# Radiation Oncology/CNS/Anaplastic glioma

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Anaplastic Glioma (WHO Grade III)

## Overview

* Includes anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), and anaplastic oligoastrocytoma (AOA)
* Management typically follows that of WHO Grade IV glioblastoma, particularly for anaplastic astrocytoma. However, several trials are specific to WHO Grade III histologies, particularly AO and AOA
* Absence of vascular proliferation and necrosis differentiates AA from GBM tumors histopathologically
* Several ongoing studies underway to address the role of RT + temozolomide (TMZ) vs. RT + procarbazine, lomustine and vincristine (PCV) but retrospective data suggests RT + TMZ appropriate for both AO and AOA patients regardless of 1p/19q codeletion. TMZ is the most commonly utilized chemotherapy in these patients in part due to their favorable toxicity profile.

## Prognosis

* RTOG RPA; 1993 (1974-1989) PMID 8478956 — "Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials." Curran WJ et al. J Natl Cancer Inst. 1993 May 5;85(9):704-10.
** See also RPA at GBM page
** Analysis of RTOG 74-01 / ECOG 1374, RTOG 79-18, and RTOG 83-02. 1578 pts included.
** Details: neurologic functional classification (class 1, able to work; class 2, able to be at home; classes 3 and 4, hospitalized), mental status (is normal or abnormal)
RPA Stages For Anaplastic Astrocytoma WHO Grade III (No TMZ) :
| Stage | Characteristics | Median Survival (mo) | 1-year OS | 2-year OS |
| I | Age <50, normal MS | 59 | 90% | 76% |
| II | Age >=50, KPS >=70, Symptoms >3 mo | 37 | 85% | 68% |
| III | Age <50, abnormal MS | 18 | 70% | 35% |
| IV | Age>=50, KPS>=70, Symptoms <=3 mo | 11 | 45% | 15% |
| V | Age>=50, KPS<70 and normal MS | 9 | 30% | 6% |
| VI | Age >=50, KPS <70, abnormal MS | 5 | 20% | 4% |
MS = Mental status

## Adjuvant RT vs. No Adjuvant RT

* SEER/Univ of Colorado PMID 25585784 — "The impact of adjuvant radiation therapy for high-grade gliomas by histology in the United States population." Rusthoven CG, et al. Int J Radiat Oncol Biol Phys. 2014 Nov 15;90(4):894-902.
* 1998-2007. Included all patients with high-grade gliomas (WHO grade 3-4) of Glioblastoma (GBM), Anaplastic Astrocytoma (AA), mixed Anaplastic Oligoastrocytoma (AOA), and Anaplastic Oligodendroglioma (AO) histology managed with upfront resection +/- adjuvant radiation therapy.
* RESULTS:
** Adj RT assoc with improved OS for GBMs (2-yr OS, 17% vs 7%, p<0.001), AAs (5-yr OS, 38% vs 24%, p<0.001), and AOAs (5-yr OS, 55% vs 44%, p=0.026). No sig diff observed for AOs (5-yr OS, with RT 50% vs 56% without RT, p=0.277).
** On MVA accounting for extent of resection, age, sex, race, year, marital status, and registry, RT assoc with sig OS benefit for GBMs (HR 0.52, p<0.001) and AAs (HR 0.57, p<0.001) but only a trend for AOAs (HR 0.70, p=0.110). Due to the observation of non-proportional hazards, Cox regressions not performed for AOs.
** A sig interaction between RT and Histology overall (GBM, AA, AOA, AO) (p<0.001) and in a model limited to the anaplastic WHO grade 3 histologies (AA, AOA, AO) (p=0.024), characterizing histology as a sig predictive factor for the impact of RT.
** Subgroup analyses demonstrated greater hazard reductions with RT among patients older-than-median-age for both GBMs and AAs (p<0.001).
* CONCLUSIONS:
** RT assoc with improved OS for AAs, with benefits similar to those observed for GBMs over the same 10-year interval. Intermediate benefits with RT observed for AOAs. No benefit of RT observed for AOs.
** Histology characterized as a sig predictive factor for the survival impact of RT, suggesting a decreased benefit of RT in the setting of an increasing oligodendroglial component.
** Authors discuss potential explanations for differing impact of RT in AO cohort, including: the potential for successful salvage RT at progression for favorable prognosis gliomas (similar to randomized data in low-grade gliomas, EORTC 22845), patterns-of-care analyses demonstrating a trend toward increased upfront chemotherapy use in the setting of RT deferral for AOs, leading to equivalent OS (akin to the randomized NOA-04, Wick et al), and AO histology as a surrogate for a higher incidence of mutational profiles associated with chemo- more so than radio-responsiveness (ie, 1p/19q codeletions, IDH mutations, MGMT promoter methylation).

