Whoon Jong Kil, MD 1,2 Christina Kulasekere, CMD 1 Craig Hatch, DMD 1 Jacob Bugno, PhD 1 Ronald Derrwaldt, DO 1. Abstract INTRODUCTION CASE REPORT

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1 Received: 17 January 2017 Revised: 23 February 2017 Accepted: 14 March 2017 DOI: /hed CASE REPORT Tongue-out versus tongue-in position during intensity-modulated radiotherapy for base of tongue cancer: Clinical implications for minimizing post-radiotherapy swallowing dysfunction Whoon Jong Kil, MD 1,2 Christina Kulasekere, CMD 1 Craig Hatch, DMD 1 Jacob Bugno, PhD 1 Ronald Derrwaldt, DO 1 1 Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 2 Medicine Service-Radiation Oncology Section, Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma Correspondence Whoon Jong Kil, Medicine Service - Radiation Oncology Section, Oklahoma City Veterans Affairs Medical Center, 921 NE 13th Street, Oklahoma City, OK whoonjong.kil@gmail.com Published This article is a U.S. Government work and is in the public domain in the USA Abstract Background: The purpose of this study was to assess whether different tongue positions change the radiation doses to swallowing organs at risks: the pharyngeal constrictor, oral cavity, and larynx during intensity-modulated radiotherapy (IMRT) for base of tongue (BOT) cancer. Methods: IMRT plans with Tongue-out (IMRT-TO) and tongue-in position (IMRT-TI) was compared in 3 cases. Results: Distance from BOT to pharyngeal constrictor was increased to cm with IMRT- TO from cm with IMRT-TI (P <.01). Compared to IMRT-TI, IMRT-TO significantly decreased the radiation dose to the anterior oral cavity, oral tongue, superior pharyngeal constrictor, middle pharyngeal constrictor, and supraglottic larynx (all P.04). IMRT-TO also had a smaller volume irradiated than IMRT-TI to the anterior oral cavity and the oral tongue receiving 30 Gy (V30) and V35, and superior pharyngeal constrictor and middle pharyngeal constrictor for V55 and V65 (all P.04). Conclusion: Dosimetric advantage with IMRT-TO over IMRT-TI may potentially reduce post- IMRT swallowing dysfunction in selected patients with BOT cancer. KEYWORDS base of tongue cancer, customized immobilization mask, intensity-modulated radiotherapy (IMRT), swallowing dysfunction, tongue-out INTRODUCTION Definitive radiotherapy (RT) concurrently with chemotherapy (chemoradiotherapy [CRT]) has shown a survival benefit and became the standard of care in patients with locally advanced head and neck cancer. 1 Although the frequency and severity of xerostomia after RT or CRT in patients with head and neck cancer has decreased with conformal RT, mainly because of salivary sparing intensity-modulated radiotherapy (IMRT), 2 post-rt or CRT-related swallowing dysfunction is still deteriorating the quality of life in patients with head and neck cancers. 3,4 In retrospective study, the probability of dysphagia has shown to be correlated with the radiation dose to the pharyngeal constrictor. 5 Recently reported Normal Tissue Complication Probability models for post-rt swallowing dysfunction has also identified the mean radiation dose (D mean ) to the superior pharyngeal constrictor and to the supraglottic larynx as 2 independent risk factors for post-rt or CRT grade 2-4 swallowing dysfunction. MD Anderson Cancer Center reported candidate anterior oral cavity (oral cavity and mainly the oral tongue) and superior pharyngeal constrictor radiation dose-volume constraints associated with preserved long-term swallowing function. 8 Swallowsparing IMRT showed better swallowing function in patients after RT Head & Neck. 2017;39:E85 E91. wileyonlinelibrary.com/journal/hed 2017 Wiley Periodicals, Inc. E85

