Ann Surg Oncol DOI 10.1245/s10434-014-3793-4
ORIGINAL ARTICLE – NEURO-ONCOLOGY
Preoperative Prognostic Neurologic Index for Glioblastoma Patients Receiving Tumor Resection Hsiang-Kuang Liang, MD1,2, Chun-Wei Wang, MD, PhD1, Han-Min Tseng, MD2, Chao-Yuan Huang, MD, PhD1, Keng-Hsueh Lan, MD, PhD1, Yu-Hsuan Chen, MD1, San-Lin You, PhD5, Jason Chia-Hsien Cheng, MD, PhD1,3,4, Ann-Lii Cheng, MD, PhD3,4, and Sung-Hsin Kuo, MD, PhD1,3,4 1
Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; 2Department of Neurology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; 3Cancer Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; 4Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; 5Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan
ABSTRACT Background. Neurologic status is one of the major prognostic factors in glioblastoma patients; however, no consensus exists on a clinical index for predicting patient outcomes. The purpose of this study was to evaluate the correlation between neurologic deficits and clinical outcomes in glioblastoma patients, and to develop a prognostic neurologic index for identifying patients with poor outcomes. Methods. Patients receiving tumor resection with pathologically confirmed glioblastoma were retrospectively evaluated. The patients’ preoperative neurologic deficits were categorized, and patients with poor overall survival (OS) were identified. Other common prognostic factors, including age, performance, imaging findings, and extent of resection, were analyzed. Results. We evaluated 162 glioblastoma patients receiving tumor resection between February 2000 and December 2011, of whom 54 received adjuvant radiotherapy (RT) alone and 84 received concurrent chemo-RT with temozolomide. At a median follow-up of 57.6 (range 26.3–
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3793-4) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 23 February 2014 S.-H. Kuo, MD, PhD e-mail: [email protected]
88.9) months, 26 patients had survived without loss to follow-up. We defined adverse neurologic status by using an index of combined increased intracranial pressure (IICP) and non-IICP signs. In univariate analysis, the median OS of patients with and without adverse neurologic status were 9.6 and 18.7 months, respectively (p \ 0.001). In multivariate analyses, adverse neurologic status remained significantly associated with poor OS (hazard ratio 2.18, 95 % confidence interval 1.54–3.10). Conclusions. Our proposed neurologic index enables significantly identifying glioblastoma patients receiving tumor resection with poor outcomes, independent of other common prognostic factors. Using the index provides a preoperative predictor of prognosis in glioblastoma patients receiving tumor resection.
Glioblastoma is the most common primary brain tumor in adults. The histological features of glioblastoma are increased cellularity, nuclear atypia, mitotic activity, microvascular proliferation, and necrosis.1 Typical image findings include necrosis in central areas and extensive peritumoral edema.2 Before the development of temozolomide, surgical resection followed by radiotherapy (RT) was primarily provided to glioblastoma patients and resulted in longer overall survival (OS) in comparison with resection without RT.3 After temozolomide development, surgical resection followed by concurrent chemo-RT (CCRT) with temozolomide became the standard treatment for glioblastoma. In Taiwan, 210–250 glioblastoma cases occur annually, accounting for approximately 40 % of
H.-K. Liang et al.
adult primary brain tumors; the male-to-female ratio of incidence is approximately 1.3–1.5.4–6 In January 2008, the Taiwan National Health Insurance program began to cover the costs of temozolomide, which enabled nearly all glioblastoma patients nationwide to receive adjuvant or definitive CCRT with temozolomide. Neurologic status is a major prognostic factor in glioblastoma patients, although the clinical outcomes of glioblastoma patients are diverse and multifactorial. Before the development of temozolomide, the Radiation Therapy Oncology Group (RTOG) developed a recursive partitioning analysis (RPA) class score for estimating the survival of glioblastoma patients as 17.9, 11.1, 8.9, and 4.6 months for classes III–VI, respectively.7 A simplified model was later applied to the updated RTOG glioblastoma database. The simplified RTOG RPA class system, which considers age, Karnofsky performance status (KPS), neurologic function, and extent of resection or biopsy, contains three classes with median survival times of 17.1, 11.2, and 7.5 months for RPA classes III–V, respectively.8 After the development of temozolomide, the median survival times and 2-year survival rates of glioblastoma patients increased to 13.4–16 months and 26.5–31 %, respectively.9–11 The modified RPA class of the European Organisation for Research and Treatment of Cancer (EORTC) Group considers age, World Health Organization performance status, mini-mental status examination (MMSE), and extent of resection or biopsy for significantly predicting the prognosis of glioblastoma patients receiving RT with or without temozolomide.12 Although both the RTOG and EORTC use age, performance, neurologic function, and extent of tumor excision as prognostic variables in glioblastoma patients, the measures of neurologic function in both class systems differ.8,12 In the RTOG class, the index of ability to work corresponds to general performance. In the EORTC class, the MMSE score represents the mental status. Individually, the neurologic index of the ability to work and MMSE are insufficient to reflect the neurologic status of a glioblastoma patient. Therefore, a more comprehensive and specific neurologic index is necessary for clinical evaluation. In this study, we reviewed the neurologic deficits of glioblastoma patients receiving brain tumor resection and developed a neurologic index for identifying patients with poor OS. We divided the data into various neurologic categories, excluding patients undergoing biopsy only, because their prognoses are substantially worse than those undergoing tumor resection according to published data.8,12,13 We also analyzed other common clinical prognostic factors for glioblastoma including age, performance, image findings, and extent of resection.
