be associated with spatial inaccuracies when linearly projected on anatomical MRI.

Gerhardt et al., indicated that semi-elastic image fusion can be used for retrospective distortion correction of DTI data acquired for image guidance, such as DTI FT as used for a broad range of clinical indications 1).


The exact utility and practical application of DTI in brain tumor resection continue to be refined. On the one hand, the historical difficulty in obtaining DTI (especially with respect to postprocessing) has made its implementation in neurosurgical practices somewhat limited. Adding to this barrier, the majority of studies describing DTI are placed within a methodological framework that emphasizes the physics and computational analysis of the modality itself, a perspective that is less directly applicable to neurosurgeons wanting to apply DTI to clinical practice. On the other hand, fundamental questions about the utility of the tool have been raised by leaders in the field 2) 3) 4) 5) 6) 7) 8) 9).


Conventional white matter (WM) imaging approaches, such as diffusion tensor imaging (DTI), have been used to preoperatively identify the location of affected WM tracts in patients with intracranial tumors in order to maximize the extent of resection and potentially reduce postoperative morbidity.

Preoperative diffusion tensor imaging (DTI) is used to demonstrate corticospinal tract (CST) position. Intraoperative brain shifts may limit preoperative DTI value, and studies characterizing such shifts are lacking.

For nonenhancing intraaxial tumors, preoperative DTI is a reliable method for assessing intraoperative tumor-to-CST distance because of minimal intraoperative shift, a finding that is important in the interpretation of subcortical motor evoked potential to maximize extent of resection and to preserve motor function. In resection of intra-axial enhancing tumors, intraoperative imaging studies are crucial to compensate for brain shift 10).

Case series

A total of 34 patients were included in this study. Pre-operative contrast-enhanced magnetic resonance imaging and DTI scans of the patients were taken into consideration. Pre- and post-operative neurological examinations were performed and the outcome was assessed.

Preoperative planning of surgical corridor and extent of resection were planned so that maximum possible resection could be achieved without disturbing the WM tracts. DTI indicated the involvement of fiber tracts. A total of 21 (61.7%) patients had a displacement of tracts only and they were not invaded by tumor. A total of 11 (32.3%) patients had an invasion of tracts by the tumor, whereas in 4 (11.7%) patients the tracts were disrupted. Postoperative neurologic examination revealed deterioration of motor power in 4 (11.7%) patients, deterioration of language function in 3 (8.82%) patients, and memory in one patient. Total resection was achieved in 11/18 (61.1%) patients who had displacement of fibers, whereas it was achieved in 5/16 (31.2%) patients when there was infiltration/disruption of tracts.

DTI provided crucial information regarding the infiltration of the tract and their displaced course due to the tumor. This study indicates that it is a very important tool for the preoperative planning of surgery. The involvement of WM tracts is a strong predictor of the surgical outcome 11).

References

1)

Gerhardt J, Sollmann N, Hiepe P, Kirschke JS, Meyer B, Krieg SM, Ringel F. Retrospective distortion correction of diffusion tensor imaging data by semi-elastic image fusion – Evaluation by means of anatomical landmarks. Clin Neurol Neurosurg. 2019 Jun 10;183:105387. doi: 10.1016/j.clineuro.2019.105387. [Epub ahead of print] PubMed PMID: 31228706.
2)

Nimsky C. Fiber tracking: we should move beyond diffusion tensor imaging. World Neurosurg. 2014;82(1-2):35–36.
3)

Farquharson STournier JDCalamante F. et al White matter fiber tractography: why we need to move beyond DTI. J Neurosurg. 2013;118(6):1367–1377.
4)

Fernandez-Miranda JC. Editorial: beyond diffusion tensor imaging. J Neurosurg. 2013;118(6):1363–1365; discussion 1365-1366.
5)

