Although AA, AO, and AOA are grouped as the same histological grade by the WHO classification system, among them exist diverse biological behaviors linked to clinical outcome, even within the same histological diagnosis. However, straightforward comparative analyses of the prognostic factors among the WHO grade III gliomas have been reported infrequently. In the present study, hierarchical stratification of prognostic variables, such as performance status, histological diagnosis, extent of resection, and adjuvant chemotherapy after radiotherapy among the WHO grade III gliomas could be deduced successfully using the RPA method. Based on the results of the present study, several conclusions could be drawn: (1) good complete resection is the most important prognostic factor for performance status, (2) the oligodendroglial component of the tumor favors better prognosis, and (3) PCV chemotherapy may be beneficial for certain groups of patients. These findings are not novel; however, using the risk group splits according to the given condition of the patients, we can estimate survival based on the chosen treatment modalities.
According to various studies, age is an invariably important prognostic factor of performance status for WHO grade III glioma[8, 13, 17, 18]. We also observed significant prognostic values for performance status in the present analysis. However, it is important to note that age was excluded as a factor during the RPA, although it was a significant variable in the univariate analysis.
Analysis of the extent of resection for WHO grade III gliomas was based on the available data collected in an uncontrolled study setting. The present analysis has pitfalls, such as that superficial, small, well-demarcated tumors tend to undergo complete resection, whereas deep-seated, extensive, diffuse tumors are more likely to undergo biopsy only or incomplete resection[7, 8]. Evidence for the prognostic impact of the extent of resection on AA remains sparse; however, randomized studies investigating a combination of multiple treatment modalities support the beneficial impact of complete resection for AO and AOA[9, 10].
Better prognosis of oligodendroglial tumors over astrocytic tumors is also supported by previous studies. This evidence was further investigated, and the underlying genetic signature, such as the 1p/19q co-deletion in oligodendroglial tumors, was found to be responsible for the favorable prognosis. Moreover, the diffuse nature of AA that precludes complete resection might have affected the outcome. It is a limitation of the present study that we could not include any molecular markers into RPA due to unavailability of appropriate tissue samples to carry on the analysis.
Radiotherapy and PCV chemotherapy, along with other alkylating agents such as nitrosoureas and temozolomide, are still considered to be the major options for the management of AA, AO, and AOA patients. Nonetheless, the role of radiotherapy in the treatment of AO/AOA and that of PCV chemotherapy for AA still requires further investigation [21–24]. Although the results of the present study show a beneficial effect of PCV chemotherapy on the outcome of the multivariate analysis, the possibility of a selection bias remains, since patients with poor performance status were excluded from further chemotherapy. Another noteworthy finding of the present study is the evidence for the diversity of the prognosis of AA, AO, and AOA patients, despite the best available treatment. The estimated survival ranged from good (group A) to bad (group D, such as glioblastoma) status. The results imply that AA, AO, and AOA patients with the best performance status, or with completely extirpated tumors, can be maintain prolonged survival without any recurrence with radiotherapy followed by PCV chemotherapy.
There are many clinical studies employing RPA to define risk groups[14, 25–28]. RPA is a robust tool for the stratification of prognostic factors and for the identification of a homogenous group of patients for a given disease and treatment strategy. However, there are limitations to RPA application. For example, it is a post-hoc test, and no predictions can be made using the final splits, since prognostic factors are selected by chance. If multiple variables that are highly correlated exist, the selection of factors may vary. Despite these limitations, the RPA method allows for a clear distinction between the WHO grade III glioma patients risk groups. The advantage of this study is that only those patients with WHO grade III glioma who received the best available treatment were included in the analysis. It is more likely that the novel anticancer agent such as temozolomide will take over the mainstream of WHO grade III glioma management sooner or later. However, we believe that the systemized analysis for classic management has its own significance because it can be solid reference for the upcoming new therapeutic strategies.