|Ahead of print publication
Intensity-modulated radiation therapy in head-and-neck carcinomas: Potential beyond sparing the parotid glands
Aman Sharma1, Amit Bahl2
1 Department of Radiotherapy and Oncology, Regional Cancer Centre, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India
2 Department of Radiotherapy and Oncology, PGIMER, Chandigarh, India
Department of Radiotherapy and Oncology, Regional Cancer Centre, Indira Gandhi Medical College, Shimla - 171 001, Himachal Pradesh
Source of Support: None, Conflict of Interest: None
Head-and-neck cancer (HNC) is in close proximity to several critical structures. Intensity-modulated radiation therapy (IMRT) has the potential of generating highly conformal and concave dose distributions around complex target and is ideally suited for HNC treatment. Conventionally, the focus of IMRT for HNC patients has been on prevention of radiation-induced parotid dysfunction. In the present article, we review the potential of IMRT to reduce the risk of posttreatment aspiration and dysphagia and spare submandibular gland. We also discuss the impact of IMRT on overall survival and quality of life (QoL) for HNC patients. Small retrospective and prospective studies show that reducing dose to adjoining organs at risks is feasible and decreases the risk of posttreatment dysphagia and aspiration without compromising local control. IMRT is associated with improved QoL in several important domains including swallowing, dry mouth, sticky saliva, social eating, and opening of the mouth; however, improvement in global QoL is inconsistent. Delivery of IMRT for HNC is associated with improved survival at nasopharyngeal subsite. Small studies demonstrate improved treatment outcomes with swallowing-sparing IMRT. These results now need validation within the prospective multicenter randomized controlled trial setting.
Keywords: Dysphagia, head-and-neck cancer, intensity-modulated radiation therapy, submandibular gland sparing, swallowing-sparing intensity-modulated radiation therapy
| > Introduction|| |
It is estimated that nearly three-fourth of head-and-neck cancer (HNC) patients, need curative radiotherapy (RT) either in a radical or in the postoperative setting. RT is preferred nonsurgical treatment for HNC and is associated with high local control with 5-year survival >80% for early stage 1–2 diseases and achieves 60% locoregional control rate for Stage 3–4 tumors. Throughout years, new RT technologies have emerged, and delivery of RT has evolved from two-dimensional (2D-RT) techniques, based primarily on X-ray images and manual calculations to three-dimensional (3D) techniques, based on computerized tomography images incorporating progressively complex computer algorithms and modern hardware tools.
Intensity-modulated radiation therapy (IMRT) is a form of conformal RT that uses nonuniform radiation beam intensities to create a sharp dose gradient between target and surrounding normal tissues. Theoretically, it allows for better target coverage and has the potential to decrease complication rate. Apart from merits, IMRT has its inherent weakness, which includes increased risk of marginal miss, increases in cost, laborious and is expensive. IMRT delivers higher total body dose because of leakage through collimator and internal scatter as a result of increased beam-on time. It has been contemplated that the use of IMRT will increase the risk of radiation-induced malignancies from 1% to 1.75% in patients who survive 10 years and beyond.
| > Intensity-Modulated Radiation Therapy In Head-And-Neck Cancer|| |
HNC is in close proximity to several critical structures such as the spinal cord, brainstem, parotid glands, optic apparatus (eyes, optic nerves, and chiasm), lacrimal glands, cochlea, and mandible. Radiation tolerance of adjoining critical organs at risk (OARs) is generally lesser than the dose required to control HNC, IMRT has the potential of generating highly conformal and concave dose distributions around complex target volumes with steep dose gradients which makes it ideally suited for HNC treatment. Although IMRT delivery is limited by availability in many countries and regions of the world, but where available IMRT is quickly superseding older treatment techniques for HNC despite hypothetical concerns about dose inhomogeneity and exposure of larger volumes of normal tissues to lower doses. Potential benefits associated with IMRT seem intuitive, Phase III data are now beginning to emerge and confirm that delivery of IMRT is associated with lower morbidity. Although data as regards to the development of radiation-induced malignancy with use of IMRT is still immature.
| > Xerostomia Reduction By Intensity-Modulated Radiation Therapy|| |
Radiation-induced xerostomia is most commonly reported late side effect of RT. Inadvertent damage to major salivary glands often results in severe reduction of salivary flow and altered salivary composition, leading to irreversible and distressing oral complaints. Salivary gland dysfunction often manifests as reduced salivary flow rates, reduction in saliva pH, changes in electrolyte and immunoglobulin saliva composition, and increased cariogenic mouth flora. While the exact mechanism of radiation-induced gland damage is unknown, it is hypothesized that radiation has direct cytotoxic effects on salivary tissue and causes indirect changes in vascular blood flow to the gland.