## Adjuvant RT vs. Chemotherapy

* NOA-04 (Germany)(1999-2005) -- RT 54-60 Gy vs. PCV vs. temozolomide
** Randomized; double randomization, 3 arms. 318 patients, supratentorial WHO Grade III glioma. Arm 1) RT 60 Gy in 6 weeks vs. Arm 2) chemotherapy. If randomized to chemotherapy, then further randomized to Arm 2A) CCN 110 mg/m2, vincristine 2 mg, procarbazine 60 mg/m2 x4 cycles vs. Arm 2B) Temozolomide 200 mg/m2 x8 cycles. Upon relapse, patients received salvage RT (if treated initially with chemo) or salvage chemo (if treated with RT). TTF was defined as failure after receiving both initial treatment and salvage.
** 2008 ASCO Abstract -- "Randomized phase III study of sequential radiochemotherapy of oligoastrocytic tumors of WHO-grade III with PCV or temozolomide: NOA-04." Wick Wolfgang W, et al. J Clin Oncol. 2008 May 20;26(15_suppl):LBA2007.
*** Outcome: median TTF RT 3.6 years vs. PCV/Temodar 3.6 years (NS), median OS 5+ years vs. 5+ years (NS)
*** Predictors: oligo component (oligodendroglioma or oligoastrocytoma), LOH 1p/19q , MGMT+
*** Toxicity: Grade 3-4 hematologic significantly higher for PCV than temozolomide
*** Conclusion: No difference in TTF between RT and chemotherapy (PCV or temozolomide)
** 2009 PMID 19901110 -- "NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide." (Wick W, J Clin Oncol. 2009 Dec 10;27(35):5874-80.) Median F/U 5.4 years
*** Outcome: No difference in TTF (3.6 years), however fewer patients in RT arm completed salvage chemo (48%) vs patients in chemo arm completed salvage RT (78%). Similar treatment course for AO and AOA, worse for AA
*** Prognostic factors: 1p/19q codeletion in 41% (AA 15%, AO 77%, AOA 59%); MGMT+ 61% (AA 50%, AO 71%, AOA 71%); IDH1 mutation 66% (AA 57%, AO 71%, AOA 73%). In multivariate model, IDH1 mutation stronger risk reduction than 1p/19q codeletion, MGMT methylation or histology
*** Conclusion: Initial RT or chemotherapy, followed by opposite salvage, achieved comparable outcomes. IDH1 mutation strongest prognostic factor
** Commentary: (DeAngelis L, JCO 2009, PMID 19901101) -- "Unfortunately, the interpretation of this study is markedly compromised by its design... Only if treatment sequence affected tumor progression after all therapy was administered could there be a difference between the study arms. Therefore, the results of the trial could have been predicted based on its design, and the data fail to guide future treatment decisions for these patients."
** Long-term, 2016 PMID 27370396 — "Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide." Wick W, et al. Neuro Oncol. 2016 Nov;18(11):1529-37.
*** to be continued ...

