Extent of resection in the treatment of gliomas Fred G. Barker II, M.D. Neurosurgical Grand Rounds...

Extent of resection Extent of resection in the treatment of gliomasin the treatment of gliomas

Fred G. Barker II, M.D. Fred G. Barker II, M.D. Neurosurgical Grand Rounds Neurosurgical Grand Rounds

Massachusetts General HospitalMassachusetts General Hospital

February 28, 2008February 28, 2008

EOR questionsEOR questions

GTR vs biopsy?GTR vs biopsy?

Debulking vs biopsy?Debulking vs biopsy?

GTR vs. near-GTR?GTR vs. near-GTR?

GTR vs. GTR plus margin of GTR vs. GTR plus margin of “normal” tissue (lobectomy)?“normal” tissue (lobectomy)?

Resection of malignant gliomaResection of malignant glioma

Cochrane Review, Metcalfe & Grant, 2001Cochrane Review, Metcalfe & Grant, 2001

““The electronic database search yielded The electronic database search yielded 2100 citations. Of these, 2 articles 2100 citations. Of these, 2 articles were identified for possible inclusion, were identified for possible inclusion, however both were excluded. The however both were excluded. The hand search and personal hand search and personal communication were similarly communication were similarly unproductive. unproductive. No studies were No studies were included in the review and no data included in the review and no data were synthesized.were synthesized.””

Goals of surgery for malignant gliomasGoals of surgery for malignant gliomas

1. Providing diagnosis1. Providing diagnosis

2. Relieving symptomatic mass 2. Relieving symptomatic mass effecteffect

3. “Setting up” postoperative 3. “Setting up” postoperative externally delivered therapiesexternally delivered therapies

4. Prolonging survival through 4. Prolonging survival through cytoreductioncytoreduction

5. Applying locally-delivered therapies5. Applying locally-delivered therapies

1. Providing a diagnosis1. Providing a diagnosis

Main differentials: stroke – DWI, vascular distribution; “infection” (i.e. encephalitis) – susceptibility, location; demyelinating disease – incomplete ring sign

T1 with gad FLAIR T1 with gad post 6 wk

Providing a diagnosisProviding a diagnosis

Nonenhancing tumors are not always Nonenhancing tumors are not always low-gradelow-grade

Chance of anaplasia increases in older patients (50% by mid-40’s)

Barker et al. (UCSF), Cancer 1997


Gliomas are notoriously Gliomas are notoriously heterogeneousheterogeneous

More extensive resections more More extensive resections more frequently provide higher grade frequently provide higher grade diagnosisdiagnosis

Glantz et al., Neurology, 1991Glantz et al., Neurology, 1991

higher grade diagnosis more likely higher grade diagnosis more likely as extent of resection increasedas extent of resection increased

Stereotactic bx: grade 2; resection grade 3Stereotactic bx: grade 2; resection grade 3



Perry et al., Cancer 1999Perry et al., Cancer 1999identification of oligo component in identification of oligo component in

grade 3 tumors was more likely as grade 3 tumors was more likely as extent of resection increased extent of resection increased (p = 0.01)(p = 0.01)

% containing oligo components:% containing oligo components:

BxBx 3%3%

STRSTR 29%29%

GTRGTR 43%43%


Aghi et al., unpublished MGH data (grade 2)Aghi et al., unpublished MGH data (grade 2)


BxBx 46% 46% ((more specimens -> more oligo)more specimens -> more oligo)

GTRGTR 89% 89% p < 0.001p < 0.001

Carter et al., unpublished SEER data (grade 2)Carter et al., unpublished SEER data (grade 2)


BxBx 32%32%

ResectionResection 62%62% p < 0.001p < 0.001

Year of diagnosis

Pro

babi

lity

1985 1990 1995 2000

0.0

0.2

0.4

0.6

0.8

1.0100%100%

AstroAstro

Year of diagnosisYear of diagnosis

19951995 20002000

Pro

bab

ilit

yP

rob

abil

ity

0%0%

20%20%

40%40%

60%60%

1990199019851985

OligoOligo

80%80%

OligoastroOligoastro

p < 0.001p < 0.001

SEER data;Carter BS et al unpublished

Probability of oligo-containing histology Probability of oligo-containing histology has increased significantly with timehas increased significantly with time

