LOW GRADE GLIOMAS. Joe Waller, MD, MPH OHSU Dept. of Radiation Medicine PGY2 3/17/2010

Transcription

1 LOW GRADE GLIOMAS Joe Waller, MD, MPH OHSU Dept. of Radiation Medicine PGY2 3/17/2010

2 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

3 Histology

4 Histology

5 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

6 Epidemiology Incidence: 1/100, : 18,820 CNS tumors 16,400 CNS primary ~10% CNS primary 8,200 gliomas» 2,000 low grade ~20-25% GBM 30% Meningioma 15% Pituitary 10% AA 10% LG astrocytomas 10% Schwannoma 5-10% Oligodendroglioma < 5%

7 Epidemiology Age: mean age 37 yrs range 7mos 78 yrs JPA yrs, Grade II yrs More common in males 1.4:1 Etiology: largely unknown NF-1 and NF-2 and astrocytomas NF1: NF2: optic glioma acoustic glioma subependymal giant cell astrocytoma Tuberous sclerosis:

8 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

9 Biology MGMT O 6 -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

10 Presentation - Sxs Seizure 67% Focal most common Generalized tonic-clonic 43% Simple partial 23% Complex partial 34% Headaches, weakness 33% Remainder < 15% Visual change/loss Personality change Focal sx NOS Sx onset to dx: 6-17mos Language dysfunction Altered sensation n/v AMS Altered consciousness Cranial neuropathy

11 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%

12 + 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 risk 3+: high risk

13 Prognosis

14 Staging None T parameter proposed by EORTC 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

15 Treatment Observation? Surgery + observation? Surgery + RT? Surgery + chemo? Surgery + chemort?

16 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%)

17 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

18 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%

19 BELIEVERS & NONBELIEVERS

20 EORTC 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: Observation 5.3 vs 3.4 yrs (p<0.001) 7.4 vs 7.2 yrs (p=0.872) 311 pts Randomized post-op 54 Gy over 30 fractions

21 EORTC 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

22 EORTC 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: 58% 59% 47% 59% EORTC Median OS 7.4 yrs Median PFS 5.3 yrs 45 Gy over 25 fractions 343 pts Randomized post-op 59.4 Gy over 33 fractions

23 EORTC QOL analysis included Kiebert, European Journal of Cancer, item questionnaire Physical Psychological Social Symptom

24 EORTC QOL

25 EORTC QOL

26 EORTC Findings No dose response above 45 Gy T parameter important prognostic factor (p<0.0001)

27 EORTC Worse QOL above 45 Gy High dose: lower functioning and higher sx burden Higher fatigue/malaise and insomnia Reduced leisure time and emotional functioning

28 INTERGROUP/NCCTG Also looked at efficacy and dose-response Shaw, JCO pts 203 pts, post op Similar inclusion criteria to Randomized post-op Equivalent 5 yr OS Low dose: 72% High dose: 64% 50.4 Gy over 28 fractions 64.8 Gy over 36 fractions

29 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

30 Radiotherapy 180 cgy x fractions to Gy Focal radiation recommended over WBRT with 2-3 cm margin outside of T2/FLAIR borders NCCTG % failures occurred within field 3% within 2 cm of treatment field 5% > 2 cm outside treatment field SRS? Gy in 1-2 fractions Max 4 cm diameter No evidence for outcomes although morbidity appears minimal in small studies to date

31 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

32 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 QOL study

33 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%

34 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%

35 Radiotherapy Toxicities (cont) SUMMARY: The weight of evidence indicates a low incidence of neurocognitive difficulties after focal conventionally fractionated ( cgy) RT using modern techniques to deliver moderate dose in adults This is for adults only!

36 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 QOL study

37 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 Gy» Tx started in 70 s better in RT techniques» Non randomized worse tumors received RT

38 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%

39 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

40 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» Gy; Gy/fraction

41 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?

42 Treatment Summary Path Proven LGG Pediatrics Adult GTR STR/Bx GTR STR/Bx Observe Asx Sx JPA A, OA, O Asx Sx Observe Prepubertal Purbertal Observe Observe or RT Observe or RT RT Chemo or RT RT or chemo

43 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: Recurrent oligodendrogliomas: 16 mos 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

44 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

45 Thank You!