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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 96-104

Real-world management and survival outcomes of patients with newly diagnosed gliomas from a single institution in China: A retrospective cohort study


Department of Neurosurgery and Neuro-Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong Province, China

Date of Web Publication27-Jun-2019

Correspondence Address:
Prof. Zhongping Chen
Sun Yat-Sen University Cancer Center, 651 Dong Feng East Road, Guangzhou 510060, Guangdong Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_14_19

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  Abstract 

Background and Aim: Guidelines recommend adjuvant treatment for patients with high-grade gliomas and low-grade gliomas with high risk of progression. In clinical practice, however, treatments may not conform to these suggested guidelines. In this study, we reviewed the treatments and outcomes in patients with gliomas at Sun Yat-Sen University Cancer Center (SYSUCC), China. Materials and Methods: Medical records and radiologic images of 1215 glioma patients who underwent surgery at the center from 2000 to 2017 were retrospectively reviewed, and their clinicopathological characteristics, treatment method, and overall survival (OS) were analyzed. The study was approved by the Ethics Committee of SYSUCC on February 20, 2019 (approval No. GZR2019-219). Results: A total of 1001 patients diagnosed with glioma (initially World Health Organization 2007 criteria, then 2016 criteria) were enrolled, including 90 patients with Grade I, 307 Grade II, 239 Grade III, and 365 Grade IV gliomas. A total of 331 of 604 patients with high-grade glioma (54.8%) and 159 of 397 with low-grade glioma (40.1%) received postsurgical radiotherapy, and 285 patients with high-grade tumors (47.1%) and 80 with low-grade tumors (20.2%) received adjuvant chemotherapy. The median OS was 17.5 months for Grade IV and 43.1 months for Grade III gliomas. The median OS of patients with low-grade glioma was not reached. The 5-year survival rates of patients with Grades I, II, III, and IV gliomas were 94.7%, 73.7%, 45.7%, and 18.6%, respectively. Multivariate analysis identified onset age, preoperative seizure, tumor location, pathological subtype, resection extent, and postsurgical treatment as independent predictors of OS in patients with high-grade gliomas. Patients with high-grade glioma who received postsurgical treatment had better survival than those without adjuvant therapy (Grade III: 52.6 vs. 20.3 months, P = 0.012; Grade IV: 22.6 vs. 12.1 months, P < 0.001). Among patients with diffuse low-grade gliomas, age, performance status, preoperative seizure, Ki-67 index, tumor subtype, and resection extent were associated with clinical outcomes. Conclusion: Glioma patients are not always treated according to guidelines. Although standard care may lead to favorable prognoses, individualized treatments may be more acceptable and result in better outcomes and should thus be considered in routine clinical practice.

Keywords: Clinical management, glioma, real-world study, retrospective cohort study, survival


How to cite this article:
Li D, Chen Y, Guo C, Zhang X, Sai K, Ke C, Zhang J, Jiang X, Chen Z, Lin F, Yang Q, Wang J, Mu Y, Chen Z. Real-world management and survival outcomes of patients with newly diagnosed gliomas from a single institution in China: A retrospective cohort study. Glioma 2019;2:96-104

How to cite this URL:
Li D, Chen Y, Guo C, Zhang X, Sai K, Ke C, Zhang J, Jiang X, Chen Z, Lin F, Yang Q, Wang J, Mu Y, Chen Z. Real-world management and survival outcomes of patients with newly diagnosed gliomas from a single institution in China: A retrospective cohort study. Glioma [serial online] 2019 [cited 2019 Aug 23];2:96-104. Available from: http://www.jglioma.com/text.asp?2019/2/2/96/261673

Depei Li and Yinsheng Chen contributed equally.



