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.
We recently reviewed in detail the pivotal late-phase trials that led to the current standard of care for patients with newly diagnosed glioblastoma. These trials are summarized in Table 2. Temozolomide is a DNA-alkylating chemotherapy agent that is designed to readily cross the blood-brain barrier to achieve therapeutic concentrations in the brain. In 2005, a large, international, randomized, phase III trial, the European Organisation for Research and Treatment of Cancer (EORTC) 26981/22981/National Cancer Institute of Canada (NCIC) CE3 trial, demonstrated prolonged survival when daily temozolomide chemotherapy (75 mg/m2 daily × 40–49 days) is added concomitantly to radiotherapy followed by 6 cycles of maintenance temozolomide (150–200 mg/m2 × 5/28 days). Based on this landmark trial, temozolomide/radiotherapy followed by maintenance temozolomide has become the worldwide standard of care for patients with newly diagnosed glioblastoma.[63,64]
Temozolomide adds a methyl group to the DNA residues at the O6, N3, and N7 positions that, if unrepaired, leads to DNA strand breaks and cytotoxicity. More than one-third of glioblastomas are deficient in O6-methylguanine-DNA methyltransferase (MGMT), a repair protein that removes the methyl adduct from the O6 guanine position. This MGMT deficiency is via methylation of the MGMT gene promoter, which leads to downregulated transcription. Glioblastoma patients with a silenced MGMT gene who are treated with an alkylating agent chemotherapy have a longer survival than those with an unmethylated MGMT and those treated with radiotherapy alone. In studies of paired tissue samples, MGMT promoter methylation is relatively conserved from the newly diagnosed to progressive disease settings, with the majority of tumors maintaining an unchanged profile over time.[66,67]
In mismatch repair–deficient conditions, the O6 guanine methyl adduct is tolerated and can be mutagenic. This may be a key mechanism in the development of glioma mutations due to temozolomide, and is described in low-grade glioma progressing to higher-grade tumors, as well as potentially in the development of a hypermutated phenotype.[68,69] The methyl adducts at N3 and N7 are addressed by the base excision repair mechanism. Inhibition of this mechanism continues to undergo investigation in trials of poly (ADP-ribose) polymerase (PARP) inhibitors.
Optimal duration of adjuvant temozolomide chemotherapy. The pivotal EORTC/NCIC study established a regimen of up to 6 adjuvant chemotherapy cycles. However, in the United States, the duration of chemotherapy may still extend for up to 12 cycles or more in non-progressive patients. While early treatment discontinuation is a concern due to the disease’s poor prognosis, cumulative toxicity, impaired bone marrow reserve for subsequent second-line chemotherapy, and increased risk of secondary malignancies are concerns with prolonged treatment. In some trials, treatment was allowed per local practice to be extended to up to 12 cycles.
A pooled meta-analysis of individual patient outcomes data stemming from four randomized trials compared the duration of maintenance temozolomide chemotherapy (6 cycles vs 7+ cycles) among individuals who were non-progressive after 6 cycles. While there was a slight improvement in progression-free survival, no difference in survival was seen for those who received 6 cycles vs more than 6 cycles of chemotherapy. This suggests that prolonged administration and dose intensification do not improve disease control. At this time, the value of temozolomide during radiotherapy, independent of adjuvant temozolomide in the treatment of glioblastoma, is unknown.
Alternative temozolomide dosing schedules. Alternative dosing schedules have been investigated in the newly diagnosed and recurrent disease settings. However, none of these regimens have been shown to be superior to the standard temozolomide dosing schedule. The randomized Radiation Therapy Oncology Group (RTOG) 0525 study found no benefit with intensified maintenance chemotherapy. Patients were randomized at the end of chemoradiotherapy to either standard maintenance therapy (150–200 mg/m2/day × 5/28 days) or an intensified daily regimen (75 mg/m2/day × 21/28 days), effectively doubling the cumulative dose of chemotherapy. No difference in outcomes was noted, and a higher incidence of grade 3/4 toxicities was observed in the investigational arm.
