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What is the Role of Tumor-treating Fields in Newly Diagnosed Glioblastoma?

Ornelas, Abbie S., MD*; Porter, Alyx B., MD*; Sharma, Akanksha, MD*; Knox, Molly G., MD*; Marks, Lisa A., MLS, AHIP; Wingerchuk, Dean M., MD, MSc, FRCP(C)*; O’Carroll, Cumara B., MD, MPH*

doi: 10.1097/NRL.0000000000000222
Critically Appraised Topics
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Alternating electrical fields can disrupt mitosis leading to apoptosis of rapidly dividing cancer cells. The device that utilizes this mechanism is known as tumor-treating fields (TTFields). TTFields can be applied by ceramic transducer arrays on a shaved scalp to deliver the alternating electric activity to patients with glioblastoma (GBM). It has FDA approval for use in both recurrent and newly diagnosed GBM. The objective is to critically appraise the current evidence for the use of TTFields as adjunctive treatment to newly diagnosed GBM. The objective was addressed through the development of a structured, critically appraised topic. We incorporated a clinical scenario, background information, a structured question, literature search strategy, evidence summary, clinical bottom lines, and expert discussion. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of neurooncology. A randomized controlled trial was selected for critical appraisal. Patients with newly diagnosed GBM completing standard radiation and chemotherapy with temozolomide (TMZ) were subsequently randomized to receive maintenance TMZ with TTFields, or TMZ alone. With the addition of TTFields, median progression-free survival was 6.7 months compared with 4 months without the addition of TTFields (95% confidence interval, 0.52-0.76; P<0.001) and overall survival was 20.9 months compared with 16.0 months without the addition of TTFields (95% confidence interval, 0.53-0.76; P<0.001). TTFields may increase both progression-free and overall survival in patients receiving standard chemoradiation therapy for GBM.

Departments of *Neurology

Library service, Division of Education Administration, Mayo Clinic, Scottsdale, AZ

The authors declare no conflict of interest.

Correspondence to: Abbie S. Ornelas, MD, 13400 East Shea Boulevard, Scottsdale, AZ 85259. E-mail: Ornelas.Abbie@Mayo.edu.

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CASE

A 74-year-old right-handed man presented after an episode of confusion and weakness concerning for seizure. Head computerized tomography revealed a mass in his frontal lobes. Magnetic resonance imaging (MRI) confirmed a 38×47×39 mm mass concerning for a butterfly glioma. Neurosurgery performed a biopsy and the mass was partially resected. Pathology confirmed a grade IV astrocytoma [glioblastoma (GBM)]. Genetically, the tumor was isocitrate dehydrogenase 1 (IDH1) wild type and the methylation status of O6-methylguanine-DNA methyltransferase (MGMT) was indeterminate. He proceeded with radiotherapy and concomitant chemotherapy with temozolomide (TMZ). Repeat MRI 1 month after completion of radiotherapy demonstrated possible tumor growth. He planned to continue TMZ maintenance therapy. Adjuvant therapy with tumor-treating fields (TTFields) was considered.

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BACKGROUND

Median progression-free survival is 14.6 to 16.7 months after diagnosis of GBM.1 Characteristics that confer a better prognosis include a large percentage of tumor resection, younger age at the time of diagnosis, higher Karnofsky performance score, supratentorial location, MGMT promoter methylation, and IDH1 mutation.2,3 In 2005, a randomized controlled trial demonstrated that concomitant and adjuvant TMZ in patients with GBM increased overall survival by ~2.5 months compared with radiotherapy alone.3 Current standard treatment of GBM includes a biopsy or maximal safe resection, 6 weeks of radiation therapy concurrent with TMZ chemotherapy, and subsequent adjuvant therapy with TMZ.3

A device, termed tumor-treating fields, delivers low intensity, intermediate-frequency alternating electric fields. Alternating electric fields disrupt mitosis leading to apoptosis of rapidly dividing cells in both cellular and animal models.4,5 In patients with GBM, the alternating electric fields are delivered through 4 ceramic transducer arrays that are placed on a shaved scalp and attached to a portable battery. In 2012, TTFields demonstrated equivalent efficacy (when worn an average of at least 18 h/d) to traditional chemotherapy in patients with recurrent GBM and had a better side effect profile.6 This study paved the way for further exploration of the utility of TTFields in patients with newly diagnosed GBM.

