|Year : 2021 | Volume
| Issue : 1 | Page : 5-11
Clinical value of neuronavigation combined with a fluorescent staining technique during microsurgery for treating supratentorial glioma: A case-control observational study
Fugang Yang, Chengshi Xu, Chao Ma, Yuhang Zhao, Zhiqiang Li
Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province, China
|Date of Submission||24-Nov-2020|
|Date of Decision||16-Dec-2020|
|Date of Acceptance||19-Jan-2021|
|Date of Web Publication||30-Mar-2021|
Dr. Zhiqiang Li
Department of Neurosurgery, Zhongnan Hospital, Wuhan University, No. 169, Road East Lake, Wuhan 430071, Hubei Province
Source of Support: None, Conflict of Interest: None
Background and Aim: Many studies have demonstrated the value of neuronavigation guided by fluorescence staining for treating glioma patients. Here, we compared the rate of overall survival (OS) and the extent of tumor resection among patients who underwent surgery with neuronavigation and fluorescence versus conventional techniques. Materials and Methods: In this case-control observational study, data from 162 patients with supratentorial glioma who underwent surgery from January 2016 to November 2017 were retrospectively analyzed, including a neuronavigation and fluorescence treatment group (combined group, n = 53) and a conventional microsurgery group (control group, n = 109). The extent of tumor resection, World Health Organization (WHO) pathological grade, eloquent areas involved, tumor diameter, preoperative Karnofsky Performance Status score, underlying diseases, chemotherapy, hospitalization days, length of operation, intraoperative blood loss, and postoperative molecular pathological indictors were recorded. OS rates were compared using the Cox proportional hazards regression model. The study was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (approval No. 2019048). Results: The total resection rate was 60.4% in the combined group and 27.5% in the control group. Multivariate logistic regression analysis revealed that involvement of eloquent areas (odds ratio [OR] = 0.455, 95% confidence interval [CI]: 0.214–0.966, P = 0.040) and the use of the combined technique (OR = 3.634, 95% CI: 1.758–7.510, P < 0.001) were independent prognostic factors affecting total glioma resection. Eloquent areas were implicated in 79 patients. Multiple logistic regression analysis revealed that the combined technique (OR = 6.041, 95% CI: 1.705–21.403, P = 0.005) was an independent prognostic factor affecting total resection. The average follow-up period was 16.4 months. Cox regression analysis revealed that the WHO tumor grade (hazard ratio [HR] = 4.782, 95% CI: 1.620-14.119, P = 0.005), chemotherapy regimen (HR = 0.324, 95% CI: 0.181–0.579, P < 0.001), IDH mutation (HR = 0.366, 95% CI: 0.154–0.870, P = 0.023), and total resection (HR = 0.458, 95% CI: 0.248–0.846, P = 0.013) were independent factors affecting the prognosis of glioma patients. Conclusions: The use of neuronavigation with fluorescent staining appears to improve the tumor resection range and the OS rate, which is an independent factor affecting the degree of resection of supratentorial glioma. The WHO tumor grade, chemotherapy regimen, IDH mutation, and total resection were independent factors affecting the prognosis of glioma patients.
Keywords: Extent of resection, fluorescent staining, glioma, neuronavigation, survival
|How to cite this article:|
Yang F, Xu C, Ma C, Zhao Y, Li Z. Clinical value of neuronavigation combined with a fluorescent staining technique during microsurgery for treating supratentorial glioma: A case-control observational study. Glioma 2021;4:5-11
|How to cite this URL:|
Yang F, Xu C, Ma C, Zhao Y, Li Z. Clinical value of neuronavigation combined with a fluorescent staining technique during microsurgery for treating supratentorial glioma: A case-control observational study. Glioma [serial online] 2021 [cited 2022 Dec 8];4:5-11. Available from: http://www.jglioma.com/text.asp?2021/4/1/5/312465
| Introduction|| |
Malignant glioma is the most common and most fatal form of primary brain tumor., It has a high recurrence rate, low cure rate, and poor prognosis, and the 5-year survival rate of patients with gliomas is very low., Recent reports on the outcomes of glioblastoma surgery have shown that gross total resection (GTR) greatly increases the rate of overall survival (OS). However, the invasive nature of the disease makes it difficult to remove the entire tumor cell population during surgery. Despite treatment strategies that combine postoperative radiotherapy with chemotherapy treatment, the OS rate is very poor with an average of 14.6-month postsurgery., Accurate visualization of tumor borders can facilitate maximal cytoreduction while preserving function. To this end, intraoperative magnetic resonance imaging (IMRI) and computed tomography techniques have been recently developed, with navigational systems and electrophysiological monitoring employed during the course of resection. The purpose of this study was to evaluate the clinical value of such neuronavigation combined with yellow fluorescence staining during microsurgery. We examined the outcome according to the degree of tumor resection and the rate of OS.
