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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 845-851

Radiation dose to dysphagia aspiration-related structures and its effect on swallowing: Comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy plans


1 Department of Radiation Oncology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
2 Department of Radiation Oncology, HCG Institute of Oncology, Bengaluru, Karnataka, India
3 Department of Medical Physics and Radiation Safety, Amrita Institute of Medical Sciences, Kochi, Kerala, India
4 Department of Community Medicine, P K Das Institute of Medical Sciences, Vaniamkulam, Palakkad, Kerala, India

Date of Web Publication25-Jul-2016

Correspondence Address:
Chelakkot G Prameela
Associate Professor, Department of Radiation Oncology, Amrita Institute of Medical Sciences, Kochi, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.163676

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 > Abstract 


Context: Radiotherapy techniques have improved over years but have also raised concerns over subsequent acute and late effects. One such complication, dysphagia, has led to much interest and optimization in treatment delivery.
Aims: The aim of this study was to compare radiation dose to dysphagia aspiration related structures (DARS) in intensity modulated radiation therapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT), and assess its relation to post-treatment swallowing status, in patients of carcinoma of the anterior two thirds of tongue.
Materials and Methods: Treatment plans of patients treated with IMRT and 3DCRT, from November 2011 to December 2012, were retrieved. Swallowing structures were contoured. Dose volume histograms were generated. Constraint doses were considered based on the statistical derivations. Swallowing status was evaluated based on University of Washington Head- and Neck-related Quality-of-Life questions addressing swallowing.
Statistical Analysis Used: IBM SPSS Statistics 20 Windows (SPSS Inc., Chicago, IL, USA) was used. Mann–Whitney U-test, Spearman's rho correlation coefficient, and receiver operating curves were used.
Results: Definitive statistical and subjective correlations were found to exist between doses of swallowing structures, especially the constrictor muscles, the base of the tongue and larynx. Probable mean dose constraints derived statistically clinically corroborates with the swallowing status of patients. IMRT had statistically significant advantage over 3DCRT, in terms of V30 (P - 0.051), V50 (P - 0.002), V60 (P - 0.002), and D80 (P - 0.023) for swallowing structures taken together.
Conclusion: Our study is probably one of the few studies predicting possible mean dose constraints for superior constrictor, the base of the tongue and larynx. Further prospective studies are required to confirm these and to improve the swallowing quality.

Keywords: Dose of radiation, dysphagia, dysphagia aspiration-related structures, intensity-modulated radiation therapy, radiation therapy, three-dimensional conformal radiotherapy


How to cite this article:
Prameela CG, Ravind R, Renil Mon P S, Sheejamol V S, Dinesh M. Radiation dose to dysphagia aspiration-related structures and its effect on swallowing: Comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy plans. J Can Res Ther 2016;12:845-51

How to cite this URL:
Prameela CG, Ravind R, Renil Mon P S, Sheejamol V S, Dinesh M. Radiation dose to dysphagia aspiration-related structures and its effect on swallowing: Comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy plans. J Can Res Ther [serial online] 2016 [cited 2019 Dec 9];12:845-51. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/845/163676




 > Introduction Top


Acute and late effects of radiation treatment, with increasing use of aggressive combined modality therapy and altered fractionation schedules for head-neck cancers in radical and adjuvant settings, have become an area of intensive interest and investigation.[1],[2] Dysphagia associated with radiation is one problem that has garnered much attention. Acute and late swallowing dysfunction rates of about 15–63%, and 3–21%, respectively, have been documented.[3] Several studies have looked into various aspects of dysphagia and the role of swallowing therapy in prevention and treatment of dysphagia.[4],[5] The superior, middle, and inferior constrictor muscles (ICMs), the cricopharyngeus muscle, and the inlet of the esophagus have all been suggested to be of importance in swallowing.[6],[7] It remains unclear as to which of the patients might develop swallowing problems due to treatment-related toxicities.[8] This study is an attempt to identify the relationship between the dose of radiation received to these anatomic structures involved in swallowing, and the swallowing status after radiotherapy for head and neck cancer; and to explore the differences, if any, in intensity-modulated radiation therapy (IMRT), and three-dimensional conformal radiotherapy (3DCRT).

