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Trismus secondary to head and neck cancerKamstra, Jolanda Ilona

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Trismus secondary tohead and neck cancer

Risk factors and exercise therapy

Jolanda I. Kamstra

ISBN: 978-90-367-9174-8ISBN e-book: 978-90-367-9171-7Bookdesign: SgaarPrinted by: Drukkerij van der Eems Copyright: J.I. Kamstra, 2016All rights reserved. No part of this publication may be re reported or transmitted, in any form or by any means, without permission of the author.

Trismus secondary to head and neck cancer

Risk factors and exercise therapy

Proefschrift

ter verkrijging van de graad van doctor aan deRijksuniversiteit Groningen

op gezag van de rector magnificus prof. dr. E. Sterken

en volgens besluit van het College voor Promoties.

De openbare verdediging zal plaatsvinden op

woensdag 9 november 2016 om 16.15 uur

door

Jolanda Ilona Kamstrageboren op 21 mei 1986

te Leeuwarden

PromotoresProf. dr. P.U. DijkstraProf. dr. J.L.N. Roodenburg

CopromotorDr. H. Reintsema

Beoordelingscommissie Prof. dr. J.H.B. GeertzenProf. dr. M.A.W. MerkxProf. dr. F.K.L. Spijkervet

ParanimfenF.A. Eggink, MScDrs. Y.J. Kleinbergen

Chapter 1General introduction and outline of this thesis

8

Chapter 1

General introduction

Head and neck cancerHead and neck cancer includes tumors of the of the lip, oral cavity, nasopharynx, oro-pharynx, hypopharynx, larynx, and salivary glands.1 Over 90% of the tumors of the head and neck are squamous cell carcinomas of these locations.2 The incidence of head and neck cancer in the Netherlands in 2000 was 2,481 persons. The incidence increased with almost 20% to 2,964 persons in 2013. In the Netherlands, 816 patients died because of their head and neck cancer in 2000, this were 875 patients in 2013. An increase of about 7%.3 Etiological factors for squamous cell carcinomas of the upper aerodigestive tract are the use of tobacco and alcohol.2, 4 In oropharyngeal cancer, the human papillomavirus (HPV) is also an important etiological factor.2 Overall prognosis of patients with a tumor associated with HPV is better than of patients who have a tumor that is not.2

Treatment modalities for head and neck cancer includes surgery and radiotherapy. Radiotherapy can be combined with chemotherapy and biologicals. During and after treatment, patients can suffer from side effects such as trismus, mucositis, and xerosto-mia.5, 6 These side effects can be a burden for patients and can impede on quality of life (QoL).7, 8 Treatment of head and neck cancer can also impede on mandibular function. Mandibular function includes speaking, eating, laughing, yawing, and social activities. Side effects and impairment of mandibular function are related to location and classification of the tumor and the treatment modalities applied.6, 9 Since the number of patients who are successfully treated for their head and neck cancer is increasing, the number of pa-tients with impaired mandibular function and QoL is also increasing.

TrismusHead and neck cancer patients frequently suffer from trismus, a limited ability to open the mouth.10, 11 A mouth opening of 35 mm or less is a commonly used cut-off point for trismus.12, 13 Trismus can be present before treatment because of invasion of the tumor in the masticatory muscles and temporomandibular joint, or their surrounded tissues.14 Surgery may lead to trismus because of scar formation in or near the masticatory mus-cles.15 Radiotherapy may cause fibrosis of the masticatory muscles, temporomandibular joint, and cheek, which can also lead to trismus.15-17 When the medial pterygoid muscle is included in the irradiated region, the risk of developing trismus increases.18 Trismus usually occurs 3 to 6 months post-radiotherapy and can continue up to 2 years post-radiotherapy.15 Trismus usually occurs 3 to 6 months post-radiotherapy and a progres-sive decrease in mouth opening can be observed up to 2 years post-radiotherapy. Large differences in prevalence and incidence of trismus in head and neck cancer patients have been reported: between the 5 and 42%.11, 13, 20 Trismus can impair oral hygiene, dental treatment, and oncological follow-up.5, 21 Trismus can also, in addition to other side effects after head and neck cancer, impact negatively on mandibular function and QoL.8, 12, 21

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Prevention and treatment of trismusA decrease in mouth opening of head and neck cancer patients cannot always prevent-ed by exercise therapy.22, 23 Therefore, preventive exercises are only advised for patients with a high risk for developing trismus.22-25 When trismus is present, generally a lim-ited increase in mouth opening can be achieved following different types of therapies, including exercise therapy and administration of pentoxifylline.15 There is no standard treatment for trismus; many different types of therapy have been described in litera-ture and are clinically applied.23-41 Stretching techniques are used as exercise therapy, for example conventional range of motion exercises that are sometimes combined with tools as dynamic bite openers, tongue depressors, and rubber plugs.23-27 Many (unusual) stretching techniques have been described in case reports and case series, for example stretching with a home-made sledgehammer device.28-31 Advanced stretching devices as the Dynasplint Trismus System® (DTS) and the TheraBite® Jaw Motion Rehabilitation System™ (TheraBite) can be used to treat trismus.32-37 Trismus can also be treated by surgical procedures that are mainly used if exercise therapy has failed. Tissue release, a coronoidectomy, or lowering the height of the mandible are applied to obtain a larger mouth opening.38-41

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Chapter 1

Outline of this thesis

General aims of this thesis are to analyze the burden of side effects after treatment of oral and oropharyngeal cancer and their influence on mandibular function, to identify risk factors for trismus after head and neck cancer, and to evaluate exercise therapy for trismus after head and neck cancer.

Side effects after treatment of oral and oropharyngeal cancerOf all side effects oral and oropharyngeal cancer patients may experience after treat-ment, it is unclear which oral symptoms are most burdensome for patients and which factors have the largest impact on mandibular function. This information may be used to prioritize preventive measures for oral symptoms in order to maintain or improve mandibular function. In Chapter 2, the oral symptoms related to oral and oropharyngeal cancer, their burden, and their association with mandibular function were analyzed. In this cross-sectional study, 89 patients who had completed their oral and oropharyngeal cancer treatment for at least 6 months were included.

Risk factors for trismus after head and neck cancerPrevious studies that aimed to identify risk factors for trismus are limited by their ret-rospective design and relatively small sample sizes. The longitudinal course of mouth opening up to 1 year following surgery and/or radiotherapy (with or without che-motherapy) has been described in 4 studies with small sample sizes, limited number of primary tumor sites, or no radiotherapy applied as part of the treatment.19, 42-44 Consequently, when several risk factors are present, it has been impossible to predict mouth opening of head and neck cancer patients after radiotherapy because of lack of statistical power. In Chapter 3.1, the longitudinal course of mouth opening up to 48 months post-radiotherapy and risk factors predicting mouth opening were analyzed. A multivariate prediction model for change in mouth opening was developed. This multi-variate prediction model for mouth opening had a limited clinical application because of its complexity. In Chapter 3.2, the incidence of trismus and risk factors for developing trismus at different time points post-radiotherapy were analyzed for adequate predic-tion of trismus, during and post-radiotherapy. In these prospective longitudinal cohort studies described in Chapter 3.1 and Chapter 3.2, 641 patients irradiated for head and neck cancer were included.

Exercise therapy for trismus after head and neck cancerIn recent years, numerous studies have been published regarding exercise therapy for trismus, which have not been evaluated in a systematic review yet. In Chapter 4.1, stud-ies regarding exercise therapy interventions for trismus secondary to head and neck cancer were identified, their methodological quality was analyzed, and the results of these studies were summarized. In this systematic review, 20 studies were included.

The effects of TheraBite exercises for the treatment of trismus in head and neck cancer patients have been described in several studies, whether or not as part of a mul-

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timodal treatment. Reported increase in mouth opening ranges between -1.9 and 13.6 mm.35-37 However, factors influencing the effect of TheraBite exercises are unknown. In Chapter 4.2, the clinical effect (as change in mouth opening in mm) of TheraBite exer-cise therapy for trismus secondary to head and neck cancer and factors influencing this effect were analyzed. In this chart review study, 69 head and neck cancer patients of 2 medical centers were included.

The effects of DTS exercises as change in mouth opening have been described in 3 retrospective studies. Reported increase in mouth opening ranges between 6.2 and 13.6 mm.32-34 The patients’ perception of DTS exercises has not been described. In Chapter 4.3, DTS exercises in head and neck cancer patients with trismus were analyzed. Effects on mouth opening, pain, mandibular function, QoL, and symptomatology and patients’ perspective regarding DTS exercises, including user-satisfaction, experiences, comfort, and compliance were analyzed. In this prospective mixed methods study, 18 patients were included.

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Chapter 1

1. Sobin LH, Gospodarowicz MK, Wittekind C, edi-

tors. TNM Classification of Malignant Tumours. :

Wiley-Blackwell; 2009. 336 p.

2. Marur S, Forastiere AA. Head and neck cancer:

changing epidemiology, diagnosis, and treatment.

Mayo Clin Proc 2008;83:489-501.

3. Integraal Kanker Centrum Nederland.

4. Argiris A, Karamouzis MV, Raben D, Ferris RL.

Head and neck cancer. Lancet 2008;371:1695-

1709.

5. Vissink A, Jansma J, Spijkervet FK, Burlage FR,

Coppes RP. Oral sequelae of head and neck radio-

therapy. Crit Rev Oral Biol Med 2003;14:199-212.

6. Zuydam AC, Lowe D, Brown JS, Vaughan ED, Rog-

ers SN. Predictors of speech and swallowing func-

tion following primary surgery for oral and oropha-

ryngeal cancer. Clin Otolaryngol 2005;30:428-437.

7. Epstein JB, Robertson M, Emerton S, Phillips N,

Stevenson-Moore P. Quality of life and oral function

in patients treated with radiation therapy for head

and neck cancer. Head Neck 2001;23:389-398.

8. Louise Kent M, Brennan MT, Noll JL, et al. Ra-

diation-induced trismus in head and neck cancer

patients. Support Care Cancer 2008;16:305-309.

9. Rogers SN, Lowe D, Brown JS, Vaughan ED.

The University of Washington head and neck

cancer measure as a predictor of outcome follow-

ing primary surgery for oral cancer. Head Neck

1999;21:394-401.

10. Dijkstra PU, Kalk WW, Roodenburg JL. Trismus in

head and neck oncology: a systematic review. Oral

Oncol 2004;40:879-889.

11. Bensadoun RJ, Riesenbeck D, Lockhart PB, et al.

A systematic review of trismus induced by cancer

therapies in head and neck cancer patients. Support

Care Cancer 2010;18:1033-1038.

12. Scott B, Butterworth C, Lowe D, Rogers SN.

Factors associated with restricted mouth opening

and its relationship to health-related quality of life

in patients attending a Maxillofacial Oncology clinic.

Oral Oncol 2008;44:430-438.

13. Dijkstra PU, Huisman PM, Roodenburg JL. Crite-

ria for trismus in head and neck oncology. Int J Oral

Maxillofac Surg 2006;35:337-342.

14. Ichimura K, Tanaka T. Trismus in patients with

malignant tumours in the head and neck. J Laryngol

Otol 1993;107:1017-1020.

15. Fischer DJ, Epstein JB. Management of patients

who have undergone head and neck cancer therapy.

Dent Clin North Am 2008;52:39-60, viii.

16. Vissink A, Burlage FR, Spijkervet FK, Jansma J,

Coppes RP. Prevention and treatment of the con-

sequences of head and neck radiotherapy. Crit Rev

Oral Biol Med 2003;14:213-225.

17. Hsieh LC, Chen JW, Wang LY, et al. Predicting the

severity and prognosis of trismus after intensity-

modulated radiation therapy for oral cancer pa-

tients by magnetic resonance imaging. PLoS One

2014;9:e92561.

18. Goldstein M, Maxymiw WG, Cummings BJ,

Wood RE. The effects of antitumor irradiation

on mandibular opening and mobility: a prospec-

tive study of 58 patients. Oral Surg Oral Med Oral

Pathol Oral Radiol Endod 1999;88:365-373.

19. Wang CJ, Huang EY, Hsu HC, Chen HC, Fang FM,

Hsiung CY. The degree and time-course assessment

of radiation-induced trismus occurring after radio-

therapy for nasopharyngeal cancer. Laryngoscope

2005;115:1458-1460.

20. Johnson J, van As-Brooks CJ, Fagerberg-Mohlin

B, Finizia C. Trismus in head and neck cancer pa-

tients in Sweden: incidence and risk factors. Med

Sci Monit 2010;16:CR278-82.

References

13

Gen

eral

intr

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tion

21. Weber C, Dommerich S, Pau HW, Kramp B. Lim-

ited mouth opening after primary therapy of head

and neck cancer. Oral Maxillofac Surg 2010;14:169-

173.

22. Loorents V, Rosell J, Karlsson C, Lidback M, Hult-

man K, Borjeson S. Prophylactic training for the

prevention of radiotherapy-induced trismus - a

randomised study. Acta Oncol 2014;53:530-538.

23. Grandi G, Silva ML, Streit C, Wagner JC. A mobili-

zation regimen to prevent mandibular hypomobility

in irradiated patients: an analysis and comparison

of two techniques. Med Oral Patol Oral Cir Bucal

2007;12:E105-9.

24. Rose T, Leco P, Wilson J. The Development of

Simple Daily Jaw Exercises for Patients Reveiv-

ing Radical Head and Neck Radiotherapy. Jour-

nal of Medical Imaging and Radiation Sciences

2009;40:32-37.

25. Ren WH, Ao HW, Lin Q, Xu ZG, Zhang B. Efficacy

of mouth opening exercises in treating trismus after

maxillectomy. Chin Med J (Engl) 2013;126:2666-

2669.

26. Dijkstra PU, Sterken MW, Pater R, Spijkervet FK,

Roodenburg JL. Exercise therapy for trismus in head

and neck cancer. Oral Oncol 2007;43:389-394.

27. Li XH, Liao YP, Tang JT, Zhou JM, Wang GH. Effect

of early rehabilitation training on radiation-induced

trismus in nasopharyngeal carcinoma patients. Ai

Zheng 2007;26:987-990.

28. Alexander SA, Renner RP. Increasing occlusal

vertical dimension with an orthodontic ‘clothes

pin appliance.’ A clinical report. J Prosthet Dent

1989;62:1-3.

29. Lund TW, Cohen JI. Trismus appliances and indi-

cations for use. Quintessence Int 1993;24:275-279.

30. Ziccardi VB, Ochs MW, Braun TW. Intraopera-

tively fabricated bite block in the management of

scar contracture hypomobility. Oral Surg Oral Med

Oral Pathol Oral Radiol Endod 1995;80:34-35.

31. Abdel-Galil K, Anand R, Pratt C, Oeppen B, Bren-

nan P. Trismus: an unconventional approach to

treatment. Br J Oral Maxillofac Surg 2007;45:339-

340.

32. Shulman DH, Shipman B, Willis FB. Treating tris-

mus with dynamic splinting: a cohort, case series.

Adv Ther 2008;25:9-16.

33. Stubblefield MD, Manfield L, Riedel ER. A pre-

liminary report on the efficacy of a dynamic jaw

opening device (dynasplint trismus system) as part

of the multimodal treatment of trismus in patients

with head and neck cancer. Arch Phys Med Rehabil

2010;91:1278-1282.

34. Baranano CF, Rosenthal EL, Morgan BA, McCol-

loch NL, Magnuson JS. Dynasplint for the manage-

ment of trismus after treatment of upper aerodi-

gestive tract cancer: a retrospective study. Ear Nose

Throat J 2011;90:584-590.

35. Buchbinder D, Currivan RB, Kaplan AJ, Urken

ML. Mobilization regimens for the prevention of

jaw hypomobility in the radiated patient: a com-

parison of three techniques. J Oral Maxillofac Surg

1993;51:863-867.

36. Tang Y, Shen Q, Wang Y, Lu K, Wang Y, Peng

Y. A randomized prospective study of rehabilita-

tion therapy in the treatment of radiation-induced

dysphagia and trismus. Strahlenther Onkol

2011;187:39-44.

37. Pauli N, Fagerberg-Mohlin B, Andrell P, Finizia C.

Exercise intervention for the treatment of trismus in

head and neck cancer. Acta Oncol 2014;53:502-509.

38. Mardini S, Chang YM, Tsai CY, Coskunfirat OK,

Wei FC. Release and free flap reconstruction for

trismus that develops after previous intraoral re-

construction. Plast Reconstr Surg 2006;118:102-

107.

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39. Bhrany AD, Izzard M, Wood AJ, Futran ND.

Coronoidectomy for the treatment of trismus

in head and neck cancer patients. Laryngoscope

2007;117:1952-1956.

40. Tsai CY, Ali RS, Wei FC, Chang YM. Reduc-

ing mandibular height to increase mouth open-

ing in unreleasable trismus. J Oral Maxillofac Surg

2010;68:1628-1630.

41. Bouman MA, Dijkstra PU, Reintsema H, Rooden-

burg JL, Werker PM. Surgery for extra-articular

trismus: a systematic review. Br J Oral Maxillofac

Surg 2015.

42. Scott B, D’Souza J, Perinparajah N, Lowe D, Rog-

ers SN. Longitudinal evaluation of restricted mouth

opening (trismus) in patients following primary

surgery for oral and oropharyngeal squamous cell

carcinoma. Br J Oral Maxillofac Surg 2011;49:106-

111.

43. Lee R, Slevin N, Musgrove B, Swindell R, Molas-

siotis A. Prediction of post-treatment trismus in

head and neck cancer patients. Br J Oral Maxillofac

Surg 2012;50:328-332.

44. Wetzels JW, Merkx MA, de Haan AF, Koole R,

Speksnijder CM. Maximum mouth opening and tris-

mus in 143 patients treated for oral cancer: A 1-year

prospective study. Head Neck 2014;36:1754-1762.

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Chapter 2Oral symptoms and functional outcome related to oral and oropharyngeal cancer

This chapter is an edited version of:Kamstra JI, Jager-Wittenaar H, Dijkstra PU, Huisman PM, van Oort RP, van der Laan BFAM, Roodenburg JLN. Oral symptoms and functional outcome related to oral and oropharyngeal cancer. Support Care Cancer 2011;19:1327-1333.

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Abstract

ObjectivesAims of this study were to assess (1) oral symptoms of patients treated for oral or oro-pharyngeal cancer, (2) how patients rank the burden of oral symptoms, and (3) the im-pact of the tumor, the treatment, and the oral symptoms on functional outcome.

MethodsEighty-nine patients treated for oral or oropharyngeal cancer were asked about their oral symptoms related to mouth opening, dental status, oral sensory function, tongue mobility, salivary function, and pain. They were asked to rank these oral symptoms ac-cording to the degree of burden experienced. The Mandibular Function Impairment Questionnaire (MFIQ) was used to assess functional outcome. In a multivariable linear regression analysis, variables related to MFIQ scores (p≤0.10) were entered as predic-tors with MFIQ score as the outcome.

ResultsLack of saliva (52%), restricted mouth opening (48%), and restricted tongue mobility (46%) were the most frequently reported oral symptoms. Lack of saliva was most fre-quently (32%) ranked as the most burdensome oral symptom. For irradiated patients, an inability to wear a dental prosthesis, a T3 or T4 stage, and a higher age were predictive of MFIQ scores. For non-irradiated patients, a restricted mouth opening, an inability to wear a dental prosthesis, restricted tongue mobility, and surgery of the mandible were predictive of MFIQ scores.

ConclusionLack of saliva was not only the most frequently reported oral symptom after treatment for oral or oropharyngeal cancer, but also the most burdensome. Functional outcome was strongly influenced by an inability to wear a dental prosthesis in both irradiated and non-irradiated patients.

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Introduction

After oral and oropharyngeal cancer treatment, patients may report several oral symp-toms, such as a restricted mouth opening, lack of saliva, an inability to wear a dental prosthesis or lack of retention of the prosthesis, loss of oral sensory function, and re-stricted tongue mobility.1-3 These oral symptoms can have a negative influence on func-tional outcome.

Functional outcome after treatment for oral or oropharyngeal cancer is related to tumor site, tumor size, and the type of treatment received.4-8 A study in patients treated for cancer of the base of the tongue, found that surgery which included the mandible (mandibulectomy or mandibulotomy) reduced functional outcome significantly more than surgery which did not include the mandible.5 In that study, functional outcome was assessed by eating, speech, and diet (eating in public and normalcy of diet). Furthermore, reconstruction with free tissue transfer resulted in a significantly worse functional out-come when compared to direct reconstruction techniques.5, 6, 8 Finally, a higher T classification (T3 or T4) and a larger resection size are also associated with a poorer functional outcome.4-6, 8

In addition to tumor and treatment characteristics, oral symptoms may also impede functional outcome. A restricted mouth opening affects mandibular function, including chewing, eating, and swallowing, and may also impede oral hygiene, dental treatment, and oncological follow-up.9 Lack of saliva, resulting from radiation-induced damage to the salivary glands or from removal of a salivary gland, impedes consolidation of a food bolus and functional outcome significantly.10, 11 Lack of retention and pain may inhibit biting and chewing in edentulous or partially dentulous patients wearing a dental pros-thesis.10 Clinically, pain in the mouth can also impede functional outcome.

To study oral symptoms related to oral and oropharyngeal cancer, and their as-sociation with functional outcome, 3 aims were formulated for this study. The first was to assess oral symptoms of patients treated for oral or oropharyngeal cancer. Before treatment of oral or oropharyngeal cancer, most patients rank being cured as the most important outcome, followed by living as long as possible, and having no pain. Only a few patients rank normal swallowing, normal taste, and normal salivation as important.12, 13 It is currently unclear which oral symptoms are most burdensome to patients after treat-ment of oral and oropharyngeal cancer. The second aim was therefore to assess how patients rank the burden of their oral symptoms. Finally, oral or oropharyngeal cancer and the consequences of treatment can influence mandibular functioning (Figure 1). However, it is unclear which factors have the largest impact on functional outcome. The third aim was to analyze the impact of the tumor, cancer treatment, and oral symptoms on functional outcome.

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Tumor characteristics- T classification- Location- Type

Treatment characteristics- Surgery - RT

Oral symptoms- Lack of mobility (tongue, lips, mandible)- Pain, lack of sensation (e.g. tongue, lips)- Salivary function - Dental status

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Mandibular functioning

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Figure 1. Clinical model of factors influencing mandibular functioning

Within this study a clinical model of factors influencing mandibular functioning was hypothesized and analyzed: (1) Tumor characteristics determine treatment modalities (extent of surgery, dose of radiotherapy etc.) (2) Besides anti-tumor effects treatments also induce adverse effects, resulting in oral symptoms. (3) These oral symptoms may result in restrictions in mandibular functioning. (4,5) However, it is possible that some tumor characteristics or treatment characteristics influence man-dibular functioning directly without actually resulting in specific oral symptoms. (6) Finally, tumor characteristics may induce oral symptoms directly.

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Methods

PatientsPatients aged of 18 years or older, who were treated for oral or oropharyngeal can-cer at the department of Oral and Maxillofacial Surgery, Division Oncology, University Medical Center Groningen (UMCG), the Netherlands, were invited to participate in this cross-sectional study. Patients were informed about the study by means of a letter sent 1 week prior to their regular follow-up appointment. During this appointment, the physician further informed the patient and invited them to participate. Assessment was performed after patients signed a written informed consent.

Included in the study were patients who had completed their treatment for oral or oropharyngeal cancer at least 6 months before study assessment. Treatment consisted of surgery or a combination of surgery and radiotherapy. Excluded were patients who did not have sufficient understanding of Dutch to be interviewed or patients who were physically or mentally not fit enough to participate. Information regarding the type and location of the tumor, TN classification, and type of treatment (surgery, radiotherapy) was retrieved from the medical records.

Oral symptoms Assessment of oral symptoms was performed by 1 observer (PMH), who asked whether the patient: - experienced a restricted mouth opening (yes, no);- was able to wear a dental prosthesis (in case of an edentulous mandible or maxilla, or a partially dentulous mandible or maxilla; yes, no);- experienced a lack of retention of the dental prosthesis (yes, no);- experienced a loss of sensory function of the tongue (yes, no), lips (yes, no), or elsewhere in the mouth (yes, no);- experienced a restricted tongue mobility (yes, no) or lip mobility (yes, no);- experienced a lack of saliva (yes, no);- experienced an excess of saliva (yes, no);- experienced pain in the mouth (yes, no);- experienced other symptoms, and if so, what kind of symptoms.These questions were the result of a consensus between 2 experts (RPO, oral maxil-lofacial prosthetist and JLNR, oral maxillofacial surgeon oncologist). These experts were asked to list the most frequently reported oral symptoms of patients being treated for oral and oropharyngeal cancer. Additionally, the patient was asked to rank the burden of their oral symptoms. The 3 most burdensome oral symptoms were recorded.

Functional outcome Functional outcome was assessed by the Mandibular Function Impairment Question-naire (MFIQ). This questionnaire consists of 11 items assessing perceived difficulties in mandibular function during social activities, speaking, taking a large bite, chewing hard food, chewing soft food, work and/or daily activities, drinking, laughing, chewing re-

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sistant food, yawning, and kissing. Additionally, 6 items assess perceived difficulties in mandibular function when eating a hard cookie, eating meat, eating a raw carrot, eat-ing French bread, eating peanuts/almonds, and eating an apple. Eating includes taking a bite, chewing, and swallowing. Possible answers were: 0, no difficulty; 1, a little difficulty; 2, quite a bit of difficulty; 3, much difficulty; and 4, very much difficulty or impossible without help. The scores are added to give a sum score (range 0 to 68). A higher score indicates more perceived mandibular function impairments and a MFIQ score of ‘0’ in-dicates no impairment in mandibular functioning. Internal consistency of the question-naire ranges between 0.80 and 0.95.14 The outcome of the questionnaire is indepen-dent of the method applied, whether by interview or filled out by the patient (r=0.95).14 The MFIQ has previously been used to assess mandibular function after treatment of a chronic closed lock, subacute non-specific temporomandibular disorders, a painful disc displacement, and to determine a functional cutoff point for trismus.15-18

Statistical analysisStatistical analysis was performed using SPSS 16.0 for Windows software (SPPS Inc., Chicago, IL, USA). Statistical analysis included univariate analyses and a multivariable linear regression analysis.

In the univariate analyses, associations between MFIQ scores and possible predic-tors were analyzed by means of independent samples t test and Pearson’s correlation coefficient (r). Possible predictors included age (years), sex (male, female), dental status (dentulous, edentulous), T classification (T1/T2, T3/T4), radiotherapy (yes, no), surgery of the mandible (yes, no), interval between last oncology treatment and time of assessment (years), and oral symptoms: lack of saliva, restricted mouth opening, reduced tongue mobility, lack of retention of the prosthesis, reduced sensation of the lips, inability to wear a prosthesis, reduced sensation of the tongue, restricted mobility of the lips, re-duced sensation elsewhere in mouth, pain in the mouth, excessive saliva, and swallowing problems (yes, no).

In the multivariable linear regression analysis, MFIQ score was used as the out-come variable. Variables related to MFIQ score in the univariate analyses (p≤0.10) were entered as predictors (stepwise-backward, entry criterion p≤0.05, removal criterion p>0.10). Interaction effects between the predictor variables were explored.

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Results

One-hundred-one patients were asked to participate. Twelve patients did not fulfill the inclusion criteria or refused to participate in the study, giving 89 patients (88%) to participate in the study. Patient characteristics, tumor type, tumor location, and treat-ment received are summarized in Table 1. Median interval (interquartile range) between the last oncology treatment and the time of assessment was 1.7 years (0.9 to 4.1). The mean MFIQ score was 24.3 (SD 16.9). MFIQ score of irradiated patients (mean 28.9, SD 14.9) was significantly higher than that of non-irradiated patients (mean 16.7, SD 17.6, p=0.001). Most patients (76%) were treated for a squamous cell carcinoma, which was most frequently located in the tongue (36%). Sixty-three percent of the patients were treated with radiotherapy.

Twenty patients (22%) did not wear their dental prosthesis during the assessment, of which 8 patients did not wear their upper dentures and 12 patients did not wear their lower dentures. Five patients wore neither their upper or lower dentures (Table 2).

The TN classification could be found in the medical records for 75% of the patients (Table 3). Patients with a missing TN classification were treated further in the past (mean 4.4, SD 4.2 years) than patients with a recorded TN classification (mean 2.8, SD 3.9 years, p=0.138). Patients with a missing TN classification were also more likely to have been previously treated in another medical center.

Lack of saliva was the most frequently reported oral symptom (52%), followed by a restricted mouth opening (48%) and restricted tongue mobility (46%). Lack of saliva was ranked as the most burdensome oral symptom by 32% of patients. Restricted tongue mobility and restricted mouth opening were ranked equally burdensome by 14% of pa-tients (Table 4).

A significant interaction between radiotherapy and restricted mouth opening was found to predict MFIQ scores. Therefore, the relationship between predictive variables and MFIQ scores were analyzed separately for irradiated and non-irradiated patients. In irradiated patients, age, sex, restricted mouth opening, an inability to wear a dental pros-thesis, surgery of the mandible, being fully edentulous, and T classification were signifi-cantly related to MFIQ scores (p≤0.10). In non-irradiated patients, a restricted mouth opening, restricted tongue mobility, reduced sensation elsewhere in mouth (other than tongue or lip), restricted lip mobility, reduced tongue sensation, an inability to wear a dental prosthesis, surgery of the mandible, and being fully edentulous were significantly related to MFIQ scores (p≤0.10).

For irradiated patients, an inability to wear a dental prosthesis, T classification (T3/T4), and older age were predictive of higher MFIQ scores. For non-irradiated patients, restricted mouth opening, an inability to wear a dental prosthesis, restricted tongue mobility, and surgery of the mandible were predictive of higher MFIQ scores (Table 5).

24

Chapter 2

Table 1. Characteristics of patients, tumor type, tumor location, and tumor treatment

Variables Mean (SD)

Age (years) 61.0 (14.0)

MFIQ Score (scoring range 0 to 68) 24.3 (16.9)

Median (IQR)

Interval between last oncology treatment and assessment (years) 1.7 (0.9-4.1)

n (%)

Sex

Male 51 (57)

Female 38 (43)

Tumor type

Squamous cell carcinoma 68 (76)

Salivary gland tumor 16 (18)

Other 5 (6)

Tumor location*

Tongue 32 (36)

Alveolar process of the mandible 21 (24)

Floor of mouth 17 (19)

Alveolar process of the maxilla 10 (11)

Salivary gland 10 (11)

Soft palate 10 (11)

Lip 9 (10)

Pharyngeal arch 7 (8)

Cheek 6 (7)

Base of the tongue 6 (7)

Tonsil 4 (5)

Lateral and dorsal wall of the oropharynx 2 (2)

Buccogingival vault of the maxilla 1 (1)

Buccogingival vault of the mandible 1 (1)

Other∞ 1 (1)

Radiotherapy

Yes 56 (63)

No 33 (37)

Surgery of the mandible

Yes 25 (28)

No 64 (72)

IQR: Interquartile range. *: In 67% of the patients the tumor was located on 1 site. In the other patients the tumor extended over several regions. Therefore, the total number of locations exceeded the total number of patients (n=137). ∞: Nasopharynx.

