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Immunotherapy for inoperable gliomas
Chapter 13
Immunotherapy for inoperable gliomas David Dadey, Kevin Chow and Gordon Li Department of Neurosurgery, Stanford University Medical Center, Stanford, CA, United States
Introduction The challenges posed by gliomas continue to drive efforts to refine surgical and postoperative care. Among the problems posed by the incidence of gliomas is the question of management when the site of tumor growth is not amenable to complete resection. Also, beyond tumor location, the problems posed by tumor size and recurrence are yet another significant barrier to curing patients who have undergone surgery. To circumvent some of these barricades in the operative phase, techniques such as awake craniotomy, intraoperative magnetic resonance imaging (MRI), and electrophysiologic mapping have evolved to allow many previously inoperable brain tumors to be treated. However, these components of the surgical armamentarium are only as successful as the methods in postoperative management allow them to be, as the morbidity of surgical resection for previously “inoperable” tumors can be significant. Thus the postoperative management of inoperable gliomas involves a multidisciplinary approach employing diligent medical surveillance, adjunct chemoradiation, and newer therapies applying the latest advances from the world of basic science. In this chapter, we focus on the postoperative management of high-grade gliomas in eloquent or unfavorable regions of the brain. Our discussion will examine the roles of the above-mentioned techniques and therapies in improving clinical outcomes for patients afflicted by these tumors.
Postoperative courses Surgical intervention for glioblastoma patients can be broadly defined by two postoperative pathways: (1) biopsy-only, and (2) craniotomy. The former being a path common to patients with high tumor burden, poor preoperative candidacy for craniotomy, or nonresectable tumors. Despite the availability of techniques to address eloquent brain tumors, some deep-seated tumors, or tumors with New Techniques for Management of ‘Inoperable’ Gliomas. https://doi.org/10.1016/B978-0-12-813633-1.00013-X © 2019 Elsevier Inc. All rights reserved.
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bilateral hemispheric involvement (extension into the corpus callosum) remain unsafe to resect without causing major postoperative neurological deficits. Without surgical resection or debulking, the postoperative course for biopsy patients is variable and is largely dictated by the nonsurgical options available to them. Current literature suggests that extent of resection (EOR) is often the most important predictor of survival, hence the survival for biopsy-only patients is often the shortest in many series.
Biopsy In general, patients who have undergone uncomplicated stereotactic needle biopsy-only surgeries of supratentorial pericortical lesions can recover well from the procedure after one night in an inpatient ward, and do not require intensive care. They are therefore at lower risk than craniotomy patients for hospitalassociated morbidities in the immediate postoperative period. Their medical management is focused on controlling pain from the surgical site and scalp wound care to minimize infection risk. However, for deep-seated lesions, the nature of the postoperative care process may vary. For example, in cases where a lesion in the brainstem is biopsied, more intensive monitoring may be indicated during the first 24 h after surgery. Specifically, care must be taken to detect symptoms suggestive of edema or hemorrhage, as compression of the fourth ventricle could result in acute hydrocephalus necessitating CSF (cerebrospinal fluid) diversion. Hence, it may be reasonable to obtain postoperative computed tomography (CT) scans when vascular tumors or high-grade gliomas involving the brainstem are the target of the biopsy. Lesions involving the thalamus can also present as difficult biopsy targets with some risk for postoperative neurological deficit. In a study of thalamic glioblastoma management spanning a 10-year period, 15% of patients suffered from neurological deficits after stereotactic biopsy.1 Of note, the study included 57 patients, of which 47 underwent stereotactic biopsy while the remaining 10 underwent craniotomy. Overall, the perioperative mortality rate was reported at 4.5% and the median survival was 12.2 months. Another study addressing biopsy of brain stem lesions found the incidence of neurological deficit to be 7.7%, with a perioperative mortality of 3.8%—while glioblastoma accounted for 19.2% of the cases, overall survival was not discussed in this study.2 Overall complication rates for patients undergoing biopsy-only surgeries are generally low and often under 6%, however, additional interventions may sometimes be warranted. One example of such a complication is intraaxial hemorrhage which can occur particularly when obtaining biopsies of malignant tumors with aberrant vascularity, or when tumors are seated in highly vascularized deep structures such as the basal ganglia. The risk for such hemorrhages may be subject to modification by the use of anticoagulants/antiplatelet agents in the perioperative period. Therefore, as with other more invasive cranial surgeries, it is common practice to hold anticoagulation for a period of weeks
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before and after biopsy procedures. In the event of a catastrophic hemorrhage occurring in the postoperative period, surgical evacuation and/or management of secondary intracranial hypertension may be warranted. In some reports, CSF diversion in the perioperative period for the management of hydrocephalus was found to provide clinically significant improvement in median overall survival.1 The next steps in management after the immediate postoperative period are dictated in large part by the histology and molecular characteristics identified by the biopsy. In the case of glioblastoma, the landmark trial by Stupp et al. demonstrated that patients who underwent biopsy-only surgeries had a median overall survival of 7.8 months with radiotherapy alone and 9.4 months when received concomitant radiation and temozolomide.3 However, newer approaches to management are actively being explored and will be discussed later in this chapter.
Craniotomy Craniotomy for tumor resection, when feasible, remains the recommended path for patients with glioblastoma. Given the invasive nature of these surgeries, the risks and morbidity associated with tumor resection can be significant as complications can occur shortly after surgery or in the late postoperative period. Much like with stereotactic biopsy surgery, neurological deficit is among the complications of primary concern especially when the target lesion involves eloquent regions of the brain. To reduce the risk of such complications, one technique that has evolved is intraoperative stimulation mapping (ISM). In this technique, an electrode probe is used to apply a current directly on cortical regions of interest. Often performed in the setting of awake craniotomy, eloquent areas of cortex can be identified by engaging the patient in tasks during stimulation and observing for induced deficits. A meta-analysis examining the impact of ISM on the occurrence of postoperative neurological deficits found that without ISM, late neurological deficits were observed in 9.4% of cases.4 On the other hand, with ISM, late neurological deficits were observed in 6.4% of cases.4 Hence techniques such as ISM, and other methods for intraoperative neuro-monitoring, may allow for greater fidelity during resection of complex lesions while also improving the postoperative course for brain tumor patients.5, 6 Postoperative care for patients who have undergone awake craniotomy, though rife with variability driven by patient characteristics and clinical practice, is generally similar to that of patients who have undergone standard craniotomy. In accordance with standard practice, patients should be monitored in an intensive care unit after completion of surgery. Among the management challenges that often present themselves in the ICU, postoperative nausea and vomiting (PONV) is very common. Providing patients with a course of steroids and antiemetics may be an effective strategy to control PONV. However, there is evidence to suggest that PONV can also be impacted by the selection of
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intraoperative anesthesia, and that patients undergoing awake craniotomy may experience relatively less PONV when compared to unconscious craniotomy.7 This highlights the importance of collaboration between neurosurgeons and anesthesiologists throughout the operative course in order to maximize positive outcomes for patients in the postoperative period. The benefits of interdisciplinary collaboration can extend to the management of seizures, which are another complication of awake craniotomies that can occur intraoperatively and early in the postoperative period. Given the use of cortical stimulation during awake craniotomy, neurosurgeons should remain vigilant for signs of seizure and be prepared to administer antiepileptic medication.8 Additionally, the standard risks of craniotomy, such as hemorrhage, cerebral hypoxia, and brain shift, should also be noted for their contribution to increased seizure risk. Midazolam, propofol, or thiopentone have successfully been used in conjunction with antiepileptic drugs (AEDs) such as phenytoin to control intraoperative seizures.8 Postoperatively, management of seizures can similarly be achieved with combinations of AEDs and sedation as needed depending on the severity and duration of seizure activity. However, patients with prior seizure history may benefit from perioperative loading of dual AEDs, as a study by Eseonu et al. demonstrated that combining levetiracetam and phenytoin lead to lower postoperative seizure rates.9 As with unconscious craniotomy, the risk of postoperative hemorrhage should also be on the neurosurgeon’s mental checklist after awake craniotomy. ICU monitoring with frequent neurological examinations is paramount for detecting progressive neurologic decline that may indicate acute hemorrhage in the postoperative period. A low threshold for obtaining CT scans should be maintained, as severe hemorrhage may necessitate emergent surgical evacuation. One study examining 611 patients who underwent awake craniotomy for glioma resection found that the overall perioperative complication rate was 10%, with postoperative hemorrhage accounting for 0.5% of complications.10 Even in the absence of head CT for hemorrhage detection, or any other complications, it is common practice to obtain MRI to evaluate EOR within 24–48 h of surgery. Increasing the availability of intraoperative MRI may improve this aspect of the surgical course, as the EOR can be monitored closely during surgery and neurosurgeons can minimize the odds of repeat craniotomy for residual tumor.
