Glioblastoma is an aggressive primary tumor of the central nervous system. This review will focus on clinical developments and management of newly diagnosed disease, including a discussion about the incorporation of molecular features into the classification of glioblastoma. Such advances will continue to shape our thinking about the disease and how to best manage it. With regards to treatment, the role of surgical resection, radiotherapy, chemotherapy, and tumor-treating fields will be presented. Pivotal studies defining our current standard of care will be highlighted, as will key ongoing trials that may influence our management of glioblastoma in the near future.
Click here to read an expert perspective from Nicholas Butowski, MD.
Glioblastoma, previously known as glioblastoma multiforme, is the most aggressive among infiltrative gliomas, a group of primary tumors arising from the central nervous system (CNS). Patients with this cancer type face significant morbidity and mortality, with over 13,000 deaths per year in the United States. Recent advances in our biological understanding of gliomas have led to important and substantive changes in their classification, in the identification of prognostic and predictive molecular markers, and in the therapeutic management of newly diagnosed glioma.
The term ‘glioblastoma multiforme’ was introduced in the 1926 classification system devised by Cushing and Bailey. ‘Multiforme,’ which refers to a heterogenous histologic appearance and proliferation of multiple cell types, was abandoned from the revised nomenclature in the 2007 World Health Organization Classification of Tumors of the Central Nervous System, and is now simply called ‘glioblastoma.’ Glioblastoma is histologically defined by neoplastic cells with astrocytic characteristics and the presence of either endothelial proliferation—often in a glomeruloid morphology—and/or necrosis, which may resemble a pseudopalisading pattern (a false fence of neoplastic cells surrounding an area of necrotic tissue).
Due to its aggressive and highly proliferative course, glioblastoma is considered a grade IV astrocytoma. Molecular characterization has allowed for further refinement of the condition’s classification and is now an integral part of the diagnosis of malignant glioma. Patients are classified into one of two distinct categories based on the presence or absence of mutations in the IDH1 or IDH2 genes.
Primary glioblastoma/IDH wild-type glioblastoma
The majority of glioblastomas are IDH wild-type and correspond to the longstanding clinical description of primary glioblastomas, which arise rapidly from non-neoplastic brain cells and progress quickly. In addition, a subgroup of lower-grade gliomas may carry molecular features and signatures similar to glioblastoma, with a similarly aggressive natural course, for which an intensive treatment strategy is advocated. These facts stress that a microscopic histologic diagnosis alone is insufficient to make informed and rational clinical decisions; therefore, it is essential that molecular alterations be integrated when diagnosing and managing glioma. This will potentially be of benefit in opening up appropriate clinical trial opportunities for this subset of patients in the future.
Secondary glioblastoma/IDH-mutated glioblastoma
Up to 10% of patients with glioblastoma harbor a mutation in the IDH1 or IDH2 genes, an early event in gliomagenesis. Since these glioblastomas often arise from a prior lower-grade glioma, they are considered secondary glioblastomas. In the past, both primary and secondary glioblastomas were considered to be the same clinical entity. However, recent studies clearly indicate that IDH-mutated glioblastomas have a more protracted natural course. As such, secondary glioblastomas are to be classified as a distinct biological and molecular entity for which different treatment strategies will ultimately be proposed. Former series of long-term survivors are commonly enriched for patients with IDH-mutated tumors.
Primary CNS tumors represent only 2% of adult cancer diagnoses; however, due to their location and often rapid clinical course, they are associated with high morbidity and mortality. About 50% of primary malignant CNS tumors are glioblastoma, with an incidence rate of 3.20 per 100,000 population for the United States. Incidence is higher in whites than in blacks (3.46 vs 1.79 per 100,000 population, respectively), with a 1.93:1 ratio (P < .05), a difference for which no biological explanation exists. Compared with whites, the incidence of glioblastoma is somewhat lower in Asians. The condition occurs more frequently in men than in women, with a 1.58:1 ratio (P < .05). Over the last 3 decades, the incidence of glioblastoma in the United States has been relatively stable; however, an aging population and better diagnostic tools may lead to a higher incidence of disease, as has been suggested in other countries. Further study is needed to confirm changes in incidence, and, if present, to determine the causal factors.
