Transcript 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
GTR vs biopsy?
Debulking vs biopsy?
GTR vs. near-GTR?
GTR vs. GTR plus margin of
“normal” tissue (lobectomy)?
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
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
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
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 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 diagnosis
Stereotactic bx: grade 2; resection grade 3
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 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Aghi et al., unpublished MGH data (grade 2)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Carter et al., unpublished SEER data (grade 2)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
1.0
100%
0.8
p < 0.001
0.6
60%
Astro
0.4
Probability
40%
0.2
Oligo
20%
Oligoastro
0.0
Probability
80%
0%
1985
1985
1990
1990
1995
1995
YearYear
of of
diagnosis
diagnosis
2000
2000
SEER data;
Carter BS et al unpublished
Probability of oligo-containing histology
vs. literature on chemo for oligos
0.4
0.3
SEER % oligos
0.2
30%
Probability
20%
10
0.2
0.1
PubMed # articles
on chemo for oligos
10%
0.0
Probability of oligo diagnosis
20
0.4
0.00
0%
1985
1985
1990
1990
1995
1995
YearYear
of of
diagnosis
diagnosis
Number of articles on chemo for oligos
40%
2000
2000
SEER, PubMed data;
Carter BS et al unpublished
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 diagnosis
MR spectroscopy can
assist in choosing a
biopsy target
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
Ciric et al., Neurosurgery 1987
neurologic condition at discharge
EOR
Improve
Same
Worse
Partial
Near GT
GT
0%
30%
41%
60%
70%
55%
40%
0%
4%
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 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
Is response to postoperative
adjuvant radiation in newlydiagnosed glioblastoma improved
by prior resection?
Neurosurgery 49:1288, 2001
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
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
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]
Subset Analysis –
Overall Survival
“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
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
Review Article
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
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
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 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 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
Proportion surviving
1.0
Survival in GM
stratified by
extent of resection
(nonrandomized)
0.8
p < 0.001
0.6
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
(nonrandomized)
Extent of
resection
MST
(months)
1-yr
2-yr
5-yr
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
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
Results
11,134 glioblastoma patients diagnosed 1988 to 2001
11,108 intracranial tumors
7,423 supratentorial lobar tumors
6021 tumors 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
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
0
0.1
Prob(bx)
0.2 0.3
0.4
0.5
Probability of biopsy rather than resection:
Relation to age and tumor size
80
60
Tu
mo
rs
80
40
ize
60
(m
m)
20
40
20
Age
0.0 0.2 0.4 0.6 0.8 1.0
Survival
Results: survival
0.0
RESECTION
BIOPSY
All pts had
postop XRT
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
Results
Biopsy rates vary by SEER registry:
13%
12%
15%
22%
15%
22%
13%
4%
23%
27%
15%
0.90
Probability of XRT vs. tumor size
for biopsied & resected patients
0.85
0.80
85%
Probability of radiation
80%
0.75
Resection
0.70
75%
70%
0.65
Biopsy
65%
0.60
Probability of postop XRT
90%
60%
00
20
20
40
40
Tumor size
(mm) (mm)
Tumor
size
60
60
80
80
Survival Rates and Patterns
Cancer 2006;106:1358
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
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)
Graph
Age and GM resection
1.0
GTR
Proportion surviving
0.8
Survival in GM
stratified by
extent of resection
0.6
STR
0.4
Bx
0.2
0.0
0.0
0.5
1.0
1.5
Years after diagnosis
2.0
Age 16 to 39
N = 47
p = 0.01
1.0
Survival in GM
stratified by
extent of resection
Proportion surviving
0.8
Age 40 to 49
N = 58
p = 0.01
0.6
GTR
0.4
STR
0.2
Bx
0.0
0.0
0.5
1.0
1.5
Years after diagnosis
2.0
1.0
Survival in GM
stratified by
extent of resection
Proportion surviving
0.8
Age 50 to 64
N = 114
p = 0.12
0.6
0.4
GTR
0.2
STR
Bx
0.0
0.0
0.5
1.0
1.5
Years after diagnosis
2.0
1.0
Survival in GM
stratified by
extent of resection
Proportion surviving
0.8
Age 65 to 79
N = 80
p = 0.04
0.6
0.4
GTR
STR
0.2
Bx
0.0
0.0
0.5
1.0
1.5
Years after diagnosis
2.0
Survival after GM resection:
subgroups
Subgroup
Age ≤ 40
Hazard ratio
biopsy vs. resection
1.97
Age > 40
1.66
Size < 3 cm
1.54
Size 3-5 cm
1.72
Size > 5 cm
1.73
Source: Aghi et al, unpub (SEER)
Grade II astro / oligo / oligoastro
Surgery
Total N = 599
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
Solid: nonrandomized
Graph
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
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
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
P = 0.035
Hazard ratio 2.7
Favors resection
Vuorinen, Acta Neurochir 2003
Malignant glioma resection – time to failure
P = 0.057
Favors resection
Vuorinen, Acta Neurochir 2003
RCT
RCT of bx vs resection for elderly
with presumed malignant glioma
was supposed to open in France
in 2007
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
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); tumorrelated (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
Publication
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
Resectability in glioma
Sawaya Nsurg 98
Resectability in glioma
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.
RTOG 9802 – surgeon-determined
GTR of LGG, then observed
(single-arm phase II trial)
111 pts entered 1998-2002
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
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
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
65% GTR 5-ALA
vs 36% GTR WL
Stummer et al., Lancet Oncol 2006
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
Apples-oranges problem
Common coin – KPS as prognostic
factor for survival
GTR/STR or STR/bx difference
roughly worth ~10 to 30 KPS
points
Table
Outcome vs. age
s/p resection of primary brain tumor
0.5
0.5
0.4
Death + LTF + STF
Death + LTF
Death
0.3
0.2
0.3
0.1
0.2
0.1
0.0
Probability
0.4
Probability
Univariate
P < 0.001
0.0
30
30
40
40
60
60
50
50
70
70
80
80
Age
Age
Barker et al., NeuroOnc 2005
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
Logo
Reoperation
Who benefits from reoperation in
glioblastoma?
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
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
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
Cox mv
p = 0.08
hazard ratio 0.66
after adj for age, KPS at failure
extent of initial resection & interval until failure: NS
Survival after first relapse
Reoperation
No reoperation
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 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)