Year of diagnosis

Pro

babi

lity

1985 1990 1995 2000

0.0

0.1

0.2

0.3

0.4

0.0

0.2

0.4

Probability of oligo-containing histologyProbability of oligo-containing histology

vs. literature on chemo for oligosvs. literature on chemo for oligos 40%40%

PubMed # articles PubMed # articles on chemo for oligoson chemo for oligos

Year of diagnosisYear of diagnosis

19951995 20002000

Pro

bab

ilit

y o

f o

lig

o d

iag

no

sis

Pro

bab

ilit

y o

f o

lig

o d

iag

no

sis

0%0%

10%10%

20%20%

30%30%

1990199019851985

SEER % oligosSEER % oligos

2020

1010

0 0

Nu

mb

er of articles o

n ch

emo

for o

ligo

sN

um

ber o

f articles on

chem

o fo

r olig

os

SEER, PubMed data;Carter BS et al unpublished


Jackson et al., Neuro-Oncol 2001Jackson et al., Neuro-Oncol 2001

81 pts referred to MD Anderson after 81 pts referred to MD Anderson after stereo bx elsewhere who were accepted stereo bx elsewhere who were accepted for resectionfor resection

>95% resection in 57% of patients>95% resection in 57% of patients

38% had different pathology even after 38% had different pathology even after central review of outside slides; 26% central review of outside slides; 26% would affect treatmentwould affect treatment

Mortality/major morbidity in 17%Mortality/major morbidity in 17%


MR spectroscopy can MR spectroscopy can assist in choosing a assist in choosing a biopsy targetbiopsy target

2. Relieve mass effect2. Relieve mass effect

Obvious and frequent success in Obvious and frequent success in most neurosurgeons’ experience most neurosurgeons’ experience in relieving neurological in relieving neurological symptoms from mass effectsymptoms from mass effect

Possible effect in increasing KPS in Possible effect in increasing KPS in malignant gliomamalignant glioma

Low grade glioma: relieving Low grade glioma: relieving medically intractable seizuresmedically intractable seizures

Relieve mass effectRelieve mass effect

Ciric et al., Neurosurgery 1987Ciric et al., Neurosurgery 1987neurologic condition at dischargeneurologic condition at discharge

EOREOR ImproveImprove SameSame WorseWorse

PartialPartial 0%0% 60%60% 40%40%

Near GTNear GT 30%30% 70%70%0%0%

GTGT 41%41% 55%55%4%4%


Sawaya et al., Neurosurgery 1998Sawaya et al., Neurosurgery 199830% of all patients had improved KPS 30% of all patients had improved KPS

after resectionafter resection

8% had decreased KPS8% had decreased KPS

% “major neurologic complications”:% “major neurologic complications”:

PartialPartial 12%12%

SubtotalSubtotal 15%15%

TotalTotal 7%7%


Fadul et al., Neurology 1988Fadul et al., Neurology 1988Neurologic deterioration Neurologic deterioration

(1 week postop)(1 week postop)

BxBx 29%29%

PartialPartial 39%39%

SubtotalSubtotal 30%30%

TotalTotal 20%20%

most hemorrhages and herniations most hemorrhages and herniations occurred after bx or partial resectionoccurred after bx or partial resection

3. “Setting up” postoperative therapies3. “Setting up” postoperative therapies

Is response to postoperative Is response to postoperative adjuvant radiation in newly-adjuvant radiation in newly-diagnosed glioblastoma improved diagnosed glioblastoma improved by prior resection?by prior resection?

