Clinical characteristics and survival outcomes of secondary glioblastoma


 Background Secondary glioblastoma (sGBM) is a specific, and prognostic factors of sGBM are still unclear. This study retrospectively investigated clinical prognosis factors of survival outcomes of sGBM.Methods All of 125 patients were recruited in this study. Clinical characteristics and survival outcomes were acquired from inpatient records and follow-ups. Kaplan‑Meier survival analysis and Cox survival analysis were applied to identifying prognostic factors.Results The median overall survival (OS) were 301 days. Gross total resection (GTR) (HR = 0.613, 95% confident interval (CI) = 0.408-0.923, p = 0.019), diagnosed sGBM without newly occurring symptoms when regular re-examination (DR) (HR= 0.481, 95% CI = 0.308-0.750, p = 0.001), higher postoperative Karnofsky Performance Status (KPS) score (HR = 0.977, 95% CI = 0.961-0.993, p = 0.006) were independently favorable prognosis factors for OS. GTR was the favorable factor for OS of sGBM patients of DR (HR = 0.238, 95% CI = 0.100-0.570, p = 0.001) and with new functional impairments (HR = 0.410, 95% CI = 0.205-0.821, p = 0.012). Additionally, postoperative KPS score not decreasing was the favorable factor for OS of sGBM patients with new functional impairments (HR = 0.401, 95% CI = 0.202-0.795, p = 0.009) and with new occurring epilepsy (HR = 0.295, 95% CI from 0.092 to 0.950, p = 0.041).Conclusions For patients with sGBM, GTR, higher postoperative KPS score, and diagnosed without newly occurring symptoms were favorable factors for the OS. The GTR was recommended for sGBM patients to improve survival outcomes.

Therefore, in the current study, we enrolled more patients and analyzed more clinical characteristics, including preoperative neurological status and preoperative epileptic status, recorded in the Chinese Glioma Genome Atlas Network. The present study aimed to retrospectively investigate the clinical prognostic factors for the OS of patients with sGBM.

Ethics statement
This investigation has been conducted in accordance with the ethical standards and according to the Declaration of Helsinki and according to national and international guidelines and has been approved by local institutional review board.

Patients
We enrolled patients with sGBM who underwent secondary tumor resection at the Glioma Treatment Center at ** Hospital between March 2006 and March 2017. To avoid the in uence of different numbers of operations, only patients who underwent two tumor resections were enrolled in the present study, the rst resection for a primary low-grade glioma and the second for sGBM. The inclusion criteria were as follows: (1) those aged from 18 to 65 years at the time of tumor resection; (2) diagnosed with sGBM as a secondary diagnosis (their primary pathological diagnosis was low-grade or anaplastic glioma); (3) who had available clinical, postoperative treatment, and follow-up information from the study period. The exclusion criteria were as follows: (1) those who underwent more than two surgeries for glioma resection; (2) those who could not be contacted or refused follow-up; (3) those who underwent biopsy before the second operation.

Data collection
We retrospectively collected patient characteristics from inpatient and follow-up records, including general information (age, sex, etc.), the rst and second histopathological diagnoses, IDH status (mutation or wildtype), EOR of the second tumor resection, onset of symptoms, preoperative seizure status, preoperative neurological status, preoperative and postoperative KPS scores, and the difference between preoperative and postoperative KPS scores.
To investigate the different prognoses of patients with various newly occurring symptoms, all patients were divided into four sub-groups as follows: (1) patients with newly occurring epileptic seizures upon diagnosis with sGBM (group E); (2) patients with newly occurring functional impairments, including paralysis, aphasia, and cognitive functional impairments, upon diagnosis with sGBM (group F); (3) patients with other newly occurring symptoms, such as headache and/or vomiting, upon diagnosis with sGBM (group O); and (4) patients without any newly occurring symptoms upon diagnosis with sGBM, based on T1 contrast-enhanced magnetic resonance imaging (MRI) during follow-up (group R).

Evaluation of the EOR
The EOR was evaluated based on the preoperative and postoperative T1 contrast-enhanced MRI by a radiologist with over 25 years of glioma-diagnosis experience. The preoperative and postoperative MRI were scanned within one week prior to surgery and within 72 hours after surgery, respectively. GTR and STR were de ned as EOR greater than 90% and between 50% and 90%, respectively.