Aims

The aim of the present study is to assess the relationship between the dose of radiation received by the muscular components of the swallowing apparatus, in both conventional 3DCRT and IMRT, and the subjective swallowing quality of patient after completion of treatment.


 > Materials and Methods Top


Patients with carcinoma of anterior two-thirds of the tongue treated at our institute, a tertiary referral center from November 2011 to December 2012, were identified by electronic medical records and computerized tomography (CT) simulator workload register. The treatment plans of patients treated using 3DCRT and IMRT were retrieved from the focal (workstation), and the swallowing structures were contoured separately. A total of 20 patients, 10 treated with 3DCRT and 10 treated with IMRT, were taken for the study.

All patients had undergone surgery and were referred for radiation. Twelve had wide local excision; two each had total glossectomy, near total glossectomy, and hemiglossectomy; and one had sub-total glossectomy. Details of one could not be obtained. In all 10 patients in the group had received chemotherapy, six in IMRT group, and four in 3DCRT group. The schedule was cisplatin 40 mg/m 2 weekly, or 100 mg/m 2 every three weeks. All patients had been treated with a tumoricidal dose of 60–66 Gy, 180–200 cGy per fraction, and 5 fractions a week, to a total of 30–33 fractions. The PTV 60 Gy included the entire tongue, oropharynx, and bilateral levels II and III nodal groups. High-risk volumes such as positive and close margins were treated with a dose of 66 Gy. Patient characteristics are provided in [Table 1].
Table 1: Patient characteristics

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The structures of swallowing or “dysphagia aspiration-related structures” (DARS) were identified as suggested by Christianen et al.[9] and delineated on axial CT-slices of each plan. The DARS include superior, middle, and inferior pharyngeal constrictor muscles, glottis, and supraglottic larynx, base of the tongue, and upper esophageal sphincter including cricopharyngeus muscle and upper esophagus. These structures were contoured based on radiation therapy oncology guidelines. Superior constrictor muscle (SCM) was defined from caudal tips of pterygoid plates through the upper edge of hyoid bone. Middle constrictor muscle (MCM) was defined from the upper edge of hyoid bone through the lower edge of hyoid and ICM was defined from below the hyoid through inferior edge of cricoid cartilage. Larynx was contoured from tip of epiglottis superiorly to the bottom of cricoid inferiorly to include supraglottic and glottic larynx. The lumen was excluded. The base of the tongue was contoured from below the soft palate to upper edge of the hyoid bone. Oesophagus was contoured from inferior border of cricoid cartilage, to caudal most extent of lower neck field, to include upper oesophageal sphincter and cricopharyngeous muscle. Volumes of larynx and supraglottis were taken as a single volume, and so also the esophagus and esophageal inlet including cricopharyngeus. A combined volume for all swallowing structures was also generated, and different doses in relation to the volumes were also determined.

Treatment plans were generated in the XIO (XIO-Electa, Inc.) software. Dose-volume histograms to the swallowing structures were obtained. The mean dose and maximum dose to individual structures of swallowing, and also for combined swallowing structures, were tabulated for IMRT and 3DCRT groups. For the combined volume, the V30 (volume of a structure receiving more than 30 Gy), V50 (volume of a structure receiving more than 50 Gy), V60 (volume of a structure receiving more than 60 Gy), V70 (volume of a structure receiving more than 70 Gy), D50 (dose received by 50% volume of a structure/median dose), and D80 (dose received by 80% volume of a structure) were also generated. A comparison of doses in both techniques was done to see the difference in the dose received by the structures. The probable mean dose constraints predicted by van der Molen et al.[10] 63 Gy to SCM and MCM, and 56 Gy to ICM was taken as limiting doses. We also took limiting doses of 63 Gy for the base of the tongue, 55 Gy for larynx, and 50 Gy for the esophagus. The swallowing status of patients was later correlated with the probable dose constraints.

