Patterns of glioblastoma treatment and survival over a 16-years period: pooled data from the German Cancer Registries

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most common primary malignant brain tumour characterized by an infiltrative growth pattern and a low survival rate, with only 6.8% of patients surviving five years post-diagnosis according to the 2019 Central Brain Tumour Registry of the United States (CBTRUS) Statistical Report (Ostrom et al. 2019). The reported incidence rate worldwide varies between 0.59 (South Korea) (Lee et al. 2010), 3.19 (USA) (Thakkar et al. 2014), 3.3 (France) (Fabbro-Peray et al. 2019), and 3.8 (Sweden) (Eriksson et al. 2019) per 100,000 persons.

The ‘standard of care’ treatment for GBM is maximal safe surgical resection, followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ) chemotherapy (Al-Holou et al. 2020). The inclusion of TMZ chemotherapy in treatment guidelines was based on the results from a clinical trial by (Stupp et al. 2005). This landmark trial demonstrated that the addition of concomitant and adjuvant TMZ to radiotherapy provided additional survival benefit to patients, with an increase in median overall survival (OS) of 14.6 months compared to 12.1 months in the radiation only arm. The addition of TMZ is considered a major contributor to survival improvement, from the median 6.9 months in those diagnosed during 1995–1996 to 10.3 months in the period 2010–2015, with 2-year survival peaking at 18%, shown by a Swedish single centre study (Eriksson et al. 2019). Several studies from the US compared survival rates in the periods pre- and post-TMZ approval, predominantly based on the Surveillance, Epidemiology and End Results (SEER) Program database (Zhu et al. 2017; Johnson and O'Neill 2012; Darefsky et al. 2012), but also from the Veterans Health Administration (VHA) dataset (Dubrow et al. 2013). These studies confirmed that survival improvement for GBM patients overlapped with the addition of TMZ to standard therapy protocols. Several European studies reported similar findings (Fabbro-Peray et al. 2019; Eriksson et al. 2019; Scoccianti et al. 2010; Ronning et al. 2012; Hansen et al. 2018). However, even with high compliance to therapy regimens, cancer registry-based studies usually report shorter median OS than those shown by clinical trials.

The aim of this study was to evaluate the distribution of treatment modalities after GBM diagnosis, such as surgery, radiotherapy, and chemotherapy, encompassing 16 years (1999–2014) of data collection by the German Cancer Registries, and to analyse their effect on survival. We hypothesized that there would be an improvement in survival due to technological advancements and more effective treatment options for GBM patients between the first and last period.

Our results showed that advancements in treatment routines, especially after 2005, led to the improvement of survival based on the Cox model estimates and improved 2-year survival for GBM patients in Germany. First, the median OS was 10 months, which is in line with results from other cancer registry studies (Fabbro-Peray et al. 2019; Eriksson et al. 2019; Zhu et al. 2017; Johnson and O'Neill 2012; Hansen et al. 2018) and the clinical trial in elderly patients by Perry et al. (Perry et al. 2017). Analyzing the age distribution, cases were mostly in the older age categories, which could explain the lower OS in the present study compared to the trial by Stupp et al. (2005), which had an upper limit (71 years) on age when enrolling participants. Taking into account that clinical trials perform a rigorous selection of patients, with a different distribution of comorbid conditions and better access to treatment, median OS is usually higher than what is observed in population-level studies (Pulte et al. 2019). Secondly, we observed that the median OS, when stratified by age, treatment and time period, improved after 2005. The addition of TMZ chemotherapy to surgical resection and radiotherapy increased median OS for the older age groups, however, it had no to little effect in the younger age groups. The interaction analysis revealed that the effect of treatment modalities changed over time, with the biggest improvement stemming from chemotherapy use and advancements in surgical treatment. We cannot answer based on currently available data whether this is a result of improved precision or the extent of surgery. However, regarding chemotherapy, the only chemotherapy agent approved for first-line treatment of GBM has been TMZ, to which we can attribute most of the improvement. Finally, the absence of cancer-related treatment was more common in the older age groups, while multimodal therapy was more customary in the younger group.

