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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 1  |  Page : 23-27

Low-grade gliomas: A single-institute experience


1 Department of Radiation Oncology, Sher-IKashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
2 Department of Medical Oncology, Sher-IKashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India

Date of Submission07-Oct-2021
Date of Decision22-Nov-2021
Date of Acceptance06-Jan-2022
Date of Web Publication09-Feb-2022

Correspondence Address:
Dr. Shahida Nasreen
Department of Radiation Oncology, Sher-IKashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_42_21

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  Abstract 


Introduction: Low-grade gliomas (LGG) are relatively rare tumors. They comprise 5% of all brain tumors and 15% of all gliomas. As per WHO classification diffuse infiltrating LGG s fall under Grade II tumors. Although these tumors are slow growing but eventually they progress to high-grade gliomas, so these patients should be treated aggressively. Materials and Methods: From January 2012 to January 2017, clinical information of patients, who had LGG, was collected retrospectively from patient registries at the radiation oncology department of our institute. Results: A total of 25 patients were analyzed. Out of the entire cohort, 64% were males, and 36% were females. The most common presenting symptom in our patients was seizures and blurring of vision (44% each). Cerebrum was the mos common site of lesion in 19 out of 25 (76.0%) cases, and among those 19 cases, frontal lobe was involved in 12 cases (63.1%). Craniotomy with tumor decompression was performed in all patients. Gross total excision was possible in only 2 (8%) out of 25 patients, whereas the remaining 23 (92%) patients underwent subtotal or near total excision only. These 23 patients received concurrent chemoradiation by cobalt-60 unit to a dose of 60 Gy with weekly temozolomide. 18 out of 23 (78.2%) patients received adjuvant six cycles temozolomidein view of residual disease after concurrent chemoradiotherapy. At the last follow-up, all the 25 patients were alive, 20 patients had no disease on contrast-enhanced magnetic resonance imaging, while five patients had stable disease. Conclusion: We conclude that LGG is a disease of young adults with seizures as most common presenting symptom. If treated with multidisciplinary treatment these patients have the long disease and disability-free survival. Neurocognitive dysfunction is low in our study group, but it needs longer follow-up.

Keywords: Chemotherapy, low-grade glioma, radiotherapy, survival


How to cite this article:
Nasreen S, Najmi AM, Andleeb A, Fatima K, Sofi MA, Banday SZ. Low-grade gliomas: A single-institute experience. J Radiat Cancer Res 2022;13:23-7

How to cite this URL:
Nasreen S, Najmi AM, Andleeb A, Fatima K, Sofi MA, Banday SZ. Low-grade gliomas: A single-institute experience. J Radiat Cancer Res [serial online] 2022 [cited 2022 May 17];13:23-7. Available from: https://www.journalrcr.org/text.asp?2022/13/1/23/337482




  Introduction Top


Low-grade gliomas (LGG) are relatively rare tumors comprising 5% of all brain tumors and 15% of all gliomas.[1],[2] As per WHO classification, diffuse infiltrating LGGs fall under Grade II tumors.[3] The most common histological subtypes of LGG include astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. They commonly affect young adults between 35 and 44 years of age group.[4] Most common presentation is seizures; focal neurological symptoms are relatively less common.[5] LGGs are indolent tumors and have a markedly better prognosis than high-grade gliomas with median survival of 13 years.[6] Eventually, many of these progress to high-grade gliomas, hence necessitating the aggressive management.


  Materials and Methods Top


From January 2012 to January 2017, we retrospectively evaluated 25 patients of LGGs presenting to the Radiation Oncology Department from patient registries. This included details about surgery, radiotherapy (RT), chemotherapy, etc., Follow-up period was a minimum of 12 months.

Surgical characteristics

Gross tumor resection was defined as no residual enhancement on postoperative magnetic resonance imaging (MRI) scans. NTR/near-total excision was defined as having thin rim of enhancement in the resection cavity only. Subtotal resection was having residual nodular enhancement.

Radiotherapy protocol

23 out of 25 patients received conventional RT by telecobalt 60 source using two lateral fields. All patients were simulated on computed tomography (CT) simulator. The prescribed total dose was 60 Gy with conventional fractionation with daily doses of 2.0 Gy treated from Monday through Friday. In the initial phase, patients received 46 Gy/23 Fr/2 Gy per Fr and target volume included the whole preoperative diseased area along with edema (on preoperative contrast-enhanced MRI [CEMRI]) and 3 cm margin. In the second phase, target volume was reduced to the original diseased area only (on preoperative CEMRI) to which a further 14 Gy/7 Fr/2 Gy per Fr was delivered.

