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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 2  |  Page : 218-223

Changes in pharyngeal constrictor volumes during head and neck radiation therapy: Implications for dose delivery


Department of Radiation Oncology, Henry Ford Health System, Detroit, MI, USA

Date of Web Publication23-Jun-2017

Correspondence Address:
Akila Kumarasiri
Department of Radiation Oncology, Henry Ford Health System, 2799 W Grand Blvd., Detroit, MI
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.183176

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 > Abstract 

Objective: The objective of this study was to evaluate the anatomical changes and associated dosimetric consequences to pharyngeal constrictor muscles (PCMs) that occur during head and neck (H and N) radiotherapy (RT).
Materials and Methods: A cohort of 13 oropharyngeal cancer patients with daily cone beam computed tomography (CBCT) was retrospectively studied. On every 5th CBCT image, PCM was manually delineated by a radiation oncologist. The anterior-posterior PCM thickness was measured at the midline level of C3 vertebral body. Delivered dose to PCM was estimated by calculating dose on daily images and performing dose accumulation on corresponding planning CT images using a parameter-optimized B-spline-based deformable image registration algorithm. The mean and maximum delivered dose (Dmean, Dmax) to PCM were determined and compared with the corresponding planned quantities.
Results: The average (±standard deviation) volume increase (ΔV) and thickness increase (Δt) over the course of 35 total fractions were 54 ± 33% (11.9 ± 7.6 cc) and 63 ± 39% (2.9 ± 1.9 mm), respectively. The resultant cumulative mean dose increase from planned dose to PCM (ΔDmean) was 1.4 ± 1.3% (0.9 ± 0.8 Gy), while the maximum dose increase (ΔDmax) was 0.0 ± 1.6% (0.0 ± 1.1 Gy). Patients who underwent adaptive replanning (n = 6) showed a smaller mean dose increase than those without (n = 7); 0.5 ± 0.2% (0.3 ± 0.1 Gy) versus 2.2 ± 1.4% (1.4 ± 0.9 Gy). There were statistically significant (P = 0.001) strong correlations between ΔDmean and Δt (Pearson coefficient r = 0.78), as well as between ΔDmean and ΔV (r = 0.52).
Conclusion: The patients underwent considerable anatomical changes to PCM during H and N RT. However, the resultant increase in dose to PCM was minor to moderate. PCM thickness measured at C3 level is a good predictor for the mean dose increase to PCM.

Keywords: Adaptive radiotherapy, deformable image registration, dose accumulation, dysphagia, pharyngeal constrictor


How to cite this article:
Kumarasiri A, Liu C, Kamal M, Fraser C, Brown S, Chetty IJ, Kim J, Siddiqui F. Changes in pharyngeal constrictor volumes during head and neck radiation therapy: Implications for dose delivery. J Can Res Ther 2017;13:218-23

How to cite this URL:
Kumarasiri A, Liu C, Kamal M, Fraser C, Brown S, Chetty IJ, Kim J, Siddiqui F. Changes in pharyngeal constrictor volumes during head and neck radiation therapy: Implications for dose delivery. J Can Res Ther [serial online] 2017 [cited 2019 Nov 15];13:218-23. Available from: http://www.cancerjournal.net/text.asp?2017/13/2/218/183176


 > Introduction Top


Head and neck (H and N) cancer patients can undergo considerable weight loss and other anatomical changes during a typical 6–7 week course of radiation therapy.[1],[2] Advances in image-guided radiation therapy have made it possible to track these anatomical changes over the treatment course.[3] If the anatomical variations are large enough to cause significant dose deviations to the target or normal tissue/organs from what was originally intended, the original treatment plan can be “adapted” to mitigate the dose deviations.[2] Changes to organs at risk (OAR) such as parotid glands during treatment have been well-established, and are typically considered when replanning is done.[4] However, there are other OARs, such as the pharyngeal constrictor muscles (PCMs), for which dosimetric consequences from the volumetric and geometric changes that occur during treatment have not been well studied.