Statistical analysis
Statistical analysis was performed with SPSS (19.0 version, IBM) and GraphPad Prism 7 (GraphPad Software Inc, San Diego, USA). The Mann-Whitney U-test was used for nonparametric comparisons between two groups. Categorical comparisons between two groups were made using the Chi-square test or Fisher's exact test according to the circumstances. The log-rank test was used to evaluate the survival differences between groups after Kaplan-Meier analysis. A two-tailed p-value < 0.05 was considered statistically signi cant.

Subgroup analysis for prognostic factors for OS
To investigate the factors that affected the OS of patients with various newly occurring symptoms, we divided all recruited patients into four sub-groups based on their new symptoms upon diagnosis with sGBM (Tables 3-6).

OS outcomes for patients with various newly occurring symptoms
After using the Kaplan-Meier method, our results showed that the independent factors GTR and diagnosis without newly occurring symptoms on follow-up could discriminate the OS of patients with sGBM (Fig. 2, the Kaplan-Meier results of other factors are shown in supplemental Fig. 1). We further subdivided the patients into four sub-groups based on their various newly occurring symptoms upon diagnosis with sGBM. Using Kaplan-Meier analysis, the different OS in these four sub-groups were shown. The OS of patients in group E was signi cantly longer than that of patients in groups F and O (Fig. 3

Discussion
In the current study, we found that GTR, diagnosis without newly occurring symptoms on follow-up, and high postoperative KPS scores were independent favorable prognostic factors for OS in all patients with sGBM. In addition, other speci c clinical characteristics were found to have value for guiding tumor resection in patients with sGBM and various newly occurring symptoms.
The value of the extent of resection in sGBM GTR is essential for improving OS in patients with GBM. [13] A previous study has veri ed that reoperation was bene cial for the prognosis of patients with rGBM. [8] Several studies have supported that GTR, especially for the second operation, was an independent favorable prognostic factor for OS in patients with rGBM. [7,10,14] However, there are limited studies that focus on the relationship between extent of resection (EOR) and OS in patients with sGBM. Our results showed that GTR was also an independent factor for improved OS in patients with sGBM. This nding helped to con rm the conclusion of our previous study, [12] because the present results were generated with multivariate Cox regression analysis, which allowed us to evaluate the independency of the prognostic factors.

The value of KPS scores in patients with sGBM
Our results were consistent with those of our previous study on sGBM, [12] which reported that a high postoperative KPS score was an independent prognostic factor for the OS of patients with sGBM, whereas preoperative KPS score was not. Undoubtedly, a worsened quality of life leads to extremely poor survival outcomes. As most studies have shown, preoperative KPS score ≥ 70 was a bene cial factor for the OS of patients with rGBM. [7,[15][16][17][18] However, this result was not similar to that in the rGBM study. [7,17] We believe this is because the preoperative KPS scores of all patients in the current study were ≥ 70. Hence, preoperative KPS had no in uence on the survival outcomes in this study.

The value of regular follow-up in patients with sGBM
The concept of patients who underwent regular follow-up being diagnosed with sGBM without newly occurring symptoms is similar to that of incidental glioma, in which glioma is diagnosed without any symptoms. Our results showed that a lack of newly occurring symptoms was a favorable independent prognostic factor for OS in patients with sGBM. These ndings were consistent with those of a previous study that focused on OS in primary incidental low-grade glioma. [19] The good prognosis for incidental glioma in that study was due to the fact that these tumors were always small and easy to resect entirely.
[20] Secondary GBM without newly occurring symptoms meant that the sGBM recurred in the original location and did not invade other functional cortices or subcortical structures. Hence, these tumors were also easy to resect completely. In addition, the postoperative KPS scores did not affect the OS of patients with sGBM in group R; therefore, GTR was recommended for these patients, even if the operation would decrease their postoperative KPS. Likewise, this nding indicates that regular follow-up was necessary for patients with low-grade glioma; if a recurrent tumor is found, then reoperation should be performed in a timely manner.