Temozolomide and supportive medications

All the 23 patients received concurrent temozolomide (TMZ) at 75 mg/m2 throughout radiotherapy (RT) period starting from the 1st day and also continued over the weekends till the last day of RT. The premedication included prophylactic antiemetics, 5HT3 inhibitors (ondansetron), and proton pump inhibitors (pantoprazole), given 30 min prior to giving drug. Temozolomide was given on an empty stomach (2 h between food and TMZ were maintained). Although edema can increase during RT, glucocorticoids were not given prophylactically but were administered only if signs and symptoms of raised intracranial pressure manifested. All patients received antiepileptic drugs like levetiracetam and phenytoin. Complete blood counts were repeated on weekly basis while on RT. The acceptable blood parameters to continue RT along with TMZ were total leukocyte counts at least 3500/mm3, platelet counts >100,000/mm3, and hemoglobin level ≥10 g/dl. Routine administration of growth factors was not considered, and if platelet counts dropped below 80,000/mm3 RT was stopped. At completion of RT, temozolomide) was also stopped. After 1 month of completion of concurrent chemoradiation, CEMRI was repeated and if patient had no residual disease they were put on follow up and if patient had residual disease they were given 6 cycles of adjuvant temozolomide.

Follow-up

First follow was done after 1 month of completion of RT with detailed clinical examination, toxicity assessment, and CEMRI of the brain for the status of disease. Subsequently 6 cycles of adjuvant TMZ at 200 mg/m2 for 5 days a month was started after checking blood counts, MRI and after reviewing patient's Eastern Cooperative Oncology Group (ECOG) performance status. Antiepileptic treatment was continued throughout. CEMRI brain was repeated after three cycles of temozolomide and at completion of six cycles. Neurocognitive functions were monitored throughout and on last follow up, proper assessment was done with Mini–Mental State Examination (MMSE).


  Results Top


A total of 25 patients were analyzed. Out of the entire cohort, 64% were males and 36% were females [Table 1]. Most of the patients had ECOG performance status of 1 (68%), and more than half of the patients were in the age group of 30–49 years (56%).
Table 1: Age distribution, gender and grade of tumor

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The most common presenting symptom in our patients was seizures and blurring of vision (44% each) followed by headache (32%), [Table 2]. On pretreatment CEMRI 28% of patients had disease, which had crossed the midline, 12% had necrosis, and 4% had hemorrhage [Table 3]. 92% of patients had solitary lesions, and only 8% had multiple lesions [Table 4].
Table 2: Presenting symptoms

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Table 3: Contrast-enhanced magnetic resonance imaging findings

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Table 4: Number of lesions as per contrast-enhanced magnetic resonance imaging

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Cerebrum was the most common site of lesion in 19 out of 25 (76.0%) cases and among those 19 cases frontal lobe was involved in the majority of cases (12) [Table 5].
Table 5: Location of tumor as per contrast-enhanced magnetic resonance imaging

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Craniotomy with tumor decompression was performed in all patients. Gross total excision was possible in only 2 (8%) out of 25 patients, whereas remaining 23 (92%) patients underwent subtotal or near-total excision only and had residual disease postoperatively. These 23 (92%) patients were subjected to postoperative concurrent chemoradiotherapy on telecobalt-60 unit by two lateral opposite portals by conventional technique to a dose of 60 Gy radiation. The two patients, who had undergone gross total excision, were put on observation after surgery. All the 23 patients received concurrent temozolomide at 75 mg/mt2 per day throughout the week. All the patients tolerated concurrent temozolomide without any severe toxicity and interruption of treatment. After completion of concurrent chemoradiation, five patients had no residual disease on CEMRI. In view of that and also because of the fact that these 5 patients had no signs or symptoms of disease, they were put on followup; rest 18 patients received six cycles of adjuvant temozolomide. After 3 cycles of adjuvant temozolomide 5 patients had stable disease, and 13 patients had partial response on CEMRI. All these patients received three more cycles of temozolomide. The adjuvant phase of temozolomide was also reasonably tolerated. Very few patients had grade 2 gastrointestinal toxicities with adjuvant temozolomide (nausea 16.6%, vomiting 11.1%). 16.6% of patients developed grade 2 thrombocytopenia while grade 3 and 4 thrombocytopenia was reported in one patient (5.5%) each [Table 6].
Table 6: Toxicity related to adjuvant chemotherapy

