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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Publication date:

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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This chapter is an edited version of: van der Geer SJ, van Rijn PV, Roodenburg JLN, Dijkstra PU. Prognostic factors for a restricted mouth opening (trismus) in head and neck cancer patients: a systematic review.

[Currently submitted to journal Head&Neck]

Prognostic factors for a restricted

mouth opening (trismus) in head

and neck cancer patients:

a systematic review

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96

ABSTRACT

Purpose: To prescribe early trismus therapy, prognostic factors influencing the restricted mouth opening should be identified first. Our aim is to present an overview of these factors in head and neck cancer patients.

Methods: Pubmed, Cochrane, EMBASE and CINAHL were searched using terms related to head and neck cancer and mouth opening. Risk of bias was assessed using the ‘Quality in Prognosis Studies’ tool. A best evidence synthesis was performed.

Results: Of the identified 1418 studies, 53 were included. Three studies had built a prognostic multivariate model for a restricted mouth opening.

Conclusions: Head and neck cancer patients will most likely develop a restricted mouth opening when they have a large tumour near the masticatory muscles that requires extensive cancer treatment. A restricted mouth opening most likely occurs within six months after cancer treatment. Further research is necessary on factors related to healing tendency or pain intensity.

Registration: Prospero CRD42017071400.

Acknowledgments:

We would like to thank S. van der Werf for her assistance with building the best possible search strategy for this review; K. Delli and B. Gareb for their input and assessment of risk of bias; K.C. Bragante and J.W. Wetzels for sharing data of their studies, X. Lu for translation of an article.

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97

INTRODUCTION

Trismus, a restricted mouth opening, is considered to be one of the three most

burdensome side effects after head and neck cancer treatment.1-3_{Daily activities, such}

as speaking, eating, and swallowing, become more difficult.4-6_{As a consequence, trismus}

impacts the quality of life.7,8

In order to prevent or to treat trismus, stretching regimens are often prescribed to increase

mouth opening.9_{In 2016, a systematic review analysed the effects of various stretching}

regimens, but none of them was found to be superior.10_{It has been suggested that early}

initiation of a therapy for trismus results in a greater improvement in mouth opening.11

However, when the effectiveness of an early, preventive stretching regimen was analysed,

no significant difference between the exercise group and control group was found.12_{Not all}

the patients may have been at risk for trismus, which would have hindered the detection of the effectiveness of the therapy. Moreover, the group of patients not at risk of developing trismus was unnecessarily burdened with an intensive stretching regimen.

Thus, factors influencing trismus should be identified so that only the patients at risk for trismus are subjected to therapy. Previous studies examined the factors associated with trismus but the criteria they applied varied (e.g., a maximal mouth opening (MMO) of

less than 20 mm13_{or less than 35 mm}14_{). They used different assessment methods (e.g.,}

objective measurement using a millimetre scale15,16_{or perceived difficulties opening the}

mouth using questionnaires17,18_{), or different study populations (e.g., patients receiving}

radiotherapy15,19_{or chemoradiotherapy}19,20_{). There is no recent systematic review available}

on prognostic factors for trismus in head and neck cancer patients in general.

The aim of this systematic review is to identify the prognostic factors for trismus (measured objectively and subjectively) in patients treated for head and neck cancer.

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98

MATERIALS AND METHODS

The protocol for this systematic review is registered in Prospero (Register code: CRD42017071400). The study will be reported according to the PRISMA statement.

Literature Search

Four databases were searched for eligible studies: PubMed, Cochrane, EMBASE and CINAHL. The search strategy was developed in cooperation with an information specialist and included MesH terms and free text regarding head and neck cancer and mouth opening (Supplementary text 1). All the databases were searched in November 2017. An update was performed in July 2019.

Eligibility criteria

Prospective longitudinal studies were included if at least two measurement moments, regarding objective measurements of trismus (trismus and MMO) or subjective assessments of trismus (perceived difficulties with opening the mouth), were reported. No distinction was made between active or passive mouth opening measurements. Studies of trismus therapies were excluded, unless they reported data on a restricted mouth opening of a control group that did not receive a form of trismus therapy. (Systematic) reviews, in vitro studies, comments, letters to the editor and case reports of less than 10 patients were excluded. There were no language or time restrictions. Studies written in languages that could not be understood by the authors were translated. Additionally, a full-text version had to be available in order to be included for further assessment and data extraction.