The preliminary data for a phase 3 clinical trial comparing maintenance chemotherapy with the addition of TTFields to maintenance chemotherapy alone following traditional chemoradiation in patients with newly diagnosed GBM was published in 2015 and demonstrated a favorable outcome for the TTFields group.7

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CLINICAL QUESTION

In patients with a new diagnosis of GBM, does adding TTFields to the standard chemoradiation increase survival compared with the standard chemoradiation alone?

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SEARCH STRATEGY

The search was conducted using the Ovid MEDLINE database. The following MeSH terms were used and all were exploded: GBM, electrical stimulation therapy, drug therapy, and radiotherapy. The text words used included: GBM, electrical field therapy, chemotherapy, and radiation therapy. Corresponding MeSH terms and text words were combined using the Boolean operator “OR” then each set of terms were combined using the Boolean operator “AND” resulting in 6 articles for review. Of these, the article selected represented the highest level of evidence available (randomized controlled trial) to answer the clinical question.

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EVIDENCE, RESULTS, AND CRITICAL APPRAISAL

Evidence

A randomized, open-label clinical trial by Stupp et al1 best addressed the clinical question. Subjects were recruited at 83 sites in North America, Europe, Korea, and Israel and were enrolled between July 2009 and December 2014. All eligible patients underwent either biopsy or maximal surgical debulking and completed the initial 6-week treatment with the standard radiotherapy with TMZ. Inclusion criteria stipulated that patients were 18 years and above of age, had a Karnofsky performance score ≥70, and had newly diagnosed and histologically confirmed supratentorial GBM. Patients were excluded if they had evidence of progressive disease following initial chemoradiation, severe comorbidities that would preclude them from maintenance TMZ, or a contraindication to using the TTFields device (pacemakers, DBS, etc.). Randomization occurred after the completion of initial chemoradiation. A central web-based system randomized 2/3 of the subjects to receive maintenance TTFields+TMZ and 1/3 of subjects to receive TMZ alone. The degree of resection and MGMT methylation status were used to stratify patients.

Subjects receiving TTFields were taught to place the electrodes and operate the device independently. Neither clinicians nor subjects were blinded. They had monthly follow-up visits for physical examination and laboratory studies. The primary outcome was progression-free survival, while the secondary outcome was overall survival. Exploratory end points included progression-free survival at 6 months, annual survival rates, quality of life, and time to significant decline in Mini-Mental Status Sxamination and Karnofsky performance scores. Progression was defined as a radiologic progression as determined by 2 blinded radiologists using the McDonald criteria.8 A third radiologist made the final decision in the event of a tie. A brain MRI with and without contrast was completed 2 weeks before starting maintenance therapy and every 2 months until second radiographic progression or 24 months had elapsed. A brain MRI was also performed within 1 week of a clinician being alerted of a clinical change.

The study sample size of 700 was calculated based upon detection of a hazard ratio (HR) of 0.78 for the primary outcome assessment with 80% power and allowing for 10% loss to follow-up. The secondary outcome was only assessed if the primary outcome was met, and it was designed to detect a HR 0.76 with 80% power.

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Results

Among the 1019 subjects screened, 695 met criteria and were randomized. The TTFields+TMZ group had 466 (67%) subjects and the TMZ group had 229 (33%) subjects. At baseline, the 2 groups had comparable demographics and clinical characteristics. The median time from diagnosis to randomization was 3.8 months. Median follow-up time was 40 months with 7.6% lost to follow-up. There was good compliance with the TTFields device with >75% of patients compliant with the device >75% of the time. Twenty-six patients switched from the TMZ alone to the TTFields+TMZ group after preliminary data demonstrated increased survival in the TTFields group, but these patients were analyzed in the group to which they were assigned using the intent-to-treat principle.