Patients were assessed for the swallowing status after a minimum period of 6 months from treatment completion. Detailed subjective evaluation was carried out using questions similar to that in University of Washington Head- and Neck-related Quality-of-Life,[11],[12],[13] for which answers are like, (1) “I swallow normally,” (2) “I cannot swallow certain solid food,” (3) “I can only swallow soft food,” (4) “I can only swallow liquid foods,” and (5) “I cannot swallow.” The nature of food that they could take without difficulty and the frequency were enquired about.

Statistical analysis was done using IBM SPSS Statistics 20 Windows (SPSS Inc., Chicago, IL, USA). For all continuous variables, results are given in mean ± standard deviation and for categorical variables as percentage. To compare the averages of continuous variables between two groups, those which are not following normal distribution, Mann–Whitney U-test was performed. Spearman's rho correlation coefficient was used for finding the association between two continuous variables. The receiver operating curves (ROC) were calculated, and the areas under the curves (AUC) were estimated, as well as sensitivity and specificity with 95% confidence intervals.


 > Results Top


Dose to the structures of dysphagia aspiration-related structures

The mean doses obtained by individual structures were tabulated as shown in [Table 2]. The possible dose thresholds were analyzed statistically using ROC, and the sensitivity and specificity were obtained. Though the AUC was not found to be significant, possibly due to limited number of cases, probable doses for each structure beyond which there was an increased risk of swallowing complications was identified as shown in [Table 3].
Table 2: Comparison of dose to individual structures of DARS in IMRT and 3DCRT

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Table 3: The probable threshold doses of structures of DARS

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Correlation between doses to the different structures of swallowing

A statistically significant correlation was found between dose obtained by SCM and the base of the tongue (r - 0.867, P - 0.001); MCM and ICM (r - 0.709, P - 0.002); MCM and larynx (r - 0.842, P - 0.002), and ICM and larynx (r - 0.794, P - 0.006), in the IMRT technique. In the 3DCRT also a statistical significance was seen in the correlation between dose of SCM and that of MCM (r - 0.927, P ≤ 0.001), ICM (r - 0.952, P ≤ 0.001), base of the tongue (r - 0.766, P - 0.010), and larynx (r - 0.952, P ≤ 0.001). A similar relation was seen between dose of MCM and that of ICM (r - 0.855 P - 0.002), base of the tongue (r - 0.620, P - 0.056), and larynx (r - 0.927, P ≤ 0.001). The correlation between that of ICM and larynx (r - 0.927, P ≤ 0.001) and base of the tongue and esophagus (r - 0.802, P - 0.005) were also significant as shown in [Table 4]. A scatter plot of the correlation is shown in [Figure 1].
Table 4: Correlation between dose to individual structures in IMRT and 3DCRT

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Figure 1: Scatter plot showing the correlation of dose to dysphagia aspiration-related structures, in three-dimensional conformal radiotherapy and intensity-modulated radiation therapy

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Comparison of volumes and the doses

The doses received in terms of volumes were tabulated for IMRT and 3DCRT techniques as shown in [Table 5]. The mean V30 dose received by the DARS taken together, for IMRT was 96.97 and for 3DCRT was 95.68 Gy (P - 0.051). As the volume increased, there was a progressive reduction in the dose in IMRT technique, which was not seen in 3DCRT, and there was a statistically significant advantage for IMRT in the V50 and V60 doses (P - 0.002 for both). The significant advantage was also seen for the IMRT in terms of D80 dose (P - 0.023).
Table 5: Comparison of dose with respect to volumes in IMRT and 3DCRT

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Posttreatment swallowing status

In IMRT group, 8 of the 10 patients (80%) and in 3DCRT, 6 of the 10 (60%) had some form of feeding support, either a nasogastric tube or a percutaneous endoscopic gastrostomy (PEG) tube. The nutritional support period extended from 22 to 393 days, with a mean of 174.14 days. Some patients persisted in having the support even after 1 year.

Among the 10 patients treated with IMRT, two were not taking anything orally, being feeding tube dependent. Of the rest, two could take only liquids, five semisolids, and only one was taking solids. The mean period for which tube was retained was 131.75 days (range 22–234). Two of these patients continued to have feeding tube even on their last follow-up, and one of them had succumbed to the disease.

