Author: Dr Matt Williams

Optune is one of the few new treatment approaches that has substantial evidence supporting its use. Data from the randomized phase 3 trial (EF-14) shows a survival advantage for newly diagnosed GBM patients who were treated with either surgery, radiotherapy, and chemotherapy as standard (the “Stupp” protocol) or the Stupp protocol with Optune. The trial demonstrated that patients who used Optune in addition to the standard treatment lived longer compared to those who received only the standard treatment. Currently, Optune is typically started after radiotherapy is complete and used continuously until there is clear disease progression.

For patients whose disease has started to grow after initial treatment (i.e., those with relapsed disease), there is evidence suggesting that Tumour-Treating Fields (TTF) are as effective as chemotherapy chosen by their oncologists. However, since TTF and chemotherapy work differently and have distinct side effects, many patients with relapsed disease may receive chemotherapy alongside TTF.

Below, we provide a detailed breakdown of the evidence surrounding TTF for those interested in understanding the trial details, or for those who may need to support funding applications.

Introduction

Brain tumours are the leading cause of cancer death in individuals under 40 years old. The most common malignant brain tumour in adults is glioblastoma (GBM), classified as a WHO grade IV glioma. Despite aggressive multi-modality treatment, including surgery, radiotherapy, and chemotherapy, the median survival for GBM patients is only 15 months.

Tumour-Treating Fields (TTF) represent a novel anti-cancer treatment that applies an alternating electrical field across cancer cells. This disrupts cell division and impairs cancer growth. The only commercially available TTF device is Optune, manufactured by Novocure.

In 2005, Roger Stupp led a large international phase 3 randomised trial of 573 patients with newly diagnosed GBM. After surgery, patients were randomly assigned to either radiotherapy alone or radiotherapy plus temozolomide (TMZ) chemotherapy followed by six months of TMZ chemotherapy (the “Stupp protocol”). The trial showed a survival advantage from adding chemotherapy to radiotherapy, improving median survival from 12.1 to 14.6 months, with a hazard ratio (HR) of 0.6. This has become the global standard of care for the treatment of GBM (Stupp 2005, Stupp 2009).

Since then, numerous trials have tested adding additional treatments to chemo-radiotherapy for newly diagnosed GBM patients, though almost all have been negative (Oster AdvNeurOnc2023).

Evidence Base

There have been several clinical studies evaluating TTF in different tumour types and disease stages. Below, we summarise a few key trials, with the EF-14 trial being the most important.

The EF-14 Trial

The EF-14 trial was a large, multi-centre, international, randomised phase 3 trial that tested the combination of chemo-radiotherapy and chemotherapy (Stupp protocol) against chemo-radiotherapy and chemotherapy plus TTF. TTF was started four weeks after the completion of chemo-radiotherapy and continued until second disease progression.

In total, 695 patients were randomised, with a 2:1 allocation in favour of TTF. Patients were treated with adjuvant temozolomide, with or without TTF. After progression, treatment was determined by local practice, but TTF could continue until second progression. The primary outcome was progression-free survival (PFS), with overall survival (OS) as a secondary outcome. Outcomes were assessed in the intention-to-treat population. The trial also measured quality of life (QoL) using QLQ C30 and BN20 scales and assessed cognitive function with the MMSE. MRI scans were done every two months and centrally reviewed with blinded evaluation. Recruitment began in July 2009 and ended in December 2014. After an interim analysis, the Independent Data Monitoring Committee (IDMC) recommended allowing crossover, which 26 patients opted for.

The patient characteristics were similar between both groups. The median age was 56, with 68% male patients. 54% of patients underwent a gross total resection, while 13% had only a biopsy. Patients completed a median of 5-6 cycles of adjuvant TMZ, and the median TTF wear time was 8 months. 75% of patients in the TTF arm wore the device for an average of 18 hours or more each day. The follow-up period lasted a minimum of 24 months, with a median of 40 months.

The addition of TTF improved median PFS from 4.0 months to 6.7 months. Overall survival improved from 16.0 to 20.9 months, with a hazard ratio of 0.63. Two-year survival was 43% versus 31%, and five-year survival was 13% versus 5%. The hazard ratio was consistent across all subgroups. The only significant difference in side effects was skin irritation: 52% of patients developed skin irritation, but only 2% experienced severe (grade 3–4) skin side effects. Quality of life was similar in both arms, except for increased skin itching in the TTF group.

Note on interpreting EF-14 outcomes: Unlike most GBM trials that randomise patients after surgery but before starting chemo-radiotherapy, EF-14 randomised patients after chemo-radiotherapy. This means the outcomes from EF-14 are somewhat shorter than those in other trials. However, this does not affect the validity of the results. When comparing across trials, survival should be considered from the same timepoint.

