|Year : 2020 | Volume
| Issue : 2 | Page : 80-86
Adjuvant use of fluorescein sodium for maximizing resection of high-grade gliomas: An institutional experience with review of the literature
Ashish Acharya1, Sarvpreet Singh Grewal2, B Paul Sudhakar John2, Ravindra Kumar Bind1
1 Department of Neurosurgery, Christian Medical College, Ludhiana, Punjab, India
2 Department of Neurosurgery, Christian Medical College and Hospital, Ludhiana, Punjab, India
|Date of Submission||11-Aug-2020|
|Date of Acceptance||29-Nov-2020|
|Date of Web Publication||26-Dec-2020|
Dr. Ashish Acharya
Department of Neurosurgery, Christian Medical College, Ludhiana, Punjab
Source of Support: None, Conflict of Interest: None
Background: The extent of resection of high-grade gliomas (HGGs), in order to limit tumor recurrence and above all to improve disease-free survival rates cannot be overstated. Several fluorescent biomarkers have been tested and are in use to aid intraoperative identification of residual tumor; 5aminolevulinic acid and fluorescein sodium are now playing a pivotal role in glioma surgery. A retrospective analysis on 29 patients operated for HGGs and the results are presented here.
Materials and Methods: Data of 29 consecutive patients with HGG have been collected in our study (16 males and 13 females; mean age: 60.3 years, range: 23–90 years). Fluorescein (7 mg/kg of body weight) was injected intravenously right after the induction of general anesthesia. A YELLOW 560 filter was used on a Leica M530 OHX surgical microscope (Leica microsystems, Wetzlar, Germany) to aid in a complete microsurgical tumor removal. Glioma resection and quality of life were evaluated preoperative and postoperatively.
Results: Gross total resection was achieved in 41.3% (n = 12) of patients. A subtotal resection (>95%) was achieved in 48.2% (n = 14) of them, while a PR (<95%) was obtained in 10.3% (n = 3) of patients. Overall, in 89.6% (n = 26) of patients who underwent fluorescence-guided surgery, the resection rate achieved was >95%. No adverse effects correlated to fluorescein have been recorded.
Conclusions: Fluorescein proved itself to be safe and abundantly effective in the resection of HGGs, allowing a high rate of gross total removal of contrast-enhanced tumor areas.
Keywords: 5-aminolevulinic acid, extent of resection, fluorescein sodium, high-grade gliomas, YELLOW 560 filter
|How to cite this article:|
Acharya A, Grewal SS, John B P, Bind RK. Adjuvant use of fluorescein sodium for maximizing resection of high-grade gliomas: An institutional experience with review of the literature. Int J Neurooncol 2020;3:80-6
|How to cite this URL:|
Acharya A, Grewal SS, John B P, Bind RK. Adjuvant use of fluorescein sodium for maximizing resection of high-grade gliomas: An institutional experience with review of the literature. Int J Neurooncol [serial online] 2020 [cited 2021 Jun 18];3:80-6. Available from: https://www.Internationaljneurooncology.com/text.asp?2020/3/2/80/305063
| Introduction|| |
Glioblastoma is the most common primary malignant adult brain tumors. Given its poor prognosis, treatment and determination of extent of resection (EOR) to enhance overall survival continue to be a greatly researched topic. Currently, the frontline treatment for newly diagnosed glioblastoma is its microsurgical resection with additional radiation therapy and chemotherapy. Notwithstanding advances in surgical procedure and technique, this multimodal approach only results in a median overall survival of 12–15 months., Given that no other modalities have appeared to supplant this surgical approach, it still remains the first-line therapy. Interestingly, the most compelling evidence exists for gliomas, where volumetric analyses have shown in both insular and hemispheric lesions, greater EOR is associated with a survival benefit, specifically improved overall survival, progression-free survival, and malignant progression-free survival. Multiple variables positively affect the prognosis for high-grade glioma (HGG) include young age, tumor location, radiological features, recurrence, and the opportunity to perform an adjuvant therapy in the postoperative course. Studies have reported a strong positive correlation among EOR of HGG and overall survival with maximal survival benefit for resection volumes of above 98% and when surgery is followed by adjuvant radiotherapy and chemotherapy.,,, Lacroix et al. were the first to demonstrate that not only resection, but EOR is associated with longer survival time in glioblastoma multiform (GBM) patients. This retrospective analysis of 416 patients, including newly diagnosed and recurrent GBM concluded that a ≥98% EOR, is necessary to improve survival significantly. Moreover, they showed a hazard ratio