NTCP Modeling of Patient Reported Xerostomia after De-Intensified Chemoradiotherapy for HPV Associated Oropharynx Cancer

Abstract

Patients with head & neck tumors are commonly treated with external radiation therapy. Due to the proximity of the parotids to the tumor they often receive high doses to a portion of their volume. We prospectively enrolled patients on an IRB-approved clinical trial to estimate the correlation between different normal tissue complication probability (NTCP) models and dosimetric indices of the parotid and submandibular glands with the patient reported severity of xerostomia 12 months post de-intensified chemoradiotherapy. 120 patients with favorable risk, HPV-associated oropharyngeal squamous cell carcinoma were treated with de-intensified chemoradiotherapy. 60Gy delivered with intensity modulated radiotherapy was prescribed to all patients, who also received concurrent weekly intravenous cancer-treating drugs (30 mg/m2). The dose constraints for contralateral parotid and submandibular glands were mean dose <26 and <35, respectively. The status of xerostomia was reported pre- and post-treatment using the patient reported outcome version of the CTCAE (PRO-CTCAE): none/mild/moderate/severe/very severe. We correlated individual patient dosimetric data from the contralateral parotid and contralateral glands (parotid and submandibular glands combined) with the changes in the severity of xerostomia at 12 month post-treatment. A change in severity (from baseline) of ≥ 2 was considered clinically meaningful. The clinical data were fitted by the Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP models. Xerostomia increased in 40 patients (33%). Median mean doses to the contralateral parotid and combined glands were 23Gy (range: 5.1-47.1Gy) and 28Gy (range: 6-50Gy), respectively. For both structures, the V15Gy and mean doses correlated best with the subsequent xerostomia (AUC = 0.68-0.70). The values for the D50, m and n parameters of the Lyman-Kutcher-Burman model are 67Gy, 0.58 and 0.01 for the contralateral parotid and 56Gy, 0.56 and 0.12 for the combined glands. The values for the D50, γ and s parameters of the Relative Seriality model are 31.0Gy, 0.46 and 1.0 for the contralateral parotid and 39Gy, 0.48 and 1.0 for the combined glands. The AUC values for the two NTCP models for the contralateral parotid and combined glands and were similar 0.65 and 0.64, respectively. A statistically significant Odds Ratio of 5.7 (95%CI: 2.0-16.1Gy) was found for the contralateral parotid at V15Gy ≤ 53% and 7.8 (95%CI: 2.2-27.5Gy) for the combined glands at V15Gy ≤ 61%. The dosimetric thresholds V15Gy ≤ 53% to the contralateral parotid and V15Gy ≤ 61% to the combined parotid and submandibular glands were found to significantly reduce the risk for xerostomia. The dose-response curve of xerostomia could be determined by fitting the clinical data with the LKB and RS NTCP models. These models can provide constraints, which can be very useful in prospective treatment plan optimization and evaluation.