A post-hoc analysis of EF-14 revealed that patients who wore the device more frequently had a greater improvement in survival.

Criticisms of EF-14

No trial is perfect, and EF-14 is no exception. There are two main criticisms of the trial:

1. Non-blinded design: Both patients and clinicians knew who was receiving treatment. This is a well-recognized problem in trials and could lead to bias.
2. Increased care: Patients receiving TTF had regular visits from a device-support specialist (DSS). It is possible that these visits improved outcomes by identifying deterioration earlier or through the intensity of care.

The Canadian CADTH review of TTF (CanJHealthTech2024) raised additional points:

1. Skewed patient inclusion criteria: The trial enrolled patients with better functional and disease status at baseline, which limits the generalizability of the results.
2. Fitter patients: Study participants were generally younger and in better health than the typical GBM patient, reducing the real-world applicability.
3. Open-label design: The trial’s open-label nature introduced uncertainty in interpreting patient-reported outcomes.
4. Crossover concerns: Some patients in the temozolomide-only arm crossed over to receive TTF, which may have affected results.
5. Evidence certainty: The evidence quality was assessed as moderate to very low due to selection bias and low generalisability.

However, there are reasonable counterarguments:

1. Non-blinded trials are not uncommon, as it’s difficult to conduct sham surgery or sham radiotherapy. Objective clinical outcomes like overall survival are less susceptible to placebo effects, which is why the results of EF-14 remain valid.
2. It’s unclear whether DSS visits directly improve survival. Analyses suggest a direct effect of TTF rather than the intensity of care, and studies show a positive correlation between TTF dose density and survival.
3. The inclusion of fitter patients is common in trials of this nature and doesn’t diminish the value of the EF-14 results.
4. The crossover of a small number of patients likely had a negligible impact on the survival benefit of TTF.
5. The lack of long-term studies is expected given TTF is a newer treatment. The minimum follow-up of 24 months aligns with the expected survival rate for standard treatments.

Use in Relapsed Disease: EF-11 and EF-19

The EF-11 trial explored TTF in patients with relapsed GBM. Two hundred and thirty-seven patients were randomised to either physician’s choice of chemotherapy or TTF. Survival was similar in both groups, with a median survival of six months. However, 80% of patients were on third-line therapy, which likely contributed to the poor outcomes in both arms. The EF-19 trial, which assessed TTF in the real-world setting, found similar results to EF-11.

Real-World Data

Although the EF-14 trial shows a survival advantage, real-world outcomes can differ significantly. Several real-world studies have examined TTF outside of clinical trials, including:

1. Post-marketing surveillance
2. The TIGER study from Germany
3. The US xCures study

Post-marketing data from 25,000 brain tumour patients treated with TTF showed that 43% developed a skin reaction. Other side effects included electric and heat sensations (Mrugala JNO 2024).

The xCures study, which pooled real-world data from 1,269 patients with newly diagnosed GBM in 2019, found survival in patients who wore TTF for more than 75% of the time was consistent with the EF-14 trial (19.3 months, Connelly JM, et al. ESMO 2024).

The TIGER study, which enrolled 710 patients from 81 centres in Germany, showed that 60% of participants began TTF. The median survival was 19.6 months, similar to the EF-14 trial. Both xCures and TIGER studies suggested a time-dependent effect, with longer TTF wear times correlating with improved survival, consistent with the EF-14 findings.

Non-brain tumours: Outside of brain tumours, there is data from three other significant trials – one in metastatic lung cancer (NSCLC), one in brain metastases from lung cancer, and one in locally advanced pancreatic cancer – all of which showed an improvement in outcomes. There was also a smaller trial in mesothelioma. However, there have been other trials in ovarian and other cancers that have been negative in terms of results.

• LUNAR trial: Randomised patients with metastatic NSCLC to systemic therapy +/- TTF. The overall survival was better in those randomised to TTF, with evidence of synergy between TTF and immunotherapy. LUNAR-2 will explore this further.
• METIS trial: Randomised patients with brain metastases from NSCLC who had previously undergone stereotactic radiotherapy to either TTF or not. Intra-cranial control was better with TTF.
• PANOVA-2 trial: Randomised patients with locally-advanced pancreatic cancer to chemotherapy +/- TTF. Overall survival was better in the TTF group.
  

Future evidence for TTF: There are ongoing trials of TTF in brain tumour patients. The key studies include:

• The TRIDENT trial, which has completed recruitment but has not yet reported results.
• The upcoming EF-41 trial, which will compare the Stupp protocol plus TTF vs. Stupp protocol plus TTF combined with Pembrolizumab.

However, it is important to note that none of these ongoing studies directly address the key question that the EF-14 trial has already answered: What is the magnitude of survival benefit from the addition of TTF to the Stupp protocol?