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Physicians' Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Acknowledgment of Commercial Support
This activity is supported by an educational grant from Novocure.
Community Practice Connections™: Overcoming Clinical Inertia in Glioblastoma Multiforme: The Experts Weigh-In on Recent Data Sets and Next Steps to Move the Field Forward
Release Date: December 21, 2018
Expiration Date: December 21, 2019
Media: Internet - based
Although there have been recent advancements in the understanding of the pathophysiology of glioblastoma multiforme (GBM), as well as modest improvements in its treatment, the overall prognosis for patients with GBM remains poor. While clinical interest in new treatment options to help improve outcomes for these patients is high, the development and incorporation of new technologies and targeted therapies into the treatment paradigm historically has been challenging.
In order to help you increase your understanding of these challenges and provide you with insights into the potential of new technologies—such as Tumor Treating Fields, and novel approaches that include targeted therapies and immunotherapies—to improve patient outcomes, this Web-based activity has been developed to cover the latest advancements. The perspectives of leading clinical experts on recent data and advancements in clinical trials that may change your clinical practice are interwoven throughout the activity with video interviews. This activity explores the management of patients with GBM in both the newly diagnosed and recurrent settings, giving you the opportunity to assess the opinions of multidisciplinary experts and optimize your approach to challenging, real-world clinical scenarios.
Acknowledgment of Commercial Support
This activity is supported by an educational grant from Novocure.
Instructions for This Activity and Receiving Credit
This education program is directed towards radiation oncologists, researchers, and other oncology healthcare professionals interested in the treatment of GBM.
At the conclusion of this activity, you should be better prepared to:
- Describe the therapeutic rationale for the use of technology and emerging treatment options in the management of patients with GBM
- Evaluate safety and efficacy outcomes from recent clinical trials of treatment for GBM
- Develop evidence-based strategies to optimize clinical application of recent data on targeted therapies, immunotherapies, and technology for patients with GBM
- Identify challenges associated with the current clinical trials landscape for patients with GBM
Faculty, Staff, and Planners' Disclosures
Chief of Neuro-oncology in the Department of Neurology
Professor of Neurological Surgery, Medicine (Hematology and Oncology) and Neurology (Neuro-oncology)
Feinberg School of Medicine
Disclosures: Other: Spouse is a full-time employee of Novartis (since January 2018), previously with Celgene. None of her activities/product portfolio have a relationship to the content of Dr. Stupp’s presentation.
Professor and Vice-Chair of Research
Department of Radiation Oncology
Co-Director, Brain Tumor Center
Laura and Isaac Perlmutter Cancer Center
NYU Langone Health
New York, NY
Disclosures: Grant/Research Support: AbbVie, Novocure; Consultant: AbbVie, Novocure, Merck
Professor, Department of Radiation Oncology
Washington University School of Medicine
Co-Medical Director, Gamma Knife Center
Chief, Central Nervous System Service
Director, Clinical Research, Department of Radiation Oncology
Siteman Cancer Center
St. Louis, MO
Disclosures: Speakers Bureau: Varian Medical Systems, Merck, AbbVie, Novocure
Co-Director, Brain & Spine Tumor Center, Northwestern Medicine Cancer Center Warrenville
Director of Research & Education, Northwestern Medicine Chicago Proton Center
Radiation Oncology Consultants
Disclosures: No relevant financial relationships with commercial interests to disclose
The staff of Physicians' Education Resource®, LLC, (PER®) have no relevant financial relationships with commercial interests to disclose.
Disclosure Policy and Resolution of Conflicts of Interest (COI)
As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.
Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.
Off-Label Disclosure and Disclaimer
This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.
