Radiation Oncology/CNS/High grade glioma/Adjuvant therapy

High Grade Gliomas Adjuvant Therapy

Radiation

RT vs. supportive care

• BTCG 69-01 and 1981 SGSG study demonstrated significant (doubled) survival with RT over supportive care, and resulted in RT becoming a standard component of treatment

• 2002 Review PMID 12242114 -- "Radiotherapy for newly diagnosed malignant glioma in adults: a systematic review." (Laperriere N, Radiother Oncol. 2002 Sep;64(3):259-73.)
  • Pooling of 6 randomized trials: significant survival benefit to post-op RT over supportive care (RR for 1-year mortality 0.81)

• SGSG, 1981 -- "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

• BTSG 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

WBRT vs. Limited-Volume RT

• Currently using regional fields (RTOG description):
  • First 46 Gy/23 fxs: the treatment volume should include the volume of contrast enhancing lesion and surrounding edema on pre-operative CT/MRI scan plus a 2 centimeter margin. If no edema is present, the margin should be 2.5 cm.
  • Boost 14 Gy/7 fxs: the tumor volume should include the contrast enhancing lesion (without edema) on the pre-surgery MRI/CT scan plus a 2.5 centimeter margin.
• Comparable outcomes to WBRT
• 80-90% recurrence is local (within 2cm of enhancing tumor on CT)
• avoidance of neurotoxicity associated with WBRT
• WBRT may be recommended for multifocal disease, but it is rare, and failure typically within original disease

• Thomas Jefferson, 2007 - PMID 17499453 -- "Multifocal glioblastoma multiforme: prognostic factors and patterns of progression." (Showalter TN, Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):820-4.)
  • Retrospective. 50 pts with multifocal GBM.
  • 32% treated with WBRT and 68% treated with 3D-CRT. Mean dose 54 Gy (dose 60 Gy, 40%; >60 Gy, 26%; <60 Gy, 34%). Concurrent chemo in 42%. Multicentric disease in 18% (defined as > 2 cm separation or in contralateral lobes). 88% of pts had 2 multifocal lesions.
  • Overall: Median TTP 3.1 months, MS 8.1 months. Predictors of TTP were: KPS <70, extent of surgery, dose < 60 Gy, lack of chemotherapy. RT type, multicentric disease, and age were not predictive of TTP. Predictors of OS were: KPS, salvage surgery, and salvage chemotherapy. RT type was not.
  • Median TTP: 1.6 mo (WBRT) vs 3.8 mo (3DRT), SS. Median OS: 3.7 vs 8.7 mo, SS.
  • No recurrences were seen distant from the original foci in the absence of significant local progression.
  • Conclusion: "Local progression was observed in all patients. On multivariate analysis, no significant difference was found in the TTP or MST between three-dimensional conformal radiotherapy and WBRT. The KPS was a consistent independent predictor of both TTP and MST. On the basis of the progression pattern, we do not recommend WBRT as a mandatory component of the treatment of multifocal glioblastoma multiforme."

• MD Anderson, 1991 - PMID 1851573 -- Outcome and patterns of failure following limited-volume irradiation for malignant astrocytomas. (Garden AS, Radiother Oncol. 1991 Feb;20(2):99-110.)
  • Retrospective. 60 patients with GBM (39) or AA (21) treated between 1982-1986.
  • RT: 53 treated with limited-volume, 7 WBRT
  • Same results limited-volume and WBRT

• BTCG 80-01, 1989 - PMID 2661738 -- Randomized trial of three chemotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. (Shapiro WR, J Neurosurg. 1989 Jul;71(1):1-9.)
  • Randomized. 571 patients to 3 chemo regimens.
  • RT patients accrued 1980-1981: WBRT 60.2 Gy
  • RT patients accrued 1982-1983: randomized to WBRT 60.2 Gy or WBRT 43 Gy + 17.2 Gy cone-down boost
  • Conclusion: no difference in survival. WBRT + boost as effective as WBRT

Margins

• Tubingen (Germany), 1994 - PMID 8184112 -- Malignant glioma: patterns of failure following individually tailored limited volume irradiation. (Hess CF, Radiother Oncol. 1994 Feb;30(2):146-9.)
  • Retrospective. 66 patients. RT: 60 Gy, with CTV = GTV + 2cm
  • 86% recurrences in treated volume
  • Conclusion: Limited fields appropriate

• Duke, 1989 - PMID 2557310 -- Radiation therapy treatment planning in supratentorial glioblastoma multiforme: an analysis based on post-mortem topographic anatomy with CT correlations. (Halperin EC, Int J Radiat Oncol Biol Phys. 1989 Dec;17(6):1347-50.)
  • 15 patients with GBM, compared biopsy with CT scans, and treatment fields
  • In 9/11 cases, contrast enhancing area + 1cm margin would have missed tumor
  • In 5/11 cases, contrast enhancing area + edema + 1cm margin would have missed tumor
  • Need contrast enhancing area + edema + 3cm margin to cover tumor (based on the 11 patients)
  • Tumor tracked along nerve pathways, and frequently crossed corpus callosum

• MSKCC, 1989 - PMID 2542195 -- Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. (Wallner KE, Int J Radiat Oncol Biol Phys. 1989 Jun;16(6):1405-9.)
  • Retrospective. 34 CT scans reviewed (GBM 25, AA 9); treated 1983-1987
  • Recurrence: 78% within 2.0 cm of presurgical tumor margin, defined as enhancing edge of tumor on CT. Only 1/34 (initially near midline) recurred in contralateral hemisphere
  • Conclusion: partial brain irradiation appropriate

• PMID 3033172 -- Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. (Kelly PJ, J Neurosurg. 1987 Jun;66(6):865-74.)
  • 40 patients with untreated glial neoplasms, serial bx (195 biopsy specimens) with CT and MRI
  • contrast enhancement most often corresponded to tumor tissue without intervening parenchyma
  • hypodensity corresponded to parenchyma infiltrated by isolated tumor cells or in some instances to tumor tissue in low-grade gliomas or to simple edema
  • isolated tumor cell infiltration extended at least as far as T2 prolongation on magnetic resonance images.

