CNS Flashcards

Question

What were the results of EORTC 22952-26001?

Answer 1

•HRQOL worse with WBRT

•Time to worse performance status unchanged, 11.7 mos vs. 9.5 mos

•OS similar, ~10.8 mos mos (NS)
•Neuro death improved with WBRT: 44% vs. 28% WBRT

Answer 2

2-yr LC surgery: 41% obs vs. 72% WBRT

2-yr LC SRS: 69% obs vs. 81% WBRT

Intracranial progression 44% vs. 28%
Subanalysis shows that surgery and SRS are similar in outcomes.

Answer 3

EORTC 22952-26001

Answer 4

1-4 brain mets <3cm

n=132

Answer 5

→SRS
vs.
→SRS+WBRT 30 Gy/10 fx

SRS dose 18-25 Gy for SRS alone.
Dose reduced 30% if with WBRT

MMSE used to measure cognitive
function

Answer 6

•WBRT decreased recurrence but no improvement in OS or neuro death.
•Median OS 8.0 mos vs. 7.5 WBRT+SRS (NS)

•1-yr OS 28% vs. 39% (NS)
•No diff in toxicity, neuro function

Answer 7

JSROG (Aoyama et al, JAMA 2006 and 2015)

Answer 8

1-3 brain mets

n=58

Answer 9

→SRS
vs.
→SRS+WBRT 30 Gy/12 fx

Primary endpoint: neuro function per HVLT-R

Answer 10

•Terminated early: SRS+WBRT showed worse neuro decline at 4 months. LC improved with WBRT, but not OS

•Neuro decline: SRS alone 24% vs. 52% SRS+WBRT

•OS worse with WBRT, 15 mos vs. 6 mos

Answer 11

MDACC (Chang et al, Lancet Oncol, 2009)

Answer 12

1-3 brain mets

(n=213)

Answer 13

→SRS
vs.
→SRS+WBRT 30 Gy/12 fx

SRS dose 18-22 Gy in SRS+WBRT
and SRS dose 20-24 Gy for SRS alone

Answer 14

-Median OS: 10.4 mos vs. 7.4 mos (p=.92)

-12-mo LC 73% vs. 90% with WBRT
-12-mo total brain control 51% vs. 85%
-Time to recurrence shorter with SRS

No effect of DS-GPA on OS

Answer 15

Alliance N0574.

Tumor reccurence is increased somewhat without WBRT but without change in OS.

Answer 16

1-3 mets

(n=333)

Answer 17

"→WBRT 37.5 Gy
vs.
→SRS+WBRT

SRS dose per RTOG 9005:
24 Gy size ≤2.0 cm
18 Gy size >2 to ≤3cm
15 Gy size >3 cm"

Answer 18

"Addition of SRS to WBRT improved LC and KPS but no change in OS
1-yr LC 71% WBRT vs. 82% SRS+WBRT

•On MVA of all patients in both arms, RPA 1 and NSCLC histology had better OS (regardless of treatment arm)
•Median OS 5.7 mos SRS vs. 6.5 mos (NS)

"

Answer 19

Recurrent primary or recurrent brain tumors s/p prior WBRT

(n=156)

Answer 20

"Phase I Dose escalation in 3 Gy increments, beginning at:
18 Gy for ≤2 cm
15 Gy for 2-3 cm
12 Gy for 3-4 cm
Grade 3-5 toxicity defined as limiting.

All had previous WBRT (range 30-60 Gy). LINAC and GammaKnife allowed. Dose to 50-90% isodose line."

Answer 21

Max tolerated doses: 18 Gy for 21-30 mm and 15 Gy for 31-40 mm. 24 Gy for ≤20 mm was the highest evaluable dose but may not be MTD; Investigators declined to escalate to 27 Gy in ≤2 cm.

Diameter associated with neurotoxicity.

Answer 22

"RTOG 9005

Prior WBRT in all patients. Established dosing for later trials. This is a phase I toxicity study and was not powered for LC. On a MVA dose was not associated with LC: lower doses may have just as effective LC. (The authors did a rudimentary LC analysis looking at GK and Linac, but arms are too imbalanced to draw conclusions.) 36% were primary tumors, 64% were mets.