2 E86 KIL ET AL. FIGURE 1 A, Customized thermoplastic mask for CT simulation and location of tongue. B, Sagittal section of CT simulations with Tongue-out and tongue-in positions showed geographic changes in the oropharynx. Red indicates gross tumor in the base of the tongue. The yellow arrow indicates the distance from the base of the tongue to the pharyngeal constrictor or CRT by reducing the radiation dose to the pharyngeal structures. 9 However, sparing swallowing function in patients with base of tongue (BOT) cancers has often been challenging as the gross tumor in BOT cancer is close to swallowing organs at risk (OARs; pharyngeal, laryngeal, and oral cavity structures). In a recent study, 10 tongue-out ( Stick-Out in the article) instead of tongue-in position during IMRT for head and neck cancer significantly decreased the radiation dose to the oral cavity and the oral tongue and increased the distance from the BOT to the pharyngeal constrictor, which might further decrease the radiation doses to swallowing OARs leading to reduced post-rt swallowing dysfunction. Herein, authors demonstrate decreased radiation doses to the pharyngeal constrictor, anterior oral cavity, oral tongue, and supraglottic larynx by applying tongue-out compared to tongue-in during IMRT for patients with BOT cancer. MATERIALS AND METHODS Three patients with histologically proven squamous cell carcinoma in the BOT who demonstrated no difficulty protruding their tongue underwent CT simulations: one with the Tongue-In and one applying the tongue-out position for planning IMRT (IMRT-TI and IMRT-TO,

3 KIL ET AL. E87 FIGURE 2 A, Oral tongue contoured on CT simulation with Tongue-out (yellow dashed line). B, Oral tongue contoured on daily cone-beam CT (CBCT) scan (blue solid line). Red contour indicates gross tumor volume (GTV) in the base of the tongue respectively) as reported. 10 Before CT simulations, an immobilization thermoplastic mask was customized to create a spot that indicated the location of the tip of the tongue (see Figure 1) during CT simulation with the tongue-out (see Figure 2). The BOT-to-pharyngeal constrictor was measured from the posterior edge of the BOT to the anterior surface of the pharyngeal constrictor at the middle of the second cervical vertebra on both CT simulations (yellow arrow in Figure 1B). The OARs were contoured for the pretreatment planning, as previously described. 10 Additionally, the superior pharyngeal constrictor was contoured from the skull base to the superior edge of the hyoid bone; the middle pharyngeal constrictor from the superior hyoid to the inferior edge of the hyoid; the inferior pharyngeal constrictor from below the hyoid to the level of the cricopharyngeus muscle at the inferior edge of the cricoid cartilage. The glottis larynx was separated from the supraglottic larynx by limiting the laryngeal volume residing between the top of the arytenoid cartilages and the bottom of the true vocal cords. Gross tumor volume was manually expanded to the clinical target volume (CTV1) at the discretion of the radiation oncologist. The CTV1 was manually expanded to CTV2 to cover the high-risk regions around the primary tumor and nodal disease. The CTV3 covered lowrisk lymph nodal stations. The planning target volumes (PTV1, PTV2, and PTV3) were generated with an isotropic expansion of 3 mm from

