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Extent of resection in the treatment of gliomas. Fred G. Barker II, M.D. Neurosurgical Grand Rounds Massachusetts General Hospital February 28, 2008. EOR questions. GTR vs biopsy? Debulking vs biopsy? GTR vs. near-GTR? GTR vs. GTR plus margin of “normal” tissue (lobectomy)?.

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extent of resection in the treatment of gliomas

Extent of resection in the treatment of gliomas

Fred G. Barker II, M.D.

Neurosurgical Grand Rounds

Massachusetts General Hospital

February 28, 2008

eor questions
EOR questions
  • GTR vs biopsy?
  • Debulking vs biopsy?
  • GTR vs. near-GTR?
  • GTR vs. GTR plus margin of “normal” tissue (lobectomy)?
resection of malignant glioma
Resection of malignant glioma
  • Cochrane Review, Metcalfe & Grant, 2001
  • “The electronic database search yielded 2100 citations. Of these, 2 articles were identified for possible inclusion, however both were excluded. The hand search and personal communication were similarly unproductive. No studies were included in the review and no data were synthesized.”
goals of surgery for malignant gliomas
Goals of surgery for malignant gliomas
  • 1. Providing diagnosis
  • 2. Relieving symptomatic mass effect
  • 3. “Setting up” postoperative externally delivered therapies
  • 4. Prolonging survival through cytoreduction
  • 5. Applying locally-delivered therapies
1 providing a diagnosis
1. 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 diagnosis
Providing a diagnosis
  • Nonenhancing tumors are not always low-grade

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

Barker et al. (UCSF), Cancer 1997

providing a diagnosis7
Providing a diagnosis
  • Gliomas are notoriously heterogeneous
  • More extensive resections more frequently provide higher grade diagnosis
  • Glantz et al., Neurology, 1991
  • higher grade diagnosis more likely as extent of resection increased
providing a diagnosis8
Providing a diagnosis
  • Stereotactic bx: grade 2; resection grade 3
providing a diagnosis9
Providing a diagnosis
  • Perry et al., Cancer 1999
    • identification of oligo component in grade 3 tumors was more likely as extent of resection increased (p = 0.01)
    • % containing oligo components:
    • Bx 3%
    • STR 29%
    • GTR 43%
providing a diagnosis10
Providing a diagnosis
  • Aghi et al., unpublished MGH data (grade 2)
    • % containing oligo components:
    • Bx 46% (more specimens -> more oligo)
    • GTR 89% p < 0.001
  • Carter et al., unpublished SEER data (grade 2)
    • % containing oligo components:
    • Bx 32%
    • Resection 62% p < 0.001
probability of oligo containing histology has increased significantly with time
Probability of oligo-containing histology has increased significantly with time

100%

p < 0.001

80%

60%

Probability

Astro

40%

Oligo

20%

Oligoastro

0%

1985

1990

1995

2000

Year of diagnosis

SEER data;

Carter BS et al unpublished

probability of oligo containing histology vs literature on chemo for oligos
Probability of oligo-containing histologyvs. literature on chemo for oligos

40%

20

SEER % oligos

30%

Number of articles on chemo for oligos

Probability of oligo diagnosis

20%

10

PubMed # articles

on chemo for oligos

10%

0

0%

1985

1990

1995

2000

Year of diagnosis

SEER, PubMed data;

