# Radiation Oncology/CNS/Glioma/Randomized

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
In process of being cross-linked from the Glioma chapter

## Low grade gliomas (WHO I-II)
### Adjuvant RT Dose

* Intergroup NCCTG/RTOG/ECOG (1986-1994) -- 50.4 Gy vs. 64.8 Gy
** 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
* EORTC 22844 (1985-1991) -- 45 Gy vs. 59.4 Gy
** 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

### Adjuvant vs Salvage Radiotherapy

* EORTC 22845 (1986-97) -- Adjuvant vs. salvage RT
** 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). 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

### Adjuvant RT +/- Chemotherapy

* 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
** 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 F/U 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 outcomes - 5 yr OS 93%; PFS 48% (Shaw et al J Neurosurg 2008)
** 10 year results(Buckner et al, NEJM 2016)
*** SS OS and PFS benefit; 10 yr OS 40% RT alone vs 60% with PCV; PFS 21% vs 51%. Median OS = 7.8 yrs RT alone 13.3 years RT+PCV, p 0.03
*** IDH mutants - median OS 13.1 yrs vs 5.1 yrs irrespective of treatment (prognostic)
*** IDH1 mutants better outcomes with PCV - 10 yr OS ~50% RT alone vs 75% RT + chemo(predictive)

## High Grade (WHO III) Gliomas
### 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
* 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

### Adjuvant RT vs. Adjuvant Chemotherapy

* NOA-04 (Germany)(1999-2005) -- RT 54-60 Gy vs. PCV vs. temozolomide
** Randomized. 318 patients, supratentorial WHO Grade III glioma. Arm 1) RT 54-60 Gy in 6 weeks vs. Arm 2) CCNU 110 mg/m2, vincristine 2 mg, procarbazine 60 mg/m2 x4 cycles vs. Arm 3) temozolomide 200 mg/m2 x8 cycles. Primary endpoint time-to-failure
** 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. J Clin Oncol 26: 2008 (May 20 suppl; abstr 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)

### Sequential chemo->RT vs RT alone

* 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

## Glioblastoma Multiforme (WHO IV)
### Temozolomide

* Greece (2000-2002) -- RT vs. RT + TMZ
** Randomized, Phase II. 130 patients with GBM, KPS >=60. Biopsoy or surgery. Arm 1) RT 60/30 vs. Arm 3) Same RT + concurrent TMZ 75 mg/m2 1 hour prior to RT, then adjuvant TMZ 150 mg/m2 x6 cycles. RT CTV1=T2 + 2 cm margin to 46/23, CTV2=T1 + 2.5 cm margin to 60/30
** 2005 PMID 15800329 -- "Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme." (Athanassiou H, J Clin Oncol. 2005 Apr 1;23(10):2372-7.)
*** Outcome: Median TTP RT 5.2 months vs. RT + TMZ 10.8 months (SS); 1-year PFS 37% vs. 8% (SS). Median OS 8 months vs. 13 months (SS); 1-year OS 16% vs. 56% (SS)
*** Toxicity: Grade 3+4 leukopenia 3%, thrombocytopenia 5%. One death from sepsis
*** Conclusion: TMZ combined with RT more effective than RT alone
* EORTC / NCIC 26981-22981 (2000-2002) -- RT vs. RT + TMZ
** Randomized. 573 patients with GBM, s/p biopsy or surgery (GTR 40%). Arm 1) RT alone vs Arm 2) RT with concurrent daily temozolomide (T) 7 days/wk followed by six cycles of adjuvant T given 5 days monthly. RT given 60/30, CTV = GTV + 2-3 cm margin. Temozolomide dose was 75 mg/m2 concurrent and 150-200 mg/m2 adjuvant.
** 2005 PMID 15758009 — "Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma." (Stupp R, New Engl J Med 352(10):987-996, 2005.) Median F/U 2.3 years
*** Outcome: median OS RT 12.1 months vs. RT + T 14.6 months (SS); 2-year OS 10% vs. 26% (SS). On subgroup analysis, no benefit if biopsy only or if PS = 2.
*** Toxicity: Grade 3-4 toxicity 7%
*** Conclusion: Addition of temozolomide resulted in clinically meaningful and statistically significant survival benefit, with minimal toxicity
** 2009 PMID 19269895; "Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial." (Stupp R, Lancet Oncol. 2009 May;10(5):459-66.) >5-year med. fu
*** Overall survival was 27·2% (95% CI 22·2—32·5) at 2 years, 16·0% (12·0—20·6) at 3 years, 12·1% (8·5—16·4) at 4 years, and 9·8% (6·4—14·0) at 5 years with temozolomide, versus 10·9% (7·6—14·8), 4·4% (2·4—7·2), 3·0% (1·4—5·7), and 1·9% (0·6—4·4) with radiotherapy alone (hazard ratio 0·6, 95% CI 0·5—0·7; p<0·0001).
*** A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60—70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy.