of 1.4 for patients who underwent subtotal resection (STR) versus gross total resection (GTR) at initial presentation, which proved to be an independent predictor of survival. Unfortunately, the similarity of intraoperative tumor appearance and subadjacent brain parenchyma under the operating microscope (OME) makes a complete tumor resection challenging without imparting new deficits. In recent years, intraoperative tumor fluorescence has emerged in glioma resection procedures to help intraoperative differentiation of neoplastic tissue from the normal parenchyma to maximize the EOR of glioma. Out of multiple fluorescent biomarkers that have been used to enhance EOR: 5-aminolevulinic acid (5ALA) and fluorescein sodium (FS) are the most promising ones in glioma resection. FiveALA is metabolized by tumoral enzymes into the fluorescent protoporphyrin IX, which has been used as a metabolic marker in glioma resection., Although its 100% specificity and a 85% sensitivity for tumoral tissues many factors limit the widespread use of 5ALA fluorescence for glioma resection: not only the high cost, but also the way of administration (oral, some hours before the induction of anesthesia) and high risk of skin sensitization within 24 h after the operation (the patient should not be exposed to sunlight or strong artificial light)., On the contrary, FS is an injectable dye that can be used for immediate improved visualization of brain tumor tissue, with no specificity for tumor cells. This dye, if viewed under a light whose wavelength is in the range of 460–500 nm, emits fluorescent light with a wavelength range of 540–690 nm. FS does not selectively accumulate in astrocytoma cells, but in extracellular tumor sites, portraying its role as a marker for damaged bloodbrain barrier (BBB) areas, as in high-grade astrocytomas. It is also widely used in ophthalmic surgery. Fluorescein is injected intravenously just before glioma resection, it virtually has no side effects and has low costs, approximately 60 ₹ each vial (1 g of FS approximately)., Its fluorescent effect is usually visible to the naked eye at high dosage (20 mg/kg body weight) and at lower doses, it is observable under the YELLOW 560 nm surgical microscope filter, allowing a better tissue discrimination with more selective color filter [Table 1]., In this study, we report our preliminary data retrospectively collected on 29 patients operated for HGGs. Our aim is to determine and demonstrate the effectiveness and safety of fluorescence-guided surgery in HGG resection and compare it with previous data with focus on histology, tumor removal rate, clinical pre- and post-operative parameters, quality of life, and any side effects of FS.
|Table 1: Features of 5aminolevulinic acid and fluorescein sodium with their main characteristics|
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| Materials and Methods|| |
In this retrospective study, after the approval of Local Ethics Committee, we collected the data of 29 patients (16 males and 13 females; mean age: 60.3 years, range: 27–86 years). All patients underwent surgery in the department of neurosurgery between June 2019 and February 2020 [Table 2]. Each patient was informed on benefits and risks associated with the study, and all of them signed an informed consent. The inclusion criteria were as follows: (1) age >10 years, (2) suspect of HGG (astrocytoma III or IV grade according WHO classification) on the basis of contrast enhancement on CE magnetic resonance imaging (MRI) brain; (3) tumor located in noneloquent areas; (4) Eastern Co-operative Oncology Group (ECOG) performance status score of 1–3. The exclusion criteria were as follows: (1) severe heart, liver, or kidney disease; (2) history of adverse reaction to FS or to other contrast agents; (3) women during the first trimester of pregnancy; (4) ECOG performance status score of 4; and (5) tumor diameter <1 cm.
In all cases, 7 mg/kg body weight of FS was injected intravenously through the peripheral line, during the craniotomy. Vital signs were monitored for 15 min. Under white light, no fluorescence was detected. The fluorescent dye was visible under the YELLOW 560 nm filter, on the Leica M530 OHX surgical microscope (Leica microsystems, Wetzlar, Germany). The fluorescence outlined the gross tumor margins [Figure 1]. All the procedures were carried out by the same senior neurosurgeon (S.S.G.) to remove interpersonal variations of surgical technique and judgement; this helped in categorizing FS as useful or not useful based on intraoperative tumor detection and distinction from the normal brain parenchyma using fluorescence. Postoperatively, all the patients were admitted in the neurosurgical intensive care unit (ICU) for postoperative care.