Dysfunction of PCM may occur after radiation therapy and is known to be a major cause of dysphagia.[5],[6] It has been recently established that there is a significant correlation between dose to PCM and patients' quality of life degradation following radiation therapy, especially in the occurrence of dysphagia.[7] Therefore, it is essential to closely follow the changes in PCM during treatment to ensure that the originally intended dose constraints are met. There are a limited number of studies that show that the thickness of PCM may increase significantly during chemo-radiation therapy for H and N cancer.[5],[6],[8] However, as of yet, there have been no studies that investigated the resultant changes to the delivered dose from these anatomical variations. In this work, the volumetric and thickness changes of PCM of 13 oropharyngeal cancer patients that occurred over the 6–7-week treatment course were evaluated, and deformable image registration-based dose accumulation was used to estimate the actual delivered dose to PCM. Correlations between dose deviations from intended dose and PCM anatomical changes were also investigated.


 > Materials and Methods Top


Dataset

A cohort of 13 H and N patients with oropharyngeal cancers, who were treated with external beam radiation therapy, was retrospectively evaluated. All patients had cone beam computed tomographies (CBCTs) obtained for daily positioning, and were treated with volumetric-modulated arc therapy, with two full gantry rotations. Treatment plans were created and optimized using Eclipse Treatment Planning System (Varian Medical Systems, Palo Alto, CA) with 6 MV photon beams. An isotropic 5 mm margin was used for clinical target volume to planning target volume (PTV) expansion. A total dose of 60–70 Gy (2 Gy × 30–35 fractions) was delivered to the high-risk PTV in a typical 6–7-week treatment course. For six patients, the initial plans were modified due to significant anatomical changes to targets and OAR. [Table 1] lists the patient details.
Table 1: Patient details; all patients were treated with RapidArc (2 arcs)

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Contouring and volumetric/thickness measurements

A radiation oncologist manually delineated PCM on every 5th CBCT (i.e., 1/week) retrospectively and re-contoured the PCM on the simulation CT for contouring consistency. PCM delineation was based on the anatomical guidelines by Christianen et al.[9] The superior constrictor, middle constrictor, and inferior constrictor muscles were contoured as a single volume of interest.

The volume and thickness of PCM contours were collected on every 5th CBCT images to track the anatomical changes. The anterior-posterior thickness was also measured at the midline and at the center of the C3 vertebral body. Measurements were taken in the axial view and at identical anatomical positions for each patient over the treatment course. [Figure 1]a shows an example of thickness measurement in the axial view.
Figure 1: Example case of cross-sections of physician-drawn pharyngeal constrictor in axial view; (a-h) pharyngeal constrictor contours at C3 level on simulation computed tomography and cone beam computed tomography images of 5, 10, 15, 20, 25, 30, and 35 fractions, (i) contours at simulation and at the last (#35) fraction overlaid on the simulation computed tomography with dose color wash, and (j) the respective DVHs at simulation (dashed line) and at fraction 35 (solid line). For this case, Dmeanincreased from 62.4 to 63.0 Gy, whereas Dmaxremained unchanged

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Dose calculation

Deformable image registration-based daily dose accumulation was used to estimate the delivered dose to PCM.[10] To overcome the small field of view (FOV) limitations and Hounsfield unit uncertainties associated with CBCT images, the planning CT was deformed and resampled onto each CBCT with a 4.2 cm uniform FOV expansion, using a parameter-optimized public-domain deformable image registration algorithm (Elastix).[11],[12] Dose of the day was calculated on these resampled CT images for all 30–35 fractions, warped, and accumulated to the planning CT to estimate the delivered dose to organs using an energy-mass mapping algorithm.[13] To perform the registration, the online rigid registration that was used for daily positioning in the clinic was applied first to the daily images, followed by the deformable registration which consisted of 4 levels of B-spline grid resolutions (160, 80, 40, and 20 mm) with normalized cross-correlation as the similarity metric. The registration volume of interest was set to encompass the complete CBCT image volume. The quality of all registrations was visually verified. Complete details of this deformable image registration-based dose accumulation and validation process are available in a previously published work.[10],[11]

The mean and maximum delivered dose (Dmean, Dmax) to the pharyngeal constrictor were determined from the dose volume histograms, and the difference between cumulative and planned dose distributions was computed.