Study selection

After removing any duplicates, the titles and abstracts were assessed for inclusion independently by JG, PR and PD. JG and PD independently assessed the full text versions for inclusion. Any disagreements between them were resolved by discussion. In case no consensus could be reached, a third observer (KD) was consulted. Inter-observer reliability was measured through Cohen’s Kappa and percentage of agreement.

Google Scholar, the references of the relevant systematic reviews and the references of the eligible studies were checked by JG for studies missed in the database search. When a study was considered eligible, the full text paper was screened and assessed by JG and PD independently, according to the original protocol.

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99 The studies that only reported descriptive data and did not perform any statistical tests to analyse the influence of factors on trismus, MMO, or perceived difficulties opening the mouth, were excluded.

Data extraction

One reviewer (JG) extracted all required information from the studies, which included sample size, patient characteristics (age, gender), tumour characteristics (tumour localization, T classification, N classification, tumour stage, histology), treatment characteristics (treatment modality), and method of outcome measurements (number of measurement points reported, follow-up time). Percentage of patients with trismus (based on a cut-off point), difference in means or medians of MMO between two measurements (one measurement after treatment minus measurement before treatment) were recorded. In case of multivariate prognostic models, the estimated effects and 95% confidence intervals were extracted.

A second reviewer (PD) extracted data from a random sample of eight studies containing only univariate analyses and the three studies containing multivariate analyses. In case any data was missing or needed clarifying, the corresponding authors were contacted by e-mail.

Risk of bias assessment

Included studies were assessed by JG and PD on risk of bias using the ‘Quality In

Prognosis Studies’ tool (QUIPS).21_{This tool is designed to assess the risk of bias in}

prognostic studies. The tool assesses the following items: study participation, study attrition, prognostic factor measurement, outcome measurement, study confounding, and statistical analysis and reporting. The risk of bias can be scored low, moderate or high. We added the option “not applicable” which could be chosen in case the studies did not provide adequate information to be able to assess that specific domain. As attrition is commonly high in studies including head and neck cancer patients due to early decease, we predefined the following criteria: when the study attrition is more than 20%, but no specifications are given, we assessed the study as high risk of bias on the study attrition domain. When the study attrition is more than 20%, but specifications are given, we assessed the study as moderate risk of bias on the study attrition domain. For the statistical analysis and reporting domain, we scored a high risk of bias if the effect of only one factor on restricted mouth opening was analysed.

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100

JG and PD were authors of two studies. These studies were assessed by two independent assessors, KD and BG, to reduce the risk of assessor bias.

To assess the overall risk of bias of a study, it was recommended to score the overall risk of bias as “low” if at least all, or the most important domains (determined a priori),

were rated as having a low risk of bias.21_{On that basis, we determined the overall risk of}

bias to be low, if at least 5 out of 6 domains were scored with a low risk of bias and the domains “study confounding” and “statistical analysis and reporting” were scored with a low risk of bias. These two domains are of major importance for analysing the influence of factors on trismus, MMO or perceived difficulties opening the mouth.

In case of disagreement between the reviewers, a consensus meeting was held. If no consensus could be reached, a third reviewer (KD) gave a binding verdict.

Best evidence synthesis

Due to clinical and methodological heterogeneity between the included studies, we did not perform a meta-analysis. Instead, we performed a best evidence synthesis. Three main domains were taken into account in order to rate the level of evidence:

quality, quantity and consistency.22,23_{We determined the evidence to be strong if two or}

more studies (quantity) with an overall low risk of bias (quality) and relatively consistent findings (consistency) of the analysed factors across the studies was found. Evidence was determined to be moderate when evidence was provided including one study with an overall low risk of bias and relatively consistent findings of the analysed factors across the studies. Evidence was determined to be limited when evidence was provided by studies with an overall high risk of bias and relatively consistent findings of the analysed factors across the studies. Evidence was determined to be limited/moderate when evidence was provided by a study with an overall high risk of bias, but in which a multivariate prognostic model was presented. The evidence was determined to be conflicting in case there were inconsistencies between the findings of the analysed factors found across the studies.

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101

RESULTS

Study selection

The first search resulted in 1703 hits. After duplicate removal, 1199 papers were included for title and abstract assessment (Cohen’s Kappa: 0.533, agreement 90%). Although 141 were deemed suitable for full text assessment after a consensus meeting (Cohen’s Kappa: 0.577, agreement 81%), 40 papers were excluded: 37 were abstracts only (e.g., conference abstract or poster abstract), one was a review, one was a comment in a forum, and one full- text could not be retrieved. The corresponding author was requested to provide the full text article, but no response was received. A further 59 of the available full text papers were excluded because they did not fulfil the inclusion criteria.