| Materials and Methods|| |
We retrospectively identified 162 patients with glioma who were treated at Zhongnan Hospital of Wuhan University, China, from January 12, 2016, to November 12, 2017 in this case-control observational study. The study was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (approval No. 2019048) and was conducted in full compliance with all principles of the Declaration of Helsinki. Data were extracted from patients' medical records. Specifically, we collected the treatment details, tumor characteristics, demographic information including assistive technologies, tumor location (the following regions were considered to be eloquent: horizontal section of the internal capsule, basal ganglia, precentral or postcentral gyrus, left inferior parietal lobule, thalamus, dentate gyrus, hypothalamus, and left superior temporal gyrus), scale of tumor (diameter), fatality, and postoperative chemotherapy from the case histories. All patients were informed that data may be used for research purposes and their rights to decline participation. The need for written informed consent was waived owing to the retrospective nature of the study, which was approved by the ethical committee. Patients were selected according to the following criteria: World Health Organization (WHO) Grade II–IV (The 2007 WHO classification of tumors of the central nervous system) supratentorial glioma according to postoperative pathology, and complete clinical data (preoperative clinical manifestations, imaging data, postoperative pathology, and postoperative treatment measures). The following patients were excluded from the study: those who did not undergo surgical resection; patients with recurrent glioma and reoperation; those with incomplete clinical data; those with major cardiovascular or cerebrovascular diseases; and patients with severe liver or kidney dysfunction. Among the qualified patients, 53 individuals who underwent tumor resection through fluorescence-guided neuronavigation comprised the research group, and 109 subjects who underwent guided surgery through conventional methods comprised the control group. When the tumor involved the eloquent areas, neuroelectrophysiological monitoring and intraoperative awakening anesthesia technology were administered routinely during resection in the two groups. After comprehensive consideration of each patient's condition, including their postoperative molecular pathological characteristics, doctors in the chemoradiotherapy department generated a chemoradiotherapy program for each individual. In general, the standard STUPP protocol was adopted. The STUPP protocol calls for the use of 60 Gy radiotherapy concurrently with temozolomide over 6 weeks after tumor resection, followed by six 28-day cycles of temozolomide alone.
The operating principle of the neuronavigation system is infrared tracking and positioning. On the day of or on the day prior to the surgical operation, skin coordinates were marked on the patient's scalp and MRI thin-layer continuous scanning was performed. The imaging data were inputted into the navigation system, three-dimensional images were reconstructed, and the operation plan was generated. The location of the skin incision was established using a probe to determine the surface projection of the lesion. This was generally verified before the scalp incision and the dural incision, and rechecked after the dural incision and surgical resection.
After general anesthesia, a small amount of sodium fluorescein was diluted and injected intravenously, followed by observation with multiparameter monitoring for approximately 15 min. If no obvious allergic symptoms were observed, the patient was considered to not have allergies to the anesthetic. For the craniotomy with neuronavigation, an intravenous injection of 20% fluorescein sodium saline was administered at a dose of 5.0 mg/kg before cutting the dura mater. A ZEISS OPMI-PENTERO-900 microscope (Carl Zeiss, Oberkochen, Germany) outfitted with a YELLOW 560 nm filter was used during the surgical operations. The operator adjusted the fluorescence imaging until it was deemed satisfactory. In the fluorescence mode, tumor tissue could be distinguished from the surrounding normal tissue according to yellow staining. In the ordinary microscope light source mode, the tumor could be observed in a conventional manner. If the resection range was close to a functional area, neuroelectrophysiological monitoring or intraoperative awakening techniques were used to avoid nerve damage. During the resection, the normal mode and fluorescence mode of the microscope were used alternately to observe the operation area and determine the degree of tumor resection.