  Introduction Top


Gliomas are the most common primary form of brain tumor, with an estimated annual incidence of 6.6/100,000 individuals in the US.[1] Gliomas are classified according to the World Health Organization (WHO) histological criteria and grading system. This system reflects the degree of glioma malignancy, with Grade I indicating a slow-growing and well-circumscribed tumor, usually associated with a favorable outcome, whereas Grades II–IV are diffusely infiltrating and malignant tumors.[2] In light of significant advances in molecular genetics, additional molecular information was incorporated into the revised 2016 WHO classification of central nervous system tumors,[3] to improve the guidance for their clinical diagnosis and management.

Approximately 70% of all gliomas are high grade (Grades III and IV), of which glioblastoma (Grade IV) is the most common and highly malignant.[1] The management of high-grade gliomas remains a major challenge for neurosurgeons, and despite current treatments involving adjuvant radiotherapy and chemotherapy after maximal safe resection, the prognosis for this devastating disease remains unsatisfactory. Irradiation with concurrent and maintenance of six cycles of temozolomide (TMZ) is the standard postsurgical care for newly diagnosed glioblastoma.[4],[5],[6] The median overall survival (OS) was 14–17 months in EORTC-NCIC and contemporary trials.[4],[7],[8],[9] Radiochemotherapy was also recommended for anaplastic (Grade III) glioma. The interim results of the CATNON trial showed that patients with anaplastic astrocytoma benefited from combined treatment with irradiation and TMZ, compared with radiotherapy alone (5-year survival 55.9% vs. 44.1%).[10] The RTOG 9402 trial-treated patients with anaplastic oligodendroglioma with isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion using radiotherapy combined with procarbazine, lomustine, and vincristine (PCV) chemotherapy, with a median OS of >14 years.[11] Low-grade gliomas have a markedly better prognosis than high-grade tumors, and adjuvant radiotherapy combined with PCV chemotherapy is recommended for patients with diffuse low-grade glioma at high risk of recurrence.

The clinical practice guidelines for glioma are based on the results of clinical trials with high levels of evidence, and patient treatment conventionally follows these guidelines. However, clinical trials generally evaluate the efficacy of a novel therapy compared with a standard treatment, and patients are enrolled according to strict criteria, which may not accurately represent the situation during routine patient management. The real-world management of gliomas involves patients unsuitable for standard treatment, such as those with poor performance status, and includes patients who refuse postoperative treatment due to personal choice or financial difficulties. The 5-year survival rates of patients with glioblastoma in population-based studies in the US and Europe were, therefore, only 4.7%–6.6%,[12],[13] which was <9.8% reported in the EORTC-NCIC trial.[7] We, therefore, conducted a real-world analysis of over 1000 patients with newly diagnosed gliomas to evaluate the treatment efficacy and survival outcomes in a clinical setting in China.


  Materials and Methods Top


Patient selection

We reviewed the medical records and radiologic images of 1215 patients with brain gliomas from the cancer registry of Sun Yat-Sen University Cancer Center (SYSUCC), China, from 2000 to 2017. Patients were enrolled according to the following criteria: (1) histological diagnosis of glioma according to the WHO criteria and grading system,[2],[3] (2) newly diagnosed brain lesions, and (3) no other malignancy history. The study was approved by the Ethics Committee of SYSUCC on February 20, 2019 (approval No. GZR2019-219), and all patients provided signed informed consent for the analysis of their medical data.

Data collection

Patients were diagnosed according to the WHO classification of central nervous system tumors (initially 2007,[2] then 2016 criteria[3]). The following data were collected: (1) clinicopathological characteristics at the time of diagnosis including sex, age, Karnofsky Performance Status (KPS),[14] neurological manifestation, histologic subtype, and WHO grade; (2) radiologic information including tumor location and size; (3) immunohistochemical expression of Ki-67, methylguanine-DNA methyltransferase (MGMT), and IDH 1R132H; (4) extent of tumor resection according to surgeon's records or postsurgical magnetic resonance imaging scans; and (5) the use of radiotherapy and chemotherapy.

Follow-up was performed through patient visits or telephone calls. Patients were interviewed 3 months' postoperatively and every 3–6 months thereafter until December 2018. OS was recorded as the duration from the date of surgery to death. All patients underwent follow-up for at least 1 year, except for patients who survived <1 year postoperatively.

