Toxicity Profiles and Survival Outcomes Among Patients With Nonmetastatic Oropharyngeal Carcinoma Treated With Intensity-Modulated Proton Therapy vs Intensity-Modulated Radiation Therapy

Abstract

ImportancePatients with oropharyngeal carcinoma (OPC) treated with radiotherapy often experience substantial toxic effects, even with modern techniques such as intensity-modulated radiation therapy (IMRT). Intensity-modulated proton therapy (IMPT) has a potential advantage over IMRT due to reduced dose to the surrounding organs at risk; however, data are scarce given the limited availability and use of IMPT.ObjectiveTo compare toxic effects and oncologic outcomes among patients with newly diagnosed nonmetastatic OPC treated with IMPT vs IMRT with or without chemotherapy.Design, Setting, and ParticipantsThis retrospective cohort study included patients aged 18 years or older with newly diagnosed nonmetastatic OPC who received curative-intent radiotherapy with IMPT or IMRT at a single-institution tertiary academic cancer center from January 1, 2018, to December 31, 2021, with follow-up through December 31, 2021.ExposuresIMPT or IMRT with or without chemotherapy.Main Outcomes and MeasuresThe main outcomes were the incidence of acute and chronic (present after ≥6 months) treatment-related adverse events (AEs) and oncologic outcomes, including locoregional recurrence (LRR), progression-free survival (PFS), and overall survival (OS). Fisher exact tests and χ2 tests were used to evaluate associations between toxic effects and treatment modality (IMPT vs IMRT), and the Kaplan-Meier method was used to compare LRR, PFS, and OS between the 2 groups.ResultsThe study included 292 patients with OPC (272 [93%] with human papillomavirus [HPV]-p16–positive tumors); 254 (87%) were men, 38 (13%) were women, and the median age was 64 years (IQR, 58-71 years). Fifty-eight patients (20%) were treated with IMPT, and 234 (80%) were treated with IMRT. Median follow-up was 26 months (IQR, 17-36 months). Most patients (283 [97%]) received a dose to the primary tumor of 70 Gy. Fifty-seven of the patients treated with IMPT (98%) and 215 of those treated with IMRT (92%) had HPV-p16–positive disease. There were no significant differences in 3-year OS (97% IMPT vs 91% IMRT; P = .18), PFS (82% IMPT vs 85% IMRT; P = .62), or LRR (5% IMPT vs 4% IMRT; P = .59). The incidence of acute toxic effects was significantly higher for IMRT compared with IMPT for oral pain of grade 2 or greater (42 [72%] IMPT vs 217 [93%] IMRT; P < .001), xerostomia of grade 2 or greater (12 [21%] IMPT vs 68 [29%] IMRT; P < .001), dysgeusia of grade 2 or greater (16 [28%] IMPT vs 134 [57%] IMRT; P < .001), grade 3 dysphagia (4 [7%] IMPT vs 29 [12%] IMRT; P < .001), mucositis of grade 3 or greater (10 [53%] IMPT vs 13 [70%] IMRT; P = .003), nausea of grade 2 or greater (0 [0%] IMPT vs 18 [8%] IMRT; P = .04), and weight loss of grade 2 or greater (22 [37%] IMPT vs 138 [59%] IMRT; P < .001). There were no significant differences in chronic toxic effects of grade 3 or greater, although there was a significant difference for chronic xerostomia of grade 2 or greater (6 IMPT [11%] vs 22 IMRT [10%]; P < .001). Four patients receiving IMRT (2%) vs 0 receiving IMPT had a percutaneous endoscopic gastrostomy tube for longer than 6 months.Conclusions and RelevanceIn this study, curative-intent radiotherapy with IMPT for nonmetastatic OPC was associated with a significantly reduced acute toxicity burden compared with IMRT, with few chronic toxic effects and favorable oncologic outcomes, including locoregional recurrence of only 5% at 2 years. Prospective randomized clinical trials comparing these 2 technologies and of patient-reported outcomes are warranted.

Toxicity with proton therapy for oral and/or oropharyngeal cancers: A scoping review

“…The most commonly reported and compared acute toxic effect was dysphagia, followed by radiation dermatitis, oral mucositis, dysgeusia and alopecia (Figure 2). Only one of the included studies recorded severe grades of any acute symptom, post proton therapy in oral and/or oropharyngeal cancer patients, 28 but the proportion of severe grade acute toxic symptoms was significantly ( p < 0.001) lower as compared to the group of patients treated with conventional radiotherapy 28 . A majority of the patients in active treatment and during follow up did not report any signs of dysphagia (38.6%) or fatigue (74.7%).…”

“…All included studies were of oral and/or oropharyngeal cancer patients. The studies included were based in different countries, including the United States, [18][19][20][21][22][23][24][25][26][27][28][29][30] Switzerland, 31 Japan, 32,33 and Germany. 26,34 All included studies [18][19][20][22][23][24][25][26]31,32,34,35 except five 21,30,33 were prospective in design.…”

“…Studies included in this review utilised a range of tools to report acute toxic effects associated with proton therapy. The xerostomia-related quality of life (XeQoLS) scale was used by two studies, 24,37 the MD Anderson Dysphagia Inventory (MDADI) was used by one 19 study, Common Terminology Criteria for Adverse Events used by eight studies 20,22,24,26,28,30,33,34,38 and the MD Anderson Symptom Inventory-Head and Neck Module was used by one study. 24 One study examined the rate of osteoradionecrosis in patients receiving proton therapy using the modified Glanzmann and Grätz grading system.…”

Proton Therapy and Incidence and Predisposing Factors of Osteoradionecrosis—On Pulling One’s Punches—Reply

“…Furthermore, the ORN scale, including radiographic grade 0 ORN used in this series, is not commonly used in other studies. We believe these reasons may explain the higher than previously published ORN rates vs others, including our prior report of 2% ORN rate (proton therapy) vs 5% ORN rate (IMRT) (Common Terminology Criteria for Adverse Events, version 5) for a consecutive cohort of patients with oropharyngeal squamous cell carcinoma . Finally, most patients who developed ORN were treated with uniform scanning (passive scattering technique).…”

Errors in Abstract and Results and Addition of Corresponding Author and Acknowledgments

“…In the Original Investigation titled “Toxicity Profiles and Survival Outcomes Among Patients With Nonmetastatic Oropharyngeal Carcinoma Treated With Intensity-Modulated Proton Therapy vs Intensity-Modulated Radiation Therapy,” published November 11, 2022, in the abstract Results, “There were no significant differences in chronic toxic effects, although there was a significant difference for chronic xerostomia of grade 2 or greater (6 IMPT [11%] vs 22 IMRT [10%]; P < .001)” was changed to “There were no significant differences in chronic toxic effects except for xerostomia.” In the Treatment Characteristics and Adverse Events subsection of the Results section, “Xerostomia was the only chronic AE for which there was a statistically significant difference in prevalence between IMPT and IMRT (6 patients receiving IMPT [11%] vs 22 receiving IMRT [10%]; P < .001)” was changed to “Xerostomia was the only chronic AE for which there was a statistically significant difference in toxicity between IMPT and IMRT.” In addition, Nancy Y. Lee, MD, was added as a corresponding author, and an Acknowledgments section was added. This article has been corrected …”