10.14639/0392-100X-N0977
Objective. This study evaluated the effect of voice intervention in patients who received chemoradiation to the neck for non-laryngeal head and neck malignancies. Methods. Twenty individuals with non-laryngeal malignancies of the head and neck who received chemoradiation were divided by block randomisation into an intervention group that received voice rehabilitation and a control group without rehabilitation. All patients underwent acoustic analysis, perceptual and subjective analysis of voice before the commencement of chemoradiotherapy and at 1, 3 and 6 months after chemoradiotherapy.Results. In both groups, all parameters were significantly altered at one month followup except for fundamental frequency (females in control group and males in intervention group). In the intervention group, all parameters returned to pretreatment levels (no statistical differences) at 6 months. In the control group, all except for a few subjective parameters (grade, breathiness and asthenia) remained significantly altered at 6 months compared to the levels before radiotherapy.Conclusions. In non-laryngeal head and neck malignancies, voice rehabilitation offered at 1 month after treatment ameliorates chemoradiation-induced dysphonia within 6 months.
application/xml
1827-675X
977
en
M. Panduranga Kamath
https://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
dysphonia
Effect of vocal rehabilitation after chemoradiation for non-laryngeal head and neck cancers
Text.Serial.Journal
https://www.actaitalica.it/
41
Head and neck
2021-05-14
2020-07-11
2021-05-17
2021-05-17
131-141
1
M. Panduranga Kamath
2021/05/14
10.14639/0392-100X-N0977
131
Department of Otorhinolaryngology and Head and Neck Surgery, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India
1827-675X
dysphonia
141
Effect of vocal rehabilitation after chemoradiation for non-laryngeal head and neck cancers
https://www.actaitalica.it/article/download/977/575
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:131-141; doi: 10.14639/0392-100X-N0977




Head and neck


Effect of vocal rehabilitation after chemoradiation
for non-laryngeal head and neck cancers
Gli effetti della riabilitazione vocale dopo chemioradioterapia per i tumori testa e collo
non laringei
Athulya Sreenivas1, Suja Sreedharan1, Manisha Narayan1, Radish Kumar Balasubramanium2, PU Prakash Saxena3,
Sourjya Banerjee3, Deviprasad Dosamane1, Vijendra Shenoy1, M. Panduranga Kamath1
1
 Department of Otorhinolaryngology and Head and Neck Surgery, Kasturba Medical College, Mangalore, Manipal Academy of
Higher Education, Manipal, Karnataka, India; 2 Department of Audiology & Speech and Language Pathology, Kasturba Medical
College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India; 3 Department of Radiation Oncology,
Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India


SUMMARY
Objective. This study evaluated the effect of voice intervention in patients who received
chemoradiation to the neck for non-laryngeal head and neck malignancies.
Methods. Twenty individuals with non-laryngeal malignancies of the head and neck who
received chemoradiation were divided by block randomisation into an intervention group
that received voice rehabilitation and a control group without rehabilitation. All patients
underwent acoustic analysis, perceptual and subjective analysis of voice before the com-
mencement of chemoradiotherapy and at 1, 3 and 6 months after chemoradiotherapy.
Results. In both groups, all parameters were significantly altered at one month follow-
up except for fundamental frequency (females in control group and males in intervention           Received: July 11, 2020
group). In the intervention group, all parameters returned to pretreatment levels (no statisti-   Accepted: October 5, 2020
cal differences) at 6 months. In the control group, all except for a few subjective parameters
(grade, breathiness and asthenia) remained significantly altered at 6 months compared to          Correspondence
                                                                                                  Suja Sreedharan
the levels before radiotherapy.
                                                                                                  Department of ENT, Kasturba Medical College
Conclusions. In non-laryngeal head and neck malignancies, voice rehabilitation offered at         Hospitals, Attavar, Mangalore, Karnataka PIN
1 month after treatment ameliorates chemoradiation-induced dysphonia within 6 months.             575001, India
KEY WORDS: chemoradiation, non-laryngeal head and neck cancer, voice handicap index,              E-mail: sujasreedharan@yahoo.com
dysphonia
                                                                                                  Funding
                                                                                                  None.
RIASSUNTO
Obiettivo. Questo studio mira a valutare l’effetto della riabilitazione vocale in pazienti        Conflict of interest
sottoposti a chemiradioterapia per tumori maligni della testa e del collo non laringei.           The Authors declare no conflict of interest.
Metodi. Venti individui con neoplasie non laringee della testa e del collo che hanno effet-
tuato trattamento chemioradioterapico sono stati divisi per randomizzazione in due gruppi:          How to cite this article: Sreenivas A, Sreed-
un gruppo ha ricevuto la riabilitazione vocale e un gruppo di controllo senza riabilitazio-         haran S, Narayan M, et al. Effect of vocal
ne. Tutti i pazienti sono stati sottoposti ad analisi acustica, analisi percettiva e soggettiva     rehabilitation after chemoradiation for non-
della voce prima dell’inizio della chemio radioterapia e a tre e sei mesi dopo la chemio            laryngeal head and neck cancers. Acta Otorhi-
radioterapia.                                                                                       nolaryngol Ital 2021;41:131-141. https://doi.
Risultati. In entrambi i gruppi, tutti i parametri sono stati alterati in modo significativo a      org/10.14639/0392-100X-N0977
un mese di follow-up ad eccezione della frequenza fondamentale (femmine nel gruppo di
controllo e maschi nel gruppo di intervento). Nel gruppo sottoposto a riabilitazione, tutti i     © Società Italiana di Otorinolaringoiatria
                                                                                                  e Chirurgia Cervico-Facciale
parametri sono tornati ai livelli di pretrattamento (nessuna differenza statistica) a 6 mesi di
follow-up. Nel gruppo di controllo, tutti tranne alcuni parametri soggettivi (grado, respiro
                                                                                                                 OPEN ACCESS
affannoso e astenia) sono rimasti significativamente alterati a 6 mesi, rispetto ai livelli
precedenti alla radioterapia.                                                                     This is an open access article distributed in accordance with
                                                                                                  the CC-BY-NC-ND (Creative Commons Attribution-Non-
Conclusioni. Nei tumori maligni della testa e del collo non laringei, la riabilitazione voca-     Commercial-NoDerivatives 4.0 International) license. The
le offerta un mese dopo il trattamento migliora la disfonia entro sei mesi.                       article can be used by giving appropriate credit and mentio-
                                                                                                  ning the license, but only for non-commercial purposes and
PAROLE CHIAVE: chemioradioterapia, cancro della testa e del collo non laringeo, indice            only in the original version. For further information: https://
di handicap vocale, disfonia                                                                      creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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A. Sreenivas et al.




