University of Groningen Trismus in head and neck cancer patients van der Geer, Joyce

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Trismus in head and neck cancer patients

van der Geer, Joyce

DOI:

10.33612/diss.112040321

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2020

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Citation for published version (APA):

van der Geer, J. (2020). Trismus in head and neck cancer patients. Rijksuniversiteit Groningen.

https://doi.org/10.33612/diss.112040321

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ISBN Printed book: 978-94-034-2295-4

ISBN E-book: 978-94-034-2296-1

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Trismus in head and neck cancer

patients

Proefschrift

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen

op gezag van de

rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties.

De openbare verdediging zal plaatsvinden op maandag 3 februari 2020 om 14.30 uur

door

Sarah Joyce van der Geer

geboren op 25 december 1992

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Prof. dr. P.U. Dijkstra Prof. dr. J.L.N. Roodenburg

Copromotor

Dr. H. Reintsema

Beoordelingscommissie

Prof. dr. E.B. Wolvius

Prof. dr. J.H.B. Geertzen Prof. dr. F.K.L. Spijkervet

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Chapter 1 General introduction 9

Criterion for trismus

Chapter 2 Criterion for trismus in head and neck cancer patients:

a verification study. 17

Factors associated with trismus

Chapter 3a Prevalence and prediction of trismus in head and neck cancer

patients: a cross- sectional study. 35

Chapter 3b Mouth opening in patients treated for head and neck cancer:

a linear mixed model analysis. 57

Chapter 4 Predictors for trismus in patients receiving radiotherapy. 73 Chapter 5 Prognostic factors for a restricted mouth opening (trismus) in

head and neck cancer patients: a systematic review. 95

Therapy for trismus

Chapter 6 The use of stretching devices for treatment of trismus in head

and neck cancer patients: a randomized controlled trial. 139

Chapter 7 General discussion 163

Summary 173

Samenvatting 177

Dankwoord 183

Curriculum Vitae 191

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Head and neck cancer

Head and neck cancer includes lip, oral cavity, salivary glands, nose (sinuses), oropharynx, nasopharynx, hypopharynx, larynx and complex skin tumours in the head and neck region. In the Netherlands, around 3100 people developed head and neck cancer in 2016.1 Most of the tumours were located in the oral cavity, oropharynx, and the larynx (crude rate: 5.13, 4.08, and 4.13 per 100.000 person years at risk respectively).

Head and neck cancer treatment side-effects

Side- effects may occur after head and neck cancer treatment (consisting mainly of surgery, radiotherapy, and/or chemotherapy), such as mucositis, hyposalivation, taste change or taste loss, osteoradionecrosis, radiation caries, dysphagia and trismus.2,3_Trismus, hyposalivation and restricted tongue mobility are the most frequently occurring and most burdensome late side-effects of treatment reported by head and neck cancer patients.4

Criterion for trismus

The prevalence of trismus ranges between 5% and 65%.5-10_{This range might be the} result of different cut-off points for trismus.6-8_{Cut-off points for trismus are, for instance,} based on dental status (such as 35 mm for dentate patients and 40 mm for edentulous patients)7_{, or based on the severity of the restriction (such as 35 mm for moderate trismus} and 20 to 25 mm for severe trismus).6,8_{Hence, the risk factors for and the effectiveness} of treating trismus cannot be analysed in a uniform manner and the research results cannot be interpreted easily.

Factors associated with trismus

The prevalence range of trismus could also be affected by the narrow inclusion criteria, consisting of specific patient, tumour and treatment characteristics, such as a particular tumour localization5,9,10_{or a particular treatment modality}5-7,9-11_{. Trismus is more likely} when the masticatory structures (the temporomandibular joint6,13,14_{, the masseter} muscle6,14,15_{, the lateral pterygoid muscle}6,13-16_{, the medial pterygoid muscle}6,13-15_{, and} the temporal muscle6,14,15_{) are affected, either by tumour infiltration or tumour treatment.} Regarding treatment modality, trismus is more likely to develop after radiotherapy and chemoradiotherapy, than after surgery alone.9,17_{Multivariate analyses are necessary, in} order to identify the patients at risk of developing trismus.

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Therapy for trismus

Once trismus develops, it is difficult to treat. Several therapies have been described for trismus, such as tissue condition enhancing18,19_{, pain reducing}20_{, surgical}21_{, and} physiotherapeutic options22_{. Tissue condition enhancing options, such as microcurrent} therapy and pentoxifylline had a minor positive effect on mouth opening (effect size 0.3 and 0.3, respectively).18,19_{Pain reducing options, such as botulinum toxin injections, are} effective in reducing pain scores and jaw spasms, but did not improve mouth opening.20 Surgical treatments, such as a coronoidectomy increases mouth opening directly post-operatively, but it decreases slightly in the six months thereafter.21,23_{Coronoidectomy} should only be considered when other therapies have no effect, mouth opening restriction is severe (<20 mm), and the cause of trismus is probably related to restrictions in the temporomandibular area. Surgical trismus release in combination with a free flap reconstruction led to a significant increase in mouth opening directly afterwards (mean gain 31.0 mm, SD 7.0), but had decreased by 71% at the follow-up (mean loss 22.1 mm, SD 7.3).24_{This procedure has been found to be particularly effective in head and neck cancer} patients who consume betel nut (mean increase: 17.4 mm, SD 6.1) compared to patients who do not (mean increase 10.5 mm, SD 5.8). It has been suggested that trismus among the patients who consume betel nut is related to the presence of superficially located oral submucous fibrosis, whereas trismus among other patients who didn’t consumed betel nut is related to fibrosis of the deeper muscular structures.24_{Physiotherapeutic options} including stretching and mobilization, using tongue depressors, rubber plugs, manual stretches or stretching devices, seem promising, but mouth opening measurements smaller than 35 mm are still found at the end of the stretching regimen.22_{It has been} suggested that early, preventive stretching regimen for trismus had greater effects on the increase of mouth opening.25_{However, still no exercise technique was superior to} another, neither regarding early or late stretching regimen.22

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AIMS OF THE THESIS

The general aims of this thesis, with respect to trismus in head and neck cancer patients, are to determine the criterion for trismus, to identify the factors associated with trismus and to assess the effectiveness of stretching regimens as a therapy for trismus.

Criterion for trismus

In order to identify which factors are associated with the development of trismus and to analyse which treatment is effective in treating trismus, one should determine first at which point patients experience trismus. A cut-off point for trismus was determined in a large study population (n= 671) based on multiple maximal mouth opening measurements and patients’ perception of difficulties opening the mouth (chapter 2).

Factors associated with trismus

Factors associated with the development of trismus were identified in large study populations with a variety of patient and tumour characteristics, that were predominantly treated with surgery (n=730) (chapter 3a and 3b) or were predominantly treated with radiotherapy (n=641) (chapter 4).

