Impact of Chemoradiation After Supra- or Infrahyoid Cancer on Aerodynamic, Subjective, and Objective Voice Assessments: A Multicenter Prospective Study

ARTICLE IN PRESS Impact of Chemoradiation After Supra- or Infrahyoid Cancer on Aerodynamic, Subjective, and Objective Voice Assessments: A Multicenter Prospective Study *,†,‡,§Jérôme R. Lechien, ‡Mohamad Khalife, *,†Kathy Huet, ‡Anne-Francoise Fourneau, †Véronique Delvaux, †Myriam Piccaluga, †,aBernard Harmegnies, and †,‡,§,aSven Saussez, *†Mons, ‡Baudour, and §Brussels, Belgium Summary: Objectives. The study aimed to investigate the impact of chemoradiotherapy (CRT) on speech and voice quality according to the anatomic localization of the head and neck cancer. Methods. Thirty-four patients treated by CRT for advanced suprahyoid (N = 17) or infrahyoid (N = 17) cancer were assessed for speech function, videolaryngostroboscopy, Voice Handicap Index, blinded Grade, Roughness, Breathiness, Asthenia, Strain, and Instability, acoustic measurements, and aerodynamic measurements. Quality of life was evaluated using the European Organization for Research and Treatment of Cancer Head and Neck 35 (EORTC QLQ-H&N35) questionnaire. Results. Patients treated for an infrahyoid tumor presented more severe values of Voice Handicap Index items, dysphonia, breathiness, asthenia, and some acoustic cues (Voice Turbulence Index, Soft Phonation Index, degree of unvoiced segments, and number of unvoiced segments) than patients treated for a suprahyoid tumor. The EORTC QLQ-H&N35 communication item was better in the suprahyoid patient group. Conclusions. Voice quality impairments associated with CRT are more severe in patients treated for advanced infrahyoid cancer, suggesting the need to develop specific posttherapy management of the dysphonia according to the tumor anatomical localization. Key Words: Chemoradiation–Head–Neck–Cancer–Voice.

INTRODUCTION Head and neck cancers and their treatments lead to a high risk of comorbidities, which negatively impact the quality of life of patients.1 Among the conservative treatments, concomitant chemoradiotherapy (CRT) is increasingly used and currently considered as a standard in patients with advanced head and neck squamous cell carcinomas.2 Indeed, CRT provides better results in terms of locoregional control, disease-free survival, and overall survival rate compared with alternative approaches, such as chemoradiotherapy induction followed by radiotherapy.3 Over the short, middle, and long terms, CRT affects swallowing, speech, and voice by acute and chronic toxicities to the tissues.4,5 To date, only a few studies have suggested that the development of these impairments depended on the anatomic localization of the primary tumor1,6 as a majority of studies have considered all anatomic sites as similarly responsible for these impairments.7 The ability to clearly distinguish some potential complications according to the anatomic localization could also have an impact on both the prevention and the management of these complications. Thus, we could imagine that patients treated for an infrahyoid cancer Accepted for publication April 17, 2017. a Contributed equally to this work and should be regarded as joint last authors. From the *Laboratory of Anatomy and Cell Biology, Faculty of Medicine, UMONS Research Institute for Health Sciences and Technology, University of Mons (UMons), Mons, Belgium; †Laboratory of Phonetics, Faculty of Psychology, Research Institute for Language Sciences and Technology, University of Mons (UMons), Mons, Belgium; ‡Department of Otorhinolaryngology and Head and Neck Surgery, EpiCURA Hospital, Baudour, Belgium; and the §Department of Otorhinolaryngology and Head and Neck Surgery, CHU SaintPierre, Brussels, Belgium. Address correspondence and reprint requests to Jérôme R. Lechien, Laboratory of Anatomy and Cell Biology, Faculty of Medicine, UMONS Research Institute for Health Sciences and Technology, University of Mons (UMons), Mons, Belgium. E-mail: Jerome.Lechien@ umons.ac.be Journal of Voice, Vol. ■■, No. ■■, pp. ■■-■■ 0892-1997 © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jvoice.2017.04.009

