Low-Grade Glioma Radiotherapy Dose

Low-Grade Glioma Radiotherapy Dose

Adjuvant radiation is often used in patients with low-grade gliomas with high-risk characteristics with a recommended dose of 45-54 Gy. Byrne et al. used the National Cancer Database (NCDB) to see which doses were being used and if any difference was seen in outcome.

They queried the NCDB for patients with WHO Grade 2 primary brain tumors treated with surgery and adjuvant radiotherapy. We divided the cohort into dose groups: 45-50 Gy, 50.4-54 Gy, and > 54 Gy. Multivariable logistic regression was used to identify predictors of low and high-dose radiation. Propensity matching was used to account for indication bias.

Results: We identified 1437 patients meeting inclusion criteria. The median age was 45 years and 62% of patients were > 40 years old. Nearly half of patients (48%) had astrocytoma subtype and 70% had a subtotal resection. The majority of patients (69%) were treated to doses between 50.4 and 54 Gy. Predictors of high dose radiation (> 54 Gy) were increased income, astrocytoma subtype, chemotherapy receipt, and treatment in a later years (2014). The main predictors of survival were age > 40, astrocytoma subtype, and insurance type. Patients treated to a dose of > 54 Gy had a median survival of 73.5 months and was not reached in those treated to a lower dose (p = 0.0041).

This analysis showed that 50.4-54 Gy is the most widely used radiation regimen for the adjuvant treatment of low-grade gliomas. There appeared to be no benefit to higher doses, although unreported factors may impact the interpretation of the results 1).


Postoperative policies of “wait-and-see” and radiotherapy for low-grade glioma are poorly defined. A trial in the mid 1980s established the radiation dose.


A phase III prospective randomized trial of low- versus high-dose radiation therapy for adults with supratentorial low-grade astrocytoma, oligodendroglioma, and oligoastrocytoma found somewhat lower survival and slightly higher incidence of radiation necrosis in the high-dose RT arm. The most important prognostic factors for survival are histologic subtype, tumor size, and age 2).


Two prospective trials found no difference in OS or PFS between different XRT doses (EORTC trial 3): 45 Gy in 5 weeks vs. 59.4 Gy in 6.6 weeks; Intergroup study 4) 50.4 vs. 64.8 Gy).


1)

Byrne E, Abel S, Yu A, Shepard M, Karlovits SM, Wegner RE. Trends in radiation dose for low-grade gliomas across the United States. J Neurooncol. 2022 Feb 23. doi: 10.1007/s11060-022-03962-4. Epub ahead of print. PMID: 35199246.
2)

Shaw E, Arusell R, Scheithauer B, O’Fallon J, O’Neill B, Dinapoli R, Nelson D, Earle J, Jones C, Cascino T, Nichols D, Ivnik R, Hellman R, Curran W, Abrams R. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol. 2002 May 1;20(9):2267-76. PubMed PMID: 11980997.
3)

Karim ABMF, Maat B, Hatlevoll R, et al. A random- ized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiation Oncology Biol Phys. 1996; 36:549–556
4)

Shaw E, Arusell R, Scheithauer B, O’Fallon J, O’Neill B, Dinapoli R, Nelson D, Earle J, Jones C, Cascino T, Nichols D, Ivnik R, Hellman R, Curran W, Abrams R. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supra- tentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol. 2002; 20:2267–2276

Low grade glioma radiotherapy

Low grade glioma radiotherapy

Postoperative policies of “wait-and-see” and radiotherapy for low grade glioma are poorly defined. A trial in the mid 1980s established the radiation dose. In 1986 the EORTCRadiotherapy and Brain Tumor Groups initiated a prospective trial to compare early radiotherapy with delayed radiotherapy.

After surgery, patients from 24 centres across Europe were randomly assigned to either early radiotherapy of 54 Gy in fractions of 1.8 Gy or deferred radiotherapy until the time to progression (control group). Patients with low-grade astrocytoma, oligodendroglioma, mixed oligoastrocytoma, and incompletely resected pilocytic astrocytoma, with a WHO performance status 0-2 were eligible. Analysis was by intention to treat, and primary endpoints were overall and progression-free survival.

157 patients were assigned early radiotherapy, and 157 control. Median progression-free survival was 5.3 years in the early radiotherapy group and 3.4 years in the control group (hazard ratio 0.59, 95% CI 0.45-0.77; p<0.0001). However, overall survival was similar between groups: median survival in the radiotherapy group was 7.4 years compared with 7.2 years in the control group (hazard ratio 0.97, 95% CI 0.71-1.34; p=0.872). In the control group, 65% of patients received radiotherapy at progression. At 1 year, seizures were better controlled in the early radiotherapy group.

Early radiotherapy after surgery lengthens the period without progression but does not affect overall survival. Because quality of life was not studied, it is not known whether time to progression reflects clinical deterioration. Radiotherapy could be deferred for patients with low-grade glioma who are in a good condition, provided they are carefully monitored 1).