Introduction                                                     the study only if the voice was deemed normal by percep-
                                                                 tual analysis.
Head and neck cancer is the most common malignancy
                                                                 A total of 32 patients met inclusion criteria. The study sub-
in India among males and fifth most common among fe-
                                                                 jects were divided into two groups by block randomisation
males 1. Surgery, along with radiotherapy and chemothera-
                                                                 using the lottery method: one group received voice therapy
py, are the three modalities employed for treatment of head
                                                                 (intervention group) and the other did not (control group).
and neck malignancies.
                                                                 Of the 32 patients, 7 were lost to follow-up and 5 died dur-
In patients with head and neck malignancies, the larynx is
                                                                 ing the study period. Of the remainder, three month follow-
frequently exposed to radiation, either for treatment of the
                                                                 up was available for 20 patients and 6 month follow-up for
primary tumour (in the case of laryngeal malignancy) or
                                                                 15 patients. At 3 months, the intervention group (Group I)
treatment of the neck fields in case of other malignancies.
                                                                 consisted of 9 patients, and the control group (Group II)
Inclusion of larynx in the radiation field reduces voice qual-
                                                                 consisted of 11 patients, divided by block randomisation.
ity, and patients complain of increased vocal effort, breathi-
                                                                 Six months post-radiotherapy, Group I consisted of 7 pa-
ness and hoarseness 2. These effects are due to impaired
                                                                 tients and Group II consisted of 8 patients.
vocal fold vibration, incomplete glottic closure, insufficient
                                                                 Among the 9 patients in the intervention group, 5 patients
lubrication/dryness of the laryngeal mucosa, muscle atro-
                                                                 (55.6%) received a total dose of 66 Gy and 4 patients
phy, fibrosis, hyperaemia and/or erythema caused by radia-
                                                                 (44.4%) received 70 Gy. Nine patents in the control group
tion 2. Reduced voice quality effects daily activities of the
                                                                 received 70 Gy, while 1 patient each received 52 Gy and
patient. This can be associated with severe functional and
                                                                 60 Gy. The “mean dose to larynx” in the control group was
psychosocial problems and reduced quality of life 3,4.
                                                                 found 71.79 Gy and in the intervention group was 71.01
The combination of chemotherapy and radiotherapy, ei-
                                                                 Gy.
ther in the adjuvant setting or concurrent setting, is be-
                                                                 All patients received chemotherapy during treatment with
lieved to enhance good locoregional control and survival
                                                                 platinum based drugs (either cisplatin or carboplatin).
outcomes 5. However, these outcomes are associated with
                                                                 Among the 9 patients in the intervention group, 2 patients
enhanced acute and long term toxicity 6, in addition to the
effects of radiation therapy.                                    received carboplatin, 6 patients received cisplatin and 1
Many studies have noted the deleterious effects of radiation     patient received cisplatin + nimotuzumab. In the control
or concurrent chemoradiation on both diseased 7,8 and un-        group, 4 patients received carboplatin, 2 patients received
diseased larynxes 6,9,10; however, the effects of voice reha-    cisplatin, 2 patients initially received cisplatin, but it was
bilitation on patients undergoing chemoradiation have only       later changed to carboplatin (due to nephrotoxicity), 2 pa-
been evaluated in laryngeal malignancies 7,8,11. Our study       tients received cetuximab and 1 patient received gefitinib
attempts to evaluate the effects of vocal rehabilitation in a    (250 mg daily). Cisplatin dose was calculated at 100 mg/m2
group of patients who underwent chemoradiation for non-          for 3 weekly cycles (on day 1, 22 and 43 of radiotherapy)
laryngeal malignancies.                                          or 40 mg/m2 for weekly cycles depending on the tolerance
                                                                 of the patient. Carboplatin dose was calculated using Cal-
                                                                 vert’s formula to attain an AUC (area under concentration)
Materials and methods                                            time curve of 1.5-2.
Patients with head and neck cancer treated with chemora-         In all cases, thorough history and detailed examination with
diation were subjected to a time-bound randomised con-           regards to age, sex, substance abuse, site of malignancy and
trolled study carried out over 2 years, between August 2016      T and N staging were recorded in a proforma.
and July 2018, in the tertiary hospitals of Kasturba Medical     The diagnosis was confirmed by biopsy and imaging. All
College, Mangalore, India.                                       patients underwent chemoradiation with or without surgery
The patients included were those diagnosed with malignan-        as per our institutional protocol. Anonymity was assured
cies of the head and neck (proven by biopsy and imaging)         and patients were given a patient information sheet. Writ-
with no involvement of the larynx or hypopharynx. All pa-        ten informed consent was received from each patient. The
tients underwent chemoradiation with or without surgery          study was approved by the Institutional Ethics Committee
as per our institutional protocol. Patients with laryngeal       Board with the reference number: IEC KMC MLR 08-
malignancy, end-stage cancer in palliation, and/or history       16/175.
of laryngotracheal trauma, laryngeal or thyroid surgery, or      All patients underwent acoustic analysis, perceptual analy-
neurological or neuromuscular disorders were excluded            sis and subjective analysis before commencement of chem-
from the study. At recruitment, voice was assessed by a          oradiotherapy and at 1 month, 3 months and 6 months after
speech language pathologist and patients were enrolled in        chemoradiation. For the intervention group, voice therapy