could substantially have more voice complication than those treated for a suprahyoid cancer who could have more speech complications. The aim of this cross-sectional study was to investigate the impact of CRT on the voice quality and speech of patients treated at least 9 months prior according to the anatomic localization of the primary tumor (infrahyoid vs suprahyoid). MATERIALS AND METHODS Subject characteristics From September 2013 to July 2016, we prospectively recruited at the otolaryngology departments of EpiCURA Baudour, Hornu, and Ath hospitals 34 patients who were recently treated for an advanced upper aerodigestive tract cancer using CRT (accepted study protocol ref. 2015/99-B707201524621). From the selected patients, 17 patients were treated for an infrahyoid cancer (laryngeal or hypopharyngeal) and 17 patients were treated for a suprahyoid cancer (oropharyngeal or oral cavity). The patients had undergone and finished CRT since at least 9 months. The patients were considered as cured after the CRT and they had no tracheotomy. The characteristics of the patient groups, including chemotherapy, radiotherapy, tumor features, anatomic groups and subgroups, and smoking, or alcohol consumption, are available in Table 1. Four patients with glottic (N = 1), medial pharyngeal wall (N = 1), and supraglottic cancers (N = 2) had an immobility of one vocal fold. Patients with tumor double localization were excluded. The groups were comparable in terms of sex ratio, age, body mass index (BMI), time since completing CRT, tobacco and alcohol use, and chronic obstructive pulmonary disease, tumor, and CRT features (tumor, node, metastasis [TNM] grade, drug, and intensity-modulated radiation schemes).

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TABLE 1. Patient Characteristics Clinical Features Sex Age BMI Time since the CRT end Tobacco history Tobacco consumption COPD Alcohol history Alcohol consumption Tumor localization Larynx Subglottic Glottic Supraglottic Hypopharynx Pyriform sinus Posterior pharyngeal wall Medial pharyngeal wall Oral Oral floor ± lateral tongue Lateral tongue Oropharynx Tongue basis Pharyngeal tonsil Posterior wall/soft palate TNM Missed T1N2 T2N0 T2N1 T2N2 T3N0 T3N1 T3N2 T4N0 T4N1 T4N2 T4N3 Grade Few differentiated Moderately differentiated Well differentiated Imprecise Chemotherapy CDDP Carboplatin Erbitux Imprecise IMRT 70 >70 <70 Imprecise

Units

Infrahyoid (N = 17)

Suprahyoid (N = 17)

Total (N = 34)

M/F Years kg/m2 Month PY Pd

13/4 60.13 ± 3.39 21.77 ± 1.80 27.29 ± 5.55 35.00 ± 13.29 0.07 ± 0.05 6 12.25 ± 3.90 0.29 ± 0.21

15/2 55.71 ± 2.53 21.74 ± 0.74 28.18 ± 3.98 33.79 ± 6.23 0.50 ± 0.19 6 12.71 ± 4.22 3.00 ± 1.25

28/6 58.41 21.98 27.82 38.67 1.05 12 12.87 1.53

–

20.59%

–

29.41%

–

7 0 1 6 10 7 1 2 –

11.76%

–

–

4 3 1 13 6 5 2

– – – – – – – – – – – –

0 0 1 0 4 4 0 4 0 0 4 0

2 1 0 1 4 1 0 4 1 0 3 0

– – – –

1 7 6 3

2 5 5 4

– – – –

14 1 1 1

15 1 0 1

Gy Gy Gy –

16 0 0 1

14 1 0 2

U/d U/d –

–

38.24%

Abbreviations: BMI, body mass index; CDDP, cis-diaminedichloroplatinum; COPD, chronic obstructive pulmonary disease; CRT, chemoradiotherapy; F, Female; Gy, Gray; IMRT, intensity-modulated radiation therapy; kg, kilogram; M, male; N, number; Pd, pack daily; PY, pack year; TNM, tumor, node, metastasis; U/d, unit daily.