Assessment of the extent of surgery
All patients received computed tomography and MRI examinations in our hospital. The degree of tumor resection was determined by comparing MRI data collected 72 h before and after the surgical operation. The patients in the combined and control groups were divided into complete and incomplete resection groups. Based on the Response Assessment in Neuro-Oncology criteria, patients with no residual contrast enhancement on the MRI scans (<72 h) during the early postoperative period were considered to have undergone GTR.
The survival rate was determined according to periodical follow-up visits with the patients. When in-person follow-up appointments were not possible, these meetings were conducted over the phone. The patients were contacted 1 month after surgery and every 2 months thereafter. The OS refers to the amount of time from the day of the operation to patient fatality or the final day of the follow-up period.
To ascertain the relative factors associated with prognosis, we analyzed the following clinical parameters: sex, preoperative Karnofsky Performance Status score, eloquent location, patient age, tumor diameter, underlying diseases, hospitalization days, intraoperative blood loss, length of operation, WHO pathological grade, extent of surgery, intraoperative assistive technique, chemotherapy, and postoperative molecular pathological indicators.
The statistical analysis was carried out using SPSS 22.0 statistical software (IBM, Armonk, NY, USA). The results of the descriptive analysis are reported as means ± standard deviation or medians (interquartile range). We used two-sample t-tests or the Mann–Whitney U-test to compare the continuous variables among the groups and Pearson's Chi-squared test to compare dichotomous variables. The Kaplan–Meier and log-rank method were used for survival analysis. The Cox proportional hazards regression model was conducted to examine the influence of statistically significant factors on patient survival time. Using univariate logistic regression and multivariate logistic regression, the factors affecting the degree and prognosis of tumor resection were then discussed. P < 0.05 was considered to possess statistical significance.
| Results|| |
In the navigation combined with fluorescence group, 31 patients were male (31/53, 58.5%), and the intermediate age was 47 years (scope: 11–72 years). In the conventional surgery group, 67 patients were male (67/109, 61.5%) and the intermediate age was 50 years (scope: 5–80 years). For ease of analysis, based on the 2007 WHO classification system, Grade I and II gliomas were considered to be low-grade gliomas, and Grade III and IV gliomas were considered to be high-grade gliomas. The treatment groups were equal in terms of age, preoperative Karnofsky Performance Status score, sex, tumor diameter, chemotherapy regime, WHO tumor classification, underlying disease, and eloquent location [Table 1].
|Table 1: Characteristics of patients with supratentorial glioma on admission|
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Extent of surgery
The data indicated that neuronavigation combined with fluorescence technology improved the rate of total resection. Specifically, complete resection took place in 32 patients (60.4%), and incomplete resection was achieved in 21 patients (39.6%). In the conventional surgical group, the rate of complete resection was 30/109 (27.5%), and the rate of incomplete resection was 79/109 (72.5%). The complete resection rate was significantly different in the two groups (P < 0.001) [Table 1]. Multivariate logistic regression analysis revealed that involvement of an eloquent area (odds ratio [OR] = 0.455, 95% confidence interval [CI]: 0.214–0.966, P = 0.040) and the use of neuronavigation plus fluorescence (OR = 3.634, 95% CI: 1.758–7.510, P < 0.001) were factors that independently influenced the rate of total resection [Table 2].
|Table 2: Univariate and multivariate logistic regression analysis of the ability of assistive technology to predict the extent of tumor resection|
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Among the 79 patients who had gliomas involving an eloquent area, total resection was achieved in 22 patients, of whom 12 (12/22, 54.5%) were treated with neuronavigation combined with fluorescence. Incomplete resection was achieved in 57 patients, of whom 9 (9/57, 15.8%) were treated with neuronavigation combined with fluorescence. The difference between the two groups (P < 0.001) was significant. Multiple logistic regression analysis revealed that the use of neuronavigation combined with fluorescence (OR = 6.041, 95% CI: 1.705–21.403, P = 0.005) was an independent factor influencing total resection [Table 3].