132
                                                                                                        Voice post chemoradiation




was initiated after the 1-month follow up. The speech lan-      Intervention
guage pathologist performing the voice analysis was blind-      Voice therapy was started at the 1 month follow up. It was
ed to the randomisation. Voice recordings of patients were      tailor made according to the needs of the patient as assessed
maintained separately until the end of the study period and     by the speech language pathologist. Basic exercises like re-
coalesced into the proforma before statistical analysis.        laxation (circumlaryngeal manual voice therapy, yawn sigh
                                                                phonation, and chewing), posture, breathing and physiologic
Acoustic measures                                               approaches (resonant voice therapy) were taught. Appropri-
Acoustical measures reflect the status of vocal function, and   ate and relevant vocal hygiene was taught which includes hy-
do not relate specifically to certain voice disorders because   dration, reflux precautions and compliance with prescribed
the biomechanical changes resulting in acoustical differences   medication regimen. First, two sessions were dedicated to
can be induced by various lesions and dysfunctions 12.          vocal hygiene, breathing and relaxation exercises and later
The Computerized Speech Lab (CSL) (Model 4150, Kay              sessions focused on resonant voice therapy. The frequency
Elemetrics Corp., Lincoln Park, NJ, USA) was used to ana-       of exercises (two times/day till the next follow up visit) to
lyse the acoustic characteristics of voice. The participants    be practiced at home were maintained uniform for all the
were asked to produce a sustained phonation of vowel /a/        participants. These eclectic approaches were adopted as it
for as long as possible at their comfortable pitch and loud-    was the protocol followed at the voice clinic in our institu-
ness. The instructions were repeated when required. A sen-      tion. Patients were guided to modify the amount and type of
sitive dynamic microphone was used to record voice sam-         voice use, and were encouraged to practice the same at their
ples from participants into the MDVP advanced module of         residence. All patients were monitored by the same clinician
the CSL software. Three recordings of phonation of /a/ was      throughout the study period.
recorded. The middle four-second recorded sample was
analysed using the CSL software. The parameters analysed        Statistical analysis
were fundamental frequency Fo,, jitter % (Jitt), shimmer %      All values were tabulated using a Microsoft Excel work-
(Shim), noise to harmonic ratio (NHR) and soft phonation        sheet. Analysis was done using frequency, percentage, chi-
index (SPI). The average of the three recorded parameters       square test, Fisher’s exact test, Mann-Whitney’s U test and
were considered for analysis.                                   descriptive statistics to calculate all measures with the use
                                                                of a statistical package (SPSS version 17.0). The post hoc
Perceptual measures                                             analysis (multiple comparisons) was done by adjusting p-
Perceptual measurement of voice was carried out using           value using Bonferroni’s correction. A p-value less than
GRBAS scoring 13, where a running speech sample on a            0.05 was considered significant, and a p-value less than
particular topic ‘About your problem’ was recorded for a        0.01 was considered highly significant.
minimum of one-minute duration using the sound recorder.
This particular scale was chosen as it is easier to use, less
                                                                Results
time consuming and has good psychometric properties 14.
The recorded samples were perceptually rated by two expe-       The study started with 32 patients randomised into the study
rienced speech pathologists in the field of voice disorders.    and intervention groups. However, by 3 months follow-up
The duration of all samples ranged from 62-73 seconds.          there were only 20 patients in the study. The clinical de-
Both speech pathologists rated the voice characteristics in     tails of the 20 patients considered for the study are outlined
both the group of participants. The inter-rater and intra-      in Table I. When variables were compared between the 2
rater reliability for the perceptual analysis recordings were   groups, gender (p value 0.028), smoking (p value 0.008),
between 89% and 96% based on kappa coefficient.                 and alcohol (p value 0.25) were significantly different in
                                                                the two groups. There was no difference in age, T and N
Quality-of-life measures                                        staging, site of malignancy or surgery to the primary or
Voice related quality of life measures was assessed using       neck between the two groups.
the Voice Handicap Index (VHI) - Kannada (local lan-
guage) questionnaire consisting of 30 questions 15. The par-    Acoustic analysis
ticipants responded to each question on a five point scale      The values of acoustic parameters of patients in the control
based on the severity of their problem. The clinician asks      and intervention groups are shown in Table II.
the individuals to rate the severity of their voice disorder
as per the grades between 0-4; 0 - never, 1 - almost never,     Comparison within the control group (Table III)
2 - sometimes, 3 - almost always, 4 - always 16.                One month after chemoradiotherapy, there was significant al-



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A. Sreenivas et al.




