Abstract
To evaluate ototoxicity in patients receiving combined cisplatin and radiotherapy in comparison to patients receiving radiotherapy alone. A prospective study was conducted in sixty (60) cases of advanced Head and Neck malignancy (stage III and IV). Patient were divided in two randomized groups (30 each), group I received chemoradiation and group II received radiation alone. Inclusion criteria were histopathologically confirmed head & neck malignancy, normal baseline audiograms. Exclusion criteria were defined as: previously treated cases with chemotherapy/radiotherapy, patients who didn’t complete treatment or lost to follow up. Ototoxicity was evaluated as per criterion established by the American speech-language-hearing association. Study participants were evaluated for ototoxicity at intervals defined as per study design. Sensorineural hearing loss (SNHL) was noticed in 56.6% and 36.6% of subjects in Group I & II respectively at 6 months follow up post completion of treatment. Incidence of sensorineural hearing loss increased significantly with cumulative dosages of chemoradiotherapy in group I and radiotherapy in group II. Incidence of SNHL in both study groups was found to be higher in patients older than 50 years. Incidence of ototoxicity in chemoradiated patients was found to be higher in comparison to patients receiving radiation alone. Ototoxicity occurred more with cumulative doses, with higher speech frequencies affected earlier in comparison to middle range frequencies. Lower frequencies were spared.
Keywords: Ototoxicity, Sensorineural hearing loss, Cisplatin, Radiotherapy, Tinnitus
Introduction
Head and neck cancer has emerged as one of major public health problems in India contributing significantly to morbidity and mortality[1]. More than 2 lakh cases of head and neck cancers are estimated to be reported in 2020 [2]. Chemotherapy, Radiotherapy, Surgery or as a combination therapy are various modalities of treatment. Out of these, combined chemotherapy and radiotherapy is widely used in patients with advanced head and neck malignancy with the intention of organ preservation. Cisplatin chemotherapy alone as well as concurrent chemoradiation is known for unwanted side effects e.g. ototoxicity, optic neuritis, neuropathy, renal damage, bone marrow suppression, irreversible sensorineural hearing loss (SNHL) [3]. Radiotherapy induced SNHL has been described as late and permanent sequele [4], etiopathogenesis being outer hair cells (OHC) destruction and sensory nerve bundle atrophy [5]. Etiopathogenesis behind cisplatin based chemotherapy indueced ototoxicity has been described as injury to Organ of Corti and Stria Vascularis [6]. Skinner et al. [7] demonstrated OHC of basal turn of cochlea are more prone and manifest earlier than apical turn OHC explaining High frequency SNHL appearing earlier. Various studies including systematic review by Niemensivu et al. [8], Pearson et al. [9], Theunissen et al. [10], Zuur et al. [11] have reported incidence of sensorineural hearing loss following chemoradiation in the range 17–88% while some authors Kwong et al. [12], Oh YT et al. [13], Wang LF et al. [14] reported no significant difference in incidence of sensorineural hearing loss in both groups. So we conducted a prospective study with the aim to assess & compare the ototoxicity in head and neck cancer patients receiving chemoradiotherapy to patients receiving radiotherapy alone.
Material and Methods
This prospective study was conducted in the Government Medical College, Patiala in the department of otolaryngology and radiotherapy during the period 2013–2016. Sixty (60) cases of advanced head and neck malignancy (Stage III and IV) were enrolled in the study. Inclusion criteria were histopathologically confirmed malignancy, normal baseline audiograms. Exclusion criteria were previously treated cases with chemotherapy/radiotherapy, patients who didn’t complete treatment. Study design was prepared with randomly divided 2 groups (Table 1). Ethical clearance (No. (Trg).EC/NEWI.INST/2020/997/11536) was taken from institute ethics committee.. Radiotherapy fields were defined as a straight line drawn from alae nasi to in front of tragus to mastoid tip. Cochlea and eighth nerve were not in Umbra field but were exposed in penumbra. Patients received 66 Gy/33#. In Phase I, 23 # (46 Gy) were given in Primary region and draining neck node region ( area of interest) followed by Phase 2, in which last 10# (20 Gy) were given in posterior triangle neck region while sparing spine from radiation field. Protection regimen used in patients to decrease the cisplatin ototoxicty was as following: 500 ml NS + ½ KCl followed by 500 ml to increase hydration followed by mannitol diuresis to facilitate excretion of drug. Patients who had experienced ototoxicity were rehabilitated after giving hearing aid trail. Majority of patients were fitted with Hearing aid in one ear and were advised for regular follow up and audiometry every 6 months. Chemoradiation and radiation groups were compared to study any additive/ neutral/ negative correlation of chemotherapy in addition to radiation. Higher frequencies were tested only upto 8 kHz. Ototoxicity was defined as per criterion established by the American Speech-Language-Hearing Association (ASHA) [15]: (a) 20 dB or greater decrease in pure-tone threshold at one frequency (b) 10 dB or greater decreased at 2 adjacent frequencies or (c) loss of response at 3 consecutive test frequencies.