## High Grade (WHO III-IV) Gliomas
### BCNU wafers (Gliadel)

* Multinational (1997-99) -- placebo vs. BCNU wafer
** Randomized. 14 countries. 240 patients, malignant gliomas (86% GBM). At primary surgical resection, Arm 1) placebo vs. Arm 2) BCNU wafers. All patients received RT 55-60 Gy.
** 2003 PMID 12672279 — "A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma." (Westphal M, Neuro-oncol. 2003 Apr;5(2):79-88.)
*** Outcome: median OS placebo 11.6 vs. BCNU wafer 13.9 months (SS); 29% reduction in risk of death. BCNU also improved time to KPS decline and neuroperformance measures decline.
*** Toxicity: comparable, except CSF leak 1% vs. 5%, intracranial HTN 2% vs. 9%
*** Conclusion: Local chemotherapy with BCNU wafers is well tolerated and offers a survival benefit to patients with newly diagnosed malignant glioma
* Turku University (Finland)(1992-1993) -- placebo vs. BCNU wafer
** Randomized. 32/100 planned patients with high grade (Grade III-IV) glioma. Closed prematurely as carmustine became unobtainable. Arm 1) Surgery + placebo vs. Arm 2) Surgery + carmustine polymer
** 1997 PMID 9218294 -- "Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study." (Valtonen S, Neurosurgery. 1997 Jul;41(1):44-8; discussion 48-9.)
*** Outcome: median OS placebo 9.2 months vs. 13.4 months (SS); for GBM 9.2 months vs. 12.3 months (SS). At end of study, 6% vs. 31% alive
*** Conclusion: Locally applied carmustine polymer at time of primary surgery has benefit on survival

### RT vs. Observation

* France (Association of French-Speaking Neuro-Oncologists) (2001-2005) -- supportive care vs RT
** Randomized. Trial stopped early due to superiority of RT. 85 patients. GBM (96%) or AA. Age >= 70, KPS >= 70. Surgery or biopsy (50%). Arm 1) Supportive care vs Arm 2) RT 50.4/28 (CTV = GTV + 2cm)
** 2007 PMID 17429084 -- "Radiotherapy for Glioblastoma in the Elderly." (Keime-Guibert F, New Engl J Med. 2007 Apr 12;356(15):1527-1535.) Median F/U 4.8 months
*** Outcome: By 5 months, 90% of patients died. Median OS supportive care 3.9 months vs. RT 6.7 months (HR 0.5, SS). Median PFS 5 weeks vs 15 weeks (HR 0.3, SS)
*** Toxicity: No difference, though both groups worsened over time
*** Conclusion: RT in elderly results in modest improvement in survival without adversely affecting QOL