The additional check in Google Scholar and the references of the relevant studies and

(systematic) reviews, resulted in 16 other papers.5,17,24-37_{After reading the full text, two}

did not meet the inclusion criteria.20,24_{A total of 56 studies were included for risk of}

bias assessment and data extraction. During the data extraction process, an additional 7 studies were excluded, because no statistical analysis was performed to identify any

factors influencing trismus (n=4)27,38-40_{or because exercises to increase mouth opening}

had been undertaken (n=2)26,41_{, or because only one measurement moment was reported}

(n=1)42_{(Figure 1).}

After an update of the search and the removal of duplicates, 203 additional papers were identified. After assessing the titles and abstracts (Cohen’s Kappa: 0.378, agreement 80%), were included for assessment of the full text (Cohen’s Kappa: 0.493, agreement 76%).

Eventually, four of those studies were included. 43-46

The above procedures resulted in a final selection of 53 studies.5,13-20,28-37,43,45-77

Study characteristics

Sample sizes ranged from 14 to 641 patients (Table 1). The number of measurement moments ranged from 2 to 20. The longest follow-up period was 5 years.

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Figure 1. Flow chart.

1199

141

42

56

Titles and abstract Exclusion: 1058 Full Text Not available: 40* Exclusion: 59 Additional search Inclusion: 16

Excusion after consensus: 2 PubMed

777 Cochrane62 EMBASE769 Cinahl95

Total 1703 49 Duplicates Exclusion: 504 Post-hoc

Exclusion: 7, because of: - no statiscal analysis:4 - Trismus exercises given: 2 - one measurement moment: 1

53 Update July 2019

Inclusion: 4

*: studies were not available, because: 37 were abstracts only (e.g. conference abstract or poster abstract), one was a review, one was a comment in a forum, and one full- text could not be retrieved.

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103 Ta bl e 1 . D at a e xtr ac tio n o bj ec tiv e a nd su bj ec tiv e m ea su re m en ts . A ut ho r ( ye ar) Samp le si ze (n) Ag e M ea n (S D ) O R M ed ia n [r an ge ] R at io M al e: Fe m al e H is tolo gy Tum our lo ca liz at io n St ag e Tr ea tm en t m oda lit y * #m ea su re s † FU ‡ R em ar ks O bj ec ti ve m ea su re m en ts - c ut -o ff p oi nt f or t ri sm us Ya n e t a l ( 20 03 ) 13 11 2 44 .6 [1 4-7 1] 83: 29 -N as op ha ry nx I-IV RT 7 60 Sc ot t e t a l ( 201 1) 14 64 59 (1 0) 40:2 4 SCC O ra l ca vi ty , O ro ph ar yn x T: 1-4 N :0 ,+ S, (C )R T 3 6 Le e e t a l ( 201 2) 47 152 -HN C Di sea se :1 -4 S, (C )R T 3 >6 Pa ul i e t a l ( 201 3) 48 75 62 [3 5-86 ] 45: 30 -HN C T: 0 -4 U ICC :I-IV S, (C )R T 4 12 P: P au li e t a l (20 16 ) 49 Pa ul i e t a l ( 201 6) 49 216 60 [2 9-87] 155 :6 2 -HN C T: x-4 (C )RT 4 12 va n d er G ee r e t a l (2 016 ) 50 641 62. 3 ( 12. 5) 451 :1 90 -HN C T: x-4 S, (C )RT 7 48 T: K am st ra e t a l (20 15 ) 15 O bj ec ti ve m ea su rem en ts m ax im al m ou th o pen in g m ea su rem en ts G ol ds te in e t a l ( 19 99 ) 51 58 -HN C -RT 2 6-1 2 W an g e t a l ( 20 05 ) 52 17 <5 0y ( n= 8) , > 50 y ( n= 9) 13: 4 -N as op ha ry nx T: 1-4 N :0 -3 D ise ase :I-I II RT 20 48 B ra ga nt e e t a l ( 201 2) 54 26 59 .0 ( 8. 8) [ 45 -7 4] 26 :0 -HN C INC A :I-IVB (C )RT 3 0 M uc ke e t a l ( 201 2) 55 96 62 .8 ( 8. 9) [4 1-82 ] 58 :3 8 SCC an te rio r f lo or of the mo ut h T: 1-4 N :0 -3 S, (C )R T 2 2-24 Ly on s e t a l ( 201 3) 56 62 <5 0y ( n= 26 ), ≥5 0y (n =3 6) b 33: 29 -HN C T: 1-4 N :0 -3 S, (C )RT 2 12-36 La za ru s e t a l ( 201 4) 57 29 58 .5 ( 9. 2) [4 1-7 8] 23: 6 -HN C A JC C: I-IVA (C )R T 3 6 Sa fd ar e t a l ( 201 4) 58 65 G ro up 1: 5 9. 7( 11 .5 ) Gr ou p2 : 6 0. 6( 13 .4 ) 45: 20 -HN C T: 1-4 S 2 6 G ro up 1: pl at ys m a re co ns tr uc tio n Gr ou p2 : su bm en ta l re co ns tr uc tio n

