Glioblastoma (GBM) remains the most common primary malignant brain tumor in adults and accounts for 16% of all primary brain tumors and for 45% of malignant primary brain tumors. Despite ample research to find better treatments the prognosis of GBM remains grim, with a less than 10% 5-year survival with maximal medical treatment.
In 2004, the European Organization for Research and Treatment of Cancer and National Cancer Institute of Canada Trails Group conducted a randomized phase III trial that led to the establishment of the current standard treatment consisting of surgical resection, radiotherapy with concomitant temozolomide, followed by temozolomide alone. Since then, multiple single and multicenter trials have sought to advance treatment of GBM further but without great success. This chapter examines lessons learned from clinical research in GBM with the hope that future patients will benefit from more effective trials and practice.
Surgery
Several retrospective as well as prospective studies have shown that extent of resection plays a key role in the overall survival and performance status of patients with GBM. Surgery is an instant way to reduce tumor burden (debulking) and, by removing mass effect, often leads to improvement and even resolution of symptoms. However, not all tumors are resectable and, especially in GBM, the tumor border is rarely clearly defined. Removing too little tumor may lead to earlier progression, whereas resecting too much brain tissue may cause unnecessary neurologic deficits. In addition, variable resectability implies a treatment bias: easily resectable tumors may have a better prognosis simply because they are less invasive, not necessarily because they were removed completely, and vice versa.
Intraoperative techniques
The recognition that maximal resection is an independent predictor of survival in patients with GBM led to the search for techniques to identify tumor tissue intraoperatively. Intraoperative visualization of the tumor enables the surgeon to gauge the extent of resection in real time and perform further resection if needed. Several methods for intraoperative visualization of tumor tissue have been studied, including intraoperative ultrasonography, MRI, and various tumor cell markers.
Intraoperative MRI
Intraoperative MRI (iMRI) has been studied extensively in the past decade. Although several groups have reported increased extent of resection with iMRI, few data exist regarding the clinical benefit of iMRI as measured by overall and progression-free survival as well as performance status. Thus far only 1 randomized controlled study confirmed that the use of iMRI led to higher rates of complete tumor resection compared with conventional surgery. This study also showed that postoperative complications and new neurologic deficits were comparable in both groups and therefore that the use of iMRI was safe. However, no improvement of progression-free survival was observed. The use of iMRI has implications in terms of cost and operative time. iMRI prolongs the surgical procedure and overall time spent in the operating room. In an era of medical care cost escalation, clinicians must decide whether the benefits outweigh the costs of acquisition and maintenance associated with MRI equipment located in the operating room. The authors have learned that difficult decisions such as these will become part of the success or failure of medical innovation in the future.
5-Aminolevulinic Acid as a Tumor Marker
In 2006, the ALA-Glioma Study Group conducted the only prospective randomized study that assessed the efficacy and safety of using 5-aminolevulinic acid (5-ALA) for the resection of malignant gliomas. 5-ALA is a hemoglobin precursor that leads to accumulation of fluorescent porphyrins in malignant glioma cells but not in healthy brain tissue. The use of 5-ALA and fluorescence-guided surgery was compared with traditional microsurgery using white light. Although the use of 5-ALA led to increased rates of complete resection and to longer progression-free survival, which were the 2 primary end points of the study, no benefit was found in overall survival, postoperative neurologic status, or Karnofsky Performance Score.