PER Pulse Recap™
PER Pulse Recap (1 of 3)
Evolution of Radiation Therapy for GBM Management
For many patients with newly diagnosed glioblastoma multiforme (GBM), the use of partial-brain fractionated radiation therapy (RT) with concurrent and adjuvant administration of temozolomide following biopsy or resection has been regarded as the standard of care. Partial-brain RT is administered with 60 Gy in 30 fractions to the contrast-enhancing tumor with a 2-3-cm margin with concomitant and adjuvant temozolomide. This treatment approach was established by the European Organisation for Research and Treatment of Cancer and the NCIC Clinical Trials Group (EORTC/NCIC) phase III randomized study of 573 patients with newly diagnosed GBM (World Health Organization performance status ≤2) who received either RT alone or RT plus concurrent and adjuvant temozolomide.1 The patients in the temozolomide group had a median survival of 14.6 months compared with 12.1 months in the group receiving RT alone. In addition, the 2-year survival rate for patients treated with chemoradiation was 26.5% compared with 10.4% in the group receiving RT alone.1 This survival advantage with the combination of temozolomide and RT has been shown to persist at 5 years, as well.2
Physiologic imaging that evaluates elements such as tumor cellularity, blood volume, vascular permeability, and proliferation can help to generate information that accurately characterizes tumor extent beyond contrast-enhancing lesions, which may be useful for both tumor resection and RT planning. In a dose-escalation study conducted by Tsien and colleagues3 to assess the maximum tolerated dose of RT with concurrent temozolomide in patients with newly diagnosed GBM, none of the patients who received 75 Gy (in 30 fractions) developed any signs of radiation necrosis. The use of methionine-positron emission tomography (MET-PET) imaging in predicting recurrence was also assessed. Twenty-two of the 32 patients who had pretreatment MET-PET uptake displayed uptake beyond the pathologic area indicated by contrast-enhanced magnetic resonance imaging.3 Central recurrence of GBM, often within 2 cm of the initial tumor margin prior to surgery, is the most common pattern of recurrence in patients treated with the standard dose of RT and temozolomide.4,5 However, changes in the pattern of failure with increased doses of RT have been observed, which may be suggestive of increased treatment efficacy.3
- Following maximal safe resection, RT remains an integral component in the treatment of GBM, and can help to improve overall survival and local control.
- The influence of previous lines of brain RT on recurrent GBM is not well understood, with some evidence suggesting that acute and delayed RT effects have the potential to influence both the tumor and its microenvironment.6
- The integration of RT with novel targeted therapies, including immunotherapy, continues to be developed and is an active area of clinical research. Furthermore, the addition of tumor-treating fields to current guidelines for both recurrent and newly diagnosed GBM has helped to improve outcomes for patients with GBM.
- Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. DOI: 10.1056/NEJMoa043330.
- 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. doi: 10.1014/S1470-2045(09)70025-7.
- Tsien CI, Brown D, Normolle D, et al. Concurrent temozolomide and dose-escalated intensity-modulated radiation therapy in newly diagnosed glioblastoma. Clin Cancer Res. 2012;18(1):273-279. doi: 10.1158/1078-0432.CCR-11-2073.
- Milano MT, Okunieff P, Donatello RS, et al. Patterns and timing of recurrence after temozolomide-based chemoradiation for glioblastoma. Int J Radiat Oncol Biol Phys. 2010;78(4):1147-1155. doi: 10.1016/j.ijrobp.2009.09.018.
- Wick W, Osswald M, Wick A, Winkler F. Treatment of glioblastoma in adults. Ther Adv Neurol Disord. 2018;11:1756286418790452. doi: 10.1177/1756286418790452.
- Duan C, Yang R, Yuan L, et al. Late effects of radiation prime the brain microenvironment for accelerated tumor growth [published online August 29, 2018]. Int J Radiat Oncol Biol Phys. 2018. pii: S0360-3016(18)3639-3. doi: 10.1016/j.ijrobp.2018.08.033.