 > Results Top


[Figure 1] shows an example case of how PCM (at C3 level) changes over the course of the treatment. For this case, the pharyngeal constrictor thickness changed from 5.2 mm [at planning, [Figure 1]a to 9.2 mm at the last fraction [Figure 1]h, a 76% change. The volume change was 20.7–to 34.5 cc (67%). [Figure 1]i shows the pharyngeal constrictor contour at simulation and the contour at the last fraction, overlaid on the simulation CT in the sagittal view with a dose color wash. The thickness increase in the anterior-posterior direction is evident, and it is more prominent in the regions of high dose (C1-C3 regions). The mean planned dose (Dmean) to PCM was 62.4 Gy, while the cumulative mean dose was estimated to be 63.0 Gy. The corresponding DVHs are also shown in [Figure 1]j.

[Figure 2] shows the volume and thickness trends of PCM for all patients, measured at 1 week intervals. The data for individual patients are shown with dashed lines, while the mean volumes and thicknesses are denoted by the solid line, with standard deviations incorporated as error bars. While the individual curves fluctuate, it is clear that both the mean volume and mean thickness show a systematic increase over the course of treatment.
Figure 2: Trends of (a) volume and (b) thickness (at C3 level) of pharyngeal constrictors plotted as a function of the fraction number. Volumes and thicknesses were calculated once every 5 fractions (i.e., weekly). The mean trends of the 13 patients are also shown in solid lines, with the standard deviation incorporated as error bars

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[Table 2] lists PCM volume, thickness, and dose changes as well as the weight loss for all patients. The mean (± standard deviation) volume increase (ΔV) over the course of treatment was 54 ± 33% (11.9 ± 7.6 cc), whereas the thickness increase (Δt) was 63 ± 39% (2.9 ± 1.9 mm). The corresponding mean volumes at planning (obtained from planning CT) and at the end of treatment (obtained from fraction 35 CBCT) were 22.5 ± 3.7 cc and 34.1 ± 8.3 cc, respectively, whereas the mean thickness at C3 level at planning and at the end of treatment were 4.3 ± 0.7 mm and 6.9 ± 1.6 mm, respectively. The largest mean volume and thickness increase were observed during the 1st week of the treatment, where 26% (6 cc) and 17% (0.8 mm) changes, respectively, were observed from the simulation CT to the 5th fraction. However, it should be noted that contouring variances between simulation CT and the CBCTs may have contributed to this considerable increase.
Table 2: Pharyngeal constrictor changes for 13 patients during treatment: Thickness (Δt), volume (ΔV), mean dose deviation (ΔDmean), and weight loss (ΔW). Whether patients underwent a replanning or not is also indicated

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The average cumulative Dmean to the pharyngeal constrictor was 63.2 ± 4.7 Gy (range: 52.5–67.3 Gy). The resultant cumulative mean dose increase from the planned dose (ΔDmean) was 1.4 ± 1.3% (0.9 ± 0.8 Gy), while the maximum dose change (ΔDmax) was approximately 0.0 ± 1.6% (0.0 ± 1.1 Gy). Patients with adaptive replanning (n = 6) showed a smaller mean dose increase of 0.5 ± 0.2% (0.3 ± 0.1 Gy) than patients who did not undergo a replanning (n = 7); 2.2 ± 1.4% (1.4 ± 0.9 Gy). There was a statistically significant (P = 0.001) strong correlation between ΔDmean and pharyngeal constrictor thickness change Δt over the treatment course (Pearson correlation coefficient r = 0.78) and between ΔDmean and ΔV (r = 0.52). [Figure 3] plots the relationship between ΔDmean and ΔV and ΔDmean and Δt, along with the linear regression fits. Negligible correlation was found between ΔDmean and weight loss ΔW (r = 0.2), as well as Δt and ΔW (r = 0.04).
Figure 3: Correlations of (a) volume ΔV, and (b) thickness increases Δt, to mean dose increases (ΔDmean). R2 values from linear regression correlation are also shown