There is sufficient and robust evidence that parotid-sparing IMRT reduces dose to parotid glands, aids recovery of saliva flow, and reduces xerostomia.,,,,,,,, However, despite better salivary flow rates, improvement in patient-reported xerostomia scores is only modest. Grade 2 or higher xerostomia is still experienced by 30%–40% of patients.,,,,,,
The submandibular gland (SMG) is rich in mucin and is the main source of saliva at resting conditions. SMG accounts for almost 95% of salivary flow during a 24-h period. It has been reported that restricting the mean dose in one SMG to <39 Gy has improved salivary flow and correlated with favorable rates of patient- and observer-rated xerostomia. We hereby discuss potential methods to reduce dose to SMG, so as to further reduce the sensation of xerostomia experienced by patients.
Salivary gland transfer
In the year 2000, salivary gland transfer (SGT) was introduced as a novel method to prevent xerostomia by transferring one SMG to the submental region. SGT preserves SMG function and prevents the development of radiation-induced xerostomia. SGT can prevent xerostomia in as high as 83% of patients. Patients subjected to SGT have higher unstimulated (75% vs. 11%) and stimulated (86% vs. 8%) salivary flow rates as compared to patients without SGT. SGT appears to be highly effective in preventing the incidence of xerostomia in patients receiving RT for HNC.
Submandibular gland-sparing intensity-modulated radiation therapy
Alternative to SGT, SMG may be spared by IMRT. Although the cellular makeup of SMG and parotid gland is different, the radiosensitivity is comparable and restricting the mean dose in one SMG to <39 Gy improves salivary flow and correlated with favorable rates of patient- and observer-rated xerostomia.,, For HNC patients it is difficult to spare SMG, as it may sometimes directly abut the primary tumor or at other times lie within the lymph node region to be irradiated. Although technically demanding, it is possible to spare at least one SMG (when contra-lateral level 1 lymph node station is not to be irradiated). At present, there are no randomized trials evaluating clinical outcomes of SMG-sparing IMRT or comparing SGT with SMG-sparing IMRT, but several studies have evaluated the effectiveness of SMG-sparing IMRT.,,,, Data in these studies have been briefly summarized in [Table 1]. Preliminary results within these series suggest that sparing of contralateral SMG with IMRT is safe, feasible, decreases xerostomia, and does not increase chances of locoregional failure. In the largest study on SMG-sparing IMRT included 114 patients of oropharyngeal carcinoma out of which 67% received contralateral SMG IMRT. The SMG could be spared to a mean dose of 30.7G, and this resulted in a significant reduction of late Grade 2+ xerostomia (6% vs. 41% at 1 year, 3% vs. 36% at 2 years) when compared to nonSMGspared group.
|Table 1: Studies evaluating submandibular gland-sparing intensity-modulated radiation therapy|
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| > Posttreatment Risk Of Aspiration And Dysphagia|| |
Among the most profound effects of RT for HNC is the impact on ability to eat and drink. The introduction of combination chemo-RT and altered fractionation RT schedules for HNC have improved disease control at the cost of higher rates of treatment-induced toxicity. It is recognized that organ-preserving regimes do not necessarily result in functional swallowing preservation. The main late sequel after treatment intensification has been increasing rates and severity of long-term dysphagia. Severe swallowing disturbances lead to nutritional deficiency, weight loss, prolonged parenteral or gastric tube feeding, higher risk for aspiration, anxiety, and depression, and diminished health-related quality of life (HRQoL).,, In fact, swallowing dysfunction after curative conformal RT (CRT) has a strong negative impact on HRQoL, which is even more than xerostomia.
