International Journal of Neurooncology

: 2020  |  Volume : 3  |  Issue : 1  |  Page : 1--7

Role of surgery in recurrent high-grade glioma: Current evidence

Ujwal Yeole, Arivazhagan Arimappamagan 
 Department of Neurosurgery, NIMHANS, Bengaluru, Karnataka, India

Correspondence Address:
Dr. Arivazhagan Arimappamagan
Department of Neurosurgery, NIMHANS, Bengaluru - 560 038, Karnataka


While the management protocol for de novo glioblastoma is well established, the role of surgery in recurrent high-grade glioma (HGG) is not yet clear. In the light of recent developments in radio and chemotherapy modalities, it has become essential to recognize true disease progression from its mimics. This article discusses the recent literature on the challenges in identifying recurrence in HGG, modalities to diagnose, indications for surgery, and the outcomes in contemporary studies. The factors identified in prognostication have been discussed.

How to cite this article:
Yeole U, Arimappamagan A. Role of surgery in recurrent high-grade glioma: Current evidence.Int J Neurooncol 2020;3:1-7

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Yeole U, Arimappamagan A. Role of surgery in recurrent high-grade glioma: Current evidence. Int J Neurooncol [serial online] 2020 [cited 2020 Dec 3 ];3:1-7
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High-grade gliomas (HGGs) are the most common primary malignant tumors of the brain in adults.[1],[2],[3] With the evolution in the technology of neurosurgery, neuro-anesthesia and various adjuvant therapies, a significant improvement has occurred in the ways these tumors could be resected safely and completely. Awake surgery, intraoperative mapping of various functions, functional magnetic resonance imaging (MRI), and other investigations have improved the safety of resection. On the other hand, neuronavigation, use of intraoperative ultrasonography, intraoperative MRI and fluorescent guided resections have enabled the surgeon to push the extent of resection further. The standard of treatment currently practiced for primary HGG is very well established and includes maximal safe resection followed by radiotherapy (RT) 60 Gy (1.8 Gy/fraction for 33 fractions) with temozolomide 75 mg/m 2 followed by 6 cycles of Temozolomide at a dose of 150–200 mg/m 2 for 5 days every 28 days. Stupp et al. in 2002 achieved a median survival of 12–15 months with 2 years survival of 31%.[4] The ultimate aim of treatment is not only to improve overall survival but also to maintain the quality of life.

Unfortunately, recurrence is the rule in HGG. The time to recur may vary based on the grade of the tumor, molecular profile, etc. As mentioned above, the standard of care for de novo HGG is very well established and followed worldwide. The factors which influence survival in primary HGG are well studied, which include age, Karnofsky performance score, extent of resection, etc., Similarly, the molecular characteristics, namely O6-methyl guanine-methyl transferase methylation, isocitrate dehydrogenase (IDH) mutation status of HGG have been identified as prognostic factors in primary HGG. On the contrary, the clinical decision making in the setting of recurrent HGG is not clear.

The unfavorable outcomes in HGG are mainly due to a high propensity for recurrence. Most of the recurrences occur within 7–9 months after completion of treatment.[5],[6],[7] There are no standardized treatment strategies for recurrent HGG. The management of recurrent high-grade glioma raises two pertinent points, which will be discussed in this article. First, how is the recurrence defined or diagnosed in the current treatment scenario. Second, when and why surgery is indicated in these recurrent HGG? The article does not cover the literature on adjuvant RT/chemotherapy and alternate therapies, which are considered in the recurrent setting.

 How is a Recurrent Tumor Diagnosed?

The high-grade gliomas are most often contrast-enhancing lesions, and therefore, even the volume measurement of these tumors was performed by measuring the enhancing lesion in 2 or three dimensions. Similarly, recurrence or progression of disease was defined as an increase in the size of lesion, primarily contrast-enhancing component by 25% or more, as per McDonald's criteria. However, the introduction of RT resulted in the phenomenon of radiation necrosis, which can result in lesions, which enhance with contrast, incite perilesional edema and can cause mass effect. They occur usually 3–12 months after RT; however, it has been noted to occur up to several years following therapy. This resulted in the development of many techniques to differentiate tumor recurrence and radiation necrosis. To make the matters more complex, the last decade has witnessed two other phenomena.