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Discussion

The current study demonstrated that a lack of saliva was not only the most frequently reported oral symptom after treatment for oral or oropharyngeal cancer, but it was also the most burdensome, with almost one-third of the patients ranking it highest. This finding has been reported previously.19 Radiotherapy causes damage to the salivary glands, resulting in reduced volume and altered composition of saliva.3 The consistency of saliva changes from thin to thick, with a reduced pH and buffering capacity.3, 19 In ad-dition to dryness of the mouth and thirst, a lack of saliva may cause an accumulation of mucus, a burning sensation, taste disturbances, difficulties in oral functioning, and problems wearing dentures.3 A restricted mouth opening and restricted tongue mobil-ity were reported by almost half of the patients. These oral symptoms were reported among the 3 most burdensome. Both symptoms are known to occur frequently after treatment for oral or oropharyngeal cancer.20, 21

Despite the fact that a lack of saliva was most frequently mentioned and was ranked most burdensome for many patients, it was not predictive for functional out-come. Generally, a lack of saliva is perceived as very inconvenient, however, patients may compensate by using artificial saliva or by drinking during meals.4, 22 Most patients prefer water as a lubricant.3 It might also be possible that the influence of lack of saliva on the multivariable linear regression analysis was obscured by low statistical power.

A mean MFIQ score of 24.3 was found, indicating that averagely patients experience a substantial amount of mandibular impairment after treatment of oral and oropharyn-geal cancer. The finding that irradiated patients had a poorer functional outcome than non-irradiated patients has been described previously.23 However, for irradiated patients and non-irradiated patients the MFIQ scores were predicted by different variables. The only common variable in the multivariable linear regression analysis an inability to wear dental prosthesis. In non-irradiated patients the impact on functional outcome was slightly larger (β=14.3) than in irradiated patients (β=10.5). Edentulous or partially dentu-lous patients may not be able to wear a dental prosthesis because of a lack of retention resulting from anatomical changes post-surgery. Pain may also prevent patients from wearing dentures, resulting in problems with biting and chewing food.1 Patients who are fitted with a dental prosthesis are known to have a better functional outcome than those who are not fitted with prosthesis, based on List’s Performance Status Scale.10

26

Chapter 2

Table 3. TN classification on the basis of the pathology report

Status T1 T2 T3 T4 Total

N0 20 13 5 8 46

N1 2 1 2 1 6

N2 1 - - - 1

N2b 1 4 1 6 12

N2c - - - 1 1

N3 - 1 - - 1

Total 24 19 8 16 67

TN classification was present in the medical records of 67 patients (75%).

In the current study, a higher T classification was associated with poorer functional outcome. As this relationship was found only in irradiated patients, the T classification may have acted as a confounding variable. Patients with larger tumors (T3, T4) generally undergo combined treatment, this treatment results in greater tissue damage and scar formation further impeding mandibular function.

In irradiated patients an older age predicted poorer mandibular function. This re-lationship might be explained by normal aging processes and additional comorbidity, known to be more frequent as age increases. Comorbidity is negatively associated with swallowing function after surgical treatment for advanced oral or oropharyngeal can-cer.23 A restricted mouth opening was expected to be a strong predictor of poor man-dibular function in irradiated patients. However, a restricted mouth opening appeared to have the largest effect in non-irradiated patients.24 Nevertheless, restricted mouth opening, as well as restricted tongue mobility, are well known for negatively affecting oral functioning.21, 25

Table 2. Dental status

Dental status Mandible dentulous

Mandible partially dentulous

Mandible edentulous

Total

Maxilla dentulous

13 5 - 18

Maxilla partially dentulous

5 9 3 17

Maxilla edentulous

- 8 46 54

Total 18 22 49 89

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It is clear that an inability to wear a dental prosthesis greatly impedes mandibular functioning. Therefore, providing patients, both irradiated and non-irradiated, with a dental prosthesis is an important measure to reduce mandibular impairment. Clinically, the dental prosthesis should have an optimal retention, although retention was not a significant factor in the multivariable linear regression analysis. Additionally, for non-ir-radiated patients, treatment of restricted mouth opening and restricted tongue mobility may reduce mandibular impairment.

Rehabilitation of patients after treatment for oral or oropharyngeal cancer should focus on preserving mouth opening and tongue mobility. However, preservation of mouth opening after radiation therapy is difficult. The average reduction in mouth opening ranges from 18 to 32%, with the greatest decrease occurring between 1 and 9 months after radiotherapy.26, 27 The currently frequently applied intensity-modulated ra-diotherapy reduces mouth opening less than conventional radiotherapy.28 Once mouth

Table 4. Oral symptoms reported by 89 patients treated for oral or oropharyngeal cancer and rank-ing of symptoms according to their perceived burden

Oral symptoms % n Most burden-some

symptom (%)(n=88)

2nd Most bur-den-some

symptom (%)(n=72)

3rd Most burden-some

symptom (%)(n=56)

Lack of saliva 52 46 32 11 5

Restricted mouth opening

48 42 14 14 18

Reduced tongue mobility

46 41 14 24 13

Lack of retention of the prosthesis

39 34 9 10 5

Reduced sensation of the lips

30 27 6 11 7

Inability to wear a prosthesis

28 25 9 7 9

Reduced sensation of the tongue

27 24 7 8 13

Restricted mobility of the lips

25 22 3 6 9

Reduced sensation else-where in the mouth

23 20 5 4 9

Pain in the mouth 17 15 2 4 5

Excess of saliva 6 5 - - -

Swallowing problems 6 5 - - -

Some patients reported only the most burdensome oral symptom (n=88) whereas others also reported the second or third most burdensome oral symptoms.

28

Chapter 2

opening has decreased it is difficult to achieve improvement. The effects of exercises on a restricted mouth opening after oral or oropharyngeal cancer are limited with in a mean increase of 5 to 6 mm.29 TheraBite treatment seems to be effective.30 Restricted tongue mobility may be improved by speech therapy, including range of motion exer-cises.31-33

Strengths of this study include the use of a standardized, valid, and reliable ques-tionnaire and the assessment of multiple symptoms related to oral and oropharyngeal cancer. Limitations of the current study include the relatively small sample size that hampered statistical analysis, the cross-sectional study design, and the substantial num-ber of missing data regarding T classification in the medical records.

More insight into the development of oral symptoms is needed to determine which should be prevented in order to maintain mandibular function and achieve optimal functional outcome.

Table 5. Results of the multivariable linear regression analysis to predict the score on the MFIQ

MFIQ score (scale range 0-68) β SE of β 95% CI β LL

95% CI β UL

p of β

Radiated patients

Not being able to wear a dental prosthesis* 10.5 4.2 2.1 18.9 0.016

T classification∞ 6.9 4.2 -1.5 15.3 0.103

Age‡ 0.5 0.1 0.2 0.8 <0.001

Constant -7.8 8.5 -24.9 9.4 0.366

r²=0.45

Non-irradiated patients

Restricted mouth opening* 22.9 3.9 14.9 30.9 <0.001

Not being able to wear a dental prosthesis* 14.3 4.9 4.4 24.3 0.006

Restricted tongue mobility* 13.0 3.8 5.2 20.9 0.002

Surgery of the mandible* 12.8 6.3 -0.1 25.7 0.052

Constant 1.5 2.5 -3.7 6.7 0.564

r²=0.72

β: Regression coefficient. SE: Standard error. 95% CI β LL: 95% confidence interval of β lower limit. 95% CI β UL: 95% confidence interval of β upper limit. r²: Explained variance of the regression model. *: Yes=1, no=0. ∞: T3/T4=1, T1/T2=0. ‡: Per year.

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ConclusionLack of saliva was not only the most frequently reported oral symptom after treatment for oral or oropharyngeal cancer, it is also the most burdensome. Functional outcome was strongly influenced by an inability to wear a dental prosthesis in both irradiated and non-irradiated patients.

30

Chapter 2

1. Chambers MS, Garden AS, Kies MS, Martin JW.

Radiation-induced xerostomia in patients with head

and neck cancer: pathogenesis, impact on quality

of life, and management. Head Neck 2004;26:796-

807.

2. Finlay PM, Dawson F, Robertson AG, Soutar DS.

An evaluation of functional outcome after surgery

and radiotherapy for intraoral cancer. Br J Oral





4. Konstantinovic VS. Quality of life after surgical

excision followed by radiotherapy for cancer of the

tongue and floor of the mouth: evaluation of 78

patients. J Craniomaxillofac Surg 1999;27:192-197.

5. Malone JP, Stephens JA, Grecula JC, Rhoades CA,

Ghaheri BA, Schuller DE. Disease control, survival,

and functional outcome after multimodal treatment

for advanced-stage tongue base cancer. Head Neck

2004;26:561-572.

6. Rogers SN, Lowe D, Brown JS, Vaughan ED.

The University of Washington head and neck

cancer measure as a predictor of outcome follow-

ing primary surgery for oral cancer. Head Neck

1999;21:394-401.

7. Rogers SN, Lowe D, Fisher SE, Brown JS, Vaughan

ED. Health-related quality of life and clinical func-

tion after primary surgery for oral cancer. Br J Oral


8. Zuydam AC, Lowe D, Brown JS, Vaughan ED, Rog-

ers SN. Predictors of speech and swallowing func-

tion following primary surgery for oral and oropha-

ryngeal cancer. Clin Otolaryngol 2005;30:428-437.





Oral Oncol 2008;44:430-438.

10. Teoh KH, Patel S, Hwang F, Huryn JM, Verbel D,

Zlotolow IM. Prosthetic intervention in the era of

microvascular reconstruction of the mandible--a

retrospective analysis of functional outcome. Int J

Prosthodont 2005;18:42-54.

11. Logemann JA, Smith CH, Pauloski BR, et al. Ef-

fects of xerostomia on perception and performance

of swallow function. Head Neck 2001;23:317-321.

12. List MA, Stracks J, Colangelo L, et al. How Do

head and neck cancer patients prioritize treatment

outcomes before initiating treatment? J Clin Oncol

2000;18:877-884.

13. List MA, Rutherford JL, Stracks J, et al. Pri-

oritizing treatment outcomes: head and neck

cancer patients versus nonpatients. Head Neck

2004;26:163-170.

14. Stegenga B, de Bont LG, de Leeuw R, Boering

G. Assessment of mandibular function impairment

associated with temporomandibular joint osteo-

arthrosis and internal derangement. J Orofac Pain

1993;7:183-195.




16. Fricton JR, Look JO, Schiffman E, Swift J. Long-

term study of temporomandibular joint surgery

with alloplastic implants compared with nonimplant

surgery and nonsurgical rehabilitation for pain-

ful temporomandibular joint disc displacement. J

Oral Maxillofac Surg 2002;60:1400-11; discussion

1411-2.

17. Pereira LJ, Steenks MH, de Wijer A, Speksnijder

CM, van der Bilt A. Masticatory function in subacute

TMD patients before and after treatment. J Oral

Rehabil 2009;36:391-402.

18. Politi M, Sembronio S, Robiony M, Costa F, Toro

C, Undt G. High condylectomy and disc reposition-

ing compared to arthroscopic lysis, lavage, and

References

31

Ora

l sym

ptom

s an

d fu

nctio

nal o

utco

me

capsular stretch for the treatment of chronic closed

lock of the temporomandibular joint. Oral Surg Oral

Med Oral Pathol Oral Radiol Endod 2007;103:27-

33.

19. Dirix P, Nuyts S, Vander Poorten V, Delaere P,

Van den Bogaert W. Efficacy of the BioXtra dry

mouth care system in the treatment of radiother-

apy-induced xerostomia. Support Care Cancer

2007;15:1429-1436.




Care Cancer 2010;18:1033-1038.

21. Pauloski BR. Rehabilitation of dysphagia following

head and neck cancer. Phys Med Rehabil Clin N Am

2008;19:889-928, x.

22. Atkinson JC, Fox PC. Salivary gland dysfunction.

Clin Geriatr Med 1992;8:499-511.

23. Kreeft AM, van der Molen L, Hilgers FJ, Balm AJ.

Speech and swallowing after surgical treatment

of advanced oral and oropharyngeal carcinoma: a

systematic review of the literature. Eur Arch Oto-

rhinolaryngol 2009;266:1687-1698.






111.

25. Van Cann EM, Dom M, Koole R, Merkx MA,

Stoelinga PJ. Health related quality of life after man-

dibular resection for oral and oropharyngeal squa-

mous cell carcinoma. Oral Oncol 2005;41:687-693.

26. Goldstein M, Maxymiw WG, Cummings BJ,

Wood RE. The effects of antitumor irradiation

on mandibular opening and mobility: a prospec-

tive study of 58 patients. Oral Surg Oral Med Oral

Pathol Oral Radiol Endod 1999;88:365-373.





2005;115:1458-1460.

28. Hsiung CY, Huang EY, Ting HM, Huang HY.

Intensity-modulated radiotherapy for nasopharyn-

geal carcinoma: the reduction of radiation-induced

trismus. Br J Radiol 2008;81:809-814.








1993;51:863-867.

31. Logemann JA, Rademaker AW, Pauloski BR, Kah-

rilas PJ. Effects of postural change on aspiration in

head and neck surgical patients. Otolaryngol Head

Neck Surg 1994;110:222-227.

32. Logemann JA, Pauloski BR, Rademaker AW, Col-

angelo LA. Speech and swallowing rehabilitation for

head and neck cancer patients. Oncology (Williston

Park) 1997;11:651-6, 659; discussion 659, 663-4.

33. Rasley A, Logemann JA, Kahrilas PJ, Rademaker

AW, Pauloski BR, Dodds WJ. Prevention of barium

aspiration during videofluoroscopic swallow-

ing studies: value of change in posture. AJR Am J

Roentgenol 1993;160:1005-1009.

Chapter 3.1Mouth opening in patients irradiated for head and neck cancer: a prospective repeated measures study

This chapter is an edited version of:Kamstra JI, Dijkstra PU, van Leeuwen M, Roodenburg JL, Langendijk JA. Mouth opening in patients irradiated for head and neck cancer: a prospective repeated measures study. Oral Oncol 2015;51:548-555.

34

Chapter 3.1

Abstract

ObjectivesAims of this prospective longitudinal cohort study were (1) to analyze the course of mouth opening up to 48 months post-radiotherapy, (2) to assess risk factors predict-ing decrease in mouth opening, and (3) to develop a multivariate prediction model for change in mouth opening in a large sample of patients irradiated for head and neck can-cer.

MethodsMouth opening was measured prior to radiotherapy (baseline) and at 6, 12, 18, 24, 36, and 48 months post-radiotherapy. The primary outcome variable was mouth opening. Potential risk factors were entered into a linear mixed model analysis (manual stepwise-backward elimination) to create a multivariate prediction model. The interaction terms between time and risk factors that were significantly related to mouth opening were explored.

ResultsThe study population consisted of 641 patients: 70.4% male, mean age at baseline 62.3 years (SD 12.5). Primary tumors were predominantly located in the oropharynx or na-sopharynx (25.3%) and oral cavity (20.6%). Mean mouth opening at baseline was 38.7 mm (SD 10.8). Six months post-radiotherapy, mean mouth opening was smallest, 36.7 mm (SD 10.0). In the linear mixed model analysis, mouth opening was statistically pre-dicted by the location of the tumor, natural logarithm of the time since radiotherapy in months (Ln(months)), sex, baseline mouth opening, baseline age, and target volume on primary tumor. All main effects interacted with Ln(months).

ConclusionThe mean mouth opening decreased slightly over time. Mouth opening was predicted by several risk factors: tumor location, time since radiotherapy, sex, baseline mouth opening, tumor classification, age, and target volume on the primary tumor. The multi-variate prediction model can be used to predict mouth opening.

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Introduction

A limited ability to open the mouth (35 mm or less), a trismus, is a well-known side ef-fect of treatment of head and neck cancer, including of radiotherapy.1-6 The prevalence of trismus following radiotherapy ranges from 25 to 46%.4-6 Trismus has a negative impact on function and quality of life.1, 7-11 It impairs eating, speech, oral hygiene, dental treatment, airway clearance, and oncological follow-up.1, 5, 12 Trismus is often progres-sive, hard to treat, and once established, only a limited increase in mouth opening can be achieved.13, 14 Therefore, the focus should be on prevention.

Trismus is most likely to develop if radiotherapy includes the masticatory muscles and region of the temporomandibular joint, particularly, when radiotherapy is combined with chemotherapy, in case of larger tumors, or when trismus is induced by the tumor itself.4, 6, 10, 15-17 Fibrosis and atrophy of irradiated tissues contribute to trismus, which is likely to develop between 1 month and 1 year post-radiotherapy.10, 18, 19 A progressive decrease in mouth opening can be observed even years after finishing radiotherapy.19 Dosages higher than 50 Gy are associated with trismus. 4, 10, 20-22 Higher incidences of trismus have been observed after external beam radiotherapy than after interstitial radiotherapy.4, 20

The main limitations of previous studies that aimed identifying risk factors for tris-mus were their retrospective design and relatively small sample sizes. The longitudinal course of mouth opening up to 1 year following surgery and/or radiotherapy (with or without chemotherapy) has been described in 4 prospective studies with 17 to 143 pa-tients. The main limitations of these studies were the small sample sizes, limited primary tumor sites, or the lack of radiotherapy as part of the treatment modalities.17, 19, 23, 24 Con-sequently, when several risk factors are present, it has been impossible to statistically predict the longitudinal course of mouth opening of head and neck cancer patients after radiotherapy.

The aims of our prospective cohort study were (1) to analyze the longitudinal course of mouth opening up to 48 months post-radiotherapy, (2) to assess risk fac-tors predicting decrease in mouth opening, and (3) to develop a multivariate prediction model for change in mouth opening based on a large sample size of patients undergoing radiotherapy for head and neck cancer.

36

Chapter 3.1

Methods

Study design and settingThis prospective longitudinal cohort study was conducted between March 2007 and June 2011 at the Department of Radiation Oncology of the University Medical Center Groningen, the Netherlands. The study was carried out according to the regulations of our institute.

Participants All patients who underwent definitive or postoperative external beam radiotherapy for head and neck cancer, either alone or in combination with chemotherapy or cetuximab, were included. Patients were excluded if their primary tumor was located outside the head and neck region, if intracranial, or if it originated from the nasal vestibule or the skin. Patients were also excluded if no data was collected regarding their mouth open-ing, or if the patient died during radiotherapy or within the first 6 months after the start of radiotherapy. Tumor classification was based on the Union for International Union Against Cancer (UICC) recommendation TNM classification (2009).

RadiotherapyPatients were treated with external beam radiotherapy using linear accelerators at the Department of Radiation Oncology according to the standard of care protocols. Details on radiotherapy have been described in detail previously.25

DataAt the outpatient clinic of the Department of Radiation Oncology, mouth opening was prospectively measured prior to radiotherapy (baseline) and at regular follow-up ap-pointments at 6, 12, 18, 24, 36, and 48 months post-radiotherapy. During these visits, patients were asked to open their mouth completely, and mouth opening was measured as maximal interincisal distance in mm, using a slide caliper. In case patients were eden-tulous and not wearing a dental prosthesis, mouth opening was measured from the alveolar ridge. Trismus was defined as a mouth opening of 35 mm or less.2

Data on tumor and treatment were also prospectively collected. Missing and bio-logically implausible data were verified and retrieved from medical records.

StatisticsThe primary outcome variable was mouth opening at different time points (baseline, 6, 12, 18, 24, 36, and 48 months post-radiotherapy). Prior to data analysis, the association between time and mouth opening was explored. Time was modelled as a linear func-tion, as a squared function, and as a logarithmic function. The model fit was best using a logarithmic function for time. Hence, Ln(months) was used. The T stage of the tumor was dichotomized into T4 tumor (yes, no) because plots showed that mouth opening over time was different in patients with T4 tumors compared to those with T1, T2, or T3 tumors. For the clinical interpretation, age was centered at 60 years.

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The potential risk factors were selected based on the assumed risk to influence mouth opening: location of the tumor (oral cavity, oropharynx or nasopharynx, salivary glands or ear, hypopharynx or supraglottic larynx, glottic or supraglottic larynx, nasal cavity or maxillary sinus, and lymph node metastases head in and neck region from an unknown primary (primary unknown), squamous cell carcinoma (yes, no), time modeled as the natural logarithm of time in post-radiotherapy in months (Ln(months)), sex (male, female), baseline mouth opening (mm), T4 tumor (yes, no), baseline age (years), total dose of irradiation (Gy), fraction dose of irradiation (Gy), target volume on primary tumor (yes, radiotherapy on primary tumor; no, radiotherapy on metastasis in head and neck re-gion), radiotherapy neck (yes, radiotherapy on neck area; no, radiotherapy only on pri-mary tumor), re-irradiation in locoregional area (yes, no), surgery on the primary tumor (yes, no), neck dissection (yes, no), and chemotherapy (yes, no).

All potential risk factors were entered in a linear mixed model analysis and suc-cessively eliminated (manual backward-stepwise elimination) to create a multivariate prediction model (SPSS 22.0 for Windows software (SPPS Inc., Chicago, IL, USA)). A risk factor was eliminated if the significance of the regression coefficient was larger than 0.05 and the model fit (-2log likelihood criterion) did not decrease significantly. In ad-dition, interaction terms between time and risk factors significantly related to mouth opening, were explored. An interaction term remained in the model if the model fit increased significantly (-2log likelihood criterion). To verify post hoc if missing data may have influenced the results of the linear mixed model analysis, we performed the same analysis with patients with complete data. Because 59 patients had complete data up to 48 months follow-up, we did this linear mixed model analysis with the cohort with complete data up to 36 months, consisting of 104 patients.

38

Chapter 3.1

Results

We initially included 788 head and neck cancer patients who were being treated with any form of radiotherapy. We excluded 98 patients for the following reasons: primary tumor located outside the head and neck region, no data regarding mouth opening, and/or and deceased during or within the first 6 months post-radiotherapy. Patients with tumors originating from the nasal vestibule (n=11), skin (n=33), and intracranial (n=3) were also excluded. For statistical reasons, patients (n=2) with rare type of tumors (myxofibrosarcoma neck and epitheloid angiosarcoma) were excluded as well. The study population therefore consisted of 641 consecutive patients (81.3% of the initial sample).

Descriptive dataThe patient, tumor, and treatment characteristics of the study population (n=641) and the cohort of patients with complete data at 36 months post-radiotherapy (n=104) are shown in Table 1 and Table 2. The majority of the patients were male (70.4%) and the mean age at baseline was 62.3 years (SD 12.5). Primary tumors were mostly located in the oropharynx or nasopharynx (25.3%) and oral cavity (20.6%).

Course of mouth openingThe mean mouth opening was 38.7 mm (SD 10.8) at baseline, 36.7 mm (SD 10.0) at 6 months post-radiotherapy, and 38.2 mm (SD 11.5) at 48 months post-radiotherapy. At baseline, 35% of the patients had trismus, which increased to 37% at 48 months post-radiotherapy. The highest percentage of patients with trismus was found at 6 months post-radiotherapy (42.9%) (Table 3). The course of mouth opening over time differed per tumor location (Figure 1).

Outcome linear mixed model analysisIn the linear mixed model analysis, mouth opening was statistically predicted by the loca-tion of the tumor, sex, Ln(months), baseline mouth opening, T4 tumor, baseline age, and target volume on primary tumor. All main effects interacted with Ln(months) (Table 4).

The results of the linear mixed model analysis can predict mouth opening post-radiotherapy statistically. For example, for a 70-year-old male with a T2 carcinoma in the oral cavity who received target volume on the primary tumor only, with a mouth opening of 40 mm at baseline, mouth opening can be estimated at 36 months post-radiotherapy by using the following equation:

‘Mouth opening=12.88 + [1.57 (oral cavity)] + [4.00*3.58 (Ln(months))] + [1.10 (male sex)] + [0.69*40 (baseline mouth opening)] + [-0.05*10 (baseline age centered at 60 years)] + [-4.76 (target vol-ume on primary tumor)] + [0.69*3.58 (oral cavity*Ln(months)] + [0.32*3.58 (male sex*Ln(months)] + [-0.10*40*3.58 (baseline mouth opening*Ln(months)] + [-0.01*10*3.58 (baseline age centered at 60 years*Ln(months)] + [-1.69*3.58 (target volume on primary tumor*Ln(months)]=35,1 mm. (Note Ln(36 months)=3.58.)’

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Table 1. Patient, tumor, and treatment characteristics

Study population (n=641) Cohort of patients with complete data (n=104)

Patient characteristics n (%) Mean (SD) n (%) Mean (SD)

Male sex 451 (70.4) 64 (61.5)

Baseline age (years) 62.3 (12.5) 59.7 (13.0)

Deceased 199 (31.0) 1 (1.0)

Months between start radiotherapy and death

17.8 (10.6) 55 (-)

Dental status

Dentulous 241 (37.6) 45 (43.3)

Fully edentulous 319 (49.8) 49 (47.1)

Partially edentulous 77 (12.0) 8 (7.7)

Not known 4 (0.6) 2 (1.9)

Baseline mouth opening (mm) 38.7 (10.8) 39.5 (10.4)

Tumor characteristics

Squamous cell carcinoma 512 (79.9) 76 (73.1)

T4 tumor 183 (28.5) 19 (18.3)

Location of the primary tumor

Oral cavity 132 (20.6) 26 (25.0)

Oropharynx or nasopharynx 162 (25.3) 19 (18.3)

Salivary glands or ear 66 (10.3) 12 (11.5)

Hypopharynx or supraglottic larynx 115 (17.9) 16 (15.4)

Glottic or subglottic larynx 116 (18.1) 23 (22.1)

Nasal cavity or maxillary sinus 24 (3.7) 4 (3.8)

Unknown primary 26 (4.1) 4 (3.8)

Treatment characteristics

Surgery primary tumor 248 (38.7) 50 (48.1)

Neck dissection 216 (33.7) 41 (39.4)

Chemotherapy 176 (27.5) 18 (17.3)

Target volume on primary tumor 610 (95.2) 98 (94.2)

radiotherapy neck area 490 (76.4) 72 (69.2)

Total dose of irradiation 65.2 (7.1) 65.9 (5.5)

Fraction dose of irradiation 2.0 (0.2) 2.0 (0.1)

Duration of radiotherapy in months 1.3 (0.2) 1.4 (0.2)

Re-irradiation in locoregional area 32 (5) -

Exercise therapy for trismus 17 (2.7) 6 (5.8)

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Chapter 3.1

Table 2. TN classification

Status N0 N1 N2a N2b N2c N2∞ N3 Total

T0 2 1 0 1 2 0 0 6

T1 62 13 4 24 7 0 2 112

T2 109 24 7 24 17 3 7 191

T3 36 17 0 17 27 1 1 99

T4 64 18 3 31 60 0 6 182

Unknown 8 8 7 11 0 0 4 38

Total 281 81 21 108 113 4 20 628*

*: Of 13 patients, no TN classification was reported. Of 38 patients, T classification was missing, in-cluding no classification applicable (n=12; for example, for a non-malignant pleiomorf adenoma). ∞: Nasopharynx.

Table 3. Mouth opening and numbers of patients with trismus

Months post-radio-therapy

n per point of time (deceased before follow-up)

n cumula-tive de-ceased patients

Mean mouth opening (SD)

Mean mouth opening (SD)*

n patients with trismus (%)

n patients with trismus (%)*

Baseline 566 0 38.7 (10.8) 39.5 (10.4) 196 (34.6) 33 (31.7)

6 473 (18) 18 36.7 (10.0) 38.7 (9.6) 203 (42.9) 29 (27.9)

12 425 (69) 87 37.3 (10.3) 39.1 (11.1) 161 (37.9) 33 (31.7)

18 392 (44) 131 37.3 (10.6) 37.9 (10.8) 160 (40.8) 43 (41.3)

24 368 (32) 163 38.0 (10.7) 38.3 (10.7) 139 (37.8) 40 (38.5)

36 230 (21) 184 38.0 (10.6) 37.2 (10.7) 83 (36.1) 39 (37.5)

48 131 (12) 196 38.2 (11.5) - 48 (36.6) -

*Cohort of patients (n=104) with complete data up to 36 months post-radiotherapy. There were 59 patients with complete data up to 48 months post-radiotherapy, however, for statistical reasons the cohort up to 36 months was used.

Mean predicted mouth opening according the multivariate prediction model differed per tumor location (Figure 2). Mouth opening of patients with tumors of all included lo-cations decreased in the first 6 months post-radiotherapy, except when the tumor was located in the salivary glands or ears. When patients had a lymph node metastasis from an unknown primary, mouth opening did not decrease in these first 6 months either.

The linear mixed model analysis was repeated for the cohort of patients with com-plete data (n=104) (Appendix 1). The differences in regression coefficients were largest for the interactions between Ln(months) and location of the primary tumor.

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Figure 1. Course of mouth opening per tumor location

Note: Y-axis starts at 30 mm.

Oral cavity

Oropharynx or nasopharynx

Salivary glands or ear

Hypopharynx or supraglottic larynx

Glottic or subglottic larynx

Nasal cavity or maxillary sinus

Unknown primary

Figure 2. Predicted mouth opening according the multivariate prediction model per tumor location

Note: Y-axis starts at 30 mm.

Oral cavity

Oropharynx or nasopharynx

Salivary glands or ear


Glottic or subglottic larynx

Nasal cavity or maxillary sinus

Unknown primary

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Table 4. Results of the linear mixed model analysis to predict mouth opening post-radiotherapy of the study population (n=641)

Risk factors β SE (β) 95% CI β LL

95% CI β UL

p (β)

Intercept 12.88 1.47 10.00 15.77 <0.001

Tumor location <0.001

Oral cavity 1.57 2.58 -3.50 6.63 0.544

Oropharynx or nasopharynx 1.04 2.62 -4.09 6.18 0.690

Salivary glands or ear 2.56 2.61 -2.57 7.68 0.328

Hypopharynx or supraglottic larynx 3.56 2.63 -1.61 8.73 0.176

Glottic or subglottic larynx 4.40 2.63 -0.76 9.57 0.094

Nasal cavity or maxillary sinus 1.26 2.68 -4.00 6.53 0.638

Unknown primary - -

Ln(months) 4.00 0.32 3.38 4.63 <0.001

Male sex 1.10 0.50 0.11 2.08 0.029

Baseline mouth opening 0.69 0.02 0.65 0.73 <0.001

T4 tumor -1.14 0.52 -2.16 -0.11 0.029

Baseline age centered at 60 years -0.05 0.02 -0.08 -0.01 0.006

Target volume on primary tumor -4.76 2.34 -9.36 -0.17 0.042

Interactions

Oral cavity*Ln(months) 0.69 0.59 -0.47 1.85 0.244

Oropharynx or nasopharynx*Ln(months) 0.47 0.60 -0.70 1.64 0.434Salivary glands or ear*Ln(months) 0.91 0.60 -0.26 2.08 0.126Hypopharynx or supraglottic larynx*Ln(months)

1.27 0.60 0.09 2.45 0.035

Glottic or subglottic larynx*Ln(months) 1.48 0.60 0.30 2.66 0.014Nasal cavity or maxillary sinus*Ln(months) 0.62 0.61 -0.57 1.82 0.307Unknown primary*Ln(months) - - Baseline mouth opening*Ln(months) -0.10 0.00 -0.11 -0.09 <0.001Male sex*Ln(months) 0.32 0.11 0.11 0.54 0.003Baseline age centered at 60 years* Ln(months)

-0.01 0.00 -0.02 0.00 0.003

T4 tumor*Ln(months) -0.27 0.11 -0.50 -0.05 0.017Target volume on primary tumor*Ln(months)

-1.69 0.54 -2.75 -0.64 0.002

β: Regression coefficient. SE: Standard error. 95% CI β LL: 95% confidence interval of β lower limit. 95% CI β UL: 95% confidence interval of β upper limit. Unknown primary is used as reference cat-egory.