In normal swallowing, there is no aspiration and minimal residue, while a pathologic swallowing dysfunction is characterized by penetration (bolus entering laryngeal vestibule without passing vocal folds) or aspiration (bolus entering the subglottic region). Normally, pathologic swallowing is defined in terms of the amount and incidence of penetration and aspiration and is associated with an increased risk of aspiration pneumonia or airway obstruction.
Acute dysphagia starts and progressively increases during CRT, while late dysphagia and aspiration are usually observed months to years later. Acute dysphagia tends to resolve shortly after treatment; late swallowing disturbances are irreversible and often progressive in time. Swallowing function may be impaired due to a number of normal tissue changes, including edema, neuropathy, and fibrosis. Acute toxicities such as mucositis and edema commonly disrupt normal swallowing during treatment but improve substantially within months following treatment. In contrast, neuropathy and fibrosis of the oral, laryngeal, and pharyngeal musculature may develop and persist long after completion of the treatment. These late effects ultimately impair the range of motion of key swallowing structures and have been implicated as the primary mechanisms of long-term dysphagia in HNC survivors. Late dysphagia after CRT returns to normal in <10% of patients, one-third of the patients show a decrease in the severity of dysphagia, whereas in nearly half percent of patients severity of dysphagia remains unchanged, and it may worsen with the passage of time in 20% of cases. At a follow-up period of >5-year, as high as 66% of cases may require gastrostomy to prevent pneumonia or for nutritional supplementation.
Factors influencing late dysphagia and dysphagia and aspiration-related structures
The incidence of late dysphagia depends on treatment modality (RT alone vs. CRT), irradiated volume, RT dose, and fractionation, and overall treatment duration it also depends on tumor site and stage, patient age, pretreatment weight loss, pretreatment dysphagia, and smoking are among other factors affecting the rates of treatment-induced swallowing disturbances.,,, Clinical parameters independent associated with dysphagia, included T3–T4, bilateral neck irradiation, weight loss prior to radiation, oropharyngeal and nasopharyngeal tumors, accelerated RT, and concomitant chemoradiation. Based on these parameters, patients can be stratified into three risk groups with a rate of dysphagia of 5%, 24%, and 46% for low-risk, intermediate-risk, and high-risk category, respectively.
Sparing of dysphagia and aspiration-related structures by intensity-modulated radiation therapy from high-dose radiation gradient
Radiation-induced damage to anatomical structures that result in the development of dysphagia includes pharyngeal constrictor muscles (PCM), upper esophageal sphincter, cricopharyngeus muscle, cervical esophagus, glottis, supraglottic larynx, and base of tongue., Prominent studies evaluating dysphagia and dose–volume relationship of these adjoining critical structures have been briefly highlighted in [Table 2].,,,,,,,,,,,,,,,, Dose–volume parameters suggest that reducing the mean dose below 50 Gy and decreasing V50 of these structures may be helpful in reducing dysphagia and aspiration. After a dose of 55 Gy to dysphagia aspiration-related structures (DARS), there is possibly a steep dose–effect relationship, with an increase in the probability of dysphagia of 19% with every additional 10 Gy. The mean dose received by PCM appears to be the most important dosimetric predictor of late swallowing disturbances. There is worsened swallowing and aspiration in patients with mean doses to PCM of 61–64 Gy, and mean doses to the supraglottic larynx of 48–54 Gy as compared to mean dose of 52–55 Gy and 36–38 Gy, respectively, to these structures. As compared with 3D plans, standard IMRT reduces V50 of pharyngeal constrictors by 10%, and dysphagia optimized IMRT reduces these volumes further by an additional 10% on average.
|Table 2: Studies evaluating dysphagia and swallowing-sparing intensity-modulated radiation therapy|
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One of the seminal study prospectively aimed to reduce dysphagia with IMRT demonstrated that this technique is safe and achieves high tumor control rates (3-year disease-free and locoregional recurrence-free survivals 88% and 96%, respectively). At 1-year posttreatment, observer-rated dysphagia was absent or minimal in all patients except four. Results within the study suggested that long-term patient-reported, observer-rated, and objective measures of swallowing were only slightly worse than pretherapy measures, representing a potential improvement compared with previous studies.