Lerner AMogensen MAKim PEShiroishi MSHwang DHLaw M. Clinical applications of diffusion tensor imaging. World Neurosurg. 2014;82(1-2):96–109.
6)

Feigl GCHiergeist WFellner C. et al Magnetic resonance imaging diffusion tensor tractography: evaluation of anatomic accuracy of different fiber tracking software packages. World Neurosurg. 2014;81(1):144–150.
7)

Duffau H. The dangers of magnetic resonance imaging diffusion tensor tractography in brain surgery. World Neurosurg. 2014;81(1):56–58.
8)

Duffau H. Diffusion tensor imaging is a research and educational tool, but not yet a clinical tool. World Neurosurg. 2014;82(1-2):e43–e45.
9)

Potgieser ARWagemakers Mvan Hulzen ALde Jong BMHoving EWGroen RJ. The role of diffusion tensor imaging in brain tumor surgery: a review of the literature. Clin Neurol Neurosurg. 2014;124C:51–58.
10)

Shahar T, Rozovski U, Marko NF, Tummala S, Ziu M, Weinberg JS, Rao G, Kumar VA, Sawaya R, Prabhu SS. Preoperative Imaging to Predict Intraoperative Changes in Tumor-to-Corticospinal Tract Distance: An Analysis of 45 Cases Using High-Field Intraoperative Magnetic Resonance Imaging. Neurosurgery. 2014 Jul;75(1):23-30. doi: 10.1227/NEU.0000000000000338. PubMed PMID: 24618800.
11)

Dubey A, Kataria R, Sinha VD. Role of Diffusion Tensor Imaging in Brain Tumor Surgery. Asian J Neurosurg. 2018 Apr-Jun;13(2):302-306. doi: 10.4103/ajns.AJNS_226_16. PubMed PMID: 29682025; PubMed Central PMCID: PMC5898096.

Extent of resection in glioblastoma

The value of incomplete resection in Glioblastoma surgery remains questionable. If gross total resection (GTR) cannot be safely achieved, biopsy only might be used as an alternative surgical strategy 1).

see Wounded glioma syndrome.

The impact of extent of resection (EOR) on survival in glioblastoma multiforme treatment (GBM) continues to be a point of debate despite multiple studies demonstrating that increasing EOR likely extends survival for these patients. In addition, contrast-enhancing residual tumor volume (CE-RTV) alone has rarely been analyzed quantitatively to determine if it is a predictor of outcome.

CE-RTV and EOR were found to be significant predictors of survival after GBM resection. CERTV was the more significant predictor of survival compared with EOR, suggesting that the volume of residual contrast-enhancing tumor may be a more accurate and meaningful reflection of the pathobiology of GBM 2).

Difficulties

It is difficult to reproducibly judge EOR in studies due to the lack of reliable tumor segmentation methods, especially for postoperative magnetic resonance imaging (MRI) scans. Therefore, a reliable, easily distributable segmentation method is needed to permit valid comparison, especially across multiple sites.

Cordova et al. report a segmentation method that combines versatile region-of-interest blob generation with automated clustering methods. Applied this to glioblastoma cases undergoing FGS and matched controls to illustrate the method’s reliability and accuracy. Agreement and interrater variability between segmentations were assessed using the concordance correlation coefficient, and spatial accuracy was determined using the Dice similarity index and mean Euclidean distance. Fuzzy C-means clustering with three classes was the best performing method, generating volumes with high agreement with manual contouring and high interrater agreement preoperatively and postoperatively. The proposed segmentation method allows tumor volume measurements of contrast-enhanced T 1-weighted images in the unbiased, reproducible fashion necessary for quantifying EOR in multicenter trials 3).

Maximal safe resection

Safely performed maximal surgical resection is shown to significantly increase progression free survival and overall survival while maximizing quality of life. Upon invariable tumor recurrence, re-resection also is shown to impact survival in a select group of patients. As adjuvant therapy continues to improve survival, the role of surgical resection in the treatment of glioblastoma looks to be further defined.


