# Radiation Oncology/CNS/Low grade glioma

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Adult Low Grade Glioma

## Overview

* Relatively slow-growing primary brain tumors
* Account for ~10% of primary CNS tumors in USA
* Median age at diagnosis is 40's for adult tumors, and teens for pilocytic astrocytoma
* Heterogenous clinical presentation ranging from seizure only to functional deficits
* Classified as Grade I or Grade II by WHO; common histologic subtypes include astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas.
* Anaplastic transformation to high grade is common, in 70-80% patients
* Surgery is typically first option
* RT may be offered as adjuvant or as salvage; while time-to-progression and control of seizures is better with adjuvant RT, there is no difference in overall survival
* There does not seem a strong dose response between 45 and 65 Gy based on two randomized trails (EORTC 22844 compared 45 Gy vs. 59.4 Gy, INTERGROUP compared 50.4 Gy vs. 64.8 Gy); as a result, NCCN recommends 45 - 54 Gy as a reasonable dose
* 5-year overall survival is 60-70%, while progression-free survival is 40-50%

## Prognostic Factors

1p/19q fusion or deletion
* NCCTG Trials; 2006 PMID 17047046 -- "A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma." (Jenkins RB, Cancer Res. 2006 Oct 15;66(20):9852-61).
** 119 patients enrolled on 2 low-grade glioma NCCTG trials. Translocation t(1;19) evaluated by FISH
** Fusion prevalence: oligodendroglioma 55%, mixed oligoastrocytoma 47%, astrocytoma 0%
** Median OS: all patients - fusion/deletion 11.9 years vs. no fusion 8.1 years (SS); oligodendroglioma only - fusion/deletion 13.0 years vs. no fusion 9.1 years (SS)
** Conclusion: t(1;19) mediates combined 1p/19q deletion, and is associated with superior OS and PFS in low-grade gliomas
Prognostic Grouping
* EORTC 22844/22845
** 2002 PMID 11956268, "Prognostic factors for survival in adult patients with cerebral low-grade glioma." (Pignatti F et al. J Clin Oncol. 2002 Apr 15;20(8):2076-84.)
** EORTC 22844 (construction set = 322 patients) and EORTC 22845 (validation set = 288 patients)
** Poor prognosis: Age >= 40, astrocytoma histology, tumor >= 6 cm, tumor crosses midline, neurologic deficits prior to surgery; no impact from extent of surgery
** Model:
* Risk Factors
* Astrocytoma histology
* Age >=40
* Tumor >=6 cm
* Tumor crossing midline
* Neurologic deficit
| Risk Group | Score | Median OS |
| Low risk | 0 - 2 | 7.8 years |
| High risk | 3 - 5 | 3.7 years |

