Living in a material world: tumor treating fields at the top of the charts.
Venue: Neuro oncology

The potential role of low intensity, intermediate frequency alternating electrical fields (tumor treating fields, or TTFields [Optune, Novocure] in treating glioblastoma has generated excitement, hope, and controversy. Initial cell line and animal model studies were quickly translated to the EF 11 Phase III trial in recurrent glioblastoma. EF 11 confirmed device safety and suggested that TTFields had antitumor activity comparable to secondand later line chemotherapy, a result leading to FDA approval but uncompelling to some neuro oncologists given the poor results with chemotherapy for recurrent glioblastoma. Stronger results emerged from EF 14, a Phase III trial in newly diagnosed glioblastoma that randomized patients postradiation to TTFields plus temozolomide versus temozolomide alone. Interim analysis of EF 14 demonstrated a 3.0 month overall survival advantage in the intent to treat analysis (4.9 months in the per protocol subset) and a 3.1 month improvement in progression free survival. These positive results were based upon the first 315 of 695 enrolled patients; analysis of the entire cohort did not substantially change the results. Consequently, in October 2015 the FDA approved the use of TTFields in newly diagnosed glioblastoma. In this issue of Neuro Oncology, Bernard Amoux and colleagues report on the results of a cost effectiveness analysis evaluating the incremental benefit of TTFields for glioblastoma in the context of the French health care system. Their principal finding is that the use of TTFields in conjunction with standard of care chemoradiation is not within the realm of what is considered "cost effective" by most regulatory bodies that have established explicit thresholds. While France does not use explicit thresholds, Commonwealth countries with national health systems, such as the UK, Australia, New Zealand, and Canada, generally consider treatment interventions that have ratios of $50 000 $100 000 per life year gained to be cost effective. In the US, regulatory authorities are prohibited from considering cost in making decisions about coverage, but informally, similar thresholds are used to label treatments as cost effective. Cost effectiveness analyses such as Bernard Amoux et al's are determined on the basis of comparing 2 alternative strategies. In this case, the comparison is between chemoradiation plus TTFields versus standard chemoradiation. The incremental cost effectiveness ratio (ICER) computes the cost of chemoradiation/TTFields versus that of chemoradiation while also assessing the benefits (expressed in terms of survival time) for these treatments. The ICER is the ratio of these differences. Several methodological points are worth noting about the reported analysis. First, this was a post hoc cost effectiveness analysis that relied entirely on the published report of the trial. Why does this matter? The modeling approach does not have data for each trial participant and therefore does not calculate the precise amount of time that each individual spent receiving protocol based treatment, no treatment without progression, second line treatment, or palliative end of life care. The analysis relies on the study reported average differences to model these parameters. The underlying assumption is that the key cost driver in this comparison stems from the costs of treatment itself. The huge cost of TTFields in the commercial setting makes this assumption reasonable, albeit uncertain. A major source of health care expenditures (in all health systems) is hospitalization. More hospitalization days in one group should correspond to higher costs. If TTFields prolong survival and keep glioblastoma patients out of the hospital, some of the excess costs of the therapy might be offset by reduced hospitalizations. However, if the intervention merely shifts hospitalizations to later time points without reducing them, then no such cost savings would be realized. Post hoc models that do not collect detailed information about cost drivers such as hospitalizations, stays in rehabilitation centers, and the use of other expensive interventions are necessarily somewhat crude estimates. A superior strategy is to embed a cost effectiveness analysis in the up front design of the clinical trial. This is often not performed when the drug or device manufacturer is the clinical trial sponsor. However, additional collection of a small amount of information can greatly facilitate the capacity for conducting a post hoc cost effectiveness analysis. For example, collection of data characterizing the total number of hospital days, ICU days, ER visits, and nursing home days for subjects in each arm would increase the validity of the cost comparison. Information about the amounts of other chemotherapy treatments received would also be helpful. Simple case report forms can be