Key Points
Question
Can hearing loss after radiotherapy and cisplatin chemotherapy in patients with head and neck cancer be accurately predicted prior to the initiation of treatment?
Findings
In this cohort study of 242 patients (482 ears), a predictive model was developed that agreed with 77% of the variability in the posttreatment 1-, 2-, and 4-kHz pure tone average. This predictive model also had a sensitivity of 80% and specificity of 75% for predicting an observed posttreatment pure tone average greater than 35 dB.
Meaning
Predictive models can provide patients with cancer accurate estimates of the changes in their hearing that will occur after irradiation and cisplatin chemotherapy.
Abstract
Importance
Accurate, accessible predictions of posttreatment hearing loss for patients with head and neck cancer prior to the initiation of treatment are a necessary part of informed patient decision-making.
Objective
To develop a prediction model for postradiotherapy and/or post–cisplatin chemotherapy hearing loss for patients with head and neck cancer.
Design, Setting, and Participants
A retrospective cohort study was conducted at a tertiary academic medical center among 242 patients (482 ears) with head and neck cancer who were treated with radiotherapy and/or cisplatin from October 1, 2014, to July 31, 2018, and had follow-up audiometric data available.
Exposures
Radiotherapy and cisplatin chemotherapy.
Main Outcomes and Measures
Patient hearing level, as measured by the mean of pure tone audiometry at 1, 2, and 4 kHz on completion of treatment. A multivariable mixed model for predicting the posttreatment pure tone average was developed using only information available to clinicians at the beginning of treatment.
Results
A total of 242 patients (482 ears; 56 women and 186 men; mean [SD] age, 60 [10] years) were included in the analysis. All patients in the study received radiotherapy, and 105 (43.4%) received cisplatin chemotherapy. The mean (SD) total cumulative cisplatin dose was 298 (109) mg/m2. Patients’ ears received a mean (SD) cochlear radiotherapy dose of 15 (13) Gy. The fixed-effects predictions from the predictive model agreed with 77% (95% CI, 73%-81%) of the variability in the posttreatment pure tone average. This predictive model also had a sensitivity of 80% and a specificity of 75% for predicting an observed posttreatment pure tone average greater than 35 dB (area under the receiver operating characteristic curve, 0.85).
Conclusions and Relevance
To our knowledge, this study develops the first accurate prediction model of posttreatment hearing in patients with head and neck cancer that is feasible for use in the clinical setting before the initiation of treatment. This research confirms that exposure of the cochlea to cisplatin chemotherapy and radiotherapy is associated with hearing loss in patients with head and neck cancer. Finally, this research motivates future studies of ototoxic effects to better understand the adverse effects of head and neck cancer treatment.
This cohort study develops a hearing loss prediction model for patients with head and neck cancer after radiotherapy and/or cisplatin chemotherapy.
Introduction
Each year, more than a half million people in the world develop head and neck cancer, and more than a quarter million people die from it.1 When treated, these patients commonly receive radiotherapy as well as cisplatin in either the adjuvant or definitive treatment setting.2,3,4,5 Radiotherapy and cisplatin are known ototoxic agents,6,7,8 and patients with head and neck cancer can experience hearing loss and many other adverse effects of treatment.9 Hearing loss can often be overlooked despite its obvious negative effect on patients’ quality of life.10
The hearing loss associated with cisplatin and radiotherapy is well documented, following a dose-response relationship in previously published models.11,12,13,14,15 However, none of these models, not even the most robust model developed by Theunissen et al,14 can predict hearing loss before treatment because they all require information that is available only after the patient has completed treatment, such as cumulative cisplatin and radiotherapy dose. Thus, these models cannot be incorporated into a pretreatment, shared patient decision-making model in which the risks and benefits of various treatment options are discussed. In addition, although innovative, some of these models do not include any measure of performance or discrimination.15 Other models have small sample sizes11,12,13 and are missing data,14 lacking generalizability as a result.