Both environmental and patient-intrinsic factors may influence the risk of developing glioblastoma. An established risk factor is prior exposure to ionizing radiation to the CNS. The lag time between radiation and the development of glioblastoma may range from years to decades.[9-11] Unlike other cancers, there is no histologic or molecular signature that is pathognomonic for radiation-induced glioblastoma. The condition is observed in several hereditary cancer syndromes, including Lynch syndrome (with mutations in MSH2, MLH1, MSH6, and PMS2) and Li-Fraumeni syndrome (with mutations in TP53). While mutations in some tumor suppressor genes increase the risk of susceptibility, the presence of an allergic disorder appears to be associated with a decreased incidence of glioma, including glioblastoma, across a number of epidemiologic and preclinical studies.[7,12-14]
Despite extensive study, the cellular origin of glioblastoma and the pathophysiologic mechanism of gliomagenesis remain uncertain. Research on the cell of origin for glioblastoma often involves targeting different precursor cell populations in transgenic mouse models and explores the effects of these interventions on the development of glioma. However, contemporary thought favors primitive pluripotent cells, including neural stem cells, glial precursor cells, and oligodendrocyte precursor cells. Numerous preclinical models have been conducted in this area, each with their favorable attributes and drawbacks.[16-19]
Research demonstrates that, amongst IDH wild-type glioblastomas, there are spatial intratumoral differences in the mutational profile and clonality of tumor cells, with approximately half of the mutations being regionally exclusive. Distinct areas found within these tumors can exhibit a hypermutated phenotype. When present, mutations in the TERT gene appeared across all clones. Recent studies utilizing xenografts in murine models have shown that these tumors consist of a slow-cycling population of stem-like cells, which give rise to a rapidly dividing progenitor cell population, a proportion of whose daughter cells develop into terminal differentiated cells, supporting a hierarchical model of gliomagenesis. A minority of the clonal population proves resistant to chemotherapy. In turn, this cell population will require different treatments. When evaluated longitudinally, recurrent glioblastoma can accumulate additional mutations, and can appear similar to the primary tumor or may resemble a distinct subclonal population.[23,24] It is thought that this genomic heterogeneity is driven, at least in part, by the uneven cellular inheritance patterns of extra-chromosomal DNA. As we garner a clearer understanding of the pathophysiology of gliomagenesis, new areas for potential therapeutic intervention will open up.
In addition to the difficulties associated with treating heterogenous tumors, which evolve over the course of the disease and harbor treatment-resistant subpopulations of cells, the blood-brain barrier is another impediment to the effective treatment of these tumors. The blood-brain barrier is a dynamic functional system, which both precludes and modulates the traversing of systemically administered therapies into the CNS, including CNS tumors. Numerous means have been utilized to overcome this obstacle. Thus far, the most successful have included systemically administered drugs with adequate CNS penetration (eg, temozolomide) and locally delivered alternating electrical fields (tumor-treating fields, TTFields). Direct intracranial application of both chemotherapy (eg, biodegradable carmustine–impregnated wafers) and radiation (eg, brachytherapy) has also been explored.
Intratumoral injection of oncolytic viruses and chimeric antigen receptor (CAR) T-cell therapies is a modern example of a similar strategy that is undergoing active investigation.[27,28] Disruption of the blood-brain barrier to facilitate transmission of a systemically administered therapy has been under investigation for many decades. Initial studies utilized intra-arterially–administered agents. A recent strategy being studied includes ultrasound to open up the barrier. Another, which has had varying degrees of success, is avoiding the need to overcome the blood-brain barrier. The utilization of therapeutics whose direct activity occurs on the luminal side of the blood-brain barrier (eg, bevacizumab)—or which act on the luminal side, with a goal of affecting function on the tumoral side of the barrier (eg, immune checkpoint inhibitors)—is another way to attempt to circumvent this obstacle. It is reasonable to surmise that more than one approach may prove to be successful.