When patients with HGG are treated with temozolomide chemotherapy, the contrast-enhancing lesion sometimes increases in size during follow-up. Such changes are noted in 10-40% of patients in various series. In most cases, they may not be associated with clinical deterioration or mild symptoms, not reflecting the imaging features. This phenomenon has been called pseudoprogression. Most cases occur around three months of completing the chemoradiation therapy, while the exact mechanism for this phenomenon remains unclear.[8],[9]

Similarly, patients who have been treated with anti-angiogenic therapies like bevacizumab demonstrate that the contrast enhancement in the lesion decreases or disappears at follow-up. Such changes have been noted in 28–63% of patients treated with bevacizumab, while around 50% of patients treated with cediranib. However, this reduction in contrast-enhancing lesion does not translate to improvement in overall survival. This phenomenon is called pseudoresponse, which occurs more likely due to changes in vascular permeability following anti-angiogenic therapy.[10],[11],[12] Moreover, it has been noted that the non-enhancing component can increase significantly in patients on treatment with anti-angiogenic therapy.

All three processes, namely, radiation necrosis, pseudoprogression, and pseudoresponse can be collectively called as treatment effect, and this must be differentiated from true tumor recurrence.

Investigations to diagnose tumor recurrence

The modified RANO criteria for the assessment of tumor response in glioblastoma (GBM) in 2017 has proposed some important changes in the assessment. It proposed that post-radiation MRI imaging be taken as a baseline for the evaluation of disease progression, with the most important justification being the highly unpredictable, transient radiographic changes that often accompany the initial chemoradiation phase. In addition, the criteria have only considered the measured tumor volume in contrast-enhanced MRI scans to define the progression of the disease. A detailed description of modified RANO guidelines is out of the scope of this article and can be obtained in the publication.[13]

Notwithstanding the lack of utility of advanced imaging technologies in defining recurrence in RANO guidelines, significant research has occurred in the recent past, which helps us in this regard. The imaging technology can be broadly classified into advanced MRI sequences like MR spectroscopy, perfusion and diffusion studies, and metabolic imaging, which comprises positron emission tomography (PET) and single, photon emission computed tomography. Many authors have described the use of single/combined advanced MRI sequences in diagnosing recurrent tumor.[14] Proton magnetic resonance (MR) spectroscopy has been found to be useful in some studies,[15] while Steidl et al. noted that myoinositol could be a biomarker in recurrent GBM treated with bevacizumab.[16] However, Zhang et al., in their systematic review and meta-analysis of the available literature, emphasized clearly that MR spectroscopy alone can only be of moderate value in differentiating recurrence from treatment effect.[17] Many recent studies have noted that a combination of the techniques offers the highest accuracy in diagnosis. Liu et al. reported that arterial spin labeling (ASL) and amide proton transfer imaging techniques showed better diagnostic capability in distinguishing recurrent tumor from treatment effect compared to diffusion-weighted imaging (DWI) and Magnetic Resonance Spectroscopy sequences.[18]

Positron emission tomography has been used with various metabolites for differentiating tumor recurrence from radiation necrosis. The most common tracer used in PET imaging is fluorodeoxyglucose (FDG) PET. Recently, other tracers like O-(2-18 F-fluoroethyl)-L-tyrosine (FET) have been evaluated. Verger et al. noted that FET PET demonstrated a sensitivity of 80%, specificity 86%, accuracy 81% in differentiating recurrent disease from treatment-related effect. They also noted that 18F-FET PET was superior to perfusion-weighted imaging (PWI) in identifying recurrence.[19] In a systematic review to elucidate the diagnostic accuracy of various PET tracers, de Zwart et al. analyzed 39 studies involving 11 tracers. They showed that 18 F-FDG had sensitivity and specificity of 84%and 84%, respectively.8 F-FET had a sensitivity of 90% and specificity of 85%, respectively.11 C-MET demonstrated a sensitivity of 93% and specificity of 82%, respectively. They proposed that 18 F-FET and 11 C-MET should be preferred over FDG PET, as they demonstrated higher sensitivity and specificity in differentiating between tumor progression and treatment-related changes in HGG.[20] While metabolic imaging may be useful, it probably is not sufficient. Many authors have stressed the fact that multi-parametric imaging involving advanced MR sequences like DWI, PWI, ASL etc., in combination with metabolic imaging can provide the highest accuracy in diagnosing the recurrent glioma.[10],[21],[22]