Beginning in 2014, a multidisciplinary program for monitoring ototoxic effects was developed at Washington University School of Medicine in St Louis. Since then, more than 600 patients have been enrolled. Using the framework of this program, our study sought to develop a pretreatment predictive model of patient hearing, as measured by pure tone averages (PTAs) at 1, 2, and 4 kHz in patients with head and neck cancer treated with radiotherapy and/or cisplatin chemotherapy. Prior to the development of this prediction model, we first sought to replicate and enhance prior models of ototoxic effects by building a standard model of ototoxic effects that relied on information that was available only after the patient had fully completed treatment. The performance of this standard model could then be used as a benchmark for a new predictive model that uses only information available to clinicians at the beginning of treatment.
Methods
Study Design
A retrospective cohort study was conducted combining prospectively gathered patient information from Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St Louis, the Washington University Oncology Data Services Cancer Registry, radiation oncology treatment planning software (Varian), and a clinical audiometric database (AudBase). The cancer registry is an American College of Surgeons–accredited registry, which includes standard data elements16 as well as information on comorbid medical conditions. The protocol for this study was approved by the Washington University School of Medicine in St Louis Institutional Review Board. A waiver of informed consent was obtained owing to the retrospective study design.
Study Population
All patients with head and neck cancer who were treated with radiotherapy and/or cisplatin from October 1, 2014, to July 31, 2018, and seen for audiologic evaluation approximately 1 month before treatment and 2 months after treatment for follow-up were identified. Patients were excluded from the study if they had previously received cisplatin or radiotherapy or were concurrently being treated with carboplatin. In addition, patients with an unknown primary tumor site, missing radiotherapy treatment planning data, and missing staging data were excluded from the study population.
Patient Demographics and Tumor Characteristics
Patient demographics, including sex, age, tobacco use, and alcohol use, were evaluated. Patient comorbidity status, or other medical conditions not associated with cancer, were determined by the hospital-based cancer registrars using the Adult Comorbidity Evaluation–27.17 Tumor stage was divided into 2 categories: (1) stages 1, 2, and 3 or (2) stage 4. Tumor histologic characteristics were grouped into 2 categories: (1) squamous cell carcinoma or (2) all other tumor histologic characteristics. Primary tumor site was grouped into 4 categories based on the approximate distance to the cochlea: far, mid-far, mid-near, or close. The rationale for this tumor site grouping is that, in general, as a patient’s primary tumor moves closer to the cochlea, the amount of radiotherapy that the patient’s cochlea receives increases. A schematic of this tumor site grouping and specific details of the categorization are presented in Figure 1.
Figure 1. Primary Tumor Site by Approximate Distance to Cochlea.
Grouping of primary tumor site based on the site’s approximate distance to the cochlea, with preference of closer categorization given to sites with a greater likelihood of receiving high doses of radiotherapy.
Patient Treatment
All major modalities of patient treatment were evaluated, including surgery, surgery with clean margins, cisplatin treatment regimen, total cumulative cisplatin dose, and mean cochlear radiotherapy dose. Planned cisplatin treatment regimens were grouped into 3 categories based on presumed ototoxic effects: (1) no cisplatin, (2) induction cisplatin in addition to high-dose cisplatin treatment, or (3) all other cisplatin regimens (induction only, low dose only, induction and low dose, and high dose only). The overall cisplatin exposure at the end of treatment was quantified via the total cumulative cisplatin dose.
To determine the mean cochlear dose, a measure of the expected radiotherapy dose received by the inner ear, the volume of the inner ear was mapped using an axial computed tomography scan. The expected radiotherapy dose was then calculated for each voxel, or volume element, of the map using radiotherapy treatment planning software (Varian). The mean of the expected radiotherapy doses of all the voxels within the cochlea, or the mean cochlear dose, was then calculated.
Audiometric Evaluation
Pure-tone audiometry was conducted in a sound-treated booth in compliance with American National Standards on Acoustics S3.6-1996 approximately 1 month before treatment and approximately 2 months after completion of treatment. Prompt audiometric evaluation after treatment was necessary to minimize the number of patients lost to follow-up. However, we elected to wait 2 months to avoid some of the short-term middle ear effusions that are common in this patient population. Air and bone conduction thresholds were measured at 250, 500, 1000, 2000, 3000, and 4000 Hz; air conduction was also measured at 6000 and 8000 Hz. High-frequency audiometry (>8000 Hz) was performed at baseline to inform chemotherapy treatment planning but was not performed on completion of treatment because it no longer had any benefit for treatment planning. The PTA of 1000, 2000, and 4000 Hz was calculated. The 1-, 2-, and 4-kHz PTA before treatment was defined as the baseline PTA. We chose the 1-, 2-, and 4-kHz PTA air conduction because most speech information, roughly 67% of the speech spectrum,18 is contained within these frequencies. The primary end point of this study was the 1-, 2-, and 4-kHz PTA approximately 2 months after completion of treatment. To ensure that predictive models of the primary end point were not overly dependent on the baseline PTA, we included a secondary, dichotomous end point of an increase of 10 dB or greater in 1-, 2-, and 4-kHz PTA.