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Discussion

Key resultsThe mean mouth opening of the study population changed marginally over time. The results of our study showed that mouth opening can be predicted statistically by a vari-ety of risk factors and their interactions. Based on the multivariate prediction model, the longitudinal course of mouth opening can be predicted statistically. We found that mean mouth opening decreased the first 6 months post-radiotherapy and gradually recov-ered up to 48 months post-radiotherapy (Table 4 and Figure 2). The longitudinal course of mouth opening differed between primary tumor locations (Figure 1 and 2).

InterpretationThe consequences of trismus are severe, and trismus secondary to head and neck can-cer is hard to treat. If the multivariate prediction model presented in our study indicates high risk of trismus, preventive measures can be taken to prevent decrease of mouth opening. For example, patients who perform exercises during radiotherapy experience a smaller decrease in mouth opening compared to those who do not exercise.16, 26, 27 Additionally, a larger increase in mouth opening is expected when exercises are started early.28 However, such preventive programs can be a burden to patients, especially dur-ing the course of radiotherapy. These programs should therefore be limited to those with the highest risks.

The interactions between location of the tumor and Ln(months) indicate that the change over time depends on the location of the tumor. The results of our study showed on average only a small decrease in mouth opening over time, with the highest percentage of patients with trismus at 6 months post-radiotherapy. The percentage of patients with trismus at 48 months post-radiotherapy was nearly the same as the percentage at baseline. The largest change in mouth opening occurred during the first 6 months post-radiotherapy, in both the course of mouth opening (Figure 1) and the predicted mouth opening according the multivariate prediction model (Figure 2). The in-teraction term between Ln(months) and mouth opening prior to radiotherapy indicates that a larger mouth opening prior to radiotherapy will result in a greater loss of mouth opening post-radiotherapy.

About 30% of the study population died, most likely the patients with T4 tumors and those who underwent more intensive treatment. Such patients are more likely to develop trismus. The dropout of these patients could explain the recovery of mouth opening over time.

Up to 48 months post-radiotherapy, only 59 patients had complete data. However, to verify the multivariate prediction model in a cohort of patients with complete data, a larger sample was preferred. Therefore, we decided to use the cohort of patients with complete data up to 36 months. The differences in the linear mixed model analysis be-tween the study population and the cohort of patients with complete data were small (Table 4 vs. Appendix 1), except for the differences between the interactions between Ln(months) and location of the primary tumor.

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About 3% of the study population received exercise therapy supported by a physical therapist for their trismus (Table 1). In our center, patients do not routinely receive ex-ercises, preventive or otherwise. In 82.4% of this subgroup of patients, exercise therapy consisted of exercises with a TheraBite® Jaw Motion Rehabilitation System™. A mean increase in mouth opening of 6.2 mm (SD 4.5) was found in a post hoc analysis.

Other studiesLongitudinal course of mouth opening following surgery and/or radiotherapy (with or with-out chemotherapy) and risk factors for decrease in mouth opening have been described in 4 prospective studies.17, 19, 23, 24 In one study, a rapid decrease of mouth opening between 1 and 9 months was found and a slower rate of decrease after 1 year in 17 patients treated for nasopharyngeal cancer following radiotherapy. An overall decrease of 32% at 4 years post-radiotherapy was found. Trismus at discharge predicted trismus at 6 months post-surgery. The authors concluded that preventive interventions should be targeted at high-risk pa-tients early in the postoperative phase.19 In another study, mouth opening of 64 patients treated for oral and oropharyngeal cancer following primary surgery was evaluated. Before surgery, 30% of the patients had trismus (35 mm or less), at discharge 65%, and 6 months post-surgery 54%. Risk factors for trismus were stage T3 or T4 tumors that required free flap reconstruction and adjuvant radiotherapy.17 In another study, mouth opening of 87 patients treated for head and neck cancer with primary surgery or primary surgery plus radiotherapy (with or without chemotherapy) was evaluated. Before treatment, 47% of the patients had trismus (35 mm or less), which increased to 71% after surgery alone, and to 79% after surgery plus radiotherapy (with or without chemotherapy). Females and those who consumed alcohol had the highest risk for developing trismus.24 Mouth opening over 1 year and risk factors for decrease in mouth opening of 143 oral cancer patients treated for oral cancer with surgery and/or radiotherapy were evaluated. Mouth opening of every pa-tient decreased, and when patients underwent surgery and radiotherapy or radiotherapy only, mouth opening did not recover, in contrast to patients who underwent surgery only. Risk factors for trismus 1 year post-treatment were having trismus prior to treatment, receiving both surgery and radiotherapy, and when the tumor was located in de maxilla or mandible. The general course of mouth opening found in this study was confirmed by the results of our study.23 Similar to the results in our study, changes over time were also seen in the 4 above mentioned studies.17, 19, 23, 24

In our study, 35% of the patients had trismus at start of the radiotherapy, which is in line with the results in other studies.17, 24 Three possible explanations can be provided for this initial trismus. First, the mouth opening can be classified as trismus at the start of the radiotherapy because of an extremely small natural mouth opening. Second, the mouth opening can decrease before radiotherapy due to mechanical restriction or pain as result of tumor growth. Third, the trismus could be the result of surgery in case of postoperative radiotherapy. This last assumption was verified in a post hoc analysis. In-deed, baseline mouth opening of patients who underwent surgery prior to radiotherapy (34.9 mm, SD 10.9, n=214) was significantly smaller (6.1 mm, 95% confidence interval 4.3 to 7.9 mm) compared to patients who were treated with definitive radiotherapy

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with or without chemotherapy (41.0 mm, SD 10.1, n=352).In previous studies, risk factors for decrease in mouth opening are reported mainly

in retrospective studies with relatively small sample sizes. Risk factors found are radio-therapy, including multimodal treatment (additional surgery and/or chemotherapy), dose of 50 Gy or more, primary tumors originating from the maxilla, mandible, nasopharynx, parotid gland, and tongue, and T4 tumors.6, 7, 10, 15, 17, 20, 22, 23 In contrast to the results from previous studies, in the linear mixed model analysis of our study, multimodal treatment did not contribute to mouth opening. When the masticatory muscles and the temporo-mandibular joint were in the irradiation field (for example tumors in the oropharynx or nasopharynx and nasal cavity or maxillary sinus), a larger decrease of mouth opening was observed.

LimitationsThe first limitation of our study is that genetic factors and some individual patient fac-tors, such as usage of alcohol and the presence of co-morbidity, were not included in the analysis. In a previous study, alcohol consumption was identified as a risk factor for decrease in mouth opening.23, 24 Co-morbidity, especially with impaired vascularity, for example in hypertension or diabetes, can also contribute to the development of fibro-sis.18 Furthermore, radiosensitivity can contribute to the development of fibrosis and atrophy, both leading to trismus.18

A second limitation concerns the decrease in the number of patients over time, which results inherently from a longitudinal evaluation over time. Another reason for this decrease is that 31% of the patients in the sample had died.

A third limitation is the method of measurement of mouth opening. Mouth open-ing was measured by different employees, which may have introduced a measurement error. Because mouth opening can be measured reliably, we assume this error had a limited effect on the outcomes of our study.29

A forth limitation is the lack of information about the use of a dental prosthesis in edentulous patients. Mouth opening was measured with or without a dental prosthesis in case of an edentulous patient, resulting in possible inter-individual variation inde-pendent of the actual change in mouth opening because of radiotherapy. There was no statistical significant difference between the standard deviations of the average mouth opening of dentulous and edentulous patients, so we assume there is a limited error in the group of edentulous patients.

Future perspectivesThe results of this study can be used to develop a preventive program (including exer-cise) for trismus. The effects of such a program should be studied.

ConclusionThe mean mouth opening decreased slightly over time with the minimal mouth opening at 6 months post-radiotherapy. Risk factors for decrease in mouth opening were sev-eral locations of the primary tumor (oropharynx or nasopharynx, nasal cavity or maxil-

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Chapter 3.1

lary sinus), more months post-radiotherapy, female sex, smaller mouth opening prior to treatment, T4 tumor, higher age, target volume on primary tumor, and the interaction terms with the number of months post-radiotherapy. The multivariate prediction model can be used to predict mouth opening. On patients at high risk for developing trismus, preventive measures can be taken.

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Appendix

Appendix 1. Results of the linear mixed model analysis to predict mouth opening post-radiotherapy with the cohort of patients with complete data (n=104)

Risk factors β SE (β) 95% CI β LL

95% CI β UL

p (β)

Intercept 10.58 2.66 5.34 15.81 <0.001

Tumor location <0.001

Oral cavity -1.00 4.09 -9.06 7.06 0.807

Oropharynx or nasopharynx -1.67 4.30 -10.15 6.81 0.699

Salivary glands or ear -0.95 4.37 -9.56 7.65 0.827

Hypopharynx or supraglottic larynx 0.69 4.36 -7.90 9.29 0.874

Glottic or subglottic larynx 1.69 4.30 -6.78 10.15 0.695

Nasal cavity or maxillary sinus -1.03 4.13 -9.17 7.12 0.804

Unknown primary

Ln(months) 3.35 .62 2.12 4.57 <0.001

Male sex 1.49 0.98 -0.43 3.42 0.128

Baseline mouth opening 0.78 0.05 0.69 0.87 <0.001

T4 tumor -0.38 1.17 -2.68 1.91 0.743

Baseline age centered at 60 years -0.09 0.04 -0.16 -0.02 0.016

Target volume on primary tumor -3.42 3.39 -10.10 3.26 0.314

Interactions

Oral cavity*Ln(months) 0.25 0.96 -1.64 2.14 0.793

Oropharynx or nasopharynx*Ln(months) -0.04 1.01 -2.03 1.95 0.968

Salivary glands or ear*Ln(months) 0.12 1.03 -1.90 2.13 0.908

Hypopharynx or supraglottic larynx*Ln(months)

0.60 1.03 -1.42 2.61 0.561

Glottic or subglottic larynx*Ln(months) 0.97 1.01 -1.01 2.96 0.336Nasal cavity or maxillary sinus*Ln(months) 0.26 0.97 -1.65 2.17 0.788Unknown primary*Ln(months)

Baseline mouth opening*Ln(months) -0.07 0.01 -0.09 -0.05 <0.001

Male sex*Ln(months) 0.33 0.23 -0.12 0.78 0.148

Baseline age centered at 60 years* Ln(months)

-0.02 0.01 -0.03 0.00 0.029

T4 tumor*Ln(months) -0.22 0.27 -0.76 0.31 0.414

Target volume on primary tumor*Ln(months)

-1.32 0.80 -2.89 0.24 0.097

β: Regression coefficient. SE: Standard error. 95% CI β LL: 95% confidence interval of β lower limit. 95% CI β UL: 95% confidence interval of β upper limit. Unknown primary is used as reference category.

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1. Scott B, Butterworth C, Lowe D, Rogers SN. Fac-

tors associated with restricted mouth opening and

its relationship to health-related quality of life in

patients attending a Maxillofacial Oncology clinic.

Oral Oncol 2008;44:430-438.

2. Dijkstra PU, Huisman PM, Roodenburg JL. Criteria

for trismus in head and neck oncology. Int J Oral


3. van der Molen L, van Rossum MA, Ackerstaff

AH, Smeele LE, Rasch CR, Hilgers FJ. Pretreat-

ment organ function in patients with advanced

head and neck cancer: clinical outcome measures

and patients’ views. BMC Ear Nose Throat Disord

2009;9:10.

4. Johnson J, van As-Brooks CJ, Fagerberg-Mohlin B,

Finizia C. Trismus in head and neck cancer patients

in Sweden: incidence and risk factors. Med Sci

Monit 2010;16:CR278-82.




Care Cancer 2010;18:1033-1038.

6. Jeremic G, Venkatesan V, Hallock A, et al. Trismus

following treatment of head and neck cancer. J Oto-

laryngol Head Neck Surg 2011;40:323-329.




173.




9. Van Cann EM, Dom M, Koole R, Merkx MA, Stoe-

linga PJ. Health related quality of life after mandibu-

lar resection for oral and oropharyngeal squamous

cell carcinoma. Oral Oncol 2005;41:687-693.



Otol 1993;107:1017-1020.



Adv Ther 2008;25:9-16.

12. Melchers LJ, Van Weert E, Beurskens CH, et al.

Exercise adherence in patients with trismus due

to head and neck oncology: a qualitative study into

the use of the Therabite. Int J Oral Maxillofac Surg

2009;38:947-954.




14. Bhatia KS, King AD, Paunipagar BK, et al. MRI

findings in patients with severe trismus following

radiotherapy for nasopharyngeal carcinoma. Eur

Radiol 2009;19:2586-2593.

15. Goldstein M, Maxymiw WG, Cummings BJ, Wood

RE. The effects of antitumor irradiation on mandib-

ular opening and mobility: a prospective study of 58

patients. Oral Surg Oral Med Oral Pathol Oral Radiol

Endod 1999;88:365-373.

16. Grandi G, Silva ML, Streit C, Wagner JC. A mobili-

zation regimen to prevent mandibular hypomobility

in irradiated patients: an analysis and comparison


2007;12:E105-9.






111.

18. Delanian S, Lefaix JL. The radiation-induced

fibroatrophic process: therapeutic perspec-

tive via the antioxidant pathway. Radiother Oncol

References

Mou

th o

peni

ng in

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diat

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nts

49

2004;73:119-131.





2005;115:1458-1460.

20. Yeh SA, Tang Y, Lui CC, Huang YJ, Huang EY.

Treatment outcomes and late complications of 849

patients with nasopharyngeal carcinoma treated

with radiotherapy alone. Int J Radiat Oncol Biol Phys

2005;62:672-679.

21. Tang Y, Shen Q, Wang Y, Lu K, Wang Y, Peng Y.

A randomized prospective study of rehabilitation

therapy in the treatment of radiation-induced


2011;187:39-44.

22. Teguh DN, Levendag PC, Voet P, et al. Trismus in

patients with oropharyngeal cancer: relationship

with dose in structures of mastication apparatus.

Head Neck 2008;30:622-630.








Surg 2012;50:328-332.

25. Beetz I, Steenbakkers RJ, Chouvalova O, et al.

The QUANTEC criteria for parotid gland dose

and their efficacy to prevent moderate to severe

patient-rated xerostomia. Acta Oncol 2013.





2009;40:32-37.

27. Li XH, Liao YP, Tang JT, Zhou JM, Wang GH. Effect

of early rehabilitation training on radiation-induced

trismus in nasopharyngeal carcinoma patients. Ai

Zheng 2007;26:987-990.

28. Kamstra JI, Roodenburg JL, Beurskens CH, Re-

intsema H, Dijkstra PU. TheraBite exercises to treat

trismus secondary to head and neck cancer. Sup-

port Care Cancer 2013;21:951-957.

29. Jager-Wittenaar H, Dijkstra PU, Vissink A, van

Oort RP, Roodenburg JL. Variation in repeated

mouth-opening measurements in head and neck

cancer patients with and without trismus. Int J Oral


Chapter 3.2

Risk factors for trismus in patients receiving radiotherapy

This chapter is an edited version of: Van der Geer SJ, Kamstra JI, Roodenburg JLN, van Leeuwen M, Reintsema H, Langendijk JA, Dijkstra PU. Risk factors for trismus in patients receiving radiotherapy. Acta Oncol 2016 (accepted).

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Abstract

ObjectivesAims of this prospective longitudinal cohort study were to determine (1) the incidence of trismus at various time points and (2) the patient, tumor, and treatment characteris-tics that predict the development of trismus post-radiotherapy in head and neck cancer patients using a large database (n=641).

MethodsMouth opening was measured prior to radiotherapy (baseline) and at 6, 12, 18, 24, 36, and 48 months post-radiotherapy. Incidence of trismus was calculated. Patient, tumor, and treatment characteristics were analyzed as potential risk factors for trismus and analyzed using multivariate logistic regression analyses.

ResultsAt 6 months post-radiotherapy, 28.1% of the patients without trismus prior to radio-therapy developed trismus for the first time. At subsequent time points the incidence declined. Over a total period of 48 months post-radiotherapy, the incidence of trismus was 3.6 per 10 person years at risk. Patients who had tumors located in the oral cav-ity, oropharynx or nasopharynx, and the salivary glands or ear, and who had a longer overall treatment time of radiotherapy, were more likely to develop trismus in the first 6 months post-radiotherapy. Mouth opening was a risk factor for developing trismus at all time points.

ConclusionThe incidence of trismus was 3.6 per 10 person years at risk. Tumor location and over-all treatment time of radiotherapy were risk factors for developing trismus the first 6 months post-radiotherapy. Mouth opening at any time point was a significant predictor for developing trismus at all subsequent time points. Regular measurements of mouth opening are needed to predict trismus.

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Introduction

Many patients with head and neck cancer suffer from trismus (a limited ability to open the mouth of 35 mm or less) following cancer treatment, especially after radiotherapy.1, 2

Fibrosis is considered one of the biological mechanisms leading to late radiation-induced side effects.3-5 When the temporomandibular joint and masticatory muscles are irradi-ated, there is a risk of developing trismus.6, 7 This risk increases in proportion to irradia-tion dose and irradiated volume of relevant anatomical structures.2, 8, 9 The reported prevalence of trismus after radiotherapy for head and neck cancer ranges from 25 to 42%.2, 9 This wide range in percentages can be explained by differences in inclusion cri-teria, tumor characteristics, interval from treatment, and/or treatment modality in stud-ies.

A previous study showed that mouth opening decreases rapidly in the first 9 months post-radiotherapy (mean decrease 2.4% per month). This restriction in mouth opening may become severe and irreversible over time.5 Recently, a multivariate predic-tion model for the course of mouth opening during and post-radiotherapy was pub-lished.10 Although that model can be used to statistically predict the course of mouth opening, the clinical application is limited because of its complexity. Prediction of trismus may enable clinicians to subscribe preventive exercise therapy (for instance using the Dynasplint Trismus System® or the TheraBite® Jaw Motion Rehabilitation System™), for the patients at risk.11, 12

In this prospective longitudinal cohort study, we aimed to determine (1) the inci-dence of trismus at various time points and (2) the patient, tumor, and treatment char-acteristics that predict the development of trismus post-radiotherapy in head and neck cancer patients using a large database (n=641).

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Methods

ParticipantsHead and neck cancer patients who received definitive or postoperative external beam radiotherapy at the department of Radiation Oncology of the University Medical Cen-ter Groningen were entered in a prospective data registration program. Prospective assessment of acute and late toxicity and patient-reported outcome measures were included. Radiotherapy was given alone or in combination with chemotherapy or cetux-imab. For our study, we used data of patients entered in the program from March 2007 until June 2011. The Ethics Committee approved our study and the study was carried out according to the regulations of our institute. Patients were invited to participate in this program and asked for permission to use their data for the program and other sci-entific purposes. Refusal of participation was recorded in their medical record.

Patients receiving radiotherapy for a primary tumor located outside the head and neck region, intra cranially, in the nasal vestibule, or on the skin, were excluded from the analyses because treatment of these tumors were not expected to influence mouth opening. Patients without data about mouth opening were excluded, as well as patients who died during radiotherapy or within 6 months thereafter.

DataPatient characteristics were sex (male, female), age at start of radiotherapy (years), de-ceased (yes, no), dental status (dentulous, edentulous, partially edentulous, and unknown), and change in dental status (yes, no). The tumor characteristics were location of the pri-mary tumor (oral cavity, oropharynx or nasopharynx, salivary glands or ear, hypopharynx or supraglottic larynx, glottic or subglottical larynx, nasal cavity or maxillary sinus, un-known primary tumor), squamous cell carcinoma (yes, no), and T classification based on the Union for International Cancer Control (UICC) TNM classification 2009 (T0, T1, T2, T3, T4, unknown). Treatment characteristics recorded were radiotherapy primary tumor (yes, no), total dose of irradiation (Gy), fraction dose of irradiation (Gy), overall treatment time of radiotherapy (months), surgery (yes, no), neck dissection (yes, no), chemotherapy (yes, no), and exercise therapy for trismus (yes, no).

Mouth openingPrior to radiotherapy (T0), mouth opening in mm was measured using a slide caliper. Mouth opening measurements were performed by well instructed nurses. All con-cerned nurses were trained in measuring maximal mouth opening by the head and neck radiation oncologists prior to the measurements. A limited number of nurses were working at the department of Radiation Oncology during the study period. Patients were asked to open their mouth as far as possible and the distance between the incisal edges of the 11 and 41 (or of the dental prosthesis) was measured. When patients were edentulous and did not wear a dental prosthesis, the alveolar ridge of mandible and/or maxilla was used (region 11 and 41). The mouth opening was measured again dur-ing subsequent time points: 6 (T6), 12 (T12), 18 (T18), 24 (T24), 36 (T36), and 48 (T48)

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months post-radiotherapy. Changes in dental status were recorded in the database. Trismus was noted as present if mouth opening was 35 mm or less. This cut-off

point correlates best with perceived restrictions of mouth opening.13, 14

Statistics Analyses were performed using SPSS 22.0 for Windows software (SPPS Inc., Chicago, IL, USA). Patients, with no missing mouth opening measurements before their last re-corded measurement, were coded as ‘without missing data’ and patients with missing mouth opening measurements were coded as ‘missing data’. Differences between pa-tients with and without missing data were analyzed using a Chi-square test, t test for independent samples, or Mann-Whitney U test, as appropriate.

To calculate the incidence of trismus, the number of patients who developed tris-mus for the first time since radiotherapy was calculated and divided by the number of patients who were at risk of developing trismus for the first time. Patients having tris-mus prior to radiotherapy were excluded from the incidence analyses. Patients who had no trismus at the last assessment, but with missing data at previous time points, were also excluded from the incidence analyses since they might have had trismus at those missing time points. To calculate the incidence based on person years at risk, patients with missing data before the time point when trismus was recorded for the first time and who had no trismus prior to radiotherapy, were included in the calculation; we as-sumed that trismus developed half way in the period between 2 recorded time points.

Multivariate logistic regression analyses were performed to predict trismus at the subsequent time points. Patient, tumor, and treatment characteristics were selected as potential risk factors. For example, at T0, we used potential risk factors to predict the risk of developing trismus at T6. Similarly, at T6 we used potential risk factors to predict the risk of developing trismus at T12.

The potential risk factors: sex, age, location of the primary tumor, squamous cell carcinoma, T4 classification, total dose of irradiation, fraction dose of irradiation, overall treatment time of radiotherapy, surgery, chemotherapy, and mouth opening at previ-ous time point were entered in the model.9, 10, 14-16 Thereafter, variables were removed if they did not contribute significantly to the multivariate logistic regression analyses (p<0.05). As part of validation, the results of the calculations of incidence and of the re-gression analyses were compared to the results of patients without missing data. From the results of the regression analyses, the risk of developing trismus was calculated for a hypothetical patient who had a nasopharynx carcinoma and was treated with radio-therapy for 6 weeks.

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Chapter 3.2

Results

Patient, tumor, and treatment characteristics Data from 788 patients who received radiotherapy in the head and neck region were entered in the prospective data registration program; in total, 145 patients were exclud-ed according to the exclusion criteria.10 Additionally, 2 patients with a rare type of tumor (myxofibrosarcoma and epitheloid angiosarcoma) were excluded for statistical reasons. Thus, the study population consisted of 641 patients (81.3%), involving 436 patients without missing data regarding mouth opening. Patients with and patients without missing data were compared. Significant differences between these groups were found in the variables deceased, overall treatment time of radiotherapy, and chemotherapy (Table 1).

Of the 641 patients, 42 (6.6%) changed dental status; 20 of these patients (3.1%) changed from dentulous to edentulous, 15 patients (1.9%) changed from partially eden-tulous to edentulous, and 5 patients (0.8%) changed from dentulous to partially edentu-lous. The change in dental status was unknown for 2 patients (0.3%).

Prevalence of trismus Prior to radiotherapy, 34.8% of the patients had trismus (Table 2). Relative to patients who did not have trismus prior to radiotherapy, trismus prior to radiotherapy was sig-nificantly associated with female sex (p<0.001), a higher age at start of radiotherapy (p=0.002), tumors located in the oral cavity and salivary glands or ear (p<0.001), T4 tu-mors (p=0.002), and a history of surgery (p<0.001) (Appendix 1).

Incidence of trismus The incidence of trismus in the total period of 48 months post-radiotherapy was 3.6 per 10 person years at risk. At T6, 28.1% of the patients at risk developed trismus for the first time (Table 2). Patients with a tumor located in the oropharynx or nasopharynx (p=0.004) and with a history of chemotherapy (p=0.024) were more likely to develop trismus at T6 (Appendix 1). The incidence of trismus declined at subsequent time points. No new cases of trismus developed after T36 (Table 2). No major differences were seen when the results of the incidence of trismus of the study population were compared to the results of the patients without missing data (Appendix 2).

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Study popu lation

Without missing data

With miss ing data

Patient characteristics n (%) n (%) n (%) p*Male sex 451 (70.4) 312 (71.6) 139 (67.8) 0.332Age at start of radiotherapy (years); Mean (SD)

62.3 (12.5) 62.4 (12.6) 61.9 (12.5) 0.698∞

Deceased 199 (31.0) 161 (36.9) 38 (18.5) <0.001Dental status 0.510

Dentulous 241 (37.6) 156 (35.8) 85 (41.5)Edentulous 319 (49.8) 219 (50.2) 100 (48.8)Partially edentulous 77 (12.0) 53 (12.2) 18 (8.8)Unknown 4 (0.6) 3 (0.7) 1 (0.5)

Change in dental status 42 (6.6) 30 (6.9) 12 (5.9)Tumor characteristicsLocation of the primary tumor 0.584

Oral cavity 132 (20.6) 93 (21.3) 39 (19.0)Oropharynx or nasopharynx 162 (25.3) 109 (25.0) 53 (25.9)Salivary glands or ear 66 (10.3) 46 (10.6) 20 (9.8)Hypopharynx or supraglottic larynx 115 (17.9) 76 (17.4) 39 (19.0)Glottic or subglottic larynx 116 (18.1) 77 (17.7) 39 (19.0)Nasal cavity or maxillary sinus 24 (3.7) 20 (4.6) 4 (2.0)Unknown primary 26 (4.1) 15 (3.4) 11 (5.4)

Squamous cell carcinoma 512 (79.9) 351 (80.5) 161 (78.5) 0.562T classification 0.931

T0 6 (0.9) 3 (0.7) 3 (1.5)T1 112 (17.5) 77 (17.7) 35 (17.1)T2 191 (29.8) 129 (29.6) 62 (30.2)T3 99 (15.4) 68 (15.6) 31 (15.1)T4 183 (28.5) 128 (29.4) 55 (26.8)Unknown 38 (5.9) 25 (5.7) 13 (6.3)

Treatment characteristicsRadiotherapy primary tumor 610 (95.2) 418 (95.7) 192 (96.6) 0.410Total dose of irradiation; Med (IQR) 70 (66-70) 66 (66-70) 70 (66-70) 0.413‡Fraction dose of irradiation; Med (IQR) 2 (2-2) 2 (2-2) 2 (2-2) 0.709‡Overall treatment time of radiotherapy (months); Med (IQR)

1.28 (1.3-1.5) 1.4 (1.3-1.5) 1.3 (1.2-1.4) 0.041‡

Surgery 248 (38.7) 175 (40.1) 73 (35.6) 0.272Neck dissection 316 (33.7) 142 (32.6) 74 (36.1) 0.378Chemotherapy 465 (72.5) 137 (31.4) 39 (19.0) 0.001Exercise therapy for trismus 21 (3.3) 14 (3.2) 7 (3.4) 0.893

Med: Median. IQR: Interquartile range.*: p of the comparison between patients with and patients without missing data. ∞: Results of t test for independent samples. ‡: Results of Mann-Whitney U test. All other p values were the result of Chi-square test.

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Chapter 3.2

Table 2. Trismus at T0, T6, T12, T18, T24, T36, and T48

Total* No trismus

Trismus No trismus to

Trismus

Trismus to no trismus

At risk for trismus for

the first time

Incidence

Time point n n (%) n (%) n (%) n (%) n n (%)T0

414270 (65.2) 144 (34.8)

76 (28.1) 45 (31.3) 270 76 (28.1)T6 239 (57.7) 175 (42.3)

T6365

225 (61.6) 140 (38.4)35 (15.6) 39 (27.9) 164 19 (11.6)

T12 229 (62.7) 136 (37.3)

T12349

225 (64.5) 124 (35.5)40 (17.8) 27 (21.8) 126 14 (11.1)

T18 212 (60.7) 137(39.3)

T18328

192 (58.5) 136 (41.5)19 (9.9) 29 (21.3) 95 7 (7.4)

T24 202 (61.6) 126 (38.4)

T24213

133 (62.4) 80 (37.6)13 (9.8) 13 (16.3) 51 3 (5.9)

T36 133 (62.4) 80 (37.6)

T36114

74 (64.9) 40 (35.1)8 (10.8) 3 (7.5) 22 0

T48 69 (60.5) 45 (39.5)

*: Number of patients for which observations are available for the time period. For example: Initially, 270 patients had no trismus, of which 76 changed status, they developed tris-mus and 194 did not change status, they remained without trismus. In total 144 patients did have trismus of which 45 changed status to ‘no trismus’ and 99 did not change status, they kept trismus. At T0, 270 patients were at risk to develop trismus for the first time. Of these 270 patients, 76 de-veloped trismus for the first time.

Multivariate logistic regression analyses In the multivariate prediction model, a smaller mouth opening at T0, a longer overall treatment time of radiotherapy, and tumors located in the oral cavity, oropharynx or nasopharynx, and the salivary glands or ear, all resulted in significantly higher odds for developing trismus at T6. A smaller mouth opening at T6 and a tumor located in the oral cavity led to significantly higher odds of developing trismus at T12. However, for the prediction of developing trismus at T18, T24, T36, and T48, only mouth opening at the previous time point contributed significantly to the regression analyses (Table 3). No major differences were seen when the results of the multivariate logistic regression analyses of the study population were compared to the results of the patients without missing data (Appendix 3).