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At completion of adjuvant temozolomide, only five patients had persistent disease on MRI and they were prescribed maintenance temozolomide for 1 year. Out of these five patients, 3 patients had stable disease on CEMRI, while 2 had progression of disease. These two patients were treated with re-irradiation 36 Gy/18 fractions. At last follow–up, all the 25 patients were alive, 20 patients had no disease on CEMRI while 5 patients had stable disease. 2 out of 23 (8.6%) patients, who received cranial radiation had cognitive impairment on MMSE, 1 (4%) patients had mild impairment while another one had severe impairment [Table 7].
Table 7: Neurocognitive results as per Mini Mental State Examination in 23 patients

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  Discussion Top


Previously, LGG were considered as a chronic and benign disease that mainly affects young adults, mostly causing seizures and rarely any major neurological deficits. Hence, the standard of care was wait and watch. However, recent studies have shown that LGG grow continuously at a rate reaching 4–5 mm per year.[7] Most of these tumors if left untreated, will eventually undergo malignant transformation, leading to more severe symptoms and impaired quality of life and ultimately leading to decreased survival.[8],[9] These patients are treated now with multimodality approach with surgery, radiotherapy, and chemotherapy.[10]

The most common age group in our study was 30–49 years contributing to more than half of the patients (56%). The most common site of involvement was the frontal lobe, and males were more in number than females. The most common symptom was seizures. All these parameters are similar to the rest of the world.[4],[11],[12]

Postoperative radiotherapy has a proven role in LGGs, especially in patients who have not had total surgical resection. However, timing of radiation is not settled yet whether to give immediately after surgery or delay radiation till progression of disease.[13],[14],[15],[16],[17] A Phase III study randomly assigned patients with low-grade glioma to either postoperative radiation or observation, with radiation given at the time of progression. Early radiation prolonged progression-free survival by close to 2 years, but there was no significant difference in overall survival, which was 7.4 years in the radiation group and 7.2 years in the observation group, but major drawback of this study was that it did not study the quality of life and neurocognitive parameters of these patients.[18] Keeping in view these results, all of our patients having sub-total resection received radiotherapy within 1 month of surgery.

Although chemotherapy is not used routinely in LGGs, there is a literature evidence of improvement in survival with concurrent and adjuvant chemotherapy. The RTOG 9802 study compared radiotherapy alone versus radiotherapy followed by procarbazine, lomustine and vincristine (PCV) chemotherapy in patients with high-risk LGG.[19] The long-term results of this trial showed a clear benefit in both PFS and OS in the arm receiving radiotherapy plus PCV, with a gain of 5.5 years in survival (13.3 versus 7.8 years).[6]

A Phase II study, RTOG 0424, evaluated a Stupplike regimen of radiation with concurrent and adjuvant temozolomide in 136 patients with low-grade glioma with at least 3 high-risk factors. The radiation treatment consisted of conformal radiotherapy with 54 Gy delivered in 30 fractions, and temozolomide 75 mg/m2 was administered daily concurrently with radiotherapy over 6 weeks and then continued at a dose of 150–200 mg/m2 on days 1–5, every 28 days, for up to 12 cycles. This study reported promising results with a 3-year OS rate of 73.1%. Although not an ideal control group, the overall survival (OS) of this study cohort was reported to be higher than a historical control group composed of patients enrolled in a prior EORTC trial.[20] In the present study also, temozolomide was given concurrently in all patients who received radiation. However, the dose prescribed was 60 Gy instead of 54 Gy, as per the departmental protocol at that time. High-risk features in patients with LGG include age older than 40 years, tumor diameter >6 cm, midline crossing, presence of neurological deficit, and astrocytic histology.[21] It has been observed that patients defined as low risk after gross total resection have a 50% risk of tumor progression at 5 years.[22] Hence, taking all these results in consideration, in addition to the fact that most of the patients in our study were symptomatic and had disease crossing midline on imaging, all 23 patients with some form of residual disease postoperatively received concurrent TMZ. Moreover, 18 out of these patients received adjuvant Temozolomide because of persistent disease. We found a good response to adjuvant temozolomide as well. At completion of treatment, overall 20 patients had no disease on last MRI. MRI alone is not an ideal investigative modality for response assessment in neuro-oncology, and we would have liked to do other investigations like MRS also for exact status of disease but those were not available.