Single-arm studies have shown that sparing of swallowing structures translate to better functional outcomes.,,,,, At present, no published randomized trial has addressed the impact of swallowing-sparing IMRT with standard IMRT. The ongoing DARS trial is the only phase III randomized trial comparing swallowing-sparing IMRT with standard IMRT. The primary endpoint of the trial is to evaluate the difference in mean MD Anderson Dysphagia Inventory composite score, measured at 12-month post IMRT.
Time and resources issues with submandibular gland sparing and dysphagia aspiration-related structures
Delivery of IMRT is demanding and labor intensive procedure. One of the most important issues of IMRT is correct and accurate delineation of target and normal adjoining OAR. Delineation of SMG and DARS adds further workload to the radiation oncologist. Delivery of swallowing-sparing IMRT is challenging in terms of achieving specified dose-volume constraints to SMG and DARS, while maintaining dose homogeneity and conformity to the target and other adjoining structures. Furthermore, during the treatment course, there could be discrepancies between planned and delivered dose to target and normal tissue due to tumor regression or patient's weight loss. This often takes added efforts and time, if the decision for replanning is taken to achieve desired results.
| > Impact Of Intensity-Modulated Radiation Therapy On Quality Of Life|| |
Patients diagnosed with cancer deal with various physical and psychosocial problems related to cancer and its treatment, including reduced physical fitness and function, reduced self-esteem, increased emotional distress and fatigue, all of which negatively affect the HRQoL. In addition to physical and psychosocial problems, patients with HNC are often confronted with oral dysfunction, dryness of mouth, swallowing, and speech problems.
Patient-reported outcomes are increasingly being used in clinical setting in addition to traditional outcome measures such as tumor control, overall survival, morbidity, and complications. There is evidence of a positive association between HRQoL and survival in cancer patients; patients with lower pretreatment HRQoL have reduced survival., A recently published study examined the association between pretreatment HRQoL and survival for 11 different cancers and found that for each cancer, the accuracy of survival increased by adding at least one HRQoL domain to clinical and demographic predictors such as age, performance status, and metastasis. For HNC, physical functioning and social functioning were independently predictive for survival. In HNC patients, HRQoL declines after treatment but recovers to baseline levels, generally within 12 months; however, xerostomia-related HRQoL deficits may remain long term. Combined chemo-RT shows a trend toward worse HRQoL compared with RT alone, and IMRT yields better HRQoL compared with conventional or 3D conformal RT.
IMRT in HNC is associated with improved quality of life (QoL) benefits, and there is statistically significant improvement with delivery of IMRT in several important QoL domains including swallowing, dry mouth, sticky saliva, social eating, and opening of the mouth at 3–12 months, although there is inconsistent improvement in global QoL with the use of IMRT. Vergeer et al. in a prospective nonrandomized large cohort of 241 patients treated with 3D-conventional RT or IMRT reported a significant difference in functional scores on the European Organisation for Research and Treatment of Cancer (EORTC)Quality of life (QLQ)-H&N35 questionnaire and QoL scores on EORTC QLQ-C30 questionnaire. In eight of the 12 functional subscales of the EORTC QLQ H and N35 (including dry mouth, sticky saliva, mouth opening, swallowing, and teeth problems), there was a statistically and clinically significant improvement in the IMRT group. In seven of the 15 QoL subscales of the EORTC QLQ-C30 (including global QoL score, role functioning, social functioning, fatigue, insomnia, and appetite loss), there was a statistically and clinically significant improvement in the IMRT group. However, other studies have failed to show improvement in global QoL. The PARSPORT trial did not find any significant improvement in global QOL with use of IMRT, although there was significant improvement in subscale scores for the dry mouth with IMRT. IMRT holds much promise as regard to sparing normal tissues, improving long-term salivary flow and reducing long-term functional deficits of RT; however, the early optimism that this would reflect an improvement in patient-reported QoL still remains unproven. The minimal impact that IMRT has had on patients' global QOL, thus far points out to further sparing of adjoining critical structures (e.g., SMGs, minor salivary glands in the oral cavity, and swallowing structures).
| > Impact Of Intensity-Modulated Radiation Therapy On Locoregional Control/Survival|| |
IMRT has quickly taken over as the standard practice for HNC; however, tight margins and the opportunity for geographic miss are possible drawbacks to IMRT. Data from prospective trials and multiple single-institution reports indicate that locoregional control and survival achieved with IMRT is at par to with treatment outcomes achieved with the use of nonIMRT/conventional RT techniques.,,,, A recently published meta-analysis also reported equivalent locoregional control and overall survival with the use of IMRT and nonIMRT techniques for HNC.
