GBM – Oncological ManagementGBM – Oncological Management

Dr H LordDr H Lord

Consultant Clinical OncologistConsultant Clinical Oncologist

AetiologyAetiology

PrimaryPrimary: arise de novo, associated : arise de novo, associated with p53 mutation, in elderly. “Part of with p53 mutation, in elderly. “Part of growing old”growing old”

SecondarySecondary: arise from pre-existing : arise from pre-existing lower grade glioma. Occur in younger lower grade glioma. Occur in younger ptspts

Pathways to a GBMPathways to a GBM

GBM - IncidenceGBM - Incidence

2-3 / 100,000 population in Europe2-3 / 100,000 population in Europe

50% of parenchymal brain tumours50% of parenchymal brain tumours

GBM - PresentationGBM - Presentation

Depends on location – first seizure, Depends on location – first seizure, dysphasia, cognitive decline, dysphasia, cognitive decline, personality change, headache and personality change, headache and n&vn&v

Ix - MRI Ix - MRI

MRI featuresMRI features

SolitarySolitary Heterogenous – necrotic centreHeterogenous – necrotic centre Ring enhancingRing enhancing Surrounding oedemaSurrounding oedema Midline shiftMidline shift

SurgerySurgery

Usually performed to gain histology or to debulk Usually performed to gain histology or to debulk maximally – never curativemaximally – never curative

PathologyPathology

PleomorphicPleomorphic High mitotic rateHigh mitotic rate Vascular Vascular

proliferation proliferation NecrosisNecrosis

PathologyPathology

All histological All histological features present features present herehere

Stains positively for Stains positively for GFAPGFAP

In future test for In future test for MGMT methylation MGMT methylation status – positive status – positive prognostic and prognostic and predictive indicatorpredictive indicator

Oncology ManagementOncology Management Depends on fitness - RPA EORTCDepends on fitness - RPA EORTC

Class IIIClass III <50yo <50yo KPS > 90KPS > 90

Class IVClass IV <50, KPS <90 <50, KPS <90 ≥ ≥50, KPS ≥ 90, complete or partial resection 50, KPS ≥ 90, complete or partial resection

and workingand working

Class VClass V ≥ 50, KPS ≥ 90, partial resection and not working ≥ 50, KPS ≥ 90, partial resection and not working ≥ ≥ 50, KPS ≥ 90, biopsy only50, KPS ≥ 90, biopsy only ≥ ≥ 50, KPS < 7050, KPS < 70

Oncology MxOncology Mx

Overall Survival Rates depend on fitness and age - RPA Class

Median Survival (months) 1 Year Survival(%)

RPA Class III 17 70 IV 11 46 V 7 28

Reference:Shawl, EG, Seiferheld, W, Scott, C, et al. (2003). "Re-examining the radiation therapy oncology group (RTOG) recursive partitioning analysis (RPA) for glioblastoma multiforme (GBM) patients". International Journal of Radiation Oncology*Biology*Physics 57 (2): S135–6. doi:10.1016/S0360-3016(03)00843-5

Radiation + chemoRadiation + chemo In RPA Class III pts: Combined Chemo XRTIn RPA Class III pts: Combined Chemo XRT

60Gy in 30#60Gy in 30# over 6 weeks, daily treatment Mon - Fri over 6 weeks, daily treatment Mon - Fri TMZ 75mg/mTMZ 75mg/m22 po daily throughoutpo daily throughout

1 month off – MRI - if no PD and well, to continue to 1 month off – MRI - if no PD and well, to continue to adjuvant: adjuvant:

TMZ 150mg/mTMZ 150mg/m22 po d1-5 q28d cycle 1po d1-5 q28d cycle 1

increasing to increasing to

TMZ 200mg/mTMZ 200mg/m22 d1-5 q28d cycle 2-6 if toleratedd1-5 q28d cycle 2-6 if tolerated

Requirements and ToxicitiesRequirements and Toxicities

Planning CTPlanning CT Visit to simulator takes 2 weeksVisit to simulator takes 2 weeks Start treatmentStart treatment

FatigueFatigue Hair lossHair loss NauseaNausea HepatotoxicityHepatotoxicity Mild skin reactionMild skin reaction

Stupp TrialStupp Trial

Randomised controlled Phase III trialRandomised controlled Phase III trial

Newly Dx GBMNewly Dx GBM

60Gy in 30# vs 60Gy in 30# plus oral 60Gy in 30# vs 60Gy in 30# plus oral Temozolamide Temozolamide (75 mg /m(75 mg /m2 2 per day, 7 days per week from the first per day, 7 days per week from the first to the last day of radiotherapy, followed by six cycles of adjuvant to the last day of radiotherapy, followed by six cycles of adjuvant temozolomide 150 to 200 mg /mtemozolomide 150 to 200 mg /m22 for 5 days during each 28-day cycle.) for 5 days during each 28-day cycle.)

The primary end point was overall survival. The primary end point was overall survival.

TrialTrial 573 patients from 85 centres 573 patients from 85 centres The median age 56 years The median age 56 years 84 % patients undergone debulking surgery. 84 % patients undergone debulking surgery.