|Figure 1: Intraoperative fluorescein images under 560 nm filter showing (a) intraoperative view of tumor in plain light (b and c) enhanced tumor tissue under 560 nm light filter and postoperative resection cavity (d)|
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Pre- and post-operative clinical assessment
Each patient general physical performance was recorded using the ECOG performance score. The median preoperative ECOG score was 2.0 (range: 0–3). Preoperative clinical evaluation was performed at the admission to the neurosurgical unit. A re-evaluation examination was conducted during the postoperative period, on discharge and at the first outpatient clinic visit approximately 1 month later. Surgery was followed by radiotherapy with concomitant and adjuvant temozolomide in 85.1% of cases, in accordance with the Stuppprotocol. Histological analyses were performed as per protocol in the department of pathology. The classification was conducted on the basis of the current WHO classification of tumors of the central nervous system.
Postoperatively, the extent of tumor resection was determined by 18 contrast-enhanced T1-weighted MRI and 11 contrast-enhanced computed tomography (CT scan) within 72 h of surgery. Three categories were distinguished: no residual tumor tissue = GTR; minimal residual tumor tissue = STR and partial resection (PR). GTR was defined as resection where no residual enhanced tumor is visible, STR was defined as nearly total (>95%), PR as <95%. Postoperative residual tumor volumes after surgery were assessed using an open-source, free medical image viewer software (3D SLICER for windows) on enhanced residual tissue (on T1 weighted MRI or CT scan) [Figure 2].
|Figure 2: Postcontrast T1 images showing preoperative left parietal deep seated high-grade gliomas axial section (a) and sagittal section (b) and postoperative resection cavity axial (c) and sagittal section (d) that shows no residual tumor|
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| Results|| |
The average duration of the surgical procedure (”skin to skin”) was 2.2 h (range: 1.5–4.1 h); the median length of hospital stay was 14 days (range: 8–62 days). Patients and tumor data and results are summarized in [Table 2] and [Table 3]. On histopathological analysis, 10 patients were diagnosed with anaplastic astrocytoma Grade III, whereas 19 patients were diagnosed with a Grade IV glioblastoma, according to the WHO classification. No side effects were observed which could be associated with the administration of FS; however, YELLOW staining of sclera and skin along with fluorescence in urine was observed in almost every case. All patients have been operated by same senior neurosurgeon (S.S.G.) allowed quantifying cases in which intraoperative fluorescence was used as “useful” and “not useful,” on the basis of a clear intraoperative distinction between the normal brain parenchyma and the tumor tissue. Postoperatively, all the patients were managed in the neurosurgical ICU.
Urine fluorescence disappeared within approximately 24 h after the surgical procedure. No abnormality was detected neither in routine blood or urine examinations, nor in liver and kidney function tests. All tumors effectively stained yellow to green in color with FS during the surgical procedure. The use of FS under YELLOW 560 nm filter was considered as “useful” in all of the cases. The resection extent was evaluated by team of radiologists, by analyzing postoperative neuroimaging examinations performed within 72 h after surgery, i.e., 18 enhanced MRI and 11 enhanced CT scans). GTR was achieved in 41.3% (n = 12) of patients. A STR (>95%) was achieved in 48.2% (n = 14) of them, while a PR (<95%) was obtained in 10.3% (n = 3) of patients. Overall, in 89.6% (n = 26) of patients who underwent fluorescence-guided surgery, the resection rate achieved was >95%. The median postoperative ECOG score was 1.0 (range: 0–3) as compared to preoperative median of 2.0 (range: 0–3). Postoperative score was higher for 16 patients and was the same as the preoperative one for 13 patients. Overall, following complications emerged: six transient postoperative hemiparesis, two postoperative brain hemorrhages, one sepsis. In eight patients, new motor deficits were observed after surgery, six of which were transient paresis, which resolved completely within 4 weeks. In three patient's seizures occurred postoperatively. There was no perioperative mortality. The overall median follow-up was 9 months (range: 3–14 months).