Carter BS et al unpublished

providing a diagnosis13
Providing a diagnosis
  • Jackson et al., Neuro-Oncol 2001
  • 81 pts referred to MD Anderson after stereo bx elsewhere who were accepted for resection
  • >95% resection in 57% of patients
  • 38% had different pathology even after central review of outside slides; 26% would affect treatment
  • Mortality/major morbidity in 17%
providing a diagnosis14
Providing a diagnosis
  • MR spectroscopy can assist in choosing a biopsy target
2 relieve mass effect
2. Relieve mass effect
  • Obvious and frequent success in most neurosurgeons’ experience in relieving neurological symptoms from mass effect
  • Possible effect in increasing KPS in malignant glioma
  • Low grade glioma: relieving medically intractable seizures
relieve mass effect
Relieve mass effect
  • Ciric et al., Neurosurgery 1987
    • neurologic condition at discharge
    • EOR Improve Same Worse
    • Partial 0% 60% 40%
    • Near GT 30% 70% 0%
    • GT 41% 55% 4%
relieve mass effect17
Relieve mass effect
  • Sawaya et al., Neurosurgery 1998
    • 30% of all patients had improved KPS after resection
    • 8% had decreased KPS
    • % “major neurologic complications”:
    • Partial 12%
    • Subtotal 15%
    • Total 7%
relieve mass effect18
Relieve mass effect
  • Fadul et al., Neurology 1988
    • Neurologic deterioration
    • (1 week postop)
    • Bx 29%
    • Partial 39%
    • Subtotal 30%
    • Total 20%
    • most hemorrhages and herniations occurred after bx or partial resection
3 setting up postoperative therapies
3. “Setting up” postoperative therapies
  • Is response to postoperative adjuvant radiation in newly-diagnosed glioblastoma improved by prior resection?

Neurosurgery 49:1288, 2001

response to radiation after surgery
Response to radiation after surgery
  • 301 GM pts treated using two prospective UCSF clinical protocols
  • age, KPS, extent of resection, radiation response recorded prospectively
  • radiation response assessed by imaging criteria (postop image compared with post-XRT image)
results
Results
  • More extensive surgical resection predicted better imaging-assessed response to postoperative adjuvant radiation in both univariate and multivariate analyses (adjusted for age, KPS)
setting up postoperative therapies
“Setting up” postoperative therapies
  • Resection and TMZ – EORTC 26981 (Stupp)
  • 2-year survival median survival
  • +TMZ -TMZ +TMZ -TMZ
  • GTR 37% 14% 18m 14m
  • STR 23% 9% 14m 12m
  • Bx 10% 5% 9m 8m

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

setting up postoperative therapies24
“Setting up” postoperative therapies
  • Keles et al. J Neurosurg 2004
  • 119 pts with recurrent GM
  • Reoperation -> TMZ
  • Volume of disease at start of chemotherapy was a significant predictor of time to progression and survival (progression risk doubled for 10-15cc residual mass c/w GTR, quadrupled for >15 cc)
4 prolong survival
4. Prolong survival
  • Cushing believed that resection extended survival in malignant gliomas but recognized shorter and shorter intervals between operation as the disease progressed – “ideally all should be operative mortalities”
  • McKenzie first to replace bone flap after resection to limit prognosis, but generally benefit of resection was not questioned
4 prolong survival27
4. Prolong survival

Nazzaro and Neuwelt, 1990

Reviewed neurosurgical literature 1940 - 1990 (184 refs)

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

nazzaro and neuwelt 1990
Nazzaro and Neuwelt, 1990
  • Failure to adjust for other prognostic factors such as age
  • Failure to adjust for difference in postop treatments*
  • Failure to use “any form of statistical analysis”
  • All studies had retrospective design
  • Failure to adjust for resectability
  • *logical fallacy – resection does influence chance of tolerating XRT as well as chance of reoperation
prolong survival
Prolong survival
  • Considering the more than 30 years of experience and apparent failure, does it not seem that the ostensible myth of the benefit of cytoreduction for the “isolated sake of cytoreduction” needs to placed on the intellectual scrap heap?
    • -- Michael L.J. Apuzzo
prolong survival30
Prolong survival
  • Many multivariate analyses of survival after resection of GM (nonrandomized) now provide evidence that extent of resection is an independent prognostic factor for survival (independent of age and KPS)
prolong survival31
Prolong survival
  • Laws et al., JNS 2003 (GO project)
  • 788 patients (1997-2001)
  • Resection was favorable prognostic factor (compared to biopsy) after correction for age, KPS, and after omission of patients with multifocal disease
survival in gm stratified by extent of resection nonrandomized
Survival in GMstratified byextent of resection(nonrandomized)