Neurosurgery 49:1288, 2001

Response to radiation after surgeryResponse to radiation after surgery

301 GM pts treated using two 301 GM pts treated using two prospective UCSF clinical prospective UCSF clinical protocolsprotocols

age, KPS, extent of resection, age, KPS, extent of resection, radiation response recorded radiation response recorded prospectivelyprospectively

radiation response assessed by radiation response assessed by imaging criteria (postop image imaging criteria (postop image compared with post-XRT image)compared with post-XRT image)

ResultsResults

More extensive surgical resection predicted better More extensive surgical resection predicted better imaging-assessed response to postoperative imaging-assessed response to postoperative adjuvant radiation in both univariate and adjuvant radiation in both univariate and multivariate analyses (adjusted for age, KPS)multivariate analyses (adjusted for age, KPS)

““Setting up” postoperative therapiesSetting up” postoperative therapies

Resection and TMZ – EORTC 26981 (Stupp)Resection and TMZ – EORTC 26981 (Stupp)

2-year survival2-year survival median survivalmedian survival

+TMZ -TMZ+TMZ -TMZ +TMZ -TMZ +TMZ -TMZ

GTRGTR 37%37% 14% 14% 18m18m 14m 14m

STRSTR 23%23% 9% 9% 14m14m 12m 12m

BxBx 10%10% 5% 5% 9m 9m 8m 8m

van den Bent et al., Eur J Cancer 2005 [abstr]

Subset Analysis – Subset Analysis – Overall SurvivalOverall Survival

““Setting up” postoperative therapiesSetting up” postoperative therapies

Keles et al. J Neurosurg 2004 Keles et al. J Neurosurg 2004

119 pts with recurrent GM119 pts with recurrent GM

Reoperation -> TMZReoperation -> TMZ

Volume of disease at start of Volume of disease at start of chemotherapy was a significant chemotherapy was a significant predictor of time to progressionpredictor of time to progression and and survival (progression risk doubled survival (progression risk doubled for 10-15cc residual mass c/w GTR, for 10-15cc residual mass c/w GTR, quadrupled for >15 cc)quadrupled for >15 cc)

4. Prolong survival4. Prolong survival

Cushing believed that resection Cushing believed that resection extended survival in malignant extended survival in malignant gliomas but recognized shorter gliomas but recognized shorter and shorter intervals between and shorter intervals between operation as the disease operation as the disease progressed – “ideally all should be progressed – “ideally all should be operative mortalities”operative mortalities”

McKenzie first to replace bone flap McKenzie first to replace bone flap after resection to after resection to limitlimit prognosis, prognosis, but generally benefit of resection but generally benefit of resection was not questionedwas not questioned

Review ArticleReview Article


Nazzaro and Neuwelt, 1990Nazzaro and Neuwelt, 1990

Reviewed neurosurgical literature 1940 Reviewed neurosurgical literature 1940 - 1990 (184 refs)- 1990 (184 refs)

““This analysis shows that there is little This analysis shows that there is little justification for dogmatic statements justification for dogmatic statements concerning the relationship between concerning the relationship between increasing patient survival times and increasing patient survival times and aggressive surgical management …”aggressive surgical management …”

Nazzaro and Neuwelt, 1990Nazzaro and Neuwelt, 1990

Failure to adjust for other prognostic Failure to adjust for other prognostic factors such as agefactors such as age

Failure to adjust for difference in postop Failure to adjust for difference in postop treatments* treatments*

Failure to use “any form of statistical Failure to use “any form of statistical analysis”analysis”

All studies had retrospective designAll studies had retrospective design

Failure to adjust for resectabilityFailure to adjust for resectability

*logical fallacy – resection does influence chance *logical fallacy – resection does influence chance of tolerating XRT as well as chance of of tolerating XRT as well as chance of reoperationreoperation

Prolong survivalProlong survival

Considering the more than 30 years Considering the more than 30 years of experience and apparent failure, of experience and apparent failure, does it not seem that the does it not seem that the ostensible myth of the benefit of ostensible myth of the benefit of cytoreduction for the “isolated cytoreduction for the “isolated sake of cytoreduction” needs to sake of cytoreduction” needs to placed on the intellectual scrap placed on the intellectual scrap heap? heap?

