Correction: Prognostic impact of tumor size on cancer-specific survival for postoperative WHO grade II oligodendroglioma: a SEER-based study

Abstract

Oligodendroglioma is an incurable and rare primary brain tumor originating from oligodendrocytes or glial precursor cells (1) and accounts for 2-5% of all central nervous system (CNS) tumors (2). According to the World Health Organization (WHO) classification guidelines, oligodendrogliomas are characterized by an IDH mutation and 1p/19q codeletion (3). Based on tumor cells' integrated histological and molecular features, oligodendrogliomas can be divided into well-differentiated WHO grade II and anaplastic WHO grade III (4).Considering their rare incidence, grade II and III oligodendrogliomas are often combined into an entity or grouped with astrocytic tumors during clinical investigations (5). Few studies identified the clinical and biological prognostic factors to predict the outcome of WHO II oligodendrogliomas (OG/II) patients (6), which are less malignant than anaplastic oligodendrogliomas (AOG). Meanwhile, the treatment for OG/II and AOG is usually different. Maximal safe surgical resection accompanied by radiation and chemotherapy is recommended for AOG (3,7). However, the therapy for OG/II remains controversial. According to the 2022 National Comprehensive Cancer Network (NCCN) guidelines, OG/II is divided into low-and high-risk groups depending on the age and extent of resection (8). Nonetheless, as one of the important clinical features, tumor size was not considered a risk factor above.In this study, we performed a retrospective analysis based on the Surveillance, Epidemiology, and End Results (SEER) database. Clinical characteristics and independent prognostic factors were analyzed in OG/II patients. Furthermore, an optimal cut-off value of tumor size to identify poor prognosis was determined, and the patients were divided into two subgroups based on tumor size. Afterward, more analyses were conducted to clarify the impacts of tumor size on the prognosis of OG/II patients, which is instructive for therapeutic strategies, such as the extent of resection, radiation, and chemotherapy.Data were collected from the SEER database (version 8.4.1), and patients diagnosed with WHO-II grade oligodendroglioma (ICD-O-3 histologic code 9450) from 1975 to 2020 were chosen in this study. Our data included age, sex, race, primary site, tumor size, surgery, radiation, survival time, and vital status.An extraction workflow of cases is presented in Figure 1. A total of 2952 cases were found in the SEER database, and we cleaned data as follows: (1) cases that lacked surgical information or were not surgical were excluded. The surgical information was classified into biopsy, subtotal resection, total resection, and extended resection. (2) cases with unknown tumor sizes were cleaned, including the CS tumor size codes 999, 990, and 000. (2) cases that died due to other diseases were omitted. The endpoint of this study was cancer-specific survival. Finally, we confirmed the grades of selected cases, and all cases were moderately differentiated, meaning grade II. All data were collected and analyzed by two independent researchers and verified by the third one.All statistical analyses were performed with R (version 4.1.3), and the following R packages were used: "rms," "foreign," "survival," "ggplot2," "survminer," and "forestplot." Statistical significance was set at P < 0.05. Univariable and multivariable regression analyses were performed in all patients using a Cox proportional hazard model, and the results were presented as hazard ratios (HR) with corresponding 95% confidence intervals (CIs). Variables considered clinically relevant or showed a univariate relationship with outcome were entered into a multivariate Cox regression model. Survival was assessed using Kaplan-Meier models, and statistical significance was determined using the log-rank test. A prognostic nomogram was constructed by R to predict the survival of patients, and calibration curves were formulated to evaluate the judgment ability of the nomogram.A total of 676 postoperative WHO-II grade oligodendroglioma (OG/II) patients were collected in this study, with the diagnostic years ranging from 2004 to 2020 (Figure 1).The clinical characteristics of selected patients are listed in Table 1. Among them, 47.52% of patients were < 40 years old, 87.15% were