Radiotherapy The benefit of radiation therapy for the treatment of anaplastic gliomas was first demonstrated in a phase III prospective randomized controlled trial conducted by Walker et al. They showed that whole brain radiotherapy of 5000–6000 rads in five fractions per week over 5–6 weeks improved the survival after surgery by approximately 20 weeks.11 A subsequent trial demonstrated no significant difference in survival between patients treated with whole brain vs local
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irradiation.12 These and other studies define the current standard radiation therapy schedule for glioblastoma patients which consists of 60 Gy over 30 fractions delivered to the gross tumor volume with a 2–3 cm margin for the clinical target volume.13 While this schedule remains the standard of care, several groups have looked at the role of hypofractionated radiotherapy (HFRT) or stereotactic radiosurgery (SRS) for the treatment of recurrent or newly diagnosed GBM. The HFRT is simply the delivery of fewer higher dose fractions compared to the conventional schedule.14 It is an attractive alternative to conventional fractionation due to the potential for increased tumor cell killing, decreased tumor cell repopulation, and decreased overall treatment time.15
Laser interstitial thermal therapy Laser interstitial thermal therapy (LITT) has seen a resurgence in the last decade and its applications to tumor treatment growing in number. This method is generally performed by inserting a laser probe into a target by utilizing stereotactic guidance. Once in the desired target, thermal energy generated by the laser is then directed toward target tissues to induce cell death. For many years, LITT as a treatment modality for brain tumors was not widely accepted due to the inability to accurately track the extent of thermal ablation during any given treatment. However, advances in imaging technology have spurred interest in LITT, as the feedback offered by intraoperative MR thermometry now allows for live monitoring and refinement of the ablation process. LITT holds particular promise for the treatment of primary inoperable deep-seated lesions, such as those involving the thalamus, corpus callosum, or basal ganglia. Furthermore, LITT has been successfully applied to the management of recurrent disease. One of the largest studies examining the applicability of LITT to patients with brain tumors was conducted by Pinakin et al. Comprising 20 patients with a range of tumors including high-grade gliomas, patients were elected for LITT for reasons such as prior treatment failure, or having surgically inaccessible tumors. Overall, this study was focused on demonstrating the procedural feasibility of MRI-guided laser ablation in brain tumor therapy, and though largely successful, it also highlighted some of the complications that can occur with LITT.16 Of note, hemorrhage secondary to the insertion of the laser catheter, postablation edema, and injury due to inaccurate targeting or image registration were observed among for patients. While the procedure can be safely performed with most patients often leaving within 1–2 days, the complications that can occur may necessitate craniotomy or external ventricular drain placement in the postoperative period. The benefits of this technology are easily seen in the case of glioblastoma, where disease recurrence is among the major barriers to improving patient longevity. For these patients, LITT provides a minimally invasive approach for delivery of focused treatments while avoiding the morbidity associated with
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undergoing multiple craniotomies. In a series published by Schwarzmaier et al., the overall survival of 16 patients after receiving LITT for recurrent GBM was 6.9 months.17 This has since been followed with another study by Mohammadi et al. where 19 patients within their cohort had recurrent high-grade gliomas that were treated with LITT—among these patients, progression-free survival was 6 months.18 Furthermore, another advantage offered by LITT in management of both primary and recurrent disease is the potential for synergism with chemotherapy. LITT has been shown to disrupt the blood-brain barrier local to the target lesions, and may be able to facilitate enhanced delivery of chemotherapy to tumors. A study by Leuthardt et al. examined this possibility in patients with recurrent glioblastoma by calculating vascular transfer constants on MRI before and after laser ablation. In addition to increased vascular transfer constants, they observed an increase in serum levels of brain-specific enolase persisting for several weeks after ablation was performed.19 Results of similar studies have raised the question of whether clinical efficacy can be enhanced by incorporating laser ablation into multimodal therapeutic regimens for brain tumors. The impact of LITT on the efficacy of chemoradiation is the subject of several clinical trials that are in early stages of organization.
Immunotherapy for “inoperable” gliomas Given the infiltrative nature of gliomas, even gross total resection of surgically accessible lesions is unlikely to remove all of the malignant cells at the margin. This of course underlies the need for adjuvant chemotherapy and radiation to try to kill the tumor cells in the periphery which are left behind. In the case of inoperable gliomas, we rely solely on systemic chemotherapy and local delivery of radiation to destroy the tumor bulk. Chemotherapy and radiation are both nonspecific therapies that rely on the difference in growth rate and sensitivity of tumor cells vs normal cells to achieve tumor killing. These therapies have limited benefit, particularly with high-grade gliomas, and can be associated with significant toxicity. As such, research into better therapies for gliomas has been widely investigated. Immunotherapy refers broadly to any therapy that utilizes the mechanisms employed by our body’s immune system to fight disease or cancer. Cancer immunotherapy can be broken down into several categories including cytokine therapies, antibody therapies, vaccine therapies, and cellular therapies. While all these therapies differ in their specific mechanism of action, as a whole they have the potential to be highly targeted with a better side effect profile than conventional chemotherapy or radiation. All of these therapies have been investigated in preclinical experiments and clinical trials for the treatment of highgrade gliomas. Here we discuss the principles relevant to immunotherapy for gliomas and highlight several clinical trials that have been conducted for glioma patients.
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Principles of glioma immunotherapy Gliomas are primary brain tumors and therefore presumed to be subject to the “immunological rules” of the brain. Historically it was thought that the brain is an “immune-privileged” site, with peripheral immune molecules and effectors being restricted from entering the brain by the blood-brain barrier. This paradigm has largely shifted to the brain being considered “immune-specialized” rather than privileged as researchers learn more about microglia, brain immunosurveillance, and brain lymphatic drainage.20 While the brain is known to undergo constant immunosurveillance, highgrade gliomas have been shown to employ various immunosuppressive strategies that allow them to escape detection and avoid eradication. GBMs secrete factors which downregulate antigen presentation, upregulate suppressive T regulatory cells, and inhibit antitumor effector T cells, effectively promoting its own survival. Immune therapies that work against these immunosuppressive strategies of GBM may provide therapeutic benefit. Additionally, GBM often express specific cell surface markers which are tumorrestricted or differentially expressed compared to the surrounding normal tissues which allow these markers to be exploited for tumor-specific targeting. Gliomaassociated antigens such as EGFRvIII, IL13Rα2, HER2, EphA2, and others can be targeted using antibodies, vaccines, or T cells to elicit an antiglioma response.