• PMID 6252514 -- Assumptions in the radiotherapy of glioblastoma. (Hochberg FH, Neurology. 1980 Sep;30(9):907-11.)
  • 35 CT scans evaluated and compared with autopsies
  • Gross and microscopic tumor extent (within 2-cm margin) defined in 29/35 patients. 4 missed due to subependymal spread
  • Multicentricity in only 4% untreated and 6% treated patients, and all lesions identified on CT
  • Recurrence within 2-cm margin in 90%. External recurrences identified on CT

CT/MRI fusion

• Michigan, 1992 - PMID 1429103 -- The clinical utility of magnetic resonance imaging in 3-dimensional treatment planning of brain neoplasms. (Thornton AF, Int J Radiat Oncol Biol Phys. 1992;24(4):767-75.)
  • MRI T1 comparable to CT tumor volume; MRI T2 comparable to CT edema
  • Need to look at both modalities: 43% of fused volume seen on both studies; 37% seen only on MRI, 21% seen only on CT

Dose Determination

• Current recommendation is 60/30
• For patients >60, can consider 40/15 or 34/10

Randomized

• MRC BR2,1991 - PMID 1654987 -- "A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party." (Bleehen NM, Br J Cancer. 1991 Oct;64(4):769-74.)
  • Randomized. 474 patients to post-op 45 Gy in 20 fx vs. 60 Gy in 30 fxs using 1:2 randomization
  • RT Arm 1: 45 Gy/20 fx to all known and potential tumor volume (focal fields)
  • RT Arm 2: 40 Gy/20 fx as Arm 1 + 20 Gy/10 fx to GTV + 1 cm
  • Median OS: 9 mo vs. 12 mo (SS); no additional acute RT toxicity

• RTOG 74-01 / ECOG 1374, 1988 - PMID 3281031, — "Combined modality approach to treatment of malignant gliomas--re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group." (Nelson DF et al. NCI Monogr. 1988;(6):279-84.)
  • Randomized. High grade glioma. 1) 60 Gy whole brain vs 2)60 Gy + 10 Gy boost vs 3)60 Gy + BCNU vs 4)60 Gy + CCNU + DTIC
  • Median OS: 60 Gy WBRT 9.3 months vs. 60 Gy WBRT + 10 Gy boost 8.2 months (NS)

Non-Randomized

• RTOG 98-03; 2004 (1998-2003)
  • 2004 ASTRO Abstract — "Phase I/II Conformal Three-Dimensional Radiation Therapy Dose Escalation Study in Patients with Supratentorial Glioblastoma Multiforme: Report of the Radiation Therapy Oncology Group 98-03 Protocol." Werner-Wasik M, et al. Int J Radiat Oncol Biol Phys. 2004 Sep;60(1 Suppl):S163–4.
    • Phase I/II. 209 patients, entered to 3D-CRT dose escalation 66 Gy, 72 Gy, 78 Gy or 84 Gy. Stratified by tumor volume. Also looking at effect of omitting treatment to edema volume
    • RT PTV1: GTV + 15mm + 3mm to 46 Gy in 2 Gy/fx
    • RT PTV2: GTV + 3mm boost to 66 Gy, 72 Gy, 78 Gy or 84 Gy in 2 Gy/fx
    • Conclusion: Dose escalation feasible, no DLT so far.
  • 2005 ASTRO Abstract — "Health-related quality of life and cognitive status in patients with glioblastoma multiforme receiving escalating doses of conformal three-dimensional radiation on RTOG 9803." Fox W, et al. Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(Suppl 1):S78.
    • to be continued ...
  • 2009 PMID 18723297 — "Phase I 3D conformal radiation dose escalation study in newly diagnosed glioblastoma: RTOG 9803." Tsien C, et al. Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):699-708.
    • to be continued ...

• Michigan 2002 - PMID 11896114 -- "Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy." (Chan JL, J Clin Oncol. 2002 Mar 15;20(6):1635-42.)
  • Retrospective. 34 patients treated to 90 Gy using 3D-CRT. Median f/u 11.7 months
  • Recurrence: 78% central, 13% in-field, 9% marginal, 0% distal. Median OS 11.7 months, 1-year OS 47%, 2-year OS 13%
  • Conclusion: continued local failure

• BTSG PMID 231022 -- "An analysis of dose-effect relationship in the radiotherapy of malignant gliomas." (Walker MD, Int J Radiat Oncol Biol Phys. 1979 Oct;5(10):1725-31.)
  • Median OS: no RT 18 weeks vs. 50 Gy 28 weeks vs. 55 Gy 36 weeks vs. 60 Gy 42 weeks

Meta-Analysis

• MRC; 2002 PMID 11937180 — "Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials." Stewart LA. Lancet. 2002 Mar 23;359(9311):1011-8.
  • Meta-analysis, 12 trials, 3004 pts. Looking primarily at chemo, but some RT analysis
  • Trials with RT 60 Gy vs. RT <60 Gy: HR 0.88 vs. HR 0.77 (p=0.1). No difference.

See further discussion in Chemotherapy section

Hyperfractionation

• RTOG 94-11, 1994-1995 - PMID 11121633 -- Phase II, two-arm RTOG trial (94-11) of bischloroethyl-nitrosourea plus accelerated hyperfractionated radiotherapy (64.0 or 70.4 Gy) based on tumor volume (> 20 or < or = 20 cm(2), respectively) in the treatment of newly-diagnosed radiosurgery-ineligible glioblastoma multiforme patients. (Coughlin C, Int J Radiat Oncol Biol Phys. 2000 Dec 1;48(5):1351-8.)
  • Phase II. 108 patients from 26 institutions. Patients assigned to RT arm based on tumor mass (20 cm3), + BCNU
  • RT: Arm A (>20 cm3): 64 Gy given 1.6 Gy/fx BID (BED comparable to 60/20) vs. Arm B (<20 cm3): 70.4 Gy given 1.6 Gy/fx BID
  • Overall MS: 9.1 mo and 11.0. Comparable with prior RTOG data. Toxicities tolerable.
  • Conclusion: shorter RT time with comparable outcome