| Discussion|| |
Radical resection in glioma surgery has been already stressed in literature and is of utmost importance. Cases of spontaneous regression of benign tumors after incomplete removal and radical resection of malignant tumor allows long-term survival have been discussed. Thus, radical surgery in brain tumor has become the main milestone of the modern neurosurgical philosophy. New generation intraoperative neuroradiological assessment devices are being used in operating theaters for that purpose. Fluorescent markers during surgical procedures to dye tumor tissue have become the primary tool in neoplastic resection. Although some literature depicts the use of intraoperative contrast enhancement mainly for vascular diseases, such a technique is progressively gaining more consent as a modern armamentarium to achieve radical removal. FS is a fluorophore, that has been a guiding tool in medical field for more than six decades. It's penetration in those areas of the brain where the BBB is damaged, allows real-time enhancement of the areas enlightened by gadolinium in MRI. If injected at high doses (20 mg/kg), fluorescence of FS can be perceived with naked eye. We can employ a low dose of FS (7 mg/kg) with the use of recent developed microscope with integrated YELLOW 560 module (Leica M530 OHX surgical microscope Leica microsystems, Wetzlar, Germany), to detect an optimal fluorescence for the tumoral tissue. A detailed analysis of the literature [Table 4], portrays that, apart from its wide and safe use in ophthalmology, fluorescein injection is a good way to obtain a high chances of GTR during malignant brain tumors surgery. The percentage of resection in the series that we have analyzed varied from 75% to 100%. In 2003, Shinoda et al. reported a series of 32 patients surgically treated for GBM. In 84.4% of these patients, for gross total removal, a high dose of FS (20 mg/kg body weight) was used. Only 30.1% obtained it with conventional white light imaging; with no difference in the overall prognosis. In 2008, Koc et al. reported a prospective nonrandomized study to evaluate the influence of FS-guided glioma resection on the extent of gross total tumor removal (GTR), overall prognosis, and side effects. Forty-seven out of the 80 patients enrolled, were administered a high dose (20 mg/kg body weight) of intravenous FS after craniotomy. A standard operating room microscope without a filter or special camera was used. A second group of 33 patients underwent ordinary resections. The results showed a significant increase in the number of patients with GTR (83% vs. 55%) when fluorescein was administered. No statistical significant difference was observed in overall survival between the two groups, i.e., 44 weeks versus 42 weeks., In 2012 Chen et al., in a cohort of 22 patients with HGGs, observed a significant improvement in progression-free survival, together with the GTR rate, in patients treated with the aid of intraoperative intravenous injection of FS (15–20 mg/kg body weight) compared to the control group's progression-free survival. In the same year, Okuda et al. reported the safety and the efficacy of a new technique of fluorescence-guided surgery for GBM surgery based on high dose FS with excitation and barrier filters on the (OME9000 Olympus). This new technique was employed in a series of 10 patients, for a detailed tumor assessment and the identification of tumor vessels and surrounding normal vessels. This dye assisted in the surgical removal with both fluorescence and under normal white xenonlight illumination. After the study of Kuroiwa et al., who was the first to describe a novel technique of integration of the fluorescence filter in the microscope (Zeiss), Schebesch in 2013 published data about a series of 35 patients with malignant brain tumor (whose 22 WHO HGGs) surgically treated with the aid of a reduced dose (3–4 mg/kg) of FS and with an intraoperative PENTERO 900 microscope equipped with the 560 nm wavelength fluorescence light filter. In all cases, the tissue fluorescence was brightly visible 30 min after administration of FS and it lasted for the entire duration of the procedure, representing a significant and “helpful” mean for the surgeon in 28 out of 35 cases. Finally, Acerbi et al. was the first group to initiate a prospective Phase II trial (FLUOGLIO) in 20 consecutive patients with HGGs. In these patients, FS was administered intravenously at the induction of anesthesia. In this case, the fluorescence visualization during the surgical procedure was obtained with BLUE 400 or YELLOW 560 filters on a PENTERO 900 microscope at a very low dose (10 mg/kg with the BLUE 400 filter and at 5 mg/kg with the YELLOW 560 filter). Data revealed a complete resection of the tumor in 80% of patients, a 6-month progression-free survival rate for 71.4%; moreover, a median survival of 11 months and a median duration of follow-up of 10 months were shown.,,, In February 2016, Hamamcıoğlu et al. presented their series of 23 high-grade tumors and seven metastatic tumors treated with the intraoperative aid of 200 mg (2–4 mg/kg) of FS. This dye was found “helpful” for tumor demarcation in 29 out of 30 operations (97%). In 23 of these 29 operations (79%), a total resection (radiologically demonstrated) was achieved regardless of the histopathology, whereas a neartotal resection was achieved in four patients (14%). A STR was achieved in the remaining two patients (7%). In another study published by Francaviglia et al. in 2017 on use of FS for resection of HGG in 47 patients, GTR was achieved in 53.2% (n = 25) of patients. A STR (>95%) was achieved in 29.8% (n = 14), while a PR (<95%) was obtained in 17% (n = 8) of patients. Overall, in 83% (n = 39) of patients who underwent fluorescence-guided surgery, the resection rate achieved was >95%.