## Adjuvant RT Dose

* EORTC 22844 (1985–1991) "Believers Trial"
** Randomized. 343 patients. Age 16-65. Included astrocytoma, oligodendroglioma, mixed oligoastrocytoma. Excluded completely excised pilocytic astrocytoma. Surgery first. Randomized to low dose 45 Gy vs high dose 59.4 Gy at 1.8 Gy/fx. RT technique: 2 cm margin around enhancing tumor to 45 Gy, reduced field 1 cm margin to 54 Gy and minimal margin to 59.4 Gy.
** 5-years; 1996 PMID 8948338, 1996 — "A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844." Karim AB et al. Int J Radiat Oncol Biol Phys. 1996 Oct 1;36(3):549-56. Median F/U 6.2 years
*** 5-year outcome: No difference in OS (58% vs 59%) or PFS (47% vs 50%)
*** Predictors: Age, size, neurologic status, amount of surgery
*** Conclusion: No dose response above 45 Gy
** Quality of life; 1998 PMID 10023313 -- "Quality of life after radiation therapy of cerebral low-grade gliomas of the adult: results of a randomised phase III trial on dose response (EORTC trial 22844). EORTC Radiotherapy Co-operative Group." (Kiebert GM, Eur J Cancer. 1998 Nov;34(12):1902-9.)
*** Questionnaire, 47 items
*** Outcome: high RT group had more fatigue/malaise, emotional functioning
*** Conclusion: 45/25 schedule better
* Intergroup NCCTG/RTOG/ECOG (1986–1994)
** Randomized. 203 patients. Age >18. Included low grade astrocytoma, oligodendroglioma, or mixed oligoastrocytoma; pilocytic astrocytomas were excluded. Randomized to 50.4 Gy vs 64.8 Gy. RT technique: 2 cm margin around preoperative tumor volume, 1 cm margin for boost after 50.4 Gy.
** 5-years; 2002 PMID 11980997 — "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." (Shaw E et al. J Clin Oncol. 2002 May 1;20(9):2267-76.) Median F/U 6.4 years
*** 5-year outcome: OS low dose 72% vs. high dose 65% (NS); time-to-progression 58% vs. 52% (NS). Failure within field 92%
*** Toxicity: more often and more severely in high dose arm (2.5% vs 5%)
*** Poor prognosis: astrocytoma, age >40, tumor >=5 cm (5-year OS if <40 and oligodendroglioma 82% vs. >40 and astrocytoma 32%)
*** Conclusion: No benefit for higher RT dose
** MMSE Cognitive; 2003 PMID 12829670 -- "Effects of radiotherapy on cognitive function in patients with low-grade glioma measured by the folstein mini-mental state examination." (Brown PD, J Clin Oncol. 2003 Jul 1;21(13):2519-24.)
*** Prospective. 203 patients evaluated with Mini-Mental State Examination at baseline and follow-up. Median F/U 7.4 years
*** 7.4-year outcome: Stable MMSE in 95% patients without tumor progression. If abnormal baseline MMSE, experienced significant improvement after treatment
*** Conclusion: Most patients had stable neurocognitive status on MMSE after RT
** Full Cognitive; 2005 PMID 15964709 -- "Cognitive function after radiotherapy for supratentorial low-grade glioma: a North Central Cancer Treatment Group prospective study." (Laack NN, Int J Radiat Oncol Biol Phys. 2005 Nov 15;63(4):1175-83.)
*** Subset. 20 patients (10 low dose, 10 high dose) treated at Mayo Clinic. Evaluated with extensive battery of tests at baseline, and then every 1.5 years. Median F/U 3 years
*** Outcome: baseline scores below average compared with age-specific norms. No changes in cognitive performance regardless of stratification (dose, age, location, type, or resection)
*** Conclusion: Cognitive function stable after RT

## Early vs Delayed Radiotherapy

* EORTC 22845 (1986–1997) "Non-Believers Trial"
** Randomized. 314 patients. Age 16-65. Supratentorial low grade astrocytoma, low grade oligoastrocytoma, or low grade oligodendroglioma. Excluded small completely resected pilocytic astrocytomas, optic nerve gliomas, brainstem gliomas, third ventricle gliomas, and infratentorial gliomas. Surgery first. Randomized to early radiotherapy with 54 Gy (1.8 Gy/fx) vs delayed radiotherapy until the time of progression. CT with contrast every 4 months until progression. Technique: preop CT + 2 cm margins to 45 Gy, reduced field to 1 cm after 45 Gy.
** 2005 PMID 16168780 — "Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial." (van den Bent MJ et al. The Lancet Volume 366, Issue 9490, 17 September 2005, Pages 985-990.) Median F/U 7.8 years
*** Outcome: Median PFS early RT 5.3 yrs vs delayed RT 3.4 yrs (SS). 5-year PFS 55% vs. 35% (SS). Median OS 7.4 vs 7.2 yrs (NS), 5-year OS 68.4% vs 65.7% (NS). 65% of pts in control group received RT at progression, 4% in early RT received salvage RT. At 1 yr, better control of seizures in early RT group (25% vs. 41%, SS).
*** After progression: survival early RT 1.0 years vs. delayed RT 3.4 years (SS). ~70% transformed to high grade tumors, regardless if they had RT or not. Most recurrences within field
*** Toxicity (compared at 1 year for patients still tumor free at 2 years): No difference in cognitive deficit, focal deficit, performance status, or headaches.
** Conclusion: Early RT lengthens PFS and controls seizures, but doesn't impact OS
** Comment: Tumor planning off CT, central path showed 26% were high grade tumors but balanced between arms, no QoL analysis. Lack of OS difference likely due to effectiveness of salvage RT