To get an overview of the factors influencing trismus in head and neck cancer patients, a systematic review was performed (chapter 5). This systematic review aimed to identify the prognostic factors for trismus (objectively measured and subjectively assessed) from patients treated for head and neck cancer. A wide range of patient, tumour and treatment characteristics were included.

Exercise therapy for trismus

Of the studied physiotherapeutic options to prevent or treat trismus, stretching devices seem promising, including: the TheraBite® Jaw Motion Rehabilitation System™(Atos Medical, Sweden) and the Dynasplint Trismus System® (Dynasplint Systems, Inc., Maryland, the United States of America). No comparison has been made yet to establish which stretching device is most effective in treating trismus. In order to compare the effectiveness of these two stretching devices on increasing maximal mouth opening, a randomized controlled trial was performed (chapter 6).

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REFERENCES

1. Integraal Kankercentrum Nederland. Cijfers over kanker. http://www.cijfersoverkanker.nl/.

Updated 2017. Last visited November 2019.

2. Epstein JB, Emerton S, Kolbinson DA, et al. Quality of life and oral function following

radio-therapy for head and neck cancer. Head Neck. 1999;21(1):1-11.

3. Vissink A, Jansma J, Spijkervet FK, Burlage FR, Coppes RP. Oral sequelae of head and neck

radiotherapy. Crit Rev Oral Biol Med. 2003;14(3):199-212.

4. Kamstra JI, Jager-Wittenaar H, Dijkstra PU, et al. Oral symptoms and functional outcome

related to oral and oropharyngeal cancer. Support Care Cancer. 2011;19(9):1327-1333.

5. Van Cann EM, Dom M, Koole R, Merkx MA, Stoelinga PJ. Health related quality of life after

mandibular resection for oral and oropharyngeal squamous cell carcinoma. Oral Oncol. 2005;41(7):687-693.

6. Lindblom U, Garskog O, Kjellen E, et al. Radiation-induced trismus in the ARTSCAN head and

neck trial. Acta Oncol. 2014;53(5):620-627.

7. Louise Kent M, Brennan MT, Noll JL, et al. Radiation-induced trismus in head and neck cancer

patients. Support Care Cancer. 2008;16(3):305-309.

8. Steiner F, Evans J, Marsh R, et al. Mouth opening and trismus in patients undergoing curative

treatment for head and neck cancer. Int J Oral Maxillofac Surg. 2015;44(3):292-296.

9. Scott B, D’Souza J, Perinparajah N, Lowe D, Rogers 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(2):106-111.

10. Chen YY, Zhao C, Wang J, et al. Intensity-modulated radiation therapy reduces radiation-in-duced trismus in patients with nasopharyngeal carcinoma: A prospective study with >5 years of follow-up. Cancer. 2011;117(13):2910-2916.

11. 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(5):548-555.

12. Wetzels J-GH, Merkx MAW, De Haan T, Koole R, Speksnijder CM. Maximal mouth opening and trismus in 145 patients treated for oral cancer: A 1-year prospective study. Oral Oncol. 2013;49:S89.

13. Goldstein M, Maxymiw WG, Cummings BJ, Wood RE. The effects of antitumour irradiation on mandibular opening and mobility: A prospective study of 58 patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88(3):365-373.

14. Pauli N, Olsson C, Pettersson N, et al. Risk structures for radiation-induced trismus in head and neck cancer. Acta Oncol. 2016;55(6):788-792.

15. Rao SD, Saleh ZH, Setton J, et al. Dose-volume factors correlating with trismus following chemoradiation for head and neck cancer. Acta Oncol. 2016;55(1):99-104.

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16. Hague C, Beasley W, Garcez K, et al. Prospective evaluation of relationships between radio-therapy dose to masticatory apparatus and trismus. Acta Oncol. 2018;57(8):1038-1042. 17. Wetzels JW, Merkx MA, de Haan AF, Koole R, Speksnijder CM. Maximum mouth opening

and trismus in 143 patients treated for oral cancer: A 1-year prospective study. Head Neck. 2014;36(12):1754-1762.

18. Chua DT, Lo C, Yuen J, Foo YC. A pilot study of pentoxifylline in the treatment of radiation-in-duced trismus. Am J Clin Oncol. 2001;24(4):366-369.

19. Lennox AJ, Shafer JP, Hatcher M, Beil J, Funder SJ. Pilot study of impedance-controlled micro-current therapy for managing radiation-induced fibrosis in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys. 2002;54(1):23-34.

20. Hartl DM, Cohen M, Julieron M, Marandas P, Janot F, Bourhis J. Botulinum toxin for radia-tion-induced facial pain and trismus. Otolaryngol Head Neck Surg. 2008;138(4):459-463. 21. Bhrany AD, Izzard M, Wood AJ, Futran ND. Coronoidectomy for the treatment of trismus in

head and neck cancer patients. Laryngoscope. 2007;117(11):1952-1956.

22. Kamstra JI, van Leeuwen M, Roodenburg JL, Dijkstra PU. Exercise therapy for trismus sec-ondary to head and neck cancer: A systematic review. Head Neck. 2016.

23. Bouman MA, Dijkstra PU, Reintsema H, Roodenburg JL, Werker PM. Surgery for extra-articular trismus: A systematic review. Br J Oral Maxillofac Surg. 2016;54(3):253-259.

24. de Pablo A, Chen YT, Chen JK, Tsao CK. Trismus surgical release and free flap reconstruction after radiation therapy in oral and oropharyngeal squamous cell carcinoma. J Surg Oncol. 2018;117(2):142-149.

25. 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(4):951-957.

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This chapter is an edited version of: van der Geer SJ, van Rijn PV, Kamstra JI, Roodenburg JLN, Dijkstra PU. Criterion for trismus in head and neck cancer patients: A verification study. Support Care Cancer. 2019;27(3):1129-1137.

Criterion for trismus in head

and neck cancer patients:

a verification study

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ABSTRACT

Purpose: Several cut-off points for trismus in head and neck cancer patients have been used. A mouth opening of 35 mm or less is most frequently used as a cut-off point. Due to the variation in cut-off points, the prevalence, prognostic factors and treatment outcomes of trismus cannot be studied uniformly. To provide uniformity, we aimed to verify the cut-off point of 35 mm or less. Additionally, we aimed to determine associated covariates with patients’ perception of difficulties opening the mouth.

Methods: In a cross-sectional design, we measured the mouth opening in 671 head and neck cancer patients at the department of Oral and Maxillofacial Surgery, at the University Medical Center Groningen. The cut-off point was determined using the Receiver Operating Characteristic curve and Youden index, with perceived difficulties opening the mouth as criterion for trismus. Cut-off points for significant covariates were also determined.

Results: The Youden index was highest at 35 mm, with a sensitivity of 0.71 and a specificity of 0.86. Of the covariates analysed, the covariate ‘treatment modality’ was significantly associated with perceived difficulties opening the mouth. The highest Youden index for patients treated with surgery alone was 37 mm and for patients treated with radiotherapy alone 33 mm.