Barone and colleagues performed a systematic review of the role of imaging guidance in brain tumor surgery, including iMRI, fluorescence-guided surgery using 5-ALA, neuronavigation, and ultrasonography. Three large databases and an extensive literature review, including 4 randomized controlled trials, were performed up to 2013. Their goal was to answer 2 essential questions: (1) is image-guided surgery more effective at removing brain tumors than surgery without image guidance? (2) Is one image guidance technology or tool better than another? Based on their review, there is low to very low evidence (according to GRADE [Grading of Recommendations Assessment, Development and Evaluation] criteria) that image-guided surgery using iMRI, 5-ALA, or diffusion-tensor imaging neuronavigation increases the proportion of patients with high-grade glioma who have a complete tumour resection on postoperative MRI. Similarly, there was poor evidence that image-guided surgery increases overall or progression-free survival or quality of life. Thus, although the 5-ALA randomized trial did meet its primary end points, it did not extend survival or quality of life, showing that a well-executed trial that does not show improvement in these metrics may fail to attain regulatory approval (at least in the United States) and acceptance as a standard of care.
Carmustine Wafers
Biodegradable polymers (wafers) containing carmustine have proved safe when implanted in the glioma tumor cavity after resection. The US Food and Drug Administration (FDA) approved this agent for the treatment of recurrent GBM based on the results of a multicenter, randomized controlled study. Carmustine wafers were inserted into the tumor bed following gross total resection of recurrent high-grade gliomas. A clear survival benefit was found in patients with GBM treated with carmustine wafers compared with placebo wafers.
The benefit of carmustine wafers in patients with newly diagnosed GBM is less clear. The first prospective, randomized, double-blinded study using carmustine wafers in newly diagnosed high-grade gliomas was performed in Finland. The subgroup analysis of patients diagnosed with GBM showed a significant survival benefit in the carmustine wafer group compared with the placebo group. Four years later, a phase III trial in 240 patients with newly diagnosed high-grade gliomas was performed. Although patients treated with carmustine wafers had a long-term overall survival benefit compared with the placebo group, no significant survival benefit was found in the GBM subgroup. None of the aforementioned studies used treatment with temozolomide in the postoperative phase because the studies were performed before temozolomide was established as standard of care for GBM.
Several retrospective studies assessed the safety and efficacy of combining carmustine wafers with radiation therapy and temozolomide (Stupp regimen ) in patients with GBM and concluded that the triple regimen was safe. Few prospective data are available comparing treatment with carmustine wafers and Stupp regimen with Stupp regimen alone in patients with newly diagnosed GBM. Only 1 prospective, but nonrandomized, study in 787 patients in France compared the survival rates and postoperative complications in both treatment groups. The carmustine plus Stupp regimen arm showed significantly longer progression-free survival, but no statistically significant benefit was observed for overall survival. In contrast with previous studies, patients receiving carmustine wafers and Stupp regimen had significantly more postoperative complications such as postoperative infections and increased intracranial pressure caused by edema compared with patients treated with the Stupp regimen only.
The advantages of carmustine wafers seem obvious: they provide localized treatment without significant systemic side effects and they are complementary to systemic therapy. However, the complications mentioned earlier associated with the wafers can also be significant. Note that most data on carmustine wafers do not differentiate between GBM and non-GBM gliomas and caution should be used when extrapolating the results to the subgroup of patients with GBM. In addition, carmustine wafers can interfere with the interpretation of MRIs because of local increase in enhancement caused by the wafers. For this reason, many GBM clinical trials exclude patients who have received carmustine wafers. Overall, despite being FDA approved, the enthusiasm for general use of the wafers seems modest based on modest efficacy and the clinical trial exclusion described earlier.
However, a phase 1 trial that increased the percentage of carmustine in wafers reached a maximum tolerated dose of 20% carmustine by weight, representing a 5-fold increase compared with the standard 3.8% wafer. However, a phase II trial at this dose was never conducted, representing a missed opportunity in drug development. Such a trial may have improved the efficacy of the wafer, showing that the phase II trials are critical to the further development of promising therapies. Further development of this technology should be explored using other agents.
