LOW GRADE GLIOMAS

Joe Waller, MD, MPH

OHSU Dept. of Radiation Medicine

www.ohsu.edu/radmedicine

PGY2

3/17/2010

Objectives

• Learn the specific histologies

• Learn basic epidemiology

• Learn common presenting s/s

• Learn EBM for treatments

• Understand the controversy of RT

• Appreciate the toxicities of radiation

• Briefly identify future directions for treatment

Histology

Histology

Histology

• Pilocytic astrocytomas (I)– ~30% of astrocytomas

– More common cerebellum of children (JPA)

– Better circumscribed, often w/ cystic component

– Rarely transform

• Diffuse astrocytomas:

Fibrillary, gemistocytic, protoplasmic (II)– Represent 70% of low grade astrocytomas

– Poorly circumscribed

– 50-72% incidence of anaplastic transformation

Epidemiology

• Incidence: 1/100,000

• 2006:

18,820 CNS tumors

16,400 CNS primary ~10%

8,200 gliomas

» 2,000 low grade ~20-25%

• CNS primaryGBM 30%Meningioma 15%Pituitary 10%AA 10%

LG astrocytomas 10%Schwannoma 5-10%Oligodendroglioma < 5%

Epidemiology

• Age: 10-49 – mean age 37 yrs

– range 7mos – 78 yrs

– JPA 10-20 yrs, Grade II 30-40 yrs

• More common in males – 1.4:1

• Etiology: largely unknown– NF-1 and NF-2 and astrocytomas

• NF1:

• NF2:

– Tuberous sclerosis:

optic glioma

acoustic glioma

subependymal giant cell astrocytoma

Biology

• DNA – 2:1 ratio of diploid to aneuploid• Tumor proliferation – Ki-67 marker (MIB-I)

– Montine 1994 study – Ki-67 index• +/- 3% expression prognostically important• Ki-67 more related to OS than grade• Other studies have not confirmed

• Cytogenic/molecular – 30-35% have 17p alterations – p53– p53 mutations – poor prognostic factor– 1p and 19q deletions more common in

oligodendrogliomas and Grade III/IV

Biology

• MGMT – O6-Methylguanine-DNA methyltransferase– DNA repair enzyme

– Repairs damage induced by alkylating agents such as Temodar

– Therefore, active MGMT poorer outcomes

– Established in HGG

– LGG?

• VEGF– Abdulrauf study: median survival 11.2 yrs v 5.3 yrs for VEGF +/-

– No such association w/ other growth factors: FGF, EGF

• Two precursor cell lines:– Type I, protoplasmic astrocytes, reside in cortex INDOLENT

– Type II, fibrillary astrocytes, found in white matter AGGRESSIVE

Presentation - Sxs

• Seizure – 67%– Focal most common– Generalized tonic-clonic 43%– Simple partial 23%– Complex partial 34%

• Headaches, weakness – 33%• Remainder < 15%

• Sx onset to dx: 6-17mos

Visual change/lossPersonality changeFocal sx NOS

Language dysfunctionAltered sensationn/v

AMSAltered consciousnessCranial neuropathy

Presentation - Signs

• 50% neurologically intact– Sensory or motor deficit 42%– AMS 23%– Papilledema 22%– Aphasia/dysphasia 20%– Decreased memory 20%– Focal deficit 15%– Altered consciousness 8%– Motor deficit 8%

• Take home: – Normal/mild neuro dysfx 65%– Moderate neuro dysfx 25%– Severe neuro dysfx 10%

+ Prognostic Factors

– Oligo component– ↑KPS prior to surgery– Age < 40 – most powerful

predictor• > 40 v 40+ mean survival of

10.7 v 8.1 yrs respectively• ~90% 10 yr survival in

children

– Seizure• 5 yr survival: 64% w/ vs

14% w/o

– Long sx to dx interval• > 6 mos

– 1p/19q deletion

– ↓ Ki-67 index– ↓MGMT (↑ methylation)

– One sided– Radical/complete

resection– T stage (< 6cm)– Previously untreated

• Median survival 9.7 mos• 2 yr OS 29%

EORTC 22844/22845 data< 3: low risk3+: high risk

Prognosis

Staging

• None

• T parameter proposed by EORTC 22844– T1a diameter <=3 cm, confined to one side

– T1b diameter <=5 cm, unilaterally or small centrally

– T2 Diameter >5 cm but < 10 cm but not crossing midline

– T3 Any size encroaching on ventricles but not crossing midline

– T4 Any massive tumor not conforming to T3, crossing the midline or tentorium

Treatment

• Observation?

• Surgery + observation?

• Surgery + RT?

• Surgery + chemo?

• Surgery + chemoRT?