white, and 56.97% were male. Regarding tumor location, most OG/II (62.23%) were in the frontal lobe.The X-tile software was applied to analyze the optimal tumor size cut-off based on survival information. The cut-off value was identified with the maximum chi-square score and minimum P value. As shown in Figure 2, 60mm was identified as a suitable cut-off value. Furthermore, we also validated the cut-off value in 5mm by univariate and multivariate Cox regression analyses (Table 2). Multivariate analysis showed that the P values of cut-off values from 30 to 75 mm were significant, and the tumor size cut-off at 60mm had a high HR (2.035, 95% CI 1.390-2.981 ) for CSS. Although the largest HR was a cut-off value of 20mm, univariate analysis has no significance. Thus, 60mm was confirmed to be the optimal cut-off value for tumor size.Univariate and multivariate COX analyses evaluated the associations of characteristics in Table 1 with cause-specific survival (CSS). Univariate analysis indicated that age (> 60 years vs. <40 years, HR 3.82, 95% CI 2.45-5.97, P < 0.01), sex (male vs. female, HR 1.45, 95% CI 1.03-2.04, P = 0.031), tumor size (> 60mm vs. ≤ 60mm, HR 2.29, 95% CI 1.59-3.30, P < 0.01), surgery (total resection vs. biopsy, HR 0.36, 95% CI 0.21-0.64, and extended resection vs. biopsy, HR 0.62, 95% CI 0.42-0.82, P = 0.019), and radiation (no vs. yes, HR 1.70, 95% CI 1.22-2.38, P = 0.002) were significantly related to CSS of OG/II patients. Meanwhile, a similar result was found in multivariate COX analyses, except for radiation (Table 3). The result suggested that age, sex, tumor size, and surgery were the key prognostic factors for OG/II patients.Kaplan-Meier curves were subsequently conducted on these four factors, and the result indicated that patients older than 60 years (Figure 3A) or males (Figure 3B) lived shorter. In contrast, those with tumor sizes smaller than 60mm (Figure 3C) or operated with total resection (Figure 3D) had a longer survival time.Based on the tumor size, the OG/II patients were divided into the low-risk group (n = 527) and the high-risk group (n = 119), and the characteristics of patients in different groups are listed in Table 4. Univariate and multivariate COX analyses were conducted (Table 5). In the low-risk group, multivariate analyses indicated that age > 60 (HR 4.05) was associated with worse CSS. In contrast, surgery, especially for total resection (HR 0.35), was related to better CSS. In the high-risk group, only age and sex were considered independent predictors for CSS. Furthermore, an unfavorable role of radiation (HR 1.58, P = 0.033) was found in the low-risk group, and a favorable tendency of radiation (HR 0.98) was observed in the high-risk group. However, the tendency lacked statistical significance.A nomogram was constructed to predict the survival of postoperative OG/II patients with a tumor size less than 60mm. As shown in Figure 4A, each patient's corresponding survival probability could be obtained by summing each predictor's total scores. For example, a 60-year-old male white patient was diagnosed with an oligodendroglioma in the occipital lobe, and he underwent a subtotal resection of the tumor without additional radiation. According to the nomogram, the predicted 3-,5-, and 10-year survival rates are about 81%, 70%, and 50% respectively. Furthermore, The calibration curves of the 3-, 5-, and 10-year survival rates showed good agreement between the nomogram predictions and actual observations (Figure 4B-D).Prediction of oligodendroglioma outcome remains challenging in the clinic owing to its rare incidence. As a type of oligodendroglioma, accurate and effective prediction of OG/II, which is crucial for individualized therapy, may be more difficult. Thus, we conducted a retrospective analysis on SEER, a database that offers an opportunity to investigate rare diseases.Our study collected and analyzed 646 postoperative OG/II cases from SEER. Four key prognostic factors were identified that related to CCS in postoperative OG/II patients, including age, sex, excision extension, and tumor size. OG/II can be classified into lowand high-risk groups based on tumor size. Total recession is recommended in the lowrisk group, while extended resection and radiation may not be beneficial. Tumor size can be a valuable factor for predicting prognosis and making therapeutic schedules, and a nomogram was established (Figure 