Hopes and disappointments with bevacizumab. The addition of the anti- angiogenic agent bevacizumab to radiotherapy and temozolomide has been explored in two phase III trials focusing on newly diagnosed glioblastoma[73,74] and one phase III trial focusing on recurrent glioblastoma. The observed and expected improvement in progression-free survival based on imaging did not translate into any improvement in overall survival when bevacizumab was added. Unplanned post-hoc analyses found an association of improved overall survival in a molecularly defined subset of patients. The addition of bevacizumab to hypofractionated radiotherapy demonstrated no improvement in overall survival compared with hypofractionated radiotherapy alone in elderly (≥ 65 years) patients with newly diagnosed glioblastoma. Based on the results of these trials, bevacizumab should not be administered as part of primary treatment of glioblastoma. Of note, some physicians utilize bevacizumab as a corticosteroid-sparing agent to decrease cerebral edema, so that treatment with standard radiotherapy and chemotherapy is feasible without high doses or prolonged use of corticosteroids.
De-escalation of treatment in the elderly. De-escalation of therapeutic interventions has been extensively explored in the elderly and in frail populations with glioblastoma. This interest is driven by the overall brief survival of elderly glioblastoma patients, and thus the desire to shorten the duration of medical intervention. This topic has recently been reviewed in detail.[78,79] Several studies have prospectively evaluated abbreviated courses of radiotherapy in these patients (as covered earlier in the “Radiation Therapy” section).
Two large randomized trials have evaluated the exclusive administration of temozolomide chemotherapy in the elderly. Consistently, both trials demonstrated that withholding radiotherapy and instead treating patients with temozolomide alone may be an option for elderly patients with tumors harboring a methylated MGMT gene promoter, while this strategy is detrimental in the absence of MGMT methylation.[80,81] Monotherapy with temozolomide offers the advantage of an oral treatment regimen without the need for daily radiotherapy. The utilization of a short-course hypofractionated radiotherapy regimen (of 40 Gy in 15 treatments) with concomitant temozolomide, followed by adjuvant temozolomide, was shown to improve outcomes in the elderly, which is consistent with the observed benefit reported 10 years earlier by the EORTC/NCIC trial in patients up to age 70 years. The clinical circumstances, including chronologic age, performance status, concurrent medical problems, MGMT promoter methylation status, and logistical concerns should all be weighed during therapeutic decision making for elderly patients with glioblastoma. In healthy MGMT-methylated elderly patients with good performance status, a more aggressive approach, including full-course radiotherapy and temozolomide, can be considered.
Poor performance status. Both de-escalation and escalation of care for patients with poor performance status have been considered. Many of these evaluations have been performed specifically in the elderly population, thus potentially limiting their generalizability to younger patients. De-escalation approaches attempt to limit the toxicity of treatment in a patient population that may not tolerate and is less likely to benefit from therapy. These approaches also attempt to shorten treatment duration, as well as the amount of travel to the treatment facility, particularly for patients with limited mobility.
The previously discussed abbreviated radiotherapy courses for elderly patients are also often used in the frail population with a poorer performance status; some prospective studies on abbreviated radiotherapy included patients on the basis of performance status alone.[83,84] The use of temozolomide chemotherapy alone has been studied in patients with poor performance status (Karnofsky Performance Score [KPS] of < 70); it was shown to be associated with an improvement in performance status or an improvement to the level of self-care (KPS ≥ 70) in one-third and one-fourth of patients, respectively. Increasing the number of concomitant therapeutics has been performed with the goals of extending survival and improving functionality. One treatment intensification approach adds bevacizumab to the standard of care, relying on the corticosteroid-sparing effects described earlier. This approach has demonstrated only a transient improvement in performance status, and the data thus far do not justify its routine employment, since median overall survival remained short at 5.6 months (95% CI, 4.4–6.4).
The addition of TTFields to maintenance temozolomide chemotherapy for newly diagnosed glioblastoma patients has recently been incorporated as a new standard of care.[87-89] TTFields are applied via multiple electrodes that are directly fixed to the scalp. These low-intensity alternating electrical fields of 200 Hz interfere with polar organelles (eg, tubulins), which are required for normal cell division. Mitotic disruption ultimately leads to cell cycle arrest, aneuploidy, and apoptosis.[90,91] Additional mechanisms potentially contributing to therapy-associated effects include a disruption of organelles and an induction or modulation of the anti-glioma immune response.