Improved survival outcome with intensity-modulated radiation therapy
Almost all series show that delivery of IMRT may not improve survival; however, there are very few studies that point have shown improved survival for HNC patients. A recently published phase III trial that enrolled nasopharyngeal carcinoma patients, showed significant improvement in survival with the delivery of IMRT (5-year overall survival rate 80% vs. 67% for 2D-RT). Similar results have been confirmed within the Surveillance, Epidemiology, and End Results database. Treatment with IMRT significantly improved the cause of specific survival (84% vs. 66%, P < 0.001) when compared to HNC patients treated with conventional RT. All subgroups of HNC patients treated with IMRT had better cause-specific survival (CSS) than those treated with non-IMRT. On multivariable survival analyses, patients treated with IMRT were associated with better CSS (hazard ratio 0.72, 95% confidence interval: 0.59–0.90).
| > Conclusions|| |
It is safe and feasible to spare SMG and “dysphagia- and aspiration-related” structures with IMRT. Delivery of swallowing-sparing IMRT translates to decrease the risk of posttreatment dysphagia and aspiration without increasing the risk of marginal recurrences. These findings now need to be validated in a multicenter prospective randomized trial setting. IMRT is associated with improved quality and has the potential to improve the global QoL. Delivery of IMRT is associated with improved survival at nasopharyngeal subsite.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Delaney G, Jacob S, Barton M. Estimation of an optimal external beam radiotherapy utilization rate for head and neck carcinoma. Cancer 2005;103:2216-27.
Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14.
Bucci MK, Bevan A, Roach M 3rd
. Advances in radiation therapy: Conventional to 3D, to IMRT, to 4D, and beyond. CA Cancer J Clin 2005;55:117-34.
Hall EJ, Wuu CS. Radiation-induced second cancers: The impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 2003;56:83-8.
Chambers MS, Garden AS, Kies MS, Martin JW. Radiation-induced xerostomia in patients with head and neck cancer: Pathogenesis, impact on quality of life, and management. Head Neck 2004;26:796-807.
Lee N, Xia P, Quivey JM, Sultanem K, Poon I, Akazawa C, et al.
Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: An update of the UCSF experience. Int J Radiat Oncol Biol Phys 2002;53:12-22.
Chao KS, Ozyigit G, Blanco AI, Thorstad WL, Deasy JO, Haughey BH, et al.
Intensity-modulated radiation therapy for oropharyngeal carcinoma: Impact of tumor volume. Int J Radiat Oncol Biol Phys 2004;59:43-50.
Pow EH, Kwong DL, McMillan AS, Wong MC, Sham JS, Leung LH, et al.
Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: Initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006;66:981-91.
Kam MK, Leung SF, Zee B, Chau RM, Suen JJ, Mo F, et al.
Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol 2007;25:4873-9.
Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, et al.
Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): A phase 3 multicentre randomised controlled trial. Lancet Oncol 2011;12:127-36.
Peng G, Wang T, Yang KY, Zhang S, Zhang T, Li Q, et al.
A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma. Radiother Oncol 2012;104:286-93.
Gupta T, Agarwal J, Jain S, Phurailatpam R, Kannan S, Ghosh-Laskar S, et al.
Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: A randomized controlled trial. Radiother Oncol 2012;104:343-8.
Marta GN, Silva V, de Andrade Carvalho H, de Arruda FF, Hanna SA, Gadia R, et al.
Intensity-modulated radiation therapy for head and neck cancer: Systematic review and meta-analysis. Radiother Oncol 2014;110:9-15.
Wang X, Eisbruch A. IMRT for head and neck cancer: Reducing xerostomia and dysphagia. J Radiat Res 2016;57 Suppl 1:i69-75.
Jha N, Seikaly H, McGaw T, Coulter L. Submandibular salivary gland transfer prevents radiation-induced xerostomia. Int J Radiat Oncol Biol Phys 2000;46:7-11.