• RTOG 90-06, 1996 - No PMID, No survival benefit of hyperfractionated radiotherapy (RT) to 72 Gy and carmustine versus standard RT and carmustine for malignant glioma patients: Preliminary results of RTOG 90-06 (Curran WJ, Proc Am Soc Clin Oncol. 1996. 15:154 Abstract)
  • Randomized to 72 Gy in 1.2 Gy/fx BID + carmustine vs. standard RT + carmustine
  • No difference
  • Patients <50 years old had decreased survival with HF RT compared with standard RT; it is speculated they lived longer to suffer from the increased treatment toxicity

• RTOG 83-02 (1983-89)
  • Phase I/II. AA + GBM. Dose-escalation of hyperfractionated RT or accelerated HF RT with BCNU.
  • 786 pts. HF (1.2 Gy BID to 64.8, 72, 76.8, or 81.6 Gy) or AHF (1.6 Gy twice daily to doses of 48 or 54.4 Gy). All received BCNU.
  • PMID 8608540, 1996 — "Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas. Radiation Therapy Oncology Group Study 83-02." Werner-Wasik M et al. Cancer. 1996 Apr 15;77(8):1535-43.
    • Mean OS 9.6 - 11 months for GBM. No difference in survival according to assigned dose.
    • For AA pts, better survival with lower HF doses (64.8 - 72). For GBM, better survival with higher HF doses (78.6 - 81.6).
  • PMID 1451073, 1992 — "A randomized trial of accelerated hyperfractionated radiation therapy and bis-chloroethyl nitrosourea for malignant glioma. A preliminary report of Radiation Therapy Oncology Group 83-02." Curran WJ Jr et al. Cancer. 1992 Dec 15;70(12):2909-17.
  • PMID 8380567, 1993 — "Hyperfractionated radiation therapy and bis-chlorethyl nitrosourea in the treatment of malignant glioma--possible advantage observed at 72.0 Gy in 1.2 Gy B.I.D. fractions: report of the Radiation Therapy Oncology Group Protocol 8302." Nelson DF et al. Int J Radiat Oncol Biol Phys. 1993 Jan 15;25(2):193-207.
  • Comment: led to 72 Gy being used in RTOG 90-06. Led to further dose escalation using AHF in 94-11.

• BTCG 77-02, 1989 (1978-80) - PMID 2542193 — "Results of a randomized trial comparing BCNU plus radiotherapy, streptozotocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following misonidazole plus radiotherapy in the postoperative treatment of malignant glioma." Deutsch M et al. Int J Radiat Oncol Biol Phys. 1989 Jun;16(6):1389-96.
  • 603 pts. All pts had surgery. RT was whole brain (60 Gy in 30-35 fx except arm 3). Arm 1: RT+BCNU IV x 3 days, repeat q8wk. Arm 2: RT+strep IV q week x 6 weeks then 2 week rest, repeat q8w. Arm 3: HF-RT+BCNU. 1.1 Gy BID x 60 fx = 66 Gy. Arm 4: RT+miso then BCNU. Miso 2x/week 4-6 hr before RT. After RT, BCNU q8weeks.
  • Conclusion: No difference in survival among groups. (60/30 vs. 66/60 1.2 Gy BID)

Hypofractionated RT

May be considered for patients ≥ 60 even with good PS

• 40 Gy in 15 fractions
• 34 Gy in 10 fractions

• European Hypofractionated (Nordic trial) -- RT 60/30 vs RT 34/10 vs TMZ x 6 cycles
  • Randomized, 3 arms. 342 patients, newly diagnosed GBM, age ≥ 60 (median 70), PS 0-2. Tumor resection 72%. Arm 1) RT 60/30 vs Arm 2) RT 34/10 vs Arm 3) temozolomide 200 mg/m2 x 6 cycles. Primary endpoint OS. Trial eventually limited to ≥ 65 after EORTC trial published.
  • 2010 ASCO Abstract — "Glioblastoma (GBM) in elderly patients: A randomized phase III trial comparing survival in patients treated with 6-week radiotherapy (RT) versus hypofractionated RT over 2 weeks versus temozolomide single-agent chemotherapy (TMZ)." (Malmstrom A, et al. J Clin Oncol. 2010 Jun 20;28(18_suppl):LBA2002.)
    • Outcome: Median OS 60/30 6 months vs RT 34/10 7.5 months vs TMZ 8 months (NS)
    • Conclusion: Standard RT should no longer be offered to the elderly patient poputlation; exclusive TMZ may be an alternative to RT.
  • 2012 PMID 22877848 — "Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomized, phase 3 trial." (Malmstrom A, et al. Lancet Oncol. 2012 Sep;13(9):916-26.)
    • Outcome: 342 patients randomized. OS 8.3 mo with TMZ alone, 7.5 mo with hypofractionated RT, and 6.0 mo with standard RT. Differences between TMZ and standard RT were statistically significant. For patients older than 70 years, OS was improved for both TMZ alone and hypofractionated RT over standard RT. MGMT predictive of TMZ benefit.
    • Cross-over: 37% of TMZ arm eventually was treated with radiotherapy.
    • Conclusion: Both TMZ and hypofractionated RT should be considered standard treatment options in elderly pts with GBM. Standard RT was associated with poor outcomes, especially in elderly. MGMT may help select patients for TMZ.

• Canada Multi-Institutional (1996-2001) -- 60/30 vs 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

3 Gy x 17 = 51 Gy

• Johns Hopkins (1975-93) - PMID 9212001, 1997 — "Short course radiotherapy is an appropriate option for most malignant glioma patients." (Kleinberg L, Int J Radiat Oncol Biol Phys. 1997 Apr 1;38(1):31-6.)
  • Retrospective. 219 pts with GBM or AA treated: 3 Gy x 10 initially to large field (often whole brain), 2 week break, followed by 3 Gy x 7 conedown boost, total of 51 Gy over 5.5 weeks. Chemotherapy in 29% (nitrosourea).
  • Median survival by RTOG RPA class: I - 68 m, II - 57 m, III - 22 m, IV - 13 m, V - 8 m, VI - 5 m. For each RPA group, similar survival as in pts treated aggressively on prior RTOG studies.
  • Conclusion: The short regimen is an appropriate treatment option for most malignant glioma patients. Do not recommend this treatment for favorable prognosis pts (RPA class 1-3) because only few pts from those groups included (21%).