Cytokine therapies Cytokines are secreted molecules which act on immune cells to coordinate and propagate immune responses within the body.21 These molecules have a wide range of functions which can be harnessed for cancer therapy. These functions include promoting cell growth, activation, costimulation, differentiation, proliferation, antigen presentation, and others. Cytokines have been used alone or in combination with other immunotherapies such as vaccines and T cells. Perhaps one of the best studied cytokines used for cancer immunotherapy is interleukin-2 (IL-2). IL-2 promotes T cell proliferation and is used in vitro to activate immune cells. Injection of IL-2 into tumors can help recruit T cells to what would otherwise be an immunosuppressed environment. Systemically administered IL-2 is approved for the treatment of metastatic melanoma and renal cell carcinoma. However, the therapeutic window is small and significant toxicities have limited its use. The use of systemically administered IL-2 for the treatment of CNS (central nervous system) disease is limited by the efficiency with which IL-2 crosses the blood-brain barrier.22 Systemic toxicities have led to the use of intrathecal, intraventricular, intratumoral, or intracavitary injections of IL-2 for the treatment of brain tumors. Even with intracerebral delivery of IL-2 in patients with recurrent glioma, morbidity in the form of headache, nausea, fatigue, and weakness were seen at higher doses.23
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Antibody therapies Antibodies are proteins that bind to specific antigens and generally recruit immune effectors to the cells expressing those antigens in order to facilitate their destruction. Antibodies for cancer immunotherapy are often designed to target specific tumor-associated antigens. For instance, cetuximab is an antiEGFR (epidermal growth factor receptor) antibody which is approved for the treatment of metastatic colon cancer.24 Its efficacy for treating GBM patients, however, has not been well demonstrated.25 Antibodies can also be conjugated with radioisotopes or chemotherapeutics to target these cytotoxic agents specifically the tumor. This strategy has been shown to be safe and well tolerated in GBM patients, although again with limited efficacy.26 Bevacizumab, an antibody targeted to vascular endothelial growth factor (VEGF), was approved for the treatment of recurrent GBM based on phase 2 trials which showed promising antiglioma activity.27, 28 However, subsequent phase 3 trials failed to demonstrate improvement in overall survival despite improvement in progression-free survival.29, 30 Given the limited options for the treatment of recurrent GBM, bevacizumab is still commonly used. Checkpoint inhibitors such as nivolumab (anti-PD-1), ipilimumab (antiCTLA-4), and pembrolizumab (anti-PD-1) are antibodies that block the negative regulators of T cell activation and have been shown to have potent antitumor activity. They have been approved for the treatment of metastatic melanoma and other cancers, and are being tested in clinical trials for recurrent GBM patients.31, 32
Vaccine therapies Cancer vaccines attempt to stimulate a patient’s “dormant” or “suppressed” immune system to recognize and eradicate foreign cancer cells in the body. Vaccines typically consist of some form of antigen substrate usually synthetic peptides or whole tumor cell lysates. These can be administered alone or in conjunction with various adjuvants. Several vaccine trials have been attempted in GBM patients.32a Here we highlight two of the more advanced vaccine therapies. DCVax-L (or DCVax-Brain) is a vaccine that is produced by maturing autologous dendritic cells with patient-derived tumor sample, after which the vaccine is injected intradermally where they can activate the host immune response to the tumor. The theoretical advantage of this approach is the use of patient-derived sample as the source of antigen which makes it personalized and multiantigen specific. Phase 1 and 2 trials demonstrated safety and evidence of T cell infiltration into several of the recurrent tumors.33, 34 A phase 3 trial is ongoing. Rindopepimut (CDX-110) is a vaccine which consists of an EGFRvIIIspecific peptide conjugated to keyhole limpet hemocyanin.35 While the
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initial phase 1 and 2 studies (VICTORI, ACTIVATE, ACTII, ACTIII) demonstrated safety of the vaccine and evidence of a specific immune response,36–39 recurrence of antigen negative tumors raised concerns that targeting a single antigen may not be optimal for such a heterogeneous tumor. Nevertheless a large randomized phase 3 trial called ACT IV was performed, which unfortunately showed no improvement in the survival of groups treated with vaccine.35
Cellular therapies Unlike vaccines which attempt to stimulate endogenous immune effectors to act, cellular therapies allow investigators to take the effector cells out of the body, activate or modify the cells to enhance their antitumor functions, and then deliver them back to the patient for therapeutic effect. Cellular therapies have evolved over several decades, with initial testing focused on IL-2 stimulated lymphokine-activated killer (LAK) cells or expansion of tumor-infiltrating lymphocytes (TILs). The latest and perhaps most promising iteration of cellular therapy technology involves the genetic modification of T cells for improved antitumor capabilities. In particular, chimeric antigen receptor-modified T cells (CAR-T cells) have shown impressive responses in patients with treatment refractory leukemia. This technology has been utilized in phase 1 trials of patients with GBM. IL13Rα2-specific CAR T cells given intracerebrally to patients with recurrent GBM are safe and appear to have some antitumor effect (City of hope study). CAR T cells specific to HER2 have been given systemically to GBM patients without major side effects. More studies will be needed to determine whether cellular therapies can have an impact on patients with gliomas, particularly inoperable ones.
Concluding remarks Advances in surgical technique, operative technology, and clinical immunology/molecular biology have contributed to significant changes in the approach to brain tumors. Cancers of the brain that were once considered inoperable can now be safely resected with awake craniotomy, or ablated with laser therapy. Refinements in the delivery of ionizing radiation now allow for high-dose therapy to be administered with surgical precision. Furthermore, with the advent of immunotherapy, the power of the immune system to synergize with surgery by eliminating microscopic residual disease may one day lead to significantly prolonged survival for GBM. Continued research of clinical outcomes and basic science will be paramount to implementing novel therapeutic strategies for the improvement of patient outcomes.
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References 1. Esquenazi Y, Moussazadeh N, Link TW, et al. Thalamic glioblastoma: clinical presentation, management strategies, and outcomes. Neurosurgery. 2017; https://doi.org/10.1093/neuros/ nyx349 nyx349-nyx. 2. Quick-Weller J, Lescher S, Bruder M, et al. Stereotactic biopsy of brainstem lesions: 21 years experiences of a single center. J Neurooncol. 2016;129(2):243–250. https://doi.org/10.1007/ s11060-016-2166-1 Epub 2016/06/14. PubMed PMID: 27291894. 3. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–466. https://doi.org/10.1016/s1470-2045(09)70025-7 Epub 2009/03/10. PubMed PMID: 19269895. 4. De Witt Hamer PC, Robles SG, Zwinderman AH, Duffau H, Berger MS. Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(20):2559–2565. https://doi.org/10.1200/jco.2011.38.4818 Epub 2012/04/25. PubMed PMID: 22529254. 5. Eseonu CI, Rincon-Torroella J, ReFaey K, et al. Awake craniotomy vs craniotomy under general anesthesia for perirolandic gliomas: evaluating perioperative complications and extent of resection. Neurosurgery. 2017;81(3):481–489. https://doi.org/10.1093/neuros/nyx023. 6. Saito T, Muragaki Y, Maruyama T, Tamura M, Nitta M, Okada Y. Intraoperative functional mapping and monitoring during glioma surgery. Neurol Med Chir. 2015;55(1):1–13. https:// doi.org/10.2176/nmc.ra.2014-0215 PubMed PMID: PMC4533401. 7. Manninen PH, Tan TK. Postoperative nausea and vomiting after craniotomy for tumor surgery: a comparison between awake craniotomy and general anesthesia. J Clin Anesth. 2002;14 (4):279–283. https://doi.org/10.1016/S0952-8180(02)00354-9. 8. Sokhal N, Rath GP, Chaturvedi A, Dash HH, Bithal PK, Chandra PS. Anaesthesia for awake craniotomy: a retrospective study of 54 cases. Indian J Anaesth. 2015;59(5):300–305. https://doi.org/10.4103/0019-5049.156878 PubMed PMID: PMC4445152. 9. Eseonu CI, Eguia F, Garcia O, Kaplan PW, Quin˜ones-Hinojosa A. Comparative analysis of monotherapy versus duotherapy antiseizure drug management for postoperative seizure control in patients undergoing an awake craniotomy. J Neurosurg. 2017;1–7. https://doi.org/10.3171/ 2017.1.jns162913 PubMed PMID: 28621631. 10. Hervey-Jumper SL, Li J, Lau D, et al. Awake craniotomy to maximize glioma resection: methods and technical nuances over a 27-year period. J Neurosurg. 2015;123(2):325–339. https://doi.org/10.3171/2014.10.jns141520 PubMed PMID: 25909573. 11. Walker MD, Alexander Jr E, Hunt WE, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg. 1978;49(3):333–343. https://doi.org/10.3171/jns.1978.49.3.0333 Epub 1978/09/01. PubMed PMID: 355604. 12. Kita M, Okawa T, Tanaka M, Ikeda M. Radiotherapy of malignant glioma—prospective randomized clinical study of whole brain vs local irradiation. Gan No Rinsho. 1989;35 (11):1289–1294 Epub 1989/09/01. PubMed PMID: 2681872. 13. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New Engl J Med. 2005;352(10):987–996. Epub 2005/03/11. PubMed PMID: 15758009 https://doi.org/10.1056/NEJMoa043330. 14. Azoulay M, Shah J, Pollom E, Soltys SG. New hypofractionation radiation strategies for glioblastoma. Curr Oncol Rep. 2017;19(9):58. Epub 2017/07/25. PubMed PMID: 28735440 https://doi.org/10.1007/s11912-017-0616-3.
