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Enhanced resection of primary high-grade gliomas using a combination of intraoperative magnetic resonance imaging and intraoperative fluorescence (5-aminolevulinic acid): A single-centre experience
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.232334
Keywords: 5-aminolevulinic acid, flourescence, glioblastoma multiforme, gliomas, intraoperative MRI
The most important goal of surgical resection of high-grade gliomas (HGG) is the radical resection of all tumor tissue that is contrast enhancing on preoperative magnetic resonance imaging (MRI), without causing any major postoperative neurological deficit. This is also independently associated with better survival.[1],[2] Unfortunately, tumor remnants can be difficult to visualize under naked eye, causing contrast-enhancing tissue to be left behind in numerous cases.[3],[4] The advent of intraoperative MRI (iMRI) has allowed neuronavigation to be updated and has helped to further excise residual tumor tissue.[5],[6],[7],[8] A few studies have already shown that continued excision of residual tumor using iMRI and updated neuronavigation is not associated with fresh neurological deficits postoperatively.[9],[10] The benefits of fluorescence-guided resection of HGGs using 5-aminolevulinic acid (5-ALA) has already been proven by a randomized phase III trial,[11] and the advantages of iMRI-guidance in increasing the extent of resection (EOR) has been shown in a randomized trial.[12] We are presenting our experience of using both iMRI and 5-ALA together to increase the EOR of the tumor in patients with HGGs, especially glioblastoma multiforme (GBM). This study was approved by our Institute's Ethical committee and conducted in a prospective manner.
Patient selection and methodology Thirty seven patients with gadolinum-enhanced lesions on preoperative MRI suggestive of HGG (World Health Organisation [WHO] grade IV including GBM) underwent surgical excision using both iMRI and 5-ALA induced fluorescence guidance. Only patients with primary HGG on the final histopathology report were included. All patients were explained regarding the benefits and risks of surgery and the advantages of using 5-ALA prior to obtaining a duly signed informed consent for the procedure. Approximately 4 hours prior to surgical incision, the patient was shifted to a dark room and given 5-ALA in an oral dose of 1 g in 30 ml drinking water. They were then shifted to the operating room covered in a blanket. The surgery was conducted under white-light conditions with a microscope using neuronavigation guidance obtained from a preoperative MRI dataset. During the surgery, the operating neurosurgeon switched between white and blue light filter of the operating microscope to achieve gross total excision until no residual tumor tissue was fluorescing in the surgical cavity.[13] At this point, or whenever there was a doubt regarding the extent of involvement during surgery, an iMRI scan (plain T1-weighted images, T2-weighted images, and gadolinium enhanced T1-weighted images) was performed using BrainSuite and the neuronavigation data was updated automatically.[8] If the iMRI images were suggestive of residual gadolinium-enhanced regions, further resection was carried out. In all cases, an immediate postoperative MRI was carried out to document the EOR. The obtained tumor tissue was sent for histopathological examination, that was conducted based upon the current World Health Organization classification.[14] Postoperatively, the patients were kept in the intensive care unit (ICU) in a dark room for at least 24 hours after ingesting the dye, and a noncontrast computed tomography (CT) scan of the brain was performed at the bedside the next morning using a portable CT machine to check for any complications. The patients were kept under close watch until the day of hospital discharge. As per the recommendations of the local tumor board discussions, the patients received adjuvant treatment based on the final histopathology report. Regular follow-up of the patients was done every 3 months, either over the phone or during their follow-up visits in the Neurosurgery or Radiation Oncology departments. We have analyzed and present various outcome parameters in our series.
Gender distribution The total number of male patients in this study were 29, whereas 8 female patients were included in the study, as per the proposed inclusion criteria. [Table 1]
Age distribution Out of the 37 patients, 15 (40%) were in the age group of 60–69 years, 11 (29%) patients were in age group of 50–59 years, whereas 4 (10%) patients were in age group of 30–39 years and 70–79 years, respectively [Table 2].