Statistical analysis

Statistical analysis was performed using SPSS software version 20 (IBM Corp., Santa Monica, CA, USA) and GraphPad Prism software version 7 (GraphPad Software Inc., La Jolla, CA, USA). Continuous variables were compared using two-tailed t-tests. Survival curves were plotted by the Kaplan–Meier method and compared using log-rank tests. Cox proportional hazard models were constructed using an enter method, adjusting for predictors previously associated with OS in univariate analysis at P < 0.1 level. P < 0.05 was considered to indicate statistical significance.


  Results Top


Baseline patient characteristics

A total of 1001 patients with newly diagnosed brain gliomas were included in the final analysis [Figure 1], including 397 low-grade gliomas and 604 high-grade gliomas. All patients underwent surgery in our center, and tissue samples were obtained for biopsy diagnosis and immunohistochemistry tests. Most oligoastrocytomas could be reclassified as oligodendrogliomas in this study, according to revised WHO criteria by detecting molecular markers, and oligoastrocytomas and oligodendrogliomas were, therefore, combined and recognized as oligodendroglial tumors.[15],[16] Ki-67 and MGMT immunohistochemistry were carried out since 2004, and immunohistochemical detection of IDH1R132H, representing the most frequent type of IDH mutation, started to be detected in 2012. The clinicopathological characteristics are summarized in [Table 1]. There were more men than women (1.3:1), especially among patients with malignant gliomas, 80.9% of the patients were aged 18–60 years, and 89.1% had a good performance status (KPS ≥70). The median onset ages in patients with Grades I, II, III, and IV gliomas were 14 (range 1–75), 35 (range 2–69), 41 (range 8–82), and 50 (range 2–86) years, respectively. The onset age was significantly older in patients with high-grade tumors compared with low-grade tumors (P < 0.001). Preoperative seizures were observed in 261 patients and were more common in patients with diffuse low-grade gliomas (145/307 patients, 47.2%).
Figure 1: Selection of newly diagnosed patients with brain gliomas in this study. SYSUCC: Sun Yat-Sen University Cancer Center, China

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Table 1: Baseline characteristics of patients with glioma in this study

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Primary patient management

Most patients underwent tumor resection, except for 14 who underwent biopsy. In patients with tumors involving eloquent areas of limb movement, such as the precentral and thalamic regions, maximal tumor resection minimizing functional damage was achieved using preoperative functional magnetic resonance imaging including diffusion tensor imaging and neuronavigation. Awake operation has recently been developed for surgeries involving the language area. Gross total glioma resection was achieved in 576 patients (57.5%). Current clinical guidelines recommend postsurgical radiotherapy and chemotherapy for most patients with gliomas, especially high-grade gliomas. However, only 331 of the 604 patients with high-grade gliomas (54.8%) and 159 of 397 patients (40.1%) with low-grade gliomas in the current cohort received radiotherapy. Most radiotherapy was conformal radiotherapy at a dosage of 40–60 Gy. Twenty-nine patients participated in clinical trials and received radiotherapy at a higher total dose (>60 Gy). 7 patients received stereotactic radiosurgery, and 285 patients with high-grade tumors (47.1%) and 80 with low-grade tumors (20.2%) received chemotherapy. TMZ has become the preferred agent for treating gliomas in our center since 2008, before which nitrosourea or cisplatin combined with teniposide were the main chemotherapy regimens. Few patients received interferon or molecular targeted treatments such as nimotuzumab and bevacizumab, in addition to standard therapy.