## Adjuvant RT +/- Chemotherapy

* EORTC 26951 (1996-2002) -- RT +/- adjuvant PCV
** Randomized. 368 patients. AO and AOA (>25% oligodendroglial elements). Median age 49. Surgery followed by RT within 6 weeks 59.4/33, then Arm 1) observation vs. Arm 2) PCV (procarbazine 60, lomustine 110, vincristine 1.4) x6 cycles. Adjuvant PCV discontinued in 38%; 80% of RT arm received chemo at progression. RT PTV1 = T2 + 2.5cm to 45/25, then PTV2 = T1 + 1.5cm to 59.4/33. Primary endpoint OS
** 5-years; 2006 PMID 16782911 — "Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial." (Van den Bent MJ et al. J Clin Oncol. 2006 Jun 20;24(18):2715-22.). Median F/U 5 years
*** Outcome: median OS RT+PCV 3.4 years vs RT 2.6 years (NS); PFS: 1.9 years vs 1.1 years (SS)
*** 1p/19q Analysis: Combined deletion in 25%; 5-year OS 74%; 5-year OS RT+PCV 74% vs. RT 75% (NS); PFS 69% vs. 50% (NS). Comparison of 5-year OS 1p/19q deleted 74% vs. 1p/19qWT ~30%
*** Conclusion: Adjuvant PCV does not prolong OS, but improves PFS. Patients with 1p/19q deletion have significantly better outcome, though not impacted by addition of PCV
** QoL; 2007 PMID 18089866 -- "Health-related quality of life in patients treated for anaplastic oligodendroglioma with adjuvant chemotherapy: results of a European Organisation for Research and Treatment of Cancer randomized clinical trial." (Taphoorn MJ, J Clin Oncol. 2007 Dec 20;25(36):5723-30.)
*** Health-related QoL assessed, baseline 78% patients, at 2.5 years post treatment 55%
*** Outcome: baseline: considerable impairment in both groups. PCV group worse appetite, drowsiness, N/V during and shortly after chemo. No long-term difference
*** Conclusion: No long term difference in QoL after PCV
** IDH1/IHD2 mutations; 2010 PMID 20160062 -- "IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group." (van den Bent MJ, Clin Cancer Res. 2010 Mar 1;16(5):1597-604. Epub 2010 Feb 16.)
*** Retrospective. 159 patients. PCR analysis of IDH1 and IDH2 mutations.
*** Outcome: IDH1 mutation in 46%, IDH2 mutation in <1%. Mutation prognostic in both RT and RT+PCV arms for PFS and OS; mutation not predictive for PCV effect. Strongly associated with 1p/19q codeletion and MGMT promoter methylation
*** Conclusion: IDH1 mutation very strong prognostic factor for OS
** 11-years; 2012 PMID 23071237 -- "Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Newly Diagnosed Anaplastic Oligodendroglioma: Long-Term Follow-Up of EORTC Brain Tumor Group Study 26951." (van den Bent MJ, J Clin Oncol -- online before print, Oct 15, 2012.)
*** Median f/u 140 months (11.6 y). OS was prolonged in the RT+PCV arm: 42.3 vs 30.6 mo. In pts with 1p/19q co-deletion (n=80), OS was increased, with a trend toward more benefit from PCV (OS in RT+PCV group not reached, vs 112 months in RT only group). IDH mutational status was also prognostic
*** Conclusion: "The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non–1p/19q-deleted tumors."
* RTOG 9402 / INT 0149 (1994-2002) -- Sequential PCV -> RT vs. RT alone