Conclusions: The cut-off point of 35 mm or less for trismus was confirmed in this large head and neck cancer population. It is recommended to use this cut-off point for future research. Patients receiving different treatment modalities may perceive difficulties opening the mouth differently.

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INTRODUCTION

Trismus, a restricted mouth opening, in head and neck cancer patients may be caused by ingrowth of the tumour in the masticatory muscles or by fibrosis after surgery or radiotherapy. Trismus can hamper normal oral intake, dental hygiene, social activities, oncological follow-up, and dental treatment.1-5

Cut-off points for trismus have been determined based on the dental status of patients: 35 mm for dentate patients and 40 mm for edentulous patients.2_{Other cut-off points for} trismus are based on the severity of the restriction, such as 35 mm for moderate trismus and 20 or 25 mm for severe trismus.6,7_{Based upon the severity of the restriction, grades} have also been used: grade 2 for a mouth opening of 10 to 20 mm, grade 3 for a mouth opening of 5 to 10 mm, and grade 4 for a mouth opening less than 5 mm.8_Sometimes cut-off points seem to be chosen arbitrarily.9_{Due to the various cut-off points used,} prognostic factors for trismus or the effectiveness of therapy for trismus cannot be analysed in a uniform manner and cannot be interpreted for the head and neck cancer population in general easily.

The most commonly used cut-off point is 35 mm or less.1,10-12_{A study determined this} cut-off point on the basis of perceived restrictions reported by head and neck cancer patients.13_{The percentage correctly predicted trismus was 81%, with a sensitivity of} 0.71, and a specificity of 0.98. Another study had a similar cut-off point of less than 35 mm based upon reported problems with chewing and diet.14_{The sample sizes were 89} and 100 patients, resulting in little or no statistical power to perform covariate analyses. The aim of the present study was to verify the cut-off point of 35 mm or less for trismus in a large head and neck cancer population. Firstly, we determined the cut-off point for trismus based upon perceived difficulties opening the mouth. Secondly, we determined cut-off points for significant covariates.

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MATERIALS AND METHODS

Patient selection

This cross- sectional study included patients who visited the Department of Oral and Maxillofacial Surgery at the University Medical Center Groningen (UMCG) (the Netherlands) for head and neck cancer between November 2012 and January 2015. Patients were included if they had a malignant tumour located in the upper aero- digestive tract, unknown primaries with metastases in the head and neck region, or a major salivary gland tumour. Patients were excluded if they were younger than 18 years, were not diagnosed with head and neck cancer, had rare types of tumours, had missing data regarding maximal mouth opening (MMO), or had missing data regarding their perception of difficulties opening the mouth. Our study was carried out according to the regulations of our institute. The Medical Ethical Committee of the UMCG concluded that our research was not subject to the Medical Research (Human Subject) Act (METc number 2016.692).

MMO measurements and difficulties opening the mouth

MMO measurements were performed by surgeons, nurse practitioners or residents, using the OraStretch®_{Range-of-Motion Scale, as part of routine patient care. MMO was measured} during every follow-up visit. As patients had several follow-up visits during the study period, multiple MMO measurements were recorded. In our analysis, we used only the first recorded MMO measurement of each included patient. MMO and dental status were recorded on a separate registration form. If the mouth opening was measured at the right upper central incisor and the right lower central incisor (of own dentition or prosthesis), the dental status was recorded as “dentate”. If the alveolar ridges at the former location of the right upper and lower central incisor were used as measurements points, the dental status was recorded as “edentulous”. If the alveolar ridge was used as the measurement point for one jaw, and the right upper or lower central incisor for the other jaw, the dental status was recorded as “partially edentulous”. Because the scale of the OraStretch®_Range of Motion Scale has a maximum of 52 mm, patients who had a MMO of 52 mm or more were measured using a sliding calliper (in mm). After recording the MMO, the patients were asked if they perceived difficulties opening the mouth (yes, no).

Additional data

Besides the data on the registration form, additional data was retrieved from the patient information system used in the UMCG, including:

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Tumour localization (tongue, floor of mouth, maxilla (including the maxilla, hard palate, and maxillary sinus), mandible, cheek, major salivary glands (including the parotid gland, submandibular gland, and sublingual gland), oropharynx (including the oropharynx, base of tongue, retromolar space, tonsils and soft palate), hypopharynx and larynx, lip, unknown primary), cT classification based on the Union for International Cancer Control (UICC) TNM classification 2009 (TX, T1-2, T3-4, unknown), and treatment modalities (no treatment, surgery alone, radiotherapy alone, combination of surgery and radiotherapy). Patients were recorded as having received radiotherapy if they received primary radiotherapy or a combination of radiotherapy and chemotherapy.

Primary analysis

Data was analysed using a receiver operating characteristic (ROC) curve, in which MMO was compared to patients’ perception of difficulties opening the mouth. Based on the ROC curve, we calculated the Area Under the Curve (AUC), sensitivity, specificity, and Youden Index. We determined the discriminant validity of patients perceiving difficulties opening the mouth to be perfect if the area under the curve (AUC) was 1, highly accurate if ≥ 0.9, moderately accurate if 0.7 ≥ AUC < 0.9, less accurate if 0.5 ≥ AUC < 0.7, and non-informative if the AUC was 0.5.15_{The Youden Index was calculated as follows:} (sensitivity + specificity) -1.16_{We determined a cut-off point for trismus on the basis of} the highest Youden Index score.

Covariate analysis

We used a t-test for independent samples to analyse an association between patients’ perception of difficulties opening the mouth and age. We used a Chi-Square test to analyse associations between patient’s perception of difficulties opening the mouth and gender, dental status, and different treatment modalities. When a significant association between perceived difficulties opening the mouth and a covariate was found (p<0.05), separate ROC curves were plotted for that covariate. Cut-off points for the subgroups of that covariate were determined in the same way as for the total group.

Post-hoc analysis

In case the results of the performed analyses need more clarification or insight in the data, additional analyses were performed.

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RESULTS

Patient characteristics

MMO measurements of 839 patients were recorded. In total, 168 patients were excluded, because they were not diagnosed with head and neck cancer (n=77), had rare types of tumours concerning localizations (for example pyriform sinus, ethmoid sinus, sphenoid sinus), metastases of primary tumours that were not part of head and neck oncology (for example mamma or kidney), or histology (neuroblastoma, lymphoma, Merkel-cell carcinoma) or a combination (n=29), or had missing data regarding MMO measurement or their perception of difficulties opening their mouth (n=62). In total, 134 patients had a MMO larger than 52 mm, of whom 109 were measured using a sliding calliper. Of 25 patients, the MMO was set on 52 mm because a sliding calliper was unavailable during the visit. The final study population consisted of 671 patients (80.0%) (Table 1). In our final study population, 278 patients (41.4%) were treated with surgery alone, 130 patients (19.4%) were treated with radiotherapy alone, and 215 patients (32.1%) were treated with a combination of surgery and radiotherapy.