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Table 3. Output multivariate logistic regression analyses at T6, T12, T18, T24, T36, and T48

Prediction mouth opening at T6 %* β OR 95% CI OR LL

95% CI OR UL

p (β)

% correctly predicted (Nagelkerke’s R2)

73.9 (0.334)

Mouth opening at T0 -0.09 0.91 0.89 0.93 <0.001

Overall treatment time (in months) 1.72 5.58 1.80 17.32 0.003

Oral cavity 0.82 2.28 1.06 4.91 0.035

Oropharynx or nasopharynx 1.44 4.21 2.04 8.68 <0.001

Salivary glands or ear 1.15 3.15 1.29 7.68 0.012

Hypopharynx or supraglottic larynx 0.31 1.37 0.61 3.06 0.445

Nasal cavity or maxillary sinus 0.69 2.00 0.54 7.41 0.299

Unknown primary tumor -0.62 0.54 0.13 2.29 0.401

Constant 0.19 1.20 0.840

Prediction mouth opening at T12


81.4 (0.506)


Oral cavity 1.32 3.74 1.44 9.74 0.007

Oropharynx or nasopharynx 0.61 1.83 0.76 4.42 0.177


Hypopharynx or supraglottic larynx 0.53 1.70 0.61 4.69 0.309


Unknown primary tumor 1.05 2.86 0.73 11.24 0.133

Constant 5.89 361.58 <0.001



81.7 (0.533)


Constant 7.53 1858.14 <0.001



85.4 (0.657)


Constant 9.26 10535.35 <0.001



88.3 (0.655)


Constant 9.70 16309.72 <0.001

Chapter 3.2

60


% correctly predicted (Nagelkerke’s R2) 85.0 (0.641)


Constant 9.23 10195.45 <0.001

β: Regression coefficient. OR: Odds ratio. 95% CI OR LL: 95% confidence interval of OR lower limit. 95% CI OR UL: 95% confidence interval of OR upper limit. Nagelkerke R2: Nagelkerke’s R Square. *: Percentage correctly predicted.Glottic or subglottic larynx is used as reference category.

Figure 1. Risk of developing trismus at T6, T12, T18, T24, T36, and T4

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

5 10 15 20 25 30 35 40 45 50 55 60 65 70

Ris

k

Maximal mouth opening (mm)

T6

T12

T18

T24

T36

T48

Arbitrarily chosen characteristics of a hypothetical patient were entered in the multivariate logistic regression analysis as a reference category. This hypothetical patient had a nasopharynx carcinoma and was treated with radiotherapy for 6 weeks.

Risk calculationAs an example of applying the multivariate prediction model, arbitrarily chosen charac-teristics of the hypothetical patient (nasopharynx carcinoma, radiotherapy for 6 weeks) were entered in the multivariate logistic regression analyses (Figure 1). No major differ-ences were seen when the results of the risk calculation of the study population were compared to the results of the patients without missing data (Appendix 4).

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Discussion

Key resultsIn our population of head and neck cancer patients, the incidence of trismus was highest 6 months post-radiotherapy and declines thereafter (Table 2). The incidence of trismus was 3.6 per 10 person years at risk, calculated over the total period of 48 months post-radiotherapy. The risk factors for developing trismus in the first 6 months post-radio-therapy found are a longer overall treatment time of radiotherapy and tumors located in the oral cavity, oropharynx or nasopharynx, and the salivary glands or ear. At all the time points, mouth opening measurement at the previous time point was a significant risk factor for developing trismus at the subsequent time point (Table 3).

Prevalence of trismusAs stated earlier, already 34.8% of the head and neck cancer patients had a trismus prior to radiotherapy. Patients with a tumor located in the oral cavity and salivary glands or ear, were more likely to have trismus prior to radiotherapy, possibly because of tumor infiltration near the masticatory muscles. Additionally, patients with a history of surgery were more likely to have trismus prior to have radiotherapy, probably due to the forma-tion of scarring after surgery.

Incidence of trismusFor the calculation of incidence, most patients had measurements at time points T0 and T6. Thereafter, the number of patients who had subsequent measurements declined. This decline was due to the patients who deceased after T6 and due to patients for whom measurements were not completed in the inclusion period (right censored data).

The results in Table 2 showed that the incidence of trismus was highest from T0 to T6. Thereafter, the incidence for trismus declined. This was also observed in 2 other studies.5, 17 The first study showed a rapid decrease in mouth opening between the first and ninth month post-radiotherapy.5 The second study showed a rapid decrease in mouth opening of 0.9% per month during the first 6 months post-radiotherapy and this decrease reduced over time to 0.3% per month, and reduced even further between the second and fifth year post-radiotherapy.17 Both studies included only patients suffering from nasopharyngeal carcinomas. In our study, patients with head and neck tumors at different locations were included, which probably increases the generalizability of our results.

The decline in incidence at subsequent time points can be related to recovery from the short-term effects of radiotherapy. In a small group of patients with nasopharyn-geal carcinomas (n=17), recovery occurred between the fifth and twelfth month post-radiotherapy.18 Due to this recovery, patients with trismus at a time point can change to no trismus at a later time point. Remarkably, in our study, recovery from trismus still occurred up to 48 months (Table 2).

62

Chapter 3.2

Risk calculation A longer overall treatment time of radiotherapy led to a higher risk of developing tris-mus six months after radiotherapy. A longer overall treatment time could be a risk fac-tor due to patients receiving chemotherapy or not. In general, in our center, patients who receive chemotherapy are treated for 7 weeks, while patients who receive radio-therapy only are treated for 6 weeks. It could be assumed, that patients with a longer overall treatment time of radiotherapy, includes predominantly patients who received chemotherapy. A combination of chemotherapy and radiotherapy is a more intensive and extensive approach, which would be expected to lead to more fibrosis and hence more trismus.

In our study, we found no significant association between the prescribed total dose and fraction dose of radiotherapy and trismus. In a retrospective study, an associa-tion between difficulty in opening the mouth and the radiation dose to the masseter muscles, pterygoid muscles, coronoid process, and mandibular condyle was found.19 It is expected that significant dose-effect relationships will be found when using specific 3D distribution parameters to relevant anatomical structures.

Future studies Analysis of specific dose distribution and anatomical structures such as the masticatory muscles and temporomandibular joint could improve the identification of patients at risk of developing trismus. We did not include the effect of the 3D dose distributions in our analysis as this is part of a future, separate project in which multivariable normal-tissue-complication probability models will be used.

Study limitations A limitation of our study was the measurement procedure of mouth opening that was performed by different assessors of the department of Radiation Oncology, which might have introduced a measurement error. However, it is stated that maximal mouth opening can be assessed reliably, regardless of the assessor, therefore we expect this error to be small.20

Another limitation was the change in dental status during the course of the study. A relatively small percentage of the patient changed dental status (6.6%). Most patients changed from dentulous to (partially) edentulous or from partially edentulous to eden-tulous, thereby resulting predominantly in an increase of mouth opening measurement. However, this does not reflect real recovery from trismus itself. The calendar dates regarding dental status changes were not available in the database, thus no direct link between dental status and the variation in number of patients with and without trismus could be made.

Finally, no other causes for trismus than secondary to the head and neck cancer were investigated.

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Conclusion The incidence of trismus was 3.6 per 10 person years at risk based on a follow-up of 48 months post-radiotherapy. Tumor location and overall treatment time of radiotherapy were risk factors for developing trismus the first 6 months post-radiotherapy. Mouth opening at any time point was a significant predictor for developing trismus at all subse-quent time points. Because mouth opening is an important risk factor, regular measure-ments of mouth opening are needed to predict trismus. High-risk patients, identified by the presence of risk factors for trismus, can be offered preventive measures.

64

Chapter 3.2

AppendicesA

ppen

dix

1. C

ompa

riso

n be

twee

n pa

tient

s w

ith n

o tr

ism

us a

t T0

, with

tri

smus

at T

0, a

nd t

rism

us a

t T6

No

tris

mus

at

T0 (n

=37

0)

Tris

mus

at T

0

(n=

196

)Tr

ism

us a

t T6

(n=

76)

Sign

ifica

nce

of t

he

diff

eren

ce b

etw

een

patie

nts

with

no

tris

mus

an

d tr

ism

us a

t T0

Sign

ifica

nce

of t

he d

iffer

ence

be

twee

n pa

tient

s w

ith

tris

mus

at T

0 a

nd T

6

n%

*n

%*

n%

*Va

lue

DF

pVa

lue

DF

p

Mal

e se

x28

577

115

58.7

526

8.4

20.8

21

<0

.00

12.

195

10

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Squa

mou

s ce

ll ca

rcin

oma

306

82.

715

076

.56

078

.93.

121

0.0

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21

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7

Ora

l cav

ity52

14.1

61

31.1

1215

.854

.76

<0

.00

119

.053

60

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phar

ynx

or n

asop

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.7

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ds o

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rynx

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23.8

189.

29

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max

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nus

123.

211

5.6

11.

3

Unk

now

n pr

imar

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mor

92.

49

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umor

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7236

.721

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9.7

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10

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99

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115

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3343

.40

.00

21

0.9

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86

10

.024

Mea

nSD

Mea

nSD

Mea

nSD

MD

95%

CI

pM

D9

5% C

I p

Age

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3.7

12.1

60

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3.5

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DF:

Deg

rees

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*: P

erce

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cted

.

65

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Appendix 2. Trismus at T0, T6, T12, T18, T24, T36, and T48 for patients without missing data only

Total* No trismus

Trismus No tris-mus to

Trismus

Trismus to no trismus

At risk for trismus for the

first time

Incidence

Time point n n (%) n (%) n (%) n (%) n n (%)T0

353230 (65.2) 123 (34.8)

60 (26.1) 40 (32.5) 230 60 (26.1)T6 210 (59.5) 143 (40.5)

T6297

190 (64.0) 107 (36.0)32 (16.8) 32 (29.9) 152 19 (12.5)

T12 190 (64.0) 107 (36.0)

T12264

173 (65.5) 91 (34.5)31 (17.9) 18 (19.8) 122 14 (11.5)

T18 160 (60.6) 104 (39.4)

T18228

139 (61.0) 89 (39.0)15 (10.8) 18 (20.2) 95 7 (7.4)

T24 142 (62.3) 86 (37.7)

T24125

78 (62.4) 47 (37.6)6 (7.7) 10 (21.3) 51 3 (5.9)

T36 82 (65.6) 43 (34.4)

T3659

37 (62.7) 22 (37.3)5 (1.4) 6 (27.2) 22 0

T48 38 (64.4) 21 (35.5)

*: Number of patients for which observations are available for the time period. For example: Initially, 230 patients had no trismus, they were at risk of developing trismus for the first time, of which 60 changed status, they developed trismus and 170 did not change status, they remained without trismus. In total 123 patients did have trismus of which 40 changed status to ‘no trismus’ and 83 did not change status, they kept trismus. At T0, 230 patients were at risk to develop trismus for the first time. Of these 230 patients, 60 developed trismus for the first time.

66

Chapter 3.2

Appendix 3. Output multivariate logistic regression analyses at T6, T12, T18, T24, T36, and T48 for patients without missing data only

Prediction mouth opening at T6 %* β OR 95% CI OR LL

95% CI OR UL

p (β)


73.9 (0.338)

Mouth opening at T0 -0.10 0.90 0.88 0.93 <0.001Overall treatment time (months) 1.73 5.62 1.68 18.84 0.005Oral cavity 0.69 1.99 0.87 4.54 0.101Oropharynx or nasopharynx 1.33 3.80 1.72 8.39 0.001Salivary glands or ear 1.08 2.93 1.13 7.64 0.028Hypopharynx or supraglottic larynx 0.46 1.59 0.66 3.80 0.301Nasal cavity or maxillary sinus 0.45 1.56 0.38 6.42 0.535Unknown primary tumor -1.01 0.36 0.07 2.01 0.246Constant 0.48 1.62 0.632Prediction mouth opening at T12


81.5 (0.488)


Oral cavity 1.74 5.69 1.98 16.40 0.001




0.60 1.82 0.60 5.56 0.291



Constant 5.65 283.57 <0.001



81.4 (0.556)


Constant 8.04 3096.67 <0.001



86.8 (0.665)


Constant 9.92 20420.54 <0.001


67

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88.0 (0.726)


Oral cavity 2.20 9.02 0.97 84.19 0.054




3.73 41.60 4.27 405.41 0.001



Constant 9.60 14707.06 <0.001



83.1 (0.642)


Constant 8.52 5028.63 <0.001

β: Regression coefficient. OR: Odds ratio. 95% CI OR LL: 95% confidence interval of OR lower limit. 95% CI OR UL: 95% confidence interval of OR upper limit. Nagelkerke R2: Nagelkerke’s R Square. *: Percentage correctly predicted.Glottic or subglottic larynx is used as reference category.

68

Chapter 3.2

Appendix 4. Risk of developing trismus at T6, T12, T18, T24, T36, or T48 months for patients without missing data only

Arbitrarily chosen characteristics of a hypothetical patient were entered in the multivariate logistic regression analysis as a reference category. This hypothetical patient had a nasopharynx carcinoma and was treated with radiotherapy for 6 weeks.

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

5 10 15 20 25 30 35 40 45 50 55 60 65 70

Ris

k

Maximal mouth opening (mm)

T6

T12

T18

T24

T36

T48

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Oncol 2004;40:879-889.




Care Cancer 2010;18:1033-1038.

3. Bengtson BP, Schusterman MA, Baldwin BJ, et al.

Influence of prior radiotherapy on the development

of postoperative complications and success of free

tissue transfers in head and neck cancer recon-

struction. Am J Surg 1993;166:326-330.

4. Louise Kent M, Brennan MT, Noll JL, et al. Radi-

ation-induced trismus in head and neck cancer






2005;115:1458-1460.

6. Bhatia KS, King AD, Paunipagar BK, et al. MRI find-

ings in patients with severe trismus following radio-

therapy for nasopharyngeal carcinoma. Eur Radiol

2009;19:2586-2593.

7. Lindblom U, Garskog O, Kjellen E, et al. Radiation-

induced trismus in the ARTSCAN head and neck

trial. Acta Oncol 2014;53:620-627.

8. O’Sullivan B, Levin W. Late radiation-related

fibrosis: pathogenesis, manifestations, and current

management. Semin Radiat Oncol 2003;13:274-

289.




Monit 2010;16:CR278-82.

10. Kamstra JI, Dijkstra PU, van Leeuwen M,

Roodenburg JL, Langendijk JA. Mouth opening in

patients irradiated for head and neck cancer: a

prospective repeated measures study. Oral Oncol

2015;51:548-555.






2010;91:1278-1282.

12. Cohen EG, Deschler DG, Walsh K, Hayden

RE. Early use of a mechanical stretching device

to improve mandibular mobility after composite

resection: a pilot study. Arch Phys Med Rehabil

2005;86:1416-1419.









111.




173.





17. Chen YY, Zhao C, Wang J, et al. Intensity-modu-

lated radiation therapy reduces radiation-induced

trismus in patients with nasopharyngeal carcinoma:

a prospective study with >5 years of follow-up.

Cancer 2011;117:2910-2916.

18. Hsiung CY, Huang EY, Ting HM, Huang HY.

Intensity-modulated radiotherapy for nasopharyn-

References

70

Chapter 3.2

geal carcinoma: the reduction of radiation-induced

trismus. Br J Radiol 2008;81:809-814.




Head Neck 2008;30:622-630.






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Chapter 4.1Exercise therapy for trismus secondary to head and neck cancer: a systematic review

This chapter is an edited version of: Kamstra JI, van Leeuwen M, Roodenburg JL, Dijkstra PU. Exercise therapy for trismus secondary to head and neck cancer: A systematic review. Head Neck 2016 (Epub ahead of print).

74

Chapter 4.1

Abstract

ObjectivesAims of this systematic review were (1) to identify exercise therapy interventions for trismus secondary to head and neck cancer, (2) to assess methodological quality of these studies, and (3) to summarize results of these studies.

MethodsFour databases were searched. The quality of observational studies and randomized controlled trials was assessed.

ResultsTwo-hundred-eleven articles were found; 20 studies were included. A large variation in research methodology, stretching techniques, duration of stretch, and repetition of exercises was found. The overall quality was moderate. Five of the 8 preventive stud-ies found that exercises during (chemo)radiotherapy could not prevent a reduction in mouth opening. In 4 therapeutic case-studies, mouth opening increased between 17 and 24 mm. In 8 other therapeutic studies mouth opening increased between -1.9 and 13.6 mm. No exercise therapy was clearly superior to the others.

ConclusionChanges in mouth opening ranged considerably and no stretching technique was supe-rior to others, neither regarding prevention or treatment of trismus. Clinical guidelines cannot be given based on this systematic review.

75

Exer

cise

the

rapy

for

tris

mus

Introduction

Treatment of cancer of the head and neck region may lead to side effects, such as dys-phagia, xerostomia, mucositis, and trismus.1 These side effects can severely impede the overall quality of life of patients and may contribute to post treatment depression.1, 2 Trismus, a limited ability to open the mouth, is considered the second most burdensome side effect of oncologic therapy in the head and neck region.3 Trismus is commonly de-fined as a mouth opening of 35 mm or less.4, 5 It occurs in 5 to 38% of patients suffering from head and neck cancer, although recent research suggested an even larger inci-dence (38 to 42%).4, 6, 7 Trismus can lead to difficulties in activities, such as biting, chew-ing, speaking, and laughing. It may also impair oral hygiene, resulting in dental caries and periodontal disease.8, 9

Surgery in head and neck cancer may lead to a limited mouth opening, because of scar formation in the muscles of mastication.9 Radiotherapy may cause fibrosis of the temporomandibular joint or of the muscles of mastication, which can lead to trismus.9-11 When the medial pterygoid muscle is included in the irradiated region, the risk of de-veloping trismus increases.12 Trismus usually occurs 3 to 6 months after radiotherapy is completed, and can continue to increase in severity up to 2 years.9, 13 Intensity-modulated radiotherapy can spare the healthy tissues and reduce the risk of developing trismus.10-12

In therapy-resistant cases, trismus can be resolved by surgical procedures, such as lowering the height of the mandible in order to obtain a larger mouth opening, tissue release followed by reconstruction using a free-flap, or a coronoidectomy.14-16 More often, however, exercise therapy is prescribed, using stretching techniques to increase the range of mouth opening.

In 2004, a systematic review was performed to identify the criteria, risk factors, and physical therapeutic interventions for trismus.17 The overall quality of the studies was considered poor, and only 4 articles could be included in the review. In 2010, in a systematic review including 22 studies, was concluded that trismus could possibly be prevented or managed by early therapy modalities. They considered the use of the Dy-nasplint® Trismus System (DTS) and the TheraBite® Jaw Motion Rehabilitation System™ (TheraBite), as well as the administration of botulinum toxin of pentoxifylline, as possible enhancers of mouth opening. However, these options were not supported by random-ized controlled trials (RCTs); therefore no clinical guidelines could be created at that time.18

In recent years, numerous studies have been published regarding exercise therapy and trismus that have not been reviewed systematically. We therefore conducted a systematic review with 3 aims: (1) to identify exercise therapy interventions for trismus secondary to head and neck cancer, (2) to assess methodological quality of these stud-ies, and (3) to summarize results of these studies.

76

Chapter 4.1

Methods

Four databases, PubMed, EMBASE, Cochrane Library, and CinAhl, were searched for articles analyzing effects of exercise therapy for trismus secondary to head and neck cancer. In all databases synonyms for trismus, physical therapy, and head and neck neo-plasms were used to create an optimal search strategy. Medical subject heading (MeSH) terms, as well as free text terms were used (Appendix 1). All databases were searched in August 2013 and the search was updated in July 2014.

To be included in this study, articles had to describe trismus secondary to head and neck cancer, for which exercise therapy was applied to prevent or treat it. No restric-tions regarding language or study type were applied. Reviews and letters to the editor were excluded. Articles were assessed for inclusion using a standardized screening form (Appendix 2). All identified articles were retrieved online, from the library of our institute, or from the corresponding author. Articles written in a language not understood by the observers were translated into English. Assessment was performed in 3 steps by 2 ob-servers (JIK and MvL). First, title and abstract were assessed for inclusion criteria, then full text was assessed for inclusion criteria, and finally full text was assessed for meth-odological quality. The quality of observational studies was assessed with an assessment tool based on the MINORS criteria (Appendix 3).19 We added the following points to the MINORS criteria: a clear definition of trismus, a description of the measurement device, and premeasurements and postmeasurements of mouth opening. RCTs were assessed using the risk of bias tool of the Cochrane Collaboration.20 The references of the includ-ed studies were checked for relevant studies missed in the searches, and these were assessed, as described above.

Cohen’s Kappa (% agreement) was calculated as a measure of inter-observer reli-ability. Discrepancies between observers were resolved by discussion. When no consen-sus could be reached, a third observer (PUD) was consulted, providing a binding opinion. The use of correct statistical analyses (criterion 14) was assessed solely by a clinical epidemiologist (PUD). The overall quality score (the number of criteria fulfilled) was dis-played as a percentage of the maximal obtainable score because not all criteria were applicable to all articles (for instance, the criterion of pre-calculated sample size for case reports).

Data were extracted from the included studies. Corresponding authors were con-tacted in case of questions regarding text and data.

77

Exer

cise

the

rapy

for

tris

mus

Results

The searches resulted in 211 articles, of which 24 studies were initially included in the analysis (Figure 1). One study written in Chinese and one in French were translated to English. Cohen’s Kappa (% agreement) as a measure for inter-observer reliability for in-cluding/excluding studies was 0.71 (87%). Consensus was reached for all studies. The 24 included studies and were assessed according to the quality criteria. During data extrac-tion, we found that 6 studies had premeasurements and postmeasurements mean (SD) of the mouth opening taken, but data (premeasurement and postmeasurement mean (SD) of mouth opening) were not provided. Therefore, these studies were excluded.21-26 A seventh study was excluded because it analyzed the effects of pentoxifylline on mouth opening.27 In July 2014 the searches were updated and 3 new studies were included for qualitative assessment. In total, 20 studies were included in this review: 4 case studies, 6 prospective studies, 5 RCTs, and 5 patient chart studies (Table 1).28-47 The sample sizes ranged from 1 to 108 patients, with a mean age ranging from 13.0 to 63.3 years. A total of 691 patients were studied. Patients underwent a variety of treatments for cancer in the head and neck region, including surgery, chemotherapy, radiotherapy, and various combinations of these modalities. Patients suffering from different types and stadia of head and neck cancer were studied. Due to the heterogeneity of the included studies, we could not perform a meta-analysis.

Identification of exercise therapy interventions for trismus secondary to head and neck cancerEight studies analyzed the effects of preventive measures on mouth opening, including with the TheraBite, active range of motion exercises (with or without chewing gum), and wooden tongue depressors.28-35

The other 12 studies analyzed the effects of therapeutic measures on mouth open-ing after trismus had occurred.27, 36-47 Therapeutic exercise modalities included dynamic bite openers, a home-made sledgehammer device, the TheraBite, active range of motion exercises, the Engstrom Jaw mobilizing device, tongue depressors, rubber plugs, and the DTS. Many different stretching techniques were used in the therapeutic studies.

Assessment of quality of included studies Cohen’s Kappa (% agreement) for the quality assessment was 0.94 (87%). The overall quality scores (in %) of the preventative studies ranged from 52 to 81% (median 65.5, in-terquartile range (IQR) 57 to 76) and of the therapeutic studies from 50 to 80% (median 65.5, IQR 57 to 76). The percentage of studies meeting the individual criteria, ranged from 0 to 100% (median 65, IQR 35 to 95) (Table 2). None of the studies reported participa-tion by an independent observer. All studies reported the sample size, age, and sex of the participants, and premeasurements and postmeasurements of mouth opening. The risk of bias assessment that was performed for the included RCTs showed that many items were unclear (Table 3). The criteria ‘overall incomplete data addressed’ and ‘free of selec-tive outcome reporting’ were predominantly scored ‘yes’.

78

Chapter 4.1

Summary of the results of studiesIn Table 4, an overview of the results of included studies is presented.28-47 Duration of ex-ercise therapy ranged from 2 weeks to 12 months. Number of exercise sessions per day varied from 2 to 10, with 3 to 40 repetitions. Duration of stretch ranged from 2 seconds to 60 minutes.

(1) Results of preventive studiesThe TheraBite was used in 5 preventive studies.28, 32-35 In 2 studies, by Ren et al. and Cohen et al., the results of the exercises were substantial, with a mean increase of 9.7 and 14.0 mm, respectively. In both these studies, exercises were started after surgery, but before radiotherapy.28, 32 In the study of Ren et al. no significant difference was found between exercises using a TheraBite and exercises with wooden tongue depressors.32 Cohen et al. reported a significant increase in mouth opening (p<0.01), but no control group was used.28 In a preventive study by Li et al., an exercise compliant group of patients was compared to a non-compliant group (between-group comparison), the decrease in mouth opening in the non-compliant group after 1 year was 18.4 mm greater than in the compliant group.30 Other preventive studies did not find large differences between dif-ferent types of intervention.29, 31, 33-35 In a RCT, Loorents et al. found a positive result after

Figure 1. Flowchart of article selection

Cinahl15

Cochrane11

EMBASE119

PubMed122

Total all databases 267

Duplicates (56 excluded)

181

Titles (30 excluded)

Abstracts (99 excluded)

Full text (59 excluded)

211

82

24

20Search update (3 included)

Post- hoc exclusion because of lack of information (6) or because oftreatment with pentoxifilin (1)

79

Exer

cise

the

rapy

for

tris

mus

12 months of mouth opening exercises with the TheraBite.35 In 5 preventive studies, a reduction of mouth opening was not prevented but less decrease was seen in patients who received preventive exercise therapy.29-31, 33, 34

The duration of therapy in preventive studies ranged from 2 weeks to 12 months; exercises were often performed for long as the duration of the (chemo)radiotherapy. The number of exercise sessions ranged from 2 to 6 per day, with 5 to 40 repetitions per ses-sion. Duration of stretch ranged from 2 seconds to 15 minutes. We detected no clear pat-tern in the duration of therapy and the increase in mouth opening following exercise ther-apy. For example, Ren et al. reported an increase of 14 mm after 2 to 6 weeks of exercises, while van der Molen et al. reported a decreased mouth opening of -0.6 mm 2 years after exercises, both with a TheraBite.32, 34 Likewise, no clear conclusion can be drawn about the number of sessions per day. Both Cohen et al. and Grandi et al. prescribed 6 exercise ses-sions per day (using TheraBite or active range of motion exercises), but reported very dis-similar results: an increase of 10 mm versus a decrease of 1.4 to 3.8 mm.28, 29

(2) Results of therapeutic studiesFour therapeutic case studies were included. In all of these studies a substantial increase in mouth opening was reported, ranging from 17 to 24 mm.36-39 In a prospective study, Pauli et al. found a significantly larger increase (a difference in mean increase of 6.4 mm) in the exercise intervention group compared to the control group (p<0.001).40 In RCTs, all but 1 intervention group had a larger mouth opening compared to the correspond-ing control group; the mean increase ranged from 4.2 mm to 13.6 mm. In their RCT, Tang et al. did not report a larger mouth opening in the intervention group, but they found a smaller decrease in mouth opening in the intervention group than in the control group (-1.9 mm versus -6.9 mm).42 Buchbinder et al. compared 3 therapies: active range of mo-tion exercises, active range of motion exercises in combination with tongue depressors, and exercises with the TheraBite. They found an increase in mouth opening of 4.4 mm, 6.0 mm, and 13.6 mm, respectively. The increase in mouth opening using the TheraBite was significantly superior (p<0.05).41 Dijkstra et al. studied a group of patients with different types of exercises (rubber plugs, tongue blades, a dynamic bite opener, and the TheraBite), which were assigned on clinical presentation of the patient. An overall increase in mouth opening of 5.5 mm was found.43 Additionally, in a chart review study by Kamstra et al., an increase of mouth opening of 5.4 mm on average was observed after exercise therapy with a TheraBite.47

The duration of therapy in therapeutic studies ranged from 1 month to 9 months. The number of exercise sessions ranged from 2 to 10, with 3 to 8 repetitions. Duration of stretch ranged from 6 seconds to 60 minutes. Due to the clinical and methodological heterogeneity of the included studies, we could not perform a meta-analysis.

80

Chapter 4.1

Tabl

e 1.

Cha

ract

eris

tics

of s

tudi

es in

clud

ed

Aut

hor

nD

rop- ou

tSe

x (M

/F)

Mea

n ag

e (S

D)[r

ange

]D

iagn

osis

Tum

or

stag

eO

ncol

ogic

tr

eatm

ent

Oth

er s

peci

fic in

clus

ion

crite

ria

Prev

entiv

e st

udie

s

Pros

pect

ive

stud

ies

Coh

en e

t al

. (20

05)

2811

44/

36

2.0

[42-

76]

Oro

phar

ynge

al

SSC

S (R

FFF)

, RT

Gra

ndi e

t al

. (20

07)

2954

-41

/13*

57.9

15-

80

]H

NC

-RT

Mas

ticat

ory

mus

cle

in

radi

atio

n fie

ldLi

et

al. (

200

7)30

108

-8

0/2

8∞

45*

[15-

76]

NPC

I-IV

RT>

15

year

s ol

d, t

rism

us

caus

ed b

y ca

rcin

oma

Ros

e et

al. (

200

9)31

45‡

--

HN

C-

(C)R

TR

adic

al r

adio

ther

apy,

jaw

in

clud

ed in

rad

iatio

n fie

ldR

en e

t al

. (20

13)32

22-

15/7

47.0

(13.

5)*

Max

illar

y ca

ncer

-S,

RT

≥16

yea

rs o

ld

RC

Ts

Van

der

Mol

en e

t al

. (20

11)33

556

39/1

057

[32-

78]

HN

C, S

CC

III-I

VC

CRT

Van

der

Mol

en e

t al

. (20

14)34

29-

23/6

60

(39

-77)

HN

C,S

CC

III-I

VC

CRT

2 ye

ar fo

llow

-up

of

prev

ious

stu

dyLo

oren

ts e

t al

. (20

14)35

66

2453

/13

59.3

(10

.7) [

38-8

4.0

] H

NC

I-IV

S, (C

)RT

MM

O >

35m

m

Ther

apeu

tic s

tudi

es

Cas

e st

udie

s

Dijk

stra

et

al. (

199

2)36

1-

-/1

13N

PC-

CT

+ R

T-

Bru

nello

et

al. (

199

5)37

1-

1/-

74O

roph

aryn

geal

SC

C-

S, R

T

Abd

el-G

alil

et a

l. (20

07)

381

-1/

-6

3A

deno

carc

inom

a-

S, R

T

Wra

nicz

et

al. (

2010

)391

-0

/147

Oro

phar

ynge

al

SCC

IIS,

RT

81

Exer

cise

the

rapy

for

tris

mus

Pros

pect

ive

stud

ies

Paul

i et

al. (

2014

)4010

11

62/

3858

.0 (-

)H

NC

I-IV

S, (C

)RT

MM

O ≤

35m

m

RC

Ts

Buc

hbin

der

et a

l. (19

93)41

2116

/556

[33-

71]

HN

C-

RTM

MO

≤ 3

0m

m

Tang

et

al. (

2011

) 42

463

32/1

149

.3 (1

1) [1

7-6

9]

NPC

-RT

No

tris

mus

/dys

phag

ia a

s pr

imar

y sy

mpt

omPa

tient

cha

rt s

tudi

es

Dijk

stra

et

al. (

200

7) 4

3 29

216

/21

44.7

(15.

9)

HN

C-

S, R

TR

efer

red

for

phys

ical

th

erap

yB

aran

ano

et a

l. (20

08

)4426

1120

/66

3.3

(11.