** Randomized. 289 patients with supratentorial AO and AOA (>25% oligodendroglioma component), KPS >=60. Randomized to PCV x4 cycles prior to RT vs RT alone after maximal surgical resection. Arm 1) PCV (procarbazine, CCNU, vincristine) x4 cycles followed by RT vs. Arm 2) RT alone. RT given 59.4/33/ PTV1 = T2 + 2cm, PTV2 = T1 + 1cm
** 2006 PMID 16782910 — "Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402." (Cairncross G, J Clin Oncol. 2006 Jun 20;24(18):2707-14.) Median F/U 5.1 years
*** Outcome: Median OS PCV->RT 4.9 years vs. RT 4.7 years (NS). PFS 2.6 years vs. 1.7 years (SS).
*** Toxicity: Grade 3-4 induction PCV 65%, RT after PCV 8% vs. RT alone 5%
*** Chromosomes: LOH 1p/19q combined in 46%, AO 57% vs. AOA 14% (SS). Lower risk of tumor progression PFS 4.0 v 1.3 years(SS), and median OS not-reached vs. 2.8 years (SS). No effect of treatment on survival
*** Conclusion: No impact on survival. Improved PFS but at significant toxicity cost. Patients with 1p/19q deletion have significantly improved outcome
** 2012 ASCO Abstract -- "Chemotherapy plus radiotherapy (CT-RT) versus RT alone for patients with anaplastic oligodendroglioma: Long-term results of the RTOG 9402 phase III study." (Cairncross JG, et al. J Clin Oncol. 2012 May 20;30(15_suppl):2008b.
*** Median f/u 11.3 yr. Median PFS 2.5 vs 1.7 yr. 1p/19q codeletion associated with median MS 8.7 yr vs 2.7 yr. For the entire cohort, no difference in MS by treatment (p=0.1). However, pts with 1p/19q deleted tumors had improved survival with PCT+RT (14.7 yr) than with RT alone (7.3 yr). No difference in MS by treatment in pts without 1q/19q del.
*** Conclusion: "PCV followed by immediate RT was a highly effective therapy for patients with 1p/19q co-deleted AO/AOA. In this setting, 1p/19q co-deletion was both prognostic and predictive, and the early PFS benefit in co-deleted cases was a harbinger of their longer OS."
** 2012 PMID 23071247 -- "Phase III Trial of Chemoradiotherapy for Anaplastic Oligodendroglioma: Long-Term Results of RTOG 9402." (Cairncross G, J Clin Oncol 2013 Jan 20;31(3):344-50)
*** For the entire cohort, no difference in MS by treatment (4.6 yr PCV+RT vs 4.7 yr RT). Pts with 1p/19q co-deleted tumors lived longer than those with noncodeleted tumors (PCV plus RT: 14.7 vs 2.6 yr, HR = 0.36; RT alone: 7.3 vs 2.7 yr, HR = 0.40).
*** Pts with co-deleted tumors -- the MS for pts treated with PCV + RT was twice that of pts receiving RT alone (14.7 vs 7.3 yrs; HR = 0.59).
*** Pts with non-codeleted tumors -- no difference in MS by treatment (2.6 vs 2.7 yrs; HR =0.85).
*** In multivariate analysis (including codeletion status), the adjusted OS for all pts was prolonged by PCV + RT (HR =0.67; SS).
*** Conclusion: "For the subset of patients with 1p/19q codeleted AO/AOA, PCV plus RT may be an especially effective treatment, although this observation was derived from an unplanned analysis."
* Washington University; 2015 PMID 25636755 -- "Impact of 1p/19q codeletion and histology on outcomes of anaplastic gliomas treated with radiation therapy and temozolomide." (Speirs CK, Int J Radiat Oncol Phys. 2015 Feb 1;91(2):268-76.)
** Restrospective Single Institution study comparing 111 patients treated with post-op radiation with concurrent TMZ compared to historical control PCV trials including EORTC 26951 and RTOG 9402.
*** 5-year OS for AO/AOA with 1p/19q codeletion: RT+TMZ 91% vs. RT+PCV 72-76% vs. RT alone 66-73%
*** 5-year OS for AO/AOA withOUT 1p/19q codeletion: RT+TMZ 68% vs. RT+PCV 32-37% vs. RT alone 25-31%
*** 5-year OS for AA: RT+TMZ 37% vs. RT+BCNU/DBD 36% vs. RT alone 29%
** Conclusion: "Compared to historical controls, RT + TMZ provided comparable OS to RT with procarbazine, lomustine, and vincristine (RT + PCV) for codeleted AO/AOA, superior OS to RT alone for non-codeleted AO/AOA, and similar OS to RT alone for AA."
* EORTC 26882 (1988-2000) -- RT +/- adjuvant BCNU/DBD