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15. Hingorani M, Colley WP, Dixit S, Beavis AM. Hypofractionated radiotherapy for glioblastoma: strategy for poor-risk patients or hope for the future? Br J Radiol. 2012;85(1017):e770–e781. https://doi.org/10.1259/bjr/83827377 PubMed PMID: PMC3487099. 16. Jethwa PR, Barrese JC, Gowda A, Shetty A, Danish SF. Magnetic resonance thermometryguided laser-induced thermal therapy for intracranial neoplasmsinitial experience. Oper Neurosurg. 2012;71(Suppl. 1):ons133–ons145. https://doi.org/10.1227/NEU.0b013e31826101d4. 17. Schwarzmaier HJ, Eickmeyer F, von Tempelhoff W, et al. MR-guided laser-induced interstitial thermotherapy of recurrent glioblastoma multiforme: preliminary results in 16 patients. Eur J Radiol. 2006;59(2):208–215. Epub 2006/07/21. PubMed PMID: 16854549 https://doi.org/10. 1016/j.ejrad.2006.05.010. 18. Mohammadi AM, Hawasli AH, Rodriguez A, et al. The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: a multicenter study. Cancer Med. 2014;3(4):971–979. Epub 2014/05/09. PubMed PMID: 24810945; PMCID: PMC4303165https://doi.org/10.1002/cam4.266. 19. Leuthardt EC, Duan C, Kim MJ, et al. Hyperthermic laser ablation of recurrent glioblastoma leads to temporary disruption of the peritumoral blood brain barrier. PLoS One. 2016;11(2) e0148613https://doi.org/10.1371/journal.pone.0148613. 20. Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–341. Epub 2015/06/02. PubMed PMID: 26030524; PMCID: PMC4506234 https://doi.org/10.1038/nature14432. 21. Lee S, Margolin K. Cytokines in cancer immunotherapy. Cancers. 2011;3(4):3856–3893. Epub 2011/01/01. PubMed PMID: 24213115; PMCID: PMC3763400 https://doi.org/10.3390/ cancers3043856. 22. Saris SC, Rosenberg SA, Friedman RB, Rubin JT, Barba D, Oldfield EH. Penetration of recombinant interleukin-2 across the blood-cerebrospinal fluid barrier. J Neurosurg. 1988;69 (1):29–34. Epub 1988/07/01. PubMed PMID: 3259980 https://doi.org/10.3171/jns.1988.69. 1.0029. 23. Merchant RE, McVicar DW, Merchant LH, Young HF. Treatment of recurrent malignant glioma by repeated intracerebral injections of human recombinant interleukin-2 alone or in combination with systemic interferon-alpha. Results of a phase I clinical trial. J Neurooncol. 1992;12(1):75–83 Epub 1992/01/01. PubMed PMID: 1541981. 24. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–1765. https://doi.org/ 10.1056/NEJMoa0804385 PubMed PMID: 18946061. 25. Hasselbalch B, Lassen U, Hansen S, et al. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial. Neuro Oncol. 2010;12(5):508–516. Epub 2010/04/22. PubMed PMID: 20406901; PMCID: PMC2940618 https://doi.org/10.1093/neuonc/nop063. 26. Li L, Quang TS, Gracely EJ, et al. A phase II study of anti-epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme. J Neurosurg. 2010;113 (2):192–198. Epub 2010/03/30. PubMed PMID: 20345222 https://doi.org/10.3171/2010.2. jns091211. 27. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(28):4733–4740. Epub 2009/09/02. PubMed PMID: 19720927 https://doi.org/10.1200/jco.2008.19.8721. 28. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol Off J Am
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Soc Clin Oncol. 2009;27(5):740–745. Epub 2008/12/31. PubMed PMID: 19114704; PMCID: PMC2645088 https://doi.org/10.1200/jco.2008.16.3055. 29. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–722. https://doi.org/10.1056/ NEJMoa1308345 PubMed PMID: 24552318. 30. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708. https://doi.org/10.1056/ NEJMoa1308573 PubMed PMID: 24552317. 31. Sampson J, Omuro A, Vlahovic G, et al. IMCT-03: safety and activity of nivolumab monotherapy and nivolumab in combination with ipilimumab in recurrent glioblastoma: updated results from checkmate-143. Neuro Oncol. 2015;17(Suppl. 5):v107. https://doi.org/10.1093/neuonc/ nov218.03. 32. Reardon DA, Kim T-M, Frenel J-S, et al. ATIM-35. Results of the phase IB KEYNOTE-028 multi-cohort trial of pembrolizumab monotherapy in patients with recurrent PD-L1-positive glioblastoma multiforme (GBM). Neuro Oncol. 2016;18(Suppl. 6):vi25–vi26. https://doi.org/ 10.1093/neuonc/now212.100. 32a.Xu LW, Chow KKH, Lim M, et al. Current vaccine trials in glioblastoma: a review. J Immunol Res. 2014;10 Article ID 796856, https://doi.org/10.1155. 33. Liau LM, Prins RM, Kiertscher SM, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005;11(15):5515–5525. Epub 2005/08/03. PubMed PMID: 16061868 https://doi.org/10.1158/1078-0432.ccr-05-0464. 34. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res. 2004;64(14):4973–4979. Epub 2004/07/17. PubMed PMID: 15256471 https://doi.org/ 10.1158/0008-5472.can-03-3505. 35. Weller M, Butowski N, Tran DD, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18(10):1373–1385. Epub 2017/08/29. PubMed PMID: 28844499 https://doi.org/10.1016/s1470-2045(17)30517-x. 36. Sampson JH, Archer GE, Mitchell DA, et al. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther. 2009;8(10):2773–2779. Epub 2009/10/15. PubMed PMID: 19825799; PMCID: PMC2991139 https://doi.org/10.1158/1535-7163.mct-09-0124. 37. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28 (31):4722–4729. Epub 2010/10/06. PubMed PMID: 20921459; PMCID: PMC3020702 https:// doi.org/10.1200/jco.2010.28.6963. 38. Sampson JH, Aldape KD, Archer GE, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011;13(3):324–333. Epub 2010/12/15. PubMed PMID: 21149254; PMCID: PMC3064599 https://doi.org/10.1093/neuonc/noq157. 39. Schuster J, Lai RK, Recht LD, et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol. 2015;17(6):854–861. Epub 2015/01/15. PubMed PMID: 25586468; PMCID: PMC4483122 https://doi.org/10.1093/ neuonc/nou348.