ARTICLE IN PRESS Jérôme R. Lechien, et al

Impact of Chemoradiation After Supra- or Infrahyoid Cancer

Patients were excluded if they met the following criteria: neurologic disease affecting voice, upper respiratory tract infections within the last month, previous history of oncological head and neck surgery, laryngeal trauma, vocal cord paralysis or paresis, benign vocal fold lesions, active seasonal allergies, untreated thyroid disease, or chemical exposure causing laryngitis (N = 2). Patients with recurrence before the voice assessment were also excluded (N = 3). Only French speakers were included in the present study. Clinical evaluations, subjective voice assessments, and quality of life An experienced otolaryngologist examined patients using videolaryngostroboscopy (StrobeLED-CLL-S1, Olympus Corporation, Hamburg, Germany) to exclude recurrence and cofactors influencing voice quality during the usual follow-up consultation. The quality of life was assessed using the French version of the European Organization for Research and Treatment of Cancer Head and Neck 35 questionnaire (Fr-EORTC H&N35).8 Patients also completed the Voice Handicap Index (VHI), and an experienced otolaryngologist blinded to the time of the recording performed the perceptual voice quality evaluation on connected speech using the Grade, Roughness, Breathiness, Asthenia, Strain, and Instability (GRBASI) scale. Aerodynamic and acoustic measurements The aerodynamic measurements assessed in patients were maximum phonation time, phonatory quotient, the slow vital capacity, the forced expiratory volume in 1 second (FEV1), and the S/Z ratio. VC and FEV1 were measured using a calibrated spirometer. To measure acoustic parameters, the subjects were instructed to produce the vowel /a/ three times for a time corresponding to the maximal phonation time (MPT). The voice recordings were performed in a sound-treated room using a highquality microphone (Sony PCM-D50; New-York City, NY) placed at a distance of 30 cm from the patient’s mouth. The acoustic parameters were measured using the Multi-Dimensional Voice Therapy (MDVP(r)) software (KayPENTAX, Montvalle, NJ), and include fundamental frequency (F0), mean fundamental frequency, standard deviation of F0, fundamental frequency variation, absolute jitter, jitter percent, relative average perturbation, pitch perturbation quotient, smoothed pitch perturbation quotient, phonatory fundamental frequency range, shimmer, shimmer percent (shim), amplitude perturbation quotient, smoothed amplitude perturbation quotient, peak-to-peak amplitude variation, noise harmonic ratio (NHR), Voice Turbulence Index (VTI), and Soft Phonation Index (SPI). Regarding some previous studies highlighting some unusual acoustic phenomena occurring in irradiated patients,4 we also measured some parameters less frequently used but informative for voice breaks, tremor, and voiceless phenomena, that is, degree of voice break, number of voice break, degree of subharmonic components, number of subharmonic components, F0-Tremor Intensity Index, Amplitude Tremor Intensity Index, fundamental frequency tremor, amplitude frequency tremor, degree of unvoiced segments (DUV), and number of unvoiced segments (NUV). The measurement of the acoustic cues was

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made on the most stable time interval of 1 second defined by the exhibition of the lowest jitter percent, shimmer percent, and NHR values.9 A correlation analysis between subjective, aerodynamic, and acoustic measurements was conducted.

Speech and orofacial motricity Speech involves dynamic and complex movements of various structures of the vocal tract controlled by cranial nerves, including the lips, tongue, velum, and pharyngeal and jaw muscles. To assess speech function, a speech therapist and an otolaryngologist evaluated the orofacial motricity, including the pronunciation of various phonemes, with a standardized clinical evaluation developed in our hospital network (Figure 1).

Statistical analysis Statistical analysis was performed using the Statistical Package for the Social Sciences for Windows (SPSS version 22.0; IBM Corp., Armonk, NY). Patients with infrahyoid tumors were compared with those with suprahyoid tumors using the MannWhitney U test. Correlations between GRBASI, aerodynamic, and acoustic parameters were calculated in the entire cohort using Spearman’s correlation test. A level of significance of 0.05 was adopted.

RESULTS Clinical and subjective voice assessment Concerning the comparison of clinical and quality of life features between the two groups, only the communication item of the Fr-EORTC QLQ H&N35 was significantly better in the suprahyoid tumor group (16.67 ± 7.17) than in the infrahyoid tumor group (40.74 ± 14.82; Z = −3,02; P = 0.003). Regarding the subjective voice quality assessments, patients treated by CRT for an infrahyoid cancer presented higher scores for all items of the VHI, including VHI functional, VHI emotional, VHI physical, and VHI total score (Table 2). Moreover, the blinded perceptual voice quality assessment revealed that the infrahyoid patients had higher scores for grade of dysphonia, breathiness, and asthenia than the suprahyoid patients (Table 2). There was no statistical difference between the groups in terms of the scores on roughness, strain, and instability.

Aerodynamic and acoustic measurements The mean value of FEV1 for patients with treated infrahyoid tumors (1.73 ± 0.51) was significantly lower than that for patients with treated suprahyoid tumors (2.50 ± 0.24; Z = −2.08; P = 0.037). There was no significant difference between the groups in terms of the values of MPT, phonatory quotient, and the S/Z ratio. As described in Table 3, the patients treated for an infrahyoid tumor had significant pejorative values of DUV, NUV, VTI, and SPI than patients treated for a suprahyoid tumor. The other values of acoustic parameters did not report significant difference between the groups.

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FIGURE 1. Standardized speech and orofacial motricity questionnaire. For each item of the questionnaire, speech therapist assessed the realization of the task between 0 (any problem) and 3 (major problem inhibiting the realization of the task). TABLE 2. Subjective Voice Quality Assessments According to the Anatomic Localization Anatomic Localization Scales VHI VHIe VHIp VHIf Blinded GRBASI Grade Roughness Breathiness Asthenia Strain Instability

