Management of low grade gliomas: overview
non pilocytic/diffuse infiltrating gliomas
Management of high grade gliomas: overview
RT does not improve symptoms: seizure may increase seizure due to increased edema compressing elooes not decreasquent areas
total of 362 eligible/analyzable pts were accrued between 1998 and 2002. Median follow-up time is 4 years. For the 111 favorable pts observed on Arm 1, OS at 2- and 5-yrs is 99% and 94%. PFS at 2- and 5-yrs is 82% and 50%
on the basis of risk factors for progression(astrocytoma histology ,Ki67 index).
which usually show abnormality beyond any enhancing or nonenhancing tumor
N F Definition 0 No neurologic symptoms; fully active at home/work without assistance. 1 Minor neurologic symptoms; fully active at home/work without assistance. 2 Moderate neurologic symptoms; fully active at home/work but requires assistance. 3. Moderate neurologic symptoms; less than fully active at home/work and requires assistance. 4 Sever neurologic symptoms; totally inactive requiring complete assistance at home or in institution-unable to work.
Walker et al. (1979) BTSG: pooled three randomized trials. Compared observation vs. WBRT 45 vs. 50 vs. 55 vs. 60 Gy. MS increased with higher doses, 4,7,9,10 month.
Walker et al. (1978) BTSG 6901 – phase III: 222 patients (90% GBM, 10% AA) surgery : randomized to observation vs. BCNU alone vs. WBRT 50–60 Gy alone vs. WBRT + BCNU. RT was WB to 50 Gy, then boost to 60 Gy. RT ± BCNU improved MS by 3–6 month vs. observation or BCNU alone
Roa et al. (2004) –
Bauman et al. (1994):
In a risk-adjusted analysis entering age ( ≤40 vs> 40 years),surgery (biopsy v resection),WHO status (0, 1 v 2), and previous surgery for low-grade glioma (yes v no), the assigned treatment remained an independent factor for OS (HR, 0.76; 95% CI, 0.60 to 0.97).
CHECK Patients tested for 1p/19q status, IDH status, and MGMT promoter methylation status had similar clinical characteristics and outcome compared with the patients who were not tested, except for a slight increase in resection in the patients tested for IDH and 1p/19q (91% v 81%, and 87% v 77%, respectively, other data not shown). Appendix Table A2 (online only) summarizes themedian OS and PFS according to 1p/19q, IDH, and MGMT status. Both PFS and OS were significantly better in the patients with codeleted tumors compared with the patients with noncodeleted tumors (PFS, 76 v 11 months; HR, 0.39; 95% CI, 0.28 to 0.53; OS, 123 v 23 months; HR, 0.36; 95% CI, 0.26 to 0.50). Similarly, OS and PFS were better in patients with MGMT promoter methylated and in IDH-mutated tumors. Table 1 summarizes the median and 5-year OS in the various subgroups in relation to assigned treatment. Patients with MGMT promoter methylation, IDH-mutated tumors, or confirmed anaplastic oligodendroglial histology seemed to derive more benefit from the addition of PCV. Tests for interaction of these characteristics with assigned treatment remained insignificant. Both MGMT promoter methylation and IDH mutational status could be determined in 158 patients and were correlated (correlation coefficient, 0.51; only two patients with a mutated IDH-1 showed an unmethylated MGMT; all other IDH-mutated patients [n 69] showed MGMT promoter methylation). The OS was similar in patients without MGMT promoter methylation compared with patients with MGMT promoter methylation but no IDH mutation (HR, 0.88; 95% CI, 0.57 to 1.36). In 150 cases, data on both 1p/19q, MGMT, and IDH results were available. In a multivariate prognostic model with these three factors, IDH and 1p/19q were independently significant but not MGMT, with a similar OS HR reduction for IDH-mutated (0.356) and 1p/19q-codeleted (0.424) tumors.