4 E88 KIL ET AL. TABLE 1 Patient characteristics Case no. Stage a Primary disease p16 Chemotherapy 1 T3N2cM0 Left BOT cross the midline extension to the vallecular 1 Cetuximab weekly 2 T3N2bM0 Right BOT extension to the vallecular and lingual surface of the epiglottis 3 T4N2bM0 Right BOT extension to the extrinsic muscle of the tongue, right parapharyngeal space, and vallecular 1 Cisplatin every 3 wk 1 Cetuximab weekly Abbreviation: BOT, base of tongue. a Stage is based on the American Joint Committee on Cancer seventh edition. TABLE 2 Geometrical changes in the oropharynx and radiation target coverage in intensity-modulated radiotherapy with different tongue positions Variables IMRT-TO IMRT-TI P value BOT-to-pharyngeal constrictor Case cm 0.2 cm Case cm 1.2 cm Case cm 1.2 cm All cases cm cm <.01 V70 for PTV70 Case % 98.9% Case % 99.4% Case % 96.7% All cases % V63 for PTV63 Case % 99.4% Case % 96.5% Case % 99.3% All cases % %.27 V56 for PTV56 Case % 99.6% Case % 97.0% Case % 97.3% All cases % %.49 Abbreviations: BOT, base of tongue; BOT-to-pharyngeal constrictor, distance from the posterior edge of the base of the tongue to the anterior surface of the pharyngeal constrictor at the level of the middle of the second cervical vertebra was measured both on CT simulation with the Tongue-out and with the tongue-in position for comparison; IMRT-TI, intensity-modulated radiotherapy with the tongue-in position; IMRT-TO, intensity-modulated radiotherapy with the Tongue-out position; PTV, planning target volume; V70, the volume receiving 70 gray (Gy). The P values were calculated using the Student s t test. Data are presented as mean 6 SD. Figures in boldface indicate statistical significance. CTV1, CTV2, and CTV3, respectively, to deliver 70 Gy (PTV1), 63 Gy (PTV2), and 56 Gy (PTV3) in 35 fractions to 95% of the PTVs. The Radiation Therapy Oncology Group-recommended dose constraints were applied. Additional dose constraints were given as D mean to the entire pharyngeal constrictor <50 Gy with superior pharyngeal constrictor volume receiving 55 Gy or higher (V55) <80% (V55 <80%) and V65 <30%. 8 Treatment planning aimed to reduce the doses to OARs as much as possible without compromising the coverage of the PTVs. The Pinnacle RT Planning System version 9.4 (Philips Healthcare, Fitchburg, WI) was used for IMRT planning. All plans were performed with 7-beam or 9-beam using 6 MV photon applied using a Varian ix Silhouette (Varian Medical System, Palo Alto, CA). To evaluate daily variations of tongue position, the oral tongue contoured on CT simulation with tongue-out was superimposed on daily cone-beam CT during IMRT-TO (yellow dashed line in Figure 2). Daily differences of oral tongue position (blue solid line in Figure 2) in length, width, and depth were measured by the offset from superimposed oral tongue contour. Statistical analysis of comparisons between IMRT-TO and IMRT-TI was done using the Student t test. Data are presented as mean 6 SD. AprobabilitylevelofaP value of <.05 was considered significant. RESULTS All patients had stage IV cancer in the BOT according to the American Joint Committee on Cancer seventh staging and treated with definitive CRT (Table 1). Compared to the tongue-in position, the Tongue-out position resulted in a 2.6 times (range approximately times) relative increase in BOT-to-pharyngeal constrictor (Table 2 and Figure 1B). An average BOT-to-pharyngeal constrictor was cm with the tongue-out and cm with the tongue-in (P <.01). Both IMRT- TO and IMRT-TI met the planning objectives requiring 95% of PTVs receiving 100% of the prescription dose. There was no statistical difference in PTV coverage between IMRT-TO and IMRT-TI (Table 2). Geometric changes in