3 Gy x 10 = 30 Gy

• Canada - PMID 8040031, 1994 — "A prospective study of short-course radiotherapy in poor prognosis glioblastoma multiforme." (Bauman GS, Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):835-9.)
  • 29 pts, GBM, with age >= 65 or KPS <= 50
  • Tumor stable or improved in 60% of pts at 1 month evaluation. Median survival 6 months. (Historical results for similar patients treated with full dose RT: 10 months; supportive care only: 1 month). Survival advantage for full dose RT for pts with KPS > 50.
  • Conclusion: Elderly pts with a low pretreatment KPS <= 50 may be treated adequately with short, palliative RT

Radiosurgery

• RTOG 93-05
  • 203 pts. GBM. All pts had surgery. Randomized to postoperative 1) SRS followed by EBRT 60 Gy + BCNU (q8w x 6), or 2) EBRT + BCNU, no SRS. SRS dose 16-24 Gy, based on size.
  • 2004, PMID 15465203 — "Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol." Souhami L et al. Int J Radiat Oncol Biol Phys. 2004 Nov 1;60(3):853-60.
    • Median f/u 5 yrs. MS 13.5 m (SRS) vs 13.6 m
  • Conclusion: no difference in survival

Reviews:

• ASTRO review, 2005 - PMID 16111571 — "The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma." Tsao MN et al. Int J Radiat Oncol Biol Phys. 2005 Sep 1;63(1):47-55.
  • Conclusion: "For patients with malignant glioma, there is Level I-III (I=randomized trial, II=controlled trial, III=opinion) evidence that the use of radiosurgery boost followed by external beam radiotherapy and BCNU does not confer benefit in terms of overall survival, local brain control, or quality of life as compared with external beam radiotherapy and BCNU. The use of radiosurgery boost is associated with increased toxicity. For patients with malignant glioma, there is insufficient evidence regarding the benefits/harms of using radiosurgery at the time of progression or recurrence. There is also insufficient evidence regarding the benefits/harms in the use of stereotactic fractionated radiation therapy for patients with newly diagnosed or progressive/recurrent malignant glioma."

Proton Therapy

• Tsukuba; 2010 PMID 19695794 -- "Phase I/II trial of hyperfractionated concomitant boost proton radiotherapy for supratentorial glioblastoma multiforme." (Mizumoto M, Int J Radiat Oncol Biol Phys. 2010 May 1;77(1):98-105. Epub 2009 Aug 19.)
  • Phase I/II. 20 patients, supratentorial GBM, enhanced area ≤ 4 cm. Combined photon/concomitant proton boost: CTV3 (MRI-T2) 50.4/28 in AM, then CTV2 (MRI-T1 + 1cm) 23.1/14 in PM first 14 fractions followed by CTV1 (MRI-T1) 23.1/14 in PM second 14 fractions. Total dose 96.6/56. Niumustine 80 mg/m2 during W1 and W4
  • Outcome: Median OS 22 months, 2-year OS 45%
  • Toxicity: Late radiation necrosis 1 patient, late leukoencephalopathy 1 patient
  • Conclusion: Hyperfractionated concomitant proton boost tolerable

• Harvard
  • 1999 PMID 10433313 -- "Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial." (Fitzek MM, J Neurosurg. 1999 Aug;91(2):251-60.)
    • Phase II. 23 patients, GBM, residual <60 ml, KPS >=70. Dose escalation with mixed photon/proton beam to 90 CGE
    • Outcome: 2-year OS 34%, median OS 20 months which was 5-11 months higher than historical RTOG/MRC control. Tumor regrowth in areas of 60-70 Gy; only 1 recurrence in 90 Gy volume
    • Conclusion: Dose of 90 CGE prevented central recurrence in almost all cases
  • 1992 PMID 1310962 -- "Comparative treatment planning: proton vs. x-ray beams against glioblastoma multiforme." (Tatsuzaki H, Int J Radiat Oncol Biol Phys. 1992;22(2):265-73.)
    • Treatment planning. 90 CGE dose. 3D-CRT vs proton comparison
    • Outcome: Protons less non-target brain than photon, especially in deep-seated structures. V70 was 175 ml for photon vs 94 ml for proton plans
    • Conclusion: For subpopulation of patients, 90 CGE could be delivered
  • 1990 (1973-1987) PMID 2165739 -- "Fractionated proton radiation therapy of cranial and intracranial tumors." (Austin-Seymour M, Am J Clin Oncol. 1990 Aug;13(4):327-30.)
    • Retrospective. 144 patients (chordoma/chondrosarcoma 110, meningioma 13, craniopharyngioma 12, glioma 9). Glioma were intermediate/high grade. Median dose >71 CGE (62.8-79.4)
    • Outcome: No patient with high grade glioma survived
    • Conclusion: Moderate dose proton therapy doesn't make a meaningful contribution to management of high grade glioma

Carbon Ion Therapy

• Chiba; 2007 (1994-2002) PMID 17459607 -- "Phase I/II clinical trial of carbon ion radiotherapy for malignant gliomas: combined X-ray radiotherapy, chemotherapy, and carbon ion radiotherapy." (Mizoe JE, Int J Radiat Oncol Biol Phys. 2007 Oct 1;69(2):390-6. Epub 2007 Apr 24.)
  • Phase I/II. 48 patients, malignant glioma (AA 16, GBM 32). Photons 50/25 + carbon ion dose escalation 16.8/8 -> 18.4/8 -> 20/8 -> 22.4/8 -> 24.8/8 GyE. Chemotherapy ACNU
  • Outcome: median OS GBM: low dose 7 months vs. intermediate dose 19 months vs. high dose 26 months. Median OS AA: 15 months vs. 35 months vs. 56 months
  • Toxicity: No Grade 3+, Grade 2 clinical 8%, Grade 2 radiographic 8%
  • Conclusion: Combined therapy shows potential efficacy; improved survival with higher carbon dose