Patients with codeletions of have a more favorable prognosis and respond better to both chemotherapy and radiotherapy, and in this subset,
MANAGEMENT OF GLIOMAS
Management Of Gliomas
Made By: Dr. Isha Jaiswal
Guided By Prof. Kamal Sahni
Date:13 January 2016
Topics to be covered
Management of low grade gliomas: overview
non pilocytic/diffuse infiltrating gliomas
Management of high grade gliomas: overview
For Cerebral oedema:
Glucocorticoids used :Dexamethasone preferred because of minimal mineral-corticoid
Lower doses :shown to be as effective as higher doses-2 to 4 mg bd preferred
should be discontinued or tapered to the lowest dose necessary, as soon as possible.
taper is necessary to prevent rebound in cerebral edema and also to allow the pituitary–
adrenal axis to recover.
Patients with seizures require anticonvulsants.
Levetiracetam preferred: non–hepatic isozymes inducing
carbamazepine, phenobarbital, and phenytoin (induce hepatic cytochrome P450
isozymes) reduce the efficacy of corticosteroids & chemotherapy.
Prophylactic anticonvulsant use remains controversial
American Academy of Neurology recommended against it because of lack of efficacy and
potential side effects like cognitive impairment, myelosuppression, liver dysfunction, and
FOR PATIENT WHO HAVE UNDERGONE ANY TREATMENT…ANY FORM OF SURGERY,BIPSY
OR RR: prophylactic anticonvulsant given for shortest period of time
*Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain
tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:1886–
• Prolong progression-free survival & overall survival
• Improve, maintain, slow the decline in neurological function
• Minimize treatment-related effects
• Includes MRI monitoring at regular intervals (e.g., every 6 months) to detect
radiologic progression before new signs and symptoms occur.
• Low grade Gliomas: considered relatively favourable natural history compared o high
• lack of proven benefit for surgery or radiation therapy in improving overall survival
• No treatment associated morbidities
• Natural history is significantly worse than that of an age- and sex matched control
Based on this observation is under treatment
Maximal Safe Surgical Resection followed by PORT improve survival , and may cure pts.
Survival curves for pts with various subtypes of low-grade glioma compared age and sex
matched control population.
,Adapted from Shaw EG: The low-grade glioma debate. Evidence defending the position of early radiation therapy. Clin Neurosurg 42:488-494, 1995.
• benefits of surgery on seizures / raised ICT are fairly dramatic
• Early Surgery delays reappearance of symptoms and tumor growth
• Imaging can be misleading in upto 40% cases ,surgery provides
• Survival advantage to gross resection in retrospective literature
• Possibility of complications in a minimally symptomatic person
With advancement in technology ,morbidity of surgery has decreased
hence surgery is the mainstay of treatment
Observation with MRI monitoring :can be reserved for very few patients with ≤ 1cm tumor
and minimal symptoms
Extent of resection :No prospective randomized trials to assess the impact of maximal
tumor resection so maximal safe resection preferred
Improves outcome in unresectable & partially resectable tumors
increased Progression Free Survival
RT does not decrease seizure
No improvement in overall survival
Increased morbidity especially in young pt :neurocognitive decline , dementia ,
behavioural changes, vasculopathy, development of 2nd malignancy.
total 362 eligible pts
accrued between 1998 and 2002.
Median follow-up time 4 years.
For 111 favourable pts observed on Arm 1,
OS at 2- and 5-yrs is 99% and 94%.
PFS at 2- and 5-yrs is 82% and 50%
Risk Factors predictive of a poorer PFS
1. Pre-operative tumor diameter of >/=4 cm
2. Astrocytoma histology
3. Residual tumor of >/=1 cm2 on Postop MR
All 3 unfavorable factors- PFS at 5years -13%
None of the three factors- PFS at 5years -70%
RT vs observation
A Phase II Study Of Observation In Favourable Low-grade Glioma And A Phase III Study
Of Radiation With Or Without PCV Chemotherapy In Unfavorable Low-grade Glioma
Indications for observation
So, on the basis of above data
Observation after surgery can be a reasonable strategy for the most favorable
age ≤ 40 years
Preoperative tumor diameter <4 cm
gross total resection (GTR).