Table 1.
Study design
| Group I (30 Patients) | Cisplatin (100 mg/m2 i.v.—3 doses at Day 1, 22, 43) + Radiotherapy: 5 fractions /week for 6 weeks (60 Gy) (2 Gy/day = 1 fraction) | |
| Group II (30 Patients) | Radiotherapy alone:5 fractions /week for 6 weeks (60 Gy)(2 Gy/day = 1 fraction) | |
| Evaluation design | ||
| Audiological evaluation | Group I | Group II |
| Baseline evaluation | Pre treatment | Pre treatment |
| 1st evaluation | 1 wk post 1st dose of cisplatin + 10 Gy RT | 1 wk post 10 Gy RT |
| 2nd evaluation | 1 wk post 2nd dose of cisplatin + 42 Gy RT | 1 wk post 42 Gy RT |
| 3rd evaluation | 1 wk post 3rd dose of cisplatin + 60 Gy RT | 1 wk post 60 Gy of RT |
| 4th evaluation | 6 months post therapy | 6 months post therapy |
Statistical Analysis
The data was compiled and analyzed with SPSS statistics (version 20.0) with Chi-Square test and Fischer Exact tests. p value ≤ 0.05 was considered significant.
Results
Total 60 patients completed the study, 30 in each group. Mean age in Group I was 52.26 years (Range-36–74 years) and Mean age in Group II was 51.63 years (Range-30–65 years). In Group I, there were 19 males and 11 females & In Group II, there were 22 males and 8 females.
Hearing Loss (Table 2)
Table 2.
Hearing loss data
| Number of subjects affected with hearing loss | Number of subjects affected as per frequency specific hearing loss | |||||||
|---|---|---|---|---|---|---|---|---|
| No | % | p value | 4 kHz | p value | 8 kHz | p value | ||
| 1st evaluation | Gp I | 9 | 30 | 0.015 S) | − | − | 9 | 0.015 (S) |
| Gp II | 1 | 3.3 | − | 1 | ||||
| 2nd evaluation | Gp I | 12 | 40 | 0.040(S) | 4 | 0.353 (NS) | 12 | 0.04 (S) |
| Gp II | 4 | 13.3 | 1 | 4 | ||||
| 3rd evaluation | Gp I | 19 | 63.3 | 0.070 (NS) | 7 | 0.166 (NS) | 19 | 0.07 (NS) |
| Gp II | 12 | 40 | 3 | 12 | ||||
| 4th evaluation (6 months follow up) | Gp I | 17 | 56.6 | 0.12 (NS) | 5 | 0.706 NS) | 17 | 0.12 (NS) |
| Gp II | 11 | 36.6 | 3 | 11 | ||||
In Group I, 30%, 40%, 63.33%, 56.66% of subjects developed sensorineural hearing loss upon evaluation at various intervals as pre-defined in study design: post 1 week 1st dose, 2nd dose, 3rd dose and 6 months follow up whereas in Group II hearing loss was noticed in 3.33%, 13.33%, 40%, 36.66% of subjects at time of completion of dosage of 10 Gy, 42 Gy, 60 Gy and 6 months follow up. The difference in ototoxicity between group I and II at 1st and 2nd evaluation was statistically significant (p value ≤ 0.0153 and 0.0409 respectively). However the difference was non-significant at post 3rd dose of cisplatin (p value ≤ 0.0706) and 6 months follow up (p value ≤ 0.1206). Maximum number of subjects experienced ototoxicity at the time of 3rd evaluation after 3rd dose of cisplatin and 60 Gy of radiotherapy when given simultaneously on 43rd day of scheduled treatment in Group I & after 3rd dose i.e. 60 Gy of radiotherapy when given on 43rd day of scheduled treatment in Group II indicating increased toxicity with cumulative dosage. There was improvement in percentage of subjects affected with ototoxicity after completion of treatment at 6 months follow up (Table 2).
Frequency Specific Hearing Loss (Table 2):
8 kHz: Percentage of subjects affected with Hearing loss at 8000 Hz was higher in group I in comparison to Group II at all pre defined evaluation intervals. The difference between Group I & II was statistically significant only at 1st dose (p value ≤ 0.015) & 2nd dose (p value ≤ 0.041).
4 kHz: Percentage of subjects affected with Hearing loss at 4000 Hz was higher in group I in comparison to Group II at all pre defined evaluation intervals except evaluation at 1 week post 1st dose chemotherapy/ 10 Gy RT where no loss was observed in both the groups. However the difference between Group I & II was statistically not significant at all evaluations.