MATERIALS AND METHODS Eligibility Patients with pathologically confirmed glioblastoma at National Taiwan University Hospital between February 2000 and December 2011 were evaluated retrospectively. Patients receiving brain tumor resection were enrolled, and those aged \20 years or undergoing tumor biopsy only were excluded. This retrospective study was approved by Institutional Review Board of National Taiwan University Hospital. Treatment Modalities Tumor resection was classified as total and subtotal excision according to the records of neurosurgeons. RT techniques included two-dimensional RT (2D-RT), 3Dconformal RT, and intensity-modulated RT (IMRT), delivered with a 60Co machine or 6 megavoltage (6 MV) linear accelerator. RT dosage ranged from 54 to 60 Gy, in fractions of 2 Gy once per day, 5 days per week. Concurrent chemotherapy with temozolomide was administered in a daily dose of 75 mg/m2, 7 days per week, from the first to the last day of RT. After a 4-week break, patients received up to six cycles of adjuvant temozolomide for 5 of 28 days. The dose was 150 mg/m2 for the first adjuvant cycle, increasing to 200 mg/m2 at the beginning of the second cycle. The regimen was adjusted according to individual patient conditions. Neurologic Data Collection and Sorting Data on neurologic status were collected from records by neurosurgeons or neurologists before patients receiving tumor resection. The neurologic deficits were categorized into increased intracranial pressure (IICP) and non-IICP signs. IICP signs, including headache, vomiting, drowsiness, and ocular palsy, typically correlate with large tumor volume and peritumor edema or the extent of obstructive hydrocephalus. Non-IICP signs, including personality change, cognitive impairment, motor weakness, objective sensory disturbance, visual field defect, movement disorder, and bulbar and cerebellar signs, typically reflect the extent of tumor invasion to different domains of the brain. Patients with combined large tumor or peritumor edema and extensive brain invasion are generally associated with poor prognosis. On the basis of these trends, we developed an index of combined IICP and non-IICP signs to define adverse neurologic status and analyzed its correlation with OS.
Preoperative Prognostic Neurologic Index
Common Prognostic Variables Other common clinical prognostic factors, including age, performance (KPS), imaging findings, and extent of resection, were analyzed concurrently. Imaging findings, from magnetic resonance imaging or computed tomography scans, included tumor location, the number of lesions, and tumor extension. Statistical Analysis OS was calculated on the basis of the date of first histological diagnosis to the date of death. Survival was calculated by the Kaplan–Meier product-limit method. Differences in survival were compared between groups by the log-rank test. Ninety-five percent confidence intervals for survival data were calculated. The variables used for univariate and Cox regression analyses were age, adverse neurologic status, KPS, multiple brain lesions (C2 tumors) or corpus callosum invasion, and extent of tumor resection. Differences were considered significant if the two-sided p value was \0.05. RESULTS Patient Characteristics and Treatment Modalities We evaluated 171 patients with pathologically confirmed glioblastoma between February 2000 and December 2011. We enrolled 162 glioblastoma patients receiving total or subtotal brain tumor resection, of whom 24 (14.8 %) received resection alone, 54 (33.3 %) received adjuvant RT, and 84 (51.9 %) received CCRT with temozolomide. The principal causes of patients not receiving adjuvant RT or CCRT were rapid progression of disease, age [70 years, and personal decision. Nine patients undergoing biopsy only were excluded. At the final followup in July 2013, 136 (84 %) of 162 patients had died, including 22 of 24 patients in the resection-alone group, 53 of 54 patients in the adjuvant RT group, and 61 of 84 in the CCRT group. Twenty-six patients had survived without loss to follow-up, with a median follow-up time of 57.6 (range 26.3–88.9) months. The median OS of patients receiving adjuvant RT alone and adjuvant CCRT with temozolomide was 12.1 and 22 months, respectively (p \ 0.001). Table 1 lists the patient characteristics and treatment modalities. We evaluated 88 men and 74 women, with a male-to-female ratio of 1.19. One hundred four patients (64.2 %) were aged C50 years, with a median age of 55 (range 20–82) years. KPS data were available for 125 of 162 patients before RT. By using the imaging results, we identified that 156 patients (96.3 %) had tumors located in
TABLE 1 Characteristics of 162 patients Characteristics
n
%
Age (years) 20–29
5
3.1
30–39
10
6.2
40–49
43
26.5
50–59
43
26.5
60–69
33
20.4
70–80
25
15.4
80–90
3
1.9
88
54.3
74
45.7
Headache
86
53.1
Vomiting
41
25.3
Drowsiness
16
6.0
Ocular palsy
5
3.1
66
40.7
23
14.2
Sex Male Female Neurologic deficit IICP signs
Non-IICP signs Weakness of any extremity Facial palsy Dysarthria
5kk
3.1
Aphasia
32
19.8
Amnesia
22
13.6
Personality change
10
6.2
Disorientation
10
6.2
Other cognitive impairment
b
10
6.2
Visual field defect Visual accuracy defect
14 4
8.6 2.5
Gait disturbance (unrelated to motor weakness)
15
9.3
5
3.1
Cerebellar signs Objective sensory defect No neurologic deficit
3
4.8
9
5.6
KPSa
125
90
53
42.4
80
36
28.8
B70
36
28.8
Tumor location Multiple lesions or corpus callosum invasion
44
27.2
Two adjacent cerebral lobes
32
19.8
Frontal
32
19.8
Temporal
32
19.8
Parietal Cerebellum
11 6
6.8 3.7
5
3.1
24
14.8
OP ? RT
54
33.3
OP ? RT ? TMZ
84
51.9
Other Treatment modality OP
H.-K. Liang et al. TABLE 1 continued Characteristics
n
%
TABLE 2 Comparison of overall survival analysis between different neurologic indices Adverse neurologic statusa
E/N
MOS
p value
0.291
Extent of surgery Total resection Subtotal resection RT dose C60 Gy \60 Gy RT techniques
51
31.5
111
68.5
One IICP sign and one non-IICP sign
138 94
68.1
44
31.9
38
27.5
Three-dimensional conformal RT
49
35.5
IMRT
51
37.0
76/89
14.0
No
60/73
16.8
One IICP with two non-IICP signs or one non-IICP with two IICP signs
138
Two-dimensional
Yes
Yes
60/63
9.6
No
76/99
18.7
\0.001*
IICP increased intracranial pressure, E event (death), N number, MOS median overall survival (months) * Statistically significant
IICP increased intracranial pressure, IMRT intensity-modulated radiotherapy, KPS Karnofsky performance status, OP operation, RT radiotherapy, TMZ temozolomide a
KPS data were available for 125 of 162 patients before RT
b
Slow response or apraxia
supratentorial areas, and 6 patients (3.7 %) had tumors located in infratentorial areas. Forty-four patients (27.2 %) had multiple brain tumors or corpus callosum invasion. Fifty-one patients (31.5 %) received total resection, and 111 patients (68.5 %) received subtotal resection. Ninetyfour (68.1 %) of 138 patients received a radiation dose of C60 Gy, whereas 44 patients (31.9 %) received a radiation dose of \60 Gy.
