The Impact of TNF-α Induction on Therapeutic Efficacy following High Dose Spatially Fractionated (GRID) Radiation

Abstract

A variety of cytokines especially TNF-α and TGF-β are known to be released in response to high dose radiation of tumors. However, these are not normally measurable in systemic circulation unless high levels of these cytokines are produced by tumor cells. This study was undertaken to see if circulating levels of these cytokines could be measured in the serum of patients treated with high dose spatially fractionated (GRID) radiation and to correlate the finding of these cytokines with clinical response to treatment. Thirty-four patients (31 patients had single treatment site and 3 patients had 2 treatment sites) treated with spatially fractionated (GRID) radiation were entered in this study. Serum samples were collected before treatment and at 24, 48 and 72 hours after GRID radiation. Sandwich enzyme linked immunosorbent assay (ELISA) was performed to estimate the levels of TNF-α and activated TGF-β1 proteins. Seven of 37 patients studied had no TNF-α protein before treatment but showed induction of TNF-α after GRID radiation. Three patients showed faint basal level of TNF-α protein before treatment and these levels were induced after treatment. Three patients showed a basal level of TNF-α protein before treatment and these levels decreased after treatment. In 21 cases no TNF-α protein was detected before or after treatment at the time points measured. In the case of TGF-β1 protein, 2 patients showed no TGF-β1 protein before GRID radiation and an induction of TGF-β1 protein was observed after treatment. Seven patients showed basal level of TGF-β1 protein prior to treatment and these levels were induced after treatment. Seventeen patients showed a basal level of TGF-β1 protein before treatment and these levels decreased after treatment. In 8 cases no TGF-β1 protein was detected before or after treatment. Complete clinical response (CR) to GRID therapy was seen in 12/37 (32%) treatment sites and partial response (PR) in 18/37 (49%) treatment sites. A strong correlation was observed between clinical CR rate and TNF-α induction. The rate of CR was 6/10 (60%) in patients where TNF-α was induced as compared to 6/27 (23%) treatment sites in patients where TNF-α induction was not seen (p = 0.029). No significant correlation with CR rate and TGF-β1 induction (44% vs. 28%, p = 0.36) was observed. High dose spatially fractionated (GRID) radiation results in significant induction of TNF-α that can be measured in serum of some patients 24 – 72 hours after radiation. Complete tumor response strongly correlated with the induction of TNF-α levels in the serum.