7)U

pper

aer

odig

es-

tive

trac

t ca

ncer

III-I

VS,

(C)R

TM

MO

≤ 3

0m

m

Shul

man

et

al. (

200

8)45

20-

10/1

044

(12)

--

RTC

ompl

eted

exe

rcis

es w

ith

DTS

,St

ubbl

efiel

d et

al. (

2010

)4620

-12

/854

[21-

78]

HN

CIV

(n=

4)S,

(C)R

TR

efer

red

for

phys

ical

th

erap

yK

amst

ra e

t al

. (20

13) 4

7 6

93

34/3

253

.9 (1

4.9

) H

NC

I-IV

S, (C

)RT

Ref

erre

d fo

r ph

ysic

al

ther

apy

M: M

ale.

F: F

emal

e. S

CC

: Squ

amou

s ce

ll ca

rcin

oma.

S: S

urge

ry; R

FFF:

Rad

ical

free

fore

arm

flap

: RT:

Rad

ioth

erap

y. H

NC

: Hea

d an

d ne

ck c

ance

r. N

PC: N

a-so

phar

ynge

al c

arci

nom

a. (C

)RT:

(che

mo)

radi

othe

rapy

. RC

Ts: R

ando

miz

ed C

ontr

olle

d Tr

ials

. CC

RT: C

onco

mita

nt c

hem

orad

ioth

erap

y. M

MO

: Max

imal

mou

th

open

ing.

*:

Cal

cula

ted

from

num

ber

prov

ided

in a

rtic

le. ∞

: Ext

ract

ed fr

om E

nglis

h ab

stra

ct. ‡

: con

trol

gro

up c

onsi

sted

of p

atie

nts

trea

ted

befo

re t

he s

tudy

.

82

Chapter 4.1

Tabl

e 2.

Qua

lity

of in

clud

ed s

tudi

es (b

ased

on

the

adju

sted

MIN

OR

S to

ol)

Author (year)

Clear goal

Inclusion criteria

Consecutive patients

Prospective

Criterion trismus

N

Sex

Age

Type of tumor

Location

Tumor stage

Type of treatment

Description of exercise therapy

Manner of measuring MMO

Pre- and post-MMO

Independent observer

Follow-up of 6 mo

<5% loss-to-follow-up

Calculated sample size

Correct analysis

Articles meeting the criterion (%)

Prev

entiv

e st

udie

s

Pros

pect

ive

stud

ies

Coh

en e

t al

. (20

05)

28Y

NN

YN

YY

YY

YN

YY

YY

NN

NN

Y57

Gra

ndi e

t al

. (20

07)

29Y

YN

YN

YY

YN

NN

YY

YY

NN

NY

N52

Li e

t al

. (20

07)

30Y

YN

NN

YY

YY

YY

YY

NY

NY

NN

Y6

2

Ros

e et

al. (

200

9)31

YY

NY

YY

YY

NY

NN

YY

YN

YN

NY

62

Ren

et

al. (

2013

)32Y

YN

YY

YY

YN

Y*

NY

YY

YN

NY

NY

67

RC

Ts

Van

der

Mol

en e

t al

. (20

11)33

YY

YY

YY

YY

YY

YY

YY

YN

NN

NY

76

Van

der

Mol

en e

t al

. (20

14)34

YY

YY

YY

YY

YY

YY

YY

YN

YN

NY

81

Loor

ents

et

al. (

2014

)35Y

YY

YY

YY

YN

YY

YY

YY

NY

NY

N76

Ther

apeu

tic s

tudi

es

Cas

e st

udie

s

Dijk

stra

et

al. (

199

2)36

N-

-N

NY

YY

YY

NY

YN

YN

Y-

--

60

Bru

nello

et

al. (

199

5)37

Y-

-N

NY

YY

YY

NY

YN

YN

Y-

--

67

Abd

el-G

alil

et a

l. (20

05)

38Y

--

NN

YY

YY

YN

YY

NY

NN

--

-6

7

Wra

nicz

et

al. (

2010

)39N

--

NY

YY

YY

YY

YY

YY

NY

--

-8

0

83

Exer

cise

the

rapy

for

tris

mus

Pros

pect

ive

stud

ies

Paul

i et

al. (

2014

)40Y

YN

YY

YY

YN

YY

YY

YY

NN

YN

Y75

RC

Ts

Buc

hbin

der

et a

l. (19

93)41

YN

NY

YY

YY

NN

NY

YN

YN

NY

NY

55

Tang

et

al. (

2011

) 42

YY

NY

YY

YY

YY

NY

YN

YN

NN

NY

65

Patie

nt c

hart

stu

dies

Dijk

stra

et

al. (

200

7) 4

3 Y

YN

NY

YY

YN

YN

YY

NY

NN

NN

Y55

Bar

anan

o et

al. (

200

8)44

YY

NN

YY

YY

YY

YY

YN

YN

NN

NY

65

Shul

man

et

al. (

200

8)45

YY

NN

YY

YY

NN

NN

YY

YN

NN

NY

50

Stub

blefi

eld

et a

l. (20

10)46

YY

YN

NY

YY

YY

NY

NN

YN

NN

NY

55

Kam

stra

et

al. (

2013

) 47

YY

YN

YY

YY

YY

YY

YY

YN

NN

NY

75

Art

icle

s m

eetin

g th

e cr

iteri

on (%

)9

070

2550

65

100

100

100

60

85

409

09

555

100

035

1510

75

MM

O: M

axim

al M

outh

Ope

ning

. Mo:

Mon

ths.

Y: Y

es. N

: No.

*:

Max

illar

y tu

mor

, exa

ct lo

catio

n no

t pr

ovid

ed.

84

Chapter 4.1

Tabl

e 3.

Ris

k of

bia

s as

sess

men

t (u

sing

the

Coc

hran

e C

olla

bora

tion

tool

)

Aut

hor

(yea

r)Se

quen

ce

gene

ratio

nA

lloca

tion

conc

ealm

ent

Blin

ding

of p

ar-

ticip

ants

, per

son-

nel a

nd o

utco

me

asse

ssor

s

Inco

mpl

ete

outc

ome

data

ad

dres

sed

Free

of s

elec

tive

outc

ome

repo

rtin

g

Free

of o

ther

so

urce

s of

bia

s

Prev

entiv

e st

udie

s

Van

der

Mol

en e

t al

. (20

11)33

YU

ncle

arU

ncle

arY

YY

Van

der

Mol

en e

t al

. (20

14)34

Y U

ncle

arU

ncle

arY

YY

Loor

ents

et

al. (

2014

)35Y

Unc

lear

Unc

lear

YY

Y

Ther

apeu

tic s

tudi

es

Buc

hbin

der

et a

l. (19

93)41

Unc

lear

Unc

lear

Unc

lear

NN

Unc

lear

Tang

et

al. (

2011

) 42

Unc

lear

Unc

lear

Unc

lear

YY

Unc

lear

Y: Y

es, t

he s

tudy

fulfi

lled

the

crite

rion

. N: N

o, t

he s

tudy

did

not

fulfi

ll th

e cr

iteri

on. U

ncle

ar: I

nsuf

ficie

nt in

form

atio

n w

as p

rovi

ded

for

the

obse

rver

s to

sc

ore

‘yes

’ or ‘

no’, o

r th

e st

udy

did

not

addr

ess

the

part

icul

ar o

utco

me.

85

Exer

cise

the

rapy

for

tris

mus

Tabl

e 4.

Inte

rven

tions

and

res

ults

of i

nclu

ded

stud

ies

Aut

hor

Phys

ioth

erap

eutic

in

terv

entio

n (n

)St

art

exer

cise

th

erap

yD

urat

ion

of e

xerc

ise

ther

apy

Sess

ions

per

da

yR

epet

ition

s x

dura

tion

of

stre

tch

Mea

n M

MO

be

fore

the

rapy

(S

D) [

rang

e] {C

I} in

mm

Mea

n M

MO

af

ter

ther

apy

(SD

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86

Chapter 4.1

RC

Ts

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87

Exer

cise

the

rapy

for

tris

mus

RC

Ts

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outh

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fiden

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terv

al. W

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utes

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ry. R

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(che

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oup

com

pari

son.

88

Chapter 4.1

Discussion

Key resultsIn this systematic review we aimed (1) to identify exercise therapy interventions for trismus secondary to head and neck cancer, (2) to assess methodological quality of these studies, and (3) to summarize results of these studies. We found a large variety in stretching techniques, duration of stretch, and repetition of exercises. Additionally, a large variation in research methodology was found, ranging from case studies to 3-arm RCTs. The overall quality of the studies was moderate. Only 6 studies had a score of 75% or more on a MINORS scale.33-35, 39, 40, 47 Finally, preventive and therapeutic studies were identified and summarized.

Some broad conclusions can be drawn about the included studies. Mean mouth opening before exercise therapy was smaller in therapeutic studies than in preventive studies, probably due to the fact that in patients who received exercise therapy, a re-duction in mouth opening had already occurred (selection bias). Five of the 8 preventive studies found that exercises during (chemo)radiotherapy could not prevent a reduction in mouth opening. Based on the means of mouth opening after exercise therapy in half of preventive studies, trismus was probably prevented by exercise therapy (Table 4).28,

31, 33, 34 In 4 therapeutic case-studies mouth opening increased between 17 and 24 mm. In 8 other therapeutic studies mouth opening changed between -1.9 and 13.6 mm. Although most therapeutic studies found an increase in mouth opening, multiple stud-ies still found a mean mouth opening smaller than 35 mm after exercise therapy (Table 4).39-44, 46, 47 This finding indicates that even after therapeutic exercises, a substantial number of patients still suffer from trismus when using this 35 mm as cut-off point. No exercise technique was clearly superior to others, neither regarding prevention or therapy of the trismus secondary to head and neck cancer.

Compliance with exercises appears to be important to the results. Both Li et al. and Stubblefield et al. found differences between compliant and non-compliant patients.30,

46 Generally, within-group comparisons and case studies reported larger increases in mouth opening than between-group comparisons. However, 1 RCT found a substantial increase for patients using TheraBite.41 These results were not confirmed in a chart review study.47 Similarly, in a cohort case series of 20 irradiated patients, Shulman et al. found an increase of 13.6 mm after exercises with the DTS, which was not confirmed in other studies.44-46 The greatest increases in mouth opening were reported in case stud-ies on exercise therapy.36-39 However, it is likely that only case studies with successful results were published.

It seems that the effect of exercises on mouth opening declines with a longer pe-riod of time between oncologic treatment and the start of mouth opening exercises. Most studies started exercises weeks or months after oncologic treatment. Kamstra et al. concluded that starting exercise therapy as soon as possible after (chemo)radio-therapy improved the results of mouth opening exercises.47 The only decrease of mouth opening we found in therapeutic studies was reported by Tang et al.; they started exer-cises 4.6 to 4.8 years after radiotherapy, and found a decrease of 1.9 mm.42

89

Exer

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rapy

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mus

Multiple studies used the TheraBite or DTS as part of the exercise therapy, in com-bination with other stretching exercises.39, 40, 42, 43, 46 In these studies, it is difficult to de-termine which intervention contributed to the change in mouth opening. Based on the results of this systematic review, it is still unclear which exercise type or technique is clearly superior to the others.

Other systematic reviewsIn a systematic review from 2004 by Dijkstra et al., only 1 article analyzing exercise therapy was included based on design, baseline assessment of trismus, and measure-ment of trismus.17 Emphasis was placed on the importance of prospective studies to as-sess risk factors and treatment strategies. Additionally, it was stated that articles should mention the location of the tumor, clear inclusion criteria, and multiple measurements of the mouth opening. In our systematic review, we found that 88% of the articles re-ported clear inclusion criteria and that 86% of the articles stated the tumor location clearly. All 20 included articles reported premeasurements and postmeasurements of mouth opening. In the previous systematic review from 2004, no case studies were included.17 Since 2004, 17 additional studies and 2 case studies were published. In 2010, Bensadoun et al. published a systematic review, and concluded that both the TheraBite and the DTS are effective in treatment of trismus induced by oncologic therapy and that exercise therapy appears to be useful in prevention of trismus.18 Overlooking the results of our systematic review, we cannot confirm their conclusion completely. Al-though the number of studies published on this topic has increased, the exercise thera-pies that are currently described have a limited and inconsistent effect. Clear guidelines for the treatment of trismus secondary to head and neck cancer cannot be derived from the results of our systematic review.

Strengths and limitationsIn our systematic review, no limitations in publication type, publication year, or language were used in the search of the databases. Four databases were searched, to ensure that no publications were missed. Independent assessment was ensured. During data ex-traction multiple authors were contacted and provided more clarity. A limitation of this review is that we did not use the original MINORS tool. We had to adjust it slightly for assessment of studies analyzing exercise therapy.

ConclusionWe found a large variation in stretching techniques, duration of stretch, repetition of exercises, and research methodology. Changes in mouth opening varied considerably. No exercise technique was clearly superior to others, neither regarding prevention or therapy of trismus secondary to head and neck cancer. Most studies, both therapeutic and preventive, found an increase in mouth opening after exercise therapy. However, multiple studies found a post-exercise mouth opening that was still smaller than 35 mm, indicating that even with exercises several patients still suffer from trismus. Starting the exercise therapy early and compliance with the exercises appear to be important for

90

Chapter 4.1

good results. Clinical guidelines cannot be given based on this systematic review.

AcknowledgementsThe authors would like to thank Xiaochen Huai for translating a Chinese article to Eng-lish. Also we are grateful for the help Gisele Fleury offered in understanding an article written in French. Lastly, we appreciate the efforts of Sjoukje van der Werff, in creating the best possible search strategies for our points of interest.

91

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cise

the

rapy

for

tris

mus

Appendices

Appendix 1. Search strategy

PubMed(“range of motion” AND (“mouth” OR mandib* OR jaw*)) OR “Trismus” OR “Mouth opening” OR In-terincisal distan*) AND (“Trismus/therapy”[Majr] OR “Physical Therapy Modalities”[MeSH] OR “Re-covery of Function”[MeSH] OR exercise* OR “rehabilitation” OR “physiotherapy” OR physical therap* OR dynasplint* OR therabite* OR “dynamic splinting”) AND (“Head and Neck Neoplasms” [MeSH] OR cancer)

EMBASE‘range of motion’/exp AND (‘mouth’/exp OR mandib* OR jaw*) OR ‘trismus’/exp OR ‘mouth opening’ OR ‘interincisal distance’ AND (‘trismus’/exp/mj/dm_th,dm_rh OR ‘convalescence’/exp OR exercise* OR ‘rehabilitation’/exp OR ‘physiotherapy’/exp OR ‘physical therapy’/exp OR dynasplint* OR therabite* OR ‘dynamic splint’/exp OR ‘dynamic splinting’) AND ‘cancer’/exp

CinahlS1: ( TX “range of motion” AND ( “mouth” OR mandib* OR jaw* ) ) OR ( TX “Trismus” OR “Mouth open-ing” OR Interincisal distan* )S2: (MH “Rehabilitation+”) OR ( TX exercise* OR “rehabilitation” OR “physiotherapy” OR physical ther-ap* OR dynasplint* OR therabite* OR “dynamic splinting” )S3: ( head and neck neoplasms ) OR cancerS4: S1 AND S2 AND S3

Cochrane (trismus or ((mouth or jaw) and opening)) AND (“physical therapy modalities” OR “Recovery of Func-tion” OR physiotherapy or excercis* or physical therapy or rehabilitation or dynasplint or therabite) AND “head and neck cancer”

92

Chapter 4.1

Appendix 2. Inclusion and exclusion criteria

Inclusion criteria Y N

1 The article discusses trismus

2 The article discusses trismus following oncologic treat-ment in the head and neck region

3 Physiotherapeutic treatment (exercise therapy) was used to relieve trismusExclusion criteria

4 The article is a review

5 The article is a letter to the editor

Conclusion Is the article included?

Y: Yes, the study fulfilled the criterion. N: No, the study did not fulfill the criterion.

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rapy

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mus

Appendix 3. Criteria used for quality assessment

1. Clearly stated goal (yes, no/unclear, not applicable)2. Clear inclusion criteria (yes, no/unclear, not applicable)3. All consecutive patients included (yes, no/unclear, not applicable) 4. Prospective study (yes, no/unclear, not applicable)5. Criterion for trismus is used in the text (yes, no/unclear, not applicable)6. Descriptive statistics (yes, no/unclear, not applicable), including:

a. Population size (n)b. Sex (%/f)c. Age (Mean& SD/Median & IQR)d. Type of tumor (%/f)e. Stage of tumor (%/f)f. Type of oncologic treatment (%/f)

7. Clear description of intervention (yes, no/unclear, not applicable)8. Description of measurement instrument (yes, no/unclear, not applicable)9. Premeasurements and postmeasurements of mouth opening reported (yes, no/unclear, not

applicable)10. Independent observer for mouth opening assessments (yes, no/unclear, not applicable)11. Six-month follow-up (yes, no/unclear, not applicable)12. Loss-to-follow-up <5% (yes, no/unclear, not applicable)13. Sample size calculated before start of study (yes, no/unclear, not applicable)14. Use of correct statistical analysis (yes, no/unclear, not applicable)

94

Chapter 4.1

1. Epstein JB, Robertson M, Emerton S, Phillips N,

Stevenson-Moore P. Quality of life and oral function

in patients treated with radiation therapy for head

and neck cancer. Head Neck 2001;23:389-398.




3. Kamstra JI, Jager-Wittenaar H, Dijkstra PU, et al.

Oral symptoms and functional outcome related to

oral and oropharyngeal cancer. Support Care Can-

cer 2011;19:1327-1333.








Oral Oncol 2008;44:430-438.

6. Pauli N, Johnson J, Finizia C, Andrell P. The inci-

dence of trismus and long-term impact on health-

related quality of life in patients with head and neck

cancer. Acta Oncol 2013;52:1137-1145.




Monit 2010;16:CR278-82.




173.




10. Hsieh LC, Chen JW, Wang LY, et al. Predicting the

severity and prognosis of trismus after intensity-

modulated radiation therapy for oral cancer pa-

tients by magnetic resonance imaging. PLoS One

2014;9:e92561.








Endod 1999;88:365-373.



Otol 1993;107:1017-1020.

14. Tsai CY, Ali RS, Wei FC, Chang YM. Reducing

mandibular height to increase mouth opening

in unreleasable trismus. J Oral Maxillofac Surg

2010;68:1628-1630.

15. Mardini S, Chang YM, Tsai CY, Coskunfirat OK,

Wei FC. Release and free flap reconstruction for

trismus that develops after previous intraoral re-

construction. Plast Reconstr Surg 2006;118:102-

107.

16. Bhrany AD, Izzard M, Wood AJ, Futran ND.

Coronoidectomy for the treatment of trismus

in head and neck cancer patients. Laryngoscope

2007;117:1952-1956.



Oncol 2004;40:879-889.




Care Cancer 2010;18:1033-1038.

19. Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y,

Chipponi J. Methodological index for non-random-

ized studies (minors): development and validation of

a new instrument. ANZ J Surg 2003;73:712-716.

References

95

Exer

cise

the

rapy

for

tris

mus

20. Higgins JP, Altman DG, Gotzsche PC, et al. The

Cochrane Collaboration’s tool for assessing risk of

bias in randomised trials. BMJ 2011;343:d5928.

21. Ahlberg A, Engstrom T, Nikolaidis P, et al. Early

self-care rehabilitation of head and neck cancer

patients. Acta Otolaryngol 2011;131:552-561.

22. Ahlberg A, Nikolaidis P, Engstrom T, et al. Mor-

bidity of supraomohyoidal and modified radical neck

dissection combined with radiotherapy for head

and neck cancer: a prospective longitudinal study.

Head Neck 2012;34:66-72.

23. Fiedler F, Stoll P, Lauer G, Otten JE. Passive and

continuous temporomandibular movement--func-

tional treatment after surgery of the temporoman-

dibular joint (TMJ). Rev Stomatol Chir Maxillofac

1993;94:178-180.

24. King GE, Scheetz J, Jacob RF, Martin JW. Elec-

trotherapy and hyperbaric oxygen: promising treat-

ments for postradiation complications. J Prosthet

Dent 1989;62:331-334.

25. Lennox AJ, Shafer JP, Hatcher M, Beil J, Funder

SJ. Pilot study of impedance-controlled microcur-

rent therapy for managing radiation-induced fibro-

sis in head-and-neck cancer patients. Int J Radiat

Oncol Biol Phys 2002;54:23-34.

26. Nicholls DW, Lowe N. Use of a modified distrac-

tion appliance to treat radiation-induced trismus. J

Oral Maxillofac Surg 2003;61:972-974.

27. Chua DT, Tian Y, Wei WI. Late oral complications

following radiotherapy for head and neck cancers.

Expert Rev Anticancer Ther 2007;7:1215-1224.





2005;86:1416-1419.

29. Grandi G, Silva ML, Streit C, Wagner JC. A mobi-

lization regimen to prevent mandibular hypomobil-

ity in irradiated patients: an analysis and comparison


2007;12:E105-9.

30. Li XH, Liao YP, Tang JT, Zhou JM, Wang GH.

Effect of early rehabilitation training on radiation-

induced trismus in nasopharyngeal carcinoma pa-

tients. Ai Zheng 2007;26:987-990.





2009;40:32-37.

32. Ren WH, Ao HW, Lin Q, Xu ZG, Zhang B. Efficacy

of mouth opening exercises in treating trismus after

maxillectomy. Chin Med J (Engl) 2013;126:2666-

2669.

33. van der Molen L, van Rossum MA, Burkhead

LM, Smeele LE, Rasch CR, Hilgers FJ. A randomized

preventive rehabilitation trial in advanced head and

neck cancer patients treated with chemoradiother-

apy: feasibility, compliance, and short-term effects.

Dysphagia 2011;26:155-170.

34. van der Molen L, van Rossum MA, Rasch CR,

Smeele LE, Hilgers FJ. Two-year results of a pro-

spective preventive swallowing rehabilitation trial in

patients treated with chemoradiation for advanced

head and neck cancer. Eur Arch Otorhinolaryngol

2014;271:1257-1270.

35. Loorents V, Rosell J, Karlsson C, Lidback M, Hult-

man K, Borjeson S. Prophylactic training for the

prevention of radiotherapy-induced trismus - a

randomised study. Acta Oncol 2014;53:530-538.

36. Dijkstra PU, Kropmans TJ, Tamminga RY. Modi-

fied use of a dynamic bite opener--treatment and

prevention of trismus in a child with head and neck

cancer: a case report. Cranio 1992;10:327-329.

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37. Brunello DL, Mandikos MN. The use of a dynamic

opening device in the treatment of radiation in-

duced trismus. Aust Prosthodont J 1995;9:45-48.




340.

39. Wranicz P, Herlofson BB, Evensen JF, Kongs-

gaard UE. Prevention and treatment of trismus

in head and neck cancer: A case report and a

systematic review of the literature. Scand J Pain

2010;1(2):84-8. .


Exercise intervention for the treatment of trismus

in head and neck cancer. Acta Oncol 2014;53:502-

509.





1993;51:863-867.





2011;187:39-44.








Throat J 2011;90:584-590.



Adv Ther 2008;25:9-16.






2010;91:1278-1282.





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Chapter 4.2TheraBite exercises to treat trismus secondary to head and neck cancer

This chapter is an edited version of:Kamstra JI, Roodenburg JL, Beurskens CH, Reintsema H, Dijkstra PU. TheraBite exercises to treat trismus secondary to head and neck cancer. Support Care Cancer 2013;21:951-957.

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Abstract

Objectives The aims of this study were (1) to evaluate the effect of TheraBite exercises on mouth opening and (2) to analyze factors influencing this effect in a patient record evaluation.

Methods Effect of exercises with a TheraBite to treat trismus was evaluated in 69 head and neck cancer patients of 2 university medical centers. Mouth opening was measured as in-terincisal distance in mm. Patient, tumor, and treatment characteristics were analyzed for their relationship with change in mouth opening. Variables univariately associated (p≤0.05) with change in mouth opening were entered in a multivariable logistic regres-sion analysis as possible predictors for an increase in mouth opening of the smallest detectable difference of 5 mm or more.

Results Mean initial mouth opening was 22.0 mm (SD 6.4); mean increase in mouth opening was 5.4 mm (SD 5.7). Chemotherapy, medical center, and time from oncological treat-ment to start exercises were significantly associated with an increase in mouth opening. In the multivariable logistic regression analysis, medical center (β=1.97) and time from oncological treatment to start exercises reduced the odds of reaching an increase in mouth opening of 5 mm or more (β=-0.11 per month).

Conclusion After TheraBite exercises, mouth opening increased averagely with 5.4 mm. The odds of an increase in mouth opening of 5 mm or more reduced when the time from oncologi-cal treatment to start exercises lengthened, corrected for the effect of medical center.

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Introduction

Trismus, a limited ability to open the mouth, is defined as a mouth opening of 35 mm or less.1-3 It is a well-known complication of cancer in the head and neck region and its treatment. The prevalence of trismus ranges from 5 to 38%.1 The consequences of trismus can be serious; it can result in problems with speech, oral hygiene, dental treat-ment, and oncological follow-up.4-6 Furthermore, trismus impacts negatively on man-dibular function and quality of life (QoL).5, 7-9

Trismus in head and neck cancer patients is difficult to treat. Many (unusual) stretching techniques have been described in case reports and case series. A sledge-hammer, tied to the mandible for 2 minutes twice a day, resulted in an increase in mouth opening of 18 mm.10 An orthodontic ‘clothes pin appliance’ inserted between the molars and thereby stretching mouth opening resulted in an increase of 6 mm.11 Further, application of a surgical mouthprop, a tapered screw, a screw-type mouth gag, fingers, tongue depressors, an intra-operatively fabricated self-curing bite block, and interarch springs attached between maxillar and mandibular restorations have been described as methods to improve mouth opening but without providing information about the actual increase in mouth opening.12-16 Injection of botulinum toxin in both masseter muscles did not show improvement of mouth opening in head and neck can-cer patients.17 Currently, no standard type of therapy to treat trismus exits.18

A historical cohort study provided evidence that conventional exercise therapy (using tongue depressors, fingers, and rubber plugs) has some effect; mean increase in mouth opening of 5.5 mm.19 Jaw-stretching devices demonstrated efficacy in improving trismus of head and neck cancer patients in several studies with different designs.18, 20-23

Exercises with the Dynasplint® Trismus System (DTS) increased mouth opening between the 6.2 and 13.6 mm, as described in a case series, a preliminary report, and in a retrospective study.18, 22, 23 Exercises with the TheraBite® Jaw Motion Rehabilitation System™ (TheraBite) increased mouth opening with 13.6 and 10 mm, as described in a randomized controlled trial with short follow-up (n=21 with 10 weeks follow-up) and in a pilot study with small sample size (n=7 with 12 to 48 weeks follow-up), respectively.20,

21 However, factors influencing the effect of TheraBite exercises are unknown. The aims of this study were to (1) evaluate the clinical effect of TheraBite exercise

therapy to treat trismus secondary to head and neck cancer and (2) to analyze factors influencing this effect in 69 head and neck cancer patients of 2 medical centers. It was hypothesized that tumor and oncological treatment characteristics, as well as time from oncological treatment to start exercises influence the effect of TheraBite exercises.

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Methods

All head and neck cancer patients of 2 university medical centers with trismus, treated with TheraBite exercise therapy between April 2004 and July 2011 were included. Characteristics regarding the cancer and its treatment were obtained from medical records. Patients were referred from the Department Head and Neck Oncology to the Department of Physical Therapy for exercise therapy. Tumor classification was based on the Union for International Cancer Control (UICC) recommendation (2009) TNM clas-sification.24 Trismus was defined as a mouth opening of 35 mm or less.1

The majority of the data was obtained retrospectively from the medical/physical therapeutic records. However, 15 patients had not completed their exercise therapy at the start of this study. Therefore, data of mouth opening of these patients was collected prospectively at follow-up appointments. All of these patients gave written permission for the use of this data for scientific purposes.

TheraBite exercise programExercises with the TheraBite are patient-controlled. The mouthpieces are placed be-tween the maxilla and mandible. The stretching effects occur when the handle of the TheraBite is squeezed. During their first visit to the Department of Physical Therapy, patients were familiarized with the use of the TheraBite and received exercise instruc-tions. Follow-up appointments were routinely planned every 2 weeks to evaluate pos-sible difficulties encountered during the exercise therapy. Generally, about 3 instruction sessions were held to inform and motivate the patient. When the patient was comfort-able with the exercises, follow-up was planned individually. Patients were instructed that pain during the stretch was normal, but excessive pain should be avoided. Additionally, patients were informed that their teeth or alveolar ridges could become painful because of the pressure. During the TheraBite exercise therapy, patients did not receive con-comitant treatments to improve mouth opening.

Exercises were performed according to instructions given by the physical thera-pist. Patients in the first medical center (Radboud University Medical Center; RUMC) received the instruction to exercise 4 sessions each day, with 6 to 8 repetitions within each session, and hold the stretch for 10 to 15 seconds. In the second medical center (University Medical Center Groningen; UMCG) the instructions were to perform the ex-ercises 5 sessions each day, with 6 repetitions within each session, and hold the stretch for 6 seconds. Patients were encouraged to continue exercising following this schedule until no further improvement in mouth opening could be achieved.

Measurement of mouth openingMouth opening was measured prior to TheraBite exercises and at regular follow-up appointments by using a slide caliper. In patients with complete frontal dentition, mouth opening was measured as the maximal interincisal distance. In edentulous patients wearing dentures, distance between the incisors of the upper and lower dentures was measured. In edentulous patients not wearing dentures, maximal distance between

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the 2 alveolar ridges was measured. In patients with 1 edentulous en 1 jaw with frontal dentition wearing dentures, distance between the incisor of denture and the incisor was measured. In patients with 1 edentulous and 1 jaw with frontal dentition not wearing dentures, distance between the alveolar ridge and the incisor was measured.

Statistical analysesStatistical analyses were performed using SPSS 18.0 for Windows software (SPPS Inc., Chicago, IL, USA). In the univariate analyses associations between patient, tumor, and treatment characteristics (predictor variables) and the increase in mouth opening of 5 mm or more (outcome variable) were analyzed by means of Mann Whitney U (MWU), Kruskal-Wallis (KW), and Spearman’s rho (ρ). Variables univariately associated (p≤0.05) with the outcome variable ‘increase in mouth opening of 5 mm or more’ (yes, no) were entered in the multivariable logistic regression analysis (stepwise backward). This in-crease of 5 mm or more corresponds with the smallest detectable difference of single measurement of mouth opening in patients with head and neck cancer.25

The following predictor variables were analyzed regarding their relationship with increase in mouth opening: sex (female, male), squamous cell carcinoma (yes, no), ra-diotherapy (yes, no), surgery (yes, no), chemotherapy (yes, no), chemoradiotherapy (yes, no), medical center (RUMC, UMCG), T classification (T1 to T3, T4), tumor site (oral cavity; oropharynx, nasopharynx, hypopharynx; temporomandibular joint region), age (years), initial mouth opening (mm), duration of exercise therapy (months), and time from onco-logical treatment (counted from last date of the surgery, chemotherapy, radiotherapy, or chemoradiotherapy) to start (TheraBite) exercises (months).

