Experience with tumour-treating fields in operable and inoperable glioblastoma multiforme

Case 1: Ongoing TTFields after three craniotomies with complete GBM excision
Presentation, treatment and response
A 56-year-old male with good past health had an episode of new-onset epi­lepsy in April 2020. Brain MRI performed shortly after showed minor enhancement over the right temporal lobe, which was initially thought to be due to infectious encephalitis. Subsequent treatment with anti-infectives failed, and the patient’s con­dition began to deteriorate with more frequent seizures. He was put on an anticon­vulsant, levetiracetam (1.5 g daily).

Another MRI of the brain in late June 2020 revealed a big (4 cm) tumour over the right temporal side. The patient was thus referred to our care, and tumour excision was performed on 26 June 2020. Postop­erative MRI performed 3 days after surgery confirmed complete excision. Pathology findings led to diagnosis of glioblastoma multiforme (GBM) with methylated MGMT promoter.

Standard Stupp regimen of concurrent chemoradiotherapy (CRT) with temozolo­mide (TMZ) was started in mid-July 2020.¹ The patient completed the full 6-week course. Tumour-treating fields (TTFields) were added to adjuvant TMZ in early September 2020, 74 days after surgery. The patient tolerated TTFields very well, without any local irritation, headaches or dizziness, and had remained in high spirits since com­mencing treatment.

Unfortunately, in December 2020, he began to experience numbness in the left upper limb. Brain MRI in February 2021 showed a small (<1 cm) new enhance­ment 2 cm away from the original lesion, in the right inferior frontal gyrus. Second craniotomy with complete excision was performed on 16 February 2021. Upon wound healing, TTFields were restarted approximately 3 weeks after the second surgery.

In view of recurrence, TMZ was deemed ineffective and adjuvant chemo­therapy was switched to lomustine. Re­grettably, lomustine led to reactivation of latent Herpes zoster infection in the form of a painful rash over the anterior chest wall. Adjuvant treatment was switched to bev­acizumab in April 2021 while the patient continued to receive TTFields.

The patient remained well until Octo­ber 2021, when he started to experience neuropathic pain in the left upper limb. MRI performed in the same month did not show any signs of recurrence. However, a new enhancement over the posterior tu­mour margin left after the second surgery and dura mater became apparent on MRI in February 2022.

A third craniotomy was carried out in early March 2022, 19 months after origi­nal diagnosis. Complete excision of the tumour was again achieved, after which a carmustine wafer was inserted into the tumour bed for localized chemotherapy re­lease. The surgery led to complete resolu­tion of left upper limb symptoms. TTFields and bevacizumab were resumed approxi­mately 3 weeks postoperatively, once the surgical wound had healed.

As of September 2022, the patient re­mained well, with intact cognitive function, no reports of epilepsy, stable body weight, only minor finger flexor weakness, and a Karnofsky performance status (KPS) of 100. He continued to receive levetirace­tam. The latest MRI scan in August 2022 did not show any disease recurrence.

Main take-aways
Early initiation of TTFields is crucial for maximizing chances of tumour control and should follow as soon as the surgical wound has healed. As GBM can be very aggressive, ideally, the gap between CRT and TTFields plus adjuvant TMZ should be minimal (≤7 weeks from the last dose of concomitant CRT) to maintain tumour sup­pression when switching between treatment modalities.²

Distant progression on TTFields, as seen in our patient, was also frequently ob­served in the pivotal EF-14 trial, where dis­tant lesions appeared at greater distances from the primary tumour in TTFields-treat­ed patients vs controls (median distance, 23.2 mm vs 14.2 mm; p=0.03). Notably, patients with distant progression (n=71) in the TTFields plus TMZ group had a sig­nificantly longer time to progression (TTP) than patients in the same group who exhibited local progression (n=235) (7.9 months vs 5.2 months; hazard ratio [HR], 0.78; confidence interval [CI], 0.59–1.03; p=0.015), while the location of recurrence was not associated with TTP in patients treated with TMZ alone.³

As our patient’s disease progressed, he continued to receive TTFields on the basis of a post hoc analysis of the EF-14 trial, where 144 patients received TTFields plus chemotherapy and 60 patients re­ceived chemotherapy alone after disease progression. At a median follow-up of 12.6 months, median overall survival (OS) was significantly longer with TTFields plus chemotherapy vs chemotherapy alone (11.8 months vs 9.2 months; HR, 0.70; 95 percent CI, 0.48–1.00; p=0.049).⁴ (Figure 1) Although TTFields significantly prolong survival, physicians should be transparent with patients regarding outcome expecta­tions, as GBM remains incurable to date.⁵

Since our patient progressed on ad­juvant TMZ, he was switched to adjuvant lomustine and, due to intolerance, beva­cizumab shortly after, while he continued to receive TTFields. Due to their unique mode of action, TTFields can be suc­cessfully used after disease progression either as monotherapy or with various other individually appropriate modalities, like those used in the EF-14 trial (ie, anti­angiogenic therapy with bevacizumab, chemotherapy, operation, operation with locally applied carmustine wafer [used after third craniotomy in our patient], ste­reotactic radiosurgery, or fractionated radiotherapy).⁶