a
Combined IICP signs and non-IICP signs, at least one of each sign. IICP signs: headache, vomiting, drowsiness, and ocular palsy. NonIICP signs: aphasia, amnesia, apraxia, disorientation, personality change, slow response, weakness of extremity, facial palsy, dysarthria, objective sensory impairment, visual field defect, visual accuracy defect, gait disturbance (unrelated to motor weakness), and cerebellar sign
patients without such factors, with a median OS of 9.6 and 18.7 months, respectively (p \ 0.001; Table 2). Using these results, we defined adverse neurologic status as the combination of one IICP with two non-IICP signs, or one non-IICP with two IICP signs. Table 2 provides detailed definitions of the neurologic index. Analysis of Prognostic Variables
Analysis of Neurologic Deficits and Indices All patients received basic neurologic evaluation before tumor resection by neurosurgeons or neurologists. We identified [380 preoperative neurologic deficits in 153 (94.4 %) of 162 patients. Nine patients (5.6 %) had no neurologic deficit (Table 1). Headache was the most common IICP sign (86 patients, 53.1 %), followed by vomiting (41 patients, 25.3 %). Weakness of extremities (66 patients, 40.7 %) and aphasia (32 patients, 19.8 %) were frequent non-IICP signs. Thirty patients (18.6 %) exhibited personality change, disorientation, or other cognitive impairment, such as slow response or apraxia. Fifteen patients (9.3 %) demonstrated disturbance of gait unrelated to motor weakness or cerebellar ataxia. In the majority of these patients, gait disturbance resulted from prefrontal lesion. We used different combinations of IICP and non-IICP signs to develop our neurologic index. When the index involved combining one IICP sign and one non-IICP sign, univariate analysis of the median OS provided nonsignificant results (p = 0.291; Table 2). In patients with one IICP and two non-IICP signs, or one non-IICP and two IICP signs, we observed significantly worse prognosis than in
We next analyzed factors of adverse neurologic status, defined according to our index and other common clinical prognostic variables including age, KPS, imaging findings, and extent of tumor resection. The median OS of patients with and without adverse neurologic status was 9.6 and 18.7 months, respectively (p \ 0.001; Fig. 1a). According to univariate analyses, other significant adverse prognostic factors for OS in all patients were age C50 years (p = 0.028), multiple brain lesions or corpus callosum invasion (p = 0.001), and nontotal resection (p = 0.008; Table 3). According to multivariate analyses, the significant adverse prognostic factors for OS in all patients were age C50 years (p = 0.015), adverse neurologic status (p \ 0.001), multiple brain lesions or corpus callosum invasion (p = 0.01), and nontotal resection (p = 0.011; Table 4). In the patients aged \50 years, the median OS of patients with and without adverse neurologic status was 13.7 and 23.1 months, respectively (p \ 0.001). In the patients aged C50 years, the median OS of patients with and without adverse neurologic status was 8.2 and 15.8 months, respectively (p \ 0.001). Most of our patients underwent adjuvant RT or CCRT within 4 weeks of tumor resection. To use all variables in the
Preoperative Prognostic Neurologic Index FIG. 1 Kaplan–Meier estimates of overall survival for patients with and without adverse neurologic status in different groups: a all (162) patients, b 125 patients with available Karnofsky performance status data, c 42 patients diagnosed after 2008 uniformly treated with radiotherapy and temozolomide, and d 89 patients with Karnofsky performance status C80
a
b
1.0
1.0 P < 0.001
0.8
0.6
0.4
Adverse neurologic status (-)
0.2 Adverse neurologic status (+)
Probality of Overall Survival
Probality of Overall Survival
P < 0.001
0.8
0.6
0.4 Adverse neurologic status (-)
0.2 Adverse neurologic status (+)
0.0
0.0 0.0
20.0
40.0
60.0
80.0
100.0
120.0
0.0
20.0
40.0
1.0
Probality of Overall Survival
P = 0.001
0.8
0.6
Adverse neurologic status (-)
0.4
Adverse neurologic status (+)
0.2
d
10.0
20.0
30.0
100.0
120.0
1.0
0.8
0.6
0.4
Adverse neurologic status (-)
0.2 Adverse neurologic status (+)
0.0
0.0 0.0
80.0
P = 0.001
Probality of Overall Survival
c
60.0
Months
Months
40.0
50.0
60.0
0.0
20.0
40.0
Months
60.0
80.0
100.0
120.0
Months
TABLE 3 Univariate analyses for overall survival Factors
With KPS (n = 125)a
All (n = 162) E/N
MOS
Yes
91/104
12.1
No
45/58
18.3
p value
E/N
MOS
66/79
15.6
35/46
18.0
44/47
13.1
57/78
18.8
27/31
10.6
74/94
18.0
71/85
13.6
30/40
23.2
b
After 2008 (n = 42) p value
E/N
MOSb
p value
13/23
26.5
0.957
12/19
24.1
12/14
14.1
13/28
40.2
4/7
30.4
21/35
21.7
20/32
21.7
5/10
40.2
Age C50 years 0.028*
0.156
Adverse neurologic status Yes
60/63
9.6
\0.001*
No 76/99 18.7 Multiple brain lesions or corpus callosum invasion Yes
41/45
8.2
No
95/117
17.7
0.001*
\0.001*
0.058
0.001*
0.902
Nontotal resection Yes
96/111
12.0
No
40/51
21.2
0.008*
0.019*
0.529
KPS B80* Yes
NA
65/72
12.5
No
NA
36/53
21.3
0.002*
E event (death), N number, KPS Karnofsky performance status, MOS median overall survival (months) * Statistically significant a
These patients received adjuvant radiotherapy with or without temozolomide
b
Survival time was calculated from date of initiation of radiotherapy
10/13
14.1
15/29
30.4
0.016*
H.-K. Liang et al. TABLE 4 Results of multivariate Cox proportional hazard model for poor overall survival Factors
HR
95 % CI
p value
All patients (N = 162)
of events, we included only the factors of KPS, adverse neurologic status, and age in subsequent multivariate analyses. In these patients, adverse neurologic status remained a significant adverse prognostic factor for poor OS (p = 0.008; Table 4).