The value of new epileptic seizures in patients with sGBM
A glioma-related history of epilepsy is a favorable prognostic factor for OS in patients with glioma. [21,22] Our results showed that patients with sGBM and new epileptic seizures had prolonged OS. This nding corresponds with our previous nding that epileptic seizures were a favorable independent prognostic factor for OS in low-grade gliomas. [23] Additionally, this result was similar to that in studies on pGBM. [21,24] We established two hypotheses that may explain these results. First, because sGBM originates from low-grade gliomas, some of the clinical and epidemiological characteristics of sGBM may be inherited from the low-grade glioma. Second, new seizures are likely correlated with the integrity of white matter bers and, therefore, indicate the reduced ability of the tumor to in ltrate the white matter. [25] Neuron discharges can extend to the subcortical structures (e.g., the thalamus and basal ganglia) and induce epileptic seizures through the white matter. When the white matter bers are not destroyed, the epileptic discharge pathway is preserved. [26] Thus, a glioma could have a higher chance to induce epilepsy than a more invasive glioma. Therefore, we can infer that the aggressiveness of a seizure-inducing sGBM is weaker than one that does not induce epilepsy, which might have in ltrated and destroyed its surrounding white matter ber bundles.
Moreover, our results showed that a static or increased postoperative KPS score was a favorable independent factor for patients in group E, whereas GTR was not. This nding indicated that, for these patients, GTR might not be necessary if tumor resection would cause a further decrease in KPS.

The value of new neurological impairments in patients with sGBM
Patients with sGBM and new neurological impairments had worse OS than those without neurological de cits and primary low-grade glioma and GBM. [27] Our ndings indicated that new neurological impairments were a detrimental factor for the OS of patients with sGBM. In addition, for patients in group F, GTR and a consistent or increased postoperative KPS score were favorable independent factors for OS.
These ndings indicated that GTR should be recommended if it will not decrease the quality of life of these patients. In contrast, if GTR would further damage the quality of life of these patients, it may not be necessary.
The value of other newly occurring symptoms in patients with sGBM In the current study, patients with sGBM and other newly occurring symptoms (such as tumor-related headache and/or vomiting) had a shorter OS. If patients had these symptoms, it indicated that their intracranial pressure was high or they had a potential cerebral hernia induced by a large tumor. [28] For these patients, this observation indicated that the sGBM had signi cantly progressed. Hence, the OS of these patients was poor, and no clinical characteristics were found to be bene t for their survival outcomes.
Although most of our results were expected, there are some limitations to the current study. The main limitation is the lack of molecular biomarker information, such as 1p/19q co-deletion and MGMT promoter methylation, because approximately half of the patients underwent primary surgery in other treatment centers. Another limitation is the lack of data on the tumor volumes and diameters; due to the follow-up time for these patients, we were unable to acquire DICOM imaging data or quantitative tumor data. In the future, a prospective observational study is needed to con rm our ndings.

Conclusions
For patients with sGBM, GTR, increased postoperative KPS score, and diagnosis without newly occurring symptoms were favorable factors for OS. For patients diagnosed without newly occurring symptoms, we strongly recommend GTR even if GTR would impact their quality of life. For patients diagnosed with newly occurring symptoms, we recommend GTR, assuming that GTR would not impact their quality of life.
Abbreviations IDH = isocitrate dehydrogenase, GTR = gross total resection, EOR = extent of tumor resection, sGBM = secondary glioblastoma, OS = overall survival, KPS = Karnofsky Performance Scale, ROC = receiver operating characteristic curve, HR = hazard ratio, CI = con dent intervention, group E = patients with newly occurring epileptic seizures upon diagnosis with sGBM, group F = patients with newly occurring functional impairments, including paralysis, aphasia, and cognitive functional impairments, upon diagnosis with sGBM, group O = patients with other newly occurring symptoms, such as headache and/or vomiting, upon diagnosis with sGBM, and group R = patients without any newly occurring symptoms upon diagnosis with sGBM, based on T1 contrast-enhanced magnetic resonance imaging (MRI) during follow-up.

Ethics approval and consent to participate
This study had been approved by IRB of Beijing Tiantan Hospital.

Consent for publication
All authors agreed that this manuscript was publicized with open access.

Availability of data and materials
Anonymized data will be made available on request.

Competing interests
There are no con icts of interest to declare.

Funding Information
This study has received funding by the Public welfare development and reform pilot project of Beijing Medical Research Institute (JYY 2019-5), Brain Tumor Precision Diagnosis and Treatment and Translational Medicine Innovation Unit, Chinese Academy of Medical Sciences (2019-I2M-5-021) and Beijing Nova Program (Z181100006218064).