Table I. Clinical parameters of patients in control and intervention groups   teration in most acoustic parameters (fundamental frequency
with T (tumour stage), N (nodal status) and type of radiotherapy (RT).        in males, jitter percent, shimmer percent, noise-harmonic
 Parameter                          Control                 Intervention      ratio, and soft phonation index) in the control group, in
                            N            %           N            %           comparison with pre chemo radiotherapy values (p = 0.00).
Age                                                                           Fundamental frequency of females did not change in during
  Below 60                   6         54.5%          5         55.6%         follow up; however, they were only two patients.
  60 and above               5         45.5%          4         44.4%         Three months after chemoradiotherapy, jitter (p = 0.04),
  Total                     11        100.0%          9        100.0%         shimmer (p = 0.02), and noise harmonic ratio (p = 0.04)
Sex
                                                                              all showed significant decreases compared with one-month
  F                          2         18.2%          6         66.7%
                                                                              post-chemoradiotherapy values, whereas fundamental fre-
  M                          9         81.8%          3         33.3%
  Total                     11        100.0%          9        100.0%         quency in males and soft phonation index showed no sig-
Malignancy                                                                    nificant differences.
  Oral cavity                5         45.5%          6         66.7%         Between 1 month and 6 months post chemo radiotherapy,
  Oropharynx                 6         54.5%          1         11.1%         there was a significant decrease noted in jitter and shimmer,
  Salivary gland             0          .0%           2         22.2%         but fundamental frequency in males, noise harmonic ratio
  Total                     11        100.0%          9        100.0%         and soft phonation index showed no significant differences.
Smoking                                                                       Six months after chemoradiotherapy, all acoustic param-
  No                         2         18.2%          7         77.8%         eters – fundamental frequency in males (p = 0.028), jit-
  Yes                        9         81.8%          2         22.2%         ter (p = 0.02), shimmer (p = 0.02), noise harmonic ratio
  Total                     11        100.0%          9        100.0%
                                                                              (p = 0.01), and soft phonation index (p = 0.02) – were sig-
Alcohol
  No                         3         27.3%          7         77.8%
                                                                              nificantly altered compared with levels before radiotherapy.
  Yes                        8         72.7%          2         22.2%
  Total                     11        100.0%          9        100.0%         Comparison within the intervention group (Tab. III)
Tobacco chewing                                                               At one month post chemoradiotherapy, there was a highly
  No                        1          9.1%           4         44.4%         significant change in almost all parameters compared to
  Yes                       10         90.9%          5         55.6%         values before radiotherapy; fundamental frequency in fe-
  Total                     11        100.0%          9        100.0%         males (p = 0.028), jitter (p = 0.008), shimmer (p = 0.008),
T                                                                             noise harmonic ratio (p = 0.008) and soft phonation index
  T1                        0           .0%           1         11.1%         (p = 0.008). There was no change in F0 in males; however,
  T2                         5         45.5%          4         44.4%
                                                                              they were three patients.
  T3                         1          9.1%          2         22.2%
                                                                              When the 3-month values were compared to the one-month
  T4                         5         45.5%          2         22.2%
  Total                     11        100.0%          9        100.0%
                                                                              values, jitter, shimmer, noise harmonic ratio and soft pho-
N                                                                             nation index showed significant decreases, while F0 in fe-
  N0                         5         45.5%          2         22.2%         males showed an increase.
  N1                         2         18.2%          4         44.4%         At the 6-month follow-up, no significant differences were
  N2                         4         36.4%          3         33.3%         observed when the acoustic parameters were compared
  Total                     11        100.0%          9        100.0%         with pre chemoradiotherapy values (i.e., all acoustic pa-
Surgery                                                                       rameters had returned to pre-chemoradiotherapy values).
  No                         8         72.7%          4         44.4%
  Yes                        3         27.3%          5         55.6%         Comparison between the control and intervention groups
  Total                     11        100.0%          9        100.0%
                                                                              (Tab. II, Figs. 1, 2)
Neck dissection
                                                                              Pre-chemoradiotherapy and one-month post-chemoradio-
  No                         8         72.7%          4         44.4%
  Yes                        3         27.3%          5         55.6%         therapy values did not show significant differences between
  Total                     11        100.0%          9        100.0%         groups.
RT type                                                                       Comparisons between groups at 3-months showed a sig-
  3DCRT                      1        9.1%            1        11.1%          nificant increase in the fundamental frequency-males
  IMRT                      10        90.9%           8        88.9%          (p = 0.036) and decrease in jitter (p = 0.006), and shimmer
Recurrence                                                                    (p = 0.00), noise-harmonic ratio (p = 0.015) and soft phona-
  No                        10         90.9%          7         77.8%         tion index (p = 0.037) in the intervention group.
  Yes                        1          9.1%          2         22.2%         At the 6-month follow-up, there was a significant increase in
  Total                     11        100.0%          9        100.0%
                                                                              fundamental frequency in males (p = 0.017) and a decrease in