<1 cm residual tumor
• phase III trial :311 pts (WHO 1–2, 51% astro., 14% oligo., 13% mixed oligo-astro)
• treated with surgery (42% GTR, 19% STR,35% biopsy)
• randomized to observation f/b RT at progression vs. post-op RT to 54 Gy.
• RT improved median PFS (5.3 year vs. 3.4 year hazard ratio 0.59, p<0.0001) but not OS median survival 7.4
years RT arm vs. 7.2 in observation arm p=0.872).
• 65% pts in observation arm received salvage RT.
• Better seizure control rates at 1 year with early RT
• No difference in rate of malignant transformation (66–72%).
• QOL not studied whether time to progression reflects clinical deterioration not known
early radiotherapy improves symptoms control & PFS but no improvement in OS
delayed radiotherapy does not jeopardize survival
EORTC 22845 (Karim et al. 2002; van den Bent et al. 2005)
• prognostic factor analysis done on Phase III adult LGG trials (EORTC 22844 and 22845):
• Risk Factors identified from EORTC 22844 & Validated in EORTC 22845
• Patients with pilocytic astrocytoma were excluded
• Multivariate analysis showed that unfavorable prognostic factors for survival were
age ≥ 40 years,
astrocytoma histology subtype
largest diameter of the tumor > or = 6 cm
tumor crossing the midline
presence of neurologic deficit before surgery
• Low Risk Patient: </= 2 factors (Median Survival- 7.7 years)
High Risk: 3 or more factors (Median Survival- 3.2 years)
• Low risk patients are typically observed postoperatively and given RT at disease progression or recurrence
Flaws in pignatti score
• KPS ,Extent of resection not taken into account
• No weightage of individual prognostic factors
• HOWEVER NOT VALIDATED IN ANY RANDOMIZED CONTROLLED TRIALS
Timing of RT : Early vs. delayed
if significant mass or symptoms
For incompletely resected unresectable or only biopsy tumors
presence of ≥3 “high-risk” features on the basis of Pignatti score
if minimal mass or symptoms
after gross total resection
≤ 2 high-risk” features on the basis of Pignatti score
DOSE OF RT:THREE PHASE III TRIALS
RT improved median PFS (5.3 year vs. 3.4
year)(p<.001) but not overall survival.
Consequently, low-dose radiotherapy, 45
-54 Gy in 1.8 Gy-2Gy per fractions, has
become an accepted practice
CTV= T2 FLAIR IMAGES +1-2 cm MARGIN may be used.
PTV = CTV +0.5cm
LGG Gliomas Do Not Enhance On Mri
If Enhancing Treated As Hgg
Target Volume For Radiotherapy in LGG
Chemotherapy for Low Grade Gliomas
• Previously no role for chemotherapy in adult patients with low-grade
INT/RTOG 9802 trial
From 1998 to 2002,
median follow up 6 years
5-year OS rates for RT versus RT/PCV were 7.5 years
versus not reached respectively (hazard ratio [HR] =
0.72, p = 0.33)
trend toward improved 5 year PFS 63 vs. 46%(p =
acute grade 3/4 toxicity occurred in 67% in RT plus
PCV, vs. 9% in RT alone.
Phase III Study Of Radiation With Or Without PCV
Chemotherapy In Unfavorable Low-grade Glioma
Initial results 2006
Conclusion: PCV do not provide a survival advantage over RT alone
median follow-up time is 11.9 years.
RT followed by PCV yielded significantly longer median survival (MST) compared to RT alone
(13.3 vs. 7.8 years, p = 0.03; HR = 0.59)
improvement in PFS (10.4 vs. 4.0 years, p = 0.002; HR = 0.50).
Treatment arm was identified as a prognostic variable in favour of RT + PCV for both OS (p =
0.003; HR = 0.59) and PFS (p < 0.001; HR = 0.49).
