Tumour-treating fields for newly diagnosed glioblastoma: Hong Kong experience

Case 1: Young patient on TTFields after initial diagnosis and following two disease progressions
Presentation, treatment and response
A 27-year-old male presented to a public hospital in June 2020 with generalized tonic-clonic convulsion, headache, dysphasia, and vomiting. Montreal Cognitive Assessment (MoCA) yielded a pathological score of 13/30.

Craniotomy with subtotal excision was performed under general anaesthesia in early June 2020 and was uneventful. (Figure 1A) The excision was stopped when subcortical mapping stimulation at 9 mAmp yielded excitation of the motor tracks, leaving some residual tumour behind. However, postoperative MRI showed complete resection of the contrast-enhancing tumour portion. Pathology assessment produced a diagnosis of IDH-mutant glioblastoma multiforme (GBM) with nonmethylated MGMT promoter.

The patient recovered well from surgery and regained his speech afterwards. He was discharged on postoperative day 13. His MoCA score at discharge was healthy at 27/30, and he was fully ambulatory.

Standard Stupp regimen of concurrent chemoradiotherapy (CRT) was started 4 weeks after surgery in July 2020.¹ The patient received a total of 60 Gy of radiation given over 30 fractions in the course of 6 weeks, with concomitant temozolomide (TMZ). He had an episode of non-neutropenic fever associated with TMZ treatment, which was conservatively managed. He also experienced some minor rash, which resolved after the first few cycles.

Tumour-treating fields (TTFields) were introduced alongside adjuvant TMZ in November 2020, 5 months after initial diagnosis.² The patient tolerated TTFields very well, without any scalp dermatitis. He was able to wear the device for >18 hours a day, including outdoors and while socializing with friends.

The patient had postoperative progression-free survival (PFS) of 17 months and remained progression-free for 12 months while on TTFields. (Figure 1B) An MRI scan in November 2021 identified a contrast-enhancing lesion, signifying disease recurrence. (Figure 1C)

Awake craniotomy for recurrent disease was performed in January 2022 and was uneventful. Postoperative MRI scan showed 99 percent excision of the contrast-enhancing lesion. The remaining 1 percent was mostly located in the corpus callosum. (Figure 1D) Postoperatively, the patient had no additional neurological deficit, and was able to speak and move normally, including walking unaided.

Although TMZ treatment was stopped after 14 cycles, following disease recurrence, treatment with TTFields was resumed 2 weeks after the second operation, once the patient’s wound had healed. The patient was enrolled in a drug trial in mid-February 2022, around the time of TTFields resumption.

The patient was using TTFields alongside the experimental drug when he began to show signs of second progression in early April 2022, at which point his participation in the clinical trial was terminated. (Figure 1E)

The patient continued to receive TTFields alongside palliative care as of June 2022. Except for a short break following his second operation, the patient had been on TTFields almost continuously for 19 months, since November 2020. When last seen in May 2022, he remained well and ambulatory, with no signs of dysphasia. However, he reported suffering generalized clonic convulsion, which was likely a sign of tumour progression. His anticonvulsant dosage was increased to enhance seizure control. The patient is currently considering third-line treatment.

Discussion
TTFields inhibit rapidly dividing tumour cells by delivering low-intensity (1–3 V/cm), intermediate-frequency (200 kHz), bidirectional, alternating electric fields via transducer arrays that are applied to the scalp and are powered by a portable battery device.³

TTFields’ efficacy in newly diagnosed GBM, like our patient’s, was demonstrated in the pivotal phase III, randomized, open-label EF-14 trial, which evaluated TTFields (applied ≥18 hours/day) plus adjuvant TMZ vs TMZ alone in 695 patients with newly diagnosed GBM who had completed concomitant CRT.⁴

After a median follow-up of 40 months, median PFS and median overall survival (OS) from randomization were significantly longer in the TTFields plus TMZ vs TMZ alone group, by approximately 3 months and 5 months, respectively (PFS: 6.7 months vs 4.0 months; hazard ratio [HR], 0.63; 95 percent confidence interval [CI], 0.52–0.76; p<0.001) (OS: 20.9 months and 16.0 months; HR, 0.63; 95 percent CI, 0.53–0.76; p<0.001).⁴

Notably, treatment with TTFields was well tolerated, with no associated systemic adverse events (AEs) and no increases in grade ≥3 AEs vs TMZ alone.⁴ Indeed, our patient reported no AEs associated with TTFields.

Case 2: Middle-aged patient treated with TTFields for 27 months
Presentation, treatment and response
A 58-year-old male sought consultation for one-sided weakness and inability to walk unaided in October 2019. Physical examination found 4/5 strength in the left upper and lower extremities. His Eastern Cooperative Oncology Group performance status (ECOG PS) was 1.

Brain MRI revealed a 7 cm tumour in the right frontal lobe. (Figure 2A) The patient was admitted to a public hospital and scheduled for tumour resection in November 2019. Standard craniotomy was performed, which achieved gross total tumour excision. The final histopathological diagnosis was GBM with wild-type IDH-1 and methylated MGMT promoter.