During surgery, identifying margins of brain tumors, particularly glioblastomas (GBMs) and highly invasive neoplasms, remains a technical challenge. Thus, for both benign and malignant brain tumors, the most common cause of relapse is local recurrence at the resection margins. At the time of the operation, surgeons typically use visual inspection and tactile discrimination to differentiate tumor margins from surrounding normal brain parenchyma. In addition, imaging adjuncts such as navigation and intraoperative ultrasound can provide value. However, this method has many limitations, which accounts for the high rate of local failure.

Intraoperative adjunctive technologies, such as imaging-based navigational systems, have been useful in allowing the surgeon to estimate areas of contrast enhancement, which likely represent tumor. Although ultrasound-based re-registration can be used to account for brain shift, navigation alone is hampered by the inaccuracies attributable to brain shift and poor resolution when performing surgery in vivo. For the past 2 decades, intraoperative fluorescent contrast agents have been proposed to aid the neurosurgeon in identifying tumor tissue during surgery. The most popular approach has been fluorescent-guided intraoperative imaging with 5 aminolevulinic acid fluorescence guided resection. This method has been studied since the 1990s 4) 5)

It is difficult to reproducibly judge extent of resection (EOR in these studies due to the lack of reliable tumor segmentation methods, especially for postoperative magnetic resonance imaging (MRI) scans. Therefore, a reliable, easily distributable segmentation method is needed to permit valid comparison, especially across multiple sites 6).

Treatment advances will depend on identifying agents that target mechanistic vulnerabilities that are relevant to specific subgroups of patients; increasing patient enrollment into clinical trials is essential to accelerate the development of patient-tailored treatments 7).


Most studies that examine the notion of gross total resection (GTR) in glioblastoma treatment are conducted with the assumption that extended survival is universally desirable 8).

There are limited data in terms of how such survival benefits should be weighed against the risk of the surgery and the impact of surgical morbidity on the patient’s quality of life 9).

To study this issue, Chen et al., designed a survey entitled Putting yourself in your patient’s shoes: a pilot study of physician personal preferences for treatment of glioblastoma (U.C.S.D. institutional review board protocol no. 151821), where they survey physician members who have cared for glioblastoma patients. These physicians are well-acquainted with the consequences of surgery performed for glioblastoma located in different regions.

They pose the question of whether the respondent would elect for GTR if s/he were afflicted with glioblastoma located in the right frontal lobe, right hemisphere, left hemisphere, or the posterior corpus callosum.

Information on physician age, marital status, medical specialty (neurosurgery, neuro-oncology, medical oncology, neuroradiology, neuropathology or radiation oncology), years of practice, and personal values will be collected.

They would like to make neurosurgeons in Europe aware of this study, and to invite them to take part in it. They hope this study will give us more insight into our own preferences as physicans, when faced with the decision we council our patients on how to make on a daily basis.

To participate in the study please go to the following webpage by 31 October 2016: http://www.surveymonkey.com/r/Eu_preference_GBM 10).

Case series

Data from Extent of resection in glioblastoma patients who underwent gross total resection (GTR), subtotal resection (STR), or open biopsybetween 2005 and 2014 were retrieved from the Surveillance, Epidemiology, and End Results database in the Seoul National University College of Medicine.

Univariate and multivariate analyses for overall survival (OS) were performed. Between 2005-2009 and 2010-2014, the proportion of GTR and STR performed increased from 41.4 to 42.3% and 33.0 to 37.1%, respectively. EOR only affected OS in the 3 years after diagnosis. Median survival in the GTR (n = 4155), STR (n = 3498), and open biopsy (n = 2258) groups was 17, 13, and 13 months, respectively (p < .001). STR showed no significant difference in OS from open biopsy (p = .33). GTR increased OS for midline-crossing tumors. Although STR was more frequently performed than GTR for tumors ≥ 6 cm in size, GTR significantly increased the OS rate relative to STR for tumors 6-8 cm in size (p = .001). For tumors ≥ 8 cm, STR was comparable to GTR (p = .61) and superior to open biopsy (p = .05). GTR needs to be performed more frequently for glioblastoma measuring ≥ 6 cm or that have crossed the midline to increase OS. STR was marginally superior to open biopsy when the tumor was ≥ 8 cm 11).