oropharyngeal structures with different tongue positions have affected on radiation dose to the pharyngeal, laryngeal, and oral cavity structures in IMRT plans (Table 3). The D mean to the pharyngeal constrictor was decreased to Gy with IMRT-TOfrom Gy with IMRT-TI (P 5.006). There was also a reduction in D mean to the superior pharyngeal constrictor with the Tongue-out compared to the tongue-in (IMRT-TO Gy vs IMRT-TI Gy; P 5.02). A smaller volume of superior pharyngeal constrictors received the radiation with IMRT-TO than IMRT-TI. For the V55 to the superior pharyngeal constrictor, there was an 18.8% reduction (IMRT-TO % vs IMRT-TI %) with increasing relative reduction at a higher radiation dose: a 50.7% relative reduction for V65 ( % vs %; all P values.03). The D mean to the middle pharyngeal constrictor was also significantly decreased with IMRT-TO ( Gy) than IMRT-TI (64.0 6

5 KIL ET AL. E89 TABLE 3 Radiation dose to organs at risk IMRT-TO IMRT-TI IMRT-TO: IMRT-TI ratio P value Anterior oral cavity D mean Gy Gy V % % V % % Oral Tongue D mean Gy Gy V % % V % % Pharyngeal constrictor D mean Gy Gy Superior pharyngeal constrictor D mean Gy Gy V % % V % % Middle pharyngeal constrictor D mean Gy Gy V % % V % % Inferior pharyngeal constrictor D mean Gy Gy V % % V % % Supraglottic larynx D mean Gy Gy Glottis larynx D mean Gy Gy Abbreviations: D mean, mean radiation dose; Gy, gray; V30, volume receiving 30 Gy or higher; IMRT-TI, intensity-modulated radiotherapy with the Tongue-in position; IMRT-TO, intensity-modulated radiotherapy with the Tongue-out position; V35, volume receiving 35 Gy or higher; V55, volume receiving 55 Gy or higher; V65, volume receiving 65 Gy or higher. The P values were calculated using the Student s t test. Data are presented as mean 6 SD. Figures in boldface indicate statistical significance. 1.8 Gy; P 5.02). For the V55 and V65 to the middle pharyngeal constrictor, there was a 29.6% and 45.5% of relative reduction with IMRT- TO (V % and V %) compared to IMRT-TI ( % and %; all P.02). Among the laryngeal TABLE 4 Daily offsets of tongue position during the course of intensity-modulated radiation therapy with the Tongue-out Cases Length Width Depth Case cm cm cm Case cm cm cm Case cm cm cm All cm cm cm Daily offset of tongue position (length, width, and depth) was measured by the difference between the oral cavity contoured on CT simulation with the Tongue-out superimposed on daily cone-beam CT during intensity-modulated radiotherapy with the tongue out. Data are presented as mean 6 SD. structures, the D mean to the supraglottic larynx was significantly lower with IMRT-TO ( Gy) than IMRT-TI ( Gy; P 5.04). Dosimetric analysis revealed that IMRT-TO lowered the radiation dose to the anterior oral cavity and oral tongue than IMRT-TI (Table 3). With the Tongue-out, there was a 22.5% relative reduction in the D mean to the anterior oral cavity (IMRT-TO Gy vs IMRT-TI Gy; P 5.01) and a 26.8% relative reduction to the oral tongue ( Gy vs Gy; P 5.01). For the V30 to anterior oral cavity and oral tongue, there was a 34.1% and 36.5% relative reduction (IMRT-TO % and % vs IMRT-TI % and %) with consistent 38.5% relative reductions in V35 to both the anterior oral cavity and oral tongue ( % and % vs % and %; all P <.04; Table 3). There were no differences in dosimetry to the PTVs or other OARs, including the inferior pharyngeal constrictor and the glottis larynx between IMRT-TO and IMRT-TI. Daily offset of tongue position during the course of IMRT-TO was cm in length, cm in width, and cm in depth of the tongue (Table 4 and Figure 2).