Infrahyoid

Suprahyoid

Z

P Value

52.33 ± 15.19 12.00 ± 5.86 21.67 ± 3.93 18.67 ± 5.90

24.00 ± 7.88 7.00 ± 2.55 6.75 ± 2.50 10.25 ± 3.50

−2.48 −2.40 −2.82 −2.64

0.013 0.016 0.005 0.008

1.60 ± 0.24 1.67 ± 0.29 1.40 ± 0.27 1.47 ± 0.26 1.20 ± 0.24 1.53 ± 0.17

0.93 ± 0.27 1.00 ± 0.28 0.57 ± 0.25 0.71 ± 0.27 0.86 ± 0.27 1.21 ± 0.24

−2.06 −1.66 −2.83 −2.10 −1.15 −1.07

0.040 0.098 0.022 0.035 0.250 0.286

The P values presented in this table were calculated using Mann-Whitney U test. Abbreviations: GRBASI, Grade, Roughness, Breathiness, Asthenia, Strain, Instability; VHIf, e, p, Voice Handicap Index functional, emotional, physic.

Speech and orofacial motricity Table 4 describes the percentage of patients presenting orofacial disorders per anatomic localization. In all scores, no significant difference between the two groups was observed according to the Mann-Whitney U test.

Correlation analysis We observed significant positive correlations between the mean scores for dysphonia (G), roughness (R), breathiness (B), asthenia (A), strain (S), and the values of absolute jitter, phonatory fundamental frequency range, fundamental frequency variation,

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Impact of Chemoradiation After Supra- or Infrahyoid Cancer

TABLE 3. Acoustic Measurements According to the Anatomic Localization Localization Acoustic Parameters Fundamental frequency F0 MF0 Fhi Flo F0 short-term perturbation cues Jita Jitt RAP PPQ sPPQ F0 midterm perturbation cues PFR STD vF0 Intensity short-term perturbation cues ShdB Shim APQ sAPQ Intensity midterm perturbation cues vAm Noise-related measurements NHR VTI SPI Voice break parameters DVB NVB Subharmonic cues DSH NSH Tremor measurements Fftr Fatr FTRI ATRI Voice irregularity cues DUV NUV

