Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias.
OBJECTIVE
The influence of the degree of resection on survival in patients with glioblastoma multiforme is still under discussion. The highly controlled 5-aminolevulinic acid study provided a unique platform for addressing this question as a result of the high frequency of "complete" resections, as revealed by postoperative magnetic resonance imaging scans achieved by fluorescence-guided resection and homogeneous patient characteristics.


METHODS
Two hundred forty-three patients with glioblastoma multiforme per protocol from the 5-aminolevulinic acid study were analyzed. Patients with complete and incomplete resections as revealed by early magnetic resonance imaging scans were compared. Prognostic factors that might cause bias regarding resection and influence survival (e.g., tumor size, edema, midline shift, location, age, Karnofsky Performance Scale score, National Institutes of Health Stroke Scale score) were used for analysis of overall survival. Time to reintervention (chemotherapy, reoperation) was analyzed further to exclude bias regarding second-line therapies.


RESULTS
Treatment bias was identified in patients with complete (n = 122) compared with incomplete resection (n = 121), i.e., younger age and less frequent eloquent tumor location. Other factors, foremost preoperative tumor size, were identical. Patients without residual tumor survived longer (16.7 versus 11.8 mo, P < 0.0001). In multivariate analysis, only residual tumor, age, and Karnofsky Performance Scale score were significantly prognostic. To account for distribution bias, patients were stratified for age (>60 or <or=60 yr) and eloquent location. Survival advantages from complete resection remained significant within subgroups, and age/eloquent location were no longer unevenly distributed. Reinterventions occurred marginally earlier in patients with residual tumor (6.7 versus 9.5 mo, P = 0.0582).


CONCLUSIONS
Treatment bias was demonstrated regarding resection and second-line therapies. However, bias and imbalances were controllable in the cohorts available from the 5-aminolevulinic acid study so that the present data now provide Level 2b evidence (Oxford Centre for Evidence-based Medicine) that survival depends on complete resection of enhancing tumor in glioblastoma multiforme.
Stummer
Walter
W
Neurochirurgische Klinik, Heinrich-Heine-Universität, Düsseldorf, Germany. stummer@uni-duesseldorf.de
Reulen
Hanns-Jürgen
HJ
Meinel
Thomas
T
Pichlmeier
Uwe
U
Schumacher
Wiebke
W
Tonn
Jörg-Christian
JC
Rohde
Veit
V
Oppel
Falk
F
Turowski
Bernd
B
Woiciechowsky
Christian
C
Franz
Kea
K
Pietsch
Torsten
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D015982:Bias; D001932:Brain Neoplasms / Q000401:mortality* / Q000601:surgery*; D018572:Disease-Free Survival; D005260:Female; D005858:Germany / Q000453:epidemiology; D005909:Glioblastoma / Q000401:mortality* / Q000601:surgery*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality* / Q000517:prevention & control; D015995:Prevalence; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D015996:Survival Rate; D016896:Treatment Outcome