Treatment toxicity

Please see the Brain Treatment Toxicity section

Targeted Therapy

Gefinitnib (Iressa)

• RTOG 0211 (2002-2004) PMID 23182702 -- "RTOG 0211: a phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients." (Chakravarti A, Int J Radiat Oncol Biol Phys. 2013 Apr 1;85(5):1206-11. doi: 10.1016/j.ijrobp.2012.10.008. Epub 2012 Nov 22.)
  • Phase I/II. 31 patients in Phase I and 147 patients in Phase II. GBM. Daily oral gefinitinib from start of RT through 18 months or progression. Microarray analysis of 68 cases for EGFR expression
  • Outcome: Gefinitnib MTD 500 mg daily, if on anti-convulsants 750 mg daily. Median OS 11.5 months; no OS benefit when compared to historical control matched by RPA. EGFR expression not prognostic
  • Toxicity: dermatologic and GI
  • Conclusion: Addition of gefitinib to RT well tolerated, but median OS similar to historical controls

Bevacizumab (Avastin)

• AVAglio Trial
  • Randomized, multicenter. 921 patients, supratentorial GBM. Standart RT 60/30 with oral temozolomide 75 mg/m2, +/- IV bevacizumab 10 mg/kg Q 2W, followed by maintenance temozolomide +/- bevacizumab x6 cycles Q 4, followed by maintenance placebo vs bevacizumab until disease progression
  • Primary Outcome; 2014 PMID 24552318 -- "Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma." (Chinot OL, N Engl J Med. 2014 Feb 20;370(8):709-22. doi: 10.1056/NEJMoa1308345.)
    • Outcome: Median PFS BEV 10.6 months vs control 6.2 months (SS). 1-year OS BEV 72% vs control 66% (SS), 2-year OS 34% vs 30% (NS)
    • Toxicity: baseline HRQOL and PS longer in BEV group, however, high risk of grade 3+ toxicity BEV 67% vs control 51%
    • Conclusion: Addition of BEV to RT-temozolomid did not improve overall survival, but did improve progression-free survival
  • HRQOL; 2015 PMID 26014298 -- "Health-Related Quality of Life in a Randomized Phase III Study of Bevacizumab, Temozolomide, and Radiotherapy in Newly Diagnosed Glioblastoma." (Taphoorn MG, J Clin Oncol. 2015 Jul 1;33(19):2166-75. doi: 10.1200/JCO.2014.60.3217. Epub 2015 May 26.)
    • EORTC QOL C30 and BN20 questionnaires completed.
    • Toxicity: No difference between arms for most items. HRQOL declined in both arms. However, BEV significant improved in deterioration-free survival BEV 6.4 months vs control 3.9 months (SS)
    • Conclusion: Addition of bevacizumab had no impact on HRQOL

• RTOG 0825 (2009 - 2011)
  • Randomized, multicenter. 637 patients with GBM. RT 60/30 (postop cavity + edema on FLAIR with 2 cm margin to 46/23, followed by boost to cavity/enhancement + 2.5 cm 14/7) with oral temozolomide 75 mg/m2, +/- IV bevacizumab 10 mg/kg Q2 weeks starting week #4 until completion of adjuvant therapy. Serial imaging Q3 months
  • 2015 PMID 24552317 -- "A randomized trial of bevacizumab for newly diagnosed glioblastoma." (Gilbert MR, N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/NEJMoa1308573.)
    • Outcome: Median OS BEV 15.7 months vs control 16.1 months (SS). PFS 10.7 months vs 7.3 months (SS) but did not reach prespecified target
    • Toxicity: "Modest increases" in hypertension, thromboembolic events, intestinal perforation, neutropenia in BEV group
    • Conclusion: First line use of bevacizumab did not improve overall survival

Chemotherapy

• RT/Temozolomide: 2-year OS benefit 26.5% vs 10.4%, median surival +2 months
• RT/other chemo: 2-year OS benefit: 20% vs. 15%, median survival +2 months (12-trial meta-analysis)

• MRC Meta-analysis, 2002: PMID 11937180 — "Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials." Stewart LA. Lancet. 2002 Mar 23;359(9311):1011-8.
  • Meta-analysis, 12 trials, 3004 pts.
  • 15% decrease in risk of death. 1-year survival increase of 6% and 2 month increase in median survival.

See further discussion in Dose determination section

• 1993: PMID 8453582 — "Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults." Fine HA et al. Cancer. 1993 Apr 15;71(8):2585-97.
  • Meta-analysis, 16 trials, 3000 pts. Compared radiation alone vs radiation + chemo for high-grade astrocytomas and GBM.
  • Increase in survival of 10% at 1 year, 8.6% at 2 yrs. Survival benefit is earlier for AA than for GBM.

Temozolomide

• An oral alkylating agent.
• Standard of care as concurrent chemotherapy with conventional RT
• Neoadjuvant TMZ does not appear to be beneficial
• Largest benefit for TMZ is in patients with low MGMT expression, but since there is nothing else to give patients with high MGMT expression, they are also treated with TMZ

• Marseille, 2007 PMID 17442989 -- "Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide." (Chinot OL, J Clin Oncol. 2007 Apr 20;25(12):1470-5.)
  • Phase II. 29 patients. Induction dose-dense TMZ (7-days on/7-days off) x4 cycles, then conventional RT.
  • Outcome: Median PFS 4 months, median OS 6.1 months.
  • Stratified by MGMT: PFS low expression 5.5 months vs. high expression 1.9 months (SS); OS 16 months vs. 5 months (SS)
  • Toxicity (Grade 3-4): thrombocytopenia 20%, neutropenia 17%
  • Conclusion: Induction dose-dense TMZ inferior to standard concomitant RT + TMZ