MMO measurements versus difficulties opening the mouth

In total, 109 (16.2%) patients perceived difficulties with opening the mouth. These patients had a mean MMO of 30.1 mm (95% Confidence Interval (CI): 28.0; 32.1 mm) (Figure 1A). Patients who did not perceive difficulties with opening their mouth had a mean MMO of 44.5 mm (95% CI: 43.8; 45.2 mm).

Primary analysis

The AUC of the ROC curve of the total study population was 0.846 (95% CI: 0.803; 0.889) (Figure 2A). The Youden index was highest at 35 mm (0.569) with a sensitivity of 0.706 and a specificity of 0.863 (Table 2).

Covariate analysis

No significant difference in age was found between patients who perceived difficulties opening the mouth and those who did not (p=0.804). No significant difference was found in gender (p=0.756) and in dental status (p=0.439) between patients who perceived difficulties opening the mouth and those who did not. Patients who were treated with radiotherapy alone perceived difficulties opening the mouth more often than patients who were treated with surgery alone (p<0.001) (Table 3).

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We plotted a ROC curve for patients who were treated with surgery alone and patients who were treated with radiotherapy alone (Figure 2B,2C). The AUC of the ROC curve for surgery alone was 0.784 (95% CI: 0.667 to 0.901). The Youden Index was highest at a MMO of 37 mm (0.496), with a sensitivity of 0.636 and a specificity of 0.859 (Table 2). The AUC of the ROC curve for radiotherapy alone was 0.811 (95% CI: 0.705; 0.917). The Youden Index was highest at a MMO of 33 mm (0.560), with a sensitivity of 0.667 and a specificity of 0.893.

Table 1. Patient, tumour and treatment characteristics.

Total (n=671) Surgery only (n=278) Radiotherapy only (n=130) n(%) n(%) n(%) Patient characteristics Male 360 (53.7) 143 (51.4) 82 (63.1)

Age (years), range 11-96; mean (SD) 63.4 (13.5) 62.6 (13.7) 63.9 (11.3) Maximal mouth opening, range 7-73; mean (SD) 42.2 (10.6) 45.0 (8.8) 41.3 (11.1) Dental status Dentate 526 (78.4) 234 (84.2) 95 (73.1) Edentulous 99 (14.8) 33 (11.9) 25 (19.2) Partially edentulous 42 (6.3) 9 (3.2) 10 (7.7) Missing 4 (0.6) 2 (0.7) 0 (0.0) Tumour characteristics Localization of primary tumour

Tongue 148 (22.1) 89 (32.0) 7 (5.4)

Floor of mouth 82 (12.2) 39 (14.0) 13 (10.0)

Maxilla 34 (5.1) 17 (6.1) 7 (5.4)

Mandible 49 (7.3) 23 (8.3) 1 (0.8)

Cheek 19 (2.8) 8 (2.9) 1 (0.8)

Major salivary glands 70 (10.4) 30 (10.8) 5 (3.8)

Oropharynx 94 (14.0) 24 (8.6) 45 (34.6)

Hypopharynx and larynx 32 (4.8) 0 (0.0) 24 (18.5)

Lip 52 (7.7) 27 (9.7) 14 (10.8) Unknown primary 12 (1.8) 2 (0.7) 8 (6.2) Missing 79 (11.8) 19 (6.8) 5 (3.8) T classification TX 9 (1.3) 1 (0.4) 2 (1.5) T1, T2 410 (61.1) 230 (82.7) 60 (46.2) T3, T4 143 (21.3) 18 (6.5) 56 (43.1) Missing 109 (16.2) 29 (10.4) 12 (9.2) Treatment characteristics No treatment 48 (7.2) 0 (0.0) 0 (0.0) Surgery 278 (41.4) 278 (100.0) 0 (0.0) Radiotherapy 130 (19.4) 0 (0.0) 130 (100.0)

Combination of surgery and radiotherapy 215 (32.1) 0 (0.0) 0 (0.0)

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Figure 1. Box and whisker plots concerning maximal mouth opening in relation to patients’

perception of difficulties opening the mouth of the total study population (A), of the population who were treated with surgery only (B), and patients who were treated with radiotherapy only (C).

Difficulties opening the mouth Difficulties No difficulties

Maximal Mouth Opening (MMO)

80 60 40 20 0 A B C

Difficulties opening the mouth

Difficulties No difficulties

80 60 40 20 0

Difficulties opening the mouth

Difficulties No difficulties

80 60 40 20

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Figure 2. Receiver Operating Characteristic curve comparing maximal mouth opening (mm) with

patients’ perception of difficulties opening the mouth for the total study population (A), the popula-tion who were treated with surgery only (B), and patients who were treated with radiotherapy only (C).

1 - Specificity 1.0 0.8 0.6 0.4 0.2 0.0 Sensitivity 1.0 0.8 0.6 0.4 0.2 0.0 1 - Specificity 1.0 0.8 0.6 0.4 0.2 0.0 Sensitivity 1.0 0.8 0.6 0.4 0.2 0.0 1 - Specificity 1.0 0.8 0.6 0.4 0.2 0.0 Sensitivity 1.0 0.8 0.6 0.4 0.2 0.0 A BBB C

2

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Table 2. Sensitivity, Specificity and Youden Index for maximal mouth opening measurements.

Total study population (n=671) Surgery only (n=278) Radiotherapy only (n=130) Cut- off point (mm)

Sensitivity Specificity J Sensitivity Specificity J Sensitivity Specificity J

20 0.202 0.988 0.189 0.091 0.992 0.083 0.259 0.990 0.250 21 0.229 0.988 0.217 0.091 0.992 0.083 0.259 0.990 0.250 22 0.266 0.986 0.252 0.091 0.992 0.083 0.370 0.990 0.361 23 0.284 0.980 0.265 0.091 0.992 0.083 0.370 0.990 0.361 24 0.312 0.980 0.292 0.091 0.992 0.083 0.407 0.990 0.398 25 0.330 0.980 0.311 0.091 0.992 0.083 0.444 0.990 0.435 26 0.394 0.977 0.371 0.091 0.992 0.083 0.444 0.981 0.425 27 0.413 0.973 0.386 0.182 0.984 0.166 0.444 0.981 0.425 28 0.468 0.959 0.427 0.182 0.977 0.158 0.481 0.971 0.452 29 0.505 0.950 0.455 0.273 0.969 0.241 0.519 0.961 0.480 30 0.523 0.940 0.462 0.273 0.961 0.234 0.556 0.951 0.507 31 0.624 0.916 0.540 0.409 0.961 0.370 0.630 0.893 0.523 32 0.642 0.909 0.551 0.455 0.957 0.412 0.630 0.893 0.523 33 0.661 0.902 0.563 0.500 0.949 0.449 0.667 0.893 0.560a 34 0.688 0.874 0.562 0.500 0.918 0.418 0.704 0.845 0.548 35 0.706 0.863 0.569a _0.545 _0.910 _0.456 _0.704 _0.835 _0.539 36 0.716 0.845 0.561 0.545 0.898 0.444 0.704 0.816 0.519 37 0.761 0.786 0.548 0.636 0.859 0.496a _0.704 _0.767 _0.471 38 0.771 0.760 0.530 0.636 0.816 0.453 0.704 0.748 0.451 39 0.780 0.747 0.527 0.682 0.805 0.487 0.704 0.718 0.422 40 0.807 0.698 0.505 0.727 0.750 0.477 0.704 0.689 0.393 41 0.817 0.681 0.498 0.727 0.730 0.458 0.741 0.670 0.411 42 0.826 0.653 0.479 0.727 0.699 0.426 0.741 0.641 0.382 43 0.862 0.544 0.407 0.773 0.594 0.366 0.778 0.544 0.321 44 0.899 0.527 0.426 0.818 0.570 0.388 0.852 0.544 0.396 45 0.908 0.500 0.408 0.818 0.547 0.365 0.852 0.505 0.357