In the 3DCRT group, among the six who were on supportive tube feeding, two were not able to take orally and had retained the tube. Of the other four patients, three were taking semisolids, and only one was taking solids. Of the four patients who were not on any feeding support during their treatment, three were taking solids, and one was taking semi solids at the last follow-up. Most of the patients on semisolids were taking blended food and the few who could not tolerate this were only on liquids. The mean time for which the feeding tube was retained was 280.83 days (range 71–393). Xerostomia, subsequent to radiation, was also impairing the swallowing status of these patients, requiring them to consume additional quantity of water in order to facilitate swallowing.

When swallowing on the basis of initial surgery was considered, in the IMRT group, one who had total glossectomy was on semisolids. Of the two hemiglossectomy patients, one was tube dependent and the other on semisolids. Six patients had wide local excision, of which one was on solids, two on semisolids, and three on liquids. One patient who was tube dependent was referred from outside, and the details were not known. Among the 3DCRT group, three patients had total or near total glossectomy, of which two were tube dependent, and one was on semisolids. Six had wide local excision of which four were on solids and two on semisolids. One patient had a sub-total glossectomy and was on semisolids. No definitive relation was observed in relation to the chemotherapy.

Swallowing in relation to the dose of dysphagia aspiration-related structures

Assessing the swallowing status on the basis of limiting doses as suggested by earlier studies, four patients in the IMRT group had received above 63 Gy to SCM. Two of these patients persisted to be feeding tube dependent while the other two were on semisolids or solids. Of the six who received <63 Gy, two did not require a feeding tube. Four of the rest were taking solids, and only two were taking liquids. In the 3DCRT group, two had received above 63 Gy but were still taking solids. Coming to the ICM, seven patients had received more than the suggested threshold dose of 56 Gy, and of these two were feeding tube dependent (28.5%). Two were taking semisolids, and three solids. The swallowing status in relation to the probable threshold dose in IMRT and 3DCRT is shown in [Table 6].
Table 6: Probable threshold dose to DARS in IMRT and 3DCRT, and the swallowing status

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 > Discussion Top


Dysphagia being one of the determinants of quality of life of patients in the postradiation setting, the structures associated with dysphagia or DARS have been much discussed in the recent literature, stressing the need for restricting dose received by these.[1] Dysphagia optimized IMRT, a step ahead of standard IMRT, where the dose to the DARS could be tailored to be contained within the limits, without compromising the dose to target volumes, has been suggested by Eisbruch et al. and is a promising avenue.[2] One significant observation of our study was that in both IMRT and 3DCRT groups, there were feeding tube dependence, and more patients on IMRT required nutritional support though for shorter periods. In the IMRT group, an extensive surgery was not associated with higher grade of dysphagia.

The dose received by the constrictor muscles has been implicated in postradiation dysphagia, with the strongest relationship for SCM, as published by pioneers like Feng et al.[14] Consumption of solids was the most important swallowing problem that patients experienced. Though xerostomia is a compounding factor, the dose of radiation does have a significant correlation to the degree of dysphagia. van der Molen et al.[10] had shown that a mean dose above 63 Gy to the SCM and the MCM resulted in a poor swallowing quality. The same was shown by Feng et al.[14] for the pharyngeal constrictors taken together. A predictive model by Kim et al.[15] suggested a 2% volume of SCM as significant. Our statistical and subjective analyses also pointed to a dose of 63.04 Gy to the SCM as the limiting dose, in IMRT, stressing that this can be taken as a limiting dose. A dose of 62.72 Gy was the calculated limiting dose to SCM in 3DCRT but was not found significant subjectively.

The probable limiting dose to MCM was found to be 63.20 Gy with a specificity of 87%, statistically derived from the 3DCRT dose values. Probably because of the low dose delivered to the MCM, and the ICM in IMRT, a definitive limiting dose could not be predicted.