Median progression-free survival was 6.7 months in the TTFields+TMZ group and was 4 months in the TMZ group [HR, 0.63; 95% confidence interval (CI), 0.52-0.76; P<0.001]. Median overall survival in the TTFields+TMZ group was 20.9 months and in the TMZ group was 16 months (HR, 0.63; 95% CI, 0.53-0.7; P<0.001). The addition of TTFields increased progression-free survival by 2.7 months and overall survival by 4.9 months. This increase in overall survival was demonstrated with every subgroup analysis including MGMT promoter methylation status, degree of resection, geographical location of treatment, age, baseline Karnofsky performance score, and sex. A larger degree of increased overall survival was seen in patients with MGMT promoter methylated tumors (10.4 vs. 2.2 mo in the unmethylated group) and a younger age of diagnosis (4.5 mo in those under age 65 vs. 3.4 mo in those 65 y and above of age). Exploratory end points demonstrated that 56% of patients achieved progression-free survival at 6 months in the TTFields+TMZ group vs. 37% in the TMZ group. At 1 year, overall survival was 73% in the TTFields+TMZ group and 65% in the TMZ group.

The most common adverse events noted in the TTFields group were mild to moderate skin irritation in 52% and severe skin irritation in 2% of patients. There were higher incidences of hematologic toxicity and systemic symptoms with the TTFields group that were ultimately attributed to the longer duration of treatment. Mini-Mental Status Examination and Karnofsky performance scores were monitored, and the TTFields group demonstrated a slower time to decline in both categories.

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Critical Appraisal

This study by Stupp et al1 is a randomized controlled trial. Neither the clinicians nor subjects were blinded which may have led to clinician bias in both treatment and imaging frequency. There was a large sample size with <10% lost to follow-up. The selection criteria for this study did choose patients with a better initial prognosis. This is important to consider when selecting patients who would most benefit from TTFields. This study also selected for a younger than average patient population. The median age of diagnosis of GBM is 64 years.8,9 The median age of enrollment for this study was 56 years of age for the TTFields group and 57 years for the control group. This younger than average cohort may have introduced selection bias, as younger patients may be better able to cope with the physical burdens of the device.

All patients were accounted for after randomization, and analysis utilized the appropriate statistical methods and the intent-to-treat principle. The randomization stratified by MGMT status and degree of tumor resection to help keep initial prognoses of patients similar between the treatment and control groups. Subgroup analyses demonstrated increased survival in all subgroups, regardless of their initial prognosis. Standard criteria were used to define progression, and the radiologists that determined progression were blinded. The investigators reported on a variety of adverse events; a second publication includes the data on quality of life measures.10

The TTFields group had more readily available access to health care professionals as there was a 24/7 hotline for troubleshooting the device. This potentially resulted in earlier detection of progression, as patients were likely encouraged to call their physicians if new symptoms or concerns were brought to the attention of the hotline operator. Importantly, any clinical change prompted an MRI to evaluate for progression.

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CLINICAL BOTTOM LINES

  • In patients with newly diagnosed GBM who did not have progressive disease after completion of initial radiation and TMZ therapy, the use of TTFields as an adjunct to maintenance TMZ resulted in a median progression-free survival after initial radiochemotherapy of 6.7 months compared with 4 months without the addition of TTFields (HR, 0.63; 95% CI, 0.52-0.76; P<0.001).
  • In patients with newly diagnosed GBM who did not have progressive disease after completion of initial radiation and TMZ therapy, the use of TTFields as an adjunct to maintenance TMZ resulted in a median overall survival after initial chemoradiation of 20.9 months compared with 16.0 months without the addition of TTFields (HR, 0.63; 95% CI, 0.53-0.76; P<0.001). This is an absolute increase in overall survival of 4.9 months with the addition of TTFields.
  • These results are relevant to patients with a new diagnosis of GBM who are younger, have MGMT promotor methylated tumors, and have more favorable initial prognostic indicators, including supratentorial tumor location, higher initial Karnofsky performance score, and no progression after initial chemoradiation.
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DISCUSSION/NEUROONCOLOGY EXPERT COMMENTARY