Lower frequencies (≤ 2 kHz): No subject experienced hearing loss at lower frequencies in both Group I & II.
Intra Group Comparison of Effect of Cumulative Dosage of Cisplatin and Radiotherapy on Hearing Loss in Group I & Radiotherapy on Hearing Loss in Group II (Table 3)
Table 3.
Intra group comparison of effect of cumulative dosage
| Group I | Group II | |||||
|---|---|---|---|---|---|---|
| 1st & 2nd dose | 1st & rd dose | 2nd & 3rd dose | 1st & 2nd dose | 1st & 3rd dose | 2nd & 3rd dose | |
| Comparison of no of patient with hearing loss | 9/12 | 9/19 | 12/19 | 1/4 | 1/12 | 4/12 |
| p value |
0.4165 (NS) |
0.0096 (HS) |
0.0706 (NS) |
0.3533 (NS) |
0.0017 (HS) |
0.0409 (S) |
Group I: The difference in incidence of hearing loss between 1st and 2nd; 2nd and 3rd cumulative dosage of cisplatin and radiotherapy was not found to be significant (p value ≤ 0.4165 and 0.0706 respectively). However, the difference in incidence of hearing loss between 1st and 3rd cumulative dosage was found to be highly significant (p value ≤ 0.0096). It indicates that incidence of hearing loss increases with cumulative dosages of cisplatin and radiotherapy.
Group II: The difference for incidence of hearing loss between st and 2nd cumulative dosage of radiotherapy was not found to be significant (p value ≤ 0.3533) and between 2nd and 3rd cumulative dose, it was found to be significant (p value ≤ 0.0409). However, the difference for incidence of hearing loss between 1st and 3rd cumulative dosage was found to be highly significant (p value ≤ 0.0017). It means that incidence of hearing loss increases with cumulative dosages of radiotherapy.
Hearing Loss in Relation to Gender
9 males in group I and 3 males in group II suffered hearing loss at 4000 Hz (p value ≤ 0.0642). 14 males in group I and 12 males in group II suffered hearing loss at 8000 Hz (p value ≤ 0.5977). 2 females in group I and 2 females in group II suffered hearing loss at 4000 Hz (p value ≤ 1)0.6 females in group I and 4 females in group II suffered hearing loss at 8000 Hz (p value ≤ 0.6985). No male and female suffered hearing loss at low speech frequency range (≤ 2 kHz) in both Group I & II. There was no statistical significant association of SNHL with sex in either of groups.
Relation of Ototoxicity with Age
In group I, 54.54% of patients with age < 50 yr suffered hearing loss as compared to 41.66% patients in group II (p value ≤ 0.5376). In group I, 73.68% of patients with age > 50 yr suffered hearing loss as compared to 72.22% patients in group II (p value ≤ 1).Hearing loss was higher for the age group greater than 50 years in both the groups I and II, but it was not statistically significant.
Tinnitus (Table 4)
Table 4.
Tinnitus evaluation in the study group
| Tinnitus (No.) | % | p value | ||
|---|---|---|---|---|
| 1ST evaluation | Gp I | 7 | 23.3 | 0.1455 (NS) |
| Gp II | 2 | 6.66 | ||
| 2nd evaluation | Gp I | 9 | 30 | 0.1068 (NS) |
| Gp II | 3 | 10 | ||
| 3rd evaluation | Gp I | 14 | 46.6 | 0.1082 (NS) |
| Gp II | 8 | 26.6 | ||
| 4th evaluation (6 months follow up) | Gp I | 12 | 40 | 0.0908 (NS) |
| Gp II | 6 | 20 | ||
In group I, 23.3%, 30%, 46.6%, 40% of patients had tinnitus at post 1 week 1st dose, 2nd dose, 3rd dose,3 months of follow up whereas in group II this percentage was found to be 6.66%, 10%, 26.66%, 20% in group II at post 1 week 1st dose, 2nd dose, 3rd dose, 6 months of follow up. The difference between group I and II was non-significant at all times (p value ≤ 0.1455, 0.1068, 0.1082, 0.0908 respectively). Percentage of patients affected with tinnitus was higher in Group I. There was no statistical significant difference in incidence of tinnitus in either of groups (Table 4).
Vestibular Complaints
No patient in group I and II experienced vertigo/giddiness/nystagmus vestibular dysfunction.