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Table 3. Comparison between patients with and without difficulties opening the mouth.

No difficulties opening the mouth (n=562) Difficulties opening the mouth (n=109) n % n % χ² DF p Patient characteristics Male gender 303 53.9 57 52.3 0.096 1 0.756 Age 63.4a _13.7b _63.7a _12.4b _-0.35c _-3.1;-2.4d _0.804* Dental status 1.646 2 0.439 Dentate 445 79.7 81 74.3 Partially edentulous 34 6.1 8 7.3 Edentulous 79 14.2 20 18.3 Treatment characteristics Treatment modality 33.528 3 <0.001 No treatment 44 7.8 4 3.7 Surgery only 256 45.6 22 20.2 Radiotherapy only 103 18.3 27 24.8

Surgery and radiotherapy 159 28.3 56 51.4

%: column percentage, χ²: Results of Chi-Square test, DF: Degrees of freedom, a: mean, b: standard deviation, c: difference in means, d: 95% confidence interval, *: t- test for independent samples.

Post-hoc analysis

To provide insight into the possible association between the time from treatment (surgery or radiotherapy) to measurement and patients’ perception of difficulties opening the mouth (yes, no), we performed additional analysis. The Mann-Whitney U test showed that the period from treatment to measurement differs significantly in relation to the perceived difficulties with opening the mouth (p=0.010) and in relation to the treatment modality (surgery or radiotherapy) (p<0.001) (Table 4). In the multivariate logistic regression analysis, treatment modality was significantly associated with perceived difficulties opening the mouth (p=0.005), but the period from treatment to measurement does not (p=0.569).

As we found a 4 mm difference between the cut-off points for different treatment modalities, we performed a Mann-Whitney U test in order to give insight into a possible association between treatment modalities and the influence on MMO. The test showed that the MMO was not significantly different after surgery alone or radiotherapy alone for the patients who perceived difficulties when opening the mouth (p=0.078) (Table 4).

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Table 4. Analysis of time from treatment to measurement (months) in patients with and without

difficulties opening the mouth and in patients who were treated with surgery only or radiotherapy only and analysis of maximal mouth opening measurement, only of patients who perceived difficulties when opening the mouth, who were treated with surgery only or radiotherapy only, using the Mann-Whitney U-test.

No difficulties opening the mouth (n=399)

Difficulties opening the mouth

(n=92)

Median IQR Median IQR MWU p

Time from treatment to

measurementa 28.2 8.9;58.3 16.1 2.1;48.0 15,174.0 0.010

Surgery only

(n=220) Radiotherapy only(n=80)

Time from treatment to

measurementa 33.9 12.6;67.4 9.6 1.5;31.7 4856.5 <0.001

Surgery only

(n=22) Radiotherapy only(n=27)

Maximal mouth opening

measurementb 34.0 29.0;43.3 29.0 20.0;43.0 209.5 0.078

a_{: 48 patients received no treatment, 132 received treatment after the measurement moment.}b_{: Only}

the patients are included who perceived difficulties when opening the mouth, IQR: Interquartile range, MWU: Mann-Whitney U test.

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DISCUSSION

Key results

For the total study population, the cut-off point for trismus was 35 mm or less. For patients who were treated with surgery alone, the cut-off point was 37 mm or less and for patients who received radiotherapy alone 33 mm or less.

Interpretation

We found that patients who were treated with radiotherapy alone perceived difficulties opening the mouth at a smaller mouth opening (33 mm) compared to patients who were treated with surgery alone (37 mm). Postoperative symptoms, such as pain, scarring and trismus, are immediately noticeable for the patient. After radiotherapy, MMO decreases more gradually.17_{On average, during radiotherapy (first 9 weeks), the MMO decreased} with 1.3% per month. In the first 9 months after radiotherapy, the MMO decreased 2.4% per month. 17_{Between 12 and 24 months after radiotherapy, the MMO decreased 0.2%} per month. This gradual decrease in MMO was also confirmed in another study.18_The prevalence of trismus in head and neck cancer patients after radiotherapy treatment was: 32% after 3 months, 34% after 6 months, and 38% after 12 months.18_{As the MMO} decreases gradually, patients may have the ability to adapt in the meantime and therefore may experience mouth opening restrictions at a smaller mouth opening.

Our assumption that patients adapt to the mouth opening restriction in time, is confirmed in our data. The period from treatment to measurement is significantly associated with perceived difficulties opening the mouth. Taking the treatment modality into account, in a multivariate logistic regression analysis, the period from treatment to measurement was not significantly associated with perceived difficulties opening the mouth. Therefore, for clinical use, only the treatment modality should be taken into account.

We observed a 4 mm difference between the cut-off points of different treatment modalities, but we also found that MMO was not significantly different after surgery alone or radiotherapy alone for the patients who perceived difficulties when opening the mouth. Therefore, we prefer to speak of a trend for an earlier perception of difficulties when opening the mouth in patients treated with surgery alone compared to patients receiving radiotherapy alone.

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Other studies

One study also determined the cut-off of 35 mm or less. That study performed one additional covariate analyses, for dental status, but did not find a significant difference.13 We were able to analyse other covariates: we found a significant difference regarding treatment modalities as covariates, but not for dental status. A second study, determined the cut-off point for trismus on the basis of reported problems with chewing and diet. This study determined the cut-off point of less than 34 mm. They determined the cut-off point in groups of 5 mm instead of 1 mm, which could therefore have resulted into a different cut-off point compared to our study. They did not perform additional covariate analyses.14

Study limitations and strengths

A limitation of our study is that the time intervals between cancer treatment and MMO measurements differed, as the MMO was measured during regular check-up visits. For example, one patient had a measurement 3 months post-treatment, while another patient had a measurement 24 months post- treatment. This difference could have led to an underestimation of patients who perceived difficulties opening the mouth, as some patients could already have adapted to their new MMO and would not perceive difficulties opening the mouth.