Sood AJ, Fox NF, O'Connell BP, Lovelace TL, Nguyen SA, Sharma AK, et al.
Salivary gland transfer to prevent radiation-induced xerostomia: A systematic review and meta-analysis. Oral Oncol 2014;50:77-83.
Murdoch-Kinch CA, Kim HM, Vineberg KA, Ship JA, Eisbruch A. Dose-effect relationships for the submandibular salivary glands and implications for their sparing by intensity modulated radiotherapy. Int J Radiat Oncol Biol Phys 2008;72:373-82.
Little M, Schipper M, Feng FY, Vineberg K, Cornwall C, Murdoch-Kinch CA, et al.
Reducing xerostomia after chemo-IMRT for head-and-neck cancer: Beyond sparing the parotid glands. Int J Radiat Oncol Biol Phys 2012;83:1007-14.
Saarilahti K, Kouri M, Collan J, Kangasmäki A, Atula T, Joensuu H, et al.
Sparing of the submandibular glands by intensity modulated radiotherapy in the treatment of head and neck cancer. Radiother Oncol 2006;78:270-5.
Wang ZH, Yan C, Zhang ZY, Zhang CP, Hu HS, Tu WY, et al.
Impact of salivary gland dosimetry on post-IMRT recovery of saliva output and xerostomia grade for head-and-neck cancer patients treated with or without contralateral submandibular gland sparing: A longitudinal study. Int J Radiat Oncol Biol Phys 2011;81:1479-87.
Chajon E, Lafond C, Louvel G, Castelli J, Williaume D, Henry O, et al.
Salivary gland-sparing other than parotid-sparing in definitive head-and-neck intensity-modulated radiotherapy does not seem to jeopardize local control. Radiat Oncol 2013;8:132.
Gensheimer MF, Liao JJ, Garden AS, Laramore GE, Parvathaneni U. Submandibular gland-sparing radiation therapy for locally advanced oropharyngeal squamous cell carcinoma: Patterns of failure and xerostomia outcomes. Radiat Oncol 2014;9:255.
Nguyen NP, Moltz CC, Frank C, Vos P, Smith HJ, Karlsson U, et al.
Evolution of chronic dysphagia following treatment for head and neck cancer. Oral Oncol 2006;42:374-80.
Platteaux N, Dirix P, Dejaeger E, Nuyts S. Dysphagia in head and neck cancer patients treated with chemoradiotherapy. Dysphagia 2010;25:139-52.
Romesser PB, Romanyshyn JC, Schupak KD, Setton J, Riaz N, Wolden SL, et al.
Percutaneous endoscopic gastrostomy in oropharyngeal cancer patients treated with intensity-modulated radiotherapy with concurrent chemotherapy. Cancer 2012;118:6072-8.
Nguyen NP, Frank C, Moltz CC, Vos P, Smith HJ, Karlsson U, et al.
Impact of dysphagia on quality of life after treatment of head-and-neck cancer. Int J Radiat Oncol Biol Phys 2005;61:772-8.
Hutcheson KA, Lewin JS, Barringer DA, Lisec A, Gunn GB, Moore MW, et al.
Late dysphagia after radiotherapy-based treatment of head and neck cancer. Cancer 2012;118:5793-9.
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.
Caudell JJ, Schaner PE, Meredith RF, Locher JL, Nabell LM, Carroll WR, et al.
Factors associated with long-term dysphagia after definitive radiotherapy for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2009;73:410-5.
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.
Langendijk JA, Doornaert P, Rietveld DH, Verdonck-de Leeuw IM, Leemans CR, Slotman BJ. A predictive model for swallowing dysfunction after curative radiotherapy in head and neck cancer. Radiother Oncol 2009;90:189-95.
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.
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.
Eisbruch A, Lyden T, Bradford CR, Dawson LA, Haxer MJ, Miller AE, et al.
Objective assessment of swallowing dysfunction and aspiration after radiation concurrent with chemotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002;53:23-8.
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.
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.
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.
Teguh DN, Levendag PC, Sewnaik A, Hakkesteegt MM, Noever I, Voet P, et al.
Results of fiberoptic endoscopic evaluation of swallowing vs. radiation dose in the swallowing muscles after radiotherapy of cancer in the oropharynx. Radiother Oncol 2008;89:57-63.