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Table II. Acoustic parameters-fundamental frequency (F0 females and F0 males), jitter (Jitt), shimmer (Shim), noise harmonic ratio (NHR), and soft phonation
index (SPI) before chemoradiotherapy and at 1-, 3- and 6-months follow-up in the control and intervention groups; comparison done using Mann Whitney test,
significant p values in bold.
   Parameter         Timing of analysis     Group         N         Mean       Std. Deviation Median                Inter-quartile range          p value
 Fo Female                  Pre RT          Control       2          199             0              199           198.95(148.95-149.475)           0.071
                                         Intervention     6          176             23             183                (162.4-190.925)
                        1 month post        Control       2          145              7             145                (105.3-112.725)             0.143
                              RT         Intervention     6          123             21             127                  (100-141.325)
                      3 months post RT      Control       2          150              5             150             (109.425-115.1025)             0.286
                                         Intervention     6          169             13             171              (161.4275-179.95)
                      6 months post RT      Control       1          133              0               .                           (-)              0.400
                                         Intervention     4          169             21             164             (152.325-191.1125)
 F0 Male                    Pre RT          Control       9          138             18             135                    (125-155.75)            0.145
                                         Intervention     3          155             13             151                   (143.7-169.8)
                       1 month post RT      Control       9          113             16             114                 (97.05-121.55)             0.600
                                         Intervention     3          118              9             114                 (112.78-128.4)
                      3 months post RT      Control       9          117             15             121              (100.305-126.235)             0.036
                                         Intervention     3          136              5             133                (132.21-141.94)
                      6 months post RT      Control       7          124             13             130                (110.67-131.48)             0.017
                                             Study        3          151              2             152                 (149.65-152.9)
 Jitt                       Pre RT          Control      11          0.95           0.38            1.00                      (0.8-1.05)           0.171
                                         Intervention     9          0.68           0.34            0.81                (0.3985-1.015)
                       1 month post RT      Control      11          2.49           1.03            2.10                     (1.64-3.59)           0.820
                                         Intervention     9          2.67           1.00            2.55                  (1.7925-3.34)
                      3 months post RT      Control      11          2.35           0.97            1.96                     (1.53-3.01)           0.006
                                         Intervention     9          1.25           0.46            1.29                    (1.115-1.55)
                      6 months post RT      Control       8          2.17           0.81            2.11               (1.4375-2.8125)             0.002
                                         Intervention     7          0.84           0.30            0.91                     (0.82-1.03)
 NHR                        Pre RT          Control      11          0.11           0.03            0.12                     (0.08-0.13)           0.320
                                         Intervention     9          0.10           0.02            0.09                    (0.08-0.115)
                       1 month post RT      Control      11          0.41           0.29            0.25                      (0.21-0.6)           0.676
                                         Intervention     9          0.40           0.23            0.34                      (0.24-0.5)
                      3 months post RT      Control      11          0.35           0.22            0.26                      (0.2-0.44)           0.015
                                         Intervention     9          0.17           0.06            0.13                (0.115-0.2205)
                      6 months post RT      Control       8          0.28           0.07            0.30                  (0.212-0.335)            0.002
                                         Intervention     7          0.12           0.03            0.12                     (0.1-0.139)
 Shim                       Pre RT          Control      11          3.36           0.54            3.20                     (2.98-3.96)           0.074
                                         Intervention     9          2.65           0.77            2.88                    (2.04-3.305)
                       1 month post RT      Control      11          5.54           1.11            5.34                      (4.6-6.71)           0.270
                                         Intervention     9          5.00           0.74            5.00                    (4.26-5.755)
                      3 months post RT      Control      11          5.22           1.18            5.10                     (4.28-6.08)           0.000
                                         Intervention     9          2.97           0.85            3.02                     (2.05-3.79)
                      6 months post RT      Control       8          4.29           0.71            4.07                  (3.865-4.345)            0.002
                                         Intervention     7          2.93           0.75            3.10                     (2.08-3.67)
 SPI                        Pre RT          Control      11         20.80           5.00           21.03                    (18.45-22.9)           0.939
                                         Intervention     9         21.75           4.21           22.03                    (17.4-24.35)
                       1 month post RT      Control      11         30.01           4.15           31.21                  (24.82-32.59)            0.425
                                         Intervention     9         31.92           5.34           31.50                (26.48-36.565)
                      3 months post RT      Control      11         28.79           2.51           29.65                  (26.54-30.65)            0.037
                                         Intervention     9         25.19           3.96           24.53                  (21.75-29.88)
                      6 months post RT      Control       8         27.14           2.32           27.44                (25.24-29.345)             0.015
                                         Intervention     7         22.42           3.21           20.92                     (20.1-23.8)




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A. Sreenivas et al.




Table III. Comparison of acoustic parameters [fundamental frequency (F0 female and F0 male), jitter (Jitt), shimmer (Shim), noise harmonic ratio (NHR), and soft
phonation index (SPI)], GRBAS scores [grade (G), roughness (R),breathiness (B), asthenia (A), Strain(S)] and Voice Handicap Index (VHI) between different time
intervals in the same group - pre and 1 month after chemo radiotherapy, 1 month and 3 months after chemo radiotherapy, 1 month and 6 months after chemo
radiotherapy, and pre and 6 months after radiotherapy in control and intervention groups; p value calculated using Wilcoxon signed rank, significant values in bold.
 Parameter                                     Time interval                                         Control group                    Intervention group
                                                                                                        P values                            P values
 G                                       Pre-RT – 1 month post RT                                         0.048                              0.026
                                    1 month post RT – 3 months post RT                                    0.317                              0.206
                                    1 month post RT – 6 months post RT                                    0.257                              0.016
                                        Pre-RT – 6 months post RT                                         0.132                              0.083
 R                                       Pre-RT – 1 month post RT                                         0.010                              0.012
                                    1 month post RT – 3 months post RT                                     1.00                              0.180
                                    1 month post RT – 6 months post RT                                    0.157                              0.024
                                        Pre-RT – 6 months post RT                                         0.014                               1.00
 B                                       Pre-RT – 1 month post RT                                         0.026                              0.015
                                    1 month post RT – 3 months post RT                                    0.334                              0.034
                                    1 month post RT – 6 months post RT                                    0.066                              0.059
                                        Pre-RT – 6 months post RT                                          1.00                               1.00
 A                                       Pre-RT – 1 month post RT                                         0.046                              0.014
                                    1 month post RT – 3 months post RT                                    0.212                              0.038
                                    1 month post RT – 6 months post RT                                    0.330                              0.020
                                        Pre-RT – 6 months post RT                                         0.589                              0.317
 S                                       Pre-RT – 1 month post RT                                         0.033                              0.038
                                    1 month post RT – 3 months post RT                                    0.206                              0.317
                                    1 month post RT – 6months post RT                                     0.739                              0.059
                                        Pre-RT – 6 months post RT                                         0.034                              0.317
 Fo Female                               Pre-RT – 1 month post RT                                         0.180                              0.028
                                    1 month post RT – 3 months post RT                                    0.180                              0.028
                                        Pre-RT – 3 months post RT                                         0.180                              0.249
 Fo Male                                 Pre RT – 1 month post RT                                         0.008                              0.109
                                        Pre RT – 3 months post RT                                         0.008                              0.109
                                        Pre RT – 6 months post RT                                         0.028                              1.000
                                    1 month post RT – 6 months post RT                                    0.043                              0.109
 Jitt                                    Pre-RT – 1 month post RT                                          0.00                              0.008
                                    1 month post RT – 3 months post RT                                     0.04                               0.01
                                    1 month post RT – 6 months post RT                                     0.04                               0.02
                                        Pre-RT – 6 months post RT                                          0.02                               0.09
 Shim                                    Pre-RT – 1 month post RT                                          0.00                              0.008
                                    1 month post RT – 3 months post RT                                     0.02                               0.01
                                    1 month post RT – 6 months post RT                                     0.01                               0.02
                                        Pre-RT – 6 months post RT                                          0.02                               0.24
 NHR                                     Pre-RT – 1 month post RT                                          0.00                              0.008
                                    1 month post RT – 3 months post RT                                     0.04                               0.01
                                    1 month post RT – 6 months post RT                                     0.09                               0.02
                                        Pre-RT – 6 months post RT                                          0.01                               0.25
 SPI                                     Pre-RT – 1 month post RT                                          0.00                              0.008
                                    1 month post RT – 3 months post RT                                     0.13                               0.01
                                    1 month post RT – 6 months post RT                                     0.16                               0.02
                                        Pre-RT – 6 months post RT                                          0.02                               0.18
                                         Pre-RT – 1 month post RT                                          0.00                               0.01
 VHI                                1 month post RT – 3 months post RT                                    0.16                                0.01
                                    1 month post RT – 6 months post RT                                    0.03                                0.03
                                        Pre-RT – 6 months post RT                                         0.01                                0.46