Age C 50 years
1.57 1.01–2.26
Adverse neurologic status
2.18 1.54–3.10 \0.001*
Multiple brain lesions or corpus callosum invasion
1.64 1.13–2.38
0.010*
Analysis According to RTOG RPA Class and KPS
Nontotal resection
1.63 1.12–2.38
0.011*
By analyzing the 125 patients with known KPS data according to the simplified RTOG RPA class, we identified that the median OS rates of patients in RPA classes III–V were 29.8, 18.0, and 11.0 months, respectively (p = 0.002; Supplementary Fig. 1). Because KPS is a significant prognostic factor for OS, according to RTOG RPA class (age \50 years, KPS C90 or not; age C50 years, KPS C70 or not) and our analyses (KPS B80 or not), we analyzed the association between adverse neurologic status and survival in three KPS subgroups (KPS C90, 80, and B70). As shown in Supplementary Fig. 2, we demonstrated that patients without adverse neurologic status had a longer median OS than those with adverse neurologic status in subgroups of KPS C90 (p = 0.035), KPS 80 (p = 0.017), and KPS B70 (trend, p = 0.263). In the patients with KPS C80, patients without adverse neurologic status were associated with longer median OS than those with adverse neurologic status (24.1 vs. 14.9 months; p = 0.001; Fig. 1d).
With KPS (N = 125)
0.015*
a
Age C50 years
1.37 0.90–2.10
0.139
KPS B80
1.63 1.07–2.48
0.023*
Adverse neurologic status
2.01 1.34–3.04
0.001*
Multiple brain lesions or corpus callosum invasion
1.37 0.87–2.14
0.173
Nontotal resection
1.60 1.00–2.50
0.036*
After 2008 (N = 42) Age C50 years
0.90 0.40–2.02
0.791
KPS B80 Adverse neurologic status
2.07 0.87–4.96 3.12 1.34–7.25
0.102 0.008*
CI confidence interval, HR hazard ratio, N number, KPS Karnofsky performance status * Statistically significant a
These patients received adjuvant radiotherapy with or without temozolomide
analysis as baseline covariates, we calculated the survival times for these patients on the basis of the date of RT initiation rather than the date of diagnosis. The median OS for patients with and without adverse neurologic status was 13.1 and 18.8 months, respectively (p \ 0.001; Fig. 1b). According to univariate analyses, other significant adverse prognostic factors for poor OS were KPS B80 (p = 0.002) and nontotal resection (p = 0.019; Table 3). The presence of multiple brain lesions or corpus callosum invasion showed a near-significant trend for association with poor OS (p = 0.058). Age C50 years was nonsignificantly associated with poor OS (p = 0.156). According to multivariate analyses, the significant adverse prognostic factors for poor OS were adverse neurologic status (p = 0.001), KPS B80 (p = 0.023), and nontotal resection (p = 0.036; Table 4). In January 2008, the Taiwan National Health Insurance program began to cover the costs of temozolomide; therefore, all 42 patients diagnosed after that date received standard adjuvant CCRT with temozolomide. The RT dose was uniformly 60 Gy, provided in 30 fractions, and was delivered to 40 patients via the IMRT technique. The median OS of patients with and without adverse neurologic status was 14.1 and 40.2 months, respectively (p = 0.001; Fig. 1c). According to univariate analyses, the other significant adverse prognostic factor for poor OS was KPS B80 (p = 0.016; Table 3). Because of the limited number
DISCUSSION The prognosis of glioblastoma is associated with age, performance and neurologic function, tumor characteristics, and treatment-related effects (surgery, RT, and combined temozolomide).8,12 In this study, we developed an original neurologic index for defining adverse neurologic status, thus demonstrating that patients with adverse neurologic status are associated with poor OS. Age and performance are major prognostic factors in RTOG and EORTC RPA classes.8,12 In both types of RPA class, neurologic function is a prognostic factor in patients aged C50 years. Our neurologic index enables identifying poor prognosis in young and old patients. Correspondingly, Shikama et al.14 determined that treatment outcomes in patients aged [70 years is equal to those in younger patients after adjustment for RPA class, and they advised that definitive treatment should not be withheld on the basis of age alone. Although data on KPS were available in only 125 patients at the beginning of RT or CCRT, we calculated the survival times of these patients on the basis of the date of RT initiation for statistical analyses. We used KPS B80 as an adverse prognostic factor, which was comparable with KPS C90 as a favorable prognostic factor in the RTOG RPA class. Our results indicate that adverse
Preoperative Prognostic Neurologic Index
neurologic status is a significant poor prognostic factor in glioblastoma patients, independent of KPS. Surgical resection is a major treatment modality for glioblastoma. A prospective study on patients with malignant glioma demonstrated that aggressive surgery is a strong prognostic factor compared with biopsy alone (p \ 0.0001).15 Surgical resection followed by CCRT with temozolomide is the standard treatment for glioblastoma. In our study, 42 patients diagnosed after January 2008 received adjuvant CCRT using a uniform dose and RT combined with temozolomide, paid for by the National Health Insurance program. These patients were associated with less likelihood of selection bias and less diversity of treatment than those diagnosed before January 2008; however, adverse neurologic status remained a significant indicator of the patients with poor prognosis. Compared with the patients evaluated in Li et al.,8 patients with simplified RTOG RPA classes III–V were associated with longer median OS because they all received tumor excision with adjuvant RT, and the majority of the patients also received temozolomide treatment. In patients with favorable performance (KPS C90 or 80), our neurologic index could still be used to identify the patients with poor prognosis. Therefore, adverse neurologic status is a significant poor prognostic factor in patients with glioblastoma who have retained normal activity (KPS C80). Our patients with multiple brain lesions or corpus callosum invasion had a shorter median OS than did those without multiple brain lesions or corpus callosum invasion (8.2 vs. 17.7 months, respectively; p = 0.001). This result was consistent with those of previous studies, suggesting that patients with multiple brain lesions or corpus callosum invasion are associated with poor prognosis.16,17 Although such patients tend to be associated with neurologic deficits that are more severe, our results suggest that adverse neurologic status is a significant poor prognostic factor in glioblastoma patients, independent of multiple brain lesions or corpus callosum invasion. Although our study was retrospective and was limited by a small patient sample, the clinical features of our population are analogous to those in previous studies. Our neurologic index enables us to identify glioblastoma patients with poor outcomes, independent of other common prognostic factors including age, performance, or imaging findings. This study provides a new concept of integrating IICP and non-IICP signs for evaluating glioblastoma patients before their receiving tumor resection. ACKNOWLEDGMENT The authors thank the Cancer Registry, Office of Medical Records, National Taiwan University Hospital, for providing the required patient information. This study was supported by research grants from the National Science Council, Taiwan (NSC 101-2314-B-002-157-MY3) and the National Health Research Institute (NHRI-EX103-10239BI).
CONFLICT OF INTEREST interest.
