Relationship between the extent of resection and the survival of patients with low-grade gliomas: a systematic review and meta-analysis

Low-grade gliomas include astrocytoma, oligodendrogliomaand oligoastrocytoma of WHO gradeI-II [1]. The incidence of low-grade gliomas is significantly lower than that of high-grade glioblastomas of all primary intracranial tumors [2]. The epidemiological features, clinical manifestations, proliferation rates, mitotic counts, as well as angiogenesis and genetic features of low-grade gliomas are different from those of high-grade gliomas [3]. Low-grade gliomas have a better prognosis than high-grade gliomas. The established risk factors influencing the prognosis of high-grade gliomas include IDH mutation, age, KPS score, and the extent of resection [4]. However, the prognostic factors of low-grade gliomas are not fully elucidated yet. So far, only IDH mutation, KPS score, age and the pathological type are recognized as factors related to the prognosis of low-grade gliomas [5], the effect on prognosis of extent of resection of low-grade gliomas has not been systematically evaluated.

Many neurosurgeons recommend performing the greatest extent of resection safely possible for both high-grade and low-grade gliomas. In the past, the available surgical techniques might make it difficult to access gliomas in deep locations or in the brain functional areas [6]. However, with the use of neuronavigator and intraoperative MRI, many difficulties in accessing the tumors in challenging locations been solved [7]. High-grade gliomas have a higher incidence and their median survival ranges from 1 to 2 years [4]. A large number of researches have tried to elucidate the association between the extent of resection and the prognosis of high-grade gliomas. There are explicit first-level evidences indicating that a gross total resection (GTR) can significantly increase the overall survival (OS) and progression-free survival (PFS) of patients as compared with a subtotal resection (STR) or biopsy(BX) [8]. In contrast, low-grade gliomas have a lower incidence and a better prognosis. The medial survival of patients with low-grade gliomas is 5 to 10 years [3]. However, there are much fewer cases of low-grade gliomas and relevant clinical trials are hindered by long trial durations and ethical principles. At present, few researches have been focused on the relationship between the extent of resection and the prognosis of low-grade gliomas. Therefore, no randomized trials or first-level evidence have demonstrated explicitly the relationship between the extent of resection and prognosis.

It remains controversial whether a greater extent of resection can increase the OS and PFS of patients with low-grade gliomas. We performed a meta-analysis to prove the relationship between the extent of resection and the prognosis of patients with low-grade gliomas, then provide a basis for the development of evidence-based medicines in low-grade gliomas.

The clinical value of surgery in low-grade gliomas is heavily disputed [29]. Researchers suggest that although surgery is conducive to pathological diagnosis and remission of symptoms, some low-grade gliomas show infiltrative growth and it is difficult to achieve radical cure through a simple surgery [30]. Low-grade gliomas are generally located in the brain functional areas with obscure boundaries. Surgical resection of low-grade gliomas may lead to dysfunction and impairment of patients’ quality of life (QOL) [31]. Some reports showed that the 5-year and 10-year survival of patients receiving GTR was comparable to those receiving STR or no surgery at all [32‐34].For this reason, GTR is not the first-line therapy for low-grade gliomas. In recent years, there has been a trend of favoring GTR in the treatment of low-grade gliomas [35, 36].Therefore, we reviewed relevant studies published up to 2017 and performed a quantitative meta-analysis. The results showed that GTR greatly increased the 5-year and 10-year survival of patients with low-grade gliomas.

Meta-analysis can enhance the credibility of conclusions by using a larger sample size and therefore can resolve the inconsistency among different studies [37]. The findings of meta-analysis are more reliable than those of a single study [38]. Twenty studies focusing on the surgical outcomes of low-grade gliomas were analyzed, as the result showed in the Table 2, patients with GTR had better prognosis than those with STR and biopsy, similarly, STR is superior to biopsy both in the 5-year and 10-year OS. Thus, patients with low-grade gliomas are expected to benefit from a greater extent of resection if their safety during the surgery can be ensured.

Better outcome following GTR can be explained by the types of growth that low-grade gliomas exhibit. Firstly, the growth of low-grade gliomas can be divided into three types: confined growth, invasive growth and malignant change. According to recent studies, low-grade gliomas show continuous and slow confined growth before malignant change, resulting in an annual increase of about 4 mm in size [30]. Invasive growth of low-grade gliomas is demonstrated as the invasion of adjacent white matter tracts, or even the invasion into the contralateral side via corpus callosum. In addition, low-grade gliomas may evolve into high-grade gliomas [39]. It was reported that 66.4% of patients with low-grade glioma sunder went de-differentiation within 5 years after surgery, resulting in a worse prognosis [40]. Therefore, early resection of tumor is very important to control infiltration and metastasis. Moreover, the reduction in the tumor load is also conducive to improve effectiveness of subsequent radiochemotherapy. Secondly, from the pathological aspect, histopathology remains the gold standard for the malignancy classification of gliomas. The accuracy of histopathological diagnosis depends on whether a submitted sample is representative [41]. Gliomas are usually associated with heterogeneity in terms of the varying types of cells and different degrees of malignancy in the tumor. That is why the representativeness of the submitted sample is crucial for pathological diagnosis [42]. In one study, a pathological diagnosis based on stereotactic biopsy of astrocytoma was compared with the diagnosis obtained from a surgically resected sample. It was found that sterotactic biopsy underestimated the grades of tumors in 10%–25% of the cases [43]. Therefore, an extensive resection of low-grade gliomas and the submission of all resected specimens for pathological examination can reduce diagnostic errors.

However, some studies might have biases due to limited technical skills and defects in their experimental designs [44]. For example, many researches concerning surgical treatment for low-grade gliomas were retrospective studies. In other studies, the extent of resection was determined based on neurosurgeons’ experience or CT scan, which might lead to inconsistent conclusions. Recently, National Cancer Institute (NCI) presented a statistics report on the survival of 2009 patients with low-grade gliomas between 1973 and 2001 [35]. The results showed that surgery prolonged the survival of these patients.

There were other limitations in our study. On the one hand, our meta-analysis included only one prospective and randomized controlled clinical trial while most of the included articles were retrospective studies. There were only four Level II studies included in our analysis while many of the remaining studies were of Level III. However, all results from Level II studies were consistent with our result which favored GTR over STR and biopsy. On the other hand, as mentioned above, low-grade gliomas have a much lower incidence than that of high-grade gliomas, leading to a smaller number of eligible trials in the meta-analysis, so large-scale randomized clinical trials for low-grade gliomas are urgently needed. Additionally, there were some covariates between studies, such as patients’ age, auxiliary treatment methods, tumor size and complications, which could bring some bias to our study.

Our meta-analysis included only one prospective and randomized controlled clinical trial while most of the included articles were retrospective studies. All evidences were consistent (four class 2 studies) in that they favored GTR over STR and biopsy. There were four class2 studies while many of the remaining studies were of class3. We believe that, as compared with STR and biopsy, GTR could significantly increase the 5-year and 10-year survival of patients with low-grade gliomas. If feasible, GTR is recommended for those patients newly diagnosed as low-grade gliomas. Based on the existing evidences, we believe that more retrospective cohort studies may not provide more useful data. Instead, for low-grade gliomas, high-quality prospective clinical trials are needed to analyze the prognostic factors such as the extent of resection, auxiliary treatment, tumor size, tumor location and complications.