136
                                                                                                                        Voice post chemoradiation




jitter (p = 0.002), shimmer (p = 0.002), noise-harmonic ratio
(p = 0.002) and soft phonation index (p = 0.015) in the interven-
tion group (Figs. 1, 2). The fundamental frequency in females
did not show a significant change between 3 and 6 months, but
there was only one patient left in the control group.

GRBAS scores
Comparison of GRBAS scores at different time intervals in
the control and intervention groups are shown in Table III.

Comparison within the control group (Tab.III)
Using the GRBAS scale, there was a significant increase             Figure 1. Box plots representing F0 Fundamental frequency (for males and
in all scores in the control group at 1 month after chemora-        females) and shimmer (Shim) in the control and study group at 6 month post-
                                                                    chemoradiotherapy.
diotherapy compared with scores before chemoradiother-
apy; significant changes were seen for grade (p = 0.048),
roughness (p = 0.01), breathiness (p = 0.026), asthenia
(p = 0.046) and strain (p = 0.033).
At 3 months, there was no significant change in the pa-
rameters compared to the scores at 1 month. There were
no significant differences between post-chemoradiotherapy
scores at 1 and 6 months.
At 6 months post-chemoradiotherapy, roughness (p = 0.014)
and strain (p = 0.034) were still significantly different from
pre-chemoradiotherapy values, while grade, breathiness,
and asthenia showed no significant differences.

Comparison within the intervention group (Tab. III)
Statistically significant differences were noted in all pa-
rameters when pre-chemoradiotherapy and 1-month
post-chemoradiotherapy values were compared; grade
(p = 0.026), roughness (p = 0.012), breathiness (p = 0.015),
asthenia (p = 0.014) and strain (p = 0.038).                        Figure 2. Box plots showing the acoustic parameters Jitter (Jitt), noise har-
Three months after radiotherapy, breathiness had improved           monic ratio (NHR) and Soft Phonation Index (SPI) in the control and intervention
significantly (p = 0.034) whereas none of the other param-          groups at 6 months post-chemoradiotherapy.
eters showed significant change compared to one-month
post RT values.
At 6 months after chemoradiotherapy, a significant differ-
ence was noted in grade (p = 0.016), roughness (p = 0.024)
and asthenia (p = 0.020) compared with the values at 1
month after chemoradiotherapy.
There were no significant differences between the pre-radi-
otherapy perceptual scores and those at 6 months.

Comparison between the control and intervention groups
(Tab. IV, Fig. 3)
The perceptual voice was normal before chemo radiother-
apy in most patients. At 1 month after radiotherapy, mild-
moderate differences were observed in both groups, with
                                                                    Figure 3. Bar diagram showing the proportion of patients with 0 (normal), 1
no significant differences between the two.
                                                                    (mild) and 2 (moderate) severity of changes in perceptual evaluation of patients
Three months after chemoradiotherapy, the perceptual                using GRBAS scores (grade, roughness, asthenia, breathiness and strain) at 6
voice parameters in the intervention group had improved             months post chemo radiotherapy in control and intervention groups.



                                                                                                                                              137
A. Sreenivas et al.




Table IV. Comparison of GRBAS scores [grade (G), roughness (R), breathiness (B), asthenia (A), Strain(S)] and Voice Handicap Index (VHI) before chemo radio-
therapy and at 1-, 3- and 6-month follow-up between control and intervention groups using Mann Whitney test, significant p values in bold.
 Parameter                     Pre chemo RT             1 month post chemo RT              3 months post chemo RT              6 months post chemo RT
                                   P value                       P value                            P value                              P value
 G                                  0.073                         1.000                              0.015                             0.001
 R                                  0.189                         0.277                              0.841                             0.100
 B                                  0.145                         0.374                              0.070                             0.267
 A                                  1.000                         0.245                              0.479                             0.130
 S                                  0.711                         0.213                              0.814                             0.012
 VHI                                0.759                         0.939                              0.011                             0.003



                                                                                creased, whereas at 3 months there was a significant de-
                                                                                crease compared scores at 1 month (p = 0.01). At 6 months,
                                                                                the VHI values had almost returned to baseline values. No
                                                                                significant differences were noted between values before
                                                                                radiotherapy and those at 6 months.

                                                                                Comparison between control and intervention groups
                                                                                (Tab. IV, Fig. 5)
                                                                                In the intervention group, voice therapy significantly im-
                                                                                proved voice quality as assessed by VHI at 3 months
                                                                                (p = 0.011). During the 6-month follow-up, VHI showed
                                                                                a highly significant improvement in the intervention group
                                                                                (p = 0.003). This trend is depicted in Figure 4.