The authors declare no conflict of
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ORIGINAL ARTICLE – NEURO-ONCOLOGY
Preoperative Prognostic Neurologic Index for Glioblastoma Patients Receiving Tumor Resection Hsiang-Kuang Liang, MD1,2, Chun-Wei Wang, MD, PhD1, Han-Min Tseng, MD2, Chao-Yuan Huang, MD, PhD1, Keng-Hsueh Lan, MD, PhD1, Yu-Hsuan Chen, MD1, San-Lin You, PhD5, Jason Chia-Hsien Cheng, MD, PhD1,3,4, Ann-Lii Cheng, MD, PhD3,4, and Sung-Hsin Kuo, MD, PhD1,3,4 1
Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; 2Department of Neurology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; 3Cancer Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; 4Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; 5Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan
ABSTRACT Background. Neurologic status is one of the major prognostic factors in glioblastoma patients; however, no consensus exists on a clinical index for predicting patient outcomes. The purpose of this study was to evaluate the correlation between neurologic deficits and clinical outcomes in glioblastoma patients, and to develop a prognostic neurologic index for identifying patients with poor outcomes. Methods. Patients receiving tumor resection with pathologically confirmed glioblastoma were retrospectively evaluated. The patients’ preoperative neurologic deficits were categorized, and patients with poor overall survival (OS) were identified. Other common prognostic factors, including age, performance, imaging findings, and extent of resection, were analyzed. Results. We evaluated 162 glioblastoma patients receiving tumor resection between February 2000 and December 2011, of whom 54 received adjuvant radiotherapy (RT) alone and 84 received concurrent chemo-RT with temozolomide. At a median follow-up of 57.6 (range 26.3–
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3793-4) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 23 February 2014 S.-H. Kuo, MD, PhD e-mail: [email protected]
88.9) months, 26 patients had survived without loss to follow-up. We defined adverse neurologic status by using an index of combined increased intracranial pressure (IICP) and non-IICP signs. In univariate analysis, the median OS of patients with and without adverse neurologic status were 9.6 and 18.7 months, respectively (p \ 0.001). In multivariate analyses, adverse neurologic status remained significantly associated with poor OS (hazard ratio 2.18, 95 % confidence interval 1.54–3.10). Conclusions. Our proposed neurologic index enables significantly identifying glioblastoma patients receiving tumor resection with poor outcomes, independent of other common prognostic factors. Using the index provides a preoperative predictor of prognosis in glioblastoma patients receiving tumor resection.
Glioblastoma is the most common primary brain tumor in adults. The histological features of glioblastoma are increased cellularity, nuclear atypia, mitotic activity, microvascular proliferation, and necrosis.1 Typical image findings include necrosis in central areas and extensive peritumoral edema.2 Before the development of temozolomide, surgical resection followed by radiotherapy (RT) was primarily provided to glioblastoma patients and resulted in longer overall survival (OS) in comparison with resection without RT.3 After temozolomide development, surgical resection followed by concurrent chemo-RT (CCRT) with temozolomide became the standard treatment for glioblastoma. In Taiwan, 210–250 glioblastoma cases occur annually, accounting for approximately 40 % of
H.-K. Liang et al.
adult primary brain tumors; the male-to-female ratio of incidence is approximately 1.3–1.5.4–6 In January 2008, the Taiwan National Health Insurance program began to cover the costs of temozolomide, which enabled nearly all glioblastoma patients nationwide to receive adjuvant or definitive CCRT with temozolomide. Neurologic status is a major prognostic factor in glioblastoma patients, although the clinical outcomes of glioblastoma patients are diverse and multifactorial. Before the development of temozolomide, the Radiation Therapy Oncology Group (RTOG) developed a recursive partitioning analysis (RPA) class score for estimating the survival of glioblastoma patients as 17.9, 11.1, 8.9, and 4.6 months for classes III–VI, respectively.7 A simplified model was later applied to the updated RTOG glioblastoma database. The simplified RTOG RPA class system, which considers age, Karnofsky performance status (KPS), neurologic function, and extent of resection or biopsy, contains three classes with median survival times of 17.1, 11.2, and 7.5 months for RPA classes III–V, respectively.8 After the development of temozolomide, the median survival times and 2-year survival rates of glioblastoma patients increased to 13.4–16 months and 26.5–31 %, respectively.9–11 The modified RPA class of the European Organisation for Research and Treatment of Cancer (EORTC) Group considers age, World Health Organization performance status, mini-mental status examination (MMSE), and extent of resection or biopsy for significantly predicting the prognosis of glioblastoma patients receiving RT with or without temozolomide.12 Although both the RTOG and EORTC use age, performance, neurologic function, and extent of tumor excision as prognostic variables in glioblastoma patients, the measures of neurologic function in both class systems differ.8,12 In the RTOG class, the index of ability to work corresponds to general performance. In the EORTC class, the MMSE score represents the mental status. Individually, the neurologic index of the ability to work and MMSE are insufficient to reflect the neurologic status of a glioblastoma patient. Therefore, a more comprehensive and specific neurologic index is necessary for clinical evaluation. In this study, we reviewed the neurologic deficits of glioblastoma patients receiving brain tumor resection and developed a neurologic index for identifying patients with poor OS. We divided the data into various neurologic categories, excluding patients undergoing biopsy only, because their prognoses are substantially worse than those undergoing tumor resection according to published data.8,12,13 We also analyzed other common clinical prognostic factors for glioblastoma including age, performance, image findings, and extent of resection.