Dirix P, Abbeel S, Vanstraelen B, Hermans R, Nuyts S. Dysphagia after chemoradiotherapy for head-and-neck squamous cell carcinoma: Dose-effect relationships for the swallowing structures. Int J Radiat Oncol Biol Phys 2009;75:385-92.
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.
Francis DO, Weymuller EA Jr., Parvathaneni U, Merati AL, Yueh B. Dysphagia, stricture, and pneumonia in head and neck cancer patients: Does treatment modality matter? Ann Otol Rhinol Laryngol 2010;119:391-7.
Christianen ME, Schilstra C, Beetz I, Muijs CT, Chouvalova O, Burlage FR, et al.
Predictive modelling for swallowing dysfunction after primary (chemo) radiation: Results of a prospective observational study. Radiother Oncol 2012;105:107-14.
Duprez F, Madani I, De Potter B, Boterberg T, De Neve W. Systematic review of dose – Volume correlates for structures related to late swallowing disturbances after radiotherapy for head and neck cancer. Dysphagia 2013;28:337-49.
Feng FY, Kim HM, Lyden TH, Haxer MJ, Worden FP, Feng M, et al.
Intensity-modulated chemoradiotherapy aiming to reduce dysphagia in patients with oropharyngeal cancer: Clinical and functional results. J Clin Oncol 2010;28:2732-8.
MD Anderson Head and Neck Cancer Symptom Working Group. Beyond mean pharyngeal constrictor dose for beam path toxicity in non-target swallowing muscles: Dose-volume correlates of chronic radiation-associated dysphagia (RAD) after oropharyngeal intensity modulated radiotherapy. Radiother Oncol 2016;118:304-14.
Starmer HM, Tippett D, Webster K, Quon H, Jones B, Hardy S, et al.
Swallowing outcomes in patients with oropharyngeal cancer undergoing organ-preservation treatment. Head Neck 2014;36:1392-7.
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.
Kumar R, Madanikia S, Starmer H, Yang W, Murano E, Alcorn S, et al.
Radiation dose to the floor of mouth muscles predicts swallowing complications following chemoradiation in oropharyngeal squamous cell carcinoma. Oral Oncol 2014;50:65-70.
Ursino S, Seccia V, Cocuzza P, Ferrazza P, Briganti T, Matteucci F, et al.
How does radiotherapy impact swallowing function in nasopharynx and oropharynx cancer? Short-term results of a prospective study. Acta Otorhinolaryngol Ital 2016;36:174-84.
Petkar I, Rooney K, Roe JW, Patterson JM, Bernstein D, Tyler JM, et al.
DARS: A phase III randomised multicentre study of dysphagia- optimised intensity- modulated radiotherapy (Do-IMRT) versus standard intensity- modulated radiotherapy (S-IMRT) in head and neck cancer. BMC Cancer 2016;16:770.
Quinten C, Coens C, Mauer M, Comte S, Sprangers MA, Cleeland C, et al.
Baseline quality of life as a prognostic indicator of survival: A meta-analysis of individual patient data from EORTC clinical trials. Lancet Oncol 2009;10:865-71.
Quinten C, Martinelli F, Coens C, Sprangers MA, Ringash J, Gotay C, et al.
A global analysis of multitrial data investigating quality of life and symptoms as prognostic factors for survival in different tumor sites. Cancer 2014;120:302-11.
Klein J, Livergant J, Ringash J. Health related quality of life in head and neck cancer treated with radiation therapy with or without chemotherapy: A systematic review. Oral Oncol 2014;50:254-62.
Vergeer MR, Doornaert PA, Rietveld DH, Leemans CR, Slotman BJ, Langendijk JA, et al.
Intensity-modulated radiotherapy reduces radiation-induced morbidity and improves health-related quality of life: Results of a nonrandomized prospective study using a standardized follow-up program. Int J Radiat Oncol Biol Phys 2009;74:1-8.
Beadle BM, Liao KP, Elting LS, Buchholz TA, Ang KK, Garden AS, et al
. Improved survival using intensity-modulated radiation therapy in head and neck cancers: A SEER-Medicare analysis. Cancer 2014: 120:702-10.
[Table 1], [Table 2]