6 E90 KIL ET AL. DISCUSSION The swallowing process begins with mechanically preparing food by chewing and salivary lubrication to become a bolus (oral preparatory phase), which is pushed by the oral tongue back toward the oropharynx during the oral phase. 11 Subsequently, the pharyngeal constrictor propels the bolus, and the larynx closes the airway while the bolus is transported toward the cervical esophagus (pharyngeal phase). It has been suggested that reducing the radiation dose to the uninvolved oral cavity (mainly the oral tongue), pharyngeal, and laryngeal structures improves post-rt or CRT swallowing dysfunction. 5 9 Levendag et al 5 reported a radiation dose-effect relationship demonstrating the probability of dysphagia increased 19% with every additional 10 Gy to the superior pharyngeal constrictor and the middle pharyngeal constrictor. In his prospective study, Schwartz et al 8 identified radiation dose-volume constrains (V55 <80% and V65 <30% for the superior pharyngeal constrictor, and V30 <65% and V35 <35% for the anterior oral cavity) predictive for objective swallowing dysfunction with IMRT. 8 Prospective studies 12,13 also demonstrated significant correlations between the D mean to the pharyngeal constrictor and larynx, as well as their partial volumes receiving Gy, and long-term post- CRT dysphagia with the D mean to the superior pharyngeal constrictor demonstrated highest correlation. Post-CRT aspiration was noticed in all patients with the D mean to the pharyngeal constrictor >60 Gy or V65 to pharyngeal constrictor >50%, and V50 to the larynx >50%. 12 The Normal Tissue Complication Probability models increased moderately with D mean without any threshold. The radiation dose causing 50% toxicity (TD 50 )andtd 25 were 63 Gy and 56 Gy for the pharyngeal constrictor, and 56 Gy and 39 Gy for the larynx, respectively. 13 Given the increasing number of human papillomavirus-positive head and neck cancer cases in younger patients, efforts to decrease the radiation doses to the swallowing OARs as low as possible is required to minimize post-imrt swallowing dysfunction. In the current study, dosimetric analysis demonstrated significant relative reductions in D mean, V30, and V35 to the anterior oral cavity and oral tongue with IMRT-TO (Table 3). Likewise reported, 10 we noticed that increased BOT-to-pharyngeal constrictor with Tongue-out ( cm) compared to the tongue-in position ( cm) resulting in significantly decreased radiation doses to the pharyngeal constrictor, superior pharyngeal constrictor, and middle pharyngeal constrictor with increasing relative reductions at higher doses than lower doses to the superior pharyngeal constrictor (50.4% reduction in V65 and 18.8% reduction in V55) and the middle pharyngeal constrictor (45.5% and 29.6%). Unexpectedly, the D mean to the supraglottic larynx was also significantly lower with IMRT-TO ( Gy) than IMRT-TI ( Gy; P 5.04). Given the roles of anterior oral cavity, oral tongue, pharyngeal constrictor, and supraglottic larynx in the swallowing process, IMRT-TO seems to be a reasonable method for sparing swallowing function by lowering the radiation dose to the swallowing OARs in selected patients with BOT cancer. With the designated spot for locating the tip of the tongue on the customized immobilization mask (see Figure 1), daily Tongue-out position was reproducible with daily variations of tongue location in length, width, and depth was <3 mm(table4). Furthermore, patients with head and neck cancer often swallow saliva during RT causing significant intrafractional movements in the tongue, 14 which could result in a suboptimal radiation dose to the PTV1 in the BOT leading to poor local disease control. Swallowing saliva during RT can be avoided with the Tongue-out and keeping the tip of the tongue at the designated spot on the customized immobilization mask while the radiation beam is on. Because our institute uses Step-and-Shot IMRT, patients have been given times to relax their tongue and swallow saliva (if needed) between every 2 or 3 beams while the gantry of radiation machine is rotating to the next beams. With other faster IMRT techniques, such as Rapid Arc or volumetricmodulated arc therapy, patients would have less time for the tongueout during RT. In addition to IMRT-TO, active swallowing exercises during and after RT or CRT and treatments de-escalation in selected patients with human papillomavirus-positive