MATERIALS AND METHODS Eligibility Patients with pathologically confirmed glioblastoma at National Taiwan University Hospital between February 2000 and December 2011 were evaluated retrospectively. Patients receiving brain tumor resection were enrolled, and those aged \20 years or undergoing tumor biopsy only were excluded. This retrospective study was approved by Institutional Review Board of National Taiwan University Hospital. Treatment Modalities Tumor resection was classified as total and subtotal excision according to the records of neurosurgeons. RT techniques included two-dimensional RT (2D-RT), 3Dconformal RT, and intensity-modulated RT (IMRT), delivered with a 60Co machine or 6 megavoltage (6 MV) linear accelerator. RT dosage ranged from 54 to 60 Gy, in fractions of 2 Gy once per day, 5 days per week. Concurrent chemotherapy with temozolomide was administered in a daily dose of 75 mg/m2, 7 days per week, from the first to the last day of RT. After a 4-week break, patients received up to six cycles of adjuvant temozolomide for 5 of 28 days. The dose was 150 mg/m2 for the first adjuvant cycle, increasing to 200 mg/m2 at the beginning of the second cycle. The regimen was adjusted according to individual patient conditions. Neurologic Data Collection and Sorting Data on neurologic status were collected from records by neurosurgeons or neurologists before patients receiving tumor resection. The neurologic deficits were categorized into increased intracranial pressure (IICP) and non-IICP signs. IICP signs, including headache, vomiting, drowsiness, and ocular palsy, typically correlate with large tumor volume and peritumor edema or the extent of obstructive hydrocephalus. Non-IICP signs, including personality change, cognitive impairment, motor weakness, objective sensory disturbance, visual field defect, movement disorder, and bulbar and cerebellar signs, typically reflect the extent of tumor invasion to different domains of the brain. Patients with combined large tumor or peritumor edema and extensive brain invasion are generally associated with poor prognosis. On the basis of these trends, we developed an index of combined IICP and non-IICP signs to define adverse neurologic status and analyzed its correlation with OS.
Preoperative Prognostic Neurologic Index
Common Prognostic Variables Other common clinical prognostic factors, including age, performance (KPS), imaging findings, and extent of resection, were analyzed concurrently. Imaging findings, from magnetic resonance imaging or computed tomography scans, included tumor location, the number of lesions, and tumor extension. Statistical Analysis OS was calculated on the basis of the date of first histological diagnosis to the date of death. Survival was calculated by the Kaplan–Meier product-limit method. Differences in survival were compared between groups by the log-rank test. Ninety-five percent confidence intervals for survival data were calculated. The variables used for univariate and Cox regression analyses were age, adverse neurologic status, KPS, multiple brain lesions (C2 tumors) or corpus callosum invasion, and extent of tumor resection. Differences were considered significant if the two-sided p value was \0.05. RESULTS Patient Characteristics and Treatment Modalities We evaluated 171 patients with pathologically confirmed glioblastoma between February 2000 and December 2011. We enrolled 162 glioblastoma patients receiving total or subtotal brain tumor resection, of whom 24 (14.8 %) received resection alone, 54 (33.3 %) received adjuvant RT, and 84 (51.9 %) received CCRT with temozolomide. The principal causes of patients not receiving adjuvant RT or CCRT were rapid progression of disease, age [70 years, and personal decision. Nine patients undergoing biopsy only were excluded. At the final followup in July 2013, 136 (84 %) of 162 patients had died, including 22 of 24 patients in the resection-alone group, 53 of 54 patients in the adjuvant RT group, and 61 of 84 in the CCRT group. Twenty-six patients had survived without loss to follow-up, with a median follow-up time of 57.6 (range 26.3–88.9) months. The median OS of patients receiving adjuvant RT alone and adjuvant CCRT with temozolomide was 12.1 and 22 months, respectively (p \ 0.001). Table 1 lists the patient characteristics and treatment modalities. We evaluated 88 men and 74 women, with a male-to-female ratio of 1.19. One hundred four patients (64.2 %) were aged C50 years, with a median age of 55 (range 20–82) years. KPS data were available for 125 of 162 patients before RT. By using the imaging results, we identified that 156 patients (96.3 %) had tumors located in
TABLE 1 Characteristics of 162 patients Characteristics
n
%
Age (years) 20–29
5
3.1
30–39
10
6.2
40–49
43
26.5
50–59
43
26.5
60–69
33
20.4
70–80
25
15.4
80–90
3
1.9
88
54.3
74
45.7
Headache
86
53.1
Vomiting
41
25.3
Drowsiness
16
6.0
Ocular palsy
5
3.1
66
40.7
23
14.2
Sex Male Female Neurologic deficit IICP signs
Non-IICP signs Weakness of any extremity Facial palsy Dysarthria
5kk
3.1
Aphasia
32
19.8
Amnesia
22
13.6
Personality change
10
6.2
Disorientation
10
6.2
Other cognitive impairment
b
10
6.2
Visual field defect Visual accuracy defect
14 4
8.6 2.5
Gait disturbance (unrelated to motor weakness)
15
9.3
5
3.1
Cerebellar signs Objective sensory defect No neurologic deficit
3
4.8
9
5.6
KPSa
125
90
53
42.4
80
36
28.8
B70
36
28.8
Tumor location Multiple lesions or corpus callosum invasion
44
27.2
Two adjacent cerebral lobes
32
19.8
Frontal
32
19.8
Temporal
32
19.8
Parietal Cerebellum
11 6
6.8 3.7
5
3.1
24
14.8
OP ? RT
54
33.3
OP ? RT ? TMZ
84
51.9
Other Treatment modality OP
H.-K. Liang et al. TABLE 1 continued Characteristics
n
%
TABLE 2 Comparison of overall survival analysis between different neurologic indices Adverse neurologic statusa
E/N
MOS
p value
0.291
Extent of surgery Total resection Subtotal resection RT dose C60 Gy \60 Gy RT techniques
51
31.5
111
68.5
One IICP sign and one non-IICP sign
138 94
68.1
44
31.9
38
27.5
Three-dimensional conformal RT
49
35.5
IMRT
51
37.0
76/89
14.0
No
60/73
16.8
One IICP with two non-IICP signs or one non-IICP with two IICP signs
138
Two-dimensional
Yes
Yes
60/63
9.6
No
76/99
18.7
\0.001*
IICP increased intracranial pressure, E event (death), N number, MOS median overall survival (months) * Statistically significant
IICP increased intracranial pressure, IMRT intensity-modulated radiotherapy, KPS Karnofsky performance status, OP operation, RT radiotherapy, TMZ temozolomide a
KPS data were available for 125 of 162 patients before RT
b
Slow response or apraxia
supratentorial areas, and 6 patients (3.7 %) had tumors located in infratentorial areas. Forty-four patients (27.2 %) had multiple brain tumors or corpus callosum invasion. Fifty-one patients (31.5 %) received total resection, and 111 patients (68.5 %) received subtotal resection. Ninetyfour (68.1 %) of 138 patients received a radiation dose of C60 Gy, whereas 44 patients (31.9 %) received a radiation dose of \60 Gy.