1.0

0.8

p < 0.001

0.6

Proportion surviving

GTR

0.4

STR

0.2

Bx

0.0

0.0

0.5

1.0

1.5

2.0

Years after diagnosis

Barker et al. (UCSF), JNS 1996

survival in gm stratified by extent of resection nonrandomized33
Survival in GM stratified by extent of resection(nonrandomized)

Extent of MST 1-yr 2-yr 5-yr

resection (months)

Gross total 17 72% 31% 12%

Subtotal 11 47% 15% 2%

Biopsy 7 23% 2% 0%

Barker et al. (UCSF), JNS 1996

survival after biopsy or resection of supratentorial lobar glioblastoma a population based study

Survival after biopsy or resection of supratentorial lobar glioblastoma: a population-based study

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.

Neurosurgical Service

Massachusetts General Hospital

Harvard Medical School

results35

11,134 glioblastoma patients diagnosed 1988 to 2001

11,108 intracranial tumors

7,423 supratentorial lobar tumors

6021tumors did not cross the midline or tentorial notch,

had not spread outside brain, through CSF or to spine, had no

contraindications to surgery, and had a surgical procedure specified

(size known for 3520 tumors)

Results
results36
Results
  • Factors predicting biopsy over resection:
  • Older age (odds ratio 1.38 per decade)
  • Smaller tumor size (odds ratio 0.84 per cm)
  • Tumor location (parietal – highest chance of biopsy, temporal lowest)
  • Histology (glioblastoma – highest chance of biopsy, giant cell glioblastoma lowest)
  • Unmarried status
  • SEER registry
probability of biopsy rather than resection relation to age and tumor size
Probability of biopsy rather than resection:Relation to age and tumor size

Prob (biopsy)

Tumor size (mm)

Age

results survival
Results: survival

1.0

RESECTION

BIOPSY

0.8

0.6

Survival

0.4

0.2

All pts had

postop XRT

0.0

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Years after diagnosis

Median survival – 12 months for resection

7 months for biopsy

results39
Results
  • Biopsy rates vary by SEER registry:

13%

12%

22%

13%

15%

4%

22%

15%

23%

27%

15%

probability of xrt vs tumor size for biopsied resected patients

Probability of XRT vs. tumor sizefor biopsied & resected patients

90%

85%

80%

Resection

Probability of postop XRT

75%

70%

Biopsy

65%

60%

0

20

40

60

80

Tumor size (mm)

survival rates and patterns
Survival Rates and Patterns

Cancer 2006;106:1358

prolong survival subgroups
Prolong survival - subgroups
  • Do all glioblastoma patients benefit equally from extensive resection?
  • Potentially important subgroups:
  • patients with mass effect
  • younger patients
mass effect and gm resection
Mass effect and GM resection
  • Kreth et al., Cancer 1999
  • Stereo bx+XRT c/w resection+XRT
  • 225 patients, supratentorial GM
  • Tumor resection effective only in group with midline shift (P < 0.01)
age and gm resection
Age and GM resection

1.0

GTR

Survival in GM

stratified by

extent of resection

0.8

0.6

Proportion surviving

STR

Age 16 to 39

N = 47

p = 0.01

0.4

Bx

0.2

0.0

0.0

0.5

1.0

1.5

2.0

Years after diagnosis

survival in gm stratified by extent of resection
Survival in GMstratified byextent of resection

1.0

0.8

Age 40 to 49

N = 58

p = 0.01

0.6

GTR

Proportion surviving

0.4

STR

0.2

Bx

0.0

0.0

0.5

1.0

1.5

2.0

Years after diagnosis

survival in gm stratified by extent of resection47
Survival in GMstratified byextent of resection