Statistical Analysis
Descriptive statistics were used to explore the distributions of patient demographics, tumor characteristics, treatment, and audiometric evaluations. The associations of patient demographics, tumor characteristics, patient treatment, and baseline 1-, 2-, and 4-kHz PTA with the primary end point, 1-, 2-, and 4-kHz PTA after treatment, was explored via linear mixed models. The standard multivariable mixed model for the primary end point was developed using all variables, including total cumulative cisplatin dose and mean cochlear radiotherapy dose, that were significant on univariable analysis or suspected to be of clinical importance. After the development of this standard multivariable model, a prediction multivariable model of the primary end point was developed including only variables whose values were known before treatment. Thus, total cumulative cisplatin dose and mean cochlear radiotherapy dose were excluded from prediction models. The SAS PROC MIXED procedure was used for all mixed models of the continuous primary end point. Mixed models were used to account for the nesting of ears within patients.
Multivariable models for the dichotomous secondary end point (ie, the increase of 10 dB or greater in 1-, 2-, and 4-kHz PTA) were developed. Again, both standard and predictive secondary models were developed. The SAS PROC GLIMMIX procedure was used for all mixed models of the dichotomous secondary end point.
Prior to assessing model performance, 10-fold stratified cross-validation was conducted using a previously developed SAS macro.19 The model performance of multivariable mixed models of the primary end point was approximated using the correlation, or R2, of the fixed-effect predictions with the actual primary end point values. Similarly, the model performance of multivariable mixed models of the secondary end point was measured using the area under the curve of the fixed-effect predictions for the actual secondary end-point values. In addition, model calibration of all multivariable models was assessed using calibration curves by decile. To provide a suitable clinical interface, interactive web-based dynamic nomograms were generated for both multivariable models of the primary end point.
Finally, to compare our predictive model of posttreatment PTA with the Theunissen et al model,14 we used a receiver operating characteristic (ROC) curve to evaluate the model’s ability to predict a posttreatment PTA at 1, 2, or 4 kHz of greater than 35 dB, a common threshold for hearing aid qualification. Based on the ROC curve, a threshold was chosen that optimally balanced sensitivity and specificity for prediction of a posttreatment PTA of at least 35 dB. Patients who began treatment with a PTA of at least 35 dB were excluded from this evaluation.
The α level for all analyses was set at .05. The Akaike information criterion was used to guide model development, and β values and 95% CIs were reported for all regression models. Analysis was performed in SAS, version 9.4 (SAS Institute Inc). Multivariable models of the primary end point were replicated in R, version 3.5.1 (R Foundation for Statistical Computing) using the lme4 library, and dynamic nomograms for these models were created using the DynNom library in R and Shiny, version 1.2.0.
Results
Patient Demographics and Tumor Characteristics
From October 2014 to July 2018, 427 patients with head and neck cancer with initial audiometric data were identified who received radiotherapy and/or chemotherapy treatment. Of these patients, 135 were excluded owing to lack of follow-up audiometric data. In addition, 50 patients were excluded secondary to previous receipt of cisplatin or radiotherapy (n = 17), concurrent treatment with carboplatin (n = 10), unknown primary tumor site (n = 8), missing radiotherapy treatment planning data (n = 17), and/or missing staging data (n = 3) (some patients were excluded for more than 1 reason). In addition, 2 patients had a single ear excluded secondary to anacusis. In total, 242 patients (482 ears) were included in the analysis.
This study included 186 men (76.9%) and 56 women (23.1%); the mean (SD) patient age was 60 (10) years. Most patients had at least mild concomitant medical comorbidities (Table 1) and were either actively using tobacco (83 of 233 [35.6%]) or had a history of tobacco use (73 of 233 [31.3%]).