Patient outcomes

A total of 219 patients with Grade IV (60%), 106 with Grade III (44.4%), 74 with Grade II (24.1%), and 6 with Grade I gliomas (6.7%) had died up to December 2018, after a median follow-up of 43.1 months (95% confidence interval [CI]: 40.3–45.9 months). The 5-year survival rates of patients with Grades I, II, III, and IV gliomas were 94.7% (95% CI: 94.1%–95.4%), 73.7% (95% CI: 73.4%–74.2%), 45.7% (95% CI: 45.2%–46.2%), and 18.6% (95% CI: 18.3%–18.9%), respectively. The median OS was 17.5 months (95% CI: 15.5–19.5 months) for Grade IV gliomas and 43.1 months (95% CI: 23.5–62.8 months) for Grade III gliomas. Among patients with Grade III gliomas, the median OS rates for patients with anaplastic astrocytomas and anaplastic oligodendroglial tumors were 33.7 months (95% CI: 23.5–43.9 months) and 109.1 months (95% CI: 43.0–175.2 months), respectively. The median OS of patients with low-grade gliomas was not reached.

Risk factors for survival outcome were identified using a Cox proportional hazards model. Univariate analysis indicated that age of onset (P < 0.001), KPS (P < 0.001), preoperative seizure (P < 0.001), neurological deficit (P < 0.001), tumor location (P < 0.001), histological subtype (P < 0.001), Ki-67 expression (P = 0.004), IDH1 mutation (P < 0.001), extent of resection (P < 0.001), and postsurgical treatment (radiotherapy and/or chemotherapy, P < 0.001) significantly affected OS in patients with high-grade gliomas. After adjustment for these factors, older age, KPS <70, and tumor in the midline were independent risk factors for poor outcome, whereas preoperative seizure, oligodendroglial tumor and astrocytoma subtype, tumor total resection, and postsurgical treatment were independent predictors of a better prognosis [Table 2]. We also performed stratification analysis to assess the prognostic significance of postsurgical treatment in different subgroups of patients divided according to the WHO grade, onset age, and resection extent. Postsurgical treatment improved the survival of patients with high-grade gliomas in each group [Figure 2]. A total of 195 patients with glioblastoma and 160 with anaplastic glioma received adjuvant therapy, with median OS rates of 22.6 months (95% CI: 18.8–26.4 months) and 52.6 months (95% CI: 27.3–77.9 months), respectively.
Table 2: Risk factors for overall survival in 1001 patients with high-grade glioma

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Figure 2: Stratification analysis of the prognostic significance of postsurgical adjuvant treatment in patients with high-grade glioma. (A–F) Kaplan–Meier analysis in patients with different WHO grades (A and B), age (C and D), and extent of resection (E and F). OS: Overall survival

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Among patients with diffuse low-grade gliomas, multivariate analysis showed that patient age and Ki-67 ≥10% were independent risk factors for shorter OS. Oligodendroglial tumor subtype and tumor total removal were also associated with prolonged survival [Table 3].
Table 3: Risk factors for overall survival in 1001 patients with low-grade glioma

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  Discussion Top


There are currently many guidelines for the diagnosis and treatment of brain gliomas in routine clinical practice,[6],[17] based on the results of high-quality randomized clinical trials and aiming to provide useful guidance for the best care of patients. However, not all the patients actually receive the treatments recommended by the guidelines, and some may decline standard therapy because of personal choice, lack of education, or financial difficulty. Furthermore, the standard treatment may not suitable for all patients, such as older patients or patients with a poor performance status. The effect of alkylating agents as currently recommended by guidelines is also controversial in patients with MGMT promoter-unmethylated gliomas.[18] Moreover, because clinical trials enroll patients based on strict criteria, the real efficacy of standard therapy for the routine management of gliomas may differ from that demonstrated in clinical trials. It is, therefore, necessary to analyze the management and survival of glioma patients in a real-world setting to complement the results of randomized clinical trials and to improve our understanding of the natural course of gliomas and guide their routine management.