The therapeutic management of newly diagnosed glioblastoma typically involves a four-pronged approach. First, surgical resection is completed to the maximal safe extent, thereby reducing the tumor load and establishing a histopathological and molecular diagnosis. Following surgery, adjuvant radiotherapy is given with concomitant and maintenance chemotherapy, as is treatment of alternating electrical fields.
Surgery plays an important diagnostic and therapeutic role in the management of glioblastoma: it offers tissue for histological and molecular diagnosis, immediate relief of the tumor-related mass effect and its associated symptoms, and potential cytoreduction. However, due to the invariably infiltrative nature of the disease, even macroscopically complete resection is not curative. Numerous retrospective studies have evaluated the value of the extent of resection in glioblastoma. While early work suggested a dichotomous picture with a need for a substantial extent of resection of the contrast-enhancing tumor, subsequent studies demonstrated the graded benefit of the extent of resection.[33,34] A more recent meta-analysis also supports a more extensive resection with improved 1- and 2-year survival rates, as well as prolonged progression-free survival. In low-grade glioma, the extent of resection is influenced by the area of increased signal on T2/fluid-attenuated inversion recovery (FLAIR) imaging.[36-39] Similarly, glioblastoma tumors are not limited to the area of enhancement but rather involve the area of increased T2/FLAIR signal. The extent of resection of this non-enhancing glioblastoma may also be of clinical impact, as demonstrated in a recent retrospective study.
Although the association between extent of resection and survival has been reported and consistently confirmed in numerous studies, it is subject to several potential confounders, biases, and occult prognostic factors. While cytoreduction may intuitively delay disease recurrence, the non-linear growth of tumor cells seen in glioblastoma could quickly recover the tumor burden that was removed during surgery, negating the survival benefit of small increments of cytoreduction. The durability of the effect of cytoreduction, and whether it leads to a survival benefit, is likely related to the rate of tumor cell proliferation. On the other hand, patients with neurological deficits have lower functional status, which ultimately impacts their overall survival. Thus, it is possible that relief of mass effect leading to improved functional status from resection might prolong survival in symptomatic patients, irrespective of cytoreduction. Finally, the tumor location may also reflect the underlying biology and dictate the natural history of the disease. Determination of the influence of these previously described variables on overall survival is complicated, since resectable tumors may have an overall better prognosis, regardless of the actual extent of resection.
Resectable tumors often present in “silent areas of the brain” that tolerate injury for a long period of time prior to becoming symptomatic. In addition, resectable tumors, such as fronto-polar tumors, are more likely to harbor IDH1 mutations, which are associated with a better prognosis. In contrast, unresectable tumors, such as midline/diencephalic or brainstem tumors, often bear H3K27 mutations, which indicate an overall more aggressive biology and a worse prognosis. Further dissection of the relationship between the extent of resection and survival requires controlling for tumor resectability. Yet, this complicated variable is difficult to capture by established scales, and is influenced by anatomical considerations, as well as neurosurgeon-related factors.
Maximizing extent of resection. A number of technological advances have been developed to safely maximize the extent of resection, although their availability and usage may vary greatly. These techniques have become more widespread over time because, in addition to maximizing the extent of resection, they also optimize the safety of intra-axial brain tumor surgery. The major technological tools that surgeons use for improving the safety and accuracy of resection can be divided into three groups, as follows.
Intraoperative navigation technology. This technology involves the use of volumetric imaging (eg, MRI or CT scan), which is used as a reference to locate a lesion/anatomical structure within the surgical field. Navigation involves an optical or electromagnetic system that uses a physical reference to register the location and position of a patient’s head in space, and allows real-time visualization of instruments within the images, which are loaded to a computer. These technologies help minimize the extent of the open craniotomy exposure; optimize a trajectory to access lesions that avoids critical neural structures, such as white matter pathways; and provides an anatomical reference during the operation. However, they are limited by the fact that the referenced images are not updated as resection progresses, and brain shift in space in relation to the skull makes this information less reliable as the case advances. To address this, several groups have introduced intraoperative MRI, which provides a real-time update of the field for navigation.[43,44] The true utility and cost-effectiveness ratio of intraoperative MRI remains a highly debated topic, since cost and added time during the procedure are not insignificant. The use of intraoperative ultrasound is a dynamic, easy to use, and affordable alternative for real-time imaging during surgery.