2017

Esquenazi et al. retrospectively evaluated 86 consecutive patients with primary GBM, managed by the senior author, using a subpial resection technique with or without carmustine wafer implantation. Multivariate Cox proportional hazards regression was used to analyze clinical, radiological, and outcome variables. Overall impacts of extent of resection (EOR) and BCNU wafer placement were compared using Kaplan-Meier survival analysis.

Mean patient age was 56 years. The median OS for the group was 18.1 months. Median OS for patients undergoing gross total, near-total, and subtotal resection were 54, 16.5, and 13.2 months, respectively. Patients undergoing near-total resection ( P = .05) or gross total resection ( P < .01) experienced statistically significant longer survival time than patients undergoing subtotal resection as well as patients undergoing ≥95% EOR ( P < .01) when compared to <95% EOR. The addition of BCNU wafers had no survival advantage.

The subpial technique extends the resection beyond the contrast enhancement and is associated with an overall survival beyond that seen in similar series where resection of the enhancement portion is performed. The effect of supratotal resection on survival exceeded the effects of age, Karnofsky performance score, and tumor volume. A prospective study would help to quantify the impact of the subpial technique on quality of life and survival as compared to a traditional resection limited to the enhancing tumor 12).

2015

Coburger et al. prospectively enrolled 33 patients with GBMs eligible for gross-total-resection(GTR) and performed a combined approach using 5-ALA and iMRI. As a control group, we performed a retrospective matched pair assessment, based on 144 patients with iMRI-assisted surgery. Matching criteria were, MGMT promotor methylation, recurrent surgery, eloquent location, tumor size and age. Only patients with an intended GTR and primary GBMs were included. We calculated Kaplan Mayer estimates to compare OS and PFS using the Log-Rank-Test. We used the T-test to compare volumetric results of EoR and the Chi-Square-Test to compare new permanent neurological deficits (nPND) and general complications between the two groups.

Median follow up was 31 months. No significant differences between both groups were found concerning the matching criteria. GTR was achieved significantly more often (p <0.010) using 5-ALA&iMRI (100%) compared to iMRI alone (82%). Mean EoR was significantly (p<0.004) higher in 5-ALA&iMRI-group (99.7%) than in iMRI-alone-group (97.4%) Rate of complications did not differ significantly between groups (21% iMRI-group, 27%5-ALA&iMRI-group, p<0.518). nPND were found in 6% in both groups. Median PFS (6 mo resp.; p<0.309) and median OS (iMRI:17 mo; 5-ALA&iMRI-group: 18 mo; p<0.708)) were not significantly different between both groups.

We found a significant increase of EoR when combining 5-ALA&iMRI compared to use of iMRI alone. Maximizing EoR did not lead to an increase of complications or neurological deficits if used with neurophysiological monitoring in eloquent lesions. No final conclusion can be drawn whether a further increase of EoR benefits patient’s progression free survival and overall survival 13).

2014

retrospective review of 128 patients who underwent primary resection of supratentorial GBM followed by standard radiation/chemotherapy was undertaken utilizing quantitative, volumetric analysis of pre- and postoperative MR images. The results were compared with clinical data obtained from the patients’ medical records.

