Glioma is the most common type of malignant brain tumors and accounts for 40%–50% of primary brain neoplasms.1 Current schemes of glioma treatment mainly involve combinations of surgery and adjuvant radio- therapy/chemotherapy.2 However, the overall prognosis of glioma is still poor despite aggressive treatments, especially in patients with high grade glioma, whose average survival time after surgery is only 8–9 months.3
The prognosis of patients diagnosed with grade III gliomas (anaplastic astrocytoma, anaplastic oligo- dendroglioma or anaplastic mixed glioma according to the WHO 2000 classification) varies significantly. Even given the same pathological diagnosis and equivalent treatments, some patients have a relatively favourable outcome, while others have a very poor prognosis.4 Therefore, it is important to understand the factors that contribute positively or negatively to the prognosis of patients with grade III gliomas. However, few studies have analyzed the prognostic factors of grade III glioma.
In this retrospective analysis, we examined data collected from 97 Chinese patients diagnosed with grade III glioma and received surgery in the Second Affiliated Hospital of Zhejiang University School of Medicine from 2000 to 2005 for prognostic factors.
The criteria for patient selection in this study were: (1) admitted and received surgery in our hospital between 2000 and 2005; (2) diagnosed with grade III glioma pathologically according to the diagnostic criteria of WHO (2000) by two independent pathologists. Patients who died of nonprimary diseases or readmitted because of postoperative tumor recurrence were excluded. The cutoff date for data collection was August 23, 2006.
The following data were collected from the medical records of patients: (1) Demographic data (age and gender) and Karnofsky Performance Scale (KPS) scores before operation. (2) Preoperative clinical symptoms: intracranial hypertension, neural irritation and depletion symptoms and its duration. (3) Preoperative/Postoperative contrast magnetic resonance imaging (MRI): before operation, contrast MRI was performed to determine whether there was tumor haemorrhage or necrosis, tumor location, extent of tumor invasion and tumor size; postoperative MRI scan was performed within 48 hours after operation to determine the presence of residual tumor. The extent of tumor invasion was based on the number of lobes with high signals in T2 weighted MRI. (4) Treatment: (a) surgical resection: the extent of tumor resection during operation/under microscope was judged by neuro-surgeons and pathologists. Complete resection was total resection of the tumor bulk as supported by the pathological evidence. Subtotal resection of the tumor bulk was less than 5% tumor residue (to protect important neurological functions). Partial resection was removal of more than 80% of the tumor bulk. Tumor residue was the intensified tissue bulk within the operation field as shown by postoperative contrast MRI. (b) Postoperative radiotherapy: postoperative radiotherapy was given to patients at a routine dosage: 40–60 Gy/28 days to the tumor focus and the peripheral oedematous region 2 cm away from it, plus with 10–14 Gy delivered to the surrounding brain region within 2 cm. (c) Postoperative chemotherapy: routine chemotherapy (200 mg temozolomide/m2 body surface area) was given at 4–6 treatment course and during radiotherapy the temozolomide dosage was halved. Some patients only managed to get 1–2 treatment course of temozolomide chemotherapy because of economic reason. (5) Postoperative pathological data: based on pathological examinations, patients were diagnosed with anaplastic astrocytoma, anaplastic oligodendroglioma or anaplastic mixed glioma. (6) Follow-up data: follow-up data include disease outcome (survival time and tumor progression) and their respective time of occurrence. Follow-up data were collected mainly when patients visited outpatient clinics and during phone interviews with patients and/or their relatives. The remaining data were collected from medical records.
Standard statistical methods were performed using SPSS v13.0. Kaplan-Meier survival, log rank method and Cox proportional hazards regression analysis were used to analyze the effect of 16 different factors selected from clinical characteristics, neuroimaging, pathological examination and treatment methods on the survival time. A P value less than 0.05 was considered as statistically significant.