We, therefore, conducted a retrospective real-world study in 604 patients with high-grade glioma from SYSUCC were analyzed. The median OS durations in patients with glioblastoma and anaplastic glioma were 17.5 and 43.1 months, respectively. Cox regression analysis identified onset age, preoperative seizure, tumor location, pathological subtype, resection extent, and postsurgical treatment as independent survival predictors in patients with high-grade glioma. Surgical resection is the cornerstone of the treatment for gliomas, and increasing evidence has suggested that total tumor removal is associated with less recurrence and longer survival.[19],[20],[21],[22] Patients in our institution with high-grade glioma who received postsurgical radiotherapy and/or chemotherapy had better prognoses than those without adjuvant therapy. The current National Comprehensive Cancer Network[17] and the European Association for Neuro-Oncology guidelines[6] recommend radiotherapy and six cycles of concomitant and maintenance TMZ chemotherapy as the standard care for adults aged ≤70 years with newly diagnosed glioblastoma with a good performance status, mainly based on the results of EORTC-NCIC and contemporary clinical trials.[4],[7],[8] However, only 160 of the 365 patients with glioblastoma (43.8%) in the current cohort received radiochemotherapy, while 35 patients (9.6%) received irradiation or chemotherapy alone. The median OS of the patients who received adjuvant therapy was 22.6 months, which was better than the outcomes of previous clinical trials (14–17 months).[4],[7],[8],[9] This may have been because the patients with glioblastoma in the present cohort were younger than those in the EORTC-NCIC trial[4] (median, 49 vs. 56 years), and the ratio of tumor total resection was also higher (60% vs. 39.4%). Younger age and total tumor resection are important indicators of longer survival in patients with glioma.[6],[20],[21] Some patients in the current study participated in and possibly benefitted from clinical trials of novel treatments (e.g., high-dose irradiation, epidermal growth factor receptor inhibitor, and addition of interferon to chemotherapy regimens). Moreover, the retrospective nature of this study means that there may have been statistical errors in follow-up and estimated survival. Nevertheless, the results indicate the need to consider personalized treatment in the routine management of patients with glioma.

Radiotherapy followed by 12 cycles of adjuvant TMZ is recommended in patients with anaplastic astrocytoma, according to the interim result of the CATNON trial,[10] which showed improved survival after combination treatment compared with irradiation alone (OS not reached in combination group vs. 41.1 months in radiotherapy group). PCV chemotherapy, either before or after irradiation, is the first-line treatment for patients with oligodendroglial tumors, based on the results of the RTOG 9402[11] and EORTC 26951 trials.[23] These two studies both found that patients benefited from the addition of PCV to radiotherapy (OS >42 months). Moreover, the survival benefit was more pronounced in patients with 1p/19q codeletion (OS >10 years). TMZ could be applied in patients who have difficulty in tolerating PCV chemotherapy, and the long-term outcome of combined TMZ and radiotherapy for anaplastic oligodendroglioma is currently being explored in a large phase III trial.[24] In the current cohort, 112 of 239 patients with anaplastic glioma (62.8%) received radiochemotherapy and 48 patients (20.1%) received irradiation or chemotherapy alone. The median OS of patients who received postsurgical treatment was 53.3 months, compared with 20.3 months in those without adjuvant therapy. The efficacy of the treatment for anaplastic gliomas in our center was thus similar to that reported in the above clinical trials. Notably, molecular detection including 1p/19q codeletion was absent in most of these patients, and further studies are warranted to clarify the real prognosis of different molecular subtypes of gliomas.

The current study also enrolled 307 patients with diffuse low-grade gliomas, and survival analysis showed that surgery extent, but not postsurgical treatment, was associated with OS. A similar result was reported in other studies[21],[22],[25] showing that adjuvant treatment, especially chemotherapy, was not an independent survival predictor in patients with low-grade gliomas. One possible explanation is that the application of radiochemotherapy in patients with low-grade gliomas depends on recurrence risk factors, including age, resection extent, and molecular markers, and not all patients benefit from postsurgical therapy. Patients at high risk of tumor progression should be treated with radiotherapy followed by PCV,[26] whereas observation after surgery should be considered in low-risk patients. In the present cohort, 163 patients with Grade II glioma (53.3%) received postsurgical therapy. TMZ is currently the main chemotherapy agent for patients with Grade II glioma in our center. However, follow-up remained incomplete given that only 24.1% of patients had died at the time of analysis; the median OS was thus not reached, and the 5-year survival was 73.7%. Further follow-up is, therefore, needed to compare the survival of these patients with the outcomes of clinical trials. Furthermore, tumor-progression time and quality of life should also be followed during the routine management of patients with low-grade glioma.