Table 1. Patient Demographics, Tumor Characteristics, and Treatment Receiveda.
| Characteristic | No. (%) (N = 242) |
|---|---|
| Sex | |
| Male | 186 (76.9) |
| Female | 56 (23.1) |
| Age, mean (SD), y | 60 (10) |
| Tobacco use | |
| Never | 77/233 (33.0) |
| Prior | 73/233 (31.3) |
| Current | 83/233 (35.6) |
| Missing | 9 |
| Comorbidity status (ACE-27) | |
| None | 68/224 (30.4) |
| Mild | 93/224 (41.5) |
| Moderate | 40/224 (17.9) |
| Severe | 23/224 (10.3) |
| Missing | 18 |
| Tumor stage | |
| 1, 2, or 3 | 69 (28.5) |
| 4 | 173 (71.5) |
| Primary tumor site by approximate distance to cochlea | |
| Far | 144/482 (29.9) |
| Mid-Far | 145/482 (30.1) |
| Mid-Near | 169/482 (35.1) |
| Close | 24/482 (5.0) |
| Treatment received | |
| Surgery | |
| No | 90 (37.2) |
| Yes | 152 (62.8) |
| Cisplatin chemotherapy | |
| No | 137 (57) |
| Yes | 105 (43.4) |
| Planned cisplatin treatment regimen | |
| None | 137 (56.6) |
| Induction and high dose | 31 (12.8) |
| Other (induction, low dose, induction and low dose, high dose) | 74 (30.6) |
| Total cumulative cisplatin dose (n = 105) | |
| Mean (SD), mg/m2 | 298 (109) |
| Mean cochlear dose by ear (n = 482) | – |
| Mean (SD), Gy | 15 (13) |
Abbreviation: ACE-27, Adult Comorbidity Evaluation–27.
Alcohol use, histologic characteristics, and surgery with clean margins were also evaluated.
Patients’ morphologic extent of cancer was predominantly stage 4 (173 [71.5%]), located in the oropharynx (132 [54.5%]), and identified as squamous cell carcinoma on pathologic testing (225 [93.0%]). Most patients’ ears were a moderate distance from the primary cancer site, falling into either the mid-near (169 of 482 [35.1%]) or mid-far (145 of 482 [30.1%]) site category. Relatively few patient ears had a primary site close to the cochlea (24 of 482 [5.0%]) (Table 1).
Patient Treatment
All patients received some amount of radiotherapy treatment, and most had surgery as well (152 [62.8%]) (Table 1). Patients’ ears received a mean (SD) cochlear radiotherapy dose of 15 (13) Gy. A little less than half the patients received cisplatin chemotherapy (105 [43.4%]). About one-third of the patients receiving chemotherapy had both high-dose and induction cisplatin treatment planned (31 [12.8%]), and the mean (SD) total cumulative dose in patients receiving cisplatin was 298 (109) mg/m2.
Audiometric Evaluation
The mean (SD) 1-, 2-, and 4-kHz PTA of patient ears at baseline was 25 (17) dB. After treatment, the mean (SD) 1-, 2-, and 4-kHz PTA in patient ears increased to 30 (19) dB. Of the 482 unique ears included in the study, 103 (21.2%) had an increase of 10 dB or greater in 1-, 2-, and 4-kHz PTA. Among the 242 patients, 36 (14.9%) experienced a 10 dB or greater loss in both ears, 31 (12.8%) experienced a 10 dB or greater loss in a single ear, and 175 (72.3%) did not experience a 10 dB or greater loss in either ear.
Multivariable Analysis of Primary End Point
Multivariable models for the primary end point, posttreatment PTA at 1, 2, and 4 kHz, are shown in Table 2. In the standard model, total cumulative cisplatin dose was strongly associated with an increase in PTA after treatment, increasing the PTA by 2.92 dB for every increase of 100 mg/m2 of cisplatin (95% CI, 2.34-3.51 dB per 100 mg/m2). The mean cochlear radiotherapy dose was also associated with hearing loss, increasing the PTA by 0.92 dB for every 10 Gy of mean cochlear dose (95% CI, 0.33-1.50 dB per 10Gy). Older patients and patients with better hearing were also more likely to experience hearing loss after treatment. After cross-validation, the fixed-effects predictions from the standard model agreed with 79% (95% CI, 75%-82%) of the variability in posttreatment PTA. This correlation between predicted and observed values is observed in the calibration curve for the standard model of posttreatment PTA (Figure 2).