"

Answer 23

4-15 brain metastases, non-melanoma

(n=72)

Answer 24

→SRS
vs.
→WBRT (62% had memantine)

Neurocognitive testing

Answer 25

Cognitive function is better with SRS

Median OS 8-10 mos, p=0.45
Distant brain failure 4.2 mos vs. 18.1 mos
LC 100% vs. 95.5%

Answer 26

"MDACC (Li et al, ASTRO, 2020)"

Answer 27

(n=1887) brain metsSRS to large brain mets

Answer 28

"Meta-analysis of 24 studies of single and multi fx SRS to brain mets. Evaluates radiation necrosis and LC

Various doses and fractionation regimens used"

Answer 29

"LC in size 4-14 cc (2-3 cm) definitive
•single fx 78% vs. multi 93%, p=0.18

LC in size >14 cc (>3cm) definitive
•single fx 78% vs. multi 79%, p=.76

LC in size >14 cc (>3cm), post op
•single fx 62% vs. multi 86%, p=0.13

"

Answer 30

Mount Sinai, NY (Lehrer et al, IJROBP, 2019) meta trial

Answer 31

1-4 brain metastases and resection of 1 lesion. STR allowed (77%% had single met, ~10% STR)

Resection cavity <5 cm and unresected lesions ≤3.0 cm

(n=194)

Answer 32

"→SRS to cavity
vs.
→WBRT to 30 or 37.5 Gy

Unresected lesions treated with SRS in both arms
"

Answer 33

"Worse LC in cavity with SRS
12-mo cavity LC 61% vs. 81% (supp data)
12-mo distant brain control 65% vs. 89%

Median OS ~12 mos, not different

-Better cognitive deterioration free survival with SRS, median 3.7 mos vs. 3.0 mos

"

Answer 34

"30 Gy and 37.5 Gy compared:
-More grade ≥3 toxicity with 37.5 Gy
-No difference in cognitive failure (p=0.64).

^{Some trend to benefit in cavity LC (p=0.14), cranial control (p=0.09), and OS (p=0.18) with 37.5 Gy}

"

Answer 35

"N107C/ CEC.3/ RTOG 1270

Brown et al, Lancet Oncol, 2017
Trifiletti et al, ASTRO, 2019

"

Answer 36

"1-4 brain metastasis and resection of all, GTR or STR (73% had single met)

One lesion >3 cm allowed

(n=271)

"

Answer 37

"Resection of all brain mets →

→SRS to cavity for STRs, observe GTRs (termed ""salvage SRS"")
vs.
→WBRT 37.5 Gy

40% in SRS arm had STR and SRS; 60% had GTR and obs

SRS doses: 24 Gy for ≤4 cc, 18 Gy for >4 cc"

Answer 38

"-Cavity LC 51% vs. 78% (WBRT)
-Median OS 15.6 mos, not different

Grade 2-4 cognitive toxicity 7.7% vs. 16.4% (WBRT)

"

Answer 39

"JCOG 0504Kayama et al, JCO, 2017"

Answer 40

This study requires resection of all brain mets. SRS was given only when resection was subtotal (40%), but not for GTR (60%), which may explain the poor LC in this study.

WBRT was 15 fractions (higher BED than 30 Gy in 10 fx).

Answer 41

1-3 brain metastases and GTR of ≥1 lesion (~62% had single met)

Resection cavity ≤4 cm and unresected lesions ≤3 cm

n=131

Answer 42

"→SRS to cavity
vs.
→Obs to cavity

Unresected lesions treated with SRS in both arms

SRS doses: 16 Gy for ≤10 cc, 14 Gy for >10.1-15 cc, 12 Gy for >15 cc"

Answer 43

"LC improved with SRS over obs
12-mo cavity LC 72% vs. 43% (obs)
Median OS 17 mos, not different
"

Answer 44

Mahajan, MDACC (Lancet Oncol 2017)

Answer 45

"Most recent multi-institutional retrospective cohort, more modern than the RPA and less subjective

"

Answer 46

"Median OS: 18 wks for no RT, 28 wks for 50 Gy, 36 wks for 55 Gy, and 42 wks for 60 Gy.