## RT +/- Chemotherapy

* RTOG 04-24 - RT + TMZ
** High risk LGG (3 or more of: age > 40, astrocytoma, bihemispheric, > 6 cm or impaired neurologic function)
*** 54 Gy in 30 fractions, with concurrent and adjuvant temozolomide
*** 129 patients - compared to historical controls
** Preliminary results; 2014 PMID 25680596 -- "Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas." Fisher BJ, et al. Int J Radiat Oncol biol Phys. 2014 Mar 1;91(3):479-504.
*** 3-year OS 73% (54% for historical control, P < 0.001), 3-yr PFS 59.2%
* RTOG 98-02 / INT (1998–2002) -- RT +/- PCV
** Randomized arm + observation arm. 362 patients, WHO Grade II supratentorial astrocytoma, oligoastrocytoma, or oligodendroglioma
*** High risk LGG (age >=40 or STR/bx; 251 patients): Arm 1) RT 54/30 alone vs. Arm 2) RT + PCV x6 cycles. RT given T2 + 2 cm block-edge margin
*** Low risk LGG (age <40 and GTR; 111 patients): Observation only
** 4-years; 2006 ASCO Abstract 1500 (slides + video) — "Initial report of Radiation Therapy Oncology Group (RTOG) 9802: Prospective studies in adult low-grade glioma (LGG)." Shaw EG et al. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 1500. Median F/U 4 years
*** Outcome:
**** High risk: 5-year OS RT 61% vs. RT + PCV 70% (NS); PFS 39% vs. 61% (NS)
**** Low risk: 5-year OS 94%; PFS 50%
*** Toxicity: Grade 3-4 RT 9% vs. RT + PCV 67%. No treatment deaths
*** Conclusion: Poor 5-year PFS in all 3 arms; no survival advantage for adding adjuvant PCV in high risk patients
** 6-years; 2008 ASCO Abstract 2006 -- "Final report of Radiation Therapy Oncology Group (RTOG) protocol 9802: Radiation therapy (RT) versus RT + procarbazine, CCNU, and vincristine (PCV) chemotherapy for adult low-grade glioma (LGG)." (Shaw EG, J Clin Oncol 26: 2008 (May 20 suppl; abstr 2006))
*** Median Follow-Up: 5.9 years
*** High risk outcome: 5-year OS RT 63% vs. RT + PCV 72% (NS); PFS 46% vs. 63% (p=0.06). In years 0-2 no difference, beyond 2 years significant benefit for RT+PCV. HR for death 0.52, for PFS 0.45
*** Conclusion: PFS but not OS were improved with addition of PCV. Beyond 2 years, OS advantage, and decreased risk of death by 48%
** Low risk group; 2008 PMID 18976072 -- "Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial." (Shaw EG, J Neurosurg. 2008 Nov;109(5):835-41.)
*** All pts had neurosurgeon-determined GTR. OS 2-yr 99% and 5-yr 93%; PFS 82% and 48%. Prognostic factors (worse PFS): tumor ≥ 4 cm, astrocytoma or oligoastrocytoma (vs oligodendroglioma), residual tumor ≥ 1 cm. Pts with residual < 1 cm had 26% recur, vs 68% for 1–2 cm, vs 89% for >2 cm.
*** Conclusion: >50% risk of tumor progression at 5 yrs.
** 2012; Initial results (Randomized arm) PMID 22851558 -- "Randomized Trial of Radiation Therapy Plus Procarbazine, Lomustine, and Vincristine Chemotherapy for Supratentorial Adult Low-Grade Glioma: Initial Results of RTOG 9802." (Shaw EG, J Clin Oncol. 2012 Sep 1;30(25):3065-70. doi: 10.1200/JCO.2011.35.8598. Epub 2012 Jul 30.)
