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Journal of Clinical Oncology, Vol 23, No 13 (May 1), 2005: pp. 3016-3023 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.07.419 Xerostomia Following Radiotherapy of the Head and Neck Affects Vocal FunctionFrom the Departments of Otolaryngology-Head and Neck Surgery and Radiation Oncology, Cancer Research Institute, Chungnam National University College of Medicine, Deajeon, Republic of Korea Address reprint requests to Jong-Lyel Roh, MD, PhD, Department of Otolaryngology-Head and Neck Surgery, Chungnam National University Hospital, 640 Daesa-Dong, Chung-Gu, Daejeon, 301-040, Republic of Korea, e-mail: rohjl{at}cnu.ac.kr
PURPOSE: To investigate whether xerostomia induced by wide-field radiotherapy (RT) of the head and neck affects vocal function. PATIENTS AND METHODS: We conducted a retrospective cohort study comparing 20 patients with early glottic cancer treated by limited RT of the larynx to 20 patients receiving wide-field RT of the primary tumor site and the lymphatic system of the entire head and neck, including the salivary glands. Salivary and vocal functions, as well as responses to questionnaires on xerostomia and quality of life were compared between groups. Twenty healthy volunteers matched for age, sex, and smoking status were included as controls. RESULTS: The wide-field RT patients showed high xerostomia-related symptom scores and significantly lower values of whole salivary flow rate compared to the limited RT and healthy patients (P < .001). Subjective vocal dysfunction and stroboscopic abnormality were observed in the wide-field RT group (P < .05), but acoustic or aerodynamic profiles showed no significant difference among groups (P > .05). Subjective and objective salivary gland hypofunction was significantly correlated to vocal dysfunction. CONCLUSION: Our results suggest that xerostomia following extensive RT of the head and neck can affect vocal function. In the treatment of head and neck malignancies, efforts to prevent post-RT xerostomia would be anticipated to contribute to the preservation of vocal function.
Voice is one of the most important human functions. Vocal quality is easily affected by alterations of physical, hormonal, emotional, and environmental conditions. Even subtle vocal changes can influence daily life or work, particularly those of professional voice users. The larynx is considered a voice generator that determines vocal function; therefore, laryngeal lesions impact vocal quality. Early stage glottic malignancy has been successfully treated by radiotherapy (RT) or voice-sparing surgery. A number of studies have investigated vocal quality after RT or tumor surgery. The vocal quality of patients treated by RT of the larynx has been described differently in several studies, although it generally remains good despite slight abnormalities in the voice profile.1-3 Post-RT evaluation of vocal function has been conducted in laryngeal cancer patients, but rarely in patients with nonlaryngeal malignancies of the head and neck. A recent report has suggested that radiation to the wide field of the head and neck results in aggravation of voice quality in patients with nonlaryngeal tumors of the head and neck.4 However, causative factors or mechanisms of vocal dysfunction by wide-field RT have not yet been elucidated clearly. RT is one of the chief treatment modalities for head and neck malignancies. RT combined with chemotherapy has been introduced for organ preservation in advanced-stage laryngeal or pharyngeal cancer.5-8 This has led to successful preservation of laryngeal function. However, high-dose irradiation of the head and neck is frequently accompanied by significant xerostomia, which causes deterioration in quality of life (QOL).9,10 Recent RT techniques of the head and neck have focused on preserving salivary gland function, but dry mouth remains one of the most common RT complications.11-13 Xerostomia has been extensively studied in the field of head and neck oncology; however, few studies have reported a correlation between xerostomia and vocal function. Post-RT vocal dysfunction may result from RT-induced xerostomia. In this study, we hypothesized that xerostomia following RT of the head and neck can affect vocal function. We first sought to determine whether wide-field RT of the head and neck, including the salivary glands, causes deterioration of salivary and vocal functions and QOL, compared to narrow-field RT of the larynx. The relationship between salivary and vocal function in patients treated by RT was also investigated.