• Greece (2000-2002) -- RT vs. RT + TMZ
  • Randomized, Phase II. 130 patients with GBM, KPS >=60. 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/CE.3 (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.
  • 2-years; 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
  • 5-years; 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.) >5yr med fu
    • Outcome: Median OS RT 12.1 mo vs RT + TMZ 14.6 mo (SS). 2-year OS 11% vs. 27%; 5-year OS 2% vs. 10%. Benefit in all subgroups, including 60-70 year old (10.9 months vs. 11.8 months). Benefit it RPA III 14.8 mo vs. 18.7 mo
    • MGMT: Methylation strongest predictor of outcome: methylated 23.4 mo vs. unmethylated 12.6 mo (SS)
    • Salvage: Second surgery 24%, repeat RT 5%, salvage chemo 54%, supportive care only 39%
    • Conclusion: Benefits of adjuvant TMZ lasted through 5 years, though few patients survive that long

	Overall Survival
Follow up	XRT & Temodar	XRT
Median OS	14.6 mo	12.1 mo
2 years	27.2%	10.9%
3 years	16.0%	4.4%
4 years	12.1%	3.0%
5 years	9.8%	1.9%

• • Please see the overview section for discussion of MGMT promoter status and other prognostic variables from this trial

BCNU (Carmustine)

• CNS Cancer Consortium (1988-1991) -- Concurrent Mitomycin C
  • Randomized. 2x2 design. 377 patients (69% GBM). Arm 1) RT alone vs. Arm 2) RT + mitomycin C. Then randomized Arm 1) BCNU vs. Arm 2) BCNU + 6-MP. RT 61.2 Gy
  • 1996 PMID 8598355 -- "A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain. CNS Cancer Consortium." (Halperin EC, Int J Radiat Oncol Biol Phys. 1996 Mar 1;34(4):793-802.)
    • Outcome: median OS initial randomization both arms 10.8 months (NS). Median OS second randomization BCNU 11.4 months vs. BCNU/6-MP 9.3 months (NS). Significantly fewer patients terminanted RT in RT only group compared with concurrent mitomycin C
    • Conclusion: No benefit for mitomycin C, more patients terminated therapy. No benefit for adding 6-MP to BCNU

• BTCG 80-01 - PMID 2661738 -- "Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001." (Shapiro WR, J Neurosurg. 1989 Jul;71(1):1-9.)
  • Randomized. 571 patients to 3 chemo regiments (BCNU, BCNU/procarbazine, BCNU/hydroxyurea/procarbazine/VM-26).
  • RT patients accrued 1982-1983: WBRT 60.2 Gy
  • RT patients accrued 1982-1983: randomized to WBRT 60.2 Gy or WBRT 43 Gy + 17.2 Gy cone-down boost
  • Conclusion: no difference in survival. WBRT + boost as effective as WBRT

• BTCG 77-02, 1989 (1978-80) - PMID 2542193 — "Results of a randomized trial comparing BCNU plus radiotherapy, streptozotocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following misonidazole plus radiotherapy in the postoperative treatment of malignant glioma." Deutsch M et al. Int J Radiat Oncol Biol Phys. 1989 Jun;16(6):1389-96.
  • 603 pts. All pts had surgery. RT was whole brain (60 Gy in 30-35 fx except arm 3). Arm 1: RT+BCNU IV x 3 days, repeat q8wk. Arm 2: RT+strep IV q week x 6 weeks then 2 week rest, repeat q8w. Arm 3: HF-RT+BCNU. 1.1 Gy BID x 60 fx = 66 Gy. Arm 4: RT+miso then BCNU. Miso 2x/week 4-6 hr before RT. After RT, BCNU q8weeks.
  • No difference in survival among groups.

• BTCG 75-01, 1983 -- PMID 6337710 -- "Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma." (Green SB, Cancer Treat Rep. 1983 Feb;67(2):121-32.)
  • Randomized. 690 patients post-op to 60 Gy RT and 1) BCNU, 2) Medrol, 3) Procarbazine, 4) BCNU + Medrol
  • Medrol alone not good. BCNU + Medrol not good in poor prognosis. Other groups comparable.

• RTOG 74-01 / ECOG 1374, 1988 - PMID 3281031, — "Combined modality approach to treatment of malignant gliomas--re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group." Nelson DF et al. NCI Monogr. 1988;(6):279-84.
  • Randomized. High grade glioma. 1) 60 Gy whole brain vs 2)60 Gy + 10 Gy boost vs 3)60 Gy + BCNU vs 4)60 Gy + CCNU + DTIC
  • No difference in survival. For pts age > 60, no benefit for chemo. For age 40-60, benefit for BCNU

• BTCG 72-01 - PMID 7001230, 1980 — "Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery." (Walker MD et al. N Engl J Med. 1980 Dec 4;303(23):1323-9.)
  • 467 pts. HGG. After surgery, randomized to MeCCNU (semustine), RT, BCNU (carmustine) + RT, or MeCCNU + RT.
  • RT +/- BCNU/MeCCNU significantly better than MeCCNU alone. RT alone comparable to RT+BCNU or RT+MeCCNU.

• NCCTG 93-72-52 / SWOG 9503 (1994-99) - PMID 16921039, 2006 — "Phase III trial of carmustine and cisplatin compared with carmustine alone and standard radiation therapy or accelerated radiation therapy in patients with glioblastoma multiforme: North Central Cancer Treatment Group 93-72-52 and Southwest Oncology Group 9503 Trials." Buckner JC et al. J Clin Oncol. 2006 Aug 20;24(24):3871-9.
  • 401 pts. 4 arm (2x2): BCNU vs BCNU + cisplatin, accelerated RT (ART) vs standard RT (SRT).
  • Chemotherapy weekly, concurrent with RT x 8 weeks. RT 64.8 Gy / 1.8 / 48 d (SRT) or 48 Gy / 1.2 Gy BID / 15 d (ART).
    • Worse toxicity with BCNU + cisplatin. No SS difference in survival at 2 yrs.
  • Conclusion: no improvement in survival

BCNU wafers (Gliadel)