Presenting complaints Most of the patients (N = 19, 51%) included in the study presented with chief complaint of headache, which was dull in nature, intermittent, and nonlocalizing. The second most common presenting symptom was memory loss or forgetfulness, which was present in 9 patients (24%). Some patients presented with focal neurological deficit which includes slurring of speech, weakness of limbs, and facial palsy, and one patient presented with foot drop. Seizures were uncommon and only one patient presented with this manifestation. One patient presented with vision loss and one with urinary incontinence. Anatomic location of lesions in the brain Majority of the lesions were found in the frontal (11 patients) and temporal (12 patients) lobes. There were 2 lesions in the parietal lobe. Twelve lesions (32%) were found to be in more than one lobe, i.e., frontotemporal (4 patients), frontoparietal (1 patient), temporoparietal (3 patients), and parieto-occipital (4 patients) [Table 3].
L ateralization of lesions We had 14 (38%) right-sided lesions and 23 (62%) left-sided lesions in which fluorescence guided surgery was done. Volume of tumor This was the most variable feature of the lesions and the volume of the lesions ranged from 1.09 cm 3 to 192.72 cm 3. Most of the lesions (N = 30) had a volume of less than 10 cm 3, whereas rest of the lesions (N = 7) had a volume of more than 50 cm 3. Percentage of resection The median preoperative tumor volume was 20 cm 3 (average 29 cm 3, range 1.09 cm 3 to 192.72 cm 3). Complete removal of all enhancing tumors, as verified by an early postoperative MRI, was achieved in 36 (97.29%) cases. In the remaining one case, the extent of tumor resection was 95% because it was located near the motor area, and further resection was not done as per the surgeon's judgement owing to the risk of postoperative neurological deficit.[14],[15],[16],[17],[18],[19],[20],[21] Intraoperative fluorescence characteristics Any tumor reaching up to the surface shows a pink fluorescence in the blue light filter. In the case of deep-seated lesions, a corticectomy was made and the tumor was identified grossly based on its grayish discoloration. [Table 5] After reaching the tumor, resection was started in white light. The blue light was switched on for identification of the tumor margin, and resection was done under the white and blue light as per the requirements. The tumor tissue showed a variable fluorescence, and blood and necrotic parts of tumors appeared darker. Most of the GBM (World Health Organisation grade IV) lesions showed an intense fluorescence as pink color on blue light activation; and, at the margins of tumor cavity, resection was done in blue light as fluorescence helped in the delineation of malignant tissue from normal tissue [Figure 1], [Figure 2], [Figure 3]. Residual lesion No residual lesion was found among 36 patients (97.29%). Residual lesion was found in 1 (2.7%) patient in whom the lesion was near the eloquent cortex, and further excision would have led to a postoperative deficit, as judged by the operating surgeon. Histology The histopathology, as per the WHO criteria, turned out to be GBM grade IV in 34 (91.89%) patients. while it was different in 3 patients. The report was anaplastic oligodendroglioma grade III in 2 patients, and oligoastrocytoma grade II progressing to grade III in 1 patient. Other histological markers for the presence of a high grade glioma (HGG) were necrosis, mitosis, and microvascular proliferation. Necrosis was present in 30 (81%) patients and mitosis was seen in 31 (83.78%) out of 37 patients. Microvascular proliferation was seen in 33 (89%) patients. Molecular markers Glial cell marker, glial fibrillary acidic protein [GFAP], was positive in all the included patients. p53 was positive in 31 patients and negative in 3 patients. Proliferation marker Ki 67 showed wide variations [Table 4].