head and neck cancer could be other methods of sparing the swallowing function. CONCLUSION Compared to IMRT-TI, IMRT-TO for selected patients with BOT cancer has significant decreased radiation doses to swallowing OARs (superior pharyngeal constrictor, middle pharyngeal constrictor, anterior oral cavity, oral tongue, and supraglottic larynx). With the designated spot on individually customized thermoplastic mask for locating the tip of the tongue, daily Tongue-out position was reproducible and might reduce intrafractional movements of PTV1 in the BOT. Further investigation is warranted to confirm whether decreased radiation doses to swallowing OAR with IMRT-TO translate into clinical benefits. ACKNOWLEDGMENTS This material is the result of work supported with resources and the use of the facility at the Cleveland Veterans Affairs Medical Center, Cleveland, Ohio. DISCLAIMER The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. The Cleveland VA Medical Center s institutional review board granted waiver for board review on this cases series. Patients have given signed consent for reporting their cases. REFERENCES [1] Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy head and neck cancer (MACH-NC): an update on 93 randomized trials and 17,346 patients. Radiother Oncol. 2019;92(1):4 14. [2] Nutting CM, Morden JP, Harrington KJ, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck

7 KIL ET AL. E91 cancer (PARSPORT): a phase 3 multicentre randomized controlled trial. Lancet Oncol. 2011;12(2): [3] Goguen LA, Posner MR, Norris CM, et al. Dysphagia after sequential chemoradiation therapy for advanced head and neck cancer. Otolaryngol Head Neck Surg. 2006;134(6): [4] Nguyen NP, Frank C, Moltz CC, et al. Impact of dysphagia on quality of life after treatment of head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2005;61(3): [5] Levendag PC, Teguh DN, Voet P, et al. Dysphagia disorders in patients with cancer of the oropharynx are significantly affected by the radiation therapy dose to the superior and middle constrictor muscle: a dose-effect relationship. Radiother Oncol. 2007;85(1): [6] Christianen ME, Schilstra C, Beetz I, et al. Predictive modelling for swallowing dysfunction after primary (chemo)radiation: results of a prospective observational study. Radiother Oncol. 2012;105(1): [7] S oderstr om K, Nilsson P, Laurell G, Zackrisson B, Jäghagen EL. Dysphagia - Results from multivariable predictive modelling on aspiration from a subset of the ARTSCAN trial. Radiother Oncol. 2017;122 (2): [8] Schwartz D, Hutcheson K, Barringer D, et al. Candidate dosimetric predictors of long-term swallowing dysfunction after oropharyngeal intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2010; 78(5): [9] Christianen ME, van der Schaaf A, van der Laan HP, et al. Swallowing sparing intensity modulated radiotherapy (SW-IMRT) in head and neck cancer: clinical validation according to the model-based approach. Radiother Oncol. 2016;118(2): [10] Kil WJ, Kulasekere C, Derrwaldt R, Bugno J, Hatch C. Decreased radiation doses to tongue with stick-out tongue position over neutral tongue position in head and neck cancer patients who refused or could not tolerate an intraoral device (bite-block, tongue blade, or mouthpiece) due to trismus, gag reflex, or discomfort during intensity-modulated radiation therapy. Oncotarget. 2016;7(33): [11] Logemann JA. Evaluation and treatment of swallowing disorders. 2nd ed. Austin, TX: Pro-ED; [12] Feng FY, Kim HM, Lyden TH, et al. Intensity-modulated radiotherapy of head and neck cancer aiming to reduce dysphagia: early dose-effect relationships for the swallowing structures. Int J Radiat Oncol Biol Phys. 2007;68(5): [13] Eisbruch A, Kim HM, Feng FY, et al. Chemo-IMRT of oropharyngeal cancer aiming to reduce dysphagia: swallowing organs late complication probabilities and dosimetric correlates. Int J Radiat Oncol Biol Phys. 2011;81(3):e93 e99. [14] Chan A. Radiation techniques and targeting. General Session I: Oral Cavity. Multidisciplinary Head and Neck Cancer Symposium. Scattsdale, AZ; presentations.aspx/17/107/781. Accessed October 1, How to cite this article: Kil WJ, Kulasekere C, Hatch C, Bugno J, Derrwaldt R. Tongue-out versus tongue-in position during intensity-modulated radiotherapy for base of tongue cancer: Clinical implications for minimizing post-radiotherapy swallowing dysfunction. Head & Neck. 2017;39:E85 E91. org/ /hed.24809