5).Nearly half of our cases were younger than 40 years, with the incidence peak at 30-39 years. A similar result, 36-40 years, was reported in a study based on the Central Brain Tumor Registry of the United States (CBTRUS) from 2000 to 2013 (9). Our analysis indicated that age is an important factor affecting the prognosis of OG/II patients, and patients over 60 years had worse survival when compared to those younger than 40 years. Age is also considered an essential prognostic factor in other types of glioma (10). Research has demonstrated that glioma is more aggressive in elderly patients (11). And older men usually did not recommend surgery and adjuvant treatment (12). Thus, younger patients are more likely to have a better prognosis.Sex is another independent prognostic factor in our study by univariate and multivariate analysis. In the present study, the male gender was related to high tumor-specific mortality compared to females. As reported, sex differences have been well-identified in many brain tumors, such as glioblastoma. Glioma patients usually present a greater tumor incidence and worse outcomes, which may be caused by different pathophysiologies in gender, including hormones, metabolic pathways, the immune system, and molecular changes (13). Understanding the role of gender in OG/II may help to create a sex-specific therapy to improve the survival of patients.Maximal safe resection of the tumor is the first and most recommended therapy for glioma. However, for OG/II, the influence of tumor resection on the prognosis seems very mild (14). The extent of surgical tumor resection remains controversial. Shawn L. et al. conducted a retrospective study on a multicenter and multinational cohort of 757 diffuse low-grade glioma (LGG) patients. Their result indicated that the extent of surgical tumor resection beginning at 75% improves over survival while beginning at 80% improves progression-free survival of LLG patients (15). However, this result relied on the combined analysis of oligodendrogliomas and astrocytomas. Connor J. et al. reported that a greater extent of surgical tumor resection is associated with improved survival in oligodendrogliomas (16), which include OG/II and AOG. Our study focused on OG/II and found that extended resection of tumors can not benefit more than subtotal resection. And patients with total resection had better cause-specific survival. Thus, we recommended a total tumor resection for OG/II.Tumor size is the maximum diameter of the tumor and has been proven to be a critical prognostic factor for many tumors, such as lung cancer (17), uterine sarcoma (18), and hepatoma (19). In neuroblastoma, Wang et al. identified a cut-off value of 4 cm for tumor size and suggested that tumor size > 4cm might predict poor prognosis (20). Lin et al. reported a tumor size of 59mm as a critical cut-off value for low-grade supratentorial glioma, and they suggest that a tumor size > 59mm represents a high risk and indicates a worsened outcome (21). However, few studies investigate the value of tumor size for OG/II patients. We identified and verified a cut-off value of 60mm for OG/II, which indicated that tumor size > 60mm was a high risk for postoperative OG/II patient survival.Therapeutic schedules for OG/II patients remain controversial and should mainly focus on prognostic factors. ASCO-SNO Guidelines suggest surgical resection accompanied by radiation and chemotherapy for oligodendroglioma, including OG/II and AOG, but the strength of the recommendation is weak(3). A risk classification system was introduced in 2022 NCCN guidelines, and OG/II is divided into low-and high-risk groups relying on the age and extent of resection (8). However, this classification did not include the tumor size, an essential prognostic factor in our analysis. Thus, we further divided the patients into a low-risk group (tumor size ≤60mm) and a high-risk group (tumor size >60mm). The result of univariate and multivariate analyses suggested subtotal or total resection in low-risk patients. However, extended resection and radiation were not recommended in patients with tumor sizes smaller than 60mm. The result agrees with the biological behavior of OG/II, which is a benign tendency with relatively slow tumor growth (15,22). It is important to consider the benefits and potential damage of treatment such as surgery, radiation, and chemotherapy when making a therapeutic