Complications Very few cases of adverse effects associated with the use of 5-ALA during glioma surgery have been reported. The main adverse effects were short lived and included itching and redness of the skin. There was no major adverse reaction due to the use of ALA dye in patients. Other complications secondary to the surgical procedure were also noted. Our operating room is separate from the MRI room. Potential patient transfer difficulties related to this design may have occurred; however, no complications directly related to the intraoperative imaging procedure were observed. To date, no untoward events have occurred in association with the use of either magnetic or nonmagnetic instrumentation in the 1.5-T high-field MRI environment. No clinically significant hemorrhage was observed in the immediate post-operative MRI scans. No anesthesia-related problems or complications have been encountered. Distribution of complications The major complications were those that required additional treatment for their management. The patients had wound infection as their main complication in 6 patients (16%). In the early postoperative period (during the first postoperative month), different complications were observed in 3 cases (8%). One patient developed hydrocephalus during the postoperative period and underwent a ventriculoperitoneal shunt insertion. One patient with a lesion situated at the left motor cortex developed increase in weakness on the opposite side; the patient partially recovered after an intensive postoperative physiotherapy and rehabilitation. One patient with a right frontal GBM developed postoperative infection of the bone flap, requiring antibiotic therapy, ultimately resulting in the removal of infected bone flap. Progression-free survival Patients were followed up after surgery till progression was detected by imaging during the follow-up period or when there was development of any new symptom. The last follow up was done in January 2016. All patients underwent postsurgery adjuvant therapies as per the standard guidelines for HGGs. Patients were followed up either during their subsequent outpatient department visits or telephonically. Survival statistics Out of the total 37 patients, 11 patients are still alive, 17 died during the follow-up period, and 9 were lost to follow-up [Table 6]. The mean survival was 587.1 days and the median survival was 491 days with a range of 342 to 943 days [Table 7], [Table 8], [Table 9], [Table 10].
Prolonged survival in HGG patients is proportional to the gross total resection (GTR), which is measured by the absence of contrast-enhanced residual tumor on postoperative scans.[16],[17],[18] It is advisable that radical resection of any GBM should be done without causing any major neurological deterioration as the postoperative functional neurological status is of significant importance in the prognosis of such patients.[19] iMRI-guided and/or 5-ALA fluorescence guided surgery for GBM are reliable methods to improve the extent of resection (EOR).[9],[12],[22],[23],[24] Newer studies, such as ours, have combined 5-ALA and iMRI to achieve the maximum EOR in GBMs or other HGGs. Both the modalities are useful in detecting any tumor tissue left behind unintentionally. The data presented here are in accordance with the findings already published in the current literature.[25] It has already been shown by various published articles that both iMRI and 5-ALA are highly specific in indicating areas of the high grade tumor, may it be in the form of contrast enhancement on T1-weighted image or fluorescence seen during surgery using 5-ALA. Histopathology reports are almost always positive for HGG, if it has already been predicted by the abovementioned modalities. Some authors have gone on to state that 5-ALA fluorescence-guided radical excision of HGGs might sometime lead to temporary neurological deficits.[26],[27] The surgical complications in our series using this modality, however, were within acceptable limits. Another drawback of using 5-ALA is that, if the residual GBM is covered with blood, instruments are placed within it, or there is sagging of the overlying brain into the cavity, it might not emit any fluorescence. This situation could potentially lead to an incomplete resection.[28] Moreover, a trivial, yet worth mentioning, factor is the photobleaching caused by white-light, that might impair the fluorescence.[29],[30] 5-ALA fluorescence has a limited sensitivity and a negative predictive value.[31] Low-field MRI alone might not be enough to detect tumor tissue, and in such cases, 5-ALA proves to be useful.[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43] A few studies reporting the combination of iMRI and 5-ALA have been published earlier, namely by Coburger et al.,[25] Roder et al.,[36] Eyüpoglu et al.,[37] Tsugu et al.,[38] and Gessler et al.[43] All these reports included a small group of patients or they were not randomized. Therefore, further studies will be required to actually ascertain the comparative or additive value of these modalities. Radical tumor resection is associated with better patient outcomes [12],[39] and prolonged survival in most cases undergoing GTR in patients with a GBM.[40] The most plausible explanation is that the cells along the margins of the tumor are frequently ignored during resection; however, in reality, they are the most important determinants of fate of the patients.[41],[42],[43],[44],[45] In our patient series, the median overall survival (OS) was more than 1 year (374 days) after surgery.[42] No major conclusions can be drawn based on the published series; however, continued work in this regard will further change the way GBM surgery has been conceptualized. Our centre is one of the very few centres in India using 5-ALA in fluorescence-guided surgery for HGGs. At the end of our follow-up period, 11 patients were still alive. Although the patients were not classified based on the latest WHO histopathological classification of 2016, future analysis will definitely include the same. We plan to continue using 5-ALA and evaluating the operative results in the follow up period regularly. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]
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