Radiation therapy
Stereotactic radiosurgery (SRS) focuses a radiation plan on a small tumor (usually ≤2–3 cm) using several techniques whereby multiple beams converge on a target to create a highly conformal delivery of a single or several high-dose fractions. SRS offers the hope that large-fraction doses, when added to radiation therapy, could overcome the radioresistance of GBM. Several trials have shown the benefit of SRS when added to whole-brain radiation therapy for patients with brain metastases. The same paradigm has been attempted in high-grade glioma trials of standard radiation therapy with or without SRS. In contrast with the benefits shown in brain metastases, the trials in high-grade gliomas have been uniformly negative and SRS has not developed a role in the management of GBM. These trials have taught clinicians that, despite the ability to target enhancing disease with SRS, the biology and infiltrative pattern of GBM, and all gliomas, is such that SRS fails to address a sufficient volume of nonenhancing tumor. As a result, newer local therapies, such as convection-enhanced delivery of chemotherapy, treat the infiltrative nonenhancing tumor that surrounds the enhancing disease. Future efforts to improve outcomes for patients with GBM will need to incorporate effective therapy for the nonenhancing tumor.
Various radiation therapy techniques have become standard management for several malignancies. These methods include brachytherapy, intraoperative radiation therapy, and targeted radionuclide therapy. These methods have largely failed in GBM trials. Two randomized trials of brachytherapy failed to produce a survival advantage, as did a trial using I-125 in a liquid solution placed in a balloon catheter inside the surgical cavity. Similarly, several radiosensitizers (eg, bromodeoxyuridine, misonidazole, motexafin gadolinium) have failed to improve local control more than radiation therapy alone. These various attempts to intensify local radiation therapy show that, most likely, the maximum safe dose of radiation therapy has not been enough to overcome radioresistance in GBM. Furthermore, it is likely that improvements in the initial therapy for GBM will require improvements in systemic agents that have activity as adjuvant agents after the completion of concurrent radiation with chemotherapy.
Chemotherapy
Angiogenesis Inhibitors
Like many malignancies, GBM requires an ample supply of blood vessels to support its high oxygen demand and metabolic activity. Angiogenesis, the formation of new blood vessels, is a hallmark of malignant tumors and is crucial for tumor growth. New blood vessels formed within tumors are abnormal, hindering delivery of oxygen and chemotherapeutic agents to the tumor. One of the main tumor-associated regulators is vascular endothelial growth factor (VEGF) A. Preclinical studies suggest that VEGF inhibitors lead to decreased formation and even regression of blood vessels in tumors and subsequently to tumor cell apoptosis. Inhibition of angiogenesis normalizes blood vessels and improves delivery of oxygen and chemotherapeutic agents, which may enhance the effects of chemotherapy and radiotherapy.
VEGF inhibitors prolong overall survival in metastatic colorectal and non–small-cell lung cancer as well as progression-free survival in metastatic renal cell and breast cancer. The VEGF inhibitor used predominantly in cancer research is bevacizumab (Avastin), a recombinant humanized monoclonal immunoglobulin G1 antibody that binds and neutralizes VEGF.
Based on the standard combination consisting of bevacizumab and irinotecan used in colorectal cancer, oncologist Stark Vance reported a series using the same regimen in patients with recurrent GBM. These striking results ultimately led to 3 trials that resulted in FDA approval of bevacizumab in recurrent GBM. Despite the benefits of bevacizumab in recurrent disease, the initial expectation of bevacizumab as a new standard of care for newly diagnosed GBM did not materialize in 2 major independent, randomized, double-blind, placebo-controlled studies (AVAglio and RTOG 0825 ). The lack of survival benefit showed that encouraging results in recurrent disease (typically a more resistant setting than newly diagnosed disease) do not a priori support the use of such agents; rigorous, adequately powered clinical trials must be done in both settings. This lesson will become more relevant with the advent of newer agents such as vaccines and other immunotherapies.