U

Infrahyoid

Suprahyoid

Z

P Value

Hz Hz Hz Hz

118.80 ± 7.61 118.36 ± 7.46 131.85 ± 11.18 109.06 ± 6.08

113.90 ± 4.83 113.55 ± 4.80 123.69 ± 6.68 106.61 ± 4.45

−0.64 −0.63 −0.09 −0.69

0.525 0.531 0.93 0.489

µs % % % %

237.87 ± 59.55 2.63 ± 0.63 1.51 ± 0.37 1.64 ± 0.41 1.84 ± 0.41

157.17 ± 33.82 1.72 ± 0.38 1.01 ± 0.23 1.03 ± 0.24 1.77 ± 0.46

−0.43 −0.57 −0.23 −0.57 −0.57

0.666 0.571 0.816 0.571 0.568

Hz %

3.72 ± 0.45 4.74 ± 1.30 3.47 ± 0.57

3.36 ± 0.54 3.11 ± 0.88 2.59 ± 0.62

−0.76 −1.56 −1.91

0.456 0.119 0.056

dB % % %

0.67 ± 0.07 7.56 ± 0.72 6.18 ± 0.59 9.07 ± 0.94

0.56 ± 0.06 6.32 ± 0.65 5.55 ± 0.45 8.91 ± 0.73

−1.58 −1.51 −0.68 −0.14

0.113 0.131 0.495 0.893

%

16.48 ± 1.18

14.21 ± 0.98

−1.13

0.257

0.19 ± 0.02 0.08 ± 0.01 10.93 ± 0.92

0.17 ± 0.01 0.05 ± 0.01 17.03 ± 1.48

−0.79 −2.48 −3.64

0.433 0.013 <0.001

%

0.02 ± 0.02 0.01 ± 0.01

0.43 ± 0.43 0.03 ± 0.03

−0.29 −0.29

0.294 0.294

%

0.47 ± 0.47 0.02 ± 0.02

0.39 ± 0.39 0.13 ± 0.13

−0.96 −0.93

0.958 0.931

Hz Hz % %

2.39 ± 0.34 3.08 ± 0.50 0.71 ± 0.20 4.46 ± 0.79

2.34 ± 0.34 3.51 ± 0.45 0.35 ± 0.06 4.49 ± 0.58

−0.94 −0.35 −0.32 −0.61

0.943 0.351 0.316 0.614

%

22.51 ± 5.11 7.42 ± 1.69

9.11 ± 3.14 2.92 ± 1.02

−2.24 −2.23

0.025 0.026

The P values presented in this table were calculated using Mann-Whitney U test. Abbreviations: APQ, amplitude perturbation quotient; ATRI, Amplitude Tremor Intensity Index; dB, decibel; DSH, degree of subharmonic components; DUV, degree of unvoiced segments; DVB, degree of voice break; F0, fundamental frequency; Fatr, amplitude frequency tremor; Fftr, fundamental frequency tremor; FTRI, F0-Tremor Intensity Index; Jita, absolute jitter; Jitt, jitter percent; Hz, Hertz; MF0, mean fundamental frequency; NHR, noise harmonic ratio; NSH, number of subharmonic components; NUV, number of unvoiced segments; NVB, number of voice break; PFR, phonatory fundamental frequency range; PPQ, pitch perturbation quotient; RAP, relative average perturbation; sAPQ, smoothed amplitude perturbation quotient; ShdB, shimmer; Shim, shimmer percent; sPPQ, smoothed pitch perturbation quotient; SPI, Soft Phonation Index; STD, standard deviation of F0; vAm, peak-to-peak amplitude variation; vF0, fundamental frequency variation; VTI, Voice Turbulence Index.

standard deviation of F0, shimmer, shimmer percent, VTI, DUV, and NUV (Table 5). DISCUSSION This cross-sectional study highlights a clear voice quality difference according to the anatomic localization of head and neck tumors treated by CRT. To date, only three trials have examined

the impact of cancer anatomic localization on voice quality and speech.6,10,11 First, concerning subjective voice quality, patients treated for an infrahyoid tumor reported higher VHI results (VHI total score, VHI emotional, VHI functional, and VHI physic) than patients treated for a suprahyoid tumor at an average of 2 years after CRT completion. In a randomized controlled trial, Kraaijenga et al

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TABLE 4. Percentage of Patients Presenting Orofacial Disorders Per Anatomic Localization Anatomic Localization Infrahyoid (%) Suprahyoid Breathing

0 (no problem) 1 (mild) 2 (moderate) 3 (severe) Face 0 (no problem) 1 (mild) 2 (moderate) 3 (severe) Reflexes 0 (no problem) 1 (mild) 2 (moderate) 3 (severe) Tongue 0 (no problem) 1 (mild) 2 (moderate) 3 (severe) Lips 0 (no problem) 1 (mild) 2 (moderate) 3 (severe) Soft palate 0 (no problem) 1 (mild) 2 (moderate) 3 (severe) Cheeks 0 (no problem) 1 (mild) 2 (moderate) 3 (severe) Jaw 0 (no problem) 1 (mild) 2 (moderate) 3 (severe)

90 0 5 5 95 5 0 0 80 5 10 5 52 38 10 0 67 33 0 0 90 10 0 0 76 19 0 5 66 24 10 0

90 10 0 0 90 10 0 0 81 14 5 0 52 38 5 5 71 19 10 0 85 10 5 0 71 24 0 5 62 19 19 0

reported similar findings at an average of 2 years after CRT. These authors showed that patients treated for infrahyoid cancer had significantly higher scores for each VHI component than patients treated for suprahyoid cancer, reflecting more severe

disabilities associated with CRT.10 The blinded perceptual voice quality analysis in the present study reported that patients treated using CRT for laryngeal or hypopharyngeal cancer exhibited stronger scores on grade of dysphonia, roughness, and asthenia than patients treated for suprahyoid cancer. To our knowledge, no previous studies have focused on the impact of CRT on perceptual voice quality according to the anatomic localization of the primitive tumor. In contrast, some trials have studied the perceptual voice quality of patients treated using CRT without distinguishing the tumor location.12–14 Broadly, these studies reported the significant impairment of perceptual voice quality in patients compared with controls at least 2 years after CRT, irrespective of the location of the cancer.12 In a cross-sectional trial focused on irradiated oropharyngeal cancer, Thomas et al reported that the scores for dysphonia, roughness, and asthenia were normal (0) or mild (1) in the majority of patient cases 2 years after CRT.15 A similar cross-sectional study focused on laryngeal tumors reported moderate and severe scores for dysphonia and roughness in a majority of patients 2 years after CRT treatment.16 These studies assessed the perceptual voice quality (GRBASI) in various ways (on a sustained vowel vs connected speech, blinded or not, etc) that, coupled with the lack of similarity to the present study, limit the comparison. From an objective standpoint, the present study reported better FEV1 values in suprahyoid patients who were no different from the infrahyoid patients according to the Chronic Obstructive Pulmonary disease state. Moreover, patients treated for an infrahyoid cancer had more pejorative values for parameters measuring unvoiced (DUV and NUV) and noise-related segments (VTI and SPI). These acoustic cues are unusual and still remain rarely used. DUV and NUV estimated relative evaluation of non-harmonic areas (where F0 cannot be detected) in the voice sample. In other words, high values of NUV and DUV indicate the presence of several unvoiced segment in the voice that may reflect the presence of breaks in the vibration cycle resulting from alterations of the biomechanical properties. VTI measures the relative energy level of high frequency noise and is correlated with the turbulence caused by incomplete or loose adduction of the vocal folds.17 SPI is an average ratio of the lower frequency harmonic energy (70–1600 Hz) to the higher frequency (1600–4500 Hz) harmonicenergy (compared with NHR and VTI). SPI values are