Results:Results: At median follow-up of 28 months:At median follow-up of 28 months:

median survival median survival 14.614.6 months with radiotherapy plus temozolomide months with radiotherapy plus temozolomide 12.112.1 months with radiotherapy alone. months with radiotherapy alone.

Unadjusted HR for death in the radiotherapy-plus-temozolomide group Unadjusted HR for death in the radiotherapy-plus-temozolomide group 0.630.63 (95% CI 0.52 to 0.75; P<0.001 by the log-rank test)(95% CI 0.52 to 0.75; P<0.001 by the log-rank test)

2 y survival rate 2 y survival rate 26.5%26.5% with radiotherapy plus temozolomide and with radiotherapy plus temozolomide and

10.4%10.4% with radiotherapy alone. with radiotherapy alone.

Concomitant treatment with radiotherapy plus temozolomide resulted in Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7% patients grade 3 or 4 hematologic toxic effects in 7% patients

Kaplan–Meier Estimates of Overall Survival According to Treatment Group.

The hazard ratio for death among patients treated with radiotherapy plus temozolomide, as compared with those who received radiotherapy alone, was 0.63 (95 % CI 0.52 to 0.75; P<0.001).

Kaplan–Meier Estimates of Progression-free Survival According to Treatment Group.

The hazard ratio for death or disease progression among patients treated with radiotherapy plus temozolomide,as compared with those treated with radiotherapy alone, was 0.54 (95% CI, 0.45 to 0.64; P<0.001).

ConclusionConclusion

The addition of temozolomide to The addition of temozolomide to radiotherapy for newly diagnosed radiotherapy for newly diagnosed glioblastoma resulted in a glioblastoma resulted in a clinically clinically meaningfulmeaningful and statistically significant and statistically significant survival benefit, with minimal additional survival benefit, with minimal additional toxicity. toxicity.

Rapidly changed practice!Rapidly changed practice!

5 year survival data 5 year survival data

OSOS(Years)(Years)

TMZ + XRTTMZ + XRT XRTXRT

22 27.2%27.2% 10.9%10.9%

33 16.0%16.0% 4.4%4.4%

44 12.1%12.1% 3.0%3.0%

55 9.8%9.8% 1.9%1.9%

RPA Class IV and VRPA Class IV and V

Consider 60Gy in 30# over 6 weeks alone, Consider 60Gy in 30# over 6 weeks alone, without chemowithout chemo

Or 30Gy in 6 # over 2 weeks, given on Or 30Gy in 6 # over 2 weeks, given on alternate daysalternate days

Or palliative care onlyOr palliative care only

AlternativesAlternatives Gliadel wafers at time of surgery – carmustine soaked Gliadel wafers at time of surgery – carmustine soaked

2007 NICE recommended Gliadel wafers can be used after 2007 NICE recommended Gliadel wafers can be used after removal of ≥90% of a newly diagnosed high grade glioma, removal of ≥90% of a newly diagnosed high grade glioma, and for relapsed GBM.and for relapsed GBM.

2005 2005 Scottish Medicines ConsortiumScottish Medicines Consortium approved Gliadel approved Gliadel wafers for newly diagnosed high grade glioma, so grade 3 wafers for newly diagnosed high grade glioma, so grade 3 or 4 glioma, alongside surgery and radiotherapy.or 4 glioma, alongside surgery and radiotherapy.

FutureFuture

MGMT status –predictive for efficacy of treatment MGMT status –predictive for efficacy of treatment and is prognostic for overall survivaland is prognostic for overall survival

Methylation of MGMT leads to less DNA repair Methylation of MGMT leads to less DNA repair occurring – so damage caused by radiation and occurring – so damage caused by radiation and chemo is not repaired and treatment is more chemo is not repaired and treatment is more effectiveeffective

Methylated in 44% GBMs – no rationale yet to Methylated in 44% GBMs – no rationale yet to test, as no proof that unmethylated tumours do test, as no proof that unmethylated tumours do not repsond to TMZ.not repsond to TMZ.

FutureFuture

BR14 trialBR14 trial – 4 arm study, Gd 3 tumours; – 4 arm study, Gd 3 tumours;

XRT vs. XRT vs. XRT + concurrent TMZ vs.XRT + concurrent TMZ vs. XRT + adjuvant TMZ vs. XRT + adjuvant TMZ vs. XRT + concurrent and adjuvant TMZXRT + concurrent and adjuvant TMZ

Ideal design, how Stupp should have been Ideal design, how Stupp should have been done.done.

TMZTMZ

Also being researched as an alternative to Also being researched as an alternative to XRT in low grade tumours ( BR13)XRT in low grade tumours ( BR13)

As an alternative to XRT in elderly pt As an alternative to XRT in elderly pt (>65yo) not fit for concurrent 6 weeks (>65yo) not fit for concurrent 6 weeks chemo XRT – Elderly Trial EORTCchemo XRT – Elderly Trial EORTC

40Gy in 15# +/- TMX40Gy in 15# +/- TMX

More Research!!More Research!!

Thank youThank you