** Randomized. Stopped early due to slow accrual. 193/212 patients, anaplastic astrocytoma. Two cohorts: 58 anaplastic astrocytoma patients from original EORTC 26882 cohort + 135 patients from extended accrual focusing on AA only. Arm 1) RT alone vs. Arm 2) RT + concurrent BCNU/DBD followed by adjuvant BCNU/DBD x1 year. RT 60/30. Primary endpoint OS.
** 2008 PMID 18248979 -- "Adjuvant dibromodulcitol and BCNU chemotherapy in anaplastic astrocytoma: results of a randomised European Organisation for Research and Treatment of Cancer phase III study (EORTC study 26882)." (Hildebrand J, Eur J Cancer. 2008 Jun;44(9):1210-6. Epub 2008 Jan 14.)
*** Pathology: At central path review, 53% of AA cases couldn't be confirmed. AA 35%, AOA 8%, AO 2%, GBM 25%, low grade glioma 23%, other diagnosis 7%
*** Outcome: median OS RT 2.0 years vs. RT + BCNU/DBD 2.3 years (NS), no difference in PFS
*** Conclusion: No benefit in OS or PFS with addition of BCNU/DBD
* CODEL (2009-) NCT00887146
** Originally designed for new WHO grade III 1p/19q codeleted anaplastic glioma, randomized to RT 59.4 Gy (arm A) vs. RT + concurrent and adjuvant TMZ (arm B) vs. TMZ alone (arm C).
** 2015 Abstract — "CODEL (ALLIANCE-N0577; EORTC-26081/2208; NRG-1071; NCIC-CEC-2): Phase III randomized study of RT vs. RT + TMZ vs. TMZ for newly diagnosed 1p/19q-codeleted anaplastic glioma. Analysis of patients treated on the original protocol design." Jaeckle K, et al. Neuro Oncol. 2015 Nov 1;17(suppl_5):v4-5. Median F/U 3.4 years.
** 2016 Abstract — "CODEL (Alliance-N0577; EORTC-26081/22086; NRG-1071; NCIC-CEC-2): Phase III randomized study of RT vs. RT + TMZ vs. TMZ for newly diagnosed 1p/19q-codeleted anaplastic oligodendroglial tumors. Analysis of patients treated on the original protocol design (PL02.005)." Jaeckle K, et al. Neurology. 2016 Apr 5;86(16 Suppl):PL02.005. Median F/U 3.5 years.
*** 36 patients. Closed arm C due to inferior PFS and death from progression. Revised arm A after EORTC 26951 and RTOG 9402 results of superiority of adjuvant PCV.
*** Conclusions: Revised to two-arm: RT + adjuvant PCV vs. RT + concurrent and adjuvant TMZ.
** Currently for anaplastic glioma WHO grade 2-3 or high-risk low grade glioma per RTOG 9802 with 1p/19q codeletion.
* CATNON (2007-)
** New anaplastic glioma without 1p/19q codeletion, 2 x 2 factorial design: randomized to RT +/- concomitant TMZ +/- adjuvant TMZ for 12 months
** First interim, 2017 PMID 28801186 — "Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study." van den Bent MJ, et al. Lancet. 2017 Oct 7;390(10103):1645-53.
*** to be continued ...
** Second interim, 2019 ASCO Abstract — "Second interim and first molecular analysis of the EORTC randomized phase III intergroup CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q codeletion." van den Bent MJ, et al. J Clin Oncol. 2019 May 20;37(15_suppl):2000.
*** to be continued ...