Molecular markers were not pre-specified; post-hoc analysis of these is ongoing.
International Journal of Radiation Oncology • Biology • Physics , Volume 90 , Issue 1 , S37 - S38
Conclusion: PCV provided significant survival advantage over RT alone
Role of temozolomide
• more preferable option compared to PCV chemotherapy
• oral administration
• better toxicity profile
• Retrospective series and small phase II studies showed objective response in disease
• First-line treatment with TMZ compared to RT did not improve PFS in high-risk LGG patients
• Further phase III trials needed
1. Hoang-Xuan K, Capelle L, Kujas M, et al. Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or
oligoastrocytomas and correlation with chromosome 1p deletions. J Clin Oncol 2004;22:3133–3138
2. Brada M, Viviers L, Abson C, et al. Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas. Ann
3. Quinn JA, Reardon DA, Friedman AH, et al. Phase II trial of temozolomide in patients with progressive low-grade glioma. J Clin Oncol
Conclusion for chemotherapy in high risk LGG*
• RTOG 9802 (1998-2002) shows significant survival advantage with PCV chemotherapy
• However, in the intervening decade novel molecular markers as well as newer
chemotherapy agents such as temozolomide have been developed.
• So optimal parameter for selecting patients for adjuvant PCV has yet to be decided
• And It is still unclear if temozolomide can replace PCV
• Hence further trials needed
*Van den Bent MJ. Practice changing mature results of RTOG study 9802: another positive PCV trial makes adjuvant
chemotherapy part of standard of care in low-grade glioma. Neuro-Oncology. 2014;16(12):1570-1574.
*Radiation Therapy Oncology Group 9802: Controversy or Consensus in the Treatment of Newly Diagnosed Low-Grade
Glioma? Seminars in Radiation Oncology Volume 25, Issue 3, July 2015, Pages 197–202
Grade I Gliomas
• Complete resection: offers excellent survival, :majority (>90%) cured of the tumor; no
adjuvant therapy is necessary.
• Incomplete resection: associated with long-term survival rates of 70% to 80% at 10 years
hence usual recommendation is for close follow-up,
• PORT: indicated in very few cases depending on the location of the tumor, the extent of
residual disease, the feasibility of repeated surgical excision, and availability for follow-up
Grade II Gliomas
• Maximal surgical resection
• Postoperative radiotherapy improves progression-free survival and seizure
control were superior. The typical radiotherapy dose is 45 to 54 Gy
• Chemotherapy: investigational
Recursive Partitioning Analysis
Curran et al1 developed a statistical tool based on RTOG trials including 1578 pts. with malignant
gliomas from 1974 to 1989 treated with RT without TMZ
identification of significant prognostic factors & classification of patients into groups with similar
six treatment-related variables were analysed.
Age & KPS are most important prognostic factor
Other prognostic factors:
• Duration of mental symptoms before any treatment
• Extent of resection
• Mental status
1. Curran WJ Jr, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J
Natl Cancer Inst 1993;85:704–710.
RTOG RPA OF MALIGNANT GLIOMA
RPA classification retains prognostic significance in patients treated with RT+temozolomide2
as evaluated in EORTC 26981 they used age, WHO performance status, extent of surgery, and
the Mini-Mental Status Examination as prognostic variable
2. Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive
partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 2006;24:2563–2569.
• More recently nomograms 3 have developed integrating variables such as MGMT
promoter methylation status, age, performance status, extent of resection, and
3. Gorlia T, van den Bent MJ, Hegi ME, et al. Nomograms for predicting survival of patients with newly diagnosed glioblastoma:
prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol 2008;9:29–38.
TREATMENT OF GBM
• Extent: Maximum safe surgical resection preferred.
• depend on
• performance status
• tumor location
• patient choice
• surgical procedures
• Other options:
• surgical debulking for mass effect
• Biopsy only
• CSF diversion procedures for inoperable site
• Extent of surgery has prognostic significance
Hardesty DA, Sanai N. The Value of Glioma Extent of Resection in the Modern Neurosurgical Era. Frontiers in Neurology. 2012;3:140.