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When the cumulative mean dose (Dmean) was considered instead of the mean dose deviation ΔDmean, the following correlations were found: Moderate correlation between Dmean and Δt (r = 0.3), strong correlation between Dmean and thickness of the constrictor at the end of the treatment (tfinal) (r = 0.55), and moderate correlation between Dmean and average thickness of the pharyngeal constrictor during the course of the treatment (tmean) (r = 0.33). tmean was estimated by averaging all the thickness measurements over the treatment course.


 > Discussion Top


The main objectives of this study were to evaluate the anatomical changes of PCM over a typical 6–7-week H and N radiation therapy course, and to correlate these changes to the dosimetric quantities, estimated via deformable image registration-based dose accumulation. We found that PCM undergoes considerable anatomical changes during treatment, which is in agreement with other previous studies.[5],[6],[8] However, new to this study, we found that the resultant mean dose changes to the organ from planned dose were small to moderate (average Dmean change 0.9 Gy, range 0.1–3.3 Gy). The average maximum dose for all patients showed no difference between the delivered dose and the planned dose.

We also found statistically significant strong correlations between mean dose deviation and PCM thickness/volume changes. As evident from [Figure 1]i, PCM thickness and volume increase occurred primarily in the high dose regions that were in proximity to the treatment targets. This explains the observed mean dose increase to some extent. The maximum dose, however, was not affected as much since the superior portion of PCM were already in the high dose region.

The cumulative mean dose received by PCM showed a strong correlation to its thickness at the last fraction (r = 0.55), as well as a strong-to-moderate correlation to the average thickness over the course of treatment (r = 0.33). Moreover, the mean dose deviation from planned dose showed strong correlations to PCM thickness change and volume change (r = 0.78 and 0.52, respectively). Therefore, the pharyngeal constrictor anatomical changes were found to be well correlated to the dosimetric deviations, although the magnitude of these dose changes was small.

Previous studies have also investigated the dose-induced anatomical changes in the pharyngeal constrictor.[5],[6] These studies showed the thickening trends of the constrictor muscles over the treatment course, which is in good agreement with what we have observed in this study. A magnetic resonance imaging (MRI) based study by Popovtzer et al. found that there was a significant increase in thickness of almost all PCMs studied.[6] Moreover, they found that PCM receiving >50 Gy showed an average thickness increase of 118% (measured at axial cut in the middle of the cranio-caudal axis of muscle), which was significantly higher (P = 0.02) than those receiving <50 Gy (average increase 66%). In our study, all patients received >50 Gy, and we observed an average thickness increase of 63%. This minor discrepancy may be attributed to the different positions of thickness measurements, as well as contouring variability between CT and MRI. A similar study by Eisbruch et al. measured the thickness of PCM before therapy and 3 months after therapy completion, and found an even larger median thickness increase; from 2.5 to 7 mm for PCM receiving >50 Gy.[5]

The patient weight loss showed a negligible correlation to mean cumulative dose, as well as the pharyngeal constrictor thickness/volume change. The thickness change in the pharyngeal constrictor was strictly dose-related, which was also demonstrated in the aforementioned studies. Moreover, adaptive replanning during the 3rd or 4th weeks of treatment appears to further limit the effects of unintended dose changes to the pharyngeal constrictor. A total of six patients had adaptive replanning in our study, and showed an average ΔDmean of 0.3 ± 0.1 Gy whereas the seven patients who did not undergo replanning showed a larger ΔDmean, 1.4 ± 0.9 Gy. However, the ΔDmean difference between these two groups (~1.1 Gy) may not be large enough to cause significant changes to clinical outcome between the two groups.