-- Michael L.J. -- Michael L.J. ApuzzoApuzzo


Many multivariate analyses of Many multivariate analyses of survival after resection of GM survival after resection of GM (nonrandomized) now provide (nonrandomized) now provide evidence that extent of resection evidence that extent of resection is an independent prognostic is an independent prognostic factor for survival (independent of factor for survival (independent of age and KPS)age and KPS)


Laws et al., JNS 2003 (GO project)Laws et al., JNS 2003 (GO project)

788 patients (1997-2001)788 patients (1997-2001)

Resection was favorable prognostic Resection was favorable prognostic factor (compared to biopsy) after factor (compared to biopsy) after correction for age, correction for age, KPSKPS, and after , and after omission of patients with omission of patients with multifocal diseasemultifocal disease

GTR

STR

Bx

Years after diagnosis

Pro

po

rtio

n s

urv

ivin

g

0.0 0.5 1.0 1.5 2.0

0.0

0.2

0.4

0.6

0.8

1.0

p < 0.001

Barker et al. (UCSF), JNS 1996

Survival in GMSurvival in GMstratified bystratified byextent of resectionextent of resection(nonrandomized)(nonrandomized)

Extent of MST 1-yr 2-yr 5-yrresection (months)

Gross total 17 72% 31% 12% Subtotal 11 47% 15% 2% Biopsy 7 23% 2% 0%

Barker et al. (UCSF), JNS 1996

Survival in GM stratified by extent of resection(nonrandomized)

Survival after biopsy or resection of Survival after biopsy or resection of supratentorial lobar glioblastoma: supratentorial lobar glioblastoma:

a population-based studya population-based study

Manish K. Aghi, M.D., Ph.D., William T. Curry Jr., M.D., Manish K. Aghi, M.D., Ph.D., William T. Curry Jr., M.D., Bob S. Carter, M.D., Ph.D. and Fred G. Barker II, M.D. Bob S. Carter, M.D., Ph.D. and Fred G. Barker II, M.D.

Neurosurgical ServiceNeurosurgical ServiceMassachusetts General HospitalMassachusetts General Hospital

Harvard Medical SchoolHarvard Medical School

ResultsResults

11,134 glioblastoma patients diagnosed 1988 to 200111,134 glioblastoma patients diagnosed 1988 to 2001

11,108 intracranial tumors11,108 intracranial tumors

7,423 supratentorial lobar tumors7,423 supratentorial lobar tumors

60216021 tumors did not cross the midline or tentorial notch, tumors did not cross the midline or tentorial notch, had not spread outside brain, through CSF or to spine, had nohad not spread outside brain, through CSF or to spine, had no

contraindications to surgery, and had a surgical procedure specifiedcontraindications to surgery, and had a surgical procedure specified

(size known for 3520 tumors)(size known for 3520 tumors)

ResultsResults

Factors predicting biopsy over resection:Factors predicting biopsy over resection:

• Older ageOlder age (odds ratio 1.38 per decade) (odds ratio 1.38 per decade)

• Smaller tumor sizeSmaller tumor size (odds ratio 0.84 per cm) (odds ratio 0.84 per cm)

• Tumor locationTumor location (parietal – highest chance of (parietal – highest chance of biopsy, temporal lowest)biopsy, temporal lowest)

• HistologyHistology (glioblastoma – highest chance of (glioblastoma – highest chance of biopsy, giant cell glioblastoma lowest)biopsy, giant cell glioblastoma lowest)

• Unmarried statusUnmarried status

• SEER registrySEER registry

20

40

60

80

Age20

40

60

80

Tumor size (mm)

00.

10.

20.

30.

40.