KPS was biased against the ≤45 Gy, group - more died in that group before completing therapy "

Answer 47

PRT of 573 pts with GBM, ages 18 to 70 with ECOG PS 0-2.

MGMT was methylated in 45%

Answer 48

"→60 Gy + conc TMZ & adj TMZ x6
vs.
→60 Gy

Later analysis evaluated effect of MGMT methylation"

Answer 49

Improved OS with TMZ.
Median OS 14.6 mos vs. 12.1 mos

^{2-yr OS 26.5% vs. 10.4%.
5-yr OS 10% vs. 2%}

Answer 50

"Adding TMZ to RT results in OS benefit. Only those with a methylated MGMT promoter benefitted, though there was trend to benefit without methylation.

Methylated MGMT:
Median OS 22 mos TMZ vs. 15 mos
2-yr OS 46% vs. 23%
5-yr OS 14% vs. 5%

Unmethylated MGMT:
Median OS 12.7 vs. 11.8 mos (p=0.06)
2-yr OS 14% vs. 2%
5-yr OS 8% vs. 0

"

Answer 51

"Glioblastoma with methylated MGMT

n=141

"

Answer 52

"→60 Gy + conc & adj TMZ
vs.
→60 Gy + TMZ + lomustine"

Answer 53

"Median OS 31 vs. 48 mos (ITT) (+Lomustine group)
Median OS 30 vs. 40 mos per protocol
"

Answer 54

CeTeG / NOA-09

Herrlinger et al, Lancet, 2019

The trial may be underpowered. The modifed ITT analysis leads to patients being excluded and even lower power. Some call for a multi-institutional trial with larger numbers (Stupp 2019). It is unclear how there can be a change in OS without a change in PFS. Perhaps lomustine has a later effect, or lomustine creates more pseudoprogression that was called progression. There were some small differences in 2nd line therapies but not major.

Answer 55

315 newly diagnosed glioblastoma

Optune tumor TTF trial

Answer 56

"RT + conc TMZ →

→adjuvant TMZ + tumor treating fields (until 2nd progression or 2 years)
vs.
→adjuvant TMZ "

Answer 57

"OS improved with TTF
Median OS 20.9 mos vs. 16.0 mos
2-yr OS 43% vs. 31%
Median PFS 6.7 vs. 4.0 mos

On subanalysis, benefit present in any MGMT status, any age

"

Answer 58

EF-14 (Stupp et al, JAMA, 2015; Kesari et al, SNO, 2015; Stupp et al, JAMA, 2017)

Tumor treating fields (TTF) mechanism: low amplitude alternating electric fields that disrupt cell division and organelles. Required to wear ≥18 hrs in protocol.

Sharp dropoff of treatment effect if device worn <50% of time. At 75% of time (18 hours), a greater benefit occurs.

Answer 59

Glioblastoma

n=978

Answer 60

60 Gy + TMZ →

→bevacizumab
vs.
→placebo

Bev started at week 4 during RT and continued as maintenance

Crossover allowed if disease progression

Answer 61

"No change in OS: 15.7 vs. 16.1 mos
PFS longer with bev: 10.7 mos vs. 7.3 mos

•Adverse effects higher in bev group: hypertension, thromboembolism, intenstinal perf, neutropenia, decline in QOL and cognitive function
•Those with Pro-B type (indicative of proneural) had improved PFS, but not OS. But non-Pro B type had worse OS

"

Answer 62

RTOG 0825

PFS may be a result of vascular changes and not tumoricidal effects.

Some say lack of OS benefit was due to crossover, but note that median OS without bev is nearly identical to EORTC Stupp trial outcome and a direct comparison is not possible (Stupp 2009). Bevacizumab also failed to show OS benefit in a randomized trial in recurrent GB (Wick 2017).