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Results

Between April 2004 and July 2011, 72 patients were provided with a TheraBite. Pre-measurements and postmeasurements of mouth opening were available of 69 patients. Of 3 patients, no measurement of final mouth opening was available because they de-ceased due to their cancer during the exercise therapy. They were excluded. Dental sta-tus of none of the patients changed between initial measurement and last measurement of mouth opening. Patient and tumor characteristics are presented in Table 1. Mean initial mouth opening was 22.0 mm (SD 6.4). Mean increase in mouth opening after TheraBite exercises was 5.4 mm (SD 5.7). In 37 patients (54%) mouth opening increased with 5 mm or more. Of 49 patients (71%) the tumor was staged as T4. Of 9 patients TN classification was missing: 5 of these patients had a recurrence, 2 patients an osteosar-coma, 1 patient an adenoid cystic carcinoma, and 1 patient had a rhabdomyosarcoma 18 years ago (Table 2).

In a patient the reconstruction plates fractured during TheraBite exercises therapy; this was diagnosed during oncological follow-up by means of an orthopantomogram. The patient was treated with surgery and postoperative radiotherapy for a pT4N0 squamous cell carcinoma in the lower jaw. The mandibular reconstruction had been performed with a free vascularized fibula transplant, fixated with titanium plates. Dur-ing exercises, the patient complained of grating sounds that were initially interpreted as crepitation arising from the temporomandibular joint. Approximately 6 weeks after the plate fracture was diagnosed, it became clear she was suffering from a large inoperable recurrence. If this patient was excluded from the statistical analysis, mean increase in mouth opening changed to 5.5 mm (SD 5.7). For further data analyses her data were excluded.

Results statistical analysesVariables significantly associated with increase in mouth opening were: chemotherapy (MWU, p=0.04), medical center (MWU, p=0.01), and time from oncological treatment to start exercises (ρ=-0.516, p<0.01) (Table 3). These variables were entered in the multi-variable logistic regression analysis. If the time between oncological treatment and start exercises lengthens, the odds of obtaining a mouth opening 5 mm or more reduced, while being treated in the RUMC increased the odds (Table 4, Figure 1).

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Table 1. Patient (n=69) and tumor characteristics

Variables Mean (SD) n (%)Female 32 (46.4)Radiotherapy 54 (78.3)Surgery 51 (73.9)Chemotherapy 14 (20.3)Chemoradiotherapy 12 (17.4)Medical center

RUMC 33 (47.8)UMCG 36 (52.2)

Age in years 53.9 (14.9)Initial mouth opening in mm 22.0 (6.4)Increase in mouth opening in mm 5.4 (5.7)Increase of 5 mm or more 37 (53.6)Duration of exercise therapy in months 6.3 (5.6)Time from oncological treatment to start exercises in months*

15.1 (38.7)

Type of tumorSquamous cell carcinoma 49 (71.0)Salivarygland carcinoma 6 (8.7)Rhabdomyosarcoma 4 (5.8)Osteosarcoma 3 (4.3)Merkel cell carcinoma 2 (2.9)Meningioma 1 (1.4)Chondrosarcoma 1 (1.4)Epidermoid cyst 1 (1.4)Adenoid cystic carcinoma 1 (1.4)Unknown∞ 1 (1.4)

Site of tumorOral cavity 33 (47.8)Oropharynx, nasopharynx, hypopharynx 28 (40.6)Temporomandibular joint region 8 (11.6)

*: Some patients started TheraBite exercise therapy before ending radiotherapy. ∞: 1 patient with a large cell carcinoma was treated with chemotherapy and radiation, no final pathology rapport was present.

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Table 2. TN classification

Status N0 N1 N2 N3 Total

T1 4 0 2 0 6

T2 4 4 5 0 13

T3 1 0 1 0 2

T4 6 4 28 1 39

Total 15 8 36 1 60

TN classification was present in the medical records of 60 patients (87%).

Table 3. Univariate analyses of independent variables related to increase in mouth opening

Variables Increase in mouth opening

Median (IQR)

Increase in mouth opening Median (IQR)

Test ρ

Sex Male Female3.0 (1.5;7.5) 5.5 (1.3;9.8) MWU 0.29

Yes NoSquamous cell carcinoma

4.0 (2.0;8.0) 5.0 (0.0;9.8) MWU 0.74

Radiotherapy 5.0 (1.0;8.0) 5.0 (2.0;7.0) MWU 0.75Surgery 6.0 (1.0;9.0) 3.0 (1.5;5.5) MWU 0.10Chemotherapy 2.0 (0.0;4.3) 6.0 (2.0;9.0) MWU 0.04Chemoradiotherapy 4.5 (2.3;6.8) 5.0 (1.0;8.5) MWU 0.81Medical center RUMC UMCG

7.0 (3.0;8.5) 2.0 (0.0;6.0) MWU 0.01T classification T1-T3 T4

6.0 (2.0;8.0) 4.0 (0.0;8.0) MWU 0.38Tumor site Oral cavity Oropharynx,

nasopharynx, hypopharynx

Temporomandib-ular joint region

6.0 (1.0;8.5) 2.5 (1.3;7.0) 8.0 (1.5;10.5)Age ρ=0.166 0.17Initial mouth opening ρ=0.014 0.91Duration of exercise therapy

ρ=-0.100 0.42

Time from oncological treatment to start exercises

ρ=-0.516 <0.01

IQR: Interquartile range. MWU: Mann Whitney U. KW: Kruskal Wallis. ρ: Spearman’s Correlation Coefficient

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Discussion

On average, mouth opening improved 5.4 mm (SD 5.7) after TheraBite exercises. The factors influencing the efficacy of TheraBite exercises were chemotherapy, medical center, and time from oncological treatment and start exercises in the univariate analy-sis. The influence of medical center on the effect of exercises may be caused by differ-ences in patient population, exercise protocol, or by compliance to the exercise therapy. Also unknown center effects may be responsible for differences between centers. Ef-fects of radiotherapy on increase in mouth opening were not found in this study, prob-ably because that the majority of the patients (78%) received radiotherapy.

The results of the multivariable logistic regression analysis showed that the odds of reaching an increase in mouth opening of 5 mm or more reduced if the time from oncological treatment to start exercises lengthened and if patients were treated in the UMCG. Chemotherapy did not significantly influence the odds of reaching an increase in mouth opening of 5 mm or more in the multivariable logistic regression analysis, maybe due to lack of adequate sample size. Thus our initial hypothesis was only partially con-firmed. Clinically our results indicate that if patients start with the exercises after 1 year after the oncological treatment in the UMCG, the odds ratio of improving mouth open-ing with 5 mm of more is 0.27, e(12*-0.108), compared to a person who starts immediately after the oncological treatment (Figure 1).

If trismus, caused by surgery or radiotherapy and the related fibrosis (scar tissue) exists for a certain period, the restriction may become more resistant to exercise ther-apy due to maturation of scar tissue.26 This maturation can explain the reduced of the effect of exercise therapy when the time from oncological treatment to start exercises lengthens. Results of previous studies suggest that TheraBite exercise therapy is supe-rior in increasing mouth opening compared to conventional exercise therapy.20, 21 Based on those results, head and neck cancer trismus patients were provided with a TheraBite routinely in our centers. However, the results of those studies could not be confirmed in our study. The superior effects of exercises with a TheraBite in those studies might also be related to the sample size, population characteristics, or time from oncological treat-ment to start exercise.

It is possible that the effect of TheraBite exercises in this study is smaller than those found in 1993 by Buchbinder et al. due to confounding by indication. This type of con-founding indicates that patients were referred only if they had a severely restricted mouth opening. When comparing the mean initial mouth opening and standard devia-tions of our patients (21.8 mm, SD 6.6) and those of Buchbinder et al. (21.3 mm, SD 1.7), it can be seen that only standard deviations differ between the groups. In our group a larger variation in initial mouth opening was present.20

In a pilot study of Cohen et al. in 2005, the mean increase in mouth opening after TheraBite exercises was 10 mm (SD 8.1). The difference in gain in mouth opening be-tween that and our study might be explained by differences in population. Additionally, patients in the study of Cohen et al. began their exercises within 6 weeks after surgery and had a less severely restricted mouth opening prior to the exercises (initial mouth

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opening of 40 mm versus 22.0 mm in our population). Moreover, only 2 of the 7 pa-tients (29 versus 78% in our population) were treated with radiotherapy before the exercise therapy started.21

Mouth opening increased with a comparable amount of mm (6.2 mm, SD 3.4) when trismus was treated with another type of mechanical stretching device, the DTS. In that study, the interval between oncological treatment and initiation of exercise therapy was approximately 4 years.23 In a preliminary report and in a case series mouth opening in-creased on average with 11.0 and 13.6 mm, respectively, after exercises with the DTS.18, 22

Regression to the mean might explain the increase in mouth opening in the cur-rent study, indicating that a patient seeks help at the peak of the burden of symptoms (a maximally restricted mouth opening). Restricted mouth opening shows a random varia-tion over time. Due to this variation, it can be expected that mouth opening increase after some time independent of any intervention. However, in head and neck cancer pa-tients, who have been treated with radiotherapy, mouth opening decreases over time.27 Thus, we assume that regression to the mean is not a likely explanation for the increase in mouth opening and that the increase can be attributed to the exercises.

Figure 1. Increase in mouth opening plotted against time from oncological treatment to start exer-cises

Time from last oncological treatment to start TheraBite exercises (months)

200180160140120100806040200-20

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The fracture of a titanium reconstruction plates during TheraBite exercises is an adverse effect that can be explained by non-union of the fibula to the mandible, by the recurrence of carcinoma, or by excessive stretching forces. When prescribing exer-cises with a TheraBite in cases of bony reconstructions of the mandible, exercise forces should be limited until consolidation of the reconstruction is completed.

Since it is difficult to treat a head and neck oncology related trismus, more attention should be paid to prevent trismus by applying intensity modulated radiotherapy when possible or by starting (TheraBite) exercises during or immediately after oncological treatment.28 However, exercises may not be effective in preventing a decrease in mouth opening.29 In our study, patients were encouraged to continue exercise therapy until no further improvement in mouth opening was achievable. Compliance to exercise therapy is dependent on internal motivation and the perceived effect of exercises. Perceiving no treatment effect, reaching the exercise goal, and an insufficient opening range of the TheraBite have a negative effect on adherence.4 None of the patients who started with the exercises after 3 years, reached more gain in mouth opening than 3 mm. Therefore, the value of this type of exercises after an interval of 3 years is limited (Figure 1).

In this study, no patients were excluded from a TheraBite for financial reasons. However, based on the outcome of this study, not every patient should straightfor-wardly be treated with exercise therapy with a TheraBite because of the high costs of the apparatus and the comparable effects of the much cheaper conventional exercise therapy. To the best of our knowledge this study included the largest sample of patients treated for a head and neck oncology related trismus using a TheraBite. The overall ab-solute increase in mouth opening using a TheraBite found in this study was comparable to conventional exercise therapy.19 Patients should be informed about the results they can expect of TheraBite exercise therapy.

Study limitationsLimitations of the current study are lack of a control group, its primarily retrospective design, lack of the assessment of compliance, and a non-blinded assessment of mouth

Table 4. Multivariable logistic regression analysis (stepwise backward) with an increase in mouth opening of 5 mm or more as outcome variable

β SE (β) OR 95% CI OR LL

95% CI OR UL

p (β)

Medical center* 1.967 0.70 7.094 1.83 27.51 0.005Time from oncological treat-ment to start exercises

-0.108 0.04 0.897 0.84 0.96 0.003

Constant 0.197 0.42 1.218 0.53 2.77 0.638

β: Regression coefficient. SE (β): Standard error. OR: Odds ratio. 95% CI OR LL: 95% confidence interval of OR lower limit. 95% CI OR UL: 95% confidence interval of OR upper limit.*UMCG is used as reference category.

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opening that may have led to an over- or underestimation of the effect of TheraBite exercises. Because most data were gathered before the intention of the study was clear, we assume a random error in measuring mouth opening. Different persons in 2 medi-cal centers measured mouth opening, but mouth opening can be measured reliably; therefore we assume that this had no systematic effect on the outcome of this study.25 Another limitation is that all patients who were referred for TheraBite exercises were included in the study, resulting in considerable heterogeneity in patient population and oncological treatment characteristics. However, this heterogeneity reflects clinical prac-tice and therefore enhances external validity. Finally, a limitation of the study is that the effect TheraBite exercise therapy only was measured as mouth opening in mm. Man-dibular function or QoL was not assessed; however, the TheraBite is primarily developed for increasing mouth opening.

Future perspectivesFurther research is needed to compare the TheraBite with the DTS in a randomized controlled trial. The costs of a DTS are about 5 times higher than those of a TheraBite. Cost effectiveness of both jaw-stretching devices should be analyzed. Effects of the exercises should ideally be measured in mm, in mandibular function, and in QoL.

ConclusionAfter TheraBite exercises, mouth opening increased averagely with 5.4 mm. The results indicate that the odds of an increase in mouth opening of 5 mm or more reduces if the time from oncological treatment to start exercises lengthens, corrected for the effect of medical center.

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Monit 2010;16:CR278-82.






2009;9:10.





2009;38:947-954.





Oral Oncol 2008;44:430-438.




Care Cancer 2010;18:1033-1038.

7. Louise Kent M, Brennan MT, Noll JL, et al. Radi-

ation-induced trismus in head and neck cancer





173.

9. Kamstra JI, Jager-Wittenaar H, Dijkstra PU, et al.

Oral symptoms and functional outcome related to

oral and oropharyngeal cancer. Support Care Can-

cer 2011;19:1327-1333.




340.

11. Alexander SA, Renner RP. Increasing occlusal

vertical dimension with an orthodontic ‘clothes

pin appliance.’ A clinical report. J Prosthet Dent

1989;62:1-3.

12. Lund TW, Cohen JI. Trismus appliances and indi-

cations for use. Quintessence Int 1993;24:275-279.

13. Rahn AO, Drone JB. Dental aspects of the prob-

lems, care, and treatment of the irradiated oral

cancer patient. J Am Dent Assoc 1967;74:957-966.

14. Ziccardi VB, Ochs MW, Braun TW. Intraopera-

tively fabricated bite block in the management of

scar contracture hypomobility. Oral Surg Oral Med

Oral Pathol Oral Radiol Endod 1995;80:34-35.

15. Brown KE. Dynamic opening device for man-

dibular trismus. J Prosthet Dent 1968;20:438-442.

16. Fonseca EP. Treatment of maxillomandibular

constrictions. J Prosthet Dent 1969;22:652-656.

17. Hartl DM, Cohen M, Julieron M, Marandas P,

Janot F, Bourhis J. Botulinum toxin for radiation-

induced facial pain and trismus. Otolaryngol Head

Neck Surg 2008;138:459-463.






2010;91:1278-1282.






References

112

Chapter 4.2



1993;51:863-867.





2005;86:1416-1419.



Adv Ther 2008;25:9-16.





Throat J 2011;90:584-590.

24. Sobin LH, Gospodarowicz MK, Wittekind C,

editors. TNM Classification of Malignant Tumours. :

Wiley-Blackwell; 2009. 336 p.








opening (trismus) in patients following primary sur-

gery for oral and oropharyngeal squamous cell car-

cinoma. Br J Oral Maxillofac Surg 2011;49:106-111.





2005;115:1458-1460.

28. Chao KS, Deasy JO, Markman J, et al. A pro-

spective study of salivary function sparing in

patients with head-and-neck cancers receiving

intensity-modulated or three-dimensional radiation

therapy: initial results. Int J Radiat Oncol Biol Phys

2001;49:907-916.

29. Grandi G, Silva ML, Streit C, Wagner JC. A mobi-

lization regimen to prevent mandibular hypomobil-

ity in irradiated patients: an analysis and comparison


2007;12:E105-9.

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Chapter 4.3Dynasplint Trismus System exercises for trismus secondary to head and neck cancer: a prospective explorative study

This chapter is an edited version of:Kamstra JI, Reintsema H Roodenburg JL, Dijkstra PU. Dynasplint Trismus System exer-cises for trismus secondary to head and neck cancer: A prospective explorative study. Support Care Cancer 2016;24:3315-3324.

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Abstract

Objectives Aims of this prospective study were (1) to determine the effects of DTS exercises on changes in mouth opening, pain, mandibular function, quality of life (QoL), and symptom-atology and (2) to analyze the patients’ perception on DTS exercises, including user-satis-faction, experiences, comfort, and compliance.

Methods Patients were instructed to exercise with the DTS for at least 16 weeks. Changes in mouth opening, pain, mandibular function, QoL, and symptomatology were evaluated, as well as the patients’ perception of DTS exercises.

ResultsEighteen consecutive patients were included. Baseline mouth opening was 22.6 mm (SD 7.6). After the DTS exercise program, mouth opening had increased significantly (7.1 mm, SD 4.7) and perceived difficulty of opening the mouth improved significantly (p<0.05). About one-third of the gained increase was lost in the follow up period. No significant effects were found in mandibular function, QoL, and overall symptomatology. Patients’ perception was diverse. They reported effectiveness, positive feelings of the results, and would recommend DTS exercises to other patients. About half of them thought DTS exercises were burdensome.

ConclusionMouth opening increased significantly after the DTS exercise program, relative to base-line. About one-third of the gained increase was lost in the follow up period. In general, patients were satisfied about the effects and the DTS exercise program.

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Introduction

Many patients experience adverse effects following treatment of head and neck cancer. Trismus, a limited ability to open the mouth (35 mm or less), is one of those adverse effects.1-4 The prevalence is between 5 and 42%.2, 4, 5 Trismus has a negative influence on quality of life (QoL) and mandibular function (including chewing, eating).1, 6, 7 It can impair speech, oral hygiene, dental treatment, nutrition, airway clearance, and oncologi-cal follow-up.7, 8 Exercise therapy is used to treat trismus in head and neck cancer pa-tients.5, 9 It appeared more effective if initiated soon after the treatment of the tumor.10 Once trismus becomes established, only a limited increase in mouth opening can be achieved.11, 12

Trismus can be treated with conventional exercises using simple tools such as tongue depressors, corkscrew devices, and rubber plugs. It can also be treated with advanced jaw stretching devices as the Dynasplint Trismus System® (DTS). The DTS provides low-torque, prolonged duration stretching with the aim of lengthening the affected connective tissue permanently. In an animal model, low-torque and prolonged duration stretching was more effective for restoring range of motion than high-torque, short duration stretching.13

The effects of DTS exercises have been described in 3 retrospective studies. In-creases of mouth opening from 6.2 to 13.6 mm were seen. None of these studies re-ported adverse events and none reported on change in pain, mandibular function, QoL, or symptomatology.14-16 Also, the patients’ perception of DTS exercises is unknown.

We therefore conducted a prospective study with the following aims: (1) to de-termine the effects of DTS exercises on changes in mouth opening, pain, mandibular function, QoL, and symptomatology and (2) to analyze the patients’ perception on DTS exercises, including user-satisfaction, experiences, comfort, and compliance.

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Methods

Study design and settingWe performed an explorative prospective study with a pre-post design, using mixed methods (quantitative and qualitative research). The study was conducted between November 2012 and February 2014 at the Department of Oral and Maxillofacial Sur-gery of the University Medical Center Groningen, the Netherlands. The study was ap-proved by the Ethics Committee and was carried out according to the regulations of our institute. After being given a verbal and written explanation, the patients signed the informed consent form.

Study populationWe included patients who were being treated for head and neck cancer (including sur-gery, radiotherapy, and chemotherapy) with trismus (mouth opening of 35 mm or less) and who wanted to increase their mouth opening. The exclusion criteria were 17 years or younger, osteoporosis, osteoradionecrosis, and inability to provide informed consent. Since this was an explorative study no sample size calculation was performed.

DTS exercise programThe DTS exercise program consisted of 3 training sessions per day with session duration of 30 minutes, with a gradual increase in time and stretching forces as tolerated. With this device, the stretching is performed passively. If the exercises were well tolerated, forces were increased every 2 weeks until maximum tolerance was reached.

Since the exercises are expected to be more effective if initiated soon after the treatment of the tumor, patients were divided into 2 groups based on the interval (in months) between primary tumor treatment and the start of DTS exercise program.10 If this interval was less than 36 months or was 36 months, patients were assigned to Group ≤36. If this interval was more than 36 months, patients were assigned to Group >36. The 2 groups were prescribed a slightly different protocol. All patients were in-structed to perform the DTS exercises for at least 16 weeks.14-16 For patients in Group ≤36, if additional gain in mouth opening was expected or if the patients wished to con-tinue after the 16 weeks, then the period of DTS exercises was extended. Patients of Group >36 were instructed to exercise for at least 16 weeks; they were instructed to continue exercising until no further gain in mouth opening was expected, up to a maxi-mum of 28 weeks.

All patients were asked to record their daily experiences. If mouth opening had increased above 35 mm and the DTS exercises went well, patients were instructed to perform additional active lateral exercises. One follow-up appointment was planned 14 weeks after the ending the DTS exercise program. An overview of the procedures per week is included in Appendix 1.

The patients received no concurrent exercise therapy during this study. If patients were unable to perform DTS exercises, they were not included and offered a different type of exercise therapy.

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DataData regarding tumor and treatment were extracted from the medical records.

(1) Effects Outcome variables were mouth opening, pain, mandibular function, QoL, and symptom-atology. Mouth opening was measured in mm using an OraStretch® Range-of-Motion Scale. Patients were asked to open their mouth as far as possible, and mouth opening was measured as the maximum interincisal distance. If patients were edentulous and not wearing a dental prosthesis, mouth opening was measured from the alveolar ridge. Pain at rest and at maximum mouth opening was scored on a Visual Analog Scale (VAS) with a score range of 0 to 100. Mandibular function was assessed by means of the score on the Mandibular Function Impairment Questionnaire (MFIQ) with a score range of 0 to 68.17 Higher scores on the MFIQ indicate a more impaired mandibular function. QoL and symptomatology were assessed by means of the European Organization for Research and Treatment of Cancer European Organization for Research and Treatment of Can-cer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) and EORTC Quality of Life Questionnaire Head & Neck 35 (QLQ-H&N35) with a score range of 0 to 100.18-20 A high score on the global health status or the symptom scale of the QLQ-C30 indicates a high QoL or a high level of symptoms, respectively. QLQ-H&N35 scores for overall symptomatology of the head and neck area (questions 1 to 30) and perceived difficulty of opening the mouth as symptomatology for mouth opening (question 10) were used. A high score on the QLQ-H&N35 indicates a high level of symptoms.

(2) Patients’ perception User-satisfaction with the DTS was measured by the score on the D-QUEST 2.0 with a score range of 12 to 60. The D-QUEST is a reliable and validated instrument to assess user-satisfaction regarding assistive device provisions.21 Higher scores indicate higher user-satisfaction. Experiences, comfort, and compliance regarding DTS exercises were assessed with a semi-structured interview and were described qualitatively (Appendix 2). Interviews were recorded and transcribed verbatim.

StatisticsPre and post DTS exercise program outcomes were analyzed with the Friedman test. Change of mouth opening was analyzed with Wilcoxon test. Independent variables pos-sibly related to change in mouth opening were analyzed for association using Spear-man’s Correlation Coefficient and Mann-Whitney U test. All analyses were performed with SPSS 22.0 for Windows software (SPPS Inc., Chicago, IL, USA).

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Chapter 4.3

Results

ParticipantsIn total, 18 consecutive patients were included: 12 in Group ≤36 and 6 in Group >36. Complete data to the end of the DTS exercise program was available for 15 patients. Half of the study population was male. Mean age was 62.1 (SD 12.7) years. Five patients had undergone a different exercise therapy for their trismus prior enrolment in the DTS exercise program (Table 1).

One patient died as result of a cardiovascular incident (Patient K). Two patients were unable to complete the DTS exercise program. One patient due to a decrease of mouth opening (Patient Q) and 1 due to a locoregional recurrence of the tumor (Patient R). Three patients could not be included for the analyses after completing the DTS exercise program: 2 patients had a locoregional recurrence and were not able to come to the follow-up appointment (Patient F and J) and 1 patient had to start with conventional exercises because of a rapid decrease in mouth opening (Patient C). Complete data up to follow-up was available for 12 patients. However, 1 of these patients quit exercising after 12 weeks because of pain (Patient N). The duration of DTS exercise program was extended after the 16 weeks in 1 patient (Patient P).

Outcome data(1) Effects Mouth opening, pain, mandibular function, QoL, and symptomatology at the different time points are presented in Figure 1 and Table 2. Mouth opening at baseline was 22.6 mm (SD 7.5) (n=18) and increased 7.1 mm (SD 4.7) after the DTS exercise program in the total study population (n=15). Of the 8 partially edentulous and edentulous patients, 1 patient was not wearing a dental prosthesis for the lower jaw, so mouth opening was measured from the alveolar ridge of the mandible. The increase in Group ≤36 was 7.3 mm (SD 4.7), in Group >36 it was 6.5 mm (SD 5.3). The increase in mouth opening was significant, both in the total study population (p<0.001, Friedman) and in Group ≤36 (p=0.001, Friedman). From the end of the DTS exercise program to follow-up, mouth opening decreased by 2.3 mm (SD 3.5) (p=0.056, Wilcoxon), a loss of 32%. Pain at maxi-mal mouth opening changed significantly (p=0.042, Friedman): between baseline and the end of DTS exercise program it decreased, but increased above the level at baseline at follow-up. Perceived difficulty of opening the mouth improved significantly (p=0.006, Friedman). There was a borderline significance (p=0.086) at overall symptomatology in the EORTC QLQ-H&N35 scores.

(2) Patients’ perceptionUser-satisfaction (n=15) of the DTS in D-QUEST score was 40.4 points (SD 5.3).

One researcher (JIK) interviewed 13 patients, but not every patient answered every question. No interview could be performed in 5 patients, 3 patients did not complete DTS exercise program. One patient had a recurrence but intended to continue with the DTS exercises during treatment. This interview was planned after the DTS exercise pro-

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gram, but the patient died. One patient was not interviewed because of logistic reasons. Patients’ experiences were diverse. Six patients stated that the DTS exercises were

burdensome, especially towards the end of the 16 weeks. Four patients had previous experience with other stretching devices, and all preferred the DTS. All patients report-ed an effect from the DTS exercise program. Nine patients stated that the effects were important for them. Four patients reported that the time required to do the DTS exer-cises was the only disadvantage, 2 patients reported pain during the DTS exercises, and 5 patients reported no disadvantage at all. All patients reported positive feelings about the results and would recommend this type of exercise therapy to other patients. Two patients were instructed to perform active lateral exercises additionally; both found


Patient characteristics n (%)*Male 9 (50)Age at baseline (years), mean (SD) 62.1 (12.7)Deceased 1 (6)Dental state

Dentulous 10 (56)Partially edentulous 4 (22)Edentulous 4 (22)

Previous exercise therapy 5 (28)Interval between primary tumor treatment and start DTS exercise program (months), median (IQR)

18.4 (12.4; 54.8)

Group ≤36, median (IQR) 13.9 (7.3-19.0)Group >36, median (IQR) 110.3 (44.1; 236.6)

Tumor characteristicsSquamous cell carcinoma 14 (78)Location of the primary tumor∞

Oral cavity 9 (50)Pharynx (oropharynx, nasopharynx, hypopharynx) 7 (39)Maxillary sinus 1 (6)Skin (region ear) 1 (6)

Stage T4 7 (39)Treatment characteristics‡Photodynamic therapy 1 (6)Surgery 11 (61)Neck dissection 10 (56)Radiotherapy 14 (78)Dose radiation on primary tumor, mean (SD) 65.3 (5.1)Chemotherapy 5 (28)

IQR: interquartile range*: n (%) unless mentioned otherwise subsequent to the variable. ∞: Exceeds 100% due to rounding. ‡: Some patients underwent a combination of treatment modalities.

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Chapter 4.3

these exercises difficult to perform and in their opinion the device was not adequate for these exercises (Appendix 3).

Eight patients reported no discomfort during the DTS exercises. One patient had to use pain medication after the DTS exercises because of the pain experienced during the exercises. Ten patients reported that operating the device and adjusting the correct stretching forces was easy. Five patients stated that the prescribed stretching schedule of 3 times 30 minutes per day was optimal, while 7 patients stated that 30 minutes of exercise per session is too long and suggested sessions between 10 and 20 minutes.

Figure 1. Progression of mouth opening

Group <36 (patients A until L, interval between primary tumor treatment and start DTS exercise program less than 36 months): gray-shades.Group >36 (patients M till R, interval between primary tumor treatment and start DTS exercise program more than 36 months): green-shades.*End of the DTS exercise program.

0 4 8 12 16 20 24 28 32 36 40 44 48 520

5

10

15

20

25

30

35

40

45

50

Patient A

Patient B

Patient C

Patient D

Patient E

Patient F

Patient G

Patient H

Patient I

Patient K

Patient L

Patient M

Patient N

Patient O

Patient P

Patient Q

Patient R

Time in weeks

Mou

th o

peni

ng in

mm

Patient J

123

DTS

exe

rcis

es

Tabl

e 2.

Mou

th o

peni

ng, p

ain,

man

dibu

lar

func

tion,

QoL

, and

sym

ptom

atol

ogy

Bas

elin

e

(n=

18)

End

of D

TS e

x-er

cise

pro

gram

(n=

15)

Follo

w-u

p

(n=

12)

Sign

ifica

nce

(Fri

edm

an)*

Bas

elin

e vs

. end

of

DTS

exe

rcis

e pr

ogra

m∞

(n

=15

)

Bas

elin

e vs

. fo

llow

-up∞

(n=

12)

Mea

n (S

D)

Mea

n (S

D)

Mea

n (S

D)

pM

ean

(SD

)M

ean

(SD

)M

outh

ope

ning

(mm

)22

.6 (7

.6)

29.7

(10

.8)

27.8

(8.3

)<

0.0

01

7.1

(4.7

)5.

0 (3

.2)

Gro

up ≤

3624

.0 (6

.8) (

n=12

)30

.6 (9

.4) (

n=11

)29

.0 (5

.3) (

n=8

)0

.00

17.

3 (4

.7) (

n=11

)5.

3 (3

.5) (

n=8

)G

roup

>36

19.7

(8.8

) (n=

6)

27.3

(15.

4) (n

=4)

25.3

(13.

1) (n

=4)

0.0

576

.5 (5

.2) (

n=4)

4.5

(3.1

) (n=

4)Pa

in a

t re

st (V

AS

scor

e 0

-10

0 p

oint

s)1.

7 (5

.0)

2.3

(6.7

)5.

2 (1

1.1)

0.5

84

0.9

(8.5

)3.

5 (1

2.1)

Pain

at

max

imal

mou

th o

peni

ng (V

AS

scor

e 0

-10

0 p

oint

s)21

.8 (1

9.3)

11.9

(13.

8)

24.8

(21.

9)

0.0

42-6

.1 (1

5.5)

3.1

(15.

5)

MFI

Q s

core

(0-6

8 p

oint

s)28

.8 (1

5.3)

24.1

(14.

8)

22.7

(11.

7)0

.920

-2.8

(13.