5P

rob(

bx)

Pro

b (

bio

psy

)P

rob

(b

iop

sy)

Tumor size (mm)

Tumor size (mm) AgeAge

Probability of biopsy rather than resection:Probability of biopsy rather than resection:Relation to age and tumor sizeRelation to age and tumor size

Results: survivalResults: survival

0.0 0.5 1.0 1.5 2.0 2.5 3.0


0.0

0.2

0.4

0.6

0.8

1.0

Su

rviv

alRESECTION

BIOPSY

Median survival – 12 months for resectionMedian survival – 12 months for resection7 months for biopsy7 months for biopsy

All pts had postop XRT

ResultsResults

Biopsy rates vary by SEER registry:Biopsy rates vary by SEER registry:

27%27%

4%4%

23%23%

13%13%

15%15%

13%13%

12%12%

15%15%

15%15%

22%22%

22%22%

Tumor size (mm)

Pro

babi

lity

of ra

diat

ion

0 20 40 60 80

0.60

0.65

0.70

0.75

0.80

0.85

0.90

ResectionResection

Tumor size (mm)Tumor size (mm)

4040 6060 8080

Pro

bab

ilit

y o

f p

ost

op

XR

TP

rob

abil

ity

of

po

sto

p X

RT

60%60%

65%65%

70%70%

90%90%

80%80%

75%75%

202000

BiopsyBiopsy

85%85%

Probability of XRT vs. tumor sizeProbability of XRT vs. tumor sizefor biopsied & resected patientsfor biopsied & resected patients

Cancer 2006;106:1358

Survival Rates and PatternsSurvival Rates and Patterns

Prolong survival - subgroupsProlong survival - subgroups

Do all glioblastoma patients benefit Do all glioblastoma patients benefit equally from extensive resection?equally from extensive resection?

Potentially important subgroups:Potentially important subgroups:

patients with mass effect patients with mass effect

younger patientsyounger patients

Mass effect and GM resectionMass effect and GM resection

Kreth et al., Cancer 1999Kreth et al., Cancer 1999

Stereo bx+XRT c/w resection+XRTStereo bx+XRT c/w resection+XRT

225 patients, supratentorial GM225 patients, supratentorial GM

Tumor resection effective only in Tumor resection effective only in group with midline shift (P < 0.01)group with midline shift (P < 0.01)

GraphGraph

GTR

STR

Bx


Pro

po

rtio

n s

urv

ivin

g

Survival in GMSurvival in GMstratified bystratified by

extent of resectionextent of resection

0.5 1.0 1.5 2.00.0

0.0

0.2

0.4

0.6

0.8

1.0

Age 16 to 39N = 47

p = 0.01

Age and GM resectionAge and GM resection

GTR

STR

Bx


Pro

po

rtio

n s

urv

ivin

g

0.5 1.0 1.5 2.00.0

0.0

0.2

0.4

0.6

0.8

1.0

Age 40 to 49N = 58

p = 0.01

Survival in GMSurvival in GMstratified bystratified byextent of resectionextent of resection

GTR

STRBx


Pro

po

rtio

n s

urv

ivin

g

0.5 1.0 1.5 2.0

0.0

0.0

0.2

0.4

0.6

0.8

1.0

Age 50 to 64N = 114p = 0.12


GTRSTR

Bx


Pro

po

rtio

n s

urv

ivin

g

0.5 1.0 1.5 2.00.0

0.0

0.2

0.4

0.6

0.8

1.0

Age 65 to 79N = 80

p = 0.04


Survival after GM resection: Survival after GM resection: subgroupssubgroups

SubgroupSubgroup Hazard ratio Hazard ratio biopsy vs. resectionbiopsy vs. resection

Age Age ≤ 40≤ 40 1.971.97

Age > 40Age > 40 1.661.66

Size < 3 cmSize < 3 cm 1.541.54

Size 3-5 cmSize 3-5 cm 1.721.72

Size > 5 cmSize > 5 cm 1.731.73

Source: Aghi et al, unpub (SEER)

Grade II astro / oligo / oligoastroGrade II astro / oligo / oligoastroSurgerySurgery

Total N = 599

Nonrandomized trialsNonrandomized trials

Most trials in neurosurgery are not Most trials in neurosurgery are not randomizedrandomized

Some topics can only be studied using Some topics can only be studied using nonrandomized methods (such as nonrandomized methods (such as volume-outcome relationship)volume-outcome relationship)