|Table 3: Univariate and multivariate logistic regression analysis of the ability of assistive technology to predict the extent of tumor resection in functional areas|
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Survival rate and prognostic factors
The intermediate survival time and survival rate in patients who underwent neuronavigation combined with fluorescence were 19 months and 73.6%, respectively. In patients who did not receive neuronavigation with fluorescence, the intermediate survival time and survival rate were 17 months and 52.3%, respectively. The difference in survival time among these groups (P = 0.010) was significant. The univariable analysis revealed that neuronavigation combined with fluorescence staining was a key element influencing survival in glioma patients [Table 4]. However, the multivariate analyses for survival rate indicated that only total resection (hazard ratio [HR] = 0.458, 95% CI: 0.248–0.846, P = 0.013), tumor grade (HR = 4.782, 95% CI: 1.620–14.119, P = 0.005), chemotherapy regimen (HR = 0.324, 95% CI: 0.181–0.579, P < 0.001), and IDH mutation (HR = 0.366, 95% CI: 0.154–0.870, P = 0.023) were independent prognostic factors for gliomas. We determined that the unregulated OS in the integrated group was higher than that in the control group [P = 0.011; [Figure 1].
|Table 4: Univariate and multivariate analyses of the survival rate in patients with supratentorial glioma|
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|Figure 1: Kaplan–Meier survival curves of 162 subjects with supratentorial gliomas, stratified by the extent of surgery (A), chemotherapy (B), grade of tumor (C), IDH mutation (D), and application of neuronavigation combined with yellow fluorescence (E)|
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| Discussion|| |
During an operation to remove a malignant glioma, the objective is to achieve maximum tumor resection while retaining the patients' neurostatus, which is associated with overall and progression-free survival. Several studies have shown that the degree of resection has a distinct impact on the rate of survival in patients with invasive tumors. However, because of the challenge involved in differentiating living tumor tissue at the edge of the resection area during the operation, complete removal of a tumor is difficult to achieve. Over the past few decades, neurosurgeons have developed a number of innovative technologies to enhance the curative effects of resection of primary malignant brain tumors, for instance. These include IMRI, neurophysiological monitoring during the operation, and a fluorescent staining technique.,,,,,
Fluorescent staining technique
Large doses of luciferin sodium have been found to be helpful as a fluorescence guide agent during tumor resection operations. Shinoda et al. reported that large doses of luciferin sodium aided in the visualization of brain tumors, increasing the GTR rate. In their study, 32 patients received intravenous injections of luciferin sodium in large doses (20 mg/kg), and 27 patients achieved GTR (84.4%). Koc et al. also found higher GTR rates owing to the use of fluorescein sodium guidance during surgery. Of the 47 patients in their study, 39 (83%) achieved GTR, compared with 18 patients (54.5%) in the control group (conventional surgical group). Chen et al. examined data from 22 patients, 10 of whom received fluorescein sodium, and 12 who comprised a conventional control group; the GTR rates of the two groups were 80% and 33.3%, respectively. However, as fluorescein is nonspecific, it may accumulate in any region where there is blood, edema, or surgical injury or trauma. In addition, the fluorescent staining technique is not sufficient to perform nonfunctional tumor resection; it must be used in combination with other strategies.
Neuronavigation plays a crucial role in neurosurgical planning and performance. However, cerebrospinal fluid aspiration, cerebral retraction, and tumor resection may lead to brain displacement. For instance, some patients who experience severe brain edema were found to have distinct brain displacement during a dural incision. Furthermore, intraoperative constriction of the brain can lead to a significant shift. Therefore, accurate surgical navigation using preoperative MRI data as a reference may not always be possible.