PER Pulse Recap (2 of 3)
Examining the Evidence: Recent Data Behind Technologies and Emerging Treatment Options for GBM
Tumor-treating fields (TTFields) is a treatment modality that has been approved for the management of patients with both newly diagnosed and recurrent glioblastoma multiforme (GBM). This therapy involves the application of low-intensity, intermediate-frequency (100-300 kHz), alternating electric fields in a continuous, noninvasive manner that blocks cell division.1 Transducer arrays are placed directly on the shaved scalp of the patient. Tumor-treating fields have been shown to have a direct effect on spindle microtubules, leading to the mitotic disruption of replicating tumor cells.1 The TTFields therapy may also increase GBM cell membrane permeability, potentially accounting for reports of the additive effects of chemotherapy and TTFields.2
In 2011, TTFields therapy was approved for recurrent GBM by the US Food and Drug Administration (FDA), based largely on the results of the EF-11 trial. The therapy is currently incorporated into National Comprehensive Cancer Network (NCCN) guidelines as a category 2B recommendation for patients with recurrent GBM.3 The FDA approved TTFields therapy for the treatment of patients with newly diagnosed GBM in 2015. This was based largely on the results of the phase III EF-14 clinical trial, in which 695 patients with newly diagnosed GBM were randomized to receive either temozolomide or temozolomide plus TTFields therapy delivered to second progression.4 There were no statistically significant differences with respect to adverse events between the 2 treatment groups, with the exception of a higher incidence of mild-to-moderate skin irritation in patients treated with TTFields. Of note, patients who wore the device for ≥18 hours daily had superior outcomes compared with those patients who wore the device for shorter periods of time. Increased compliance with this treatment modality has been shown to be independently prognostic for improved survival.5
Systemic Therapies: Historical Efforts and Emerging Approaches
Because GBM is highly vascularized, antiangiogenic therapies have been explored as a means of treating this malignancy. Two large, randomized, placebo-controlled studies added bevacizumab to standard treatment of patients with newly diagnosed GBM.6,7 PARP inhibitors have also been studied in the treatment of patients with GBM, with veliparib demonstrating the capacity to enhance the efficacy of temozolomide in patients whose tumors have MGMT promoter hypermethylation.8 Antibody-drug conjugates (ADCs) are also being studied in the management of patients with GBM. In particular, depatuxizumab mafodotin, which binds to cells with EGFR amplification, has been studied in combination with temozolomide for patients with EGFR-amplified, recurrent GBM.9
- New technologies such as TTFields have been incorporated into NCCN guidelines for both newly diagnosed and recurrent GBM, and are a category 1 recommendation for patients with newly diagnosed GBM.
- Numerous studies investigating treatment modalities such as PARP inhibitors and ADC therapy are ongoing, and may have the potential to further improve upon outcomes for patients with GBM.
- Giladi M, Schneiderman RS, Voloshin T, et al. Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells. Sci Rep. 2015;5:18046. doi: 10.1038/srep18046.
- Chang E, Patel CB, Pohling C, et al. Tumor treating fields increases membrane permeability in glioblastoma cells. Cell Death Discov. 2018;4:113. doi: 10.1038/s41420-018-0130-x.
- NCCN Guidelines. Version 2.2018. Central Nervous System Cancers. National Comprehensive Cancer Network webite. https://www.nccn.org/professionals/physician_gls/recently_updated.aspx. Accessed December 26, 2018.
- Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;218(23):2306-2316. doi: 10.1001/jama/2017.18718.
- Toms SA, Kim CY, Nicholas G, Ram Z. Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial [published online December 1, 2018]. J Neurooncol. 2018. doi: 10.1007/s11060-018-03057-z.
- 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. doi: 10.1056/NEJMoa1308573.
- Chinot OL, Wick W, Henriksson R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709-722. doi: 10.1056/NEJMoa1308345.
- Gupta SK, Kizilbash SH, Carlson BL, et al. Delineation of MGMT hypermethylation as a biomarker for veliparib-mediated temozolomide-sensitizing therapy of glioblastoma. J Natl Cancer Inst. 2015;108(5). pii: djv369. doi: 10.1093/jnci/djv369.
- Lassman AB, van den Bent MJ, Gan HK, et al. Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: results from an international phase I multicenter trial [published online July 5, 2018]. Neuro Oncol. 2018. doi: 10.1093/neuonc/noy091.