Immunotherapy for inoperable gliomas David Dadey, Kevin Chow and Gordon Li Department of Neurosurgery, Stanford University Medical Center, Stanford, CA, United States
Introduction The challenges posed by gliomas continue to drive efforts to refine surgical and postoperative care. Among the problems posed by the incidence of gliomas is the question of management when the site of tumor growth is not amenable to complete resection. Also, beyond tumor location, the problems posed by tumor size and recurrence are yet another significant barrier to curing patients who have undergone surgery. To circumvent some of these barricades in the operative phase, techniques such as awake craniotomy, intraoperative magnetic resonance imaging (MRI), and electrophysiologic mapping have evolved to allow many previously inoperable brain tumors to be treated. However, these components of the surgical armamentarium are only as successful as the methods in postoperative management allow them to be, as the morbidity of surgical resection for previously “inoperable” tumors can be significant. Thus the postoperative management of inoperable gliomas involves a multidisciplinary approach employing diligent medical surveillance, adjunct chemoradiation, and newer therapies applying the latest advances from the world of basic science. In this chapter, we focus on the postoperative management of high-grade gliomas in eloquent or unfavorable regions of the brain. Our discussion will examine the roles of the above-mentioned techniques and therapies in improving clinical outcomes for patients afflicted by these tumors.
Postoperative courses Surgical intervention for glioblastoma patients can be broadly defined by two postoperative pathways: (1) biopsy-only, and (2) craniotomy. The former being a path common to patients with high tumor burden, poor preoperative candidacy for craniotomy, or nonresectable tumors. Despite the availability of techniques to address eloquent brain tumors, some deep-seated tumors, or tumors with New Techniques for Management of ‘Inoperable’ Gliomas. https://doi.org/10.1016/B978-0-12-813633-1.00013-X © 2019 Elsevier Inc. All rights reserved.
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bilateral hemispheric involvement (extension into the corpus callosum) remain unsafe to resect without causing major postoperative neurological deficits. Without surgical resection or debulking, the postoperative course for biopsy patients is variable and is largely dictated by the nonsurgical options available to them. Current literature suggests that extent of resection (EOR) is often the most important predictor of survival, hence the survival for biopsy-only patients is often the shortest in many series.
Biopsy In general, patients who have undergone uncomplicated stereotactic needle biopsy-only surgeries of supratentorial pericortical lesions can recover well from the procedure after one night in an inpatient ward, and do not require intensive care. They are therefore at lower risk than craniotomy patients for hospitalassociated morbidities in the immediate postoperative period. Their medical management is focused on controlling pain from the surgical site and scalp wound care to minimize infection risk. However, for deep-seated lesions, the nature of the postoperative care process may vary. For example, in cases where a lesion in the brainstem is biopsied, more intensive monitoring may be indicated during the first 24 h after surgery. Specifically, care must be taken to detect symptoms suggestive of edema or hemorrhage, as compression of the fourth ventricle could result in acute hydrocephalus necessitating CSF (cerebrospinal fluid) diversion. Hence, it may be reasonable to obtain postoperative computed tomography (CT) scans when vascular tumors or high-grade gliomas involving the brainstem are the target of the biopsy. Lesions involving the thalamus can also present as difficult biopsy targets with some risk for postoperative neurological deficit. In a study of thalamic glioblastoma management spanning a 10-year period, 15% of patients suffered from neurological deficits after stereotactic biopsy.1 Of note, the study included 57 patients, of which 47 underwent stereotactic biopsy while the remaining 10 underwent craniotomy. Overall, the perioperative mortality rate was reported at 4.5% and the median survival was 12.2 months. Another study addressing biopsy of brain stem lesions found the incidence of neurological deficit to be 7.7%, with a perioperative mortality of 3.8%—while glioblastoma accounted for 19.2% of the cases, overall survival was not discussed in this study.2 Overall complication rates for patients undergoing biopsy-only surgeries are generally low and often under 6%, however, additional interventions may sometimes be warranted. One example of such a complication is intraaxial hemorrhage which can occur particularly when obtaining biopsies of malignant tumors with aberrant vascularity, or when tumors are seated in highly vascularized deep structures such as the basal ganglia. The risk for such hemorrhages may be subject to modification by the use of anticoagulants/antiplatelet agents in the perioperative period. Therefore, as with other more invasive cranial surgeries, it is common practice to hold anticoagulation for a period of weeks
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before and after biopsy procedures. In the event of a catastrophic hemorrhage occurring in the postoperative period, surgical evacuation and/or management of secondary intracranial hypertension may be warranted. In some reports, CSF diversion in the perioperative period for the management of hydrocephalus was found to provide clinically significant improvement in median overall survival.1 The next steps in management after the immediate postoperative period are dictated in large part by the histology and molecular characteristics identified by the biopsy. In the case of glioblastoma, the landmark trial by Stupp et al. demonstrated that patients who underwent biopsy-only surgeries had a median overall survival of 7.8 months with radiotherapy alone and 9.4 months when received concomitant radiation and temozolomide.3 However, newer approaches to management are actively being explored and will be discussed later in this chapter.
Craniotomy Craniotomy for tumor resection, when feasible, remains the recommended path for patients with glioblastoma. Given the invasive nature of these surgeries, the risks and morbidity associated with tumor resection can be significant as complications can occur shortly after surgery or in the late postoperative period. Much like with stereotactic biopsy surgery, neurological deficit is among the complications of primary concern especially when the target lesion involves eloquent regions of the brain. To reduce the risk of such complications, one technique that has evolved is intraoperative stimulation mapping (ISM). In this technique, an electrode probe is used to apply a current directly on cortical regions of interest. Often performed in the setting of awake craniotomy, eloquent areas of cortex can be identified by engaging the patient in tasks during stimulation and observing for induced deficits. A meta-analysis examining the impact of ISM on the occurrence of postoperative neurological deficits found that without ISM, late neurological deficits were observed in 9.4% of cases.4 On the other hand, with ISM, late neurological deficits were observed in 6.4% of cases.4 Hence techniques such as ISM, and other methods for intraoperative neuro-monitoring, may allow for greater fidelity during resection of complex lesions while also improving the postoperative course for brain tumor patients.5, 6 Postoperative care for patients who have undergone awake craniotomy, though rife with variability driven by patient characteristics and clinical practice, is generally similar to that of patients who have undergone standard craniotomy. In accordance with standard practice, patients should be monitored in an intensive care unit after completion of surgery. Among the management challenges that often present themselves in the ICU, postoperative nausea and vomiting (PONV) is very common. Providing patients with a course of steroids and antiemetics may be an effective strategy to control PONV. However, there is evidence to suggest that PONV can also be impacted by the selection of
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intraoperative anesthesia, and that patients undergoing awake craniotomy may experience relatively less PONV when compared to unconscious craniotomy.7 This highlights the importance of collaboration between neurosurgeons and anesthesiologists throughout the operative course in order to maximize positive outcomes for patients in the postoperative period. The benefits of interdisciplinary collaboration can extend to the management of seizures, which are another complication of awake craniotomies that can occur intraoperatively and early in the postoperative period. Given the use of cortical stimulation during awake craniotomy, neurosurgeons should remain vigilant for signs of seizure and be prepared to administer antiepileptic medication.8 Additionally, the standard risks of craniotomy, such as hemorrhage, cerebral hypoxia, and brain shift, should also be noted for their contribution to increased seizure risk. Midazolam, propofol, or thiopentone have successfully been used in conjunction with antiepileptic drugs (AEDs) such as phenytoin to control intraoperative seizures.8 Postoperatively, management of seizures can similarly be achieved with combinations of AEDs and sedation as needed depending on the severity and duration of seizure activity. However, patients with prior seizure history may benefit from perioperative loading of dual AEDs, as a study by Eseonu et al. demonstrated that combining levetiracetam and phenytoin lead to lower postoperative seizure rates.9 As with unconscious craniotomy, the risk of postoperative hemorrhage should also be on the neurosurgeon’s mental checklist after awake craniotomy. ICU monitoring with frequent neurological examinations is paramount for detecting progressive neurologic decline that may indicate acute hemorrhage in the postoperative period. A low threshold for obtaining CT scans should be maintained, as severe hemorrhage may necessitate emergent surgical evacuation. One study examining 611 patients who underwent awake craniotomy for glioma resection found that the overall perioperative complication rate was 10%, with postoperative hemorrhage accounting for 0.5% of complications.10 Even in the absence of head CT for hemorrhage detection, or any other complications, it is common practice to obtain MRI to evaluate EOR within 24–48 h of surgery. Increasing the availability of intraoperative MRI may improve this aspect of the surgical course, as the EOR can be monitored closely during surgery and neurosurgeons can minimize the odds of repeat craniotomy for residual tumor.