• RCT by BTCG demonstrated a clear survival benefit to the use of RT with without
nitrosoureas after surgery for malignant gliomas
• Standard dose:60 Gy in 30 fractions.
• Walker et al. reported a dose–response analysis in BTSG Trial.
• WBRT 45 vs. 50 vs. 55 vs. 60 Gy.
• significant improvement in MS from 28 to 42 weeks with doses of 50 to 60 Gy
• MRC study also showed a significant survival advantage with 60 Gy/30 fx.
• randomized 474 patients to 45 Gy/20 fx vs. 60 Gy/30 fx.
• No adjuvant chemo.
• MS 12 month (60 Gy) vs. 9 month (45 Gy, p = 0.007)
Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J
Radiat Oncol Biol Phys 1979;5:1725–1731
Bleehen NM, Stenning SP. 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. British J Cancer 1991;64:769–774.
DOSE ESCALATION TECHNIQUES
• majority of tumor recurrences occurring within the irradiation field
• poor outcomes associated with standard therapy
• Various techniques used to deliver a larger dose to improve local control and
hyperfractionation accelerated treatment
Proton therapy & Boron neutron capture therapy
• Studies have shown no benefit in median survival from dose escalation beyond
• For patients with poor pretreatment prognostic factors
• Older patients (>65 years) KPS≤50
• limited expected survival ,not able to tolerate conventional treatment of 6week
• a shorter course of treatment provides good palliation
• 40 Gy/15 fx Roa et al. (2004)
• phase III: 100 patients with GBM age ≥60 and KPS ≤50
• randomized to 60 Gy/30 fx vs. 40 Gy/15 fx. Enhancing tumour and oedema plus 2.5 cm margin
• No difference in MS (5.1 vs. 5.6 month).
• Fewer patients in short course RT arm required increased steroids (23 vs. 49%).
• 30 Gy/10 fx Bauman et al. (1994):
• single arm prospective study. 29 pts with GBM age ≥65 and KPS ≤50
• treated with WBRT 30 Gy/10 fx
• RT increased MS vs. best supportive care (10 vs.1 month).
OTHER OPTION 25Gy/5# in INDIAN studies
• Phase III trial 573 patients, age 18 -70 years WHO PS 0–2
• newly diagnosed glioblastoma (16% biopsy only, 40% GTR, 44% STR)
• For 485 (85%) of 573 patients, slides or tumour tissue was available for central pathology
review, glioblastoma was confirmed in 450 (93%) of these.
• Randomized to RT alone 60 Gy/30 fx. vs. RT + concurrent and adjuvant TMZ
• Concurrent daily (75 mg/m2/day) 7 days/week & adjuvant (150–200 mg/m2/day × 5days)
q4 weeks × 6 month.
• primary endpoint was overall survival
(Stupp et al. 2005, 2009)
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–996.
Stupp R, Hegi ME, Mason WP, et al. 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. Lancet Oncol 2009;10:459–466
Initial results: 2005
• median follow-up of 28 months
• Concurrent and adjuvant TMZ significantly improved MS (14.6 vs. 12.1 month) P<0.001
by the log-rank test)
• 2-year survival rates of 26% and 6%,
• Toxicity :7% grade 3/4 hematologic toxicities in Combined arm vs. none in RT alone
• median follow-up of 61 months (range 11 days to 79 months).
• 278 /286 (97%) pts. in RT alone & 254/287 (89%) in combined- group died during 5
years of follow-up
• 5-year OS (9.8 vs. 1.9%)
• benefit in all subgroup
• including patients aged 60–70 years.
• MGMT methylation was strongest predictor for benefit from TMZ
Kaplan-Meier estimates of overall survival by treatment
RPA class III (A). RPA class IV (B). RPA class V (C).
