Re-Irradiation for Head and Neck Cancer: Cumulative Dose to Organs at Risk and Late Side Effects

Abstract

Re-irradiation in head and neck cancer is challenging, and cumulative dose constraints and dose/volume data are scarce. In this study, we present dose/volume data for patients re-irradiated for head and neck cancer and explore the correlations of cumulative dose to organs at risk and severe side effects. We analyzed 54 patients re-irradiated for head and neck cancer between 2011 and 2017. Organs at risk were delineated and dose/volume data were collected from cumulative treatment plans of all included patients. Receiver-operator characteristics (ROC) analysis assessed the association between dose/volume parameters and the risk of toxicity. The ROC-curve for a logistic model of carotid blowout vs. maximum doses to the carotid arteries showed AUC = 0.92 (95% CI 0.83 to 1.00) and a cut-off value of 119 Gy (sensitivity 1.00/specificity 0.89). The near-maximum dose to bones showed an association with the risk of osteoradionecrosis: AUC = 0.74 (95% CI 0.52 to 0.95) and a cut-off value of 119 Gy (sensitivity 1.00/specificity 0.52). Our analysis showed an association between cumulative dose to organs at risk and the risk of developing osteoradionecrosis and carotid blowout, and our results support the existing dose constraint for the carotid arteries of 120 Gy. The confirmation of these dose-response relationships will contribute to further improvements of re-irradiation strategies.

Keywords: carotid blowout; composite DVH; cumulative dose; head and neck cancer; late side effects; organs at risk; osteoradionecrosis; re-irradiation.

Figure A1

Time to grade ≥3 side effect. Re-irradiation cohort (re-RT cases) compared to whole reference cohort (registry) and subgroups of reference cohort divided by dose to the larynx (Figure A1a,b) and dose to the parotid glands (Figure A1c,d). (a) All dysphagia grade ≥3. (b) Late dysphagia grade ≥3. (c) All trismus grade ≥3. (d) Late trismus grade ≥3. Abbreviations: AE—adverse event, re-RT—re-irradiation, RT—radiotherapy, perc—percentile.

Figure 1

Delineation of organs at risk: larynx (yellow), spinal cord (green), mandible (brown), carotid artery (pink).

Figure 2

Time to event for all investigated severe side effects. Plots showing both time to any severe side effect and time to severe late side effect. AE—adverse event, grade ≥3 side effect. Others—one patient with grade 5 acute radiation-induced toxicity, one patient with neuropathy of the hypoglossal nerve, one patient with aspiration pneumonia.

Figure 3

Histograms of cumulative dose in EQD2 in all included patients. Red bars indicating patient with severe side effect. The time between irradiations and the time to follow-up are indicated for each patient. (a) Maximum dose (D1cc) to carotid artery and carotid blowout syndrome. (b) Maximum dose (D1cc) to bones and grade ≥3 osteoradionecrosis. (c) Mean dose to larynx and grade ≥3 dysphagia. (d) Maximum dose (D1cc) to spinal cord and no events of neuropathy. Abbreviations: ID—identification number of subject, Re-RT—re-irradiation.

Figure 4

Composite dose volume histograms (DVH) highlighting the individual DVHs of patients with severe side effects. (a) Dose in EQD2 to carotid artery and blowout syndrome. (b) Dose in EQD2 to bones and grade ≥3 osteoradionecrosis. (c) Dose in EQD2 to larynx and grade ≥3 dysphagia.

Figure 5

Receiver–operator characteristics (ROC) curve for logistic model. (a) Maximum dose (D1cc) to carotid artery and carotid blowout syndrome. AUC 0.92 (95% CI 0.83 to 1.00) and a cut-off value of 119 Gy (sensitivity 1.00/specificity 0.89). (b) Maximum dose (D1cc) to bones and grade ≥3 osteoradionecrosis. AUC = 0.74 (95% CI 0.52 to 0.95) and a cut-off value of 119 Gy (sensitivity 1.00/specificity 0.52). (c) Mean dose to larynx and grade ≥3 dysphagia. AUC = 0.67 (95% CI 0.49 to 0.85).