1.0

0.8

Age 50 to 64

N = 114

p = 0.12

0.6

Proportion surviving

0.4

GTR

0.2

STR

Bx

0.0

0.0

0.5

1.0

1.5

2.0

Years after diagnosis

survival in gm stratified by extent of resection48
Survival in GMstratified byextent of resection

1.0

0.8

Age 65 to 79

N = 80

p = 0.04

0.6

Proportion surviving

0.4

GTR

STR

0.2

Bx

0.0

0.0

0.5

1.0

1.5

2.0

Years after diagnosis

survival after gm resection subgroups
Survival after GM resection: subgroups

Source: Aghi et al, unpub (SEER)

nonrandomized trials
Nonrandomized trials
  • Most trials in neurosurgery are not randomized
  • Some topics can only be studied using nonrandomized methods (such as volume-outcome relationship)
  • Recent studies have shown that when nonrandomized trials use concurrent controls eligible for the experimental treatment, results are often reasonably similar to randomized trial results
graph52

Graph

Solid: nonrandomized

rct of resection for glioma
RCT of resection for glioma
  • Design of RCT for resection in glioma
  • Enrollment and randomization based on imaging diagnosis (sometimes bx is required in non-resected group)
  • All tumors must be considered resectable
  • Postop deaths and severe morbidities should not be excluded (i.e. no loss to followup based on results of surgery)
loss to followup
Loss to followup
  • Of 28 malignant glioma trials included in NS review paper, 24 were either cooperative group trials (with explicit performance status criteria) or single-center trials (often with frank exclusion of poor results)
  • 15/24 showed benefit of EOR – compared with 1 of 4 population based studies
better study design 1 rct
Better Study Design #1 - RCT
  • Only RCT of resection for malignant glioma: Vuorinen et al, Acta Nchir 2003
  • Age > 65, KPS > 60
  • 30 pts randomized; 10/14 had resection (refusal, hematoma, lymphoma, infarct), 13/16 had biopsy (met x 2, hematoma)
  • 9/10 resected pts, 10/13 biopsied pts started XRT (remainder: poor clinical condition)
malignant glioma resection survival
Malignant glioma resection - survival

P = 0.035

Hazard ratio 2.7

Favors resection

Vuorinen, Acta Neurochir 2003

malignant glioma resection time to failure
Malignant glioma resection – time to failure

P = 0.057

Favors resection

Vuorinen, Acta Neurochir 2003

slide58
RCT
  • RCT of bx vs resection for elderly with presumed malignant glioma was supposed to open in France in 2007
adjustment for resectability
Adjustment for resectability
  • While many nonrandomized studies of EOR in glioma have included “adjustment for location”, none have included adjustment for resectability

Barker et al., JNS 96

resectability
Resectability
  • In fact, resectability is a complex concept that is a frequent subject of disagreement between surgeons
  • Factors influencing rates of resection include pt-related (age, KPS, marital status); tumor-related (size, location, fuzziness of borders) and provider-related (specialist status, volume of practice, training and experience, economic and professional incentives)
  • Resectable and nonresectable tumors may well have different molecular pathology
resectability in glioma
Resectability in glioma
  • Two published attempts at defining a scale of resectability in gliomas
  • Vorster and Barnett (Nsurg Focus 98)
  • Eloquent / noneloquent
  • Eloquent areas: sensorimotor, visual, language cortices, internal capsule, basal ganglia
better study design 2
Better study design – # 2
  • Nonrandomized study in which all tumors were eligible for resection, but heterogeneity of surgeons’ practices pseudorandomizes patients to bx/resection (or STR/GTR)
  • Propensity score for balancing (as in Barker Nsurg 98)
an example shaw et al
An example – Shaw et al.
  • RTOG 9802 – surgeon-determined GTR of LGG, then observed (single-arm phase II trial)
  • 111 pts entered 1998-2002
rtog 9802
RTOG 9802
  • PFS
  • < 1 cm residual (59%) 74%
  • 1 – 2 cm residual (32%) 32%
  • > 2 cm residual (9%) 11%
  • 82% relapsed <2cm from resection cavity; 2% distant