Recent studies have shown that when Recent studies have shown that when nonrandomized trials use concurrent nonrandomized trials use concurrent controls eligible for the experimental controls eligible for the experimental treatment, results are often treatment, results are often reasonably similar to randomized trial reasonably similar to randomized trial results results

Solid: nonrandomized

GraphGraph

RCT of resection for gliomaRCT of resection for glioma

Design of RCT for resection in gliomaDesign of RCT for resection in glioma

Enrollment and randomization based Enrollment and randomization based on imaging diagnosis (sometimes bx on imaging diagnosis (sometimes bx is required in non-resected group)is required in non-resected group)

All tumors must be considered All tumors must be considered resectableresectable

Postop deaths and severe morbidities Postop deaths and severe morbidities should not be excluded (i.e. no loss should not be excluded (i.e. no loss to followup based on results of to followup based on results of surgery)surgery)

Loss to followup Loss to followup

Of 28 malignant glioma trials Of 28 malignant glioma trials included in NS review paper, 24 included in NS review paper, 24 were either cooperative group were either cooperative group trials (with explicit performance trials (with explicit performance status criteria) or single-center status criteria) or single-center trials (often with frank exclusion of trials (often with frank exclusion of poor results)poor results)

15/24 showed benefit of EOR – 15/24 showed benefit of EOR – compared with 1 of 4 population compared with 1 of 4 population based studiesbased studies

Better Study Design #1 - RCTBetter Study Design #1 - RCT

Only RCT of resection for malignant Only RCT of resection for malignant glioma: glioma: Vuorinen et al, Acta Nchir 2003Vuorinen et al, Acta Nchir 2003

Age > 65, KPS > 60 Age > 65, KPS > 60

30 pts randomized; 10/14 had resection 30 pts randomized; 10/14 had resection (refusal, hematoma, lymphoma, infarct), (refusal, hematoma, lymphoma, infarct), 13/16 had biopsy (met x 2, hematoma)13/16 had biopsy (met x 2, hematoma)

9/10 resected pts, 10/13 biopsied pts 9/10 resected pts, 10/13 biopsied pts started XRT (remainder: poor clinical started XRT (remainder: poor clinical condition)condition)

Malignant glioma resection - survivalMalignant glioma resection - survival

Vuorinen, Acta Neurochir 2003

P = 0.035Hazard ratio 2.7Favors resection

Malignant glioma resection – time to failureMalignant glioma resection – time to failure

Vuorinen, Acta Neurochir 2003

P = 0.057Favors resection

RCTRCT

RCT of bx vs resection for elderly RCT of bx vs resection for elderly with presumed malignant glioma with presumed malignant glioma was supposed to open in France was supposed to open in France in 2007in 2007

Adjustment for resectabilityAdjustment for resectability

While many nonrandomized studies While many nonrandomized studies of EOR in glioma have included of EOR in glioma have included “adjustment for location”, none “adjustment for location”, none have included adjustment for have included adjustment for resectabilityresectability

Barker et al., JNS 96

ResectabilityResectability

In fact, resectability is a complex concept In fact, resectability is a complex concept that is a frequent subject of disagreement that is a frequent subject of disagreement between surgeonsbetween surgeons

Factors influencing rates of resection include Factors influencing rates of resection include pt-related (age, KPS, marital status); tumor-pt-related (age, KPS, marital status); tumor-related (size, location, fuzziness of borders) related (size, location, fuzziness of borders) and provider-related (specialist status, and provider-related (specialist status, volume of practice, training and experience, volume of practice, training and experience, economic and professional incentives)economic and professional incentives)

Resectable and nonresectable tumors may Resectable and nonresectable tumors may well have different molecular pathologywell have different molecular pathology

PublicationPublication

Resectability in gliomaResectability in glioma

Two published attempts at defining a Two published attempts at defining a scale of resectability in gliomasscale of resectability in gliomas

Vorster and Barnett (Nsurg Focus 98)Vorster and Barnett (Nsurg Focus 98)