*** MS 7.5 yr (RT) vs not reached (RT+PCV); 5-yr OS 63% vs 72% (HR 0.72, NS). Median PFS 4.4 yr vs not reached; 5-yr PFS 46% vs 63% (HR 0.6, p=0.06). OS and PFS curves were similar between years 0-2, then separated after 2 yrs favoring RT+PCV.
*** Conclusion: "PFS but not OS was improved for adult patients with LGG receiving RT + PCV versus RT alone. On post hoc analysis, for 2-year survivors, the addition of PCV to RT conferred a survival advantage, suggesting a delayed benefit for chemotherapy."
** 12-years; 2016 PMID 27050206 -- "Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma" (Buckner JC, N Engl J Med 2016;374:1344-55)
*** Median Follow-Up: 11.9 years
*** Median OS 13.3 years (RT+PCV) vs 7.8 years (RT) (HR 0.59, p=0.003); 5y-OS 72% vs 63%; 10y-OS 60% vs 40%; no clear difference until 4 years from randomization; favorable prognostic variables: addition of chemotherapy, histopathology of oligodendroglioma, age < 40 years
*** Median PFS 10.4 years (RT+PCV) vs 4.0 years (RT) (HR 0.50, p<0.001), 5y-PFS 61% vs 44%, 10-y PFS 51% vs 21%; no difference during first 2 years; favorable prognostic variables: addition of chemotherapy, histopathology of oligodendroglioma, IDH1 mutation
*** Conclusion: PCV in addition to RT improved OS and PFS but resulted in higher toxicity
* RTOG 04-24 (Closed)
** Phase II. High risk LGG (at least 3 risk factors: age >=40, tumor diameter >=6 cm, tumor crossing midline, astrocytoma subtype, pre-op neurologic deficit). RT + Temozolomide. Comparison will be to historical EORTC patient population. Study closed with accrual met.
*** 3YR OS 73% (Significantly higher than historical controls 54%) Biomarker analysis is pending
* EORTC 22033 (2005–2010)
** RT vs. TMZ LGG with one of the following aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms.
** 2016 [PMID 27686946]
*** Median OS not yet reached (48 months). Median PFS for TMD 39 months vs RT 46 months (NS).
*** Improved PFS with RT vs TMD in IDHmt/non 1p19q codeleted tumors, IDHmt/codel and IDHwt NS.
*** Conclusion: No PFS difference between RT and TMD overall. Neurocognitive analysis to be published.

## Observation

* RTOG 98-02 (1998–2002) -- RT +/- PCV
** Randomized arm + observation arm. (see above). 362 patients, WHO Grade II supratentorial astrocytoma, oligoastrocytoma, or oligodendroglioma. Low risk LGG (age <40 and GTR; 111 patients): Observation only
** 2006 ASCO Abstract 1500 (slides + video) — "Initial report of Radiation Therapy Oncology Group (RTOG) 9802: Prospective studies in adult low-grade glioma (LGG)." Shaw EG et al. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 1500. Median F/U 4 years
*** Outcome: Low risk 5-year OS 94%; PFS 50%
*** Conclusion: Poor 5-year PFS
** 2012 PMID 22851558 -- "Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802." (Shaw, J Clin Oncol. 2012 Sep 1;30(25):3065-70.)
*** Conclusion: PFS but not OS was improved for adult patients with LGG receiving RT + PCV versus RT alone. On post hoc analysis, for 2-year survivors, the addition of PCV to RT conferred a survival advantage, suggesting a delayed benefit for chemotherapy.

## Optic Pathway Glioma

* Please see the Optic Pathway Glioma chapter