TABLE 5. Correlation Study Between Perceptual Voice Quality Assessments and Probant Acoustic Measurements Probant Acoustic Measurements Blinded Grade Roughness Breathiness Asthenia Strain Instability

Jita

PFR

STD

vF0

ShdB

Shim

VTI

SPI

DUV

NUV

0.004 0.003 0.001 0.004 0.031 0.082

0.003 0.005 0.009 0.018 0.011 0.228

0.007 0.049 0.028 0.101 0.087 0.228

<0.001 0.001 0.003 0.003 0.004 0.057

0.001 0.002 0.001 0.001 0.005 0.047

0.001 0.001 0.001 0.001 0.004 0.042

0.001 0.002 0.005 0.001 0.001 0.02

0.045 0.089 0.077 0.01 0.002 0.153

<0.001 <0.001 <0.001 0.001 <0.001 0.003

<0.001 <0.001 <0.001 0.001 <0.001 0.003

The P values presented in this table were calculated using Spearman’s correlation test. Abbreviations: DUV, degree of unvoiced segments; Jita, absolute jitter; NUV, number of unvoiced segments; PFR, phonatory fundamental frequency range; ShdB, shimmer; Shim, shimmer percent; SPI, Soft Phonation Index; STD, standard deviation of F0; vF0, fundamental frequency variation; VTI, Voice Turbulence Index.

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Impact of Chemoradiation After Supra- or Infrahyoid Cancer

also correlated with incomplete or looselyadducted vocal folds during phonation.17 The alteration of these two acoustic parameter families, together with the aerodynamic results obtained in the present study, may reflect a more severe vocal adduction disorder in patients treated using CRT for an infrahyoid cancer than in other patients. In a prospective trial, Kraaijenga et al observed better acoustic measurements along the post-CRT timeline in patients treated using CRT for a suprahyoid cancer compared with patients treated for an infrahyoid neoplasia.10 Interestingly, using a different acoustic analysis than the present study, these authors highlighted the presence of more voicedness in the signal of patients treated by CRT for an infrahyoid cancer, at baseline and over the long term after CRT, supporting more voice breaks in the speech signal, consistent with our acoustic observations.10 Unfortunately, these authors did not measure the VTI and the soft palate index of the software used. Our observations coupled with those of Kraaijenga et al could suggest the use of some acoustic parameters as voice outcomes, particularly unusual acoustic parameters, such as DUV, NUV, VTI, and SPI, in patients treated by CRT.10 However, we should be prudent in the comparison of our acoustic measurement results with those of previous studies. Indeed, as recently demonstrated for some voice disorders, the methodological approach used to measure acoustic cues (eg, software, interval time and place in the voice signal, voice samples, etc) may significantly impact the final result exhibiting the presence or absence of acoustic differences between two patient states.9,18 Speech involves vocal source and articulatory structures. The incidence of speech disorders and orofacial motricity after CRT for head and neck squamous cell carcinomas varies from 34% to 65%.15 In the present study, we did not observe significant differences between groups in terms of orofacial motricityinvolved speech function. Although seemingly surprising, these results are consistent with previous studies. Indeed, Thomas et al reported that patients with oropharyngeal cancer were characterized by good speech intelligibility as 60% of patients had a dysarthria rating of 0 (=normal intelligibility, no dysarthria) at an average of 22 months after the completion of CRT.15 Similarly, even if speech was assessed at only 6 months after CRT, limiting the comparison with the results of the present study, Woodson et al reported that patients with infrahyoid tumors had similar oral communication scores as patients with suprahyoid cancer.11 In addition, Kraaijenga et al did not observe a significant difference in the orofacial musculature, particularly mouth opening, according to the anatomic localization of the primitive tumor.10 In contrast, in a prospective trial of 34 patients treated by CRT, Jacobi et al observed better results in the fine articulation of various phonemes in patients treated for laryngeal, hypopharyngeal, or nasopharyngeal cancers than those treated for oral or oropharyngeal neoplasia 1 year after CRT.19 Despite epistemological differences, in a general sense, several studies have observed that patients with suprahyoid cancer treated by CRT had no more speech disorders than patients with infrahyoid cancer. These multiple observations do not support the more severe radiation damages on orofacial motricity (tongue, cheeks, and jaw muscles) when the radiation field is focused on the oral cavity.20 Thus, a potential bias, which could affect this observation, concerns the low proportion of oral cancers compared