Another possible limitation is that several professionals measured maximal mouth opening, which could have introduced an inter-observer measurement error. Nonetheless, a previous study shows that inter- observer variability is minimal.19

As the sliding calliper was not always available during the MMO measurements, 25 patients could not be measured. Their MMO was set on 52 mm. We expect that the patients with a MMO larger than 52 mm do not perceive difficulties when opening the mouth. Therefore, the results of the mean MMO of patients who do not perceive difficulties when opening the mouth might be slightly lower than the actual mean MMO. The strength of our study is the large study population and many MMO measurements. Due to our large database, we were able to perform covariate analyses with enough statistical power. Due to our covariate analyses, we were able to make a distinction between the patients’ perception of difficulties when opening the mouth after receiving radiotherapy or surgery. Now clinicians can take into account that patients’ perception of a restricted mouth opening differ after surgery or radiotherapy. As the cut-off point of 35 mm or less is now confirmed in a large head and neck cancer population, clinicians

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could use this cut-off point as an indicator to start preventive measures. We recommend to use this cut-off point for future research as well; to explore prognostic factors for trismus, to report prevalences of trismus and for evaluating the effectiveness of therapy for trismus.

Conclusion

We have verified the cut-off point of 35 mm or less for trismus in the total head and neck cancer population. Patients receiving different treatment modalities could differ in their perception of difficulties opening their mouth. To improve comparison of future studies concerning trismus in head and neck cancer patients, we recommend using the cut-off point of 35 mm or less.

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REFERENCES

1. Weber C, Dommerich S, Pau HW, Kramp B. Limited mouth opening after primary therapy of

head and neck cancer. Oral Maxillofac Surg. 2010;14(3):169-173.

2. Louise Kent M, Brennan MT, Noll JL, et al. Radiation-induced trismus in head and neck cancer

patients. Support Care Cancer. 2008;16(3):305-309.

3. Van Cann EM, Dom M, Koole R, Merkx MA, Stoelinga PJ. Health related quality of life after

mandibular resection for oral and oropharyngeal squamous cell carcinoma. Oral Oncol. 2005;41(7):687-693.

4. 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(8):1033-1038.

5. Melchers LJ, Van Weert E, Beurskens CHG, 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(9):947-954.

6. Lindblom U, Garskog O, Kjellen E, et al. Radiation-induced trismus in the ARTSCAN head and

neck trial. Acta Oncol. 2014;53(5):620-627.

7. Steiner F, Evans J, Marsh R, et al. Mouth opening and trismus in patients undergoing curative

treatment for head and neck cancer. Int J Oral Maxillofac Surg. 2015;44(3):292-296.

8. LENT SOMA tables. Radiother Oncol. 1995;35(1):17-60.

9. Ozyar E, Cengiz M, Gurkaynak M, Atahan IL. Trismus as a presenting symptom in

nasopha-ryngeal carcinoma. Radiother Oncol. 2005;77(1):73-76.

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(5):548-555.

11. Wetzels JW, Merkx MA, de Haan AF, Koole R, Speksnijder CM. Maximum mouth opening and trismus in 143 patients treated for oral cancer: A 1-year prospective study. Head Neck. 2014;36(12):1754-1762.

12. Gebre-Medhin M, Haghanegi M, Robert L, Kjellen E, Nilsson P. Dose-volume analysis of radi-ation-induced trismus in head and neck cancer patients. Acta Oncol. 2016;55(11):1313-1317. 13. Dijkstra PU, Huisman PM, Roodenburg JLN. Criteria for trismus in head and neck oncology.

Int J Oral Maxillofac Surg. 2006;35(4):337-342.

14. Scott B, Butterworth C, Lowe D, Rogers SN. Factors associated with restricted mouth open-ing and its relationship to health-related quality of life in patients attendopen-ing a maxillofacial oncology clinic. Oral Oncol. 2008;44(5):430-438.

15. Swets JA. Measuring the accuracy of diagnostic systems. Science. 1988;240(4857):1285-1293. 16. Schisterman EF, Perkins NJ, Liu A, Bondell H. Optimal cut-point and its corresponding youden

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17. Wang CJ, Huang EY, Hsu HC, Chen HC, Fang FM, Hsiung CY. The degree and time-course assessment of radiation-induced trismus occurring after radiotherapy for nasopharyngeal cancer. Laryngoscope. 2005;115(8):1458-1460.

18. Nagaraja S, Kadam SA, Selvaraj K, Ahmed I, Javarappa R. Trismus in head and neck cancer patients treated by telecobalt and effect of early rehabilitation measures. J Cancer Res Ther. 2016;12(2):685-688.

19. Jager-Wittenaar H, Dijkstra PU, Vissink A, van Oort RP, Roodenburg JLN. Variation in repeated mouth-opening measurements in head and neck cancer patients with and without trismus. Int J Oral Maxillofac Surg. 2009;38(1):26-30.

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This chapter is an edited version of: van der Geer SJ, van Rijn PV, Kamstra JI, Langendijk JA,

van der Laan BFAM, Roodenburg JLN, Dijkstra PU. Prevalence and prediction of trismus in patients with head and neck cancer: A cross-sectional study. Head Neck. 2019;41(1):64-71.

Prevalence and prediction

of trismus in head and

neck cancer patients:

a cross-sectional study

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ABSTRACT

Purpose: Trismus occurs frequently in head and neck cancer patients. Determining the prevalence and associated factors of trismus would enable prediction of the risk of trismus for future patients.

Methods: Based on maximal mouth opening measurements, we determined the prevalence of trismus in 730 head and neck cancer patients. Associated factors for trismus were analysed using univariate analyses and multivariate logistic regression analyses. Based on the regression model, a calculation tool to predict trismus was made.

Results: Prevalence of trismus was 23.6%. Factors associated with trismus were: advanced age, partial or full dentition, tumours located at the maxilla, mandible, cheek, major salivary glands, or oropharynx, an unknown primary, a free soft tissue transfer after surgery, re-irradiation, and chemotherapy.

Conclusions: About one quarter of head and neck cancer patients develops trismus. Based on prevalence and associated factors of trismus, a simple calculation tool predicts the risk of trismus in these patients.

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INTRODUCTION

Trismus, also referred to as a restricted mouth opening, is a common problem in head and neck cancer patients.1_{Patients with trismus often perceive difficulties in performing} activities of daily living, such as eating, drinking, laughing, and kissing.2-5_{These difficulties} adversely affect their quality of life.2-7_{Moreover, as the access to the oral cavity is restricted,} intubation, dental treatment, and oncological follow-up may become more complicated.2,6,7 A wide variety in prevalence of trismus (ranging from 5% to 65%) and factors associated with trismus have been found due to narrow inclusion criteria (such as one single tumour localization5,8,9_{or one treatment modality}4,5,8-11_{), small sample sizes}8,9_{, and different} cut-off points for trismus.8,11,12

Due to this wide variety and lack of clarity about the prevalence of trismus and the associated factors, clinicians are uncertain about when to take precautionary measures to prevent trismus. If patients at risk for trismus could be identified early, they could potentially benefit from preventive measures. In this study, based on a large study population (n=730) with a variety of tumour and treatment characteristics, we therefore (1) determined the prevalence of trismus and (2) identified associated factors for trismus in head and neck cancer patients.