In contrast to the mean dose of 56.9 Gy suggested by van der Molen et al. to the ICM, the dose we could obtain statistically was 61.91 Gy in the 3DCRT. However, subjective assessment had shown that a dose above 56 Gy has an adverse relation to dysphagia, with feeding tube dependence of 28.5%, among the 3DCRT patients. No IMRT patients had received a dose above this.

van der Molen et al. had suggested that the base of the tongue, larynx, and esophagus with the cricopharyngeus muscle, the other structures of DARS, which they had not looked into, also had a significant role in the dysphagia status. Our study had looked into these structures as well. A cut-off dose statistically derived for the base of the tongue was 65.18 Gy in IMRT and 62.76 Gy in 3DCRT. Three of eight (37.5%) patients who had received more than 63 Gy were found to be feeding tube dependent. Mean dose above 41 Gy,[16] or above 50 Gy,[17] to larynx was predicted to be associated with PEG tube dependence. Our analysis showed a subjective and statistical significance for a dose of 55.10 Gy to larynx, where, patients who had received a dose beyond this in the 3DCRT group had significant dysphagia with feeding tube dependence. Thus, our study would suggest probable limiting doses for dysphagia for the base of the tongue as 63 Gy and for larynx as 55 Gy.

Statistically significant correlations between the doses of MCM and ICM have been brought out in prospective evaluations.[10] We also found a statistically significant correlation between doses of MCM and ICM (r - 0.709, P - 0.022, IMRT; r - 0.855, P - 0.002, 3DCRT), and MCM and larynx (r - 0.842, P - 0.002, IMRT; r - 0.952, P ≤ 0.001, 3DCRT). The correlation between the dose of ICM and larynx was also statistically significant (r - 0.794, P - 0.006, IMRT; r - 0.927, P ≤ 0.001, 3DCRT). There was similar correlations between dose to SCM and that of the base of the tongue (r - 0.867, P - 0.001 IMRT; r - 0.766, P - 0.010, 3DCRT). This may be significant in the light that limiting doses to both these structures were found to be 63 Gy.

A very significant advantage for IMRT over 3DCRT was observed while comparing the dose to volumes in both these groups. The mean V30 dose for the DARS taken together had a borderline advantage for IMRT technique (P - 0.051). The V50 and V60 doses showed statistically significant advantage for IMRT (P - 0.002 for both). An advantage for IMRT was also observed in D80 dose (P - 0.023). The progressive reduction, in dose for the constrictors and the larynx and esophagus observed in the IMRT, also has to be taken as an advantage for IMRT. The limiting dose for DARS arrived at statistically in our study was corroborated on evaluation of posttreatment swallowing status.

Being retrospective, proper evaluation of the initial swallowing status has not been done, and the extent to which the surgical procedures could have contributed to swallowing problems was not assessed. Moreover, due to financial constraints involved, swallowing assessments with video-fluoroscopy was not done in these patients, and only subjective assessment has been opted for.


 > Conclusion Top


This retrospective analysis of swallowing profiles of postsurgery patients with cancer of anterior two-thirds of the tongue, treated with an advanced state-of-art technique of IMRT and conventional 3DCRT, has shown that a relationship does exist between the dose received by the swallowing structures and dysphagia, thereby acting as a prime factor deciding the quality of life. A probable mean limiting dose could be arrived at, as suggested by earlier literature, for the SCM. Ours could be one of the few studies that could also predict a probable mean constraint dose for the base of the tongue, and larynx. Further prospective evaluation is required for confirming these doses. A moderate advantage for conventional IMRT has been observed in our study also. All studies, including ours, emphasize the need for contouring and delineating the swallowing structures, and diligent planning to optimize their dose, for improving the quality of life of these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Teguh DN, Levendag PC, Noever I, van Rooij P, Voet P, van der Est H, et al. Treatment techniques and site considerations regarding dysphagia-related quality of life in cancer of the oropharynx and nasopharynx. Int J Radiat Oncol Biol Phys 2008;72:1119-27.  Back to cited text no. 1
    
2.
Eisbruch A, Schwartz M, Rasch C, Vineberg K, Damen E, Van As CJ, et al. Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: Which anatomic structures are affected and can they be spared by IMRT? Int J Radiat Oncol Biol Phys 2004;60:1425-39.  Back to cited text no. 2
    