Answer 63

"Glioblastoma age ≥65"

Answer 64

"→40 Gy/15 fx + conc and adjuvant TMZ
vs.
→RT alone 40 Gy/15 fx"

Answer 65

"Median OS and PFS improved with TMZ
Median OS 9.3 mos vs. 7.6 mos
Median PFS 5.3 mos vs. 3.9 mos

Methylated MGMT median OS 13.5 mos vs. 7.7 mos---->statistically significant
Un-methylated MGMT median OS 10.0 mos vs 7.9 mos---->NOT statistically significant

"

Answer 66

EORTC 26062/TROG/CCTG?

Pts with MGMT methylation benefit most from RT + TMZ with a ~6-month improvement in OS.

Answer 67

"NOA-08 (Wick, Lancet Oncology 2012)

TMZ was noninferior to RT in elderly or poor KPS GB. TMZ is ideal for methylated MGMT and RT is ideal for unmethylated MGMT.

RT and TMZ noninferior:
OS 9.6 mos vs. 8 mos
-With MGMT methylation, longer EFS with TMZ: 8.4 vs. 4.6 mos
-With no MGMT methylation, outcomes poor but RT better: 4.6 vs. 3.3 mos

"

Answer 68

High grade glioma in age ≥60

n=342

Answer 69

→60 Gy/30 fx
vs.
→34 Gy/10 fx
vs.
→TMZ alone

Answer 70

MS was significantly improved for pts
receiving TMZ alone (8 mos) versus standard RT (6 mos) but not versus hypofractionated
RT (7.5 mos).

Answer 71

GBM, age ≥60 and KPS≥50

n=100

Answer 72

→60 Gy/30 fx
vs.
→40 Gy/15 fx

Answer 73

MS was 5.1 mos for standard (60Gy/30) versus 5.6 for shorter course RT (40Gy/15) (p = NS)

26% pts stopped long-course RT versus 10% in short-course arm

Answer 74

Roa, Canadian (JCO 2004)

Answer 75

GBM + age ≥50, KPS 50-70, or age ≥65 KPS 50-100

n=98

Answer 76

→25 Gy/5 fx
vs.
→40 Gy/15 fx

Answer 77

Pts receiving 25 Gy/5 fx had noninferior OS compared to those receiving 40 Gy/15 fx, and no difference in PFS or QOL.

Conclusion: Short-course RT delivered in 1 week (25Gy/5 fx) is a treatment option for elderly and/or frail pts with newly diagnosed GBM.

Answer 78

Keime-Guibert, France (NEJM 2007)

Median OS 7.3 mos RT (50 Gy/28 fx) vs. 4.3 mos
No diff in QOL or cognition

Answer 79

MSKCC Clarke et al, IJROBP, 2017

Recurrent glioblastoma or anaplastic astrocytoma, size ≤40cc; Phase 1 with 15pts

SRT delivered to GTV plus 2-5 mm PTV margin

Answer 80

EORTC 26101(Wick et al, NEJM, 2017)

→lomustine plus bevacizumab
vs.
→lomustine alone

in first progression of GBM

Answer 81

Anaplastic Oligoastrocytoma (AOA), and Anaplastic Oligodendroglioma (AO) s/p surgery

n=289

Answer 82

"→neoadj dose escalated PCV x4 (procarbaine, CCNU, vincristine) → RT 59.4 Gy
vs.
→RT 59.4 Gy"

Answer 83

Anaplastic Oligoastrocytoma (AOA), and Anaplastic Oligodendroglioma (AO) s/p surgery

n=368

Answer 84

"→RT 59.4 Gy → adj PCV x6
vs.
→RT alone (PCV allowed at progression)"

Answer 85

EORTC 26951 van den Bent et al, JCO, 2006 and JCO, 2013

^{RTOG 9402 was neoadjuvant PCV}

Answer 86

"AA (some AO, AOA), KPS≥70

n=274

[""AOA"" diagnosis is now strongly discouraged in WHO 2016]