Figura 4. Box plot showing Voice Handicap Index (VHI) in the control and in-    Discussion
tervention groups at 6 months post-chemoradiotherapy.
                                                                                Head and neck malignancies are common malignancies in
                                                                                India, and surgery, chemotherapy and radiotherapy are the
compared to the control group; significant improvement                          three modalities employed in the management of these tu-
was seen for grade (p = 0.015).                                                 mours. Radiation damage to the larynx is expected when
Six months after chemoradiotherapy, a significant improve-                      laryngeal disease is treated with radiation; the larynx can
ment in grade (p = 0.001) and strain (p = 0.012) were noted in                  also suffer radiation damage when the neck is included in
the intervention group in comparison with the control group.

Voice handicap index
Comparison of VHI scores at different time intervals in
control and intervention groups are shown in Table III.

Comparison within the control group
Subjective analysis of quality of voice using VHI showed
a significant increase in the scores 1 month after chemo
radiotherapy (p = 0.00). Between 1- and 3-months, no
significant differences were noted in VHI. Significant
differences (p = 0.01) were seen when the values before
chemoradiotherapy and 6 months after radiotherapy were
compared.
                                                                                Figura 5. Graph depicting the trend in Voice Handicap Index (VHI) between
Comparison within the intervention group                                        the intervention and control group before radiotherapy, and at 1, 3 and 6
At 1 month after radiotherapy, VHI scores significantly in-                     months after radiotherapy.



138
                                                                                                          Voice post chemoradiation




the radiation fields in non-laryngeal disease. The radia-          aim was to evaluate the effect of voice therapy on various
tion damage to the larynx can be acute or chronic. Acute           objective or subjective voice parameters in a randomised
voice changes are attributed to oxidative damage resulting         controlled study. However, in the third month there
in injury to both diseased and normal tissue; this can lead        were only 11 patients in the control group (females = 2,
to mucosal oedema, necrosis and epithelial sloughing. As           males = 9) and 9 patients in the study group (males = 3,
the acute phase subsides, a fibroblastic response develops         females = 4). By 6 months, control group had only 1 female
which causes long-term deposition of collagen and fibrosis.        (n = 7) and the study group had 3 males and 4 females.
Fibrosis leads to reduced tissue viscosity, which reduces          Since all the investigators were blinded, this gender varia-
the normal vibratory patterns that are required for normal         tion between the groups was noticed only in the end of the
voice. These tissue changes make long-term rehabilitation          study. The increased number of males in the control group
difficult 17.                                                      also resulted in an increase in smoking and alcohol use in
The addition of chemotherapy to radiotherapy provides a            the study group.
synergistic effect between the two therapies. The chemo-
therapeutic agent may act as an enhancer or potentiator of         Acoustic parameters
radiation. Some of these drugs interfere with cellular DNA         In the control group, all acoustic parameters showed mild
repair after sub-lethal or potentially lethal damage, while        improvement at 6 months, but were still significantly dif-
others reduce tumour cell repopulation by enhancing the            ferent (except F0 females) from levels before radiotherapy.
cytotoxic effects of radiotherapy 18. The addition of chemo-       In the intervention group, all acoustic parameters returned
therapy to radiotherapy is done in various settings in the         to pre-treatment levels by 6 months.
management of head and neck cancer: as part of the organ           In the intervention group, improvement in jitter, and shim-
preservation protocol, as an adjuvant to surgery in loco-          mer was found to be highly different from the control group
regionally advanced head and neck cancer, and as palliation        at 6 months. Fundamental frequency in males, soft phona-
in inoperable head and neck cancer. While chemoradiation           tion index and noise-harmonic ratio had significantly im-
has a beneficial effect on tumour tissue, it unfortunately         proved in the intervention group at 6 months compared to
has a highly toxic effect on normal tissues in the irradiated      the control group.
field, such as the larynx.                                         In a study by Fung et al., fundamental frequency and har-
Non-pharmacologic treatment is the main line of rehabili-          monic noise ratio significantly worsened (compared with
tation for a radiated larynx, and consists of indirect voice       age- and gender-matched controls) while jitter and shim-
therapy in the form of vocal hygiene and direct voice ther-        mer showed no statistical significance at 1 year after irra-
apy in the form of vocal exercises.                                diation of the non-diseased larynx 23.
Vocal hygiene primarily focuses on hydration. Radiation            These results show that in the absence of voice interven-
to the larynx causes damage to laryngeal salivary tissue,          tion, some of the acoustic parameters will show significant
which results in laryngeal desiccation. As a result, vocal         worsening compared to controls at one year post-radiation.
performance is affected 19,20. This can occur either as an ear-    Our results show that most acoustic parameters can im-
ly- or late- phase response to radiation. Patients are taught      prove with voice therapy as early as 6 months.
to maintain adequate systemic hydration to maximise vocal           However, the benefits of intervention seem to be limited in
function during and after radiation treatment. Local hydra-        patients with laryngeal cancer. In their study of 69 males
tion using environmental humidification or steam inhala-           with laryngeal cancer undergoing chemoradiation, Tuomi
tion is also beneficial 17. Voice therapy focuses on helping       et al. found no significant change in acoustic variables in
the patient produce voice without using inefficient compen-        the intervention group when compared with a control group
satory behaviours such as increased laryngeal strain and           at 6 months 8. Assessment of vocal range profile (VRP)
supraglottic constriction 2. Tuomi et al. recommended that         also showed no significant differences between the two
voice rehabilitation should be focused on relaxation and on        groups 24.
decreased phonatory effort with more support from respi-
ration. This is expected to improve the harmonic noise ra-         Perceptual voice analysis
tio and perturbation results, improving patient-rated voice        At 1 month post-chemoradiation, all perceptual voice pa-
quality outcomes 8.                                                rameters in both the control and intervention groups showed
Many studies have evaluated vocal function in patients with        significant differences when compared with pre-treatment
laryngeal tumours treated with radiotherapy, but only a few        levels. At 6 months after treatment, roughness and strain in
have concentrated on the un-diseased larynx receiving radia-       the control group remained significantly altered compared
tion to the neck as a part of the treatment protocol 21, 22. Our   to pre-treatment levels. Grade, breathiness and asthenia had