Patient Eligibility and Study Design This was a retrospective cohort study. In total, 60 eligible patients were included; their demographic data are summarized in Table 1. Forty patients were treated by external beam RT between 1997 and 2003 at the Chungnam National University Hospital, and 20 volunteers were included as a non-RT control group. The RT patients were divided into two groups according to whether head and neck lymphatics were involved. Twenty patients with early glottic cancer had undergone limited or narrow-field RT of the larynx, and 20 patients had received wide-field RT of the primary tumor site and the entire head and neck lymphatic system, including the larynx and salivary glands. Patients with documented, pre-existing articulation impairment or laryngeal dysfunction caused by anomaly, trauma, infection, or surgery were excluded because of their possible influences on vocal function. No patients had previously undergone major head and neck surgery except for primary tumor biopsy. All patients were free of disease at the time of inclusion and were followed for longer than 12 months (mean, 32.7 months) after completion of RT. The 20 volunteers also had no history of RT or head and neck surgery. Potential confounding variables such as sex, age, and smoking status were controlled in all groups by including only male smokers over the age of 50. All patients included in this study were nonprofessional voice users.
All RT patients were retrospectively reviewed from medical records, with attention given to demographic data, tumor characteristics, and treatment profile. A radiation oncologist (M.J.C.)reviewed radiotherapy sheets and simulation films to determine RT volume, dosage, technique, and fractionation.14-16 The wide-field RT group was treated by external beam RT, and half of the patients underwent neoadjuvant chemotherapy of two or three cycles with cisplatin (100 mg/m2, intravenous drip infusion, day 1) and fluoruracil (1,000 mg/m2, 24-hour continuous intravenous infusion, days 1 to 5). Patients with a history of laryngeal or hypopharyngeal cancer were enrolled onto this study if they were free of tumors and significant laryngeal edema at time of the study.17,18 The presence of laryngeal edema could be easily ascertained because all patients had been followed with regular physical, endoscopic, and radiological examinations of the head and neck region after completion of treatment. Only patients who were followed-up for longer than 12 months after completion of RT were included to control for time-dependent RT effects.19-22 Patients satisfying inclusion and exclusion criteria were selected and invited to participate in this study by telephone. Two otolaryngologists (J.-L.R. and A.-Y.K.) examined all patients during a clinic visit, checked questionnaires about xerostomia and QOL, and evaluated the salivary and vocal functions of the patients. The groups were compared based on questionnaire score, whole salivary flow rate, and vocal function. Informed consent procedures were approved by the Chungnam National University Review Board for Clinical Research, and consent was obtained from all participants in the study.
Radiotherapy Technique Twenty patients at risk of regional metastasis were treated by wide-field external beam RT, which included the primary tumor site and the entire head and neck lymphatics. RT field area and target volume were determined by computed tomography (CT) scanning. The technique of parallel-opposed lateral fields covering the primary tumor and both sides of the neck was used. An anteroposterior supraclavicular field was used to cover the lower neck and supraclavicular lymph nodes. The treatment volume for the parallel-opposed lateral fields at the midplane central axis was irradiated with daily fractions of 1.8 Gy for 5 days per week. A supraclavicular field dose was given to a depth of 3 cm. A continuous course of RT was delivered to all patients. Bilateral parotid and submandibular gland sparing was not used for these patients. The total dose delivered to the parotid, submandibular/sublingual glands, and oral cavity was calculated for each patient. For this purpose, we assumed that the prescribed dose for the treatment volume had a homogenous isodose distribution and that there was no dose variation. We also assumed that the salivary glands and oral cavity received at least the same dose as the target volume, and therefore used this as the dose delivered to the salivary glands and oral cavity.23 Normal anatomic positions of the salivary glands and oral cavity were determined through the pretreatment CT images. We then checked whether the salivary glands and oral cavity were included in the treatment volume on the simulation films from each patient. Total dose delivered to the salivary glands and oral cavity was calculated by summation of the daily fractional doses in the treatment volume.14,24 The total radiation doses to the salivary glands and oral cavity were 50 to 75 Gy (mean, 61 Gy). The RT field included the larynx in all patients, and the mean total dose to the larynx was 64 Gy.