• Meta-Analysis; 2007 (UK) PMID 17999840 -- "The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation." (Garside R, Health Technol Assess. 2007 Nov;11(45):iii-iv, ix-221.)
  • Meta-analysis, Markov modeling for effectiveness and cost-effectiveness. BCNU: 2 RCT and 2 observations studies
  • Outcome: No difference in OS, but unpublished long-term follow-up suggests significant survival benefit based on very few patients at risk. No difference in PFS. Subgroup analysis for WHO Grade IV no significant OS benefit.
  • Cost estimate: Surgery + RT is ~£17,000. BCNU additional £6,600, for 0.122 QALYs. Incremental cost-effectiveness ratio (ICER) £54,500/QALY. Assuming pay threshold £30,000, BCNU wafer not cost effective in 89% simulations; in 15% simulations BCNU wafer did more harm than good
  • Conclusion: BCNU wafers survival benefit not proven in Grade III, and not present in Grade IV. The intervention will likely not be considered cost-effective by NHS

• 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
  • Comment (PMID 17999840 above): Published analysis was stratified by country. Per-protocol unstratified analysis of data (submitted to FDA) reveals no OS advantage (p=0.08). Further updated data (submitted to FDA) reveals OS advantage (p=0.02) but this is driven by few patients, mostly Grade III, with long survival. There is no difference in 1 or 2 year OS.

• 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

Phase II Protocols

• Thessaloniki, 2006 (Greece) PMID 17214326 -- "Post-operative combined radiation and chemotherapy with temozolomide and irinotecan in patients with high-grade astrocytic tumors. A phase II study with biomarker evaluation." (Fountzilas G, Anticancer Res. 2006 Nov-Dec;26(6C):4675-86.)
  • Phase II. 45 patients (38 GBM, 7 AA) treated with RT 60 Gy + TMZ + irinotecan. 22 patients completed 6 cycles. Medium F/U 50 months
  • Toxicity: Neutropenia 37%, N/V 66%, diarrhea 31%, infection 44%. 5/45 fatal vaso-occlusive disease
  • Survival: overall 12.8 months, progression-free 7.7 months
  • Conclusion: too toxic

• RTOG 94-17 (1995-97) - Tirapazamine
  • 124 pts. GBM. Phase II. RT 60 Gy + tirapazamine (3x/week x 12). Two dose levels.
  • 2000: PMID 10715295 — "Single-arm, open-label phase II study of intravenously administered tirapazamine and radiation therapy for glioblastoma multiforme." (Del Rowe J, J Clin Oncol. 2000 Mar;18(6):1254-9.)
  • For summary, see results presented in chart below (Summary - ASCO Abstract 2002, Seiferheld)
  • Conclusion: "Survival in the population treated with radiation and tirapazamine was equivalent to the control population."

• RTOG 86-12 - IUdR
  • "Survival improvement in anaplastic astrocytoma, combining external radiation with halogenated pyrimidines: final report of RTOG 86-12, Phase I-II study."
  • PMID 8407393 (1993), PMID 8985039 (1996)

• Summary ASCO Abstract -- Five years of glioblastoma multiforme(GBM) phase II trials at the Radiation Therapy Oncology Group (RTOG). (Seiferheld W, ASCO Abstracts, 2002)
  • Conclusion: "None of the experimental agents from these studies demonstrated statistically significant improvement in survival from the historical control after adjusting for RPA class. On the other hand, it is important to realize that several of the studies exhibited survival similar to the historical control, and with fewer life-threatening toxicities. These results question the standard practice of concurrent BCNU for GBM patients."

RTOG Phase 2 Trials

Trial	Agent	N	MOS (Observed)	MOS (Expected)	p-value
94-17	Tirapazamine (159mg/m2)	53	10.8	10.8	NS
94-17	Tirapazamine (260mg/m2)	68	9.5	9.7	NS
95-13	Topotecan	79	9.3	10.1	NS
96-02	Paclitaxel	61	9.7	9.6	NS
97-10	ß-Interferon	60	13.2	10.2	NS
98-06	Thalidomide	89	10.0	9.5	NS

Alternating Electric Fields

Novocure/Optune trial -- glioblastoma, 2:1 randomization tumor-treating fields (TTF) + maintenance chemo or maintenance chemo alone; all received upfront maximal safe resection and radiation with concurrent temozolomide prior to study enrollment.

Randomized 695 patients, multi-center, Europe, North America, S. Korea and Israel

• 2017 PMID 29260225 -- "Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma," (Stupp R, JAMA 2017)
• Outcome: median PFS TTF 6.7 months, chemo alone 4.0 months (SS), median OS TTF 21 months, chemo alone 16 months (SS).
• Conclusion: Addition of TTF resulted in a statistically significant improvement in OS and PFS.

Elderly Patients

See also Hypofractionated RT above, as some trials are mentioned there.

Randomized:

• NOA-08 -- Randomized patient 65+ years to adjuvant dose-dense temozolomide alone vs radiation alone (60 Gy/30 Fx)
  • 2010 ASCO abstract — "NOA-08 randomized phase III trial of 1-week-on/1-week-off temozolomide versus involved-field radiotherapy in elderly (older than age 65) patients with newly diagnosed anaplastic astrocytoma or glioblastoma (Methusalem)." Wick W, et al. J Clin Oncol. 2010 Jun 20;28(18_suppl):LBA2001.
    • to be continued ...
  • 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.)
    • Outcomes: 373 patients. 195 in TMZ arm and 178 in RT arm. Median OS was 8.6 mo with TMZ and 9.6 mo with RT (NS). Medians event-free survival 3.3 mo with TMZ vs 4.7 mo with RT (NS). EFS longer in patients with MGMT promoter methylation who received TMZ. EFS longer in patients without MGMT promoter methylation who received RT.
    • Conclusions: Similar outcomes. MGMT may help select patients for TMZ.
  • Long-term, 2018 EANO abstract — "Long-term analyses of the NOA-08 randomized phase III trial of temozolomide versus radiotherapy for elderly patients with malignant astrocytomas." Wick A, et al. Neuro Oncol. 2018 Sep 1;20(suppl_3):iii230–1.
    • to be continued ...