From 2000 to 2005, 431 patients diagnosed with glioma received neurosurgery in our department. Among them, 122 cases were diagnosed with grade III glioma and 97 patients included according to the criteria as mentioned above. In 75 cases, patients received a complete tumor resection. The rest 22 cases received a partial resection. Fifty-four patients received MRI examination within 48 hours after surgery (results showed that among them, 37 cases had no tumor residue, while 17 cases had some residual tumor).
Based on pathological examinations, 76 patients were diagnosed with anaplastic astrocytoma, 6 with anaplastic oligodendroglioma and 15 with anaplastic mixed glioma. Sixty-six cases received postoperative radiotherapy and 18 cases received both postoperative radiotherapy and chemotherapy. Only 25 patients were still alive at the end of this study (Table 1). The median survival time was 15 months and the 1-year and 2-year survival rates were 53.8% and 22.3%, respectively (Figure 1). Fifty-four cases suffered from tumor recurrence with a median progression time of 12 months (Figure 2).
|view in a new window |
Table 1. Data of the 97 patients and the results of univariate analysis
|view in a new window |
Figure 1. The survival curve of patients with grade III gliomas after surgery.
|view in a new window |
Figure 2. The influences of tumor relapse and progression on the survival curve of patients with grade III gliomas after surgery.
It was reported previously that 7 factors exerted a significant influence on survival time: age, preoperative KPS score, extent of tumor invasion, resection degree, tumor residue, postoperative radiotherapy and chemotherapy
(Table 1).7,8 Among these factors, extent of tumor invasion was the most significant factor (P <0.001) (Figure 3). However, to preserve certain essential brain functions, a complete resection was always difficult in patients with two or more brain lobes invaded by tumor.
|view in a new window |
Figure 3. The influences of tumor invasion on the survival curve of patients with grade III gliomas after surgery.
Patients with wider tumor invasion usually have lower preoperative KPS scores. Therefore, it was important to exclude preoperative KPS score and resection degree on the survival time when evaluating the relationship between the survival time and the extent of tumor invasion. Survival curve analysis was then used to evaluate the extent of tumor invasion on survival time in patients with KPS score <70 and only had partial tumor resection. We found that the extent of tumor invasion was still an important factor for these 16 patients' prognosis (P <0.05) (Figure 4).
|view in a new window |
Figure 4. The influences of tumor invasion on the survival curve of patients with KPS <70 and partial tumor resection.
Cox proportional hazards regression analysis
Cox proportional hazards regression analysis was used to evaluate the independent prognostic factors of survival time. All the factors with significant effects on survival time were included in the analysis. Four independent factors were discovered in the model. They were age (P <0.01), extent of tumor invasion (P <0.01), postoperative radiotherapy (P <0.05) and tumor residue (P <0.05) (Table 2).
|view in a new window |
Table 2. Cox model analysis of the prognostic factors for grade III gliomas
The median survival time of patients with grade III gliomas in this study was 15 months, with a median progression time of 12 months, 1-year survival rate 53.8% and 2-year rate 22.3%. These results were worse than those of previous reports.5 Perhaps the exclusion of grade III glioma patients who were treated again for postoperative tumor recurrence in the current study may partially explain the difference. In addition, there were more patients who received postoperative chemotherapy in the previous report than the current study, which may also influence the results.6 Nevertheless, this study reveals that age, preoperative KPS score, extent of tumor invasion, tumor resection degree, residue tumor shown by postoperative MRI and postoperative radiotherapy are all prognostic factors for patients with grade III gliomas. Furthermore, this study provides important information on the correlations between factors, such as age, extent of tumor invasion, residue tumor shown by postoperative MRI and postoperative radiotherapy, and the patient prognosis.
A significant correlation was found between the extent of tumor invasion and prognosis both in the entire cohort (P <0.000) and in patients with KPS score <70 who only received partial tumor resection (P <0.023). Among all the factors studied in the Cox analysis, the extent of tumor invasion was confirmed as the most significant factor influencing the survival time (P <0.001). A possible explanation could be that more extensive tumor invasion usually leads to larger brain tissue resection during the surgery, which in turn usually results in a worse prognosis. However, Li et al7 did not find any significant relationship between extent of tumor invasion and prognosis. Therefore, further investigation is needed to assess whether the extent of tumor invasion is indeed an independent factor that could be used to predict the patients' prognosis.