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MATERIALS AND METHODS

Patients

In this cross- sectional study, head and neck cancer patients were included, who visited the Department of Oral and Maxillofacial Surgery of the University Medical Center Groningen (Netherlands) between November 2012 and January 2015. Their maximal mouth opening was measured as part of routine care. Patients were included if they had a tumour located in the upper aero-digestive tract, unknown primaries with metastases in the head and neck region, or a major salivary gland tumour. Patients were excluded if they visited the Oral and Maxillofacial Surgery Department for a consultation, but were not diagnosed with head and neck cancer, or had a rare type of tumour, were younger than 18 years, or had missing data regarding maximal mouth opening (MMO) measurements. Our study was carried out according to the regulations of our institute. The Medical Ethical Committee of the University Medical Center Groningen concluded that our research was not subject to the Medical Research (Human Subject) Act (METc number 2016.692).

Maximal mouth opening measurement and dental status

The MMO was measured and recorded on a registration form by one of the Oral and Maxillofacial surgeons, nurse practitioners, or residents, using the OraStretch® Range-of-Motion Scale (Craniomandibular Rehab, Inc., Denver, USA) during a visit at the department of Oral and Maxillofacial Surgery. This visit could have taken place before or after head and neck cancer treatment. The OraStretch®_{Range-of-Motion Scale is a disposable paper} measurement tool, which measures MMO in millimetres (mm), with a scale range from 3 to 52 mm. Because OraStretch® _{Range-of-Motion Scale is limited to 52 mm, patients} with a MMO of 52 mm or more were measured using a sliding calliper (in mm).

Additionally, the dental status was recorded. Patients were recorded as “dentate”, when they had frontal dentition or wore prosthesis. The incisal edge of the right upper central incisor and the right lower central incisor was used as measurement point. Patients were recorded as “edentulous” if they had no frontal dentition and wore no prosthesis. The top of the alveolar ridge at the former location of the right upper and lower central incisor were used as measurement points. Patients were recorded as “partially edentulous”, if they had a frontal dentition or wore prosthesis in one jaw (upper or lower jaw) and had no dentition or wore no prosthesis on the other jaw (upper or lower jaw).

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Data

The following data were recorded on the registration form: patient ID number, date of birth, gender, dental status (dentate, partially edentulous, and edentulous), MMO measurement (mm), and date of measurement. Additional data was retrieved from the patient file in the hospital information system: tumour localization (tongue, floor of mouth, maxilla, mandible, cheek, major salivary glands, oropharynx, hypopharynx and larynx, lip, unknown primary, others), clinical T classification based on the Union for International Cancer Control (UICC) TNM classification 2009 (TX, T1-2, T3-4, unknown), squamous cell carcinoma (yes, no), surgery (no surgery, surgery, multiple surgical procedures), neck dissection (yes, no), reconstruction after surgery (no reconstruction, skin graft, soft tissue flap, plates, bony tissue flap), radiotherapy (no radiotherapy, radiotherapy, re-irradiation), chemotherapy (yes, no), and trismus therapy (yes, no). To classify the extension of the primary tumour, the clinical T (cT) classification was used instead of the pathological T (pT) classification, because the cT classification had least missing data. Not every tumour was treated surgically, so pT staging was often not available.

No reconstruction was recorded in case of primary wound closure or in case no surgery was performed. A soft tissue flap was recorded in case of a pectoralis major flap, nasolabial flap, or radial forearm flap. A bony tissue flap was recorded in case of a fibular osteocutaneous flap. Although the soft tissue flaps involve different procedures and are harvested from different locations, we have chosen to combine these flaps in the univariate and multivariate analyses in order to enable sufficient numbers in each group for analyses and preserve as much data as possible. Specified information about the soft tissue flaps will be displayed in the descriptive table (Table 1).

Statistics

Prevalence of trismus was calculated using the cut-off point of a MMO of 35 mm or less. Chi-Square test and t-test for independent samples were used to analyse the differences between patients with and without trismus in age, gender, dental status, cT classification, tumour localization, surgery, reconstruction after surgery, radiotherapy, and chemotherapy. Based on statistical significance (p<0.10), variables were entered in the multivariable logistic regression analyses. A p-value of 0.10 was chosen in order to prevent missing potential associated factors. Thereafter, variables with a p-value of >0.05 were removed stepwise. If the model fit improved significantly (based on the Omnibus Tests of Model Coefficients), the variables remained in the model. Interaction effects were explored as well. In the final model, the variable ‘age’ was standardized to

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improve clinical interpretation; the individual age was subtracted from the mean age of the study population. The validity of our final model was tested based on the assessment of discrimination (using the Area Under the Curve) and calibration (using the Hosmer- Lemeshow Test).

A risk score for trismus was calculated as the sum of the regression coefficients of our final logistic regression model. The reference categories were given a value of zero for their regression coefficients.

For the variable “standardized age”, the mean age was subtracted from the age of the patient. The standardized age was multiplied by the regression coefficient for the variable “standardized age”. For the interaction effect ‘standardized age*radiotherapy’, the standardized age is multiplied by the corresponding regression coefficient. The regression coefficient of the “constant” was always added to the calculation. We calculated a range of probabilities (P) based on the formula “ln (P/1-P) = risk score for trismus”. Using the calculated risk score for trismus, the risk for trismus for future patients can be estimated. Our study population consisted of patients who had had head and neck cancer. Of this study population, some patients had multiple tumours receiving multiple treatments. To verify the final logistic regression model, we also studied a population that only had one primary tumour.

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RESULTS

Study population

The MMO of 839 patients was recorded during visits at the department of Oral and Maxillofacial Surgery. In total, 109 patients were excluded because 78 patients were not diagnosed with head and neck cancer; 29 patients had rare types of tumours, and 2 patients had missing data regarding MMO measurement. Of the 138 patients who had a MMO of 52 mm or larger, 112 patients were measured with a sliding calliper and 26 patients were recorded as having a MMO of 52 mm, because a sliding calliper was unavailable at that time. Ultimately, the total study population consisted of 730 patients (87.0%) (Table 1). The results of the total study population are reported. The results of the study population with only primary tumours are reported in the supplementary tables and figures. The univariate analysis of the study population with only primary tumours differs from the univariate analysis of the total study population, as the variables dental status and surgery are not significantly associated with trismus (Table 2 and Supplementary Table 2). For the multivariate logistic regressions model the same variables are inserted into the model, to analyse which variables contribute significantly to the equation. The multivariate logistic regression model of the study population with only primary tumours shows that dental status contributes significantly to the equation. The interaction ‘standardized age*radiotherapy’ did not contribute significantly to the equation. (Table 3 and Supplementary Table 3).