At analysis, 8% of patients were alive, and no patients were lost to follow-up. The overall median survival was 13.8 months, with a median Karnofsky Performance Scale (KPS) score of 90 at presentation. The median contrast-enhancing preoperative tumor volume (CE-PTV) was 29.0 cm3, and CE-RTV was 1.2 cm3, equating to a 95.8% median EOR. The median T2/F-RV was 36.8 cm3. CE-PTV, CE-RTV, T2/F-RV, and EOR were all statistically significant predictors of survival when controlling for age and KPS score. A statistically significant benefit in survival was seen with a CE-RTV less than 2 cm3 or an EOR greater than 98%. Evaluation of the volumetric analysis methodology was performed by observers of varying degrees of experience-an attending neurosurgeon, a fellow, and a medical student. Both the medical student and fellow recorded correlation coefficients of 0.98 when compared with the attending surgeon’s measured volumes of CE-PTV, while for CE-RTV, correlation coefficients of 0.67 and 0.71 (medical student and fellow, respectively) were obtained.

CE-RTV and EOR were found to be significant predictors of survival after GBM resection. CERTV was the more significant predictor of survival compared with EOR, suggesting that the volume of residual contrast-enhancing tumor may be a more accurate and meaningful reflection of the pathobiology of GBM 14).

2013

Of 345 patients, 273 underwent open tumor resection and 72 biopsies; 125 patients had gross total resections (GTRs) and 148, incomplete resections. Surgery-related morbidity was lower after biopsy (1.4% versus 12.1%, P = 0.007). 64.3% of patients received radiotherapy and chemotherapy (RT plus CT), 20.0% RT alone, 4.3% CT alone, and 11.3% best supportive care as an initial treatment. Patients ≤60 years with a Karnofsky performance score (KPS) of ≥90 were more likely to receive RT plus CT (P < 0.01). Median overall survival (OS) (progression free survival; PFS) ranged from 33.2 months (15 months) for patients with MGMT-methylated tumors after GTR and RT plus CT to 3.0 months (2.4 months) for biopsied patients receiving supportive care only. Favorable prognostic factors in multivariate analyses for OS were age ≤60 years [hazard ratio (HR) = 0.52; P < 0.001], preoperative KPS of ≥80 (HR = 0.55; P < 0.001), GTR (HR = 0.60; P = 0.003), MGMT promoter methylation (HR = 0.44; P < 0.001), and RT plus CT (HR = 0.18, P < 0.001); patients undergoing incomplete resection did not better than those receiving biopsy only (HR = 0.85; P = 0.31).

The value of incomplete resection remains questionable. If GTR cannot be safely achieved, biopsy only might be used as an alternative surgical strategy 15).

1999

retrospectively analyzed preoperative and postoperative radiographic tumor volumes in 92 patients who underwent hemispheric glioblastoma multiforme operations (107) to determine the factors that affect time to tumor progression (TTP) and overall survival.

METHODS: Quantification of tumor volumes was based on a previously described method involving computerized image analysis of contrast enhancing tumor on computerized tomography or magnetic resonance imaging scans.

RESULTS: Among the variables analyzed, preoperative Karnofsky Performance Status (KPS) (p < 0.05), chemotherapy (p < 0.05), percent of resection (POR) (p < 0.001), and volume of residual disease (VRD) (p < 0.001) had a significant effect on TTP. Factors that affected survival were age (p < 0.05), preoperative KPS (p = 0.05), postoperative KPS (p < 0.005), POR (p < 0.0005), and VRD (p < 0.0001). Greater resections did not compromise the quality of life, and patients without any residual disease had a better postoperative KPS than those patients who received less than total resections.

CONCLUSIONS: The extent of tumor removal and the amount of residual tumor volume, documented on postoperative imaging studies, are highly significant factors affecting the median time to tumor progression and median survival for patients with glioblastoma multiforme of the cerebral hemisphere 16).

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Grabowski MM, Recinos PF, Nowacki AS, Schroeder JL, Angelov L, Barnett GH, Vogelbaum MA. Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma. J Neurosurg. 2014 Sep 5:1-9. [Epub ahead of print] PubMed PMID: 25192475.
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