Dose-dense Temozolomide
Methylation status of O 6 -methylguanine DNA methyltransferase (MGMT) is an important prognostic and predictive factor in newly diagnosed GBM. GBMs with MGMT promoter methylation are associated with improved overall and progression-free survival in patients treated with temozolomide. Patients with unmethylated and therefore preserved activity of MGMT are relatively resistant to temozolomide and have a significantly weaker response to treatment with the drug. Several trials, the largest of which treated 90 and 120 patients, have been conducted seeking to overcome this resistance by altering the temozolomide regimen. The theory behind these trials is that a more sustained exposure to temozolomide would lead to depletion of cellular MGMT and thereby overcome resistance to temozolomide. In addition, some preclinical studies have suggested that metronomic dosing of temozolomide has an antiangiogenic effect on tumor cells. However, a phase III randomized trial, RTOG 0525 (Radiation Therapy Oncology Group), compared dose-intensive adjuvant temozolomide with standard adjuvant temozolomide in patients with newly diagnosed GBM and did not show a benefit in overall or progression-free survival in patients treated with the dose-dense temozolomide regimen compared with standard dosing.
Contradictory data exist regarding the use of dose-dense temozolomide in recurrent GBM. Although a randomized trial comparing standard-dose with dose-dense temozolomide showed significantly higher rates of progression-free and overall survival in the standard-dose arm, a meta-analysis of 33 phase II and retrospective studies showed a significant progression-free and overall survival benefit with individual dose-dense regimens. No differences were detected in objective response or clinical benefit in either report.
At this time, there is no level 1 evidence favoring the use of dose-dense temozolomide more than the current standard therapy. More is not always better, and parameters like adverse reactions and quality of life must be considered when using higher or prolonged doses of a cytotoxic medication. A prospective randomized controlled study may shed light on the question of which dose regimen is superior for a given agent. Although such a trial using temozolomide is unlikely to be performed, future agents may need to be evaluated in this manner if dose intensity for the given agent is thought to be potentially important. As has been shown in other solid tumors, even in the most chemotherapy-sensitive tumors, dose intensity most often does not translate into improved outcomes.
Epidermal Growth Factor Receptor Inhibitors
Epidermal growth factor receptor (EGFR) is commonly mutated or amplified in GBM cells, which leads to increased tumor growth and aggressiveness. EGFR expression is an independent negative prognostic indicator in patients with GBM, a potential treatment target, and a subject of extensive research. Preclinical studies reported promising results on the effect of EGFR inhibitors on GBM cells but thus far no large randomized controlled study has been attempted to translate those results into clinical practice. Conflicting data exist regarding the benefit of adding the EGFR inhibitor erlotinib to standard therapy for newly diagnosed GBM. One single-institution prospective phase II study reported significantly longer progression-free survival as well as overall survival in patients who received erlotinib in addition to standard therapy. A multicenter prospective phase I/II trial did not find any survival benefit from adding erlotinib to standard treatment. Yet another trial had to be stopped early because of unacceptable toxicity.
EGFR variant III (EGFRvIII) is the most commonly found EGFR mutation, seen in approximately one-third of GBM. Sampson and colleagues took a novel treatment approach in a phase II multicenter study of the immune response and survival in patients by adding an EGFRvIII vaccine to standard adjuvant therapy in patients with GBM. The results were promising: patients who received intradermal injection with an EGFRvIII vaccine had significantly longer progression-free and overall survival without an increase in adverse events compared with the control group that received standard therapy alone. Almost half of the vaccinated patients developed a humoral immune response to the vaccine, which was associated with prolonged overall survival. Another striking finding was that 82% of the patients who had received the EGFRvIII vaccine lost EGFRvIII expression at tumor recurrence.