"

Answer 87

→60 Gy (Arm A)
vs.
→PCV/TMZ (Arm B1/B2)

Crossover at toxicity or progression:
•Arm A→PCV or tem
•Arm B→RT

Primary endpoint: TTF

Answer 88

"•Median TTF, PFS, and OS were similar for arms A and B1/2

•IDH1 mutation is strongest prognostic factor, even more than 1p19q codel
•methylated-MGMT and oligo histology also associated with better PFS (methylated-MGMT gave same prognosis with chemo and RT)

"

Answer 89

NOA-04 Wick et al (JCO, 2009; Neuro Oncol 2016)

Molecular diagnosis is superior to histology to convey prognosis.

No differential activity of chemo vs. RT in any subgroup.

Answer 90

"anaplastic glioma without 1p19q co-deletion"

Answer 91

"→RT alone 59.4 Gy
vs.
→RT with conc TMZ
vs.
→RT with adj TMZ
vs.
→RT with conc & adj TMZ"

Answer 92

○ Interim results for arms ± adjuvant TMZ: 5y OS 44→ 56%, MPFS 19→ 43 mo. IDHmt benefit from adjuvant TMZ.

○ ASCO results for ± concurrent TMZ: HR 0.97. 5y OS ~50%. Trend to benefit with concurrent TMZ for IDHmt.

Answer 93

CATNON (van den Bent et al, ASCO, 2019)

Answer 94

grade III with 1p19q codel glioma and grade II oligo with age≥40 or subtotal resection

→TMZ alone

vs.
→RT 59.4 Gy then PCV
vs.
→RT + conc and adj TMZ

Answer 95

WHO Grade II astrocytoma, oligoastrocytoma, or oligodendroglioma

n=365

Answer 96

"High risk (age ≥40 or STR):

→54 Gy RT → PCV x6
vs.
→54 Gy RT

Low risk: obs

PCV= procarbazine/CCNU/vincristine"

Answer 97

"PFS and OS improved with PCV
Median OS 13.3 yrs vs. 7.8
Median PFS 10.4 yrs vs. 4.0

•On subanalysis, benefit only in IDH-mutant (non-codeleted or codeleted). There is no benefit to chemo in IDH-wt

"

Answer 98

RTOG 9802 Shaw et al (JCO, 2012, Buckner et al, NEJM, 2016, Bell et al, JCO, 2020)

On subanalysis, benefit only in IDH-mutant (non-codeleted or codeleted). There is no benefit to chemo in IDH-wt

Answer 99

WHO I-II disease s/p surgery

n=203

Answer 100

"→50.4 Gy
vs.
→64.8 Gy"

Answer 101

No difference in OS or PFS
5-yr OS 72% low dose vs. 64%

•More Grade 3-5 toxicity with high dose.
•Favorable prognostic factors: age <40, oligo histo

Answer 102

INT/NCCTG 86-72-51(Shaw et al, JCO, 2002, Breen et al, Neuro Oncol, 2020)

Answer 103

WHO I-II disease s/p surgery

n=343

Answer 104

→45 Gy
vs.
→59.4 Gy

low-grade astrocytomas, oligodendrogliomas, and mixed oligoastrocyatoma,
ages 16 to 65, KPS ≥60, randomized to 45 Gy/25 fx versus 59.4 Gy/33 fx after
surgery (any degree of resection).

Answer 105

"No difference in 5-yr OS (59% vs. 58%) or PFS (50% vs. 47%) with dose escalation (45Gy vs 59.4)

Prognostic variables: size ≥6 cm, age ≥40, tumor crossing midline, astrocytoma, neuro deficits [mnemonic: ""SATAN"" criteria]
3-5 factors is high risk

"

Answer 106

Believers trial EORTC 22844

Pignatti risk factors (SATAN) : preop S ize ≥ 6 cm, A ge ≥ 40y, bihemispherical T umor, A A, or a pre op N euro fxn status >1.