Prevalence

In our study, 23.6% of the patients had trismus (n=172). Compared to patients without trismus, patients with trismus were older, were partially edentulous or dentate more frequently, had tumours located near the maxilla, mandible, cheek, oropharynx or had an unknown primary more frequently, had advanced tumours (T3, T4) more frequently, underwent multiple surgical procedures, neck dissections, and/or reconstruction after surgery more frequently, and received radiotherapy, re-irradiation, or chemotherapy more frequently (Table 2).

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Table 1. Patient, tumour and treatment characteristics of total study population (n=730).

Characteristics Number of patients

n (%) Patient characteristics

Male 388 (53.2)

Deceased 63 (8.6)

Age (years), Mean (SD) 63.6 (13.5)

Dental status Dentate 575 (79.4) Partially edentulous 45 (6.2) Edentulous 104 (14.4) Tumour characteristics Tumour localization Tongue 164 (25.4) Floor of mouth 92 (14.2) Maxilla 36 (5.6) Mandible 51 (7.9) Cheek 21 (3.3)

Major salivary glands 73 (11.3)

Oropharynx 111 (17.2)

Lip 54 (8.4)

Unknown primary 12 (1.9)

Hypopharynx and larynx 32 (5.0)

cT classification

T1,T2 450 (74.4)

T3,T4 155 (25.6)

Squamous cell carcinoma 510 (69.9)

Treatment characteristics Surgery

Surgery 444 (60.8)

Multiple surgical procedures 62 (8.5)

Neck dissection

Neck dissection 251 (34.4)

Multiple neck dissections 25 (3.4)

Reconstruction after surgery

Skin graft 118 (16.2)

Soft tissue flap 31 (4.2)

Soft tissue flap and reconstruction plate 11 (1.5)

Bony tissue flap 46 (6.3)

Radiotherapy

Radiotherapy 236 (32.3)

Re-irradiation 22 (3.0)

Chemotherapy 95 (13.0)

Exercise therapy 47 (6.5)

Missing values (no. of patients; %): dental status (6; 0.8), cT classification (125; 17.1), tumour localization (84; 11.5), squamous cell carcinoma (84; 11.5), neck dissection (1; 0.1), reconstruction (32; 4.4).

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Table 2. Comparison between patients with and without trismus.

Number of patients without trismus (n=558) Number of patients with trismus (n=172) n % n % χ² DF p Patient characteristics Male gender 304 54.5 84 48.8 1.681 1 0.195 Age 62.9a _13.6b _65.9a _12.9b _-3.0c _{-5.3; -0.7}d _0.011* Dental status 6.650 2 0.036 Dentate 437 79.0 138 80.7 Partially edentulous 29 5.2 16 9.4 Edentulous 87 15.7 17 9.9 Tumour characteristics Tumour localization 42.683 9 <0.001 Tongue 134 27.6 30 18.6 Floor of mouth 76 15.7 16 9.9 Maxilla 21 4.3 15 9.3 Mandible 30 6.2 21 13.0 Cheek 10 2.1 11 6.8

Major salivary glands 55 11.3 18 11.2

Oropharynx 74 15.3 37 23.0

Lip 50 10 4 2.5

Unknown primary 8 1.6 4 2.5

Hypopharynx and Larynx 27 5.6 5 3.1

cT classification 23.059 2 <0.001 T1, T2 360 79.3 90 59.6 T3, T4 94 20.7 61 40.4 Treatment characteristics Surgery Surgery 348 62.4 96 55.8 10.677 2 0.005

Multiple surgical procedures 37 6.6 25 14.5

Neck dissection

Neck dissection 173 31.1 78 45.3 15.791 2 <0.001

Multiple neck dissections 16 2.9 9 5.2

Reconstruction after

surgery 25.083 4 <0.001

Skin graft 85 16.0 33 19.8

Soft tissue flap 16 3.0 15 9.0

Soft tissue flap and

reconstruction plate 7 1.3 4 2.4

Bony tissue flap 27 5.1 19 11.4

No reconstruction 396 74.6 96 57.5

Radiotherapy

Radiotherapy 163 29.2 73 42.4 13.926 2 0.001

Re-irradiation 14 2.5 8 4.7

Chemotherapy 59 10.6 36 20.9 12.458 1 <0.001

%: column percentage, χ²: Results of Chi-Square test, DF: Degrees of freedom, a: mean, b: standard deviation, c: difference in means, d: 95% confidence interval, *: t- test for independent samples.

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Table 3. Results of multivariate logistic regression analysis to identify the contribution of factors

associated with trismus.

β OR 95% Confidence Interval Sig. Lower Upper Patient characteristics Age * 0.030 1.031 1.006 1.055 0.013 Dental status 0.002 Dentate 1.186 3.274 1.679 6.382 0.000 Partially edentulous 1.254 3.504 1.346 9.123 0.010 Edentulous RC† _0.000 _1.000 Tumour characteristics Tumour localization 0.000 Tongue 0.702 2.018 0.680 5.985 0.206 Floor of mouth 0.286 1.331 0.405 4.374 0.637 Maxilla 1.736 5.673 1.610 19.991 0.007 Mandible 1.586 4.883 1.407 16.941 0.012 Cheek 2.062 7.858 1.854 33.299 0.005

Major salivary glands 1.166 3.208 0.994 10.355 0.051

Oropharynx 1.154 3.171 1.079 9.323 0.036

Lip -0.311 0.733 0.171 3.138 0.675

Unknown primary 1.685 5.392 1.054 27.577 0.043

Hypopharynx and Larynx RC† _0.000 _1.000

Treatment characteristics

Reconstruction after surgery 0.010

Skin graft 0.492 1.636 0.921 2.908 0.093

Soft tissue flap 1.403 4.067 1.739 9.511 0.001

Plates 0.596 1.816 0.411 8.017 0.431

Bony tissue flap 0.844 2.326 1.036 5.223 0.041

No reconstruction RC† _0.000 _1.000 Radiotherapy 0.000 Radiotherapy 0.974 2.648 1.622 4.324 0.000 Re-irradiation 1.756 5.789 1.757 19.070 0.004 No radiotherapy RC† _0.000 _1.000 Chemotherapy 1.418 4.129 2.210 7.715 0.000 Interaction effect Age * x Radiotherapy ‡ _0.039 Age * x Radiotherapy ‡ _-0.001 _0.999 _0.966 _1.034 _0.968 Age * x Re-irradiation ‡ _-0.137 _0.872 _0.784 _0.970 _0.011 Constant Constant -3.999 0.018 0.000

* age is standardized; the mean age of 63.6 will be subtracted from the individual age.

†RC: Reference category (variable): edentulous (dental status); hypopharynx and larynx (tumour localization); no reconstruction (reconstruction); no radiotherapy (radiotherapy). ‡: interaction effect of standardized age and radiotherapy.