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Peponi E, Glanzmann C, Willi B, Huber G, Studer G. Dysphagia in head and neck cancer patients following intensity modulated radiotherapy (IMRT) Radiat Oncol 2011;6:1.  Back to cited text no. 3
    
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Murphy BA, Gilbert J. Head and neck cancer: Dysphagia in head and neck cancer patients treated with radiation: assessment, sequelae, and rehabilitation. Seminars in Radiation Oncology 2009;19: 35-42..  Back to cited text no. 4
    
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Nguyen NP, Vos P, Moltz CC, Frank C, Millar C, Smith HJ, et al. Analysis of the factors influencing dysphagia severity upon diagnosis of head and neck cancer. Br J Radiol 2008;81:706-10.  Back to cited text no. 5
    
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Levendag PC, Teguh DN, Voet P, van der Est H, Noever I, de Kruijf WJ, 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;85:64-73.  Back to cited text no. 6
    
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Suen AW, Chen PY, Chao K, Galerani AP, Martinez AA. Clinical Correlation of Radiation Dose to Anatomic Structures with Treatment Related Chronic Dysphagia in Definitive Chemoradiotherapy for Head and Neck Cancers. Proceedings of the 49th Annual ASTRO Meeting. Int J Radiat Oncol Biol Phys. 2007;69:S419–S420.  Back to cited text no. 7
    
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Roe JW, Carding PN, Rhys-Evans PH, Newbold KL, Harrington KJ, Nutting CM. Assessment and management of dysphagia in patients with head and neck cancer who receive radiotherapy in the United Kingdom – A web-based survey. Oral Oncol 2012;48:343-8.  Back to cited text no. 8
    
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Christianen ME, Langendijk JA, Westerlaan HE, van de Water TA, Bijl HP. Delineation of organs at risk involved in swallowing for radiotherapy treatment planning. Radiother Oncol 2011;101:394-402.  Back to cited text no. 9
    
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van der Molen L, Heemsbergen WD, de Jong R, van Rossum MA, Smeele LE, Rasch CR, et al. Dysphagia and trismus after concomitant chemo-Intensity-Modulated Radiation Therapy (chemo-IMRT) in advanced head and neck cancer; dose-effect relationships for swallowing and mastication structures. Radiother Oncol 2013;106:364-9.  Back to cited text no. 10
    
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Laraway DC, Rogers SN. A structured review of journal articles reporting outcomes using the university of Washington quality of life scale. Br J Oral Maxillofac Surg 2012;50:122-31.  Back to cited text no. 11
    
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Senkal HA, Hayran M, Karakaya E, Yueh B, Weymuller EA Jr, Hosal AS. The validity and reliability of the Turkish version of the University of Washington quality of life questionnaire for patients with head and neck cancer. Am J Otolaryngol 2012;33:417-26.  Back to cited text no. 12
    
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D'cruz AK, Yueh B, Das AK, McDowell JA, Chaukar DA, Ernest AW. Validation of the University of Washington quality of life questionnaires for head and neck cancer patients in India. Indian J Cancer 2007;44:147-54.  Back to cited text no. 13
    
14.
Feng FY, Kim HM, Lyden TH, Haxer MJ, Feng M, Worden FP, 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;68:1289-98.  Back to cited text no. 14
    
15.
Kim DR, Duprez F, Werbrouck J, Sabbe N, Sofie de L, Boterberg T, et al. A predictive model for dysphagia following IMRT for head and neck cancer: Introduction of the EMLasso technique. Radiother Oncol 2013;107:295-9.  Back to cited text no. 15
    
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Caudell JJ, Schaner PE, Desmond RA, Meredith RF, Spencer SA, Bonner JA. Dosimetric factors associated with long-term dysphagia after definitive radiotherapy for squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2010;76:403-9.  Back to cited text no. 16
    
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Caglar HB, Tishler RB, Othus M, Burke E, Li Y, Goguen L, et al. Dose to larynx predicts for swallowing complications after intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2008;72:1110-8.  Back to cited text no. 17
    


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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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