Table 2. Standard and Predictive Models of 1-, 2-, and 4-kHz PTA After Treatment.
| Model | β (95% CI) |
|---|---|
| Standard model | |
| Age (per 10 y) | 0.05 (0.08 to 2.03) |
| Baseline 1-, 2-, and 4-kHz PTA | 0.95 (0.90 to 1.01) |
| Total cumulative cisplatin dose (per 100 mg/m2 of cisplatin) | 2.92 (2.34 to 3.51) |
| Mean cochlear radiotherapy dose (per 10 Gy) | 0.92 (0.33 to 1.50) |
| Predictive model | |
| Age (per 10 y) | 1.08 (0.08 to 2.08) |
| Baseline 1-, 2-, and 4-kHz PTA | 0.95 (0.90 to 1.01) |
| Planned cisplatin regimen | |
| None | 0 [Reference] |
| Induction and high-dose | 13.57 (10.53 to 16.62) |
| Othera | 5.35 (3.14 to 7.56) |
| Primary tumor site by approximate distance to cochlea | |
| Far | 0 [Reference] |
| Mid-Far | 1.57 (0.48 to 3.62) |
| Mid-Near | 1.97 (0.15 to 3.79) |
| Close | 2.46 (–1.02 to 5.93 |
Abbreviation: PTA, pure tone average.
Other includes induction, low-dose, induction and low-dose, and high-dose regimens.
Figure 2. Calibration Curves for the Standard and Predictive Models of Posttreatment Pure Tone Average (PTA).
Calibration curves for the cross-validated standard and predictive models of posttreatment PTA, which plot the predicted and observed values by decile. The vertical lines indicate 95% CIs. The diagonal dashed line indicates a perfect model for which the predicted and observed values match exactly.
In the predictive model, the planned cisplatin treatment regimen was predictive of posttreatment PTA, with patients who received both induction and high-dose cisplatin treatment experiencing a mean increase in posttreatment PTA of 13.57 dB (95% CI, 10.53-16.62 dB) (Table 2). Primary tumor site produced a stepwise increase in PTA, with sites closer to the cochlea having greater increases in posttreatment PTA than those further away. Older patients and patients with better hearing had more hearing loss after treatment in the predictive model as well. On cross-validation, the fixed-effects predictions from the predictive model agreed with 77% (95% CI 73%-81%) of the variability in posttreatment PTA. This correlation between predicted and observed values was again demonstrated in the calibration curve for the predictive model of posttreatment PTA (Figure 2). Screenshots of the dynamic nomogram that was created for this predictive model and that could be used in the clinical setting for pretreatment patient counseling are available in eFigure 2 in the Supplement.
Multivariable Analysis of the Secondary End Point
Multivariable models for the secondary end point (ie, an increase in posttreatment 1-, 2-, and 4-kHz PTA of 10 dB or greater) are provided in the eTable in the Supplement. The same predictor variables were included in these multivariable models with the exception of baseline PTA, which was not a significant predictor. After cross-validation, the area under the ROC curve of the fixed-effects predictions for an increase in posttreatment PTA of 10 dB or greater was 0.82 for the standard model and 0.78 for the predictive model. Calibration curves for these models are also included in eFigure 1 in the Supplement.
Comparison With the Theunissen et al Model
Figure 3 displays the ROC curve for predicting a posttreatment PTA at 1, 2, and 4 kHz of greater than 35dB via the predictive model, using only variables available prior to initiation of treatment. The area under this ROC curve was 0.85. An optimal threshold of a predicted posttreatment PTA greater than 27.4 dB predicted an observed posttreatment PTA greater than 35 dB with a sensitivity of 80% and specificity of 75%.
Figure 3. Receiver Operating Characteristic (ROC) Curve for Predicting a Pure Tone Average (PTA) of Greater Than 35 dB After Treatment.