The quality of life following radiation therapy is an important aspect in patient comfort. Recent studies showed that dose to PCM was significantly associated with swallowing dysfunction. It has been reported that limiting the mean PCM dose to <60 Gy results in better swallowing outcomes and fewer complications in swallowing and aspiration.[7],[14] A study by Feng et al. found significant correlations between video fluoroscopy-based aspirations and the mean doses to PCM and supraglottic larynx.[15] Similarly, Levendag et al. found that dysphagia disorders in patients with oropharynx cancer are significantly affected by the radiation therapy dose to the superior and middle constrictor muscles.[16] In contrast, a study by Bhide et al. showed no statistically significant correlation between the radiation dose to PCM and observer-assessed dysphagia grade of patients.[17]

However, all these studies were based on the planned dose to PCM. Considering that PCM anatomical changes during treatment are well established,[5],[6] and since this study shows small, but nonnegligible dosimetric consequences to PCM, it is possible that the actual cumulative (rather than planned) dose delivered to the organ may be a better indicator of dysphagia following radiation therapy. More work is needed to establish this cumulative dose–effect relationship. It should also be noted that in addition to the pharyngeal constrictor, glottic and superglottic larynx and base of tongue also contribute to the swallowing function. No single organ/dysfunction has been shown to determine the overall swallowing and protection of airways ability.[15] Therefore, investigating the dose-volume effects for these organs is also a necessity.

In this study, the thickness and volume measurements were based on physician-drawn contours. However, it should be noted that accurate contouring of PCM is challenging because of the limited contrast from the surrounding soft tissues. Some of the previous studies on PCMs used MRI images for better contrast.[6],[18] However, MRI images were not available in this study. Moreover, use of CT data with Hounsfield unit information was necessary to calculate the dose of the day for the cumulative dose estimation. Hence, a combination of MRI (for contouring) and CT data (for dose calculation) may be preferable for further studies. Contouring variation is also observed in [Figure 1] to some degree, and is also noticeable in the pharyngeal constrictor volume and thickness trend plots [Figure 2]. The trend plots of each individual patient are somewhat oscillatory, which is indicative of the uncertainty in physician contouring. However, the average plots over all patients show a clear trend of increasing volume and thickness as a function of the treatment fraction. It should be noted that the results of the cumulative dose were unaffected by the physician contouring uncertainty because only the planning CT contour set was used to calculate the cumulative dose-volume histograms.

The quality of deformable image registration directly influences the accuracy of the resultant cumulative dose distribution. To minimize the registration errors, we reviewed all registrations individually using software tools, reviewing both pixel similarities as well as the underlying displacement vector fields. Unacceptable registrations were corrected using rigid landmark structures. A rigidity penalty term was incorporated into the registration loop to help constrain the optimization, where necessary.


 > Conclusion Top


The PCMs were found to undergo considerable thickness and volume changes during H and N RT. However, the resultant maximum and mean dose deviations to the pharyngeal constrictor were small, especially for patients with a mid-course adaptive replanning. The results in this study are also indicative that the pharyngeal constructor thickness, measured at the C3 level, is a good predictor for this minor dosimetric change to the organ.

Acknowledgments

This work was supported in part by a Research Grant from Varian Medical Systems, Palo Alto, CA, USA.

