Tumor treating fields: Will the evidence gap ever be filled?

Tumor Treating Fields (TTFs) deliver low-intensity electric fields through adhesive skin arrays and have been approved in different oncology indications. However, concerns remain regarding the evidence supporting their benefit. Here, we highlight four limitations. First, TTFields utilization includes 24/7 assistance, home deliveries, and regular home-based interactions for array changes. In the absence of sham-controlled randomized trials, which are the equivalent of placebo-controlled trials for devices, the specific contribution of TTFields cannot be distinguished from the additional supportive care and infrastructure accompanying device use. Second, although a mechanistic rationale exists, the biological plausibility remains limited, particularly because of the lack of validated human in vivo dosimetry data. Third, while reviewing six pivotal randomized trials, we describe the use of suboptimal control arms in half of them, including two trials that reported a survival gain. As a result, it remains unclear whether such a benefit would also be observed in settings with optimal access to contemporary standard-of-care treatments. Fourth, we describe occurrences of protocol changes and unusual censoring patterns, both warranting further examination. The specificities of regulatory pathways for medical devices permit greater evidentiary flexibility than for drugs, while post-market evidence generation remains insufficiently transparent. In contrast to other types of devices, a single company has generated the main evidence base with no substantial replication from competing manufacturers to date. High-quality sham-controlled trials and harmonized post-market obligations are needed to isolate the specific contribution of TTFs and determine the extent to which the observed clinical benefit derives from the device itself as compared with the care surrounding its use. This is particularly relevant in patients with a poor prognosis, as increased clinical attention and supportive care may themselves contribute to improved outcomes.