An open-label, phase II trial performed by Schuster and colleagues confirmed the survival advantage by adding rindopepimut, an EGFRvIII vaccine, to standard adjuvant GBM therapy. The same group evaluated the use of rindopepimut in recurrent GBM by adding it to standard-of-care bevacizumab in the randomized phase II ReACT study. Preliminary results of this study are promising with regard to 6-month progression-free survival, overall survival, and 2-year survival, as well as the use of steroids. All 3 studies are phase II trials and the number of patients who received EGFRvIII vaccination was small: 18, 65, and 36, respectively. However, in a pattern similar to that of bevacizumab, a large, phase III trial of rindopepimut in patients with newly diagnosed GBM was terminated after an interim analysis determined that the study would likely fail to meet its primary end point of overall survival. Again, in GBM, excellent results in recurrent disease trials do not always portend similar outcomes for patients with newly diagnosed GBM.
Tumor treating fields
Tumor treating fields (TTF) are low-intensity intermediate-frequency alternating electric fields delivered transcutaneously via arrays placed on the scalp. These fields inhibit tumor growth by an antimicrotubule mechanism. A randomized trial in 237 patients with recurrent GBM showed equivalent efficacy but was associated with a better quality of life without chemotherapy toxicities. Recently, a large, randomized controlled, international multicenter study was terminated early after an interim analysis showed that adjuvant temozolomide combined with TTF was associated with significantly increased overall and progression-free survival compared with adjuvant temozolomide alone. The incidence and severity of adverse events were comparable in both groups. However, the final analysis of the study population, including subgroup analysis, is pending at this time.
These results are encouraging and have led to regulatory approval for TTF. This method may face a problem with regard to feasibility and compliance. Patients are required to wear the TTF electrodes more or less around the clock and may have difficulties putting the mask back on correctly. However, this device is in clinical trials in a variety of other malignancies, showing that central nervous system (CNS) tumors can serve as the preliminary site of development of local noninvasive therapies for cancer given the relative (compared with other tumors) proximity of brain tumors to the exterior surface of the body, thus facilitating the application of novel treatment technologies.
Seizures and antiepileptic agents
From 29% to 49% of patients with GBM present with seizures or develop them later in the disease course. Controlling seizures in patients with brain tumors is of utmost importance because uncontrolled seizures have a detrimental impact on quality of life and can lead to long-term disability. When treating brain tumor–related epilepsy (BTRE), providers encounter certain challenges: BTRE is notorious for its refractoriness and multidrug resistance ; enzyme-inducing AEDs (EIAEDs) increase the metabolism of some chemotherapeutic agents as well as steroids, necessitating dose escalation of those medications; side effects from AEDs (AEDs) occur more frequently in patients with BTRE than in the overall population ; many AEDs lead to worsening of cognitive performance in patients with brain tumors. The lesson learned from this experience is that non-EIAEDs are a much preferred group of agents for use in patients with GBM or any brain tumors in patients who need them. Another relevant lesson is that most current GBM trials, especially early-stage studies, now exclude the use of EIAEDs as a criterion for trial eligibility in order to obtain more uniform and predictable pharmacokinetic properties an agent. A current randomized trial ( NCT01432171 ) is comparing lacosamide with placebo to evaluate the role for this non-EIAED in the prophylaxis of seizures in patients with newly diagnosed high-grade gliomas.
Challenges in assessing treatment efficacy and effectiveness
Investigators face several challenges when assessing the efficacy and effectiveness of a therapeutic agent. Most of the trials discussed earlier focused on survival rates, with some reports measuring radiologic or clinical criteria to determine disease stability or progression.
Until recently, the MacDonald criteria, established in 1990, served as the standard tool to assess treatment response in high-grade gliomas. They were based on imaging features, like enhancement and new lesions, and on clinical features such as corticosteroid requirement and clinical disease stability. In 2010, Wen and colleagues published the updated Response Assessment in Neuro-oncology (RANO) criteria, which for the most part have replaced the MacDonald criteria. Implementation of the RANO criteria redefined the radiologic appearance of progressive disease. One of the main reasons for the revised criteria is the phenomenon of pseudoprogression, which is a treatment-related imaging finding typically seen within 3 months after radiochemotherapy. Pseudoprogression radiographically appears to be disease progression but resolves spontaneously without treatment within a few months. Diagnosis of disease progression often has implications on disease management (eg, premature withdrawal of adjuvant therapy or reoperation), which can be detrimental for some patients, especially when these measures are unnecessary because of being based on a misleading imaging finding. Therefore, distinguishing treatment-induced imaging changes (pseudoprogression) from true progression is extremely important for patient care.