Answer 107

WHO I-II s/p surgery (any kind)

n=311

Answer 108

"→54 Gy / 30 fx
vs.
→obs (RT allowed at recurrence)"

Answer 109

"5-yr PFS improved RT 55% vs. 35%
5-yr OS unchanged at 66-68%

•Rate of malignant transformation 72% vs. 66% (NS)
•No changes in cognitive deficits after treatment
•RT helped to control seizures

"

Answer 110

Nonbelievers trial EORTC 22845

Note that 65% of pts in observation arm eventually received RT salvage contributing to higher than expected surival.

Answer 111

LGG with ≥1 high-risk feature (Age ≥40, progressive mass, new or worsening neuro symptoms, intractable seizures)

n=477

Answer 112

→50.4 Gy
vs.
→dose dense TMZ (75 mg/m2 days 1–21 of a 28-day cycle, max 12 cycles)

Answer 113

PFS 46 mos with RT vs. 39 mos TMZ, p=0.22

•If IDHmt/non-codel, RT had longer PFS. No different in PFS with IDHmt/codel and IDHwt tumors
•Median OS not reached
•No differences in HRQOL or global cognitive function between groups

Answer 114

Baumert, EORTC 22033-26033 (Lancet Oncol 2016)

Criteria used in this study are similar to the so called SATAN criteria from the EORTC Believers' study but modified (Karim 1996).

Answer 115

Low grade glioma (high risk) with ≥3 risk factors (age ≥40, astrocytoma, crosses midline, size 6 cm, pre-op neuro function status >1)

n=129

Answer 116

Phase II
54 Gy + conc and adj TMZ

Answer 117

"3-yr OS 74% [improved from historical control 54%]

Median OS 8.2 yrs
Median PFS 4.5 yrs
MGMT associated with improved OS

"

Answer 118

Fisher, RTOG 0424 (IJROBP 2015)

Answer 119

Meningioma

Low risk: Grade I GTR and STR
Int risk: Grade I recurrent or grade II GTR
High risk: Grade II recurrent or STR, or grade III any

n= 244

Answer 120

"Phase II
•Low risk (G1, GTR/STR): obs
•Int risk (G1 recur, G2 GTR): 54 Gy (with CTV 1.0 cm, 0.5 cm CTV at barriers)
•High risk (G2 recur/STR, G3 STR): 54 Gy (2.0 cm CTV) and 60 Gy (1.0 cm CTV)

Edema and dural tail are not included in volumes"

Answer 121

ARUBA (2020)

Unruptured AVM

(Characteristics: Spetzler-Martin grade I-III in ~30% each, and grade IV in ~10%)

Answer 122

-Mean f/u of 50 mos
-Death or stroke 3.39 (medical mngmt) vs. 12.32 per 100 pt-years
-Adverse events 59% vs. 79%

Answer 123

"International Stereotactic Radiosurgery Society

Tuleasca et al, J Neurosurg, 2020

65 studies, 6461 patients

"

Answer 124

-Mean freedom from pain 80-87%
-(no difference in GK, LINAC, or CK)
-Mean time to relief 15-81 days
-Hypoesthesia ranges 0-17%
-Mean recurrence 25-32%
-(For recurrence, LINAC was better than GK. No difference between GK and CK)
7-yr pain relief 22-60%
10-yr pain relief 30-45%

Answer 125

"n=207

surgery vs. GKS
•CN VII disturbance: 37% vs. 0%
•V disturbancs: 29% vs. 4%
•Hearing preserved: 37.5% vs. 70%
•Hospital stay: 23 days vs. 3 days

"

Answer 126

SRS v FSRT

•Tumor control 98% SRS vs. 97% FSRT
•CNV preservation 95% vs. 93%
•CNVII preservation 98% vs. 98%
•Hearing preservation 33% vs. 81%

Answer 127

"n=1317

Uveal melanoma, selected T2 tumors (medium)

•12-yr all-cause mortality 41-43%, not different
•LF <10%
•But, 3-yr blindness 43%

"

CNS Flashcards

(159 cards)