The patient recovered well after surgery. He was able to walk unaided after a short course of rehabilitation.

Stupp regimen was started 1 month after the surgery, in December 2019.¹ The remaining tumour tissue became metabolically static and his blood tests were normal. The patient tolerated this treatment well, with minor nausea as the only complaint.

After completing CRT, the patient was given TTFields in February 2020 alongside six cycles of adjuvant TMZ.² (Figure 2B) The patient responded well to treatment and continued to receive TTFields until November 2021, during which time his condition remained stable, including retained appetite, ability to walk unaided and carry out usual activities of daily living. (Figures 2C–E) At this time, his ECOG PS was 1.

Although the patient remained grossly asymptomatic with only a subtle deterioration in movement, an MRI scan performed in November 2021 noted first disease progression, 21 months after starting TTFields.(Figure 2F)

Throughout the entire duration of treatment with TTFields, the patient’s only complaint was minor scalp dermatitis, which was managed by a topical steroid. He demonstrated very good compliance with TTFields, wearing it >80 percent of the time, including in public.

The patient was referred for participation in a clinical trial in January 2022 and was continuing with his TTFields treatment when last seen in May 2022. At 27 months of continuous TTFields use, the current case represents one of the longest GBM survivors treated with TTFields in Hong Kong.

Discussion
The EF-14 trial represents a landmark study, as it was the first trial in a decade to show an increase in OS for patients with newly diagnosed GBM since the introduction of TMZ to standard care.^5,6 Not only did the addition of TTFields to TMZ maintenance significantly increase median OS by 4.9 months, but it also did not show any significant increase in rates of systemic AEs (grade 3/4, 48 percent vs 44 percent with TMZ alone; p=0.58), due to being a localized treatment modality.⁴ Although there is a perceived burden of patients having to carry and wear the device with high compliance, objective data suggest that continuous use of TTFields appears to be associated with maintained quality of life.⁷

A retrospective analysis of real-world data collected from GBM patients (n=80; median age, 51 years; male, 53.7 percent) receiving TTFields under the care of Shanghai Huashan Hospital in China demonstrated a higher incidence of adverse skin reactions (all grades, 72.9 percent; grade 3, 2.5 percent) than previously published data, which was mainly acquired from North American and European clinical trial centres.^4,8 The observed difference is likely due to Shanghai’s more humid climate, which in that respect somewhat resembles Hong Kong’s. At the same time, most TTFields-related skin reactions are of grade 1–2 and can be managed conservatively with topical steroids, as was the case for our patient.^4,8,9

The high tolerability of TTFields is reflected in the high compliance demonstrated in clinical trials, as well as by our patient. A subgroup analysis of the EF-14 trial recorded a compliance of ≥75 percent (ie, ≥18 hours/day) in 58.9 percent of the patients.⁴ Notably, patients with compliance ≥90 percent showed extended median OS (24.9 months) and 5-year OS rate (29.3 percent).¹⁰

In addition to high daily use, prolonged overall use of TTFields is also associated with extended PFS and OS, according to real-world data in Chinese patients. In patients who received TTFields for >6 months, median PFS was 17.3 months, compared with 6.3 months in patients who had been receiving TTFields for ≤6 months (HR, 0.30; 95 percent CI, 0.15–0.58; p<0.001). Median OS was not reached vs 15.0 months in the respective groups (HR, 0.34; 95 percent CI, 0.15–0.77; p<0.01).⁸

In the same real-world data set, median PFS and OS in newly diagnosed patients were 12.4 months and 20.0 months, respectively, and 7.5 months and 13.0 months, respectively, for recurrent cases.⁸ Taken together with positive survival data reported with extended use of the treatment modality, these findings support the use of TTFields beyond progression, which offers a well-tolerated maintenance option that can be used even while enrolled in a clinical trial, like our patient.

Practical insights
While the use of TTFields is not restricted by tumour biomarkers, a number of factors can improve patients’ compliance, leading to increased chances of response to treatment. Therefore, multidisciplinary teams of neurosurgeons and medical oncologists evaluate the potential use of TTFields on a case-by case basis.

Among the important criteria is the presence of a caregiver who would be able to assist the patient with regular scalp shaving, which is necessary for maintaining good contact with device arrays. In addition, the caregiver would need to help the patient reapply the arrays every few days, following detailed instructions from the manufacturer’s device support specialist team. In order to maintain optimal compliance of using the device for ≥18 hours/day, patients also need to be suitably motivated and feel supported by their social circle, which has been noted for the two patient cases described above.

As well as being conducive to compliance, patients’ PS and cognitive status play a role in decision-making, with a higher Karnofsky PS showing association with longer OS in patients receiving TTFields maintenance.⁴ Furthermore, patients’ broad understanding of TTFields’ mechanism of action, which remains unique in oncology, enhances motivation and compliance.