In the current SEER-based study, we analyzed the clinicopathological features that are potentially associated with the efficacy of chemotherapy to identify certain patient populations that might be more likely to benefit from chemotherapy. Also, we explored the prognostic factors of GBM by univariate and multivariate Cox analyses. We observed that chemotherapy was associated with improved OS and GBMSS. Besides, the benefits of chemotherapy were greater in patients who were younger than 65 years old, with a tumor grade I/II, or underwent additional treatments. Age at diagnosis, race, tumor size, tumor location, surgery, and radiotherapy were the major factors of prognosis.
The validated chemotherapeutic agents TMZ and BEV were approved by the FDA in 2005 and 2009 respectively. The population enrolled in our study was diagnosed with GBM between 2004 and 2015. The median survival of patients who received chemotherapy reported in this study was significantly longer than patients who did not. The benefit of chemotherapy has been proved in previous studies. However, it has generally accepted the improvements provided by the current treatment are limited. The progression-free survival of patients with lomustine plus BEV was 2.7 months longer than lomustine alone, while the median OS of patients with the addition of BEV was not increased significantly compared to lomustine alone [20]. Dose-dense TMZ for newly diagnosed GBM didn’t improve overall survival or progression-free survival compared to standard TMZ [21]. One of the reasons is that some cases are resistant to TMZ, and O6 -methylguanine-DNA methyltransferase (MGMT) mainly contributes to the TMZ chemoresistance [22]. Toxicity of drugs and BBB are the potential factors that limit the efficacy of chemotherapy. A cumulative dose of TMZ increases the risk of lymphopenia [23]. BEV may cause toxicity, bleeding events, stroke, and wound-healing complications [24]. Although BBB is disrupted partly, increased expression of pro-angiogenic factors and increased interstitial fluid pressure still limit small-molecule drugs through the BBB and towards the site of tumor [25]. Local drug delivery vehicles, including carmustine (BCNU)-loaded polyanhydride wafers, convection-enhanced delivery, microsphere formulations, drug-loaded nanoparticles, intraventricular delivery, intrathecal delivery, intranasal delivery are used for accelerating the delivery of therapeutic compounds to the brain [26]. In addition to promising new drug delivery materials, the optimal therapeutic regimen is being determined. A study analyzed data from the French Brain Tumor DataBase, compared to standard 6 cycles, patients received adjuvant TMZ beyond 6 cycles had improved survival [27]. The delay in the initiation of chemotherapy and radiation following resection longer than 6 weeks was associated with worse OS [28].
The current care standard regimen is based on the study involved patients under 70 years, while the median age of GBM patients is 64.0 years and the incident rate of GBM appears to correlate with increased age [19]. There was increased use of chemotherapy and radiotherapy from 40.3% in 2004 to 59.8% in 2012 among patients aged 70 years and older [29]. Therefore, the efficacy of adjuvant therapy in the elderly population needs to be discussed. In our study, all ages were included and divided into three age groups with the median age 63 years. Elderly patients aged 65 years or over had the worst median OS (5 months) and GMBSS (5 months) among all age groups. Although young patients benefited most from chemotherapy, the survival of elderly patients was also improved by chemotherapy. A trial involving 562 patients aged 65 years or older showed that radiotherapy plus TMZ had longer median OS compared to patients with radiotherapy alone [11]. Thus, chemotherapy should be considered as an effective treatment for all ages.
We found that there was a relationship between tumor location and survival, and most GMB was supratentorial tumor with better survival than other locations. A study showed that 61% primary gliomas occur in the four lobes of the brain, frontal (25%), temporal (20%), parietal (13%), and occipital region (3%), brainstem and cerebellum only accounts for 1.2% and 0.9%, respectively [30]. Patient characteristics, histologic features, and genomic profiles are different between supratentorial glioblastoma and cerebellar glioblastomas [31]. The most impacted function region was eloquent cortex [32]. Patients with tumors in the right deep periventricular white matter region had poor survival [33]. Tumor location impacts the extent of resection and postoperative tumor volume. A study involved patients younger than 20 years old suggests that aged 0–4 years, infratentorial tumor location, and subtotal resection were associated with higher mortality [34]. In addition to tumor location, our study found that the diameter of the tumor over 4 cm was associated with poorer survival. A clinical trial showed that the median preoperative tumor volume was 24.9 cm3, and patients aged over 60 years showed significantly increased tumor volume which was 30.9 cm3. Postoperative tumor volume remained was a significant prognostic factor. The median postoperative tumor volume was 0.1 cm3; the difference in residual tumor volumes between older and younger patients was not significant [35].
In our study population, most patients received multiple treatments. Among patients who received chemotherapy, 85.41% underwent surgery and 82.34% underwent radiotherapy. Moreover, surgery and radiotherapy were prognostic factors for patients with GBM. We observed that surgery or radiotherapy improved survival when combined with chemotherapy, compared to chemotherapy alone. The high infiltration nature of GBM cells makes it difficult to achieve complete eradication of the primary tumor and leads to a high recurrence rate. Surgery is the pivotal treatment for GBM, the extent of resection (EOR) and residual volume are significantly associated with prognosis. Increased EOR and reduced residual volume were associated with longer survival and delayed recurrence of patients who received adjuvant therapies, including TMZ and radiotherapy [36]. Radiotherapy is involved in the standard regimen and is an effective treatment for unresectable GBM. Some studies have shown that the chemoradiation strategy is more effective than radiotherapy alone [6,12༌37].
In our study, gender was one of the prognostic factors for OS. Females with GBM often had a better outcome than males,gender disparity involved mechanisms and immune function contribute to different outcomes [38༌39]. Gender differences also reflect in different molecular subtypes of GBM, mesenchymal subtype, proneural subtype, and neural subtype most occur in males, while the classical subtype is equally prevalent in males and females. We found that white patients were associated with higher risk of death. A study showed that non-Hispanic whites had higher incidence and lower survival rates [40].
There are potential limitations to our study. First, information about chemotherapy is deficient. According to the SEER data, there exists a certain number of patients whose chemotherapy status is not sure, and that may cause misclassification. Although some results are consistent with previous studies, there still have some biases inevitably. Second, regarding treatments, we did not further discuss the detailed treatment modality, the radiotherapy sequence with surgery and chemotherapy information of individual patients.
In summary, our study supports the idea that combined therapy, namely, surgery or radiotherapy plus chemotherapy, might bring about more survival benefits than chemotherapy, surgical resection, or radiotherapy alone, which, in clinical settings, suggests that after considerate assessments, clinicians should encourage eligible patients to receive chemotherapy with surgery or radiotherapy to maximize their survival benefits.