Radiotherapy The benefit of radiation therapy for the treatment of anaplastic gliomas was first demonstrated in a phase III prospective randomized controlled trial conducted by Walker et al. They showed that whole brain radiotherapy of 5000–6000 rads in five fractions per week over 5–6 weeks improved the survival after surgery by approximately 20 weeks.11 A subsequent trial demonstrated no significant difference in survival between patients treated with whole brain vs local
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irradiation.12 These and other studies define the current standard radiation therapy schedule for glioblastoma patients which consists of 60 Gy over 30 fractions delivered to the gross tumor volume with a 2–3 cm margin for the clinical target volume.13 While this schedule remains the standard of care, several groups have looked at the role of hypofractionated radiotherapy (HFRT) or stereotactic radiosurgery (SRS) for the treatment of recurrent or newly diagnosed GBM. The HFRT is simply the delivery of fewer higher dose fractions compared to the conventional schedule.14 It is an attractive alternative to conventional fractionation due to the potential for increased tumor cell killing, decreased tumor cell repopulation, and decreased overall treatment time.15
Laser interstitial thermal therapy Laser interstitial thermal therapy (LITT) has seen a resurgence in the last decade and its applications to tumor treatment growing in number. This method is generally performed by inserting a laser probe into a target by utilizing stereotactic guidance. Once in the desired target, thermal energy generated by the laser is then directed toward target tissues to induce cell death. For many years, LITT as a treatment modality for brain tumors was not widely accepted due to the inability to accurately track the extent of thermal ablation during any given treatment. However, advances in imaging technology have spurred interest in LITT, as the feedback offered by intraoperative MR thermometry now allows for live monitoring and refinement of the ablation process. LITT holds particular promise for the treatment of primary inoperable deep-seated lesions, such as those involving the thalamus, corpus callosum, or basal ganglia. Furthermore, LITT has been successfully applied to the management of recurrent disease. One of the largest studies examining the applicability of LITT to patients with brain tumors was conducted by Pinakin et al. Comprising 20 patients with a range of tumors including high-grade gliomas, patients were elected for LITT for reasons such as prior treatment failure, or having surgically inaccessible tumors. Overall, this study was focused on demonstrating the procedural feasibility of MRI-guided laser ablation in brain tumor therapy, and though largely successful, it also highlighted some of the complications that can occur with LITT.16 Of note, hemorrhage secondary to the insertion of the laser catheter, postablation edema, and injury due to inaccurate targeting or image registration were observed among for patients. While the procedure can be safely performed with most patients often leaving within 1–2 days, the complications that can occur may necessitate craniotomy or external ventricular drain placement in the postoperative period. The benefits of this technology are easily seen in the case of glioblastoma, where disease recurrence is among the major barriers to improving patient longevity. For these patients, LITT provides a minimally invasive approach for delivery of focused treatments while avoiding the morbidity associated with
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undergoing multiple craniotomies. In a series published by Schwarzmaier et al., the overall survival of 16 patients after receiving LITT for recurrent GBM was 6.9 months.17 This has since been followed with another study by Mohammadi et al. where 19 patients within their cohort had recurrent high-grade gliomas that were treated with LITT—among these patients, progression-free survival was 6 months.18 Furthermore, another advantage offered by LITT in management of both primary and recurrent disease is the potential for synergism with chemotherapy. LITT has been shown to disrupt the blood-brain barrier local to the target lesions, and may be able to facilitate enhanced delivery of chemotherapy to tumors. A study by Leuthardt et al. examined this possibility in patients with recurrent glioblastoma by calculating vascular transfer constants on MRI before and after laser ablation. In addition to increased vascular transfer constants, they observed an increase in serum levels of brain-specific enolase persisting for several weeks after ablation was performed.19 Results of similar studies have raised the question of whether clinical efficacy can be enhanced by incorporating laser ablation into multimodal therapeutic regimens for brain tumors. The impact of LITT on the efficacy of chemoradiation is the subject of several clinical trials that are in early stages of organization.
Immunotherapy for “inoperable” gliomas Given the infiltrative nature of gliomas, even gross total resection of surgically accessible lesions is unlikely to remove all of the malignant cells at the margin. This of course underlies the need for adjuvant chemotherapy and radiation to try to kill the tumor cells in the periphery which are left behind. In the case of inoperable gliomas, we rely solely on systemic chemotherapy and local delivery of radiation to destroy the tumor bulk. Chemotherapy and radiation are both nonspecific therapies that rely on the difference in growth rate and sensitivity of tumor cells vs normal cells to achieve tumor killing. These therapies have limited benefit, particularly with high-grade gliomas, and can be associated with significant toxicity. As such, research into better therapies for gliomas has been widely investigated. Immunotherapy refers broadly to any therapy that utilizes the mechanisms employed by our body’s immune system to fight disease or cancer. Cancer immunotherapy can be broken down into several categories including cytokine therapies, antibody therapies, vaccine therapies, and cellular therapies. While all these therapies differ in their specific mechanism of action, as a whole they have the potential to be highly targeted with a better side effect profile than conventional chemotherapy or radiation. All of these therapies have been investigated in preclinical experiments and clinical trials for the treatment of highgrade gliomas. Here we discuss the principles relevant to immunotherapy for gliomas and highlight several clinical trials that have been conducted for glioma patients.
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Principles of glioma immunotherapy Gliomas are primary brain tumors and therefore presumed to be subject to the “immunological rules” of the brain. Historically it was thought that the brain is an “immune-privileged” site, with peripheral immune molecules and effectors being restricted from entering the brain by the blood-brain barrier. This paradigm has largely shifted to the brain being considered “immune-specialized” rather than privileged as researchers learn more about microglia, brain immunosurveillance, and brain lymphatic drainage.20 While the brain is known to undergo constant immunosurveillance, highgrade gliomas have been shown to employ various immunosuppressive strategies that allow them to escape detection and avoid eradication. GBMs secrete factors which downregulate antigen presentation, upregulate suppressive T regulatory cells, and inhibit antitumor effector T cells, effectively promoting its own survival. Immune therapies that work against these immunosuppressive strategies of GBM may provide therapeutic benefit. Additionally, GBM often express specific cell surface markers which are tumorrestricted or differentially expressed compared to the surrounding normal tissues which allow these markers to be exploited for tumor-specific targeting. Gliomaassociated antigens such as EGFRvIII, IL13Rα2, HER2, EphA2, and others can be targeted using antibodies, vaccines, or T cells to elicit an antiglioma response.