The WHO classification of central nervous system tumors has been revised, with the incorporation of a molecular classification for gliomas and an emphasis on the role of molecular markers in pathological diagnosis and prognosis prediction.[3] The IDH mutation is a pivotal biomarker for glioma diagnosis and prognosis, with IDH mutations occurring in >80% of low-grade gliomas (Grades II and III) and secondary glioblastomas, but in <10% of primary glioblastomas. Patients with primary glioblastomas with IDH mutation also demonstrated better survival than those without the mutation.[27] The R132H mutation is the most frequent IDH mutation and can be detected by immunohistochemistry, while less common IDH mutations can be analyzed by DNA sequencing.[6] IDH mutation detection, including immunohistochemistry and DNA sequencing, has been in practice at our center since 2012. Immunohistochemistry showed that the IDH1 mutation was associated with longer survival in patients with high-grade gliomas but not in those with diffuse low-grade gliomas; however, the sample of tumors subjected to IDH1 immunohistochemistry in this study may have been too small to allow an accurate assessment of the prognostic value of IDH mutation in low-grade gliomas. Nevertheless, other studies have also reported that patients with low-grade gliomas with IDH mutation had a lower risk of tumor progression and better survival than those without mutation.[21],[28],[29]

Alkylating agents, especially TMZ, represent the main chemotherapy choice for gliomas. Patients with MGMT promoter methylation are less chance resistant to alkylating agents and experience better outcomes than those without,[18] and MGMT promoter methylation status may thus be used to guide therapeutic decisions regarding the use of chemotherapy. Our center has performed immunocytochemistry detection of MGMT since 2004, and our results showed that its expression was not associated with OS in patients with glioma, regardless of the grade. This apparent discrepancy may be because our personalized chemotherapeutic protocol often avoided alkylating agents in patients with MGMT-positive gliomas. Immunocytochemistry is no longer recommended for establishing MGMT promoter methylation status,[6],[30] and a molecular genetic approach, such as methylation-specific polymerase chain reaction,[6] is now recommended and has recently been developed in our center (data not show). Ki-67, also known as MIB-1, is a widely used cellular marker for proliferation and can help pathologists to identify a high proliferative subset of tumors and to diagnose high-grade gliomas.[31] We found that the results of Ki-67 immunocytochemistry were associated with clinical outcomes in glioma patients, and higher expression (≥10%) was an independent predictor of shorter OS in patients with diffuse low-grade gliomas. Immunocytochemical detection of Ki-67 thus has diagnostic and prognostic values in the routine management of glioma patients.


  Conclusion Top


This retrospective, single-center study of >1000 newly diagnosed brain glioma patients provided real-world data regarding the pattern and efficacy of the treatment for gliomas in routine clinical practice in southern China. Patients are not always treated according to the guidelines. Although standard care may improve prognosis, personalized treatment may be more acceptable and may produce better outcomes in some patients and should thus be considered during the routine management of patients with glioma.

Acknowledgments

The authors would like to thank all the participating physicians. We also appreciate Ms. Xue Ju from SYSUCC, Guangzhou, China, for the maintenance of glioma database.

Financial support and sponsorship

This study was supported by grants from the National Basic Research Program of China (973 Program) (No. 2015CB755505), the National Natural Science Foundation of China (No. 81872059 and 81772677), the Science and Technology Planning Project of Guangdong Province of China (No. 2016A020213004), and the Guangzhou Science Technology Project of China (No. 201508020125 and No. 201803010056).

Institutional review board statement

The study was approved by the Ethics Committee of Sun Yat-Sen University Cancer Center (GZR2019-219) on February 20, 2019.

Conflicts of interest

There are no conflicts of interest.

Declaration of patient consent

The authors certify that they have obtained the patient consent form. In the forms, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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