Case 2: Complete remission of inoperable GBM following 13 months of TTFields
Presentation, treatment and response
A 59-year-old male sought consulta­tion for persistent headache over 3 weeks and an episode of syncope during driving, which led to a minor traffic accident in Oc­tober 2020. He had unremarkable medical history apart from pulmonary tuberculosis 20 years ago. Brain MRI in October 2020 showed a ring-enhancing lesion of 3.0 x 2.7 x 2.1 cm in the right thalamus. (Figure 2A) Extensive perifocal oedema was also noted, which was caused by the mass effect of the tumour leading to hydroceph­alus. Subsequent PET-CT revealed no ex­tracranial lesions.

Navigation-guided core needle biop­sy, performed in late October 2020, led to the diagnosis of WHO grade 4 wild-type IDH-1 GBM with methylated MGMT pro­moter. The tumour was assessed to be too deep-seated for resection. Drainage for decompressing hydrocephalus was considered, but close observation was preferred instead since the patient was relatively asymptomatic and the degree of hydrocephalus was mild. His Eastern Co­operative Oncology Group (ECOG) perfor­mance status (PS) was 1 at the time.

A standard 6-week course of CRT was commenced in early November 2020.¹ The patient tolerated this treatment well and his condition remained stable, with oc­casional mild headaches, some dizziness and no neurological deficit. He was given as-needed oral steroids and complet­ed CRT without major complications by mid-December 2020.

Review MRI of the brain carried out 3 days after CRT completion showed some shrinkage of the tumour down to 2.5 x 2.2 x 1.8 cm, with no progression of the hydro­cephalus. (Figure 2B)

TTFields were started on 27 Decem­ber 2020, followed by adjuvant TMZ in early January 2021. Two days after com­pleting the first cycle of adjuvant TMZ, the patient complained of bilateral weakness in his lower limbs, with greater weakness felt in the left leg. TTFields were stopped for sever­al days and then resumed with the addition of dexamethasone.

The patient’s lower-limb weakness con­tinued to progress. In early February 2020, he presented with slurred speech and un­steady gait. All treatment was suspended until further investigations. An MRI showed shrinkage of the solid component of the tumour, but a new area of ischaemia was found in the right internal capsule. (Figure 2C) This cerebrovascular event was deemed un­related to tumour treatment, and the patient resumed TTFields and adjuvant TMZ shortly afterwards. Steroid dosage was temporarily stepped up and his symptoms improved.

MRI in April 2021 showed continued shrinking of the main tumour, but two new nodules (5 mm and 7 mm) were noted in the oedematous zone of the primary tumour. Recurrent GBM was initially suspected, al­though radiation effect could not be ruled out. (Figure 2D) Imaging in the intervening months showed resolution of the nodules and further shrinking of the main tumour bulk. The last MRI before completing the 1-year course of adjuvant TMZ in December 2021 was carried out in November 2021 and showed the same positive dynamic. (Figure 2E)

The patient was treated with TTFields alone between December 2021 and February 2022, when an MRI scan showed complete remission (CR), with no visible tumour remaining. (Figure 2F)

While receiving TMZ, the patient’s compliance with TTFields was around 80–90 percent. However, having complet­ed his TMZ course and achieved CR of the tumour, the patient became somewhat complacent and only wore the TTFields device half of the time.

Last seen October 2022, the patient remained well and continued to receive TTFields without any evidence of tumour recurrence as shown by the latest MRI in the same month. Following the cerebro­vascular event, left-sided body weakness persisted. The patient thus required the aid of a walking stick, but he retained full con­sciousness and was able to speak with mi­nor slurring, resulting in an ECOG PS of 2.

The patient experienced mild grade 1 scalp dermatitis with TTFields and used topical steroids as necessary. He also took regular breaks in wearing the arrays even at the time of his peak compliance and made sure they were repositioned slightly at each subsequent application.

Main take-aways
In GBM, extent of resection is asso­ciated with survival. According to a me­ta-analysis and systematic review of 37 GBM studies, the risk of mortality at 1 year was significantly reduced for any resection vs biopsy (relative risk, 0.77; 95 percent CI, 0.71–0.84; p<0.001), implying a poor prognosis for our inoperable patient.⁷

Nevertheless, biopsy-only patients (n=89; 13 percent of intent-to-treat popu­lation) included in the EF-14 trial achieved one of the most compelling HRs among all prespecified prognostic subgroups treated with TTFields plus TMZ vs TMZ alone (HR, 0.50; 95 percent CI, 0.30–0.84), making TTFields plus TMZ an appropriate choice for our patient.⁸

Importantly, another analysis of the EF-14 trial demonstrated that a TTFields compliance level of ≥75 percent was an independent predictor of OS, regard­less of resection/biopsy status. Further­more, patients with >90 percent com­pliance had maximal survival benefit, with a median OS of 24.9 months and a 5-year survival rate of 29.3 percent.⁹ These findings should be highlighted to patients during the joint treatment decision-making process.