Surgery for recurrent high grade glioma

Unlike de novo HGG, wherein surgical resection is the first management option, the role and need for surgery in recurrent setting are less clear. Once the dilemma of true progression of the disease versus treatment effect is settled based on the above discussion, the clinician is faced with the tough act of deciding the next course of action. The next step of management is dependent on a multitude of factors, some patient-related, and some treatment related. The management plan must be made with complete involvement of the patient and relatives, after carefully weighing the risk/benefits of each option, gains in overall survival and quality of life for the patient.

The decision for treatment after recurrence mostly depends on the expectation of the patient and family, because recurrence and the possible treatment is associated with greater morbidity and mortality.[23] The outcome in recurrent HGG depends on the type of treatment strategy adopted, and median survival varies from as low as a month [24] to >9 months [24],[25],[26] Various treatment options are considered for recurrent HGG based on the clinical and imaging conditions, namely re-surgery, RT, chemotherapy with TMZ or alternate combinations, anti-angiogenic therapy, etc., Various studies have noted that the incidence of re-surgery in patients with recurrent HGG ranges from 13 to 37%.[27],[28],[29]

 When is Surgery Considered?

Surgery can be considered when (1) the procedure can reasonably improve the quality of life of the patient (2) the procedure can reduce the raised intracranial pressure (3) the patient is in a better functional status (4) the procedure would not cause significant new neurological deficit or morbidity, precluding further adjuvant therapy. Furthermore, surgery is considered when the disease is focal and not involving deep structures or both hemispheres. The factors that improve the outcome after surgery have been identified in studies as younger age, better performance status, recurrence in non-eloquent region, WHO grade III tumors, extent of resection, and the interval between operations ≥6 months. The surgery can be effective if all of the above-mentioned factors co-exist, which rarely occurs.[25],[30],[31],[32]

The outcome is often variable and re-surgery involves additional morbidities like wound infection and dehiscence after immune-suppressing adjuvant therapies.[33] Hence, it becomes even more essential to establish the goal of treatment. The goals of surgery should be to relieve the mass effect due to recurrent tumor, to achieve radical resection,[34],[35],[36] which improves survival and also the overall effect of adjuvant therapy. It can also help establish further molecular markers for novel adjuvant therapies, immunotherapies, and prognostication.

Outcomes following surgery

Many retrospective studies have reported overall survival and PFS in cohorts of patients with recurrent HGG [25],[36],[37],[38],[39],[40] [Table 1].{Table 1}

While many studies demonstrated the benefit of re-surgery in recurrent setting, some differed. Franceschi et al. noted that no significant effect of re-surgery was found, with age (P = 0.001), MGMT methylation (P = 0.002) and PFS at 6 months (P = 0.0001) being significant prognostic factors on multivariate analysis.[39] Two meta-analyses analyzed all the studies in contemporary literature to provide meaningful insight into the utility of surgery and the effect of other factors. Montemurro et al. reported the analyses of data from 19 studies on recurrent GBM. The data revealed that the median time from the second surgery until death from any cause was 9.7 months, and the median OS (duration from the time of diagnosis to death) was 18.5 months, respectively. Furthermore, they noted that 13 studies, which included 1017 patients, reported data regarding PFS, which was 9.2 months.[56] In a more recent analysis, Lu et al. analyzed eight observational studies and noted that re-surgery conferred a statistically significant survival compared with no surgery at recurrence in the pooled cohort (HR, 0.722; P < 0.001). Furthermore, newer studies trended toward a more superior prognostic advantage of repeat surgery compared with earlier studies (P = 0.012). The median PFS of the cohorts ranged from 5.6 to 11.2 months after primary treatment. From the available data, the median OS from primary diagnosis and recurrence ranged from 8.4 to 29 months and 4.7–11.4 months, respectively.[27]

Through their study, Park et al. tried establishing guidelines for considering reoperation. By using a set of prognostic factors, an NIH recurrent GBM Scale was developed. They considered a KPS of ≥70 and ependymal involvement and devised a scale with a total sum score of 0–2. Although this scoring system is not universally accepted because of the distinction of presumed eloquence based on tumor location. However, it can be useful objective criteria for counseling patients for reoperation.[43]

The major limitations of these studies are due to their retrospective nature, leading to selection bias. Patients who underwent reoperation for recurrent WHO grade III or IV gliomas may have had a survival benefit resulting from younger age, better neurological function, lack of medical comorbidities, and more aggressive adjuvant therapies.