a
Combined IICP signs and non-IICP signs, at least one of each sign. IICP signs: headache, vomiting, drowsiness, and ocular palsy. NonIICP signs: aphasia, amnesia, apraxia, disorientation, personality change, slow response, weakness of extremity, facial palsy, dysarthria, objective sensory impairment, visual field defect, visual accuracy defect, gait disturbance (unrelated to motor weakness), and cerebellar sign
patients without such factors, with a median OS of 9.6 and 18.7 months, respectively (p \ 0.001; Table 2). Using these results, we defined adverse neurologic status as the combination of one IICP with two non-IICP signs, or one non-IICP with two IICP signs. Table 2 provides detailed definitions of the neurologic index. Analysis of Prognostic Variables
Analysis of Neurologic Deficits and Indices All patients received basic neurologic evaluation before tumor resection by neurosurgeons or neurologists. We identified [380 preoperative neurologic deficits in 153 (94.4 %) of 162 patients. Nine patients (5.6 %) had no neurologic deficit (Table 1). Headache was the most common IICP sign (86 patients, 53.1 %), followed by vomiting (41 patients, 25.3 %). Weakness of extremities (66 patients, 40.7 %) and aphasia (32 patients, 19.8 %) were frequent non-IICP signs. Thirty patients (18.6 %) exhibited personality change, disorientation, or other cognitive impairment, such as slow response or apraxia. Fifteen patients (9.3 %) demonstrated disturbance of gait unrelated to motor weakness or cerebellar ataxia. In the majority of these patients, gait disturbance resulted from prefrontal lesion. We used different combinations of IICP and non-IICP signs to develop our neurologic index. When the index involved combining one IICP sign and one non-IICP sign, univariate analysis of the median OS provided nonsignificant results (p = 0.291; Table 2). In patients with one IICP and two non-IICP signs, or one non-IICP and two IICP signs, we observed significantly worse prognosis than in
We next analyzed factors of adverse neurologic status, defined according to our index and other common clinical prognostic variables including age, KPS, imaging findings, and extent of tumor resection. The median OS of patients with and without adverse neurologic status was 9.6 and 18.7 months, respectively (p \ 0.001; Fig. 1a). According to univariate analyses, other significant adverse prognostic factors for OS in all patients were age C50 years (p = 0.028), multiple brain lesions or corpus callosum invasion (p = 0.001), and nontotal resection (p = 0.008; Table 3). According to multivariate analyses, the significant adverse prognostic factors for OS in all patients were age C50 years (p = 0.015), adverse neurologic status (p \ 0.001), multiple brain lesions or corpus callosum invasion (p = 0.01), and nontotal resection (p = 0.011; Table 4). In the patients aged \50 years, the median OS of patients with and without adverse neurologic status was 13.7 and 23.1 months, respectively (p \ 0.001). In the patients aged C50 years, the median OS of patients with and without adverse neurologic status was 8.2 and 15.8 months, respectively (p \ 0.001). Most of our patients underwent adjuvant RT or CCRT within 4 weeks of tumor resection. To use all variables in the
Preoperative Prognostic Neurologic Index FIG. 1 Kaplan–Meier estimates of overall survival for patients with and without adverse neurologic status in different groups: a all (162) patients, b 125 patients with available Karnofsky performance status data, c 42 patients diagnosed after 2008 uniformly treated with radiotherapy and temozolomide, and d 89 patients with Karnofsky performance status C80
a
b
1.0
1.0 P < 0.001
0.8
0.6
0.4
Adverse neurologic status (-)
0.2 Adverse neurologic status (+)
Probality of Overall Survival
Probality of Overall Survival
P < 0.001
0.8
0.6
0.4 Adverse neurologic status (-)
0.2 Adverse neurologic status (+)
0.0
0.0 0.0
20.0
40.0
60.0
80.0
100.0
120.0
0.0
20.0
40.0
1.0
Probality of Overall Survival
P = 0.001
0.8
0.6
Adverse neurologic status (-)
0.4
Adverse neurologic status (+)
0.2
d
10.0
20.0
30.0
100.0
120.0
1.0
0.8
0.6
0.4
Adverse neurologic status (-)
0.2 Adverse neurologic status (+)
0.0
0.0 0.0
80.0
P = 0.001
Probality of Overall Survival
c
60.0
Months
Months
40.0
50.0
60.0
0.0
20.0
40.0
Months
60.0
80.0
100.0
120.0
Months
TABLE 3 Univariate analyses for overall survival Factors
With KPS (n = 125)a
All (n = 162) E/N
MOS
Yes
91/104
12.1
No
45/58
18.3
p value
E/N
MOS
66/79
15.6
35/46
18.0
44/47
13.1
57/78
18.8
27/31
10.6
74/94
18.0
71/85
13.6
30/40
23.2
b
After 2008 (n = 42) p value
E/N
MOSb
p value
13/23
26.5
0.957
12/19
24.1
12/14
14.1
13/28
40.2
4/7
30.4
21/35
21.7
20/32
21.7
5/10
40.2
Age C50 years 0.028*
0.156
Adverse neurologic status Yes
60/63
9.6
\0.001*
No 76/99 18.7 Multiple brain lesions or corpus callosum invasion Yes
41/45
8.2
No
95/117
17.7
0.001*
\0.001*
0.058
0.001*
0.902
Nontotal resection Yes
96/111
12.0
No
40/51
21.2
0.008*
0.019*
0.529
KPS B80* Yes
NA
65/72
12.5
No
NA
36/53
21.3
0.002*
E event (death), N number, KPS Karnofsky performance status, MOS median overall survival (months) * Statistically significant a
These patients received adjuvant radiotherapy with or without temozolomide
b
Survival time was calculated from date of initiation of radiotherapy
10/13
14.1
15/29
30.4
0.016*
H.-K. Liang et al. TABLE 4 Results of multivariate Cox proportional hazard model for poor overall survival Factors
HR
95 % CI
p value
All patients (N = 162)
of events, we included only the factors of KPS, adverse neurologic status, and age in subsequent multivariate analyses. In these patients, adverse neurologic status remained a significant adverse prognostic factor for poor OS (p = 0.008; Table 4).