The effect of TTFields was evaluated in two large, prospective, non-blinded randomized trials. In recurrent disease, TTFields failed to show superiority over best physicians’ choice therapy in patients with recurrent glioblastoma. In a pivotal large, randomized, phase III trial, 695 patients with newly diagnosed glioblastoma were randomized to receive adjuvant temozolomide and TTFields or standard maintenance therapy of temozolomide alone after the end of initial treatment with temozolomide/radiotherapy. Patients who received adjuvant temozolomide and TTFields fared much better than those treated with temozolomide alone. Survival was prolonged, with a hazard ratio of 0.63 (95% CI, 0.52–0.76; P < .001), and durable survival was achieved in some patients. This improvement was observed without a measurable negative impact on health- related quality of life. In the real-world setting, the rate of compliance among patients utilizing TTFields is high. The primary toxicity noted in the trials was mild-to-moderate cutaneous toxicity, which typically resolves with minimal intervention.
Impact of Other Medications
It has been hypothesized that certain medications commonly used to treat other conditions may potentially benefit patients with glioblastoma. These range from those prescribed for tumor-related conditions—such as epilepsy[97,98] and cerebral edema—to those which are independent of the neoplastic disease, including hypertension, hyperlipidemia, and venous thromboembolism.[99,100] Thus far, none have been proven to be beneficial. When thoroughly evaluated, none of the associations observed in several studies could be validated in larger cohorts, underscoring the importance of prospective (rather than retrospective) trials with strong biological hypotheses.
Corticosteroids are frequently used to decrease cerebral edema. Their off-target effects also lead to the suppression of immune system activity. Recent preclinical and clinical work suggests that these unfavorable effects contribute to shortened survival. This is of particular importance as we evaluate the role of immunotherapeutic approaches for the treatment of glioma. Despite the lack of a clear benefit in survival, bevacizumab has been shown to decrease the utilization of corticosteroids in patients with glioblastoma in numerous trials.[73,74,103-105] In routine clinical practice, functional improvement is often seen in association with radiographic improvement; however, it has not been proven to correlate with improved overall survival.
Efforts are continuously being undertaken to improve outcomes for patients with newly diagnosed glioblastoma. The diminishing return of second- and subsequent-line oncologic therapies supports the testing of promising new therapeutic approaches in the newly diagnosed population. This is underscored by the strong survival benefit seen among patients treated with TTFields in the newly diagnosed setting compared with those with progressive disease. A number of novel regimens are being studied in the newly diagnosed setting (Table 3). While many contemporary trials for newly diagnosed glioblastoma build upon the standard of care, as previously described, trials for patients with unmethylated MGMT promoter status may omit temozolomide without losing treatment efficacy.[106-108]
Epidermal growth factor receptor (EGFR) remains an attractive therapeutic target, since it is frequently upregulated in glioblastoma, and its expression is associated with a worse prognosis; it is constitutionally activated in 30% of glioblastomas with a VIII variant. However, randomized trials targeting EGFR have repeatedly failed.[109,110] The addition of a novel peptide vaccine, rindopepimut, to the standard of care has been studied in a phase III trial. While the preclinical and early-phase studies held substantial promise, the phase III trial failed to demonstrate improved survival. Phase III trial evaluation of the antibody-drug conjugate depatuxizumab mafodotin (ABT-414) in combination with standard-of-care treatment for patients with EGFR-amplified newly diagnosed glioblastoma is eagerly awaited. Finally, the results of two separate trials evaluating the anti–programmed death 1 monoclonal antibody nivolumab in newly diagnosed glioblastoma patients with unmethylated (CheckMate-498) and methylated (CheckMate-548) MGMT promoter status are anticipated. Biomarkers that may help predict benefit from immunotherapies will require prospective evaluation, but may provide insight into the role of immunotherapeutic approaches in glioblastoma.