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with oropharyngeal cancers. Indeed, in our study compared with those of Jacobi et al, Thomas et al, and Woodson et al, the proportion of oral cavity cancers is less than 30%, leading to an overrepresentation of oropharyngeal cancers in the suprahyoid group characterized by less destruction of some anterior muscles (cheeks, lips, and tongue body and apex) more involved in speech and intelligibility.11,15,20 During the analysis and interpretation of the speech results in our study, we gave particular attention to having comparable groups based on age, language or dialect, diseases, and dentures as articulatory precision, speech, and intelligibility may be influenced by these characteristics.21 The voice, speech, and swallow disorders associated with CRT are known to impair the quality of life of patients.1,10,22–25 Based on the utilization of Fr-EORTC QLQ H&N35, our results showed pejorative scores in both patient groups, with significantly more severe values of communication items in the infrahyoid group. These observations are consistent with our observed impairments of voice quality that reduced the effectiveness of patient communication. There are currently no studies on the quality of life differences between patients according to the anatomic site. In contrast, several studies have used EORTC QLQ H&N35 to assess the quality of life of CRT patients irrespective of tumor location.7 Overall, these studies showed comparable pejorative scores to ours, particularly in swallowing (including oral pain, senses alteration, social eating, and contact), speech dry mouth, and sticky saliva items in patients treated by CRT 1–2 years after the completion of CRT.26,27 Indeed, radiation to the wide field of the head and neck leads to voice quality impairment even in patients with suprahyoid cancer.28 The results of the present study suggest that the impairment is higher in irradiated laryngeal and hypopharyngeal cancers. From a pathophysiological standpoint, CRT affects both vocal fold biomechanical properties and resonance mechanisms, resulting in the altered response of these structures to the glottal airflow. Aerodynamic and acoustic measurements may help demonstrate and understand the pathophysiological mechanisms leading to voice quality deterioration. During the first 6–9 months, an acute residual edema associated with radiation persists and may predominantly explain the voice disorders, other functional defects, and the quality of life impairment.7,13,14,24 After this period, the edema is mainly resorbed, and fibrosis is initiated in the aerodigestive tract tissues. Thus, over the mid- and long-term periods after CRT, the voice quality impairments could be explained by several mechanisms, partially and indirectly explaining our acoustic results. First, both the chronic inflammatory reaction and fibrosis may change the biomolecular composition of the vocal folds with a loss of elastic fibers at the expense of collagen and other fibers associated with fibrosis.7 The first reaction is known to considerably affect the elasticity of the vocal fold margin.29,30 Second, fibrosis occurs at the submucosal and muscular levels, leading to muscular atrophy and dysfunction that limit vocal fold movements.30 These vocal features may explain the presence of the glottal incomplete closure and adduction limit indirectly detected in our acoustic and aerodynamic analyses. Third, the partial destruction of the mucosecretory glands of the laryngeal mucosa29 may disturb the lubrication of the vocal folds, impairing vibration movement. Finally, coupled with the

ARTICLE IN PRESS 8 fibrosis destructive process, we could imagine the occurrence of a dryness of the residual Reinke space that negatively impacts the vibration of the margin of the vocal folds. In a general way, the main limitations of the present study concern the low number of patients and the lack of prospective follow-up (pre- to posttreatment), but this study is a first step in the realization of a prospective study concerning the mid- and long-term impact of CRT on the occurrence of voice and speech disorders and the related quality of life according to the anatomic localization of tumors. Another limitation of our study concerns the difficulty of comparing our results with the current literature due to the lack of trials taking into consideration the anatomic localization of the irradiated tumor in the assessment of CRT on voice and speech functions. The epistemological differences between studies (populations and treatment characteristics, methodological approaches used to assess voice and speech, posttherapy evaluation period, etc) also limit the comparison of our results with the current literature. Thus, as recently demonstrated in other voice disorders, only one difference between studies can significantly impact the results and lead to biased conclusions.9,18 Moreover, when it is specified, some authors systematically prescribed speech therapy to reduce disagreements related to CRT effects. However, speech therapy programs vary between institutions, differently impacting voice and speech evolutions after CRT. Another bias that may impact our results and those of the other studies concerns the direct effect of the primitive tumor before CRT on the tissue destruction and, de facto, on the voice and speech function. To date, even if our two groups did not differ according to the TNM grading and the locoregional extension, it still remains difficult in a cross-sectional study to differentiate the impact of the primary tumor versus the secondary effects of the CRT on speech and voice function after the completion of the treatment. Some clinical characteristics such as vocal fold paresis due to the initial tumor invasion must be taken into consideration in future studies studying the impact of CRT on voice quality. The last parameter that may negatively bias the results concerns the extension of the radiation field to the lymph node areas. Indeed, it has been demonstrated that radiation doses greater than 43.5 Gy lead to the development of voice problems or chronic edema located far from the primary tumor site and, de facto, the main radiation site.31,32 This effect can therefore reduce the differences in voice problems secondary to CRT between patients with suprahyoid primary tumors and patients with infrahyoid primary tumors.10 Even if we did not directly assess this point, regarding the matching between groups concerning the TNM stage and the CRT features, we may postulate that the effect of radiation on lymph node areas is equilibrated in our study. These different epistemological and methodological biases must be considered in the realization of future studies to make these future trials comparable. CONCLUSION The results of the present study suggest that voice quality impairment is higher in patients with laryngeal and hypopharyngeal irradiated cancers than in patients with suprahyoid cancer, which negatively impacts the communication aspect of the quality of life of the patients. Considering the pathophysiological evidence, some