This study represents the best current evidence for evaluating the efficacy of TTFields in newly diagnosed GBM. It demonstrates that adding TTFields to traditional chemoradiation may increase progression-free and overall survival. However, the results should be interpreted with some caution given that both patients and investigators were unblinded to treatment allocation.

It is important to note the selection criteria and the results of the subgroup analysis when considering which patients would benefit most from the addition of TTFields. This study selected for patients with the best initial prognosis by excluding those with infratentorial tumors, lower Karnofsky performance scores, and progression after initial induction therapy with radiation and TMZ. Subgroup analysis demonstrated a greater degree of increased overall survival in patients older than 65 years and those with MGMT promotor methylated tumors (regardless of age). This data can be used to help clinicians and patients determine who would most benefit from the addition of TTFields.

The physical burden and side effects of the TTFields device creates some limitations. In order to operate the device, patients must shave their heads, attach the scalp electrodes, and carry a battery pack for 18 hours per day. Patients are taught to operate the device independently, but compliance may be limited without assistance from a caregiver. Older or debilitated patients may have more difficulty wearing and transporting the device. This study selected a relatively younger patient sample which may have inflated the number of people who were able to tolerate and operate the device. The device itself also causes local skin irritation in >50% of patients, and with its prominent location, patients must be comfortable publicizing their disease. Despite these limitations, there was no significant difference in the quality of life between patients in the TTFields and control groups (other than the skin irritation).10

GBM is a devastating diagnosis with a fatal outcome; novel advances that prolong survival while maintaining or improving quality of life are necessary. TTFields is an adjunctive therapy that may meet these objectives in a select group of people with this tumor type but confirmatory studies are needed.

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APPENDIX

  • Mayo Clinic Evidence-based Clinical Practice, Research, Informatics, and Training (MERIT) Center Cofounders: Bart M. Demaerschalk and Dean M. Wingerchuk.
  • MERIT Codirectors: Cumara B. O’Carroll and Dean M. Wingerchuk.
  • Faculty: Bart M. Demaerschalk.
  • Medical Library Sciences and Evidence-based Searching & Informatics Director: Lisa A. Marks.
  • Evidence appraisers: Abbie S. Ornelas, Molly G. Knox, Cumara B. O’Carroll, Dean M. Wingerchuk, and conference participants.
  • Content experts: Alyx B. Porter and Akanksha Sharma.
  • Date of appraisal: May 23, 2018.
  • Date of expiry: May 23, 2020.
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REFERENCES

1. 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;318:2306–2316.
2. Lamborn KR, Chang SM, Prados MD. Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis. Neuro Oncol. 2004;6:227–235.
3. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med. 2005;352:987–996.
4. Kirson ED, Dbalý V, Tovarys F, et al. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007;104:10152–10157.
5. 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.
6. Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012;48:2192–2202.
7. Stupp R, Taillibert S, Kanner AA, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015;314:2535–2543.
8. Macdonald DR, Cascino TL, Schold SC Jr, et al. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8:1277–1280.
9. Tamimi AF, Juweid M. Epidemiology and outcome of glioblastoma. In: De Vleeschouwer S, ed. Glioblastoma. Brisbane, AU: Codon Publications; 2017. Available at: https://www.ncbi.nlm.nih.gov/books/NBK470003/. Accessed October 10, 2018.
10. Taphoorn MJB, Dirven L, Kanner AA, et al. Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma: a secondary analysis of a randomized clinical trial. JAMA Oncol. 2018;4:495–504.
Keywords:

glioblastoma; tumor-treating fields; alternating electric field therapy; randomized controlled trial; critically appraised topic; evidence-based medicine

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