The severity of neurocognitive deficits ranges from mild or moderate to dementia with progressive mental slowing and deficits in attention and memory, occurring in as many as 12% of patients who received radiotherapy.[23] 2 out of 23 patients in our study group, who received cranial radiotherapy, had a neurocognitive deficit. This is lower than observed in the rest of the world, but our follow-up period is <5 years which is lower than other studies. Hence we need to follow these patients for longer periods of time to fully assess their neurocognitive state.

Limitations

The first limitation is lack of molecular profiling. IDH status of our patients is not known. Reason for this is that our data is from 2012 to 2017 and testing for a specific range of molecular parameters was not a standard diagnostic procedure before during that period.

Second limitation is we have not analyzed cyclin-dependent kinase inhibitor 2A (CDKN2A). For IDH-mutant astrocytic gliomas, homozygous deletion of the CDKN2A gene has recently been shown to be a powerful predictor of poor outcome.

Third limitation is that our data is retrospectively acquired and therefore not recorded in accordance with a predefined study protocol.


  Conclusion Top


We conclude that LGG is a disease of young adults with seizures as most common presenting symptom. If treated with multidisciplinary treatment, these patients have long disease and disability-free survival. Neurocognitive dysfunction is low in our study group, but it needs longer follow-up time.

Financial support and sponsorship

This study was financially supported by Radiation Oncology, Medical Oncology, Internal Medicine.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114:97-109.  Back to cited text no. 3
    
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Ostrom QT, Gittleman H, Xu J, Kromer C, Wolinsky Y, Kruchko C, et al. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2009-2013. Neuro Oncol 2016;18:v1-75.  Back to cited text no. 4
    
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Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR, et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 2016;374:1344-55.  Back to cited text no. 6
    
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Pallud J, Blonski M, Mandonnet E, Audureau E, Fontaine D, Sanai N, et al. Velocity of tumor spontaneous expansion predicts long-term outcomes for diffuse low-grade gliomas. Neuro Oncol 2013;15:595-606.  Back to cited text no. 7
    
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Martino J, Taillandier L, Moritz-Gasser S, Gatignol P, Duffau H. Re-operation is a safe and effective therapeutic strategy in recurrent WHO grade II gliomas within eloquent areas. Acta Neurochir 2009;151:427-36.  Back to cited text no. 8
    
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Kim YH, Nobusawa S, Mittelbronn M, Paulus W, Brokinkel B, Keyvani K, et al. Molecular classification of low-grade diffuse gliomas. Am J Pathol 2010;177:2708-14.  Back to cited text no. 9
    
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Pouratian N, Asthagiri A, Jagannathan J, Shaffrey ME, Schiff D. Surgery Insight: The role of surgery in the management of low-grade gliomas. Nat Clin Pract Neurol 2007;3:628-39.  Back to cited text no. 11
    
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Dong M, Cioffi G, Wang J, Waite KA, Ostrom QT, Kruchko C, et al. Sex differences in cancer incidence and survival: A pan-cancer analysis. Cancer Epidemiol Biomarkers Prev 2020;29:1389-97.  Back to cited text no. 12
    
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Berger MS, Deliganis AV, Dobbins J, Keles GE. The effect of extent of resection on recurrence in patients with low grade cerebral hemisphere gliomas. Cancer 1994;74:1784-91.  Back to cited text no. 13
    
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Piepmeier J, Christopher S, Spencer D, Byrne T, Kim J, Knisel JP, et al. Variations in the natural history and survival of patients with supratentorial low-grade astrocytomas. Neurosurgery 1996;38:872-8.  Back to cited text no. 14
    
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Recht LD, Lew R, Smith TW. Suspected low-grade glioma: Is deferring treatment safe? Ann Neurol 1992;31:431-6.  Back to cited text no. 15
    
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Papagikos MA, Shaw EG, Stieber VW. Lessons learned from randomised clinical trials in adult low grade glioma. Lancet Oncol 2005;6:240-4.  Back to cited text no. 16
    
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van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: The EORTC 22845 randomised trial. Lancet 2005;366:985-90.  Back to cited text no. 18
    
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Fisher BJ, Hu C, Macdonald DR, Lesser GJ, Coons SW, Brachman DG, et al. Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas: Preliminary results of Radiation Therapy Oncology Group 0424. Int J Radiat Oncol Biol Phys 2015;91:497-504.  Back to cited text no. 20
    
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22.
Shaw EG, Berkey B, Coons SW, Bullard D, Brachman D, Buckner JC, et al. Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: Results of a prospective clinical trial. J Neurosurg 2008;109:835-41.  Back to cited text no. 22
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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