Comment on ‘Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma'

Sir,

In this manuscript, Dr Wong and colleagues observed that patients with recurrent glioblastoma who underwent therapy with tumor treating alternating electrical fields and were on higher doses of dexamethasone had lower T-lymphocyte counts and shorter survival (Wong et al, 2015). The investigators attributed these outcomes entirely to ‘global immunosuppression by dexamethasone'. In fact, this patient population receives three therapies that are highly toxic to lymphocytes – glucocorticoids, radiation, and temozolomide. Recent studies have demonstrated that 40% of patients with newly diagnosed glioblastoma develop grade III and IV lymphopenia with CD4 counts <200 cells mm⁻³ 2 months after beginning radiation and temozolomide (Grossman et al, 2011). This profound lymphopenia lasts for over 1 year and on multivariate analysis is independently associated with inferior survival. Treatment-induced lymphopenia has also been studied in other solid tumors that are not treated with dexamethasone or temozolomide; data from these studies strongly point to radiation as the primary causative factor in treatment-induced lymphopenia. These studies reported rates of lymphopenia that were very similar to those seen in glioblastoma and again identified an association between treatment-induced lymphopenia and survival in patients with pancreatic cancer, non-small cell lung cancer, and breast cancer. (Balmanoukian et al, 2012; Campian et al, 2013; Wild et al, 2013; Tang et al, 2014; Afghahi et al, 2015) Two hypotheses have been advanced to explain this phenomenon. The first relates to the inadvertent radiation of circulating lymphocytes (MacLennan and Kay, 1978; Yovino et al, 2013). The second stems from observations that IL-7 levels are inappropriately low in irradiated patients with severe treatment-related lymphopenia (Ellsworth et al, 2014). We agree that immune status is an important prognostic factor in patients with recurrent glioblastoma. However, as radiation-associated lymphopenia is common and long-lasting in patients with glioblastoma, as well as in patients with pancreatic, lung, and breast cancer, where dexamethasone is not an integral part of therapy, it is likely that the immunosuppression described by Dr Wong et al was due to prior radiation exposure, rather than to dexamethasone treatment. At a minimum, this issue should be formally addressed in this manuscript and in subsequent work regarding this important topic.

The authors declare no conflict of interest.