(P046) Use of Intensity-Modulated Radiotherapy (IMRT) With Daily Image Guidance and Reduced Treatment Margins Is the Most Significant Predictor of Reduced Late Toxicity in Patients With Human Papillomavirus–Associated (HPV+) Oropharyngeal Cancer

Shlomo A. Koyfman, Trevor B. Bledsoe, Joslyn Barnett, Chandana A. Reddy, MS, Tobenna Nwizu, MD, Deborah Chute, MD, Jerrold P. Saxton, MD, Brian B. Burkey, MD, John F. Greskovich, MD, David J. Adelstein, MD; Departments of Radiation Oncology, Solid Tumor Oncology, and Head and Neck Surgery, Cleveland Clinic

Purpose and Objectives: We hypothesize that patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive chemoradiotherapy (CRT) with intensity-modulated radiotherapy (IMRT), daily image guidance, and reduced planning margins will have fewer significant late effects and improved functional outcomes than those treated with conventional techniques.

Materials and Methods: Patients with stage III–IVb OPSCC and known tumor human papillomavirus (HPV) status treated with CRT between 2002 and 2012 and rendered disease-free were identified from an institutional review board (IRB)-approved registry. HPV+ disease included patients who tested positive for HPV DNA by in situ hybridization or had diffuse and strong (> 75%) staining for p16 by immunohistochemistry. RT was administered once (79%) or twice daily (21%) to a total dose of 70–74.4 Gy. A 3-field approach (3D-RT) with standard margins and weekly ports was used in the earlier years of the study, while IMRT with daily cone-beam CT and 2–3-mm clinical target volume (CTV) and planning target volume (PTV) expansions, respectively, was used more recently. Most patients were treated with cisplatin and 5-fluorouracil (5-FU) (62%), while more recently, patients were treated with cisplatin (26%) or cetuximab (9%) at standard dosing. Toxicity was scored according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Significant late toxicity was defined as any grade ≥ 3 or any persistent grade 2 fibrosis, dysphagia, osteoradionecrosis, trismus, pain, hoarseness, or hearing loss that occurred > 3 months after the completion of treatment. Xerostomia and taste and skin changes were excluded from this combined endpoint. Logistic regression analysis was performed to identify patient-, tumor-, and treatment-related variables associated with significant late toxicity.

Results: Of the 197 patients included in this study, the majority were Caucasian (95%) and male (91%), and 32% were never-smokers. The median age was 56 years, median Karnofsky performance score (KPS) was 90, and median follow-up was 39.4 months (range: 3.1–137.8 mo). A total of 129 patients (65%) were treated with 3D-RT, while 68 (35%) were treated with IMRT and image-guided radiation therapy (IGRT) with reduced treatment margins. At last follow-up, 91% of patients returned to a normal diet, while 6.5% had a limited oral diet and 2.5% were feeding tube–dependent. Of the 41 patients (20%) who required dilation for a stricture, 21 had their dysphagia resolve. The use of fluorouracil (5-FU)-based chemotherapy (76% vs 37%; P < .0001) and the use of 3D-RT (70% vs 44%; P = .0005) were independently associated with the need for a feeding tube. Similarly, 5-FU–based chemotherapy (43% vs 16%; P ≤ .0001) and 3D-RT (44% vs 13%; P < .0001) were associated with higher rates of significant late toxicity. In patients treated with once-daily IMRT and non–5-FU-based chemotherapy, the rate of significant late toxicity was 5.7%. On multivariate analysis, not using IMRT was associated with the highest risk of significant late toxicity (odds ratio [OR] = 3.4; P = .005), overshadowing smoking status, T stage, neck dissection, and chemotherapy type.

Conclusion: The use of IMRT with daily IGRT and reduced treatment margins dramatically reduces significant late effects for patients with HPV+ OPSCC. Nearly all patients treated with IMRT and non–5-FU-based chemotherapy have minimal significant late effects and excellent long-term function.