• Nordic Trial -- Randomized patient 60+ years to 3 arms: (1) Standard-dose TMZ alone, (2) Standard fractionation RT alone (60 Gy/30 Fx), (3) Hypofractionated RT (34 Gy/10 Fx)
  • See Hypofractionated RT above.

• France (Association of French-Speaking Neuro-Oncologists) (2001-2005) -- supportive care vs RT 50.4/28
  • 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

Non-Randomized:

• National Cancer Database -- Cohort study of patients 65+ years treated with 4 adjuvant strategies: (1) Combined RT + Chemo (CMT), (2) RT alone, (3) Chemo Alone, (4) No adjuvant therapy
  • 2016 PMID 27214765 -- "Combined-Modality Therapy With Radiation and Chemotherapy for Elderly Patients With Glioblastoma in the Temozolomide Era: A National Cancer Database Analysis." (Rusthoven CG, JAMA Neurol. 2016 May 23. doi: 10.1001/jamaneurol.2016.0839 [Epub ahead of print])
    • Outcomes: 16,717 patients treated in TMZ era (2005-2011). The median OS by treatment was 9.0 mo with CMT (8435 patients), 4.7 mo with RT alone (1693 patients), 4.3 mo with CT alone (1018 patients), and 2.8 mo with no therapy (5571 patients). The OS advantage of CMT over CT alone and RT alone was consistent in sequential age subgroups (65-69, 70-74, 75-79, and ≥80 years).
    • Conclusions: OS was superior with CMT compared with CT alone and RT alone. Survival was similar between CT alone and RT alone, and both CT alone and RT alone were superior to no therapy. This analysis supports the use of combined-modality therapy for elderly patients with newly diagnosed glioblastoma, similar to strategies used in younger patients.

• France (Association of French-Speaking Neuro-Oncologists) -- Temozolomide
  • 2010 PMID 20058048 -- "Up-front temozolomide in elderly patients with glioblastoma." (Laigle-Donadey F, J Neurooncol. 2010 Jan 8. [Epub ahead of print])
    • Retrospective. 39 patients eligible for the trial, but refused. Treated with TMZ alone, mean 5 cycles (1-12 cycles)
    • Outcome: Median OS 8.3 months; median PFS 4.6 months
    • Toxicity: Grade 3-4 in 20%
    • Conclusion: Preliminary results support randomized study comparing TMZ with RT

• France (Association of French-Speaking Neuro-Oncologists; ANOCEF) (2007-2009) -- Temozolomide. Phase II.
  • 70 pts. Age >70 with KPS < 70. Treatment with Temozolomide (150-200 mg/m2/d) days 1-5 q4weeks until progression.
  • 2011 PMID 21709196 -- "Temozolomide in Elderly Patients With Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial." (Perez-Larraya JG, J Clin Oncol. 2011 Jun 27. [Epub ahead of print])
    • Median PFS 16 wk, MS 25 wk (compares favorably to MS of 12-16 weeks from supportive care only). 33% with clinical improvement, with 26% becoming capable of self care (KPS ≥ 70). Improved overall quality of life and cognition until disease progression. In pts with methylated MGMT, improved PFS (26 wk vs 11 wk) and OS (31 wk vs 19 wk).
    • Conclusion: Temozolomide has an acceptable tolerance in elderly patients, improves functional status and appears to increase survival, especially in pts with methylated MGMT.

• Italy -- RT+TMZ
  • Single arm, prospective. 32 pts age > 70. RT 60 Gy with concurrent + adj TMZ.
  • 2008 PMID 18250965 -- "Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients." (Minniti G, J Neurooncol. 2008 May;88(1):97-103.)
  • Conclusion: Standard RT plus concomitant and adjuvant temozolomide is a feasible treatment for elderly patients with newly diagnosed glioblastoma who present with good prognostic factors.

• USA(Multi-institutional) (1991-2002) -- RT vs TMZ
  • Retrospective. 86 pts age >70; 32 received TMZ, 54 RT.
  • 2003 PMID 12712481 -- "Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas." (Glantz M, Cancer. 2003 May 1;97(9):2262-6.)
    • No difference in OS between groups. KPS was only predictor of survival.
    • Conclusion: TMZ is as effective as irradiation as a treatment of elderly patients with MG. It is an alternative and, perhaps, a superior therapeutic option to irradiation, based on its ease of administration and low morbidity.

• Italy (1993-2000) -- RT vs RT+PCV vs RT+TMZ
  • Non-randomized, prospective. 79 pts, age >= 65 with good PS (KPS >= 60). First cohort: RT alone 59.4 Gy. Second: RT + PCV. Third: RT + adjuvant Temodar (no concurrent TMZ).
  • 2003 PMID 12548608 -- "A prospective study on glioblastoma in the elderly." (Brandes AA, Cancer. 2003 Feb 1;97(3):657-62.)
    • Higher OS for Group C (RT+TMZ) vs RT alone; no difference between A&B or C&B.
    • Conclusion: Age alone should not preclude appropriate treatment in elderly patients with good performance status, for whom definitive radiation therapy and adjuvant chemotherapy with temozolomide is advised.

Trials that failed

• Dose escalation > 60 Gy - Michigan, RTOG 74-01
• Accel. hyperfract - RTOG
• Radiosurgery - RTOG 93-05
• Brachytherapy - NCI-Canada, BTSG
• Proton boost - MGH
• BCNU
• Hyperfract (72 Gy) - RTOG 83-02, 90-06, BTCG 77-02
• Neoadj. chemo - ECOG
• Boron neutron capture (BNC)

Trials to add

RTOG trials to add:

• 7611 - neutron boost
• 7918 - WBRT + (BCNU vs misonidazole and BCNU)
• 8007 - neutron boost
• 8409 - WBRT + AZQ (aziridinylbenzoquinone)
• Meta-analysis of neutron trials (PMID 20004126): Non-significant (6%) decrease in 2-year mortality

Review

• Multi-institutional; 2008 PMID 18712283 -- "Radiation therapy of pathologically confirmed newly diagnosed glioblastoma in adults." (Buatti J, J Neurooncol. 2008 Sep;89(3):313-37. Epub 2008 Aug 20.)