The ROC curve for predicting a posttreatment PTA of greater than 35 dB using the predictive model of posttreatment PTA has an area under the ROC curve of 0.85. The circle shows the location on the ROC, which provides an optimal balance of sensitivity (81%) and specificity (74%). This point on the ROC curve corresponds to a threshold for predictions of posttreatment PTA of 27.4 dB or greater.
Discussion
In this study, we confirmed that age, baseline PTA, cisplatin dose, and mean cochlear radiotherapy dose are associated with posttreatment hearing in patients with head and neck cancer. In addition, we developed an accurate prediction model for posttreatment hearing that has the potential to be used in the clinical setting for patient counseling and treatment planning.
To our knowledge, this is the first truly predictive model of ototoxic effects because it is based exclusively on information that is available prior to treatment. Furthermore, the variables included in our predictive model can be easily obtained by any member of a multidisciplinary team, and both models of posttreatment PTA are provided in an accessible, easy-to-use, online interface.
The predictive model in this study compares favorably with prior models of ototoxic effects. When compared with the standard model developed by Theunissen et al,14 our predictive model has much better discrimination and overall performance (increase in area under the ROC curve from 0.68 to 0.85) and provides a greater balance of sensitivity (increase from 27% to 81%) and specificity (decrease from 97% to 74%). In comparison with the same Theunissen et al model,14 our model also suggests a greater role for cisplatin chemotherapy in determining patient hearing after treatment for head and neck cancer (increase of 3 dB per 100 mg/m2 rather than 2 dB per 100 mg/m2 at 1-, 2-, and 4-kHz PTA) and a diminished importance of mean cochlear radiation dose (increase in PTA of 1 dB instead of 2 dB per 10 Gy).
Limitations
The limitations of this study are similar to those in prior literature evaluating ototoxic effects in patients with head and neck cancer. Several patients were excluded from the study owing to prior or current treatment regimens as well as missing data, and only patients with follow-up audiometric data were included in our study population. Thus, there is the potential for selection bias in our study cohort; it is unclear how this selection bias may affect the results of the study. We recognize that radiotherapy and cisplatin treatment may continue to affect patients’ hearing well beyond 2 months after completion of treatment. However, assessing these long-term effects is beyond the scope of this study. This study was also unable to delineate between conductive hearing loss from middle ear effusion and sensorineural hearing loss. We were also able to evaluate only standard treatment regimens during the study period and could not appreciate how new treatment practices, such as immunotherapy, will affect predictions for future patients. Finally, patient-reported outcome measures for hearing loss and quality of life were not included in this study.
In the future, we plan to validate the predictive model of posttreatment hearing developed in this study in a new cohort of patients with head and neck cancer. Once validated, this predictive model could be accessed online for clinical use during patient counseling and treatment planning, especially in the setting of equivocal treatment regimens. Future studies may build on the results of this study by including patient-reported measures of hearing loss and quality of life to obtain a more complete perspective of the associations of head and neck cancer treatment with patients’ hearing.
Conclusions
To our knowledge, this study develops the first accurate prediction model of posttreatment hearing in patients with head and neck cancer that is feasible for use in the clinical setting before the initiation of treatment. This research confirms that exposure of the cochlea to cisplatin chemotherapy and radiotherapy is associated with hearing loss in patients with head and neck cancer. Finally, it motivates future studies of the ototoxic effects in patients with head and neck cancer to better understand the adverse effects of head and neck cancer treatment.
eTable. Standard and Predictive Models of an Increase of 10dB or Greater in 1-2-4 kHz Pure Tone Average (PTA) After Treatment
eFigure 1. Calibration Curves for the Standard and Predictive Models of an Increase of 10dB or Greater in 1-2-4 kHz Pure Tone Average (PTA) After Treatment
eFigure 2. Dynamic Nomogram Screenshot
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Associated Data
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Supplementary Materials
eTable. Standard and Predictive Models of an Increase of 10dB or Greater in 1-2-4 kHz Pure Tone Average (PTA) After Treatment
eFigure 1. Calibration Curves for the Standard and Predictive Models of an Increase of 10dB or Greater in 1-2-4 kHz Pure Tone Average (PTA) After Treatment
eFigure 2. Dynamic Nomogram Screenshot