## Proton Therapy

* Harvard; 2001 (1993-1996) PMID 11516862 -- "Dose-escalation with proton/photon irradiation for Daumas-Duport lower-grade glioma: results of an institutional phase I/II trial." (Fitzek MM, Int J Radiat Oncol Biol Phys. 2001 Sep 1;51(1):131-7.)
** Phase I/II. Closed early due to toxicity without meaningful benefit. 20 patients (Daumas-Duport Grade 2 in 7, Grade 3-4 in 13). Dose 68.2 CGE in Grade 2 and 79.7 CGE in Grade 3, conventional fractionation. Median proton dose 84% depending on cyclotron availability, photons 3D-CRT. Median age 36 years. Median time-to-RT 2.9 months. Median F/U 5 years for alive patients
** Outcome: 5-year OS Grade 2 71%, Grade 3 23%. New gado enhancement in 16/20 patients, 14/16 had specimen (50% radiation necrosis, some with tumor recurrence). Most recurrences in high dose area
** Conclusion: Dose escalation failed to improve outcome relative to published series; significant rate of radiation necrosis

## Treatment of the Elderly

* France (2000-2005) -- Temozolomide
** Retrospective. 44 pts, age > 70 with AO or AOA (WHO Grade III). Treatment with Temozolomide (150-200 mg/m2/d) days 1-5 q28d until tumor progression or toxicity.
** 2011 PMID 20556480 -- "Up-front temozolomide in elderly patients with anaplastic oligodendroglioma and oligoastrocytoma." (Ducray F, J Neurooncol. 2011 Feb;101(3):457-62.)
*** Median age 74; Median KPS 70. Tumor unresectable in 75%. 1p/19q analysis in 14 pts (1 tumor with complete 1p/19q loss; 13 with partial or complete loss of 1p and/or 19q). Median cycles of TMZ: 5.
*** PR in 32%, SD in 41%, PD in 27%. Clinical improvement in 30%. Median PFS 6.9 mo (12.6 mo in pts with PR, 7.1 mo with SD, 2.5 mo with PD). MS 12.1 mo (18 mo with PR, 14.2 mo PR, 5.4 mo PD). Pts with methylated MGMT had longer PFS and OS;no difference in PR rate, but duration of PR was longer in those with methylated MGMT.
*** Conclusion: "A substantial number of elderly patients with AOT can achieve prolonged survival with up-front chemotherapy using TMZ. Further investigation is needed to determine whether this treatment is preferable to initial radiation therapy."

## Other

Does more aggressive treatment negatively impact survival?
* PMID 2689399, 1989 — "Radiation Therapy Oncology Group (RTOG) survival data on anaplastic astrocytomas of the brain: does a more aggressive form of treatment adversely impact survival?" Laramore GE et al. Int J Radiat Oncol Biol Phys. 1989 Dec;17(6):1351-6.
** With data from several RTOG trials, compared 47 pts treated with photons alone, 78 with photons + chemo, and 38 photons + neutron boost.
** Median survival 3.0, 2.3, and 1.7 years, with decreasing survival with more aggressive treatment.
* PMID 1659173, 1991 — "Long-term survival in treated anaplastic astrocytomas. A report of combined RTOG/ECOG studies." Fischbach AJ et al. Am J Clin Oncol. 1991 Oct;14(5):365-70.
** Similar study as above (Laramore), looking at mostly the same trials, reaching the same conclusion.

## Reviews

Anaplastic Gliomas:
* 2009 PMID 19901101 -- "Anaplastic glioma: how to prognosticate outcome and choose a treatment strategy." (DeAngelis LM, J Clin Oncol. 2009 Dec 10;27(35):5861-2.)
Anaplastic Oligo:
* 2009 No PMID PDF -- "Management of Newly Diagnosed Anaplastic Oligodendogliomas" (Lassman AB, ASCO Educational Book 2009)

## Other Resources

* ASTRO/ARRO Journal Club Webinar 2012 - "ChemoRT vs. RT alone in anaplastic oligodendroglioma: long-term results of RTOG 9402" with Minesh Mehta, MB, ChB, FASTRO