Discussion
This study was conducted with the aim of evaluating and comparing incidence of ototoxicity in Head & neck cancer patients receiving radiation versus chemoradiation. In our study, at 6 months post completion of treatment, hearing loss was observed in 56.6% of subjects who received chemoradiation/Group I. Bhandare et al. [16] reported a study of 325 patients, hearing loss was observed in 30% of subjects who received chemoradiation and in 18% of subjects in Radiation group. Cheraghi et al. [17] study of 29 patients, hearing loss was observed in 77% of subjects who received chemoradiation and in 51% of subjects in Radiation group subjects. Low et al. [18] reported sensorineural hearing loss in 42% of subjects who received chemoradiation as compared to 28.30% of subjects who received just radiation. Pearson et al. [4] reported sensorineural hearing loss in 24/37 (65%) subjects who received chemoradiation. In our study group, hearing loss in Radiotherapy/Group II was reported in 36.6% of subjects. Similar findings were reported by Upadhaya I et al. [19] reported sensorineural hearing loss in 46. 80% of subjects in Post irradiated patients. Li et al. [23], Yilmaz et al. [24] and Wang et al. [14] reported post radiation therapy SNHL in 60%, 47% & 37% subjects respectively. Incidence of hearing loss was found to be highest at time of 3rd evaluation in both the groups I and II (63.33% and 40% respectively) indicating toxicity due to cumulative effect. Schafer SD et al. [20] reported cisplatin-induced SNHL correlation with the cumulative dose in study of 24 Head & neck cancer patients (Table 5).
Table 5.
Comparison table illustrating various relevant literature
| Author name | No. of subjects | Type of study | Chemo-radiation group | Radiation group | Follow up |
|---|---|---|---|---|---|
| Current study | 60 | Prospective | 56.66% | 36.66% | 6 months |
| Bhandare et al 16 | 325 | Retrospective | 30% | 18% | 5.4 years |
| Cheraghi et al17 | 29 | Prospective | 77% | 51% | 6 months |
| Low et al18 | 115 | Prospective | 42% | 28.30% | 2 years |
| Pearson et al9 | 37 | Retrospective | 85% | X | Not well defined |
| Upadhaya et al19 | 58 | Prospective | X | 46.80% | 6 months |
| Li et al23 | 24 | Prospective | X | 60% | 5 years |
| Yilmaz et al24 | 19 | Prospective | X | 47% | 12 months |
| Wang et al14 | 45 | Prospective | X | 37% | 2 years |
In our study also, hearing loss was confined only to 8000 kHz and 4000 Hz frequencies. Cheraghi et al. [17] reported preservation of lower frequencies in 75% of subjects. Bhandare et al. [16] reported incidence of sensorineural hearing loss in 11% of the subjects of age < 50 years and 18% in subjects of age > 50 years. Cheraghi et al. [17] reported hearing loss in 64% of subjects older than 45 years in comparison to 50% of subjects of age < 45 years. Malgonde MS et al. [21] reported percentage of patients with hearing loss in radiotherapy alone group was 19.23% in < 50 years and 72.5% in > 50 years at 6 month follow up whereas percentage of subjects affected with ototoxicity in chemoradiotherapy group 41.17% in < 50 years and 94.11% in > 50 years at 6 months follow up. In our study, 73.68% of subjects in group I and 72.22% of subjects in group II with age > 50 years suffered hearing loss. 54.54% and 41.66% of patients with age < 50 years, suffered from hearing loss in group I and II respectively. So age group older than 50 years have higher probability of ototoxicity whether they receive Radiotherapy or chemoradiotherapy in comparison to patients younger than 50 years. Hwang et al. [25] discussed deterioration of hearing threshold with increasing age, which can be a significant factor that can be one of the reasons behind the higher incidence of SNHL in patients of age > 50 years.
In our study tinnitus was observed in 46% (Group I) and 26% (Group II) of subjects following 3rd dose. Lee et al. [22] reported tinnitus in 11.6% out of 211 subjects who received radiotherapy. Niemensivu et al. [9] reported tinnitus in > 50% of subjects after chemoradiation.
Majority of patient affected with ototoxicity reported loss only in higher frequencies (more than 4 kHz) and didn’t complain of any difficulty in day to day conversation. Only 2 patients opted for rehabilitation with hearing aid. Rest of the patients were advised to remain under regular follow up and yearly audiometry checkup. Role of Otoprotective agents like thio compounds, heavy metal chelators is still not well proven [26]. Further research is required to establish role of otoprotective agents.
Strengths and Limitations
Strengths of our study are prospective study, frequency specific assessment of hearing loss, real time comparative groups. Limitations of our study is small sample size. Further studies with large sample size and longer follow-up will help in further understanding the pathogenesis of ototoxicity.
Conclusion
Incidence of ototoxicity is higher in patients receiving chemoradiotherapy in comparison to patients receiving radiotherapy alone. Ototoxicity appears more with cumulative doses, with higher speech frequencies more prone to ototoxicity. All ENT practitioners, head and neck cancer surgeons, radiation oncologists and medical oncologists should be vigilant about ototoxicity and steps should be taken to decrease additional morbidity due to ototoxicity.
Funding
Nil
Declarations
Conflicts of interest
Nil
Footnotes
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