PER Pulse Recap (3 of 3)
Overcoming Clinical Inertia in GBM: Clinical Trials and Therapeutic Applications
Emerging technologies have the potential to improve upon current survival outcomes for patients with glioblastoma multiforme (GBM) and change the treatment paradigm. Unfortunately, there are numerous obstacles to the establishment of new treatment approaches, including poor clinical trial enrollment, long development times, and suboptimal decision-making.1 New modalities are often driven by clinical trials, and some analyses estimate that only 8% to 11% of patients with GBM are currently enrolled in clinical trials.1 In addition, provider bias, reticence to commit financial resources, and regulatory challenges also limit the scope of clinical trials that are conducted. Patients with GBM have been shown to have a survival advantage when they are enrolled in clinical trials. In a retrospective analysis of 564 patients with newly diagnosed GBM, clinical trial participation, patient age, and Karnofsky Performance Status at the time of diagnosis were significant predictors of survival.2
In the era of precision medicine and molecular assessment, patients with GBM are undergoing reclassification, as in the case of the 2016 World Health Organization guidelines that use molecular parameters to establish specific brain tumor diagnoses.3 Historically, concern has been expressed regarding the implications of waiting for molecular classification on outcomes. However, studies have shown a wide range of results with respect to influence on outcomes, with a couple of larger studies actually showing a positive impact on survival with waiting for molecular classification information.4
The incorporation of tumor-treating fields (TTFields) therapy into clinical trial design is currently evolving. In the Alliance A071102 study, which is assessing the treatment of patients with newly diagnosed GBM, one of the stratification elements that was incorporated was planned TTFields use (yes or no).
One study that is expanding the reach of investigation of treatments for GBM is the phase II Individualized Screening Trial of Innovative GBM Therapy (INSIGhT).5 The trial is designed to allow additional arms to be added to the study as opportunities arise. Another initiative that is being pursued is the GBM Adaptive Global Innovative Learning Environment (GBM AGILE),6 a platform trial that has been crafted to address the challenge of how to answer a large number of testable hypotheses in an efficient manner. The GBM AGILE is made up of 2 stages. The screening stage is designed to identify therapies that are effective based on OS comparison with common controls, as well as to pinpoint the patient population for whom the therapy holds the greatest degree of promise, based on biomarker status and clinical indication.6 The second stage uses fixed randomization to verify first-stage findings to support registration. As the trial progresses over time, therapeutic arms with biomarkers may be added. Patients with both methylated and unmethylated MGMT promoter status will be eligible.6
- Molecular analysis of GBM is now a routine component of clinical assessment.
- The incorporation of newer technologies into current clinical trials may allow for more rapid improvement in the standard of care for patients with GBM.
- Novel adaptive and/or biomarker-driven trials can facilitate more rapid assessment of treatments with the fewest possible number of patients.
- Vanderbeek AM, Rahman R, Fell G, et al. The clinical trials landscape for glioblastoma: is it adequate to develop new treatments? Neuro Oncol. 2018;20(8):1034-1043. doi: 10.1093/neuonc/noy027.
- Shahar T, Nossek E, Steinberg DM, et al. The impact of enrollment in clinical trials on survival of patients with glioblastoma. J Clin Neurosci. 2012;19(11):1530-1534. doi: 10.1016/j.jocn.2012.04.005.
- Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803-820. doi: 10.1007/s00401-016-1545-1.
- Han SJ, Englot DJ, Birk H, et al. Impact of timing of concurrent chemoradiation for newly diagnosed glioblastoma: a critical review of current evidence. Neurosurgery. 2015;62(Suppl 1):160-165. doi: 10.1227/NEU.0000000000000801.
- ClinicalTrials.gov. Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT). https://www.clinicaltrials.gov/ct2/show/NCT02977780. Updated February 28, 2018. Accessed December 26, 2018.
- Alexander BM, Ba S, Berger MS, et al. Adaptive Global Innovative Learning Environment for Glioblastoma: GBM AGILE. Clin Cancer Res. 2018;24(4):737-743. doi: 10.1158/1078-0432.CCR-17-0764.
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