                                                                                                                              139
A. Sreenivas et al.




improved, although they did not reach normal levels. Six         abnormal voice 23. Quality of life assessment using the Swed-
months after radiotherapy, perceptual voice parameters in        ish Self-Evaluation of Communication Experiences after La-
the intervention group had improved to pretreatment levels.      ryngeal Cancer (S-SECEL) found a significant improvement
A few studies have evaluated the effects of chemoradiation       in the Environmental, Attitudinal, and Total domains be-
on the perceptual quality of voice in the non-diseased lar-      tween baseline and 6 months, after which it remained more
ynx. In one such study, perceptual voice parameters showed       or less constant for up to 12 months after chemoradiation 24.
significant deterioration from pre-treatment values to early     Another study in Sweden on patients with primary laryngeal
post-treatment values (mean 16.5 weeks), but by the late         cancer found that the intervention group showed significant
post-treatment evaluation (12 months), had returned to           improvement in all domains, except in the general domain of
baseline values 6. Van der Molen et al. noted that in patients   S-SECEL 25.
treated with chemoradiation, perceptual voice parameters         Our study shows that the changes in perceptual, acoustic
(GRBAS) at 1 year showed significant improvements in             and patient-reported voice quality measures brought about
overall voice quality, roughness and breathiness compared        by chemoradiation can be reversed by voice therapy in 6
with the voice at 10 weeks after radiation 10. Analysing         months. Unfortunately, although we started with 32 patients,
these results along with ours, help us conclude that in non-     we lost 7 patients to follow-up, and 5 to death, which is a
laryngeal head and neck cancer, the changes in the percep-       characteristic of cancer studies in India. This resulted in a
tual parameters of voice brought about by chemoradiation         small sample size. The preponderance of males in the control
revert to almost normal levels by one year. However, our         group with increased usage of alcohol and inhaled tobacco
study has shown that intervention with voice therapy leads       in the past may have impacted the results; further studies are
to early normalisation of voice.                                 needed to clarify this point. The number of sessions of voice
The effects of intervention on the after-effects of radiation    therapy was also limited, since some of the patients were
in laryngeal cancer patients seem to be less beneficial. Van     not local residents. Moreover, since our maximum follow-
Gogh et al. reported that roughness and breathiness in la-       up was only 6 months, we do not know whether the benefits
ryngeal cancer patients did not change significantly when        seen at 6 months will be retained at a later date. Further stud-
vocal intervention was offered after treatment with either       ies are recommended with a larger sample size and longer
radiotherapy or laser. After 16 sessions of voice therapy, a     follow up. A longer follow-up is important since radiation
significant decrease was seen only in vocal fry 7.               induced fibrosis can cause late changes in voice. If a longer
                                                                 follow up reveals recurrent or late changes in voice, patients
Voice handicap index                                             may require prolonged vocal rehabilitation.
In both the control and intervention groups, VHI deterio-        Radiotherapy comes with many complications; dysphonia,
rated significantly at one month post-treatment when to          with its negative impact on communication and quality of
pre-treatment levels. At 6 months, VHI was not significant-      life, is certainly one of them. Our study indicates that voice
ly different from pre-treatment levels in the intervention       therapy has a positive impact on patients undergoing chem-
group, while the opposite was true of the control group.         oradiation for non-laryngeal head and neck malignancies.
In the study by Paleri et al. on advanced non-laryngeal ma-      We recommend that voice therapy be included as a part of
lignancies undergoing chemoradiation, patient-reported           the routine rehabilitation protocol in patients undergoing
voice quality (VoiSS) deteriorated during the initial assess-    chemo-radiation. This would render patients more compli-
ment (12-20 weeks) and even further during the 12-month          ant and receptive to treatment, and would also reduce the
assessment 6.                                                    social and psychological impact associated with dyspho-
Our study suggests that early voice intervention can ef-         nia. Because a speech language pathologist is present at
fectively counter these effects and return VHI back to pre-      most hospitals/centres, a multidisciplinary approach that
treatment levels.                                                includes them will make radiation treatment as comfort-
When radiation or chemoradiation is used for the treatment       able as possible for the patient, with a minimal impact on
of laryngeal cancers, significant changes in voice quality and   quality of life.
communication occur; these can last up to a year 24. Though
voice handicap parameters improve by themselves to a cer-
tain extent, vocal intervention greatly improves quality and
                                                                 Conclusions
communication. Fung et al. found that 27% of patients had        Acoustic, perceptual and subjective evaluation of voice
moderate to severe voice handicap at 1 year after radiation of   showed that all patients with non-laryngeal cancers un-
laryngeal cancer; it was surmised that deterioration of vocal    dergoing chemoradiation to the neck had severe damage
function over time is likely potentiated by ongoing use of an    to voice at 1 month post-treatment except for F0 females



140
                                                                                                                                Voice post chemoradiation




(control group) and F0 males (study group). Six months                             term efficacy of voice therapy in patients with voice problems after
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cant alterations in these parameters compared to baseline.                    12
                                                                                   Dejonckere PH, Bradley P, Clemente P, et al. A basic protocol for
In the vocal intervention group, all parameters returned to                        functional assessment of voice pathology, especially for investigat-
normal at 6 months.                                                                ing the efficacy of (phonosurgical) treatments and evaluating new
                                                                                   assessment techniques Guideline elaborated by the Committee on
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