With the increasingly popularization of the concept of precision medicine, the accurate prediction of patients’ prognosis is becoming much more critical[13,14]. Many previous studies have shown the accurate predictive ability of nomograms for predicting overall survival in patients with low-grade endometrial stromal sarcoma[10], adrenocortical carcinoma[15], hepatoblastoma[16], and many other system cancers. So far, only a few sporadic studies have investigated the straightforward application of nomograms in glioma based on the SEER database[17-20]. WHO grade II/III glioma is a relatively rare tumour, with no individualized prognostic predictive tool to manage follow-up and aid accurate prognostic assessment. Based on this, we developed two nomograms for predicting OS and CSS, respectively. Eleven and ten variables were screened through stepwise regression and incorporated into the OS and CSS nomograms, respectively. The nomograms were validated to have accurate predictive ability, with high C-indexes. Besides, the area under the ROC curve (AUC) is used to demonstrate the nomograms' excellent predictive ability. The calibration curve plots also showed that the predicted probability of 3-, 5-, and 8-year survival rates corresponded well with the actual observed OS and CSS rates concerning both the training & validation datasets.
The concept of lower-grade glioma (LGG, WHO Grades II and III) was proposed after the update to classify the central nervous system tumors by WHO in 2016[3]. Compared to glioblastoma, LGGs were known to have a better prognosis and more prolonged survival and shared some similar molecular alterations[21,22], clinical and pathological features [21], or even treatment modalities[22,23]. Therefore, LGGs could not be clustered in the group of low-grade gliomas or high-grade glioma simply, and both the research of Zhao et al[17] and the study of Yang et al[20] were not well applicable for LGGs. Furthermore, the OS and CSS nomograms in the current research fit well with our observation of survival for LGGs, and the inclusion of each covariable in the models may improve the accuracy of prognosis prediction.
According to our nomograms, age at diagnosis was confirmed as the most critical outcome predictor for LGGs. Previous research divided the low-grade glioma patients more simply into two groups according to age and found the younger one (age ≤ 39y) exhibiting a relatively good prognosis[17]. The young adult may share analogous biology, epidemiology, and outcomes with the adolescent and be different from older age groups regarding central nervous system tumors[24-26]. The present study had the same founding and further suggested that the age score in both scales of nomograms increased with age. The efficient precise subgrouping of age would optimize the prediction models and improve its predictive ability.
A safe maximal excision of the glioma without neurological functioning deficiency was the main therapeutic strategy as strong evidence has demonstrated that more extensive resections can prolong patients' survival time [6,27,28]. Both the OS and CSS nomograms in the study showed that surgery was a strong individual predictive factor for LGGs and gross total resection (GTR) is recommended under permissive conditions. When GTR was challenging to achieve, patients still can benefit from subtotal surgical resection compared to no surgery performed. MCCreate suggested that with increasing the extent of resection, pediatric high-grade gliomas' survival time was gradually prolonged[29]. Radiotherapy is another essential modality in LGGs during cancer treatment as a curative modality[30]. In contrast, postoperative radiotherapies (PORTs) were not recommended for LGGs by both OS and CSS nomograms in the study as it was associated with shorter survival duration. PORTs are often used for low-grade gliomas and provides improved progression-free survival but does not extend overall survival[31]. A large phase III randomized study, EORTC 22845, which revealed similar conclusions challenged the role of immediate PORTs, but it appears worthwhile to attempt PORTs for young patients who present with minimal symptoms[32]. Additionally, chemotherapy plays a key role in patients' treatment and prognosis with glioma[33]. PCV (procarbazine, CCNU or lomustine, and vincristine) and temozolomide chemotherapy were initially proved to have a useful role in LGGs by multiple pieces of research [34-37]. Likewise, chemotherapies in our study were factors with protective properties and associated with a more favorable OS. Although chemotherapy did not significantly improve CSS, more patients have more significant benefit from it indeed. Surgery, radiotherapy, and chemotherapy are a continuous process as surgery could help obtain molecular profiling and assist clinicians with a guideline to provide more appropriate therapeutic regimens for individualized precision therapy in LGGs.
The WHO grade is the critical prognostic factor for LGGs, and numerous studies have provided evidence that grade II gliomas had a significantly better prognosis than grade III[38-40]. Both OS and CSS nomograms gave high-er scores to patients with grade III gliomas that were more likely to have death. Also, according to our nomograms, the magnitude of poor prognosis was associated with increased tumour size. Pignatti[41] defined high-risk patients with low-grade glioma as the largest diameter of the tumour ≥ 6 cm, and Gorlia[42] suggested that the numerical value was accurate to 5cm. Then the value was rapidly lowered to 2.6cm in patients with high-grade gliomas[43]. Taken together, it is more reasonable than the value was determined to be 4.9cm by our research and the value would make the parameter more suitable to serve as a prognostic and/or predictive factor for LGGs. In the previous study, researchers analyzed the prognosis in different tumour locations. The analyses showed that the tumour's frontal location had a significant positive prognostic value for both PFS and OS in low-grade gliomas[44], while only the temporal lobe was significant for OS in both low and high-grade gliomas[42]. Frontal location was found to be protective factor LGGs in both OS and CSS nomograms and we can only speculate on that different tumour locations were associated with IDHmut status which in turn affects the disease[45,46]. Information on tumour laterality was not systematically analyzed so far, and only a small number of studies showed that tumour crossing the midline was associated with poorer overall survival[41,42]. We reported that survival of unilateral tumours is better than bilateral and other LGGs.
OS and CSS nomograms support may contribute to a better prognosis among married and female patients with LGGs. Additionally, the previous study of glioma incidence and survival across a long period demonstrates substantial variation by race or ethnicity[47]. Indeed, blacks have a higher risk than whites[48,49], which is coherent with the findings of our study. However, only a few reports of the association between yellows and disease are available in the literature[50,51]. The effect of the level of yellows on the survival of LGGs was similar according to survival models. Notably, yellows were one of the most protective of the factor in OS and CSS models. However, racial differences in cancer susceptibility and survival matter more than the skin colour [52]. Different cultural, socioeconomic, language, diet, and cultural identity all of those had important implications[53]. Further, we suspect that it may be a more intuitive and specific presentation of genetic variants that influence human disease risk.
Our analysis developed more objective and scientific nomograms that incorporated a vast number of candidate variables about patients' characteristics, tumour characteristics, and treatment history. By performing DCA, we consider that both OS and CSS nomograms could present net benefit for LGGs. Using nomograms to identify some specific groups of patients with a more homogeneous prognosis, clinicians can evaluate a diverse range of prognostic factors with more objectiveness and precision LGGs so that the interpretation of clinical outcomes and treatment strategies become clearer. Moreover, OS nomograms might be more feasible in routine clinical practice, because it may provide clinicians with a guideline to develop more appropriate therapeutic regimens for individualized precision therapies in LGGs.
There were several non-negligible limitations in this study. In particular, the lack of specific information concerning the use of chemotherapy and radiotherapy which have been consistently reported as an essential treatment for gliomas[54-56], hindered optimization of the treatment protocol to optimize clinical outcomes further. Another limitation is that our nomograms were constructed using only a series of clinicopathological factors. Indeed, some certain additional variables (e.g., biological markers or genes) were defined to provide potential prognostic information for LGGs; however, these key variables were not included in the nomogram because they are not currently available the SEER database.