3)-2

.0 (1

0.1

)EO

RTC

QLQ

-C30

sco

res

(0-1

00

poi

nts)

Glo

bal h

ealth

sta

tus

(QoL

)75

.5 (2

1.9

)8

1.1

(17.

4)8

6.8

(15.

3)0

.141

0.0

(11.

4)6

.9 (1

1.1)

Sym

ptom

atol

ogy

over

all

13.1

(15.

6)

10.3

(11.

8)

9.4

(13.

7)0

.779

-0.7

(10

.8)

0.4

(11.

9)

EORT

C Q

LQ-H

&N

35 s

core

s (0

-10

0

poin

ts)

Sym

ptom

atol

ogy

over

all

22.9

(15.

8)

17.5

(13.

4)13

.1 (9

.6)

0.0

86

-1.9

(8.3

)-5

.4 (9

.1)

Perc

eive

d di

fficu

lty o

f ope

ning

the

m

outh

83.

3 (2

0.6

)6

0.0

(31.

4)58

.3 (3

2.2)

0.0

06

-20

.0 (2

4.6

)-2

2.2

(29.

6)

*: S

igni

fican

ce le

vel o

f the

com

pari

son

of t

he d

ata

of b

asel

ine,

end

of D

TS p

rogr

am, a

nd fo

llow

-up

(3 r

elat

ed s

ampl

es).

∞: O

nly

patie

nts

with

com

plet

e da

ta

wer

e in

clud

ed in

the

se r

esul

ts fo

r th

e pa

ired

obs

erva

tions

.

124

Chapter 4.3

Tabl

e 3.

Inde

pend

ent

vari

able

s re

late

d to

cha

nge

in m

outh

ope

ning

Bas

elin

e vs

. end

of e

xerc

ises

(n=

15)

Bas

elin

e vs

. fol

low

-up

(n=

12)

ρM

ean

(SD

)p

Test

ρM

ean

(SD

)p

Test

Initi

al m

outh

ope

ning

(mm

)0

.49

40

.06

1Sp

earm

an-0

.021

0.9

48Sp

earm

anTi

me

from

tre

atm

ent

of

prim

ary

tum

or to

sta

rt o

f ex

erci

ses

(mon

ths)

-0.0

85

0.7

63

Spea

rman

0.0

81

0.8

02

Spea

rman

Gro

up0

.69

4M

WU

1.0

00

MW

UG

roup

≤36

7.3

(4.7

)5.

2 (3

.5)

Gro

up >

366

.5 (5

.2)

4.5

(3.1

)St

age

T40

.044

MW

U0

.213

MW

UYe

s5.

2 (4

.1)

7.3

(2.6

)N

o10

.7 (3

.7)

4.4

(2.4

)

ρ: S

pear

man

’s C

orre

latio

n C

oeffi

cien

t. M

WU

: Man

n-W

hitn

ey U

.

125

DTS

exe

rcis

es

Seven patients stated that they were motivated to exercise by the positive effects and 4 patients by self-discipline. Seven patients reported no difficulties in compliance with the DTS exercise program, and 3 patients reported difficulties with fitting the DTS exercises into their daily routine. Eight patients reported that they exercised according to the schedule the whole period; the other 2 patients reported that they exercised in the last weeks only a couple times.

Prognostic factorsThe change in mouth opening between baseline and end of the DTS exercise program was significantly less in the 7 patients with a stage T4 tumor (p=0.044, Mann-Whitney U). No other variables were related to change in mouth opening (Table 3).

126

Chapter 4.3

Discussion

Key resultsMouth opening increased after the DTS exercise program. For the total study popula-tion and Group ≤36 this increase was significant. For Group>36, the increase was not significant. Despite the decrease from the end of DTS exercise program to follow-up, the increase was still significant at the follow-up appointment compared to baseline. In patients with a T4 tumor, the effect of DTS exercise program was significantly smaller. Perceived difficulty of opening the mouth improved significantly after the DTS exercise program and improved even further at follow-up, despite the decrease in mouth open-ing during this period. No significant effects were found in mandibular function, QoL, and overall symptomatology.

All interviewed patients noticed effects, had positive feelings about the results, and would recommend this type of exercise therapy to other patients. Most patients detect-ed a change in mouth opening because eating was easier and reported that the effects of the DTS exercise program were important. Patients reported that the DTS was easy to use. About half of the patients thought the DTS exercises were burdensome.

InterpretationFrom the end of the DTS exercise program to follow-up, mouth opening decreased by 2.3 mm (SD 3.5). This means that about one-third of the increase achieved during the DTS exercise program was lost during the follow-up period of 14 weeks. The different changes in mouth opening in Group ≤36 and Group >36 were expected and the proto-col prescribed therefore was slightly different for the groups.10 However, the DTS exer-cise program was actually extended for only 1 patient (Patient P) since the other patients did not wish to continue. The non-significant increase in mouth opening in Group >36 supports that early detection of trismus and the start of exercise therapy are important for better outcome of mouth opening.10

Notably, following the decrease in pain at maximal mouth opening between base-line and end of the DTS exercise program, increased pain above the level at baseline was found between the end of the DTS exercise program and follow-up. However, in the semi-structured interviews or at follow-up, none of the patients mentioned an increase of pain. We hypothesize that this might be the result of increased awareness of the situa-tion and problems these patients have to deal with.

Mean user-satisfaction assessed as D-QUEST score was 40.4 (SD 5.3), indicating that patients scored their satisfaction with the DTS between ‘more or less satisfied’ and ‘quite satisfied’. Although this score does not seem to be very high, all interviewed pa-tients reported positive feelings about the DTS exercise program.

Other studiesEffects of DTS exercises in head and neck cancer patients have been described previ-ously in 3 retrospective studies, none of these reported about the follow-up of mouth opening after ending DTS exercises. In 2008, Shulman et al. evaluated 20 patients that

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rcis

es

received radiotherapy had a mean increase in mouth opening of 13.6 mm (SD not re-ported). No information regarding initial mouth opening was reported.14 The results of that study may be an overestimate since only those patients who completed the pro-gram were analyzed (selection bias). In 2010, Stubblefield et al. reported in a preliminary report about 20 patients who received a multimodal treatment, including DTS exercises. Median improvement was 5.0 mm (range -4.0 to 15.0). Compliant patients showed greater median gain than the noncompliant patients (7.0 (range 0 to 15) versus -1.0 mm (range -4.0 to 5.0) respectively).15 Because of the other interventions besides the DTS exercises, the change in mouth opening cannot be attributed to the DTS only. In 2011, Baranano et al. studied 26 patients treated for trismus; mean gain in mouth opening was 6.2 mm (SD 3.4). In the first 6 weeks the most gain in mouth opening was achieved.16 The design and the results of this study are most comparable with the results of our study.

In general, the results of TheraBite® Jaw Motion Rehabilitation System™ (TheraBite) exercise therapy in literature seem similar to the results of DTS exercises, mouth open-ing changed between -1.9 mm and 13.6 mm.10, 22-24 However, a head to head comparison between the TheraBite and DTS in a RCT has not been done. Exercise adherence regard-ing exercise therapy with a TheraBite was described qualitatively in 2009.25 It was found that motivation to exercise was bases on perceived effects, self-discipline, and having a clear goal. Comparably, we found in our study that the effects of the DTS exercises and self-discipline motivated patients.

Problems and negative experiencesOne patient was not included because the mouth opening was too small (7.0 mm) to use a DTS. The range of motion of the DTS is 9 to 50 mm, so patients with a mouth opening less than 9 mm are unable to perform DTS exercises. For exercises with other stretching devices, such as the TheraBite, a mouth opening of at least 9 mm is also re-quired. Consequently, this patient could only be treated with conventional exercises.

Three patients experienced problems during or after the exercise therapy. The first patient wanted to quit after 6 weeks of exercising because of a decrease in mouth opening (week 0: 21 mm, week 4: 23 mm, and week 6: 20 mm) (Patient Q). This patient had greatly increased the force adjustment of the DTS on his own volition, despite the therapist’s advice to the contrary and he did not wish to continue exercising with low-ered force. The second patient had to quit after 12 weeks instead of after 16 weeks because of pain in the temporomandibular joint (contralateral to the side of tumor) (Pa-tient N). The third patient contacted us 4 weeks after ending the DTS exercise program because of a rapid decrease in mouth opening (from 46 mm to 32 mm); conventional exercises were started and mouth opening increased again (Patient C).

Two patients were instructed to perform lateral exercises, but both found these lateral exercises inadequate, despite being satisfied with the range of motion exercises. Because of these findings, no analyses of active lateral exercises were performed.

About half of the patients thought the DTS exercises were burdensome. In a post-hoc analysis was this burden apparently unrelated to the increase in mouth opening (median 9.0 mm, range 5.0 to 13.0, interquartile range 7.3 to 13.0 of these 6 patients).

128

Chapter 4.3

Clinical relevance and future perspectivesThe results of our explorative study show results of the DTS exercise program in mouth opening, pain, mandibular function, QoL, and symptomatology. Additionally, it provides insight into the patients’ experiences regarding DTS exercises. This can be used in mak-ing a decision for the choice of treatment of trismus and to inform patients about the expected results. The findings need to be verified in a RCT. The results of our study can be used to determine the sample size for future studies.

Strengths and limitationsStrengths of our study are the prospective design, assessment of multiple outcome variables, assessment of the patients’ experiences and compliance, and adequate follow-up after ending the DTS exercise program. The limitations are lack of blinding of ob-server, the small size of the study population, lack of a control group, and missing data at the end of the DTS exercise program and follow-up.

ConclusionMouth opening increased 7.1 mm after the DTS exercise program, a significant increase relative to baseline. However, for the subgroup of patients who were treated for their cancer longer than 36 months previously, no significant increase in mouth opening was achieved. This supports that early detection of trismus and the start of exercise therapy are important for better outcome of mouth opening. About one-third of the gained increase was lost in the follow up period. In general, patients were satisfied about the effects and the DTS exercise program.

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es

Appendices

Appendix 1. Overview of the procedures per week

Baseline Receive instructions (oral and written) regarding the DTS exercise program and informed con-

sent Measurement of mouth opening Fill in the questionnaires (MFIQ, EORTC QLQ-H&N35 and QLQ-C30) Start DTS exercise program

During the DTS exercise program Every 4 weeks, routine follow-up appointment, including measurement of mouth opening Patients can ask the therapist questions about the DTS exercises and stretching forces

End of DTS exercise program Stop DTS exercises Measurement of mouth opening Fill in the questionnaires (MFIQ, EORTC QLQ-C30 and QLQ-H&N35, and D-QUEST 2.0) Qualitative research by means of a semi-structured interview to analyze experiences, comfort,

and compliance

Follow-up (14 weeks after ending the DTS exercise program) Measurement of mouth opening Fill in the questionnaires (MFIQ, EORTC QLQ-C30 and QLQ-H&N35)

130

Chapter 4.3

Appendix 2. Topics addressed during the semi-structured interview

Experiences1. How did you experience exercising with the DTS? 2. Did you previously exercise with other stretching devices and what was your experience? Which

device do you prefer and why?3. What are the effects of the DTS exercise program?4. How important are these effects for you?5. How did you detect change in mouth opening?6. Have you experienced changes in the functioning of your mouth?

During: a. Social activitiesb. Speaking, including understandabilityc. Eating, including less food dropping from cutleryd. Drinkinge. Laughingf. Yawning g. Swallowing h. Pain i. Biting j. Chewing

7. What benefits of the DTS exercise program have you experienced?8. What adverse effects of the DTS exercise program have you experienced?9. How did your diet change since the DTS exercise program?10. What do you think of the results of the DTS exercise program?11. Would you recommend the DTS exercise program to other patients?12. What suggestions do you have to improve exercise therapy with a DTS?

Comfort (stretching forces)1. How did you experience the forces applied by the DTS on the jaws while exercising?2. How did you experience operating the DTS?3. How did you experience adjusting the correct stretching forces?4. What problems arose during the DTS exercises?5. How did you cope with pain during stretching?6. What is the optimal stretching time for you?7. What happened to your jaw during stretching and what did you feel?

Compliance1. What do you think about exercising regularly according to your protocol prescribed?2. What do you think about keeping the exercise diary?3. How often did you exercise?4. Which factors motivated you to follow the exercise protocol?5. What difficulties did you experienced in following to exercise protocol?6. Were you able to exercise regularly according to the protocol? If not, did you follow your own

schedule?

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Appendix 3. Active lateral exercises

Baseline (n=18)

End of DTS exercise program

(n=15)

Follow-up (n=12)

Mean (SD) Mean (SD) Mean (SD)Left active lateral exercises of the mandible left (mm)

5.4 (3.0) 6.4 (3.0) 6.8 (3.5)

Right active lateral exercises of the mandible (mm)

4.4 (2.7) 5.5 (3.3) 5.5 (3.1)

132

Chapter 4.3

1. Scott B, Butterworth C, Lowe D, Rogers SN. Fac-

tors associated with restricted mouth opening and

its relationship to health-related quality of life in

patients attending a Maxillofacial Oncology clinic.

Oral Oncol 2008;44:430-438.









2009;9:10.




Monit 2010;16:CR278-82.




Care Cancer 2010;18:1033-1038.







173.






Oncol 2004;40:879-889.








12. Bhatia KS, King AD, Paunipagar BK, et al. MRI

findings in patients with severe trismus following

radiotherapy for nasopharyngeal carcinoma. Eur

Radiol 2009;19:2586-2593.

13. Usuba M, Akai M, Shirasaki Y, Miyakawa S. Ex-

perimental joint contracture correction with low

torque--long duration repeated stretching. Clin

Orthop Relat Res 2007;456:70-78.



Adv Ther 2008;25:9-16.






2010;91:1278-1282.





Throat J 2011;90:584-590.

17. Stegenga B, de Bont LG, de Leeuw R, Boering

G. Assessment of mandibular function impairment

associated with temporomandibular joint osteo-

arthrosis and internal derangement. J Orofac Pain

1993;7:183-195.

18. Bjordal K, de Graeff A, Fayers PM, et al. A 12

country field study of the EORTC QLQ-C30 (ver-

sion 3.0) and the head and neck cancer specific

module (EORTC QLQ-H&N35) in head and neck

patients. EORTC Quality of Life Group. Eur J Cancer

2000;36:1796-1807.

References

133

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exe

rcis

es

19. Bjordal K, Hammerlid E, Ahlner-Elmqvist M, et al.

Quality of life in head and neck cancer patients: vali-

dation of the European Organization for Research

and Treatment of Cancer Quality of Life Question-

naire-H&N35. J Clin Oncol 1999;17:1008-1019.

20. Singer S, Wollbruck D, Wulke C, et al. Validation

of the EORTC QLQ-C30 and EORTC QLQ-H&N35

in patients with laryngeal cancer after surgery. Head

Neck 2009;31:64-76.

21. Wessels RD, De Witte LP. Reliability and valid-

ity of the Dutch version of QUEST 2.0 with users

of various types of assistive devices. Disabil Rehabil

2003;25:267-272.





1993;51:863-867.




509.

24. Tang Y, Shen Q, Wang Y, Lu K, Wang Y, Peng Y.

A randomized prospective study of rehabilitation

therapy in the treatment of radiation-induced


2011;187:39-44.





2009;38:947-954.

Chapter 5General discussion, future perspectives, and conclusions

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General discussion

Aims of this thesis were to analyze the burden of side effects after treatment of oral and oropharyngeal cancer and their influence on mandibular function, to identify risk factors for trismus after head and neck cancer, and to evaluate exercise therapy for trismus after head and neck cancer.Firstly, the results of the studies in Chapter 2, Chapter 3.1, Chapter 3.2, Chapter 4.1, Chapter 4.2, and Chapter 4.3 will be discussed. Secondly, future perspectives and con-clusions will be described.

Side effects after treatment of oral and oropharyngeal cancerIn Chapter 2, it was found that the experienced lack of saliva was the most frequently reported and the most burdensome oral symptom after treatment of oral or oropha-ryngeal cancer. Trismus and restricted tongue mobility were reported by almost half of the patients and were reported among the 3 most burdensome. Patients experienced a substantial impairment of mandibular function, including speaking, eating, laughing, yaw-ing, and social activities. Lack of saliva did not statistically predict impairment of mandib-ular function. For irradiated patients and non-irradiated patients, impairment of man-dibular function was statistically predicted by different variables. However, in all patients, MFIQ scores were strongly influenced by an inability to wear a dental prosthesis.

A previous study did also describe lack of saliva as frequently occurring and bur-densome symptom after treatment of oral or oropharyngeal cancer.1 Trismus and a re-stricted tongue mobility have been also described as frequently to occur.2, 3 In Chapter 2, trismus and a restricted tongue mobility statistically predicted impairment of man-dibular function in non-irradiated patients only. However, this finding may be a result of lack of statistical power since in previous studies they are found to impair mandibular function in irradiated patients also.3, 4 In general, patients who are able to wear a dental prosthesis are known to have better mandibular function than those who are not.5

Risk factors for trismus after head and neck cancerIn Chapter 3.1, it was found that longitudinal course of mouth opening over time dif-fered between tumor locations. Overall, mouth opening decreased the first 6 months post-radiotherapy and gradually recovered up to 48 months post-radiotherapy. Mouth opening post-radiotherapy was predicted by tumors located in the oropharynx or nasopharynx and nasal cavity or maxillary sinus, more time since radiotherapy, female sex, smaller mouth opening prior to radiotherapy, T4 tumors, higher age, and irradiation dose. All main effects interacted with time since radiotherapy, indicating that change of mouth opening over time depends on tumor location and on mouth opening prior to radiotherapy.

In Chapter 3.2, it was found that he incidence of trismus is highest at 6 months post-radiotherapy (28.1%) and declines thereafter. The incidence of trismus was 3.6 per 10 person years at risk calculated over the total period of 48 months post-radiotherapy. In the first 6 months post-radiotherapy, risk factors for developing trismus were tu-

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mors located in the oral cavity, oropharynx or nasopharynx, and the salivary glands or ear and a longer overall treatment time of radiotherapy. At all time points, mouth open-ing at that time point was a risk factor for developing trismus at the subsequent time point.

Four previous studies described the longitudinal course of mouth opening follow-ing surgery and/or radiotherapy (with or without chemotherapy) and risk factors for trismus. Changes over time were also seen in those studies.6-9 In previous studies iden-tifying risk factors for trismus in head and neck cancer patients, radiotherapy as part of a multimodal treatment (post-operative and/or combined with chemotherapy and biologicals), a dose of 50 Gy or more, irradiation of the pterygoid muscles, T4 tumors, and primary tumors originating from the maxilla, mandible, nasopharynx, parotid gland, and tongue were found.4, 6, 8, 10-14 These studies were mainly retrospective and had small sample sizes. In Chapter 3.1, higher irradiation dose was found to be a risk factor for trismus in contrary to in Chapter 3.2. In both Chapter 3.1 and Chapter 3.2, multimodal treatment was not found as a risk factor for trismus. In literature, multimodal treatment as well as the prescribed irradiation dose were found as risk factors for trismus.6, 8, 10, 12-14 However, the prescribed dose levels do not correspond with the actual dose to relevant anatomical structures like the masticatory muscles and temporomandibular joint. When the actual dose characteristics to those structures are taken into account, significant dose effect relationships may be found. Another explanation might be that there was not much variation in the irradiation dose in our study population, which can possibly explain the lack of a significant association between dose levels and mouth opening.

Exercise therapy for trismus after head and neck cancerIn Chapter 4.1, it was found that studies analyzing exercise therapy for trismus after head and neck cancer reported a large variation in stretching techniques, duration of stretch, and repetition of exercises. All but 1 of the 20 included studies found positive effects (i.e. less decrease in case of preventive studies or an increase of mouth open-ing in therapeutic studies) after exercise therapy. In half of the studies where exercise therapy was applied as prevention for trismus, trismus could not be prevented (a mean mouth opening of 35 mm or less).15-18 In two-third of the studies were exercise therapy was applied to treat trismus, patients still had trismus after the exercise therapy.19-25 Compliance to the exercise therapy appeared to improve the results.25, 26 No exercise technique was clearly superior, neither regarding prevention or treatment of trismus secondary to head and neck cancer.

In Chapter 4.2, it was found that mean mouth opening increased 5.4 mm (SD 5.7) after exercises with a TheraBite® Jaw Motion Rehabilitation System™ (TheraBite). Fac-tors that significantly influenced the efficacy of TheraBite exercises were chemotherapy, medical center, and time from oncological treatment to the start of the exercises. The odds of reaching an increase in mouth opening of 5 mm or more reduced if the time between oncological treatment and start of TheraBite exercises increased. The influence of medical center may be caused by differences in patient population, exercise protocol, or compliance to the exercise therapy.

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In Chapter 4.3, it was found that mean mouth opening increased 7.1 mm (SD 4.7) after exercises with a Dynasplint Trismus System® (DTS). For the total study popula-tion and for the patients who were treated for their cancer shorter than or 36 months previously, this increase was significant. The perceived difficulty of opening the mouth improved significantly for all patients. All interviewed patients noticed effects because of the exercise therapy, had positive feelings about the results, and would recommend this exercise technique to other patients. However, about half of the patients thought the DTS exercises were burdensome.

Two previous systematic reviews analyzed the treatment of trismus secondary to head and neck cancer including exercise therapy.2, 27 In the first systematic review (2004), only 1 study analyzing exercise therapy for trismus secondary to head and neck cancer could be included. Case studies were not included. Since publication of that sys-tematic review, 19 additional studies were published.27 In the second systematic review (2010) was concluded that both the TheraBite and the DTS are effective to treat tris-mus secondary to head and neck cancer and that exercise therapy seems useful to pre-vent trismus.2 In Chapter 4.1, that conclusion was only partially confirmed in the results found.

Three previous studies described the effects of TheraBite exercises to treat trismus in head and neck cancer patients.20-22 In the TheraBite group of the first study, consist-ing of 9 irradiated patients, mouth opening increased 13.6 mm (SD 1.6).21 In Chapter 4.2, the described effect of TheraBite exercises are possibly smaller because of confounding by indication, indicating that patients were referred only if they had a severely restricted mouth opening. In the second and third study, TheraBite exercises were part of a mul-timodal rehabilitation program.20, 22 In this second study, mouth opening decreased with 1.9 mm (SD 5.0).22 In this third study, mouth opening increased with 6.4 mm (95% con-fidence interval 4.8 to 8.0).20 These effects cannot be attributed to TheraBite exercises only since they were combined with other techniques of exercises.

Three previous (retrospective) studies described the effects of DTS exercises in head and neck cancer patients.24, 25, 28 In the first study, 20 irradiated patients had a mean increase in mouth opening of 13.6 mm (SD not reported).28 Only patients who completed the program were analyzed, therefore the increase in mouth opening may be an overestimation. In the second study 20 patients received DTS exercises as part of a multimodal rehabilitation program, therefore the effects cannot be attributed to DTS exercises only. Median improvement was 5.0 mm (range -4.0 to 15.0). Compliant patients showed more median increase than the noncompliant patients.25 In the third study, 26 patients were treated for trismus. Mean increase in mouth opening was 6.2 mm (SD 3.4).24 In Chapter 4.3, the design and the results of that study were similar to this third study. In general, the results of TheraBite exercises to treat trismus seem simi-lar to the results of DTS exercises. However, a head to head comparison between the TheraBite and DTS in a randomized controlled trials has not been performed.

RelevanceThis thesis aimed to analyze the burden of side effects after treatment of oral and oro-

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pharyngeal cancer and their influence on mandibular function, to identify risk factors for trismus after head and neck cancer, and to evaluate exercise therapy for trismus after head and neck cancer. The results of this thesis provide insight in the development of trismus after head and neck cancer. Based on the risk factors for trismus found, trismus post-radiotherapy can be predicted and possibly prevented. Additionally, the results of this thesis provide insight in the effects and limitations of exercise therapy. The impor-tance of timing and the patients’ compliance of exercise therapy for trismus is shown. The efficacy of the different exercise techniques was analyzed. Indirectly, the results of this thesis can contribute to improve mandibular function and quality of life of patients who are successfully treated for cancer in the head and neck region when prediction, prevention, and treatment of trismus become more successful.

Several risk factors for trismus are identified in this thesis, namely higher age, female sex, location of the tumor (oral cavity, oropharynx or nasopharynx, nasal cav-ity, maxillary sinus, salivary glands, and ear), T4 tumors, higher irradiation dose, smaller mouth opening prior or during radiotherapy, and more time since radiotherapy. Despite not being found as risk factor in this thesis, multimodal treatment is expected to be risk factor as well. The risk factors can be used to predict trismus. For prevention, risk factors should be eliminated or positively influenced. However, risk factors that can-not be modified are patient characteristics as age and sex. Additionally, the location of the tumor cannot be modified. Some risk factors can possibly be influenced positively, for example mouth opening prior or during radiotherapy. Already a substantial amount of the head and neck cancer patients have trismus prior to radiotherapy. This can be caused by invasion of the tumor in the masticatory muscles and temporomandibular joint or their surrounding tissues, by surgery in case of post-operative radiotherapy, or by a naturally small mouth opening (inter-individual variation). Treatment modalities, including multimodal treatment and irradiation dose, can be modified. However, these modifications should not lower the survival rate or should not result in an increase of the number of recurrences. By means of regular measurements of mouth opening per- and post-radiotherapy, trismus can be identified early. It is possible to positively influ-ence mouth opening by means of exercise therapy. Exercise therapy could increase or maintain mouth opening and inherently lower the risk for trismus. The size of the tumor at first presentation of the patient cannot be modified. However, early detection of tu-mors in general can contribute to prevention of T4 tumors. Early detection can be sup-ported by increasing the knowledge about premalignant lesions and tumors of the head and neck amongst the population. Additionally, specific attention of the dentist during regular visits to patients with a high risk for premalignant lesions and tumors of the oral cavity and oropharynx may enhance early detection.

Exercise therapy for trismus after head and neck cancer was evaluated in this the-sis. Not one exercise technique was found to be superior. A larger increase in mouth opening can be expected when exercise therapy is initiated early after the treatment of head and neck cancer or even during the treatment in case of radiotherapy. However, despite positive effects, the effects of exercise therapy are limited since trismus can-not not always be prevented or treated. The results of this thesis can be used to inform

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patients about the expected results of exercise therapy. A larger increase of exercise therapy can also be expected in compliant patients. Therefore, therapists should focus on an early initiation of the exercise therapy and should stimulate the patients’ compli-ance to the exercise therapy. Early initiation of exercise therapy can be a part of preven-tive rehabilitation program. Since such programs can be a burden to patients, especially during radiotherapy, these programs should be limited to those with the highest risks. The multivariate prediction models presented in this thesis can be used to select the patients for a preventive rehabilitation program.

Strengths & limitations of this thesisStrengths of this thesis include the assessment of risk factors predicting trismus up to 48 months post-radiotherapy by using a large sample of patients (n=641) with all of the most frequently occurring types of head and neck cancer. Strengths also include that all exercise techniques were evaluated in this thesis. Finally, strengths include the assess-ment of multiple outcome variables and patients’ perception on DTS exercises, including user-satisfaction, experiences, comfort, and compliance.

This thesis had several limitations. A limitation is that genetic factors and some pa-tient characteristics, such as the use of alcohol and presence of co-morbidity, were not included as potential risk factors for trismus. In previous studies, alcohol use has been identified as a risk factor.7, 8 Another limitation is the method of measurement of mouth opening. In Chapter 3.1, Chapter 3.2, Chapter 4.2, and Chapter 4.3 measurements were performed by different assessors. This may have introduced a measurement error. However, mouth opening can be measured reliably, we therefore assume that this er-ror has only a small effect on the results of this thesis.29 In (partially) edentulous patients not wearing a dental prosthesis, a larger mouth opening is measured than in (partially) edentulous patients wearing a dental prosthesis. This difference has not been taken into account to determine if the patient had trismus when using the cut-off point of 35 mm or less. No different criteria for trismus exist for dentulous patients and (partially) eden-tulous patients not wearing a dental prosthesis. This is an additional limitation of the measurement of mouth opening.

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Future perspectives

Risk factors for trismus in head and neck cancer patients identified in this thesis should, where possible, be eliminated or positively influenced for the prevention of trismus. Treatment modalities, including multimodal treatment and irradiation dose, may be modified but should not worsen treatment outcomes. Possibly the use of proton therapy instead of photon therapy in case of radiotherapy may reduce incidence of tris-mus, as the irradiation dose of the surrounded structures of the tumor can be reduced. High-risk patients should be identified by the presence of risk factors for trismus. Of these patients, regular measurements of mouth opening should take place during and after the treatment of head and neck cancer.

Attention should be paid to the development of a preventive rehabilitation program for those patients with a high risk of developing trismus or for patients with a decrease in mouth opening. Since exercise therapy is burdensome, expensive, and cannot always prevent trismus, it should not routinely be advised to every patient. The prevention of trismus should be integrated in the supportive care program for head and neck cancer patients; like the prevention of malnutrition, support of oral hygiene including fluoride prophylaxis, and exercises to prevent arm and shoulder problems after a neck dissec-tion. Such a preventive rehabilitation program for trismus should be evaluated and clini-cal guidelines should be established.

For patients who developed trismus, the search for the most effective exercise therapy to treat trismus should be continued. Regular measurement of mouth opening should be performed to identify patients with (developing) trismus so they can receive exercise therapy early. Effects of exercises with a TheraBite and a DTS should be com-pared in randomized controlled trial, including change in mouth opening, cost effective-ness, compliance, and patients’ perspective regarding the exercises. Since in exercise therapy and rehabilitation programs, compliance is a well-known problem for patients, it is important to gain information about patients’ perspective on different exercise tech-niques to improve compliance. The results of Chapter 4.2 and Chapter 4.3 can be used to determine the sample size for future studies.

For reaching the most optimal results, the exercise therapy should be initiated as early as possible and therapists should stimulate patients’ compliance. Patients should be informed that sometimes, a reduction of further decrease in mouth opening is the best feasible result.

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Conclusions

After head and neck cancer, patients often suffer from side effects of the treatment. Impact of side effects on mandibular function, in particular of trismus, restricted tongue mobility, and the inability to wear dental prosthesis, were found in thesis.

The identified risk factors for trismus in this thesis are: higher age, female sex, sev-eral locations of the tumor (oral cavity, oropharynx or nasopharynx, nasal cavity or max-illary sinus, and salivary glands or ear), T4 tumors, irradiation dose, smaller mouth open-ing prior or during radiotherapy, and more time since radiotherapy. Of patients treated with radiotherapy, mouth opening can be predicted by means of the multivariate pre-diction models. Mouth opening of irradiated patients decreased slightly over time with the minimal mouth opening at 6 months post-radiotherapy. Course of mouth opening and trismus can be predicted by a variety of risk factors. Additionally, trismus can be predicted for different time points post-radiotherapy. Despite the identification of risk factors for trismus, it is not realistic to prevent trismus since most of these risk factors cannot be modified. Therefore, preservation of mouth opening in head and neck cancer patients, especially after radiotherapy, is difficult.