Some authors analyzed the utility of re-surgery in the elderly at the time of recurrence.[38],[57] D' Amico RS et al. reported a cohort of pts with GBM >65 years. They either underwent biopsy, single surgery or resurgery when required, followed by adjuvant therapy. The median survival for the reoperation group, single-surgery group, and biopsy only group was 18.4, 8.9, and 3.4 months, respectively. The reoperation group had greater total survival than the single surgery group as a whole (log-rank P < 0.05; hazard ratio 2.078;95% confidence interval [CI] 1.348–3.203), and the single-surgery group had greater total survival than the biopsy group (log-rank P < 0.05; hazard ratio 2.626; 95% CI 1.941–3.552). However, the incidence of complications was noted to be 21.9%. The authors concluded that age alone need not be criteria for denying re-surgery.[57]

As can be seen, most of the data are retrospective, therefore the strength of inferences are modest. The effect of extent of resection in recurrent HGG is yet unclear. Montemurro et al. concluded that extent of resection at reoperation improves overall survival, even in patients with subtotal resection at the initial operation.[56] On the contrary, De Bonis et al. noted in their series that survival analysis showed no significant differences between patients receiving gross total (11 patients) or partial (22 patients) tumor resection (Breslow test, P = 0.20; log-rank test, P = 0.27; respective median OS, 10 months [CI 95%, 1–20] and 9 months [CI 95%, 4–14]).[44] Notwithstanding a randomized prospective data, it might be difficult to emphasize the influence of extent of resection. The analysis of the role of surgery and extent of resection of recurrent GBM, in DIRECTOR trial, which is a prospective trial analysing different dose regimes of TMZ, sheds some light on this issue.[58] Suchorska et al. published the role of re-surgery in patients who were a part of DIRECTOR trial recruited prospectively and followed up.[28] The analysis was performed on recurrent GBM patients who underwent complete resection (n = 40), incomplete resection (n = 19) or no surgery (n = 34). Though they belonged to one of the two arms of TMZ dose, since the original DIRECTOR trial demonstrated similar outcomes in both arms, this provided a good possibility to evaluate the role of other variables like re-surgery. Also, the incidence of re-surgery was 68% in this trial, as opposed to the range of 13%–37% in standard practice. The authors noted that patients, complete resection of contrast-enhancing tumor (n = 40) versus incomplete resection (n = 19) was associated with improved post recurrence survival (PRS) (12.9 months [95% CI: 11.5–18.2] vs. 6.5 months [95% CI: 3.6–9.9], P,.001) and better quality of life. Incomplete tumor resection was associated with inferior PRS compared with patients who did not undergo surgery (6.5 vs. 9.8 months, P = 0.052). However, it has to be noted that preoperative tumor volumes at recurrence were larger in patients with incomplete resection (P = 0.004), and tumors with incomplete resection were more often localized in eloquent regions (P = 0.178).[28]

Molecular markers like MGMT, 1p19q deletion, IDH mutation have been well established as prognostic factors in HGG. However, in the recurrent setting, their utility has not been demonstrated satisfactorily. Various studies have addressed this issue with mixed results.[39],[56],[59] Brandes et al. noted in their study that MGMT methylation status determined at first surgery had prognostic value; however, it was not predictive of outcome following the second surgery. They also noted that MGMT status at the time of the second surgery in patients with GBM is neither prognostic for OS nor for RFS after second surgery.[60]


The present evidence suggests that surgery has a definite role in the setting of recurrence in HGG. Identification of true progression and differentiation from treatment-related changes is very important before considering surgical treatment. Multiparametric imaging, including molecular imaging, should be utilized in decision making routinely. The patient selection should be based on clinical factors, resectability of lesion, and the quality of life gains. Complete resection would significantly improve survival in recurrent GBM, when feasible and should be considered.

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Conflicts of interest

There are no conflicts of interest.


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