|Table 4: Clinical series of patients with high-grade gliomas treated with a fluorescein sodium-aided surgery. Literature review|
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In our experience, the use of FS together with YELLOW 560 nm filter has been found “useful” in tumor removal in all the surgical procedures, allowing a better visual discrimination between the brain parenchyma and the fluorescent-stained tumor tissue. This also seemed to be more comfortable to the surgeon eyes and was also reversible to use microscope under normal white and alternating 560 nm filter. The enhancement of tumoral tissue, which corresponds to the contrast enhancement of preoperative MRI, was visible immediately after dural opening, usually within 15 min of FS administration, and lasted until the end of surgery. The rate of tumor removal in our study was similar to that of previous studies. GTR was achieved in (41.3%) (n = 12) of patients. A STR (>95%) was achieved in (48.2%) (n = 14) of them, whereas a PR (<95%) was obtained in 10.3% (n = 3) of patients. Globally, in 89.6% (n = 26) of patients who underwent fluorescence-guided surgery, the resection rate achieved was >95% in patients who underwent fluorescence-guided surgery which is in accordance to our trends also. Moreover, FS appeared to be safe and effective in aiding the intraoperative removal of tumor by demarcating tumor from normal brain tissue. The median postoperative ECOG score was 1.0 (range: 0–3). Comparing pre- and post-operative scores, the latter was found higher in 16 patients, and stable in 13 patients. As in Schebesch et al., series, we also report the use of low dose FS about 2 mL (5 mg/kg body weight). This low dose, together with YELLOW 560 nm filter, allowed an easier intraoperative management than higher doses of FS or 5ALA, without the need to wait for the dye peak.,, FS is widely accepted in several fields of medicine as a very safe molecule. The reported side effects of fluorescein administration, such as skin reactions, syncope, respiratory or cardiac adverse effects, and seizures, did not occur in this series. Except for an expected and transitional change of skin color, sclera, and urine, which became slightly yellow (this effect disappeared completely within 24 h after fluorescein administration) none of the patients complained about any systemic or local side effect. Although our study is limited by the small number of cases and lack of control group, the results are still in accordance with reported trends. It is clear that the use of intravenous fluorescein during the surgical removal of HGGs with a specific yellow filter, may prove to be a very effective, safe, and relatively inexpensive way to achieve a gross total removal of the tumor. The cost of one application of 5ALA is approximately 180 times higher than one administration of FS. The use of specific filters on surgical microscope allows an optimal delineation of tumoral tissue with low dose of drug administration, still ensuring the identification of the fluorescent areas, and distinguishing them from the peritumoral brain parenchyma and from vessels, which appear of “more natural” colors. The FS shows BBB breakdowns, corresponding to the areas marked by the contrast agent in MRI. Consequently, a resection based on FS fluorescence, allows the removal of those neural tissue portions in which the BBB is interrupted. It does not necessarily allow resection of the full extent of infiltrating tumor cells, thus potentially reducing the accuracy of tumor identification. Moreover, the necrotic portion of the tumor does not stain with fluorescein, due to its lack of cerebral vasculature which is a disadvantage.,
| Conclusions|| |
The intraoperative identification of tumor tissue and maximizing EOR of HGGs is a significant and important challenge in neurosurgery. In our series, fluorescence-guided surgery of HGGs using FS has been a good tool in achieving GTR and enhanced STR, thereby increasing tumoral resection of >95% by distinguishing tumor from normal brain tissue. Larger-scale studies, however, are still needed to quantify the efficacy of fluorescein-guided surgery in improving the EOR and its impact on progression-free and overall patient survival.
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Conflicts of interest
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]