The therapeutic management of newly diagnosed glioblastoma is well-defined and includes surgery, radiation, temozolomide, and TTFields. Nuances to management in the elderly or frail exist; in these populations, treatment de-escalation is often considered on a patient-specific basis. The addition of other systemic therapies—such as antiangiogenic agents or other routinely administered medications, such as anti-epileptic or blood pressure agents—has not been shown to improve survival in newly diagnosed glioblastoma. Concerns exist, substantiated by both preclinical and clinical data, that corticosteroid utilization may negatively impact outcomes of immunotherapeutic approaches for the treatment of these patients. This will need to be carefully considered in the design, administration, and interpretation of clinical trials for this disease. As outcomes in glioblastoma remain poor, continued investigation into promising therapeutics is necessary.
Financial Disclosure: Dr. Lukas, Dr. Wainwright, Dr. Sonabend, and Dr. Stupp receive funding support from P50CA221747 SPORE for Translational Approaches to Brain Tumors. Dr. Lukas is a consultant for AbbVie, and has served as a consultant for NewLink Genetics and ReNeuron; he has also served on an advisory board for Monteris Medical; served as a medical editor for EBSCO and MedLink Neurology; and has presented CME board review courses for the American Physician Institute. Dr. Wainwright receives funding support from the NIH/National Institute of Neurological Disorders and Stroke R01NS097851 grant. Dr. Sonabend is a consultant for AbbVie. Dr. Stupp receives travel support from NovoCure; he also served on one-time advisory boards for Boehringer Ingelheim, Celgene, and Northwest Biotherapeutics. Dr. Ladomersky and Dr. Sachdev have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
Nicholas Butowski, MD
Glioblastoma remains a macabre tumor with only incremental improvement over the last 4 to 5 decades. Fortunately, we practice in a time of remarkable growth in our neuroscience and cancer biology knowledge base. This leads one to hope that innovation in the management of glioblastoma is close at hand.
In the near future, operative methods will continue to trend toward decreased invasiveness, through techniques such as guided laser thermal ablation. Surgical precision will improve through fluorescence-guided resection of tumors. Drug delivery, too, will be optimized with the use of transport vesicles steered by engineered proteins and nanoparticles, used as vehicles to deliver therapeutic agents across the blood-brain barrier. Consequently, many drugs previously thought unsuitable for glioblastoma due to systemic toxicity or blockage by the blood-brain barrier may prove useful.
Moreover, it is expected that big data, next-generation sequencing, and genetic identification algorithms will guide operative intervention, clinical trials, and medication selection. Such methods will also account for the marked heterogeneity in glioblastoma and lead to an era of molecular polytherapy, guided by analysis from numerous tumor samples from the same patient. Such tailored ‘molecular cocktails’ will improve efficacy by targeting upstream initiators, alterations enabling cell growth, and predicted downstream compensation/resistance mechanisms. Recent advances in sequencing of tumor DNA from circulating tumor markers will make such clinical trials easier to perform and less reliant on operative procedures such as invasive tumor biopsies. Hope, too, remains that combination immunotherapy will play a role in glioblastoma management, whether by tailoring immune cells to target glioblastoma or by reinvigorating appropriate microglial function.
Insights on stem cell biology will also help to advance our management of glioblastoma. While radiation and traditional chemotherapy may serve a waning role in the future, their efficacy will be improved by simultaneous use of agents targeting tumor stem cell quiescence. Realistically, though, salvage therapy will still be required, and one can envision the use of self-replicating viruses to fight tumor stem cells, finally partially fulfilling the promise inherent in our present knowledge base.
To completely fulfill our promise to our patients, we’ll have to accept that glioblastoma is a disease of information and mixed-up signals among the genome, epigenome, microbiome, proteome, transcriptome, and metabolome, among others. As such, we’ll need a better bibliome of all the expanding information that separates the inessential from the pertinent.
Financial Disclosure: Dr. Butowski has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
Dr. Butowski is a Professor of Neurological Surgery; Director of Translational Research and Director of the UCSF Fellowship in the Division of Neuro-Oncology; and Chair of the CNS Tumors Site Committee at UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, California. He is also a Neuro-Oncologist in the Department of Neurological Surgery at the University of California, also in San Francisco.
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