Cytokine therapies Cytokines are secreted molecules which act on immune cells to coordinate and propagate immune responses within the body.21 These molecules have a wide range of functions which can be harnessed for cancer therapy. These functions include promoting cell growth, activation, costimulation, differentiation, proliferation, antigen presentation, and others. Cytokines have been used alone or in combination with other immunotherapies such as vaccines and T cells. Perhaps one of the best studied cytokines used for cancer immunotherapy is interleukin-2 (IL-2). IL-2 promotes T cell proliferation and is used in vitro to activate immune cells. Injection of IL-2 into tumors can help recruit T cells to what would otherwise be an immunosuppressed environment. Systemically administered IL-2 is approved for the treatment of metastatic melanoma and renal cell carcinoma. However, the therapeutic window is small and significant toxicities have limited its use. The use of systemically administered IL-2 for the treatment of CNS (central nervous system) disease is limited by the efficiency with which IL-2 crosses the blood-brain barrier.22 Systemic toxicities have led to the use of intrathecal, intraventricular, intratumoral, or intracavitary injections of IL-2 for the treatment of brain tumors. Even with intracerebral delivery of IL-2 in patients with recurrent glioma, morbidity in the form of headache, nausea, fatigue, and weakness were seen at higher doses.23
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Antibody therapies Antibodies are proteins that bind to specific antigens and generally recruit immune effectors to the cells expressing those antigens in order to facilitate their destruction. Antibodies for cancer immunotherapy are often designed to target specific tumor-associated antigens. For instance, cetuximab is an antiEGFR (epidermal growth factor receptor) antibody which is approved for the treatment of metastatic colon cancer.24 Its efficacy for treating GBM patients, however, has not been well demonstrated.25 Antibodies can also be conjugated with radioisotopes or chemotherapeutics to target these cytotoxic agents specifically the tumor. This strategy has been shown to be safe and well tolerated in GBM patients, although again with limited efficacy.26 Bevacizumab, an antibody targeted to vascular endothelial growth factor (VEGF), was approved for the treatment of recurrent GBM based on phase 2 trials which showed promising antiglioma activity.27, 28 However, subsequent phase 3 trials failed to demonstrate improvement in overall survival despite improvement in progression-free survival.29, 30 Given the limited options for the treatment of recurrent GBM, bevacizumab is still commonly used. Checkpoint inhibitors such as nivolumab (anti-PD-1), ipilimumab (antiCTLA-4), and pembrolizumab (anti-PD-1) are antibodies that block the negative regulators of T cell activation and have been shown to have potent antitumor activity. They have been approved for the treatment of metastatic melanoma and other cancers, and are being tested in clinical trials for recurrent GBM patients.31, 32
Vaccine therapies Cancer vaccines attempt to stimulate a patient’s “dormant” or “suppressed” immune system to recognize and eradicate foreign cancer cells in the body. Vaccines typically consist of some form of antigen substrate usually synthetic peptides or whole tumor cell lysates. These can be administered alone or in conjunction with various adjuvants. Several vaccine trials have been attempted in GBM patients.32a Here we highlight two of the more advanced vaccine therapies. DCVax-L (or DCVax-Brain) is a vaccine that is produced by maturing autologous dendritic cells with patient-derived tumor sample, after which the vaccine is injected intradermally where they can activate the host immune response to the tumor. The theoretical advantage of this approach is the use of patient-derived sample as the source of antigen which makes it personalized and multiantigen specific. Phase 1 and 2 trials demonstrated safety and evidence of T cell infiltration into several of the recurrent tumors.33, 34 A phase 3 trial is ongoing. Rindopepimut (CDX-110) is a vaccine which consists of an EGFRvIIIspecific peptide conjugated to keyhole limpet hemocyanin.35 While the
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initial phase 1 and 2 studies (VICTORI, ACTIVATE, ACTII, ACTIII) demonstrated safety of the vaccine and evidence of a specific immune response,36–39 recurrence of antigen negative tumors raised concerns that targeting a single antigen may not be optimal for such a heterogeneous tumor. Nevertheless a large randomized phase 3 trial called ACT IV was performed, which unfortunately showed no improvement in the survival of groups treated with vaccine.35
Cellular therapies Unlike vaccines which attempt to stimulate endogenous immune effectors to act, cellular therapies allow investigators to take the effector cells out of the body, activate or modify the cells to enhance their antitumor functions, and then deliver them back to the patient for therapeutic effect. Cellular therapies have evolved over several decades, with initial testing focused on IL-2 stimulated lymphokine-activated killer (LAK) cells or expansion of tumor-infiltrating lymphocytes (TILs). The latest and perhaps most promising iteration of cellular therapy technology involves the genetic modification of T cells for improved antitumor capabilities. In particular, chimeric antigen receptor-modified T cells (CAR-T cells) have shown impressive responses in patients with treatment refractory leukemia. This technology has been utilized in phase 1 trials of patients with GBM. IL13Rα2-specific CAR T cells given intracerebrally to patients with recurrent GBM are safe and appear to have some antitumor effect (City of hope study). CAR T cells specific to HER2 have been given systemically to GBM patients without major side effects. More studies will be needed to determine whether cellular therapies can have an impact on patients with gliomas, particularly inoperable ones.
Concluding remarks Advances in surgical technique, operative technology, and clinical immunology/molecular biology have contributed to significant changes in the approach to brain tumors. Cancers of the brain that were once considered inoperable can now be safely resected with awake craniotomy, or ablated with laser therapy. Refinements in the delivery of ionizing radiation now allow for high-dose therapy to be administered with surgical precision. Furthermore, with the advent of immunotherapy, the power of the immune system to synergize with surgery by eliminating microscopic residual disease may one day lead to significantly prolonged survival for GBM. Continued research of clinical outcomes and basic science will be paramount to implementing novel therapeutic strategies for the improvement of patient outcomes.
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References 1. Esquenazi Y, Moussazadeh N, Link TW, et al. Thalamic glioblastoma: clinical presentation, management strategies, and outcomes. Neurosurgery. 2017; https://doi.org/10.1093/neuros/ nyx349 nyx349-nyx. 2. Quick-Weller J, Lescher S, Bruder M, et al. Stereotactic biopsy of brainstem lesions: 21 years experiences of a single center. J Neurooncol. 2016;129(2):243–250. https://doi.org/10.1007/ s11060-016-2166-1 Epub 2016/06/14. PubMed PMID: 27291894. 3. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–466. https://doi.org/10.1016/s1470-2045(09)70025-7 Epub 2009/03/10. PubMed PMID: 19269895. 4. De Witt Hamer PC, Robles SG, Zwinderman AH, Duffau H, Berger MS. Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(20):2559–2565. https://doi.org/10.1200/jco.2011.38.4818 Epub 2012/04/25. PubMed PMID: 22529254. 5. Eseonu CI, Rincon-Torroella J, ReFaey K, et al. Awake craniotomy vs craniotomy under general anesthesia for perirolandic gliomas: evaluating perioperative complications and extent of resection. Neurosurgery. 2017;81(3):481–489. https://doi.org/10.1093/neuros/nyx023. 6. Saito T, Muragaki Y, Maruyama T, Tamura M, Nitta M, Okada Y. Intraoperative functional mapping and monitoring during glioma surgery. Neurol Med Chir. 2015;55(1):1–13. https:// doi.org/10.2176/nmc.ra.2014-0215 PubMed PMID: PMC4533401. 7. Manninen PH, Tan TK. Postoperative nausea and vomiting after craniotomy for tumor surgery: a comparison between awake craniotomy and general anesthesia. J Clin Anesth. 2002;14 (4):279–283. https://doi.org/10.1016/S0952-8180(02)00354-9. 8. Sokhal N, Rath GP, Chaturvedi A, Dash HH, Bithal PK, Chandra PS. Anaesthesia for awake craniotomy: a retrospective study of 54 cases. Indian J Anaesth. 2015;59(5):300–305. https://doi.org/10.4103/0019-5049.156878 PubMed PMID: PMC4445152. 9. Eseonu CI, Eguia F, Garcia O, Kaplan PW, Quin˜ones-Hinojosa A. Comparative analysis of monotherapy versus duotherapy antiseizure drug management for postoperative seizure control in patients undergoing an awake craniotomy. J Neurosurg. 2017;1–7. https://doi.org/10.3171/ 2017.1.jns162913 PubMed PMID: 28621631. 10. Hervey-Jumper SL, Li J, Lau D, et al. Awake craniotomy to maximize glioma resection: methods and technical nuances over a 27-year period. J Neurosurg. 2015;123(2):325–339. https://doi.org/10.3171/2014.10.jns141520 PubMed PMID: 25909573. 11. Walker MD, Alexander Jr E, Hunt WE, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg. 1978;49(3):333–343. https://doi.org/10.3171/jns.1978.49.3.0333 Epub 1978/09/01. PubMed PMID: 355604. 12. Kita M, Okawa T, Tanaka M, Ikeda M. Radiotherapy of malignant glioma—prospective randomized clinical study of whole brain vs local irradiation. Gan No Rinsho. 1989;35 (11):1289–1294 Epub 1989/09/01. PubMed PMID: 2681872. 13. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New Engl J Med. 2005;352(10):987–996. Epub 2005/03/11. PubMed PMID: 15758009 https://doi.org/10.1056/NEJMoa043330. 14. Azoulay M, Shah J, Pollom E, Soltys SG. New hypofractionation radiation strategies for glioblastoma. Curr Oncol Rep. 2017;19(9):58. Epub 2017/07/25. PubMed PMID: 28735440 https://doi.org/10.1007/s11912-017-0616-3.