Electrophysiological monitoring and functional brain mapping. Wilder Penfield and George Ojemann pioneered the use of electrodes to functionally map sensory and motor primary cortical regions and related subcortical circuits as the spinothalamic and corticospinal tracts to avoid postoperative deficits.[45-48] Over the last few decades, work by George Ojemann, Hugues Duffau, Mitchell Berger, and others has incorporated the routine use of awake brain mapping techniques, which have greatly improved the surveillance of motor circuits, language/comprehension, coordination, vision, and some higher cognitive functions by enabling them to be mapped and preserved.[49-53]
Fluorescent markers to maximize tumor visualization. Fluorescent dyes—which are either metabolized by tumor cells, or accumulate in areas of blood-brain barrier breakdown—have been incorporated to maximize tumor tissue visualization in the operating room. This is helpful, as gross tumor tissue often has a similar texture or color as the surrounding edematous brain and is not always easy to distinguish under bright light. The use of 5-aminolevulinic acid under blue light allows the neurosurgeon to view residual tumor in real-time during surgery. A phase III trial demonstrated an improved rate of complete resection (65% vs 36%; P < .0001) and an improved 6-month progression-free survival rate (41% vs 21%; P = .0003) for contrast-enhancing tumor with 5-aminolevulinic acid compared with conventional microsurgery with white light. However, this did not translate into an improvement in overall survival. Fluorescein has also been used to visualize enhancing tumor, as this dye leaks through areas with defective blood-brain barrier.[55,56] Here, no special light source is needed.
Radiotherapy has been shown to improve survival in glioblastoma and plays a key role in treatment. Modern conformal radiotherapy—which utilizes three-dimensional computerized planning and multi-beam modulation—focally treats MRI-evident disease plus margin to a cumulative absorbed dose of 60 Gy. Given in daily doses of 1.8 to 2.0-Gy fractions, total treatment lasts approximately 6 weeks and is usually initiated 3 to 4 weeks after surgery. While some reports have suggested that delayed radiotherapy has a detrimental effect, other investigators have reported better outcomes; this question has yet to be definitively answered.[57,58] Up to 6 to 7 weeks of postoperative recovery is considered acceptable as part of the established standard of care.
Earlier studies have examined doses of more than 60 Gy, some of which incorporated stereotactic radiosurgery. However, they failed to demonstrate improved outcomes with doses of up to 76 Gy. An ongoing randomized phase II study, NRG BN001 (ClinicalTrials.gov identifier: NCT02179086), is evaluating dose escalation to 75 Gy compared with standard 60-Gy radiotherapy. This study includes distinct cohorts utilizing photons or protons, and the primary endpoint is survival.
For elderly patients or those with substantially altered performance status and poor prognosis, an abbreviated course of “hypofractionated” radiotherapy allows for a shortened overall treatment time. Long-term toxicity is of less concern in this population due to a commonly short survival. Hypofractionated radiation, which has been widely investigated, has been utilized to improve tolerability of radiotherapy (Table 1). Tumor volume often guides the selection of a radiation regimen because the risk of toxicity is theoretically greater with high vs low daily doses. Omitting radiotherapy (even less than the standard 60 Gy) leads to significantly worse survival compared with best supportive care alone. Recent prospective data have demonstrated that abbreviated courses can also be safely and effectively combined with concurrent chemotherapy, as covered in the section below regarding treatment strategies for elderly patients.
A direct prospective comparison between full-course radiotherapy with concurrent and adjuvant chemotherapy vs abbreviated-course radiotherapy with concurrent and adjuvant chemotherapy has not been conducted. In addition to an abbreviated course of radiotherapy, the shorter course also employs a shorter course of concomitant chemotherapy. This lack of direct comparison leaves an important question not fully answered. In many clinical practices, the full course of radiotherapy and chemotherapy will be utilized in elderly patients with good performance status.
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