by ecancer reporter Clare Sansom

Glioblastoma, which is also known as grade IV astrosarcoma, is the most common and the most deadly form of brain tumour.

About 20% of all tumours that form inside the skull are glioblastomas, and the median survival with current standard-of-care therapies is only about 15 months.

That standard of care involves surgical removal of as much of the tumour as is safe, followed by radiation therapy and then maintenance treatment with the chemotherapy drug temozolomide.

Temozolomide is a DNA alkylating agent that is characterised by its ability to cross the blood-brain barrier, which enables the orally delivered drug to reach the brain.

There have been no significant improvements to the treatment or prognosis of glioblastoma since this drug was introduced to the clinic in the early 2000s.

Alternating electric field therapy or tumour treating fields (TTFields) is an experimental cancer therapy in which low intensity alternating electromagnetic fields are applied to the shaved scalp of a brain tumour patient.

Their exact mechanism of action is unknown but they are believed to disrupt the formation of the mitotic spindle, leading to mitotic arrest and apoptosis of dividing cells.

A Phase III clinical trial has shown that TTFs alone do not prolong progression-free or overall survival in comparison with chemotherapy alone.

However, preclinical data has suggested that they may act in synergy with chemotherapy.

Roger Stupp of University Hospital Zurich, Switzerland and a large, international team of researchers and clinicians designed a Phase III study to test the combination of TTFs with standard maintenance chemotherapy with temozolomide against temozolomide alone¹.

Patients with histologically confirmed glioblastoma were recruited from sites in the US, Canada, Europe, Israel and South Korea between July 2009 and November 2014.

A total of 695 patients were randomised 2:1 to receive maintenance chemotherapy with temozolomide according to a standard protocol with or without the addition of continuous treatment with TTFields.

TTFields treatment could be carried out at home once the patients had been trained to operate the device.

It was considered neither appropriate nor feasible to offer a sham or placebo ‘TTFields’ treatment to the control (standard treatment) arm, so the study was open-labelled with all patients and their physicians knowing which arm they had been assigned to.

During the follow-up period, patients were examined monthly and their quality of life was assessed every three months using questionnaires.

The primary end point was progression-free survival in the intent-to-treat population, with overall survival tested only once the threshold for significance had been reached in interim analysis.

This interim analysis included 210 patients in the combined therapy group and 105 patients in the standard treatment group, all of whom had completed at least 18 months of follow-up.

It found a mean progression-free survival of 7.1 months (95% confidence interval 5.9-8.2 months) in the combination therapy group and 4.0 months (95% CI 3.3-5.2 months) in the temozolomide only group, giving a hazard ratio of 0.62 and a p-value of 0.001.

Median overall survival was analysed in the per-protocol group of patients only and found to be 20.5 months (95% CI 16.7-25.0 months) in the combination group and 15.6 months (95%CI 13.3-19.1 months) in the temozolomide group.

Furthermore, the addition of TTFields did not cause any significant increase in systemic toxicity over that associated with temozolomide alone.

Skin irritation at the device site was observed in almost half the patients receiving TTFields, but this was very rarely severe.

These results were sufficient to show that the addition to TTFields to temozolomide significantly increased progression-free and overall survival after allowing for any placebo effect, and the trial was terminated.

The robustness of the analysis and the promising nature of this novel therapy were highlighted by John H. Sampson of Duke University, Durham, North Carolina, USA in a JAMA editorial².

References

1. Stupp, R.,Taillibert, S., Kanner, A.A. and 27 others (2015). Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: A randomized clinical trial. JAMA 314(23): 2535-2543

2. Sampson, J.H. (2015). Alternating electric fields for the treatment of glioblastoma. JAMA 314(23): 2511-2513 (Editorial)