Measurement of Salivary Flow, Xerostomia, and QOL Questionnaires The oral cavity and pharynx of each patient were checked and graded according to the late radiation morbidity scoring scheme of the Radiation Therapy Oncology Group (RTOG) and the European Organisation for Research and Treatment of Cancer (EORTC).27 Each patient was asked to complete a patient-reported xerostomia questionnaire consisting of eight items that rated symptoms on an 11-point ordinal Likert scale from 0 to 10, with higher scores indicating greater dryness or discomfort due to dryness.13 Each item score was added, and the sum was transformed linearly to produce the final summary score ranging from 0 to 100, with higher scores representing greater levels of xerostomia. In addition, the patients were asked to complete the EORTC QOL questionnaire (head & neck module; QLQ-H&N35).28-30 The EORTC QLQ-H&N35 has 35 items: HN 1 to HN 30 scored on four-point Likert-type categoric scales ("not at all," "a little," "quite a bit," "very much") and HN 31 to HN 35 with a "no/yes" response format. The time frame of the module was "during the past week" and the format was similar to that of the core QLQ-C30.31 The scores were transformed into 0 to 100 scales, with a higher score implying a higher level of symptoms or problems. All above-mentioned questionnaires were translated into Korean without loss of original meaning and were understood by all participants.
Vocal Function Voice quality was blindly assessed by two laryngologists via the GRBAS (grade, rough, breathy, asthenic, strained) scale,34 acoustic and aerodynamic analysis, and stroboscopic examination. The voice of each patient was recorded during /a/ phonation at comfortable pitch and intensity levels using a microphone at a constant distance (10 cm) from the mouth and analyzed by Speech Studio (Laryngograph Ltd, London, UK). Acoustic parameters included fundamental frequency (Fo), jitter, shimmer, and harmonics-to-noise ratio. Aerodynamic data were obtained and analyzed using Aerophon II (Kay Elemetrics Co, Lincoln Park, NJ). Each patient was asked to sustain a vowel /a/ phonation for as long as possible and to repeat the vowel-consonant-vowel train /ipi/ at a comfortable intensity level. Maximal phonation time and average airflow were measured during sustained vowel /a/ production. The larynges of all patients were examined and images were digitally recorded using rigid and rhino-larynx stroboscopes into a laryngograph precision system (Laryngograph Ltd). Two laryngologists blindly evaluated the larynx according to a stroboscopic evaluation form that included parameters of vocal fold edge, amplitude, mucosal wave, phase symmetry, glottal closure, and supraglottic activity.34 We added two new items of vocal fold dryness and stickiness of laryngeal and hypopharyngeal secretions to the stroboscopic assessment sheet. Scores ranged from 0 to 3, with a higher score indicating a higher level of abnormality.
Statistical Analysis All measurements were obtained from patients who were more than 12 months post-RT (mean, 32.7 months) and compared to values from healthy patients. A Mann-Whitney U test showed no significant differences (P > .3) in subjective and objective measurements of xerostomia, QOL, and voice function among patients receiving wide-field RT with or without chemotherapy. In addition, laryngeal involvement of primary tumors had no significant effect (P > .5) on any of these measurements. Therefore, all patients in the wide-field RT group were included in this study regardless of chemotherapy or laryngeal involvement of primary tumors. The correlations among whole saliva flow rate, results of the xerostomia questionnaire, and variables with statistical significance were analyzed by Spearman's rho correlation coefficients (r). P < .05 was considered statistically significant.
Both unstimulated and stimulated whole salivary flow rates were lowest in the wide-field RT group (Table 2). The mean salivary flow rate of the limited RT group was approximately four-fold higher than that of the wide-field RT group, but did not differ from that of healthy patients (P > .5). Complete absence of salivary function was found in 20% of wide-field RT patients. An unstimulated salivary flow rate < 0.1 mL/min was found in 50% of wide-field RT patients, in 10% of the limited RT patients, and in none of the control group. Citric acid stimulation increased whole salivary flow rate to > 0.15 mL/min in the limited RT patients but not in the wide-field RT patients, who showed less sensitivity to salivary stimulation than the limited RT patients.
The late RT morbidity grades on the oral and pharyngeal mucous membrane were higher in the wide-field RT group (40% in grade 1, 45% in grade 2, and 15% in grade 3) than in the limited RT group (90% in grade 0, 10% in grade 1) or healthy patients (100% in grade 0). Xerostomia symptom scores were significantly higher in the wide-field RT group, indicating that the severity of patient perception was moderate to high given the scores. Sixty percent of patients in the wide-field RT group had a total score of > 50 in the xerostomia questionnaire. The senses, speech, social eating, and social contact scales of EORTC QLQ-H&N35 showed significantly higher values in the wide-field RT group than in two other groups (Table 3). Of individual items, dry mouth and sticky saliva showed significantly higher scores in the wide-field group than in the limited RT or non-RT group. The scores of "no/yes" items (hn31 to hn35) did not differ between groups. In the wide-field RT patients, dryness and saliva stickiness were the most significant symptoms with a moderate to severe degree, but the functional scales of senses, speech, social eating, and social contact showed mild to moderate grades in terms of their severity.