Surgery

• Extent resection– 39% GTR or major subtotal

– 23% STR

– 38% minor subtotal or bx

• General 5 yr Survival– GTR 87% (82-100%)

– < GTR 60% (24-64%)

Adjuvant Treatment

• Observe?– Favorable natural history of LGG– Survival benefit from surgery-RT has not yet been supported by

prospective clinical trials– Can always treat when see progression of disease– Potential comorbidities of treatment

• Treat?– Natural history worse than age and sex matched control population –

including pilocytic astrocytoma– Retrospective studies have shown survival benefit for surgery or RT

Observe

• RTOG 98-02, Shaw (unpublished)– 111 pts– Low risk: < 40 y/o, GTR– Oligo and oligo dominant-OA and < 4 cm

• 2 and 5 yr PFS 93% and 78% respectively

– Diffuse astro and astro dominant-OA and > 4 cm• 2 and 5 yr PFS 67% and 34% respectively

• Shaw, J Neurosurg 1989– First study comparing observation vs RT– Retrospective study– Survival benefit

• 5/10 yr OS – Surgery alone 30/10%– Surgery + < 53 Gy 50/20%– Surgery + > 53 Gy 67/40%

BELIEVERS

&

NONBELIEVERS

EORTC 22845

• “Non-believers Trial” – immediate vs delayed RT

– Karim, IJROBP, 2002

– Van den Bent, Lancet, 2005

• Included astro, O, OA, no JPA

• Median f/u: 7.8 yrs

–Median PFS:

–Median OS:

311 pts

Observation54 Gy over 30 fractions

Randomized post-op

5.3 vs 3.4 yrs (p<0.001)

7.4 vs 7.2 yrs (p=0.872)

EORTC 22845

• Findings– Significant improvement in 5 yr PFS

– No improvement in 5 yr OS likely 2/2

effectiveness of salvage RT

• 2/3 pts in observation arm received

RT at progression

– 2 yr progression free for both groups had similar cognitive deficits, KPS, headache

• Improved seizure control (25 v 41%) at 1 yr with RT arm

– No QOL data

EORTC 22844

• “Believers Trial” – radiation works, but at what dose?

– Karim, IJROBP, 1996– Included astro, O, OA, no JPA– Median f/u: 74 mos

– Equivalent 5 yr OS• Low dose: • High dose:

– Equivalent 5 yr PFS• Low dose: • High dose:

343 pts

45 Gy over 25 fractions

59.4 Gy over 33 fractions

Randomized post-op

58%59%

47%59%

EORTC 22845

Median OS 7.4 yrs

Median PFS 5.3 yrs

EORTC 22844

• QOL analysis included

– Kiebert, European Journal of Cancer, 1998

– 47 item questionnaire

• Physical

• Psychological

• Social

• Symptom

EORTC 22844 QOL

EORTC 22844 QOL

EORTC 22844

• Findings

– No dose response above 45 Gy

– T parameter important prognostic factor (p<0.0001)

EORTC 22844

– Worse QOL above 45 Gy

– High dose: lower functioning and higher sx burden

• Higher fatigue/malaise and insomnia

• Reduced leisure time and emotional functioning

INTERGROUP/NCCTG

• Also looked at efficacy and dose-response

• Shaw, JCO 2002

• 203 pts, post op

• Similar inclusion criteria to 22844

–Equivalent 5 yr OS• Low dose: 72%

• High dose: 64%

203 pts

50.4 Gy over 28 fractions

64.8 Gy over 36 fractions

Randomized post-op

Believers vs Nonbelievers

• Pro-RT– LGG respond to RT– Reduced tumor volume– Less probability of dedifferentiation

• Debatable if RT alters transformation

– Imaging/RT methods improved – less toxic– Surgeons poor judge of extent removal– Improved seizure control

• Con-RT– No OS benefit– Sequelae of RT– Delayed RT equally effective

Radiotherapy

• 180 cGy x 25-30 fractions to 45-54 Gy• Focal radiation recommended over WBRT with 2-3 cm

margin outside of T2/FLAIR borders– NCCTG 86-72-51

• 92% failures occurred within field• 3% within 2 cm of treatment field• 5% > 2 cm outside treatment field

• SRS?– 16-50 Gy in 1-2 fractions – Max 4 cm diameter– No evidence for outcomes although morbidity appears

minimal in small studies to date

Radiotherapy

• Toxicities– Taphoorn, Annals of Neurology 1994– Analyzed subset of pts from EORTC 22844/22845– Mean f/u 3.5 years– Three arms: surgery, surgery+RT, control (heme malignancy w/o neuro

involvement)• Neuropsych tests similar for LGG arms, better than control group – disease is

underlying cause for cognitive dysfunction• L hemispheric tumors had better scores w/ RT than w/o• LGG regardless of RT higher frequency of:

– Fatigue– Memory/concentration/speech difficulties– Depression– Tension– Impediment of ADLs

• “RT had no negative impact on neurological, functional, cognitive, and affective status”

Radiotherapy

• Toxicities (cont)– Klein, Lancet 2002

• Update to Taphoorn

• LGG pts, regardless of RT, lower ability in all cognitive domains

• Poor cognitive function w/ daily RT fractions > 200 cGy

• “The tumor itself has the most deleterious effect on cognitive dysfunction and that RT mainly results in additional long-term cognitive disability when high fraction doses are used.”

