Due to the retrospective design of this study, high percentages of missing values were seen. This might be explained by the fact that audiometric testing is time consuming, especially when ultra-high frequencies and bone conduction thresholds are included. Patients enduring intensive treatment schemes may sometimes be too tired or too ill to perform the whole audiometric procedure. Assuming that data were randomly missing, we imputed these using a MICE imputation mechanism.25 Furthermore, the prediction model requires 5 inputs (figure 1) including a baseline pure tone audiogram, cisplatin dose and the radiation dose to the inner ear. Fortunately, PTAs 0.5-1-2 and 1-2-4 kHz are automatically calculated by the audiology system.
However, 8-10-12.5 kHz calculations are not yet automated and radiation dose to the cochlea may not be available by default. However, we do feel that in patients suffering hearing loss due to treatment, it is still worth to record these variables.
Future directions
Before implementation in a clinical setting, external validation of the present model is required. As a first step we used the ’10-fold cross-validation’, reducing the effect of over-optimistic assessment of a model built and validated on the same data. In the future, an internal patient cohort should be used to further test our statistical model.
Thereafter, external validation should be attempted. Furthermore, the current model is based on patients treated with chemoradiation as their primary treatment for head and neck cancer. In clinical practice, the problem of hearing loss as an adverse event is also seen in patients treated with cisplatin for lung, bladder, gynecological cancer, or applied in a postoperative setting. So, to use the prediction model in other patient cohorts, further external validation in other patient cohorts is needed.
CH 04
CONCLUSION
Overall, our prediction model is a step towards improving individual counseling of patients with head and neck cancer at risk for CCRT-related hearing loss. However, future research concerning more variables as risk factors for hearing loss is needed.
Furthermore, before implementation in a clinical setting, external validation of the present model is required.
AKNOWLEGMENTS
This work was supported by an unrestricted grant from the Riki Stichting.
CH 04
1. Pignon JP, le Maitre A, Maillard E, Bourhis J. Me-ta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. Jul 2009;92(1):4-14.
2. Pignon JP, Bourhis J, Domenge C, Designe L.
Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemo-therapy on Head and Neck Cancer. Lancet. Mar 18 2000;355(9208):949-955.
3. Hetu R. The stigma attached to hearing impairment.
Scand Audiol Suppl. 1996;43:12-24.
4. Prestes R, Daniela G. Impact of tinnitus on quality of life, loudness and pitch match, and high-frequency audiometry. Int Tinnitus J. 2009;15(2):134-138.
5. Mujica-Mota M, Waissbluth S, Daniel SJ. Charac-teristics of radiation-induced sensorineural hearing loss in head and neck cancer: a systematic review.
Head Neck. Nov 2013;35(11):1662-1668.
6. Zuur CL, Simis YJ, Lamers EA, et al. Risk factors for hearing loss in patients treated with intensity-mo-dulated radiotherapy for head-and-neck tumors. Int J Radiat Oncol Biol Phys. Jun 1 2009;74(2):490-496.
7. Skinner R, Pearson AD, Amineddine HA, Mathias DB, Craft AW. Ototoxicity of cisplatinum in children and adolescents. Br J Cancer. Jun 1990;61(6):927-931.
8. Zuur CL, Simis YJ, Lansdaal PE, et al. Risk factors of ototoxicity after cisplatin-based chemo-irradiation in patients with locally advanced head-and-neck can-cer: a multivariate analysis. Int J Radiat Oncol Biol Phys. Aug 1 2007;68(5):1320-1325.
9. Honore HB, Bentzen SM, Moller K, Grau C. Sen-sori-neural hearing loss after radiotherapy for nasop-haryngeal carcinoma: individualized risk estimation.
Radiother Oncol. Oct 2002;65(1):9-16.
10. Zuur CL, Simis YJ, Lansdaal PE, et al. Ototoxicity in a randomized phase III trial of intra-arterial com-pared with intravenous cisplatin chemoradiation in patients with locally advanced head and neck cancer.
J Clin Oncol. Aug 20 2007;25(24):3759-3765.
11. van Buuren S, Boshuizen HC, Knook DL. Multiple imputation of missing blood pressure covariates in survival analysis. Stat Med. Mar 30 1999;18(6):681-694.
12. Raghunathan TE, Lepkowski JM, Hoenwijk v. A multivariate technique for multiply imputing missing values using a sequence of regression models. Sur-vey Methodology. 2001;27(1):85-95.
13. Barnard J, Rubin DB. Small-sample degrees of free-dom with multiple imputations. Biometrika 1999;86:948-955.
14. Rubin DB: Multiple imputation for nonresponse in survey. Inc., Hoboken, NJ, USA, John Wiley& Sons, 1987, pp 75-79
15. Dutch Health Insurance; article 2.10.a: Hulpmid-delen ter compensatie van beperkingen in het luiste-ren of bedienen van communicatieappartuur.
16. Johnson A, Tarima S, Wong S, Friedland DR, Run-ge CL. Statistical model for prediction of hearing loss in patients receiving cisplatin chemotherapy. JAMA Otolaryngol Head Neck Surg. Mar 2013;139(3):256-264.
17. Dille MF, Wilmington D, McMillan GP, Helt W, Fausti SA, Konrad-Martin D. Development and validation of a cisplatin dose-ototoxicity model. J Am Acad Audiol. Jul-Aug 2012;23(7):510-521.
18. Low WK, Kong SW, Tan MG. Ototoxicity from combined Cisplatin and radiation treatment: an in vi-tro study. Int J Otolaryngol. 2010;2010:523976.
19. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiothera-py in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. Jan 1 2003;21(1):92-98.
20. Waissbluth S, Daniel SJ. Cisplatin-induced oto-toxicity: transporters playing a role in cisplatin toxici-ty. Hear Res. May 2013;299:37-45.
REFERENCES
CH 04 21. Pussegoda K, Ross CJ, Visscher H, et al.
Repli-cation of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children. Clin Pharmacol Ther. Apr 10 2013.
22. Steyerberg EW: Clinical Prediction Models, Uni-versity Medical Center Rotterdam, The Netherlands, Springer, 2009, pp. 135