Early radiotherapy (RT) (54 Gy in fractions of 1.8 Gy) is recommended as adjuvant therapy and is shown to prolong median progression free survival (PFS) from 3.4 to 5.3 years but does not affect overall survival 2).

In patients with the tumor radically resected, early RT did not prolong PFS and is recommended to be deferred until progression. Following incomplete resection, early RT significantly prolongs PFS and disease specific survival 3).

Two prospective trials found no difference in OS or PFS between different XRT doses (EORTC trial 4): 45 Gy in 5 weeks vs. 59.4 Gy in 6.6 weeks; Intergroup study 5) 50.4 vs. 64.8 Gy).


In a cohort of patients with low grade glioma who were younger than 40 years of age and had undergone subtotal resection or who were 40 years of age or older, progression free survival and overall survival were longer among those who received combination chemotherapy in addition to radiation therapy than among those who received radiation therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00003375.) 6).

There was no significant difference in progression free survival in patients with low grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices 7).

The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma 8).

Adverse effects

Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who undergo early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation-induced malignant transformation of LGG. However, it remains unclear whether there are differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated 9).


Twenty adult patients with supratentorial low-grade glioma were treated with 50.4 Gy (10 patients) or 64.8 Gy (10 patients) localized RT. The patients then were evaluated with an extensive battery of psychometric tests at baseline (before RT) and at approximately 18-month intervals for as long as 5 years after completing RT. To allow patients to serve as their own controls, cognitive performance was evaluated as change in scores over time. All patients underwent at least two evaluations.

Baseline test scores were below average compared with age-specific norms. At the second evaluation, the groups’ mean test scores were higher than their initial performances on all psychometric measures, although the improvement was not statistically significant. No changes in cognitive performance were seen during the evaluation period when test scores were analyzed by age, treatment, tumor location, tumor type, or extent of resection.

Cognitive function was stable after RT in these patients evaluated prospectively during 3 years of follow-up. Slight improvements in some cognitive areas are consistent with practice effects attributable to increased familiarity with test procedures and content 10).

Dose

A phase III prospective randomized trial of low- versus high-dose radiation therapy for adults with supratentorial low-grade astrocytoma, oligodendroglioma, and oligoastrocytoma found somewhat lower survival and slightly higher incidence of radiation necrosis in the high-dose RT arm. The most important prognostic factors for survival are histologic subtype, tumor size, and age 11).

References

1) , 2)

van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K, Malmström PO, Collette L, Piérart M, Mirimanoff R, Karim AB; EORTC Radiotherapy and Brain Tumor Groups and the UK Medical Research Council. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005 Sep 17-23;366(9490):985-90. Erratum in: Lancet. 2006 Jun 3;367(9525):1818. PubMed PMID: 16168780.
3)

Hanzely Z, Polgar C, Fodor J, Brucher JM, Vitanovics D, Mangel LC, Afra D. Role of early radiotherapy in the treatment of supratentorial WHO Grade II astrocytomas: long-term results of 97 patients. J Neurooncol. 2003; 63:305–312
4)

Karim ABMF, Maat B, Hatlevoll R, et al. A random- ized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiation Oncology Biol Phys. 1996; 36:549–556
5)

Shaw E, Arusell R, Scheithauer B, O’Fallon J, O’Neill B, Dinapoli R, Nelson D, Earle J, Jones C, Cascino T, Nichols D, Ivnik R, Hellman R, Curran W, Abrams R. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supra- tentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol. 2002; 20:2267–2276
6)

Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR, Coons S, Ricci P, Bullard D, Brown PD, Stelzer K, Brachman D, Suh JH, Schultz CJ, Bahary JP, Fisher BJ, Kim H, Murtha AD, Bell EH, Won M, Mehta MP, Curran WJ Jr. Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma. N Engl J Med. 2016 Apr 7;374(14):1344-55. doi: 10.1056/NEJMoa1500925. PubMed PMID: 27050206; PubMed Central PMCID: PMC5170873.
7)

Baumert BG, Hegi ME, van den Bent MJ, von Deimling A, Gorlia T, Hoang-Xuan K, Brandes AA, Kantor G, Taphoorn MJ, Hassel MB, Hartmann C, Ryan G, Capper D, Kros JM, Kurscheid S, Wick W, Enting R, Reni M, Thiessen B, Dhermain F, Bromberg JE, Feuvret L, Reijneveld JC, Chinot O, Gijtenbeek JM, Rossiter JP, Dif N, Balana C, Bravo-Marques J, Clement PM, Marosi C, Tzuk-Shina T, Nordal RA, Rees J, Lacombe D, Mason WP, Stupp R. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016 Nov;17(11):1521-1532. doi: 10.1016/S1470-2045(16)30313-8. Epub 2016 Sep 27. PubMed PMID: 27686946; PubMed Central PMCID: PMC5124485.
8)