A key factor that influenced survival was the age at diagnosis. The survival disparity between the different age groups was expected since survival declines with increasing age (Laperriere et al. 2013). A recent clinical trial by Perry et al. examined the treatment paradigm for patients older than 65 years, and concluded that the addition of TMZ to short-course radiotherapy resulted in longer survival than radiotherapy alone (Perry et al. 2017). This is relevant for clinical practice, taking into account that 35% of our cases were in the 70 and older age category. Additionally, molecular prognostic factors for GBM are correlated with age. These include O⁶-methylguanine-DNA methyltransferase (MGMT) gene promotor methylation and isocitrate dehydrogenase (IDH1) mutations (Weller et al. 2009). About 10% of GBMs are IDH gene mutated and this is associated with a better prognosis, while typically GBMs are IDH wild-type. Elderly patients are more likely to have IDH wild-type, which indicates a shorter survival compared to younger patients (Zhu et al. 2017). Additionally, older patients are burdened with more comorbidities and have more treatment-related side effects (Brandes et al. 2009). However, this group often has methylation of the MGMT promotor, which offers chemosensitivity and increased benefit from TMZ treatment (Perry et al. 2017; Wick et al. 2012; Hegi et al. 2005).

Survival rates for patients with GBM have shown little notable improvement in the last two decades. Our results are comparable to the median OS and 2-year survival rates reported by other population-based registry studies using SEER, VHA, CRN (Cancer Registry of Norway) (Ronning et al. 2012), the FBTDB (French Brain Tumor Database) (Fabbro-Peray et al. 2019) and the Danish Neuro-Oncology Registry (Hansen et al. 2018). According to the study by Dubrow et al. (2013), addition of TMZ chemotherapy to standard therapy protocols explained the improved survival observed on a population level, even though they showed much lower median OS (6.4 months). Our results are comparable to the study by Zhu et al. (2017) that reported 10 months median OS and a 2-year survival rate of 16.8%. Other European studies, such as from France, reported 11.2 months (Fabbro-Peray et al. 2019), Norway, 8.3 and 10.1 months in the pre-TMZ and TMZ eras, respectively (Ronning et al. 2012), and Denmark, 11.2 months (Hansen et al. 2018). A clear explanation why there is little change in survival from GBM in Germany during 16 years is difficult. One possible reason could be that cases diagnosed at an older age, whose numbers increased substantially due to demographic changes or improved case ascertainment in the cancer registry, are subjected to less aggressive treatment protocols. A study from Fabbro-Perray et al. (2019), stated that in ‘real-world’ setting, only 60% of patients initiate standard treatment, and while we are unable to confirm this from our data, the overall use of surgery, radio- and chemotherapy was relatively high and increased in subsequent periods, meaning this could not completely explain the discrepancy.

Glioblastoma multiforme is a costly disease due to hospitalization and life-years lost in the post-diagnosis period, hospice care, and claims for physical, occupational and speech therapy (Aly et al. 2019). Before our analysis, we expected a more substantial improvement in survival of GBM patients, considering advances in surgical techniques and the introduction of postoperative radio-chemotherapy with adjuvant chemotherapy as a standard treatment after 2005. The implementation of neuronavigation and the introduction of intraoperative 5-aminolevulinic acid (5-ALA) fluorescent microscopy have enhanced the possibility to achieve a better gross total tumor resection. Our analyses revealed that surgery is associated with better survival, as also reported by another study (Al-Holou et al. 2020). The effect of radiotherapy advancements was more modest even though there were several novel radiotherapy choices. Intensity-modulated radiation therapy represents an advance option in terms of conformal treatment. Additionally, tumor-treating fields (TTFs) are an important cancer treatment modality with antimitotic effects against rapidly dividing tumor cells (Fabian et al. 2019). This is an upcoming new standard of care for both newly diagnosed and recurrent GBM cases (Kazda et al. 2018). More aggressive treatment of recurrent disease, with the application of stereotactic radiotherapy and improvements in palliative care, might also contribute to better survival. Regarding chemotherapy, the use of TMZ has been consistently associated with improved survival. Co-administration of radiotherapy and TMZ has nearly tripled the 2-year survival of GBM patients in the last two decades from 10 to 27% and quadrupled to 47% in patients with MGMT promotor methylation (Kazda et al. 2018). However, current clinical trials have reported improved chemotherapy benefits only in patients with prognostically positive molecular profiles, and this is important evidence toward the implementation of a personalized treatment strategy (Herrlinger et al. 2019; Bent et al. 2019). Several known and newly discovered chemotherapy and immunotherapy agents have been tested, offering modest or no improvement in median OS (Gilbert et al. 2014; Weller et al. 2017), but no second-line treatment has been established. Regardless of modern state-of-the-art treatment, due to the highly invasive nature of GBM, median OS remains between 10 and 14 months (Seyfried et al. 2019). Additional research is needed to improve the poor prognosis of these patients.

While the median OS did not improve significantly during the three periods, there was a slight increase in 2-year survival and a notable survival improvement after 2005 for all treatment modalities. The addition of TMZ chemotherapy improved survival more evidently in the older age groups but had a lesser effect in the younger age groups. Survival improvement depends on several factors and accentuates the need for a personalized strategy in GBM treatment management.