Reirradiation of Recurrent and Second Primary Head and Neck Cancer With Proton Therapy

Abstract

COPurpose/Objective(s): Head and neck squamous cell carcinomas (HNSCCs) afflict over half a million patients annually worldwide. In the absence of disease at distant sites, salvage treatment may provide durable disease control in only approximately 15% of such patients. Our research goal is to improve radiation therapy for aggressive HNSCCs by identifying novel targets for radiosensitization. The EphB4 receptor is ubiquitously expressed in HNSCCs and has been shown to promote tumorigenic and invasive properties of HNSCCs but the effect of EphB4 on cellular radiosensitization has not been investigated. We hypothesize that knockdown of EphB4 receptor will enhance radiosensitization of HNSCCs by inhibiting EphB4 targets involved in radioresistance. Materials/Methods: To fulfill our objective, we used EphB4-targeting siRNA and performed clonogenic assays in HNSCC cell lines to determine the in vitro radiosensitization effect following EphB4 knockdown. Effects of EphB4-siRNA on cell cycle progression, DNA damage response, and cell death pathways were also investigated. Results: We observed a decrease in the survival fractions in HNSCC cell lines following knockdown of EphB4 at increasing doses of radiation. Cell cycle analysis showed an enhanced G2 arrest of HNSCC cells following EphB4 knockdown and radiation exposure. In addition, we observed an increase in the expression of p-H2AX, a DNA damage marker protein, in HNSCC cells suggesting activation of DNA damage response pathway following EphB4 knockdown and radiation exposure. This was further accompanied by DNA fragmentation and modulation of key apoptotic markers. Studies are currently underway to determine the effect of EphB4 inhibition on radiosensitization in an in vivo patient-derived xenograft model of HNSCC. Conclusion: Our findings support the hypothesis that EphB4 promotes resistance of HNSCCs to ionizing radiation and its targeted inhibition will therefore result in enhanced radiosensitization. In conclusion, the successful completion of this study will allow us to design functional analyses of EphB4 targets responsible for radioresistance. From translational point of view, these targets could serve as the basis for development of combined therapy, prognostic biomarkers, or patient selection strategies in future clinical trials.

Reirradiation of head and neck cancer using modern highly conformal techniques

“…Overall, the more recent larger series seem to report locoregional control outcomes that are comparable with IMRT reports, with 2-year locoregional control rates of 73% and 80% in 2 studies compared to 50% and 60%, 14,40 respectively, among the IMRT studies. The late G3 or higher toxicity rates were 20% and 25% in the 2 studies reporting it.…”

“…McDonald et al 40 reported on 61 patients receiving proton reirradiation primarily for skull base lesions. Proton therapy was delivered with the PSPT technique to a median dose of 66 Gy (RBE) for those with microscopic residual disease and 70.2 Gy (RBE) for those with gross disease.…”

“…A few studies have reported that higher reirradiation doses have been predictors of improved locoregional control. 33,40 In addition, some studies reported an association of reirradiation dose with OS, with improvements observed with a dose 50 Gy with IMRT 30 and as a continuous variable. Four studies using conventionally fractionated irradiation (3 with IMRT, and 1 with proton therapy) showed an improvement in locoregional control with higher doses.…”

“…23,29 The studies varied widely in terms of patient populations, radiation dose/fractionation, and the use of concurrent systemic therapy (CRT). We have summarized these studies in Table 1, [11][12][13][14]23,[29][30][31][32][33][34][35][36][37][38][39][40] and below present a more detailed summary of the larger, more relevant studies.…”

Proton beam therapy reirradiation for breast cancer: Multi‐institutional prospective PCG registry analysis

“…Proton beam therapy for reRT has been investigated at other disease sites including head and neck, 38,39 central nervous system, 40,41 lung, 42,43 gynecological, 44 and gastrointestinal malignancies. [45][46][47] A recent systematic review found that reRT with PBT is safe and effective.…”