Reijneveld JC, Taphoorn MJ, Coens C, Bromberg JE, Mason WP, Hoang-Xuan K, Ryan G, Hassel MB, Enting RH, Brandes AA, Wick A, Chinot O, Reni M, Kantor G, Thiessen B, Klein M, Verger E, Borchers C, Hau P, Back M, Smits A, Golfinopoulos V, Gorlia T, Bottomley A, Stupp R, Baumert BG. Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016 Nov;17(11):1533-1542. doi: 10.1016/S1470-2045(16)30305-9. Epub 2016 Sep 27. PubMed PMID: 27686943.
9)

Sarmiento JM, Venteicher AS, Patil CG. Early versus delayed postoperative radiotherapy for treatment of low-grade gliomas. Cochrane Database Syst Rev. 2015 Jun 29;6:CD009229. doi: 10.1002/14651858.CD009229.pub2. PubMed PMID: 26118544; PubMed Central PMCID: PMC4506130.
10)

Laack NN, Brown PD, Ivnik RJ, Furth AF, Ballman KV, Hammack JE, Arusell RM, Shaw EG, Buckner JC; North Central Cancer Treatment Group. Cognitive function after radiotherapy for supratentorial low-grade glioma: a North Central Cancer Treatment Group prospective study. Int J Radiat Oncol Biol Phys. 2005 Nov 15;63(4):1175-83. Epub 2005 Jun 20. PubMed PMID: 15964709.
11)

Shaw E, Arusell R, Scheithauer B, O’Fallon J, O’Neill B, Dinapoli R, Nelson D, Earle J, Jones C, Cascino T, Nichols D, Ivnik R, Hellman R, Curran W, Abrams R. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol. 2002 May 1;20(9):2267-76. PubMed PMID: 11980997.

Spinal myxopapillary ependymoma and the role of Radiotherapy

Treatment for spinal myxopapillary ependymoma mainly involves surgical excision of the tumour.

Radiotherapy

If the capsule ruptures or the tumour is not confined to the filum terminale, the mass could infiltrate and adhere to the cauda equina and/or conus medullaris or disseminate via the cerebral spinal fluid 1) 2).
Therefore, adjuvant radiotherapy is recommended when en bloc excision (removal of the entire tumour as one piece) cannot be accomplished 3) 4).
However, the efficacy of radiation therapy has not been established and can result in adverse effects such as radiation myelopathy 5) 6) and residual dysuria 7).
In the series of Tsai et al., the median age at diagnosis was 35 years (range, 8-63 years). Twenty patients (39%) had surgery alone, 30 (59%) had surgery plus radiotherapy (RT), and 1 (2%) had RT only. At a median follow-up of 11 years (range, 0.2-37 years), 10-year overall survival (OS), progression free survival (PFS), and local control (LC) for the entire group were 93%, 63%, and 67%, respectively. Nineteen patients (37%) had disease recurrence, and the recurrence was mostly local (79%). Twenty-eight of 50 patients who had surgery (56%) had gross total resection; 10-year LC was 56% after surgery vs 92% after surgery and RT (log-rank P = .14); the median time of LC was 10.5 years for patients receiving gross total resection plus RT, and 4.75 years for gross total resection only (P = .03). Among 16 patients with subtotal resection and follow-up data, 10-year LC was 0% after surgery vs 65% for surgery plus RT (log-rank P = .008). On multivariate analyses adjusting for resection type, age older that 35 years at diagnosis and receipt of adjuvant radiation were associated with improved PFS (hazard ratio [HR]: 0.14, P = .003 and HR: 0.45, P = .009) and LC (HR: 0.22, P = .02 and HR: 0.45, P = .009).
Postoperative radiotherapy after resection of MPE was associated with improved PFS and LC 8).
1) , 5) Sakai Y, Matsuyama Y, Katayama Y, et al. Spinal myxopapillary ependymoma: Neurological deterioration in patients treated with surgery. Spine. 2009;34:1619–1624.
2) , 3) , 7) Nakamura M, Ishii K, Watanabe K, et al. Long-term surgical outcomes for myxopapillary ependymomas of the cauda equine. Spine. 2009;34:E756–760.
4) , 6) Volpp PB, Han K, Kagan AR, Tome M. Outcomes in treatment for intradural spinal cord ependymomas. Int J Radiation Oncology Biol Phys. 2007;69:1199–1204.
8) Tsai CJ, Wang Y, Allen PK, Mahajan A, McCutcheon IE, Rao G, Rhines LD, Tatsui CE, Armstrong TS, Maor MH, Chang EL, Brown PD, Li J. Outcomes after surgery and radiotherapy for spinal myxopapillary ependymoma: update of the MD anderson cancer center experience. Neurosurgery. 2014 Sep;75(3):205-14. doi: 10.1227/NEU.0000000000000408. PubMed PMID: 24818785.
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