All scores of the VHI were high in the wide-field group, and functional and physical subscales and total scores showed a statistical significance (Table 4). A total VHI score of a moderate degree or more was found in one third of patients in the wide-field RT group who had higher values in functional and physical subscales representing a greater difficulty of verbal communication and more physical complaints due to vocal problems. GRBAS scales were slightly elevated in the wide-field RT group, although there were no significant differences between groups. Acoustic and aerodynamic functions seemed to be impaired in the wide-field RT group, although the differences were not significant. In the wide-field RT group, stroboscopic examination demonstrated a subjectively greater posterior gap, decreased mucosal wave, and phase asymmetry of the vocal fold, which also showed no statistical significance compared to the limited RT and healthy patients. However, the wide-field RT group showed a higher incidence and severity of supraglottic activity, vocal fold dryness, and stickiness of laryngeal and hypopharyngeal secretions compared to the other groups.
In the correlation analysis among whole salivary flow rate, results of the xerostomia questionnaire, and the above-mentioned variables that showed statistical significance, all variables were significantly correlated to both unstimulated and stimulated salivary flow rates and total xerostomia questionnaire scores (Table 5). In addition, xerostomia symptoms appeared to be highly correlated with whole salivary flow rate, which was considered to represent actual salivary gland function.
Subjective vocal dysfunction induced by wide-field RT of the head and neck was clearly observed in this study. Limited RT of the larynx, however, did not affect vocal function compared to sex, age, and smoking status–matched controls. Subjective and objective voice data showed no statistical differences between the limited RT group and healthy patients (P > .5). Several studies have shown that RT for early glottic cancer improves vocal function as a result of reduced tumor bulk and subsequent improvement in vocal fold vibration, although vocal function does not actually normalize completely.3,35 In our study, the objective data of vocal function in the limited RT group did not differ from those of healthy patients despite treatment of the larynx with RT. This may have resulted from successful preservation of salivary function and possible limitations of the objective evaluation. This can also be inferred from previous studies that have reported differently on this topic.1-3,35-37 In our study, voice quality seemed not to be affected by limited RT, but was significantly affected by wide-field RT. Subjective voice performance was worse in patients more than 1 year after wide-field RT of the head and neck compared with limited RT or healthy patients. However, objective data to assess voice function in wide-field RT patients did not significantly differ from those of limited RT patients. Acoustic and aerodynamic data were generally poor in the wide-field RT group, although none reached statistical significance. Interestingly, mean scores of all items in the wide-field RT group, including vocal function, showed no difference according to whether tumors involved the larynx before RT (P > .5). The scores seemed not to be affected by the site of primary tumors but mainly by the extent of the RT field. The addition of chemotherapy to RT had no significant effects on QOL, voice, or salivary function in the wide-field RT group (P > .3). This may have resulted from the small patient number, although chemotherapy combined with RT may have slightly increased vocal dysfunction from laryngeal edema, salivary hypofunction, or other causes compared to RT alone. This question warrants further examination with controlled studies of greater numbers of patients. In this study, moderate to severe salivary hypofunction and mild to moderate mucosal changes were clearly observed in patients treated by wide-field RT of the head and neck. The reduced salivary function seemed to result from radiation > 50 Gy to major and minor salivary glands. Subjective xerostomia was the most prominent symptom of all QOL-related questionnaires and was highly correlated to salivary gland dysfunction in wide-field RT patients.38 Patient-reported QOL questionnaires suggested that decreased salivary function resulted in speech and eating problems and subsequently reduced social contact or activity. This remains to be confirmed through objective tests in further clinical studies. The VHI was strongly correlated with subjective and objective salivary functions. All of the findings mentioned strongly suggest that xerostomia following wide-field RT of the head and neck can