Pseudoprogression is a phenomenon mainly described after standard therapy with radiation and temozolomide. A complicating factor is that chemoradiation with temozolomide is also associated with early necrosis. Pseudoprogression and treatment-related necrosis have similar, often indistinguishable, appearance on MRI, which poses another challenge for monitoring disease and treatment in patients with GBM.
An additional pitfall in assessing success is treatment-induced pseudoresponse, which is another radiographic phenomenon seen after treatment with antiangiogenic therapy, such as the VEGF inhibitor bevacizumab. Radiologic response rates with antiangiogenic agents have been attributed to normalization of tumor vessel permeability and do not necessarily indicate a true antitumor effect. The discrepancy between the striking improvement seen on imaging and the minor benefit on survival should again prompt practitioners to approach a radiologic response after VEGF inhibitor treatment with caution. Similar challenges with imaging analysis have occurred with the advent of TTF and immunotherapy, in which in both instances response can be delayed such that MRI early in the treatment course may falsely suggest progressive disease.
Does the drug reach the tumor?
One fundamental question to ask when treating any disease, and brain tumors in particular, is whether the therapeutic agent gets to the diseased tissue. Answering this question for brain tumors is particularly difficult because the blood-brain barrier (BBB) prevents the entry of exogenous substances into the CNS. In addition, drug concentrations measured in serum or cerebrospinal fluid do not reliably reflect drug concentrations at the target site because of a multitude of factors, including the chemical properties of the drug, physical and chemical obstruction by the BBB, active drug transport mechanisms, and drug metabolism at the BBB and within the brain. Insufficient drug levels within the diseased tissue may lead to treatment failure and poor clinical outcome. One lesson is that molecules capable of BBB penetration should ideally be small (<500 kDa) and generally lipid soluble. In contrast, several agents do not need to cross the BBB to give patients benefit. One example of an agent that does not need to cross the BBB is bevacizumab because it works on the vasculature and not directly on the tumor. Similarly, the emerging group of checkpoint inhibitors and other immune therapies work outside the BBB.
An emerging tool to measure concentrations of a drug at a specific site more directly is microdialysis. Microdialysis is a technique that continuously quantifies the concentration of an agent in the extracellular fluid in a body tissue. Microdialysis to assess chemotherapeutic response or toxicity has been studied in non-CNS tumors with promising results. Intracerebral microdialysis is fairly safe and has been applied in conditions like epilepsy, traumatic brain injury, and intracerebral hemorrhage. Few studies have been performed to determine the concentration chemotherapeutic agents at the tumor. These studies found considerable regional differences within the brain with higher drug concentrations measured in contrast-enhancing tissue, which usually consists of tumor or tumor-surrounding tissue, whereas healthy brain tissue accumulated less drug. Portnow and colleagues measured temozolomide concentrations in nonenhancing tissue surrounding the resection bed in patients with newly diagnosed GBM. Temozolomide was given orally 1 hour before radiation as per the Stupp protocol. The time to peak of temozolomide concentration in the brain (1.2–3.4 hours after ingestion) was longer than the time to peak in serum (approximately 1 hour after ingestion), as described previously. Based on these findings, the authors instruct patients receiving concurrent radiation and temozolomide to take temozolomide approximately 1.5 to 3 hours before radiation treatment to obtain the maximum radiation sensitization effect. Because the kinetics of brain penetration differ from serum pharmacokinetics, the intracerebral kinetics should be determined if possible and should ideally inform the dosing schedules for drugs for which interaction with radiation will be maximized.
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