*Consistent w/ EORTC 22844 QOL study

Radiotherapy

• Toxicities (cont)– Kleinberg, IJROBP 1993

• Localized RT vs WBRT

• KPS decline– Localized: 0/14

– WBRT: 3/16 (19%)

• Employment 1 yr post RT– Localized: 80%

– WBRT: 38-46%

• Moderate-severe memory deficits– Localized: 6%

– WBRT: 43%

Radiotherapy

• Toxicities (cont)– INTERGROUP / NCCTG study

• Subset of pts in both 50.4 Gy and 64.8 Gy arm• Psychometric testing before and up to 5 yrs post RT• No significant loss in:

– General intellect– New learning– Memory

• Mean scores higher post RT on all (non significant)• Mild decline seen in 4 pts from 64.8 arm

– 2 yr incidence of severe/life threatening/fatal radionecrosis: • 50.4 Gy: 1%• 64.8 Gy: 5%

Radiotherapy

• Toxicities (cont)

• SUMMARY:

The weight of evidence indicates a low incidence of neurocognitive difficulties after focal

conventionally fractionated (180-200 cGy) RT using modern techniques to deliver moderate

dose in adults

This is for adults only!

Radiotherapy

• Toxicities:– Klein, Lancet 2002

• Update to Taphoorn

• LGG pts, regardless of RT, lower ability in all cognitive domains

• Poor cognitive function w/ daily RT fractions > 200 cGy

• “The tumor itself has the most deleterious effect on cognitive dysfunction and that RT mainly results in additional long-term cognitive disability when high fraction doses are used.”

*Consistent w/ EORTC 22844 QOL study

Radiotherapy

• Toxicities– Update to Klein/Taphoorn– Douw, Lancet 2009– Followed out to 12 yrs

• Long term survivors w/o RT had stable cognitive fx• Long term survivors w/ RT

– Progressive decline in attentional and executive functioning– Deficits noted in 5/18 neuropsych test parameters

» 17 (53%) in RT arm vs 4 (27%) who were RT naive– Even for < 2 Gy– Associated with radiographic findings

» Doses were 56-69 Gy» Tx started in 70’s – better in RT techniques» Non randomized – worse tumors received RT

Radiotherapy

• Pediatric toxicity

– North, Cancer 1990

– Assessed IQ < 70, special education, and other major neuro sequelae (require supervision, hospitalization, nursing care)

– Surgery alone: 40%

– Surgery + RT: 54%

Chemotherapy

• PCV therapy and oligo dominant tumors

– Response rates

• up to 90% w/ PCV

• Up to 47% w/ Temodar

– 1p/19q deletion?

– Part of RTOG 9802 trial

Treatment Summary

• JPA/piloctyic astrocytoma (G1)

– OPERATE

• Complete resection– >90% cure rates

– No adjuvant therapies recommended

• Partial resection– Survival rates 70-80% at 10 yrs

– Close f/u is standard

– Adjuvant RT

» 50-55 Gy; 1.8-2.0 Gy/fraction

Treatment Summary

• Diffuse astrocytomas, O, OA – OPERATE

• Complete resection– Rarely achieved

– Observe; no adjuvant currently recommended

• Subtotal resection– Adjuvant RT

» Immediate: high risk, older, symptomatic, astro dominant

» Delayed: low risk, young, asx, oligo dominant

• Chemotherapy for 1p/19q deletions?

• SRS/SBRT?

Treatment Summary

Path Proven LGG

Pediatrics

GTR

Observe

STR/Bx

Asx

Observe

Sx

Prepubertal

Chemo or RT

Purbertal

RT or chemo

Adult

GTR

JPA

Observe

A, OA, O

Observe or RT

STR/Bx

Asx

Observe or RT

Sx

RT

Recurrence

• Poor prognosis in general– Majority likely with high-grade transformation– Median survival 9.7 mos– 2 yr OS 29%

• Depends on histology– Leighton J Clin Onc 1997

• Median survival: 39 mos• Recurrent diffuse astrocytomas: 16 mos• Recurrent oligodendrogliomas: 60 mos

• Is it recurrence or it is radiation necrosis?– Forsythe J neurosurg 1995

• Suspected recurrence bx– 59 % tumor, median survival 10 mos– 33% tumor + necrosis, median survival 22 mos– 6% radionecrosis only; no deaths

Future directions

• RTOG 9802 results pending– Observe < 40 y/o and GTR– Assess adjuvant RT alone vs chemoRT w/ PCV (procarbazine,

lomustine, and vincristine) for older and < GTR

• RTOG 0424 is assessing the role of concurrent/adjuvant Temodar w/ radiation for high-risk LGG

• SRS, SBRT, IORT, brachytherapy

Thank You!