Financial support and sponsorship

Department of Radiation Oncology, Henry Ford Health System holds master research agreements and receives research grants from Varian Medical Systems, Palo Alto, CA and Philips Healthcare, Best, Netherlands.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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Barker JL Jr., Garden AS, Ang KK, O'Daniel JC, Wang H, Court LE, et al. Quantification of volumetric and geometric changes occurring during fractionated radiotherapy for head-and-neck cancer using an integrated CT/linear accelerator system. Int J Radiat Oncol Biol Phys 2004;59:960-70.  Back to cited text no. 1
    
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Schwartz DL. Current progress in adaptive radiation therapy for head and neck cancer. Curr Oncol Rep 2012;14:139-47.  Back to cited text no. 2
    
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Intensity Modulated Radiation Therapy Collaborative Working Group. Intensity-modulated radiotherapy: Current status and issues of interest. Int J Radiat Oncol Biol Phys 2001;51:880-914.  Back to cited text no. 3
    
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Lee C, Langen KM, Lu W, Haimerl J, Schnarr E, Ruchala KJ, et al. Evaluation of geometric changes of parotid glands during head and neck cancer radiotherapy using daily MVCT and automatic deformable registration. Radiother Oncol 2008;89:81-8.  Back to cited text no. 4
    
5.
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. 5
    
6.
Popovtzer A, Cao Y, Feng FY, Eisbruch A. Anatomical changes in the pharyngeal constrictors after chemo-irradiation of head and neck cancer and their dose-effect relationships: MRI-based study. Radiother Oncol 2009;93:510-5.  Back to cited text no. 6
    
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Frowen J, Hornby C, Collins M, Senthi S, Cassumbhoy R, Corry J. Reducing posttreatment dysphagia: Support for the relationship between radiation dose to the pharyngeal constrictors and swallowing outcomes. Pract Radiat Oncol 2013;3:e187-94.  Back to cited text no. 7
    
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Ricchetti F, Wu B, McNutt T, Wong J, Forastiere A, Marur S, et al. Volumetric change of selected organs at risk during IMRT for oropharyngeal cancer. Int J Radiat Oncol Biol Phys 2011;80:161-8.  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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Kumarasiri A, Liu C, Siddiqui F, Zhong H, Chetty IJ, Kim J. Target and organ dose estimation from intensity modulated head and neck radiation therapy using 3 deformable image registration algorithms. Pract Radiat Oncol 2015;5:e317-25.  Back to cited text no. 10
    
11.
Kumarasiri A, Siddiqui F, Liu C, Yechieli R, Shah M, Pradhan D, et al. Deformable image registration based automatic CT-to-CT contour propagation for head and neck adaptive radiotherapy in the routine clinical setting. Med Phys 2014;41:121712.  Back to cited text no. 11
    
12.
Klein S, Staring M, Murphy K, Viergever MA, Pluim JP. Elastix: A toolbox for intensity-based medical image registration. IEEE Trans Med Imaging 2010;29:196-205.  Back to cited text no. 12
    
13.
Siebers JV, Zhong H. An energy transfer method for 4D Monte Carlo dose calculation. Med Phys 2008;35:4096-105.  Back to cited text no. 13
    
14.
Jensen K, Lambertsen K, Grau C. Late swallowing dysfunction and dysphagia after radiotherapy for pharynx cancer: Frequency, intensity and correlation with dose and volume parameters. Radiother Oncol 2007;85:74-82.  Back to cited text no. 14
    
15.
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. 15
    
16.
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. 16
    
17.
Bhide SA, Gulliford S, Kazi R, El-Hariry I, Newbold K, Harrington KJ, et al. Correlation between dose to the pharyngeal constrictors and patient quality of life and late dysphagia following chemo-IMRT for head and neck cancer. Radiother Oncol 2009;93:539-44.  Back to cited text no. 17
    
18.
Kuno H, Onaya H, Fujii S, Ojiri H, Otani K, Satake M. Primary staging of laryngeal and hypopharyngeal cancer: CT, MR imaging and dual-energy CT. Eur J Radiol 2014;83:e23-35.  Back to cited text no. 18
    


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