Benefit In class III-V
Maximum in Class III
DOSE INTENSE TMZ
• 833 pts Eligibility criteria included age > 18 yrs, KPS ≥ 60,
• randomized to receive standard therapy TMZ plus RT followed by
• Arm 1: standard TMZ (150-200 mg/m2 x 5 d) or Arm 2: dd TMZ (75-100 mg/m2 x 21 d) q 4 wks
for 6-12 cycles.
• Primary Endpoint was OS. Secondary analyses evaluated impact of MGMT status.
• No statistical difference was observed between Arms 1 and 2 for median OS (16.6, 14.9 mo, p =
0.63), or median PFS (5.5, 6.7 mo, p = 0.06), or by methylation status.
• MGMT methylation was associated with improved OS (21.2, 14 mo, p < 0.0001), PFS (8.7, 5.7
mo, p < 0.0001) and response (p = 0.012).
• There was increased grade ≥ 3 toxicity in Arm 2 (19%, 27%, p = 0.008); mostly lymphopenia and
Gilbert MR, Wang M, Aldape KD, et al. RTOG 0525: A randomized phase III trial comparing standard adjuvant
temozolomide with a dose-dense schedule in newly diagnosed glioblastoma. J Clin Oncol 2011;29:abstr 2006.
Management of GBM : summary
• Maximal surgical resection
• Postoperative radiotherapy 60 Gy in 6 weeks along with standard
dose TMZ , given during and after radiotherapy
Anaplastic astrocytoma ( WHO GRADE 3)
Anaplastic gliomas constitute approximately 25% of high-grade gliomas in adults
anaplastic mixed oligoastrocytomas
1p-19q co deletion is prognostic in anaplastic oligodendroglioma
• Maximal surgical resection is generally associated with more favorable
outcome and is recommended whenever feasible.
• Postoperative radiotherapy has been shown to provide a survival advantage in
several clinical trials (included WHO grade III and IV tumors; no trial for only
grade III tumors has been conducted)
• Dose:60Gy/30# @ 2 Gy/#
Chemotherapy in grade III gliomas
• The role and which chemotherapy to be used remains undefined.
• Patients with co deletions of 1p and 19q have a more favorable
prognosis and respond better to both chemotherapy and
Between August 13, 1995, and March 3, 2002
368 patients newly diagnosed anaplastic oligodendroglioma
Central pathology review confirmed presence of an oligodendroglial tumor in 257
patients (AOD, 175; mixed AOA, 82)
randomly assigned to either 59.4 Gy of RT or same RT f/b 6 cycles of adjuvant PCV.
primary end points :overall survival (OS) and PFS.
Patients tested for 1p/19q status, IDH status, and MGMT promoter methylation status
exploratory analysis of the correlation between 1p/19q status and survival was part of
median follow-up of 140 months
OS in the RT/PCV arm was significantly longer (42.3 v
30.6 months in the RT arm, hazard ratio [HR], 0.75; 95%
CI, 0.60 to 0.95).
PFS was significantly better after RT/PCV (median PFS,
24.3 months after RT/PCV v 13.2 months with RT only;
HR, 0.66; 95% CI, 0.52 to 0.83;
Subgroup Analysis by 1p/19q Status: OVDERALL SURVIVAL
In 80/316 cases (25%) with tissue available for 1p/19q
assessment,codeletion of 1p/19q was found.
In these patients with codeleted
tumors, OS was not reached in the RT/PCV group versus 112
months in the RT group (HR, 0.56; 95% CI, 0.31 to 1.03;
( Fig 3A).
In the patients with noncodeleted tumors, the risk reduction was
OS of 25 versus 21 months (HR, 0.83; 95% CI, 0.62 to 1.10;
In codeleted group, PFS was 157 months after RT/PCV and 50
months after RT only (HR, 0.42; 95%CI, 0.24 to 0.74;
In the patients with noncodeleted tumors,
PFS was 15 months in RT/PCVgroup and 9 months in RTonly
group (HR, 0.73; 95% CI, 0.56 to 0.97;
Subgroup Analysis by 1p/19q Status: PROGRESSION FREE SURVIVAL
In anaplastic oligodendroglioma pt only
1994 to 2002 :291 eligible pts randomly assigned: 148 to PCV plus RT and 143 to RT.
primary end point: overall survival (OS).