Eloquent / noneloquentEloquent / noneloquent

Eloquent areas: sensorimotor, Eloquent areas: sensorimotor, visual, language cortices, internal visual, language cortices, internal capsule, basal gangliacapsule, basal ganglia


Sawaya Nsurg 98Sawaya Nsurg 98

Better study design – # 2Better study design – # 2

Nonrandomized study in which all Nonrandomized study in which all tumors were eligible for resection, tumors were eligible for resection, but heterogeneity of surgeons’ but heterogeneity of surgeons’ practices pseudorandomizes practices pseudorandomizes patients to bx/resection (or patients to bx/resection (or STR/GTR)STR/GTR)

Propensity score for balancing (as Propensity score for balancing (as in Barker Nsurg 98)in Barker Nsurg 98)

An example – Shaw et al.An example – Shaw et al.

RTOG 9802 – surgeon-determined RTOG 9802 – surgeon-determined GTR of LGG, then observed GTR of LGG, then observed (single-arm phase II trial)(single-arm phase II trial)

111 pts entered 1998-2002111 pts entered 1998-2002

RTOG 9802RTOG 9802

PFSPFS

< 1 cm residual (59%)< 1 cm residual (59%) 74%74%

1 – 2 cm residual (32%)1 – 2 cm residual (32%) 32%32%

> 2 cm residual (9%)> 2 cm residual (9%) 11%11%

82% relapsed <2cm from resection 82% relapsed <2cm from resection cavity; 2% distantcavity; 2% distant

Shaw et al., JNS in revision 2008

Better Study Design #3Better Study Design #3

While it may be difficult to randomize pts While it may be difficult to randomize pts between biopsy and resection, at least between biopsy and resection, at least two RCTs of surgical adjuncts to improve two RCTs of surgical adjuncts to improve EOR have been completed and reportedEOR have been completed and reported

For an effective adjunct (with no For an effective adjunct (with no indempendent treatment effect) this indempendent treatment effect) this would in effect randomize between would in effect randomize between different EORsdifferent EORs

Neuronavigation trial was negative (Willems Neuronavigation trial was negative (Willems JNS 104:360, 2006)JNS 104:360, 2006)

Prolonging survival Prolonging survival

Stummer et al. RCT of fluorescence-guided Stummer et al. RCT of fluorescence-guided GM resectionGM resection

Pts for resection of presumed GM Pts for resection of presumed GM randomized to optimal white-light randomized to optimal white-light resection or fluorescence-guided (5-ALA)resection or fluorescence-guided (5-ALA)

5-ALA group had 65% GTR c/w 36% for WL 5-ALA group had 65% GTR c/w 36% for WL groupgroup

6-mo PFS doubled in 5-ALA group (41% vs. 6-mo PFS doubled in 5-ALA group (41% vs. 21%)21%)

Stummer et al., Lancet Oncol 2006

Malignant glioma resection - PFSMalignant glioma resection - PFS


65% GTR 5-ALAvs 36% GTR WL

Prolonging survival Prolonging survival

Could an unexpected photodynamic Could an unexpected photodynamic treatment effect of 5-ALA at low light treatment effect of 5-ALA at low light intensity account for results?intensity account for results?

Unpublished subgroup analyses – no Unpublished subgroup analyses – no difference in survival between difference in survival between groups after GTR; minimal groups after GTR; minimal improvement in PFS in STR group improvement in PFS in STR group with 5-ALAwith 5-ALA

Suggests benefits are a direct result of Suggests benefits are a direct result of improved resectionimproved resection


Balance against riskBalance against risk

Apples-oranges problemApples-oranges problem

Common coin – KPS as prognostic Common coin – KPS as prognostic factor for survivalfactor for survival

GTR/STR or STR/bx difference GTR/STR or STR/bx difference roughly worth ~10 to 30 KPS roughly worth ~10 to 30 KPS points points