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15. Hingorani M, Colley WP, Dixit S, Beavis AM. Hypofractionated radiotherapy for glioblastoma: strategy for poor-risk patients or hope for the future? Br J Radiol. 2012;85(1017):e770–e781. https://doi.org/10.1259/bjr/83827377 PubMed PMID: PMC3487099. 16. Jethwa PR, Barrese JC, Gowda A, Shetty A, Danish SF. Magnetic resonance thermometryguided laser-induced thermal therapy for intracranial neoplasmsinitial experience. Oper Neurosurg. 2012;71(Suppl. 1):ons133–ons145. https://doi.org/10.1227/NEU.0b013e31826101d4. 17. Schwarzmaier HJ, Eickmeyer F, von Tempelhoff W, et al. MR-guided laser-induced interstitial thermotherapy of recurrent glioblastoma multiforme: preliminary results in 16 patients. Eur J Radiol. 2006;59(2):208–215. Epub 2006/07/21. PubMed PMID: 16854549 https://doi.org/10. 1016/j.ejrad.2006.05.010. 18. Mohammadi AM, Hawasli AH, Rodriguez A, et al. The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: a multicenter study. Cancer Med. 2014;3(4):971–979. Epub 2014/05/09. PubMed PMID: 24810945; PMCID: PMC4303165https://doi.org/10.1002/cam4.266. 19. Leuthardt EC, Duan C, Kim MJ, et al. Hyperthermic laser ablation of recurrent glioblastoma leads to temporary disruption of the peritumoral blood brain barrier. PLoS One. 2016;11(2) e0148613https://doi.org/10.1371/journal.pone.0148613. 20. Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–341. Epub 2015/06/02. PubMed PMID: 26030524; PMCID: PMC4506234 https://doi.org/10.1038/nature14432. 21. Lee S, Margolin K. Cytokines in cancer immunotherapy. Cancers. 2011;3(4):3856–3893. Epub 2011/01/01. PubMed PMID: 24213115; PMCID: PMC3763400 https://doi.org/10.3390/ cancers3043856. 22. Saris SC, Rosenberg SA, Friedman RB, Rubin JT, Barba D, Oldfield EH. Penetration of recombinant interleukin-2 across the blood-cerebrospinal fluid barrier. J Neurosurg. 1988;69 (1):29–34. Epub 1988/07/01. PubMed PMID: 3259980 https://doi.org/10.3171/jns.1988.69. 1.0029. 23. Merchant RE, McVicar DW, Merchant LH, Young HF. Treatment of recurrent malignant glioma by repeated intracerebral injections of human recombinant interleukin-2 alone or in combination with systemic interferon-alpha. Results of a phase I clinical trial. J Neurooncol. 1992;12(1):75–83 Epub 1992/01/01. PubMed PMID: 1541981. 24. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–1765. https://doi.org/ 10.1056/NEJMoa0804385 PubMed PMID: 18946061. 25. Hasselbalch B, Lassen U, Hansen S, et al. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial. Neuro Oncol. 2010;12(5):508–516. Epub 2010/04/22. PubMed PMID: 20406901; PMCID: PMC2940618 https://doi.org/10.1093/neuonc/nop063. 26. Li L, Quang TS, Gracely EJ, et al. A phase II study of anti-epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme. J Neurosurg. 2010;113 (2):192–198. Epub 2010/03/30. PubMed PMID: 20345222 https://doi.org/10.3171/2010.2. jns091211. 27. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(28):4733–4740. Epub 2009/09/02. PubMed PMID: 19720927 https://doi.org/10.1200/jco.2008.19.8721. 28. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol Off J Am
192
New techniques for management of ‘inoperable’ gliomas
Soc Clin Oncol. 2009;27(5):740–745. Epub 2008/12/31. PubMed PMID: 19114704; PMCID: PMC2645088 https://doi.org/10.1200/jco.2008.16.3055. 29. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–722. https://doi.org/10.1056/ NEJMoa1308345 PubMed PMID: 24552318. 30. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708. https://doi.org/10.1056/ NEJMoa1308573 PubMed PMID: 24552317. 31. Sampson J, Omuro A, Vlahovic G, et al. IMCT-03: safety and activity of nivolumab monotherapy and nivolumab in combination with ipilimumab in recurrent glioblastoma: updated results from checkmate-143. Neuro Oncol. 2015;17(Suppl. 5):v107. https://doi.org/10.1093/neuonc/ nov218.03. 32. Reardon DA, Kim T-M, Frenel J-S, et al. ATIM-35. Results of the phase IB KEYNOTE-028 multi-cohort trial of pembrolizumab monotherapy in patients with recurrent PD-L1-positive glioblastoma multiforme (GBM). Neuro Oncol. 2016;18(Suppl. 6):vi25–vi26. https://doi.org/ 10.1093/neuonc/now212.100. 32a.Xu LW, Chow KKH, Lim M, et al. Current vaccine trials in glioblastoma: a review. J Immunol Res. 2014;10 Article ID 796856, https://doi.org/10.1155. 33. Liau LM, Prins RM, Kiertscher SM, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005;11(15):5515–5525. Epub 2005/08/03. PubMed PMID: 16061868 https://doi.org/10.1158/1078-0432.ccr-05-0464. 34. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res. 2004;64(14):4973–4979. Epub 2004/07/17. PubMed PMID: 15256471 https://doi.org/ 10.1158/0008-5472.can-03-3505. 35. Weller M, Butowski N, Tran DD, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18(10):1373–1385. Epub 2017/08/29. PubMed PMID: 28844499 https://doi.org/10.1016/s1470-2045(17)30517-x. 36. Sampson JH, Archer GE, Mitchell DA, et al. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther. 2009;8(10):2773–2779. Epub 2009/10/15. PubMed PMID: 19825799; PMCID: PMC2991139 https://doi.org/10.1158/1535-7163.mct-09-0124. 37. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28 (31):4722–4729. Epub 2010/10/06. PubMed PMID: 20921459; PMCID: PMC3020702 https:// doi.org/10.1200/jco.2010.28.6963. 38. Sampson JH, Aldape KD, Archer GE, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011;13(3):324–333. Epub 2010/12/15. PubMed PMID: 21149254; PMCID: PMC3064599 https://doi.org/10.1093/neuonc/noq157. 39. Schuster J, Lai RK, Recht LD, et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol. 2015;17(6):854–861. Epub 2015/01/15. PubMed PMID: 25586468; PMCID: PMC4483122 https://doi.org/10.1093/ neuonc/nou348.