### RT vs. Temozolomide

* NOA-08 (Germany)(2005-2009) -- RT 60 Gy vs. temozolomide week on-week off
** Randomized. 412 patients, age older than 65, KPS 60 or higher, anaplastic astrocytoma and glioblastoma. Arm 1) 100 mg/m2 temozolomide, given on days 1–7 of 1 week on, 1 week off vs. Arm 2) 60 Gy in 1.8-2 Gy fx, gross tumour volume (pre-op MRI) plus a 2 cm margin. Cross-over to other arm in case of progression. Primary endpoint overall survival. Non-inferiority trial.
** 2012 PMID 22578793 -- "Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial." (Wick W et al, Lancet Oncol. 2012 Jul 13(7):707-15). Median F/U 25.2 months
** Median OS 8.6 months in TMZ group, 9.6 months in XRT group (hazard ratio [HR] 1·09, 95% CI 0·84–1·42, p (non-inferiority)=0·033)
** MGMT methylation found in 35% of pts. MGMT methylation associated with longer OS. EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5–11·7] vs 4·6 [4·2–5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0–3·5] vs 4·6 months [3·7–6·3]).
** Conclusion: TMZ is non-inferior to XRT in elderly patients. MGMT helps guide treatment choice.

### WBRT vs. Observation

* SGSG, 1981 PMID 6164465-- "Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: a prospective multicenter trial of the Scandinavian Glioblastoma Study Group." (Kristiansen K, Cancer. 1981 Feb 15;47(4):649-52.)
** Randomized. 118 patients Grade III/IV randomized post-op to 1) 45 Gy WBRT + bleomycin, 2) 45 Gy WBRT, 3) support care
** Median OS: 10.8 mo vs. 10.8 mo vs. 5.2 mo (SS)
** Conclusion: RT dramatically better than supportive treatment. No effect of bleomycin
* BTCG 69-01 -- BCNU vs RT vs RT + BCNU vs Observation
** Randomized, 4 arms. 303 patients, anaplastic gliomas, treated with surgery and steroids. Arm 1) BCNU alone, Arm 2) RT alone, Arm 3) RT + BCNU, Arm 4) best supportive care. BCNU was given on days 1-3 q6-8 wks. RT was 50-60 Gy to whole brain.
** 1978 PMID 355604 — "Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial." (Walker MD, J Neurosurg. 1978 Sep;49(3):333-43.)
*** Outcome: median OS OBS 3.2 months vs. BCNU 4.2 months vs. RT 8.1 months vs. RT + BCNU 8.0 months (SS)
*** Toxicity: Acceptable thrombocytopenia and leukopenia
** Note: This trial established first evidence for post-op RT over supportive management

### Dose

* Canada Multi-Institutional (1996-2001) -- RT 60/30 vs RT 40/15
** Randomized. 100 patients. Age >60 years, KPS >50 (RPA Class IV 11%, V 45%, VI 44%). Arm 1) RT 60/30 over 6 weeks vs Arm 2) 40/15 to PTV1 over 3 weeks. Standard RTOG fields, start within 6 weeks of surgery
** 2004 PMID 15051755 -- "Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial." (Roa W, J Clin Oncol. 2004 May 1;22(9):1583-8.)
*** Outcome: Median OS standard 5.1 mo vs. short 5.6 months (NS). Fewer patients on 40/15 required corticosteroids, and more completed RT (90% vs 74%). No difference in KPS
*** Conclusion: reasonable treatment option for older patients
* Australia (1990-1996) -- 60/30 vs 35/10
** Randomized. Closed prematurely due to poor accural. 68 patients, anaplastic astrocytoma (excluded age <45 and ECOG 0-2) or glioblastoma multiforme. Median age 59. Arm 1) 60/30 to tumor volume + oedema with 3 cm margin vs Arm 2) 35/10 to whole brain
** 2003 PMID 12885448 -- "A randomized trial comparing 35 Gy in ten fractions with 60 Gy in 30 fractions of cerebral irradiation for glioblastoma multiforme and older patients with anaplastic astrocytoma." (Phillips C, Radiother Oncol. 2003 Jul;68(1):23-6.)
*** Outcome: Median OS 60 Gy 10.3 months vs. 8.7 months (HR 1.5, NS)
*** Toxicity: No late toxicity per protocol, <30% completed QoL questionnaire
*** Conclusion: No significant difference, but wide confidence intervals due to small number of patients