Age C 50 years
1.57 1.01–2.26
Adverse neurologic status
2.18 1.54–3.10 \0.001*
Multiple brain lesions or corpus callosum invasion
1.64 1.13–2.38
0.010*
Analysis According to RTOG RPA Class and KPS
Nontotal resection
1.63 1.12–2.38
0.011*
By analyzing the 125 patients with known KPS data according to the simplified RTOG RPA class, we identified that the median OS rates of patients in RPA classes III–V were 29.8, 18.0, and 11.0 months, respectively (p = 0.002; Supplementary Fig. 1). Because KPS is a significant prognostic factor for OS, according to RTOG RPA class (age \50 years, KPS C90 or not; age C50 years, KPS C70 or not) and our analyses (KPS B80 or not), we analyzed the association between adverse neurologic status and survival in three KPS subgroups (KPS C90, 80, and B70). As shown in Supplementary Fig. 2, we demonstrated that patients without adverse neurologic status had a longer median OS than those with adverse neurologic status in subgroups of KPS C90 (p = 0.035), KPS 80 (p = 0.017), and KPS B70 (trend, p = 0.263). In the patients with KPS C80, patients without adverse neurologic status were associated with longer median OS than those with adverse neurologic status (24.1 vs. 14.9 months; p = 0.001; Fig. 1d).
With KPS (N = 125)
0.015*
a
Age C50 years
1.37 0.90–2.10
0.139
KPS B80
1.63 1.07–2.48
0.023*
Adverse neurologic status
2.01 1.34–3.04
0.001*
Multiple brain lesions or corpus callosum invasion
1.37 0.87–2.14
0.173
Nontotal resection
1.60 1.00–2.50
0.036*
After 2008 (N = 42) Age C50 years
0.90 0.40–2.02
0.791
KPS B80 Adverse neurologic status
2.07 0.87–4.96 3.12 1.34–7.25
0.102 0.008*
CI confidence interval, HR hazard ratio, N number, KPS Karnofsky performance status * Statistically significant a
These patients received adjuvant radiotherapy with or without temozolomide
analysis as baseline covariates, we calculated the survival times for these patients on the basis of the date of RT initiation rather than the date of diagnosis. The median OS for patients with and without adverse neurologic status was 13.1 and 18.8 months, respectively (p \ 0.001; Fig. 1b). According to univariate analyses, other significant adverse prognostic factors for poor OS were KPS B80 (p = 0.002) and nontotal resection (p = 0.019; Table 3). The presence of multiple brain lesions or corpus callosum invasion showed a near-significant trend for association with poor OS (p = 0.058). Age C50 years was nonsignificantly associated with poor OS (p = 0.156). According to multivariate analyses, the significant adverse prognostic factors for poor OS were adverse neurologic status (p = 0.001), KPS B80 (p = 0.023), and nontotal resection (p = 0.036; Table 4). In January 2008, the Taiwan National Health Insurance program began to cover the costs of temozolomide; therefore, all 42 patients diagnosed after that date received standard adjuvant CCRT with temozolomide. The RT dose was uniformly 60 Gy, provided in 30 fractions, and was delivered to 40 patients via the IMRT technique. The median OS of patients with and without adverse neurologic status was 14.1 and 40.2 months, respectively (p = 0.001; Fig. 1c). According to univariate analyses, the other significant adverse prognostic factor for poor OS was KPS B80 (p = 0.016; Table 3). Because of the limited number
DISCUSSION The prognosis of glioblastoma is associated with age, performance and neurologic function, tumor characteristics, and treatment-related effects (surgery, RT, and combined temozolomide).8,12 In this study, we developed an original neurologic index for defining adverse neurologic status, thus demonstrating that patients with adverse neurologic status are associated with poor OS. Age and performance are major prognostic factors in RTOG and EORTC RPA classes.8,12 In both types of RPA class, neurologic function is a prognostic factor in patients aged C50 years. Our neurologic index enables identifying poor prognosis in young and old patients. Correspondingly, Shikama et al.14 determined that treatment outcomes in patients aged [70 years is equal to those in younger patients after adjustment for RPA class, and they advised that definitive treatment should not be withheld on the basis of age alone. Although data on KPS were available in only 125 patients at the beginning of RT or CCRT, we calculated the survival times of these patients on the basis of the date of RT initiation for statistical analyses. We used KPS B80 as an adverse prognostic factor, which was comparable with KPS C90 as a favorable prognostic factor in the RTOG RPA class. Our results indicate that adverse
Preoperative Prognostic Neurologic Index
neurologic status is a significant poor prognostic factor in glioblastoma patients, independent of KPS. Surgical resection is a major treatment modality for glioblastoma. A prospective study on patients with malignant glioma demonstrated that aggressive surgery is a strong prognostic factor compared with biopsy alone (p \ 0.0001).15 Surgical resection followed by CCRT with temozolomide is the standard treatment for glioblastoma. In our study, 42 patients diagnosed after January 2008 received adjuvant CCRT using a uniform dose and RT combined with temozolomide, paid for by the National Health Insurance program. These patients were associated with less likelihood of selection bias and less diversity of treatment than those diagnosed before January 2008; however, adverse neurologic status remained a significant indicator of the patients with poor prognosis. Compared with the patients evaluated in Li et al.,8 patients with simplified RTOG RPA classes III–V were associated with longer median OS because they all received tumor excision with adjuvant RT, and the majority of the patients also received temozolomide treatment. In patients with favorable performance (KPS C90 or 80), our neurologic index could still be used to identify the patients with poor prognosis. Therefore, adverse neurologic status is a significant poor prognostic factor in patients with glioblastoma who have retained normal activity (KPS C80). Our patients with multiple brain lesions or corpus callosum invasion had a shorter median OS than did those without multiple brain lesions or corpus callosum invasion (8.2 vs. 17.7 months, respectively; p = 0.001). This result was consistent with those of previous studies, suggesting that patients with multiple brain lesions or corpus callosum invasion are associated with poor prognosis.16,17 Although such patients tend to be associated with neurologic deficits that are more severe, our results suggest that adverse neurologic status is a significant poor prognostic factor in glioblastoma patients, independent of multiple brain lesions or corpus callosum invasion. Although our study was retrospective and was limited by a small patient sample, the clinical features of our population are analogous to those in previous studies. Our neurologic index enables us to identify glioblastoma patients with poor outcomes, independent of other common prognostic factors including age, performance, or imaging findings. This study provides a new concept of integrating IICP and non-IICP signs for evaluating glioblastoma patients before their receiving tumor resection. ACKNOWLEDGMENT The authors thank the Cancer Registry, Office of Medical Records, National Taiwan University Hospital, for providing the required patient information. This study was supported by research grants from the National Science Council, Taiwan (NSC 101-2314-B-002-157-MY3) and the National Health Research Institute (NHRI-EX103-10239BI).
CONFLICT OF INTEREST interest.
The authors declare no conflict of
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