affect vocal function and speech performance. Radiation affects secretion of seromucous glands widely distributed in the upper aerodigestive tract as well as major salivary glands. In our study, this was confirmed by stroboscopic examination, which showed that vocal fold dryness and stickiness of secretions increased in the wide-field RT group. Hydration level has been postulated to affect vocal function and phonatory effort by changes in the viscosity of vocal fold tissue.39-41 We showed that the changes in the viscosity of laryngeal secretions by radiation may affect vocal function, although direct measures of tissue viscosity, except by stroboscopy, are lacking. Vocal fold viscosity seemed to be affected by functional losses of whole seromucous glands in the upper aerodigestive tract, including major salivary glands, during extensive RT of the head and neck. This may be inferred from the fact that xerostomia symptoms or secretion-related stroboscopic findings were prominently observed in wide-field RT patients. Radiation is associated with soft tissue changes such as mucosal atrophy, telangiectasia, edema, fibrosis, and effects on lymphatic drainage and microcirculation.42-44 This may affect the biomechanical properties of vocal folds, extralaryngeal muscles, and resonance characteristics of the upper airway, leading to changes in acoustic and aerodynamic properties.4,45 However, we found that the objective voice profile was less affected by wide-field RT than the subjective VHI was. In this study, impairment of subjective vocal function and speech performance in patients receiving wide-field RT of the head and neck tended to be mild to moderate, although intelligible communication could be achieved by most patients. Results from VHI and EORTC-QLQ showed that one third of patients in the wide-field RT group experienced communication problems and physical complaints of a moderate or more severe degree due to vocal problems. The subjective voice and speech dysfunctions seemed to result from xerostomia, which can be inferred from the significant correlation between subjective and objective salivary hypofunction and scores of the VHI and EORTC QLQ-H&N35 (Table 5). Despite success of laryngeal preservation in the treatment of advanced head and neck cancer, most survivors receiving chemoradiotherapy suffered from voice and swallowing difficulties of a mild to moderate degree, which probably resulted in poor QOL status.46-48 The importance of our study is that it is the first to show that post-RT xerostomia does affect voice function. We have suggested that vocal function can be affected by xerostomia following wide-field RT. In fact, because voice is multidimensional, many factors can affect vocal function. Therefore, we acknowledge that only one causative factor is insufficient to explain vocal dysfunction in patients treated with wide-field RT of the head and neck. However, our data imply that xerostomia can in part contribute to poor vocal function in patients receiving extensive RT of the head and neck. This is the first study to investigate the correlation between xerostomia and vocal dysfunction following RT of the head and neck. In the treatment of head and neck malignancies, efforts to prevent post-RT xerostomia would be anticipated to contribute to the preservation of vocal function.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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41. Fisher KV, Ligon J, Sobecks JL, et al: Phonatory effects of body fluid removal. J Speech Lang Hear Res 44:354-367, 2001 42. Nomayr A, Lell M, Sweeney R, et al: MRI appearance of radiation-induced changes of normal cervical tissues. Eur Radiol 11:1807-1817, 2001[CrossRef][Medline] 43. Rabin BM, Meyer JR, Berlin JW, et al: Radiation-induced changes in the central nervous system and head and neck. Radiographics 16:1055-1072, 1996[Abstract] 44. Baker DG, Krochak RJ: The response of the microvascular system to radiation: A review. Cancer Invest 7:287-294, 1989[Medline] 45. Fung K, Yoo J, Leeper HA, et al: Effects of head and neck radiation therapy on vocal function. J Otolaryngol 30:133-139, 2001[Medline]
46. Carrara-de Angelis E, Feher O, Barros AP, et al: Voice and swallowing in patients enrolled in a larynx preservation trial. Arch Otolaryngol Head Neck Surg 129:733-738, 2003 47. Meleca RJ, Dworkin JP, Kewson DT, et al: Functional outcomes following nonsurgical treatment for advanced-stage laryngeal carcinoma. Laryngoscope 113:720-728, 2003[CrossRef][Medline]
48. Hanna E, Sherman A, Cash D, et al: Quality of life for patients following total laryngectomy vs chemoradiation for laryngeal preservation. Arch Otolaryngol Head Neck Surg 130:875-879, 2004 Submitted November 29, 2004; accepted February 2, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. 