Journal of Voice, Vol. ■■, No. ■■, 2017

unusual acoustic parameters assessing noise-related measurements and unvoiced segments could be interesting for the vocal follow-up with patients during the posttherapy period. Future prospective studies are needed to confirm our observations, and to clarify the part of the CRT and the primary tumor invasion in the development of the voice disorders. These studies could support the need to have specific posttherapy management of voice disorders according to the anatomic localization of the cancer. Acknowledgment This research has been subsidized by the ARC N°AUWB-201212/17-UMONS convention from Communauté Française de Belgique. REFERENCES 1. Verdonck-de Leeuw IM, Buffart LM, Heymans MW, et al. The course of health-related quality of life in head and neck cancer patients treated with chemoradiation: a prospective cohort study. Radiother Oncol. 2014;110:422– 428. 2. Samant S, Kumar P, Wan J, et al. Concomitant radiation therapy and targeted cisplatin chemotherapy for the treatment of advanced pyriform sinus carcinoma: disease control and preservation of organ function. Head Neck. 1999;21:595–601. 3. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349:2091–2098. 4. 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. 2003;129:733–738. 5. Lazarus CL. Effects of chemoradiotherapy on voice and swallowing. Curr Opin Otolaryngol Head Neck Surg. 2009;17:172–178. 6. Cmelak AJ, Li S, Goldwasser MA, et al. Phase II trial of chemoradiation for organ preservation in resectable stage III or IV squamous cell carcinomas of the larynx or oropharynx: results of Eastern Cooperative Oncology Group Study E2399. J Clin Oncol. 2007;25:3971–3977. 7. Jacobi I, van der Molen L, Huiskens H, et al. Voice and speech outcomes of chemoradiation for advanced head and neck cancer: a systematic review. Eur Arch Otorhinolaryngol. 2010;267:1495–1505. 8. Allison PJ. Health-related quality of life comparisons in French and English-speaking populations. Community Dent Health. 2001;18:214–218. 9. Lechien JR, Delvaux V, Huet K, et al. Phonetic approaches of laryngopharyngeal reflux disease: a prospective study. J Voice. 2016;31:119, e11-119.e20. 10. Kraaijenga SA, Oskam IM, van Son RJ, et al. Assessment of voice, speech, and related quality of life in advanced head and neck cancer patients 10-years+ after chemoradiotherapy. Oral Oncol. 2016;55:24–30. 11. Woodson GE, Rosen CA, Murry T, et al. Assessing vocal function after chemoradiation for advanced laryngeal carcinoma. Arch Otolaryngol Head Neck Surg. 1996;122:858–864. 12. Hamdan AL, Geara F, Rameh C, et al. Vocal changes following radiotherapy to the head and neck for non-laryngeal tumors. Eur Arch Otorhinolaryngol. 2009;266:1435–1439. 13. Paleri V, Carding P, Chatterjee S, et al. Voice outcomes after concurrent chemoradiotherapy for advanced nonlaryngeal head and neck cancer: a prospective study. Head Neck. 2012;34:1747–1752. 14. van der Molen L, van Rossum MA, Jacobi I, et al. Pre- and posttreatment voice and speech outcomes in patients with advanced head and neck cancer treated with chemoradiotherapy: expert listeners’ and patient’s perception. J Voice. 2012;26:664, e25-33. 15. Thomas L, Jones TM, Tandon S, et al. Speech and voice outcomes in oropharyngeal cancer and evaluation of the University of Washington Quality of Life speech domain. Clin Otolaryngol. 2009;34:34–42. 16. Dubois MD, Crevier-Buchman L, Martin C, et al. Epidermoid carcinoma of piriform sinus after chemo-radiotherapy: acoustic evaluation and voice handicap. Rev Laryngol Otol Rhinol (Bord). 2006;127:299–304.

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Impact of Chemoradiation After Supra- or Infrahyoid Cancer

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