TableTable

Age

Pro

babi

lity

30 40 50 60 70 80

0.0

0.1

0.2

0.3

0.4

0.5

Death + LTF + STFDeath + LTFDeath

UnivariateUnivariatePP < 0.001 < 0.001

AgeAge

3030 4040 5050 6060 7070 8080

Pro

bab

ilit

yP

rob

abil

ity

0.00.0

0.10.1

0.20.2

0.50.5

0.40.4

0.30.3

Barker et al., NeuroOnc 2005

Outcome vs. ageOutcome vs. ages/p resection of primary brain tumors/p resection of primary brain tumor

ConclusionsConclusions

Surgical resection is an independent prognostic Surgical resection is an independent prognostic factor for survival in GM and LGG in factor for survival in GM and LGG in nonrandomized trialsnonrandomized trials

Whether this would persist after adjustment for Whether this would persist after adjustment for resectability has been controversial; single resectability has been controversial; single RCT now available with confirmatory resultsRCT now available with confirmatory results

Burden of proof increasingly rests on nihilists; Burden of proof increasingly rests on nihilists; no likelihood of new LGG randomized trial no likelihood of new LGG randomized trial anytime soon, new trial in MG is possibly in anytime soon, new trial in MG is possibly in planning stagesplanning stages

LogoLogo

ReoperationReoperation

Who benefits from reoperation in Who benefits from reoperation in glioblastoma?glioblastoma?

Reoperation for GM: selection factorsReoperation for GM: selection factors

223 patients with documented failure before 223 patients with documented failure before death; multivariate logistic regression to death; multivariate logistic regression to predict patients who will undergo reoperationpredict patients who will undergo reoperation

ageage < 40 < 40 34%34%

p = 0.02p = 0.02 40-6040-60 23%23%

60+60+ 11% 11%

extent of initial surgeryextent of initial surgery GTR GTR 32%32%

p = 0.02p = 0.02 STRSTR 22%22%

BxBx 4%4%

Reoperation for GM: Reoperation for GM: relieving symptomsrelieving symptoms

KPS after second resection:KPS after second resection:

28% improved28% improved

49% stable49% stable

23% declined (by 10-30 points)23% declined (by 10-30 points)

more likely benefit when more likely benefit when recurrence was symptomaticrecurrence was symptomatic

Reoperation for GM: Reoperation for GM: comparison to unoperated patientscomparison to unoperated patients

Median survival after first failure (KPS known)Median survival after first failure (KPS known)

reoperated (36 pts)reoperated (36 pts) 41 wk41 wk

not reoperated (136 pts)not reoperated (136 pts) 23 wk23 wk

univariateunivariate hazard ratio 0.71hazard ratio 0.71 p = 0.036p = 0.036

CoxCox mvmv hazard ratio 0.66hazard ratio 0.66 p = 0.08p = 0.08after adj for age, KPS at failureafter adj for age, KPS at failure

extent of initial resection & interval until failure: NSextent of initial resection & interval until failure: NS

Survival after first relapseSurvival after first relapse

ReoperationReoperationNo reoperationNo reoperation

Reoperation for GM: survival benefitReoperation for GM: survival benefit

Cox simulation for “typical” patientCox simulation for “typical” patient

55 years old55 years old

KPS at recurrence of 80KPS at recurrence of 80

initial resection STR or GTRinitial resection STR or GTR

recurrence at/near original tumor siterecurrence at/near original tumor site

predicted difference in median survival between predicted difference in median survival between reoperated and nonreoperated groups:reoperated and nonreoperated groups: 8 weeks8 weeks

Barker et al. (UCSF), NS 1998


Kowalczuk et al., Neurosurg 1997Kowalczuk et al., Neurosurg 1997

75 patients with malignant gliomas75 patients with malignant gliomas

significant: age, KPS, tumor grade, significant: age, KPS, tumor grade, complications within 30 days after complications within 30 days after surgery, XRT dose administeredsurgery, XRT dose administered

not significant: 17 other factors, not significant: 17 other factors, including extent of resection including extent of resection (volumetric analysis)(volumetric analysis)

Extent of resection in the treatment of gliomas Fred G. Barker II, M.D. Neurosurgical Grand Rounds...

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