Combined fluorescence and neuronavigation
In the present study, we examined outcomes in patients who had undergone intraoperative yellow fluorescence staining with neuronavigation, which could theoretically improve the accuracy of lesion localization. The surgical navigation system was used to provide information regarding the position or structures in the practical operation area through coordinate representation, and the image could be referred to easily throughout the procedure. Intraoperative fluorescence staining, which is not affected by brain displacement, was used to assist in the location of tumor boundaries. Consistent with previous studies, our results indicate that neuronavigation combined with fluorescence can enhance the degree of tumor resection for patients with supratentorial glioma. Furthermore, our multiple logistic regression analysis revealed that the use of the neuronavigation technique combined with fluorescence was an independent prognostic factor in the rate of total resection, which is consistent with previous studies. However, the total resection rate in this study was far lower than the results reported in the previous study. This may be mainly due to the lack of experience in the application of these two technologies in our center. In addition, given the particularities of locations of functional areas, the surgeon must find a balance between total resection of the tumor and postoperative loss of nerve function. Thus, total resection of gliomas in functional areas can be very difficult to achieve, even when using imaging techniques.
A few studies have examined the application of preoperative functional imaging and its flexibility with respect to the IMRI system. Surgical removal is usually limited in brain areas that are considered to be eloquent. However, surgeons will generally attempt to remove as many tumors as possible even if they are close to eloquent areas, if function is threatened. In our study, neuroelectrophysiological monitoring and intraoperative arousal were applied during the removal of tumors in the eloquent cortex. Nerve function was observed during the procedure to maximize tumor removal while avoiding nerve damage. We conducted a subgroup analysis of gliomas involving functional areas, and our multiple logistic regression analysis showed that neuronavigation combined with yellow fluorescence staining was an independent factor affecting the tumor resection rate in patients with gliomas in general and functional brain areas.
Lack of a direct effect of the intraoperative assistive technology on survival rate
When estimating the integrated effects of neuronavigation and fluorescence on the survival rate of patients with supratentorial gliomas, we determined that the unregulated OS in the integrated group was higher than that in the control group. After controlling for confounding variables, our multivariate analysis indicated that these surgical methods enhanced the possibility of achieving GTR and increased the OS by affecting the resection status. There are several possible explanations for this finding. First, GTR was more prevalent among the combined technique group. GTR is a known predictor of survival, and it is reasonable to expect that using multiple techniques may maximize the resection range. Second, the prognosis for patients with high-grade gliomas is very poor, especially those with glioblastoma. This study included both patients with low-grade and high-grade malignant gliomas. Furthermore, the number of patients at each level was insufficient to analyze the influence of different factors in patients with Grade IV or III tumors. The number of patients with each tumor grade in our study was not uniform. The inclusion of patients with different WHO tumor grade levels may have affected the results of our analysis regarding the effects of navigation combined with fluorescence staining. Therefore, future studies with larger samples of patients with high-grade gliomas, especially glioblastoma, are necessary.
This research has several limitations. First and foremost, this was a monocentric retrospective study of patients with gliomas. The patients were not selected to undergo the tumor resection methods at random. Second, patients may have chosen to undergo fluorescence-guided surgery because of the personal preferences of the surgeon and the patient. However, our data show that the two patient groups were similar in terms of age and gender. To exclude potential bias, a prospective random test is necessary.
| Conclusions|| |
The implementation of neuronavigation combined with fluorescence technology during neurosurgery led to a more positive outcome in patients with malignant neoplasm of the cerebrum. Our research indicates that, compared with a control technique, the integrated technique was able to improve the resection range of supratentorial gliomas. However, the use of the assistive technique itself was not a statistically significant prognostic factor after adjusting for various confounding factors. To address this, prospective random tests are necessary. Future analysis of procedures with larger-scale alignments may reveal the genuine advantages of integrated techniques during surgery to remove brain tumors.
Financial support and sponsorship
This work was supported by grants from National Health Commission of China (2018ZX-07S-011), and Medical Science Advancement Program of Wuhan University of China (No. TFJC2018003).
Institutional review board statement
The study was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University, China (approval No. 2019048) and was conducted in full compliance with all principles of the Declaration of Helsinki.
Declaration of patient consent
The authors certify that they have obtained the patient consent forms. In the form, patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their name and initials will not be published and due efforts will be made to conceal their identity.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]