Shaw et al., JNS in revision 2008

better study design 3
Better Study Design #3
  • While it may be difficult to randomize pts between biopsy and resection, at least two RCTs of surgical adjuncts to improve EOR have been completed and reported
  • For an effective adjunct (with no indempendent treatment effect) this would in effect randomize between different EORs
  • Neuronavigation trial was negative (Willems JNS 104:360, 2006)
prolonging survival
Prolonging survival
  • Stummer et al. RCT of fluorescence-guided GM resection
  • Pts for resection of presumed GM randomized to optimal white-light resection or fluorescence-guided (5-ALA)
  • 5-ALA group had 65% GTR c/w 36% for WL group
  • 6-mo PFS doubled in 5-ALA group (41% vs. 21%)

Stummer et al., Lancet Oncol 2006

malignant glioma resection pfs
Malignant glioma resection - PFS

65% GTR 5-ALA

vs 36% GTR WL

Stummer et al., Lancet Oncol 2006

prolonging survival71
Prolonging survival
  • Could an unexpected photodynamic treatment effect of 5-ALA at low light intensity account for results?
  • Unpublished subgroup analyses – no difference in survival between groups after GTR; minimal improvement in PFS in STR group with 5-ALA
  • Suggests benefits are a direct result of improved resection

Stummer et al., Lancet Oncol 2006

balance against risk
Balance against risk
  • Apples-oranges problem
  • Common coin – KPS as prognostic factor for survival
  • GTR/STR or STR/bx difference roughly worth ~10 to 30 KPS points
outcome vs age s p resection of primary brain tumor

Outcome vs. ages/p resection of primary brain tumor

0.5

Univariate

P < 0.001

0.4

0.3

Probability

0.2

0.1

0.0

30

40

50

60

70

80

Age

Barker et al., NeuroOnc 2005

conclusions
Conclusions
  • Surgical resection is an independent prognostic factor for survival in GM and LGG in nonrandomized trials
  • Whether this would persist after adjustment for resectability has been controversial; single RCT now available with confirmatory results
  • Burden of proof increasingly rests on nihilists; no likelihood of new LGG randomized trial anytime soon, new trial in MG is possibly in planning stages
reoperation
Reoperation
  • Who benefits from reoperation in glioblastoma?
reoperation for gm selection factors
Reoperation for GM: selection factors

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

age < 40 34%

  • p = 0.02 40-60 23%
  • 60+ 11%
  • extent of initial surgery GTR 32%
  • p = 0.02 STR 22%
  • Bx 4%
reoperation for gm relieving symptoms
Reoperation for GM: relieving symptoms
  • KPS after second resection:
  • 28% improved
  • 49% stable
  • 23% declined (by 10-30 points)
  • more likely benefit when recurrence was symptomatic
reoperation for gm comparison to unoperated patients
Reoperation for GM: comparison to unoperated patients
  • Median survival after first failure (KPS known)
  • reoperated (36 pts) 41 wk
  • not reoperated (136 pts) 23 wk
  • univariate hazard ratio 0.71 p = 0.036
  • Coxmv hazard ratio 0.66 p = 0.08
  • after adj for age, KPS at failure
  • extent of initial resection & interval until failure: NS
survival after first relapse
Survival after first relapse

Reoperation

No reoperation

reoperation for gm survival benefit
Reoperation for GM: survival benefit
  • Cox simulation for “typical” patient
  • 55 years old
  • KPS at recurrence of 80
  • initial resection STR or GTR
  • recurrence at/near original tumor site
  • predicted difference in median survival between reoperated and nonreoperated groups:8 weeks

Barker et al. (UCSF), NS 1998

4 prolong survival83
4. Prolong survival
  • Kowalczuk et al., Neurosurg 1997
  • 75 patients with malignant gliomas
  • significant: age, KPS, tumor grade, complications within 30 days after surgery, XRT dose administered
  • not significant: 17 other factors, including extent of resection (volumetric analysis)