Seventy-five cases in this study received complete resection and 22 cases received partial resection. A significant difference was found between the two groups in univariate analysis (P <0.003), however the difference no longer existed in multifactor analysis (P <0.214). Among the 54 patients receiving postoperative MRI examination, 37 cases were found free of tumor residue and 17 cases had tumor residue. The effect of tumor residue on prognosis was confirmed in both univariate and multifactor analyses. However, there is no consensus in the literature on whether tumor residue is a prognostic factor for glioma patients.8,9 This disagreement may due to the lack of an agreed criterion for judging the extent of tumor resection.10 Early postoperative contrast MRI examination may be helpful in evaluating patients' prognosis.
Age is a significant prognostic factor in univariate and multifactor analysis in the current study. However, there was no significant association in multifactor analysis between preoperative KPS score and outcome. It was reported that the main prognostic factors of high grade gliomas were age, KPS score, and tumor grade.6 The health of patients with high grade glioma deteriorate very quickly, especially for those patients with intracranial hypertension and a KPS score <70. KPS score <70 is also a contraindication for repeat surgery for patients with glioma recurrence.
In conclusion, age, postoperative radiotherapy and residual tumor indicated by MRI after the surgery correlate significantly with the prognosis of patients with grade III glioma. The extent of tumor invasion may be an independent prognostic factor for patients with grade III glioma. Intensified postoperative radiotherapy may be helpful in improving patients' outcome. However, a prospective clinical study with a larger sample of patients is necessary to elucidate prognostic factors in clinical practice.
1. Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomized trials. Lancet 2002; 359: 1011-1018.
2. Perry J, Laperriere N, Zuraw L, Chambers A, Spithoff K, Cairncross JG. Adjuvant chemotherapy for adults with malignant glioma: a systematic review. Can J Neurol Sci 2007; 34: 402-410.
3. Pang BC, Wan WH, Lee CK, Khu KJ, Ng WH. The role of surgery in high-grade glioma: is surgical resection justified? A review of the current knowledge. Ann Acad Med Singapore 2007; 36: 358-363.
4. Ron IG, Gal O, Vishne TH, Kovner F. Long-term followup in managing anaplastic astrocytoma by multimodality approach with surgery followed by postoperative radiotherapy and PCV-chemotherapy: phase II trial. Am J Clin Oncol 2002; 25: 296-302.
5. Jeremic B, Milicic B, Grujicic D, Dagovic A, Aleksandrovic J, Nikolic N. Clinical prognostic factors in patients with malignant glioma treated with combined modality approach. Am J Clin Oncol 2004; 27: 195-204.
6. Laws ER, Parney IF, Huang W, Anderson F, Morris AM, Asher A, et al. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. J Neurosurg 2003; 99: 467-473.
7. Li J, Zhang R, Zhang D. The most important prognostic factors for 736 patients with adenocarcinoma of the gastric cardia: a multivariate analysis using COX proportion hazard model. Chin J Oncol (Chin) 1996; 18: 134-136.
8. De Witte O, Levivier M, Violon P, Brotchi J, Goldman S. Quantitative imaging study of extent of surgical resection and prognosis of malignant astrocytomas. Neurosurgery 1998; 43: 398-399.
9. Keles GE, Chang EF, Lamborn KR, Tihan T, Chang CJ, Chang SM, et al. Volumetric extent of resection and residue contrast enhancement on initial surgery as predictors of outcome in adult patients with hemispheric anaplastic astrocytoma. J Neurosurg 2006; 105: 34-40.
10. Cairncross JG, Pexman JH, Rathbone MP, DelMaestro RF. Postoperative contrast enhancement in patients with brain tumor. Ann Neurol 1985; 17: 570-572.