Changes in mouth opening after exercise therapy varied considerably. In this the-sis, no exercise technique was found clearly superior and the results varied consider-ably. Mouth opening increased averagely 5.4 mm after TheraBite exercises. The odds of an increase in mouth opening of 5 mm or more reduced if the time from oncologi-cal treatment to start exercises lengthens, corrected for the effect of medical center. Mouth opening increased averagely 7.1 mm after DTS exercises. For the total study population and for the patients who were treated for their cancer shorter than or 36 months previously, this increase was significant. As a result of exercise therapy, less de-crease (in case of preventive exercises) or a larger increase in mouth opening (in case of therapeutic exercises) can be expected in compliant patients and when exercise therapy initiated early. If there is an indication for exercise therapy to prevent trismus, this should be integrated in the supportive care program. Despite positive results of exercise therapy in general, trismus secondary to head neck cancer cannot always be prevented or treated.

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1. Dirix P, Nuyts S, Vander Poorten V, Delaere P,

Van den Bogaert W. Efficacy of the BioXtra dry

mouth care system in the treatment of radiother-

apy-induced xerostomia. Support Care Cancer

2007;15:1429-1436.




Care Cancer 2010;18:1033-1038.

3. Pauloski BR. Rehabilitation of dysphagia following

head and neck cancer. Phys Med Rehabil Clin N Am

2008;19:889-928, x.




173.

5. Teoh KH, Patel S, Hwang F, Huryn JM, Verbel D,

Zlotolow IM. Prosthetic intervention in the era of

microvascular reconstruction of the mandible--a

retrospective analysis of functional outcome. Int J

Prosthodont 2005;18:42-54.






111.




Surg 2012;50:328-332.









2005;115:1458-1460.

10. Jeremic G, Venkatesan V, Hallock A, et al. Trismus

following treatment of head and neck cancer. J

Otolaryngol Head Neck Surg 2011;40:323-329.



Otol 1993;107:1017-1020.





Endod 1999;88:365-373.

13. Yeh SA, Tang Y, Lui CC, Huang YJ, Huang EY.

Treatment outcomes and late complications of 849

patients with nasopharyngeal carcinoma treated

with radiotherapy alone. Int J Radiat Oncol Biol Phys

2005;62:672-679.




Head Neck 2008;30:622-630.





2005;86:1416-1419.





2009;40:32-37.

17. van der Molen L, van Rossum MA, Burkhead

LM, Smeele LE, Rasch CR, Hilgers FJ. A randomized

preventive rehabilitation trial in advanced head and

neck cancer patients treated with chemoradiother-

References

144

Chapter 5

apy: feasibility, compliance, and short-term effects.

Dysphagia 2011;26:155-170.

18. van der Molen L, van Rossum MA, Rasch CR,

Smeele LE, Hilgers FJ. Two-year results of a pro-

spective preventive swallowing rehabilitation trial in

patients treated with chemoradiation for advanced

head and neck cancer. Eur Arch Otorhinolaryngol

2014;271:1257-1270.

19. Wranicz P, Herlofson BB, Evensen JF, Kongsgaard

UE. Prevention and treatment of trismus in head

and neck cancer: A case report and a systematic re-

view of the literature. Scand J Pain 2010;1(2):84-8. .




509.





1993;51:863-867.





2011;187:39-44.








Throat J 2011;90:584-590.






2010;91:1278-1282.

26. Li XH, Liao YP, Tang JT, Zhou JM, Wang GH.

Effect of early rehabilitation training on radiation-

induced trismus in nasopharyngeal carcinoma pa-

tients. Ai Zheng 2007;26:987-990.



Oncol 2004;40:879-889.



Adv Ther 2008;25:9-16.






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Chapter 6Summary

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IntroductionHead and neck cancer can be treated with different modalities, including surgery, radio-therapy, and chemotherapy. During and after treatment, patients can suffer from side-effects such as mucositis and xerostomia. Head and neck cancer patients also frequently suffer from trismus: a limited ability to open the mouth. The cancer treatment and its side-effects can impede mandibular function. Mandibular function includes speaking, eating, laughing, yawing, and social activities. Side-effects and impairment of mandibular function can be a burden for patients and can impede on quality of life (QoL).

A mouth opening of 35 mm or less is a commonly used cut-off point for trismus. Large differences in prevalence and incidence of trismus in head and neck cancer pa-tients have been reported: between the 5 and 42%. Trismus can be caused by the tumor itself (invasion in the masticatory muscles and temporomandibular joint, or their sur-rounded tissues) or by the treatment of it (scar formation and fibrosis as a result of sur-gery and radiotherapy).

A decrease in mouth opening of head and neck cancer patients cannot always be prevented by exercise therapy. When trismus is present, generally a limited increase in mouth opening can be achieved. There is no standard treatment for trismus; many dif-ferent types of exercise therapy have been described in literature and are clinically ap-plied.

Studies in this thesisIn Chapter 2, the oral symptoms of 89 patients treated for oral or oropharyngeal cancer were assessed. Additionally, it was assessed how these patients rank the burden of oral symptoms and how the tumor, the treatment, and the oral symptoms impacts on func-tional outcome. The Mandibular Function Impairment Questionnaire (MFIQ) was used to assess functional outcome. Lack of saliva was not only the most frequently reported oral symptom, but also the most burdensome. The second and third most frequently reported oral symptoms were a restricted mouth opening and restricted tongue mobil-ity, respectively. For irradiated and non-irradiated patients, different risk factors for im-pairment of mandibular function were found. However, in all patients, MFIQ scores were strongly influenced by an inability to wear a dental prosthesis.

In Chapter 3.1, the course of mouth opening of 641 patients up to 48 months post-radiotherapy for head and neck cancer was analyzed, risk factors predicting decrease in mouth opening were assessed, and a multivariate prediction model for change in mouth opening was developed. Mouth opening was measured prior to radiotherapy (baseline) and at 6, 12, 18, 24, 36, and 48 months post-radiotherapy. Mean mouth opening at base-line was 38.7 mm (SD 10.8). The smallest mean mouth opening found at 6 months post-radiotherapy, namely 36.7 mm (SD 10.0). Overall, mouth opening decreased the first 6 months post-radiotherapy and gradually recovered up to 48 months post-radiotherapy. Mouth opening was predicted by the sex and age of the patient, the location and clas-sification of the tumor, baseline mouth opening, the irradiation dose, and the time since radiotherapy. The model can be used to predict mouth opening. In Chapter 3.2, the inci-dence of trismus at various time points and risk factors for the development of trismus

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post-radiotherapy in head and neck cancer patients were assessed. The same patient population and measurements of mouth opening as in Chapter 3.1 were analyzed. Over a total period of 48 months post-radiotherapy, the incidence of trismus was 3.6 per 10 person years at risk. Six months post-radiotherapy, 28.1% of the patients without trismus prior to radiotherapy developed trismus. Tumor location and overall treatment time of radiotherapy were risk factors for developing trismus the first 6 months post-radiotherapy. Mouth opening at any time point was a significant predictor for developing trismus at all subsequent time points. Therefore, regular measurements of mouth open-ing are needed to predict trismus. High-risk patients, identified by the presence of risk factors for trismus, can be offered preventive measures.

In Chapter 4.1, studies regarding exercise therapy interventions for trismus second-ary to head and neck cancer were systematically reviewed. The quality of the included studies found was assessed and the results were summarized. Of the 211 found studies, 20 could be included. The included studies had a large variation in research methodol-ogy, stretching techniques, duration of stretch, and repetition of exercises. The overall quality was moderate. In 5 out of the 8 preventive studies, a reduction in mouth opening was not prevented. In 4 therapeutic case-studies, mouth opening increased between 17 and 24 mm. In 8 other therapeutic studies, mouth opening changed between -1.9 and 13.6 mm. Better results were found if the exercise therapy started early and in compli-ant patients. No exercise therapy was clearly superior. Clinical guidelines could not be given based on this systematic review. In Chapter 4.2, the effect of TheraBite® Jaw Mo-tion Rehabilitation System™ (TheraBite) exercises on mouth opening in 69 head and neck cancer patients of 2 university medical centers (University Medical Center Groningen and Radboud University Medical Center) was evaluated. Additionally, factors influencing this effect were analyzed. An increase of 5 mm or more was studied, which corresponds with the smallest detectable difference. Baseline mouth opening was 22.0 mm (SD 6.4), the mean increase was 5.4 mm (SD 5.7). Chemotherapy, the medical center, and the time from oncological treatment to start TheraBite exercises were significantly associ-ated with an increase in mouth opening. The odds of an increase in mouth opening of 5 mm or more reduced when the time from oncological treatment to start TheraBite exercises lengthened. In Chapter 4.3, the effects of Dynasplint Trismus System® (DTS) exercises on changes in mouth opening, pain, mandibular function, QoL, and symptom-atology of 18 consecutive head and neck cancer patients were determined. Additionally, user-satisfaction, experiences, comfort, and compliance of these exercises were analyzed. Baseline mouth opening was 22.6 mm (SD 7.6), the mean increase was 7.1 mm (SD 4.7) (significant). About one-third of the gained increase was lost in the follow up period of 14 weeks. The perceived difficulty of opening the mouth improved significantly. No other significant effects were found. Patients’ perception was diverse. However, in general, pa-tients were satisfied about the DTS exercises.

Future perspectivesRisk factors for trismus in head and neck cancer patients that were identified in this thesis should, where possible, be eliminated or positively influenced to prevent trismus.

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High-risk patients should be identified by the presence of risk factors for trismus. Of these patients, regular measurements of mouth opening should take place during and after the treatment of head and neck cancer. Attention should be paid to the develop-ment of a preventive rehabilitation program for those patients with a high risk of devel-oping trismus or for patients with a decrease in mouth opening. Since exercise therapy is burdensome, expensive, and cannot always prevent trismus, it should not routinely be advised to every patient. The prevention of trismus should be added or integrated in the supportive care program for head and neck cancer patients; like the prevention of malnutrition, the support of oral hygiene including fluoride prophylaxis, and exercises to prevent arm and shoulder problems after a neck dissection.

For patients who developed trismus, the search for the most effective exercise ther-apy to treat trismus should be continued. The effects of exercises with a TheraBite and a DTS should be compared in randomized controlled trial.

For reaching the most optimal results, the exercise therapy should be initiated as early as possible and therapists should stimulate patients’ compliance. Patients should be informed that sometimes, a reduction of further decrease in mouth opening is the best feasible result.

ConclusionsAfter treatment of head and neck cancer, many patients suffer from side-effects, includ-ing trismus. In this thesis, the identified risk factors for trismus are: higher age, female sex, several locations of the tumor (oral cavity, oropharynx or nasopharynx, nasal cavity, max-illary sinus, salivary glands, and ear), T4 tumors, irradiation dose, smaller mouth opening prior or during radiotherapy, and more time since radiotherapy. Of patients treated with radiotherapy, mouth opening can be predicted by means of the prediction models. Addi-tionally, trismus can be predicted for different time points post-radiotherapy. Despite the identification of risk factors for trismus, it is not realistic to prevent trismus since most of these risk factors cannot be modified. Therefore, preservation of mouth opening in head and neck cancer patients, especially after radiotherapy, is difficult.

In this thesis, no exercise technique was found clearly superior and the results varied considerably. As a result of exercise therapy, less decrease (in case of preventive exer-cises) or a larger increase in mouth opening (in case of therapeutic exercises) can be expected in compliant patients and when exercise therapy initiated early. Despite positive results of exercise therapy in general, trismus secondary to head neck cancer cannot always be prevented or treated.

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Chapter 7Nederlandse samenvatting

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IntroductieVoor de behandeling van hoofd-halskanker zijn een aantal modaliteiten beschikbaar, onder andere chirurgie, radiotherapie en chemotherapie. Gedurende en na de behan-deling kunnen patiënten last krijgen van de bijwerkingen van de behandeling, bijvoor-beeld ontstoken slijmvliezen van de mond en keel en een droge mond door te weinig speeksel. Veelvuldig ontwikkelen hoofd-halskankerpatiënten een trismus: een beperkte mondopening. Door de behandeling van hoofd-halskanker en de bijwerkingen daarvan kan het functioneren van het kauwstelsel beperkt worden. Onder functioneren van het kauwstelsel wordt onder andere spreken, eten, lachen, gapen en het participeren in sociale activiteiten verstaan. Bijwerkingen en een beperking van functioneren van het kauwstelsel kan een belasting zijn voor de patiënt en kan de kwaliteit van leven negatief beïnvloeden.

Trismus wordt over het algemeen gedefinieerd als een beperkte mondopening van 35 mm of minder. Grote verschillen in prevalentie en incidentie van trismus bij hoofd-halskankerpatiënten zijn beschreven: tussen de 5 tot 42%. Trismus kan veroorzaakt worden door de tumor (ingroei in de kauwspieren, het kaakgewricht of de omliggende weefsels) of door de behandeling ervan (het ontstaan van littekenweefsel en fibrose door chirurgie en radiotherapie).

Afname van de mondopening van hoofd-halskankerpatiënten kan niet altijd voor-komen worden door middel van oefentherapie. Over het algemeen kan er slechts een beperkte winst in mondopening worden bereikt wanneer trismus reeds ontstaan is. Er is geen standaardbehandeling voor trismus. Er zijn veel verschillende soorten oefenthe-rapie in de literatuur beschreven en in de kliniek toegepast.

Studies in dit proefschriftIn Hoofdstuk 2 werden de bijwerkingen bij 89 patiënten die behandeld zijn voor mond-holte- en orofarynxtumoren onderzocht. Ook werden de ervaren belasting van deze bijwerkingen en mogelijke voorspellers voor kauwfunctie onderzocht. Voor het bepalen van kauwfunctie werd de Mandibular Function Impairment Questionnaire (MFIQ) ge-bruikt. Gebrek aan speeksel werd het meest frequent als bijwerking gerapporteerd en als meest belastende bijwerking genoemd. Als tweede en derde meest voorkomende bijwerking werden respectievelijk een beperkte mondopening en beperkte beweeg-lijkheid van de tong genoemd. Voor bestraalde en niet-bestraalde patiënten werden verschillende risicofactoren voor een beperking van kauwfunctie gevonden. Voor alle patiënten bleek dat de MFIQ-scores vooral sterk beïnvloed werden door het niet kun-nen dragen van een gebitsprothese.

In Hoofdstuk 3.1 werd het verloop van mondopening van 641 patiënten tot 48 maanden na de behandeling met radiotherapie voor hoofd-halskanker geanalyseerd, werden risicofactoren voor een afname van mondopening onderzocht en werd een voorspellingsmodel voor verandering van mondopening ontwikkeld. Mondopening werd gemeten bij aanvang van de radiotherapie en 6, 12, 18, 36 en 48 maanden na de radiotherapie. Gemiddelde mondopening bij aanvang van de radiotherapie was 38,7 mm (SD 10,8). De gemiddelde mondopening nam af over de tijd, met de kleinst gevonden

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gemiddelde mondopening 6 maanden na radiotherapie, namelijk 36,7 mm (SD 10.0). Het model kan worden gebruikt voor het voorspellen van mondopening in de kliniek. De mondopening bleek afhankelijk van het geslacht en de leeftijd van de patiënt, de locatie en classificatie van de tumor, de mondopening bij aanvang van de radiotherapie, de dosis van de radiotherapie en de tijd na de radiotherapie. In Hoofstuk 3.2 werden de inciden-tie en de voorspellers van trismus na radiotherapie onderzocht. Dezelfde patiënten en metingen van mondopening als in Hoofdstuk 3.1 werden geanalyseerd. De incidentie van trismus over de totale periode van 48 maanden was 3,6 per 10 persoonsjaren at risk. Zes maanden na de radiotherapie had 28,1% van de patiënten zonder trismus vooraf aan de radiotherapie, trismus ontwikkeld. De locatie van de tumor en de totale duur van de radiotherapie voorspelden het ontstaan van trismus in de eerste 6 maanden na radiotherapie. De laatst gemeten mondopening was een voorspeller voor trismus op het volgende meetmoment, daarom zijn er reguliere controles van mondopening nodig om trismus te voorspellen. Voor patiënten met een hoog risico op trismus, geïdentificeerd door middel van de aanwezigheid van risicofactoren, kunnen preventieve maatregelen genomen worden.

In Hoofdstuk 4.1 werden studies naar de effecten van oefentherapieën op trismus secundair aan hoofd-halskanker systematisch geanalyseerd. De kwaliteit van de geïnclu-deerde studies werd bepaald en de resultaten werden samengevat. Van de 211 gevon-den studies konden er 20 geïncludeerd worden. Er was een grote variatie in opzet van de studies, in soorten rektechnieken en in de duur en hoeveelheid van de oefeningen. De kwaliteit van de geïncludeerde studies was over het algemeen matig. In 5 van de 8 studies naar oefentherapie ter preventie van trismus, werd een afname van mondope-ning niet voorkomen. In 4 casusbeschrijvingen waarin trismus werd behandeld, werd een toename in mondopening tussen 17 en 24 mm gezien. In 8 andere studies naar oefentherapie ter behandeling van trismus, werd een verandering in mondopening tus-sen de -1,9 en 13,6 mm gezien. Betere resultaten werden behaald bij een vroege start van de oefentherapie en bij therapietrouwe patiënten. Er was geen bepaalde soort oefentherapie duidelijke de beste. Op basis van deze review kunnen geen klinische richt-lijnen opgesteld worden. In Hoofdstuk 4.2 werd het effect van TheraBite® Jaw Motion Rehabilitation System™ (TheraBite)-oefeningen bij 69 hoofd-halskankerpatiënten uit 2 universitaire medische centra (Universitair Medisch Centrum Groningen en Radboud Universitair Medisch Centrum) onderzocht. Ook werden de factoren die het effect van deze oefentherapie beïnvloedden geanalyseerd. Er werd gekeken naar een toename van mondopening van 5 mm of meer, omdat dit het kleinst te meten verschil is. Bij aanvang was de gemiddelde mondopening 22,0 mm (SD 6,4), de gemiddelde toename was 5,4 mm (SD 5,7). Toename van mondopening was significant geassocieerd met chemo-therapie, het medisch centrum en de tijd tussen de behandeling van de tumor en start van de TheraBite-oefeningen. De kans op een toename in mondopening van 5 mm of meer nam af naar mate de tijd tussen de behandeling van de tumor en de start van de TheraBite-oefeningen langer werd. In Hoofdstuk 4.3 werden de effecten van Dynasplint Trismus System® (DTS)-oefeningen op de mondopening, pijn, kauwfunctie, kwaliteit van leven en ervaren klachten bij 18 hoofd-halskankerpatiënten onderzocht. Ook werden

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gebruiksgemak, ervaringen en therapietrouw van deze oefeningen geanalyseerd. Bij aanvang was gemiddelde mondopening 22,6 mm (SD 7,6), de gemiddelde toename was 7,1 mm (SD 4,7) (significant). Ongeveer een derde van de verkregen toename ging ver-loren in de follow-up periode van 14 weken. De ervaren beperking van mondopening verbeterde ook significant. Er werden geen andere significante effecten gevonden. De beleving van deze oefeningen van deze oefentherapie was divers maar over het alge-meen waren patiënten tevreden over de DTS-oefeningen.

ToekomstperspectievenDe risicofactoren voor trismus die in dit proefschrift werden gevonden dienen, waar mogelijk, weggenomen of positief beïnvloed te worden ter preventie van trismus. Indien er risicofactoren voor trismus bij patiënten aanwezig zijn, dient dit aanleiding te geven voor het regelmatig meten van de mondopening gedurende en na de behandeling van hoofd-halskanker. Er moet aandacht zijn voor de ontwikkeling van een preventief reva-lidatieprogramma waaraan patiënten met een risico op trismus of met een afname van mondopening kunnen deelnemen. Gezien oefentherapie een belasting voor patiënten is, het kosten met zich meebrengt en trismus niet altijd voorkomen kan worden ondanks de toegepaste behandeling, moet preventieve behandeling niet routinematig aan elke patiënt geadviseerd worden. De preventie van trismus kan geïntegreerd worden in een ondersteunend zorgprogramma, net zoals de preventie van ondervoeding, de onder-steuning van de mondhygiëne inclusief fluoride profylaxe en oefeningen om arm- en schouderproblemen na een halsklierdissectie te voorkomen.

Voor patiënten die reeds een trismus hebben ontwikkeld, zal de zoektocht naar de meest effectieve behandeling moeten worden gecontinueerd. De effecten van oe-fentherapie met een TheraBite en een DTS zullen in een gerandomiseerde studie met elkaar moeten worden vergeleken.

Voor het optimale resultaat moet de oefentherapie zo vroeg mogelijk gestart wor-den en dienen de behandelaars de therapietrouw te stimuleren. Patiënten moeten uitleg krijgen dat het best haalbare resultaat soms bestaat uit beperken van de afname van hun mondopening.

ConclusiesNa de behandeling van hoofd-halskanker, lijden veel patiënten aan bijwerkingen, waar-onder trismus.

De risicofactoren voor trismus gevonden in dit proefschrift zijn: hogere leeftijd, vrouwelijk geslacht, bepaalde locaties van de tumor (zoals in de mondholte, orofarynx, neusholte, sinus maxillaris, speekselklieren en het oor), T4 tumoren, de dosis van de ra-diotherapie, een kleinere mondopening voorafgaande en gedurende de radiotherapie en langere tijdsperiode na de radiotherapie. Bij patiënten die behandeld zijn met radio-therapie, kan mondopening voorspeld worden door voorspel-modellen. Daarnaast kan trismus voorspeld worden op de verschillende tijdstippen na radiotherapie. Ondanks de identificatie van risicofactoren voor trismus, is het niet haalbaar om trismus altijd te voorkomen. De meeste van deze risicofactoren zijn namelijk niet te beïnvloeden. Daar-

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door blijft het behoud van een goede mondopening bij hoofd-halskankerpatiënten, met name na behandeling met radiotherapie, lastig.

In dit proefschrift bleek geen van de onderzochte rektechnieken superieur en wa-ren de resultaten ervan erg variabel. Bij het toepassen van oefentherapie kan minder afname (bij een preventieve behandeling) of een grotere toename (bij een therapeutisch behandeling) van mondopening verwacht worden bij patiënten die therapietrouw zijn en wanneer oefentherapie vroeg gestart wordt. Ondanks de, over het algemeen, po-sitieve resultaten van oefentherapie kan trismus secundair aan hoofd-halskanker niet altijd voorkomen of behandeld worden.

Chapter 8Dankwoord en curriculum vitae

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Wat is het fijn dat mijn proefschrift er nu is! Zonder velen was het mij de afgelopen jaren niet gelukt om aan dit project te kunnen werken en het te kunnen voltooien. Graag wil ik eenieder bedanken die een bijdrage heeft geleverd aan het ontstaan van dit proef-schrift. Hierbij wil ik een aantal personen in het bijzonder noemen.

Mijn eerste dank gaat uit naar de patiënten die betrokken zijn bij de verschillende on-derzoeken in dit proefschrift. Bedankt voor het vertrouwen en uw participatie.

Geachte eerste promotor prof. dr. P.U. Dijkstra, beste Pieter. Inmiddels is het al heel wat jaren geleden dat ik kennismaakte met jou en deze onderzoekslijn. Wat begon als een kennismaking met wetenschappelijk onderzoek resulteerde, mede dankzij jouw ideeën en inspanningen, in dit proefschrift. Bedankt voor de goede begeleiding, samenwerking en het laagdrempelige, persoonlijke contact.

Geachte tweede promotor prof. dr. J.L.N. Roodenburg, beste professor. Voor een stage via de faculteit tandheelkunde heb ik, inmiddels ongeveer 10 jaar geleden, met u en de afdeling Mondziekten, Kaak- en Aangezichtschirurgie (MKA-chirurgie) van het Univer-sitair Medisch Centrum Groningen (UMCG) kennisgemaakt. Hiermee is mijn interesse voor het vak gewekt en deze is niet meer overgegaan. Bedankt voor de ondersteuning en de goede begeleiding, zowel binnen het onderzoek als binnen de opleiding.

Geachte copromotor dr. H. Reintsema, beste Harry. Bedankt voor de goede begeleiding, je heldere klinische blik, inzet en motiverende woorden gedurende mijn onderzoek.

Geachte prof. dr. J.H.B. Geertzen, prof. dr. M.A.W. Merkx en prof. dr. F.K.L. Spijkervet, le-den van de beoordelingscommissie. Bedankt voor de deskundige beoordeling van mijn proefschrift.

Geachte prof. dr. F.K.L. Spijkervet, beste Fred, afdelingshoofd en opleider van de MKA-chirurgie van het UMCG. Bedankt voor de geboden mogelijkheid om mijn opleidingstra-ject tot MKA-chirurg te combineren met mijn promotieonderzoek.

Geachte prof. dr. L.G.M. de Bont, beste professor, voormalig afdelingshoofd en opleider van de MKA-chirurgie van het UMCG. Bedankt voor de mogelijkheid om te kunnen het starten met opleidingstraject tot MKA-chirurg.

Beste Joyce, Marianne en Phillip, student-onderzoekers. Bedankt voor jullie hulp en sa-menwerking.

Beste dr. K.P. Schepman en dr. M.J.H. Witjes, beste Kees Pieter en Max, MKA-chirurgen-oncoloog. Beste mw. Dopheide en mw. Popma, beste Rachel en Madelon, nurse practio-ners. Beste Angela, Colette, Corriet en Jenny, assistentes. Bedankt voor jullie hulp bij het onderzoek, met name voor het verzamelen van de vele, vele metingen op de polikliniek.

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Dr. B. van Minnen, beste Baucke, chef de clinique. Bedankt voor al jouw hulp en inspan-ningen bij de vele wijzigingen in mijn ingewikkelde opleidingsschema.

Beste dames van het secretariaat en van de administratie van de afdeling MKA-chirur-gie. Bedankt voor de ondersteunende werkzaamheden bij mijn onderzoek en opleiding.

Beste stafleden van de afdeling MKA-chirurgie. Bedankt voor het delen van jullie kennis en kunde van alle facetten van de MKA-chirurgie en de interesse in mijn onderzoekstra-ject.

Beste (oud-)aios van de afdeling MKA-chirurgie. Bedankt voor de samenwerking en gezelligheid, zonder jullie was het lang zo leuk niet om in opleiding te zijn.

Beste (overige) collega’s van de afdeling MKA-chirurgie van het UMCG. Bedankt voor de prettige sfeer en samenwerking die ik vanaf 2010 met jullie ervaar.

Lieve oud-collega’s Alies en Maaike. Samen de meisjes van de MKA met een goede kop koffie aan het begin van de dag. Inmiddels ben ik nog de enige in Groningen en wonen we nogal ver uit elkaar, maar gelukkig blijft het contact. Bedankt voor jullie vriendschap.

Lieve teamgenootjes van GHBS. Bedankt voor de ontspanning en gezelligheid op en naast het hockeyveld.

Lieve meisjes van JC Coco. Bedankt voor alle drankjes, pasjes, ons jaarlijkse clubweekend en vriendschappen. Maar ook bedankt voor het begrip voor het missen van allerlei ge-zelligheid vanwege drukte door studie en werk.

Lieve meisjes van Fort Noxx, voorheen HDH. Bedankt voor mijn thuis gedurende mijn studententijd, voor de gemaakte vriendschappen en het scala aan idiote, prachtige en fijne herinneringen.

Lieve Florine en Frederieke, naast clubgenootjes zijn we ook huisgenootjes geweest. Vanaf het moment dat onze club gevormd is, zijn we maatjes. Bedankt voor jullie be-trokkenheid en vriendschap.

Lieve Fenne en Ilsalien, samen de drie musketiers. Wat fijn dat we nog steeds met elkaar in Groningen zitten. Ik ben nummer twee met een boekje, nummer drie is in de maak. Wie had dat gedacht toen we als huisgenootjes vele uren met elkaar doorbrachten. Be-dankt voor de gezelligheid, steun en jullie vriendschap.

Lieve paranimf Florine, we wonen inmiddels al heel wat jaren in jouw geboortestad en we hebben samen al vele leuke avonturen ondernomen. Je eerlijkheid en inzet bij alles wat je doet waardeer ik zeer. Nu eerst mijn promotie als volgend avontuur, dan op naar

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die van jou! Bedankt dat je mijn paranimf wil zijn.Lieve paranimf Jurrijn, vrijwel tegelijk zijn we met de opleiding gestart. Al snel waren we maatjes binnen en buiten de opleiding. Al heb ik je met mijn gekke planning, zoals jezelf zegt, wel in de steek gelaten. Bedankt dat je mijn paranimf wil zijn.

Lieve Evert, Joke en Maarten, bedankt voor de liefdevolle opname in jullie gezin. Lieve Evert en Joke, bedankt dat jullie er iedere week voor onze kindjes zijn.

Lief zusje Marijke, zolang als ik me kan herinneren ben jij er. Vaak was je in de afgelopen jaren ver weg, toch was je altijd dichtbij. Bedankt voor je humor, gezelligheid en luiste-rend oor. Dear Sam, happy to have you in the family.

Lief broertje Jan Johan, met jou is het nooit saai. We bevinden ons meestal in een andere levensfase maar recentelijk waren we toch even beiden student. Bedankt voor je gezel-ligheid en ook zeker voor je gekkigheid.Lieve Manon, fijn dat je bij ons in de familie gekomen bent.

Lieve papa en mama, zolang als ik me kan herinneren hebben jullie mij gemotiveerd om te doen wat denkbaar is. Bedankt voor jullie onvoorwaardelijke steun en liefde. Lieve mama, bedankt dat je er iedere week voor onze kindjes bent.

Liefste Wim, Ellemijn en Philine, met jullie is het leven leuker! Bedankt dat jullie er zijn.

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Curriculum vitae

Jolanda I. Drouven-Kamstra was born in Leeuwarden (May 21st 1986). After completing her pre-university education at the Piter Jelles College (Leeuwarden) in 2004, she at-tended dental school at the University of Groningen. In 2008 she started her research at the department of Oral and Maxillofacial Surgery and Rehabilitation of the University Medical Center Groningen (UMCG). That same year, she went to the Memorial Sloan Kettering Cancer Center (New York City, USA) for a research and medical internship at the Head and Neck Oncology department. In 2010 she obtained her dental degree. In the same year, she started an integrated program, combining her residency Oral and Maxillofacial Surgery in the UMCG (head: prof. dr. F.K.L. Spijkervet, former head: prof. dr. L.G.M. de Bont) with medical school at the University of Groningen. In 2012 she obtained an Agiko Stipendium (ZonMw) for her PhD project. In 2016 she obtained her medical degree. Jolanda is married to Wim Drouven and together they have 2 daughters, Ellemijn (2014) and Philine (2016).

The printing and distribution of this thesis was kindly supported by:

Atos MedicalDam MedicalDentaidExamVisionJC EsthetiekEvert en Joke DrouvenKamstra TransportKLS MartinKoninklijke Nederlandse Maatschappij tot bevordering der Tandheelkunde (KNMT)Laverman specialistisch en tandtechnisch laboratoriumMKA-chirurgie Treant Zorggroep, locatie Scheper ZiekenhuisMondfotografie Henk ButeijnNederlandse Vereniging voor Gnathologie en Prothetische Tandheelkunde (NVPGT)Nederlandse Vereniging voor Mondziekten, Kaak- en Aangezichtschirurgie (NVMKA)Noord Negentig accountants en belastingadviseursRijksuniversiteit GroningenStraumannTessier FoundationUniversitair Medisch Centrum Groningen

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