At first analysis, PCV did not appear to improve survival for any subgroup.
In a recent updated analysis :survival benefit from PCV in 1p19q codeleted subset.
At median follow-up of >11 years. (range, 0.5 to 16.8 years)
median overall survival for patients receiving RT alone or RT plus PCV was similar.
Unplanned analysis showed, 126 pts with 1p19q codeleted had much longer MS than 135 pts non
1p19q codeletion: (8.7 vs 2.7 years.
1p19q codeletion predicted the benefit from adding PCV to RT.
1p-19q co del in RT arm1p-19q co del in RT+CT arm
OS by treatment grp OS 1p-19q non co del arm OS in 1p-19q co del arm
Role of Temozolomide
• temozolomide has shown activity in patients with recurrent
anaplastic astrocytoma. (Yung et al pahse II trial )
• this trial suggest that temozolomide has antitumor activity with an
acceptable safety profile for anaplastic astrocytoma.
• Role is being tested in ongoing phase III clinical trial of non–1p19q-
codeleted anaplastic glioma patients
• CATNON Intergroup trial: To assess whether concurrent and adjuvant
temozolomide improves overall survival as compared to RT alone in
patients with non-1p/19q deleted anaplastic glioma.
Management of Grade III glioma: summary
• Maximal safe resection.
• Postoperative radiotherapy 60 Gy in 6 weeks.
• The role of chemotherapy remains undefined for the non-codeleted
• Temozolomide is active in recurrent anaplastic astrocytoma and is
currently being tested in the up-front setting.
• PCV chemotherapy has a proven survival advantage over
radiotherapy alone in 1p and 19q codeleted patients.
immobilization : individualized headrest &
RTP scans using i.v contrast are taken with 1–3 mm
slices from the vault to the base of the skull
CECT-RTP data fused with MRI data
target volumes were defined using CT-MR fusion
Single phase treatment
EBRT dose: 1.8 Gy/fx to 50.4–54 Gy.
GTV =T2/FLAIR IMAGES
CTV = GTV + 1–2 cm margin.
PTV = CTV + 0.3–0.5 cm.
Whole brain RT (WBRT) vs. Partial Brain RT (PBRT) in HGG and margins
WBRT Vs PBRT
• RCT (n=303) of WBRT-60Gy vs WBRT -43Gy + PBRT boost-17Gy
• No difference in outcome (Shapiro, J Neurosurg, 1989).
• Autopsy studies reveal that microscopic tumour within 2cm of enhancing margins on scan in
90% and only 3% multicentric (Hochberg FH, Pruitt A. Assumptions in the radiotherapy of
glioblastoma. Neurology 1980;30:907–911)
• 78% (25 of 32) of tumors recurred within 2 cm & 56% (18 of 32) in 1 cm of the initial tumor
margin.( Wallner KE, Gallcich JH, Krol G, et al. Patterns of failure following treatment for
glioblastoma multiforme and anaplastic astrocytoma. IJROBP1989;16:1405–1409.)
Standard Of Care - PBRT encompassing the enhancing tumour + 2-3 Cm
EBRT: 1.8–2 Gy/fx to 45–46 Gy followed
by boost to 59.4–60 Gy
• GTV1 = T1 enhancement + T2/FLAIR.
• CTV1 = GTV1 + 2 cm margin.
• PTV = CTV + 0.3–0.5 cm
Phase 2 :
• GTV2 = T1 enhancement.
• CTV2 = GTV2 + 2 cm
• PTV = CTV + 0.3–0.5 cm
AMERICAN VS EUROPIAN SCHOOLS FOR RT INHGG
EUROPIAN :1 PHASE