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104 Ta bl e 1 . (C on tin ue d) A ut ho r ( ye ar) Samp le si ze (n) Ag e M ea n (S D ) O R M ed ia n [r an ge ] R at io M al e: Fe m al e H is tolo gy Tum our lo ca liz at io n St ag e Tr ea tm en t m oda lit y * #m ea su re s † FU ‡ R em ar ks W et ze ls e t a l ( 201 4) 16 143 Gr ou p1 : 6 8. 4( 12 .2 ) G ro up 2: 6 6.9 (1 2. 6) G ro up 3: 6 2. 3 ( 12 .9 ) G ro up 1: 17 :17 Gr ou p2 : 28 :26 Gr ou p3 : 33: 22 -O ra l ca vi ty T: 1-4 S, RT 4 12 G ro up 1: m ax ill a Gr ou p2 : m an di ble Gr ou p3 : to ng ue / f lo or o f mou th B ra ga nt e e t a l ( 201 5) 53 56 58 .7 (1 0. 8) 52 :4 -UA D T Di sea se : I – IV S, (C )RT 2 0 Fo ng e t a l (2 01 5) 59 27 5 8.7 (9 .5 ) 16 :1 1 -N as op ha ry nx A JCC :I-IV S, (C )RT 4 12 A I Co nt ro l G ro up onl y K am st ra e t a l ( 201 5) 15 641 62. 3 ( 12. 5) 451 :1 90 -HN C T: 0-4, N :0 -3 S, (C )RT 7 48 M an ak tal a e t al (2 015 ) 60 24 -HN C RT 5 18 G y N ay ar e t a l ( 201 6) 61 55 -HN C -S, RT 2 1-2 A l-Sa le h e t a l ( 201 7) 43 16 G ro up 1: 5 4. 2( 12 .5 ) G ro up 2: 5 0. 6(1 1.9 ) G ro up 1: 6 :3 G ro up 2:5 :2 -O ra l c av ity , O ro ph ar yn x T: 1-4 N :0 -3 S 2 1. 5-2 Gr ou p1 m an di bul oto m y sur ge ry G ro up 2 tra ns ora l sur ge ry La lla e t a l (2 01 7) 62 37 2 59 .8 (1 0. 9) 28 4: 88 SCC HN C -S, (C )RT 2 6 Th or e t a l ( 201 7) 63 19 6 60 (1 1) 141 :5 5 -HN C T: 0-4 N :0 -4 (C )RT 4 12 P: P au li e t a l (20 16 ) 57 Su bj ec ti ve m ea su rem en ts D e G ra ef f e t a l ( 19 99 ) 17 75 60 [2 9-7 5] 54 :21 SCC O ra l c av ity , O ro ph ar yn x A JCC :I-IV S, RT 3 12 P: D e G ra ef f e t al (20 00 ) 29 D e G ra ef f e t a l ( 20 00 ) 29 10 7 60 [3 1-7 3] 86 :21 SCC HN C A JCC :0 -I V S, RT 5 36 Ep st ei n e t a l ( 20 00 ) 5 35 7 63 [1 8-88] 25 6: 10 1 -HN C D ise ase :I-I V S, (C )R T 6 12 B jo rd al e t a l ( 20 01 ) 28 20 53 .4 [38 -7 8] 12 :8 -HN C A JCC :I-IV RT 3 6

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105 Ta bl e 1 . (C on tin ue d) A ut ho r ( ye ar) Samp le si ze (n) Ag e M ea n (S D ) O R M ed ia n [r an ge ] R at io M al e: Fe m al e H is tolo gy Tum our lo ca liz at io n St ag e Tr ea tm en t m oda lit y * #m ea su re s † FU ‡ R em ar ks H amm erl id e t al (2 00 1) 18 232 61 [18 -8 5] 16 2: 70 -HN C D ise ase :I-I V S, (C )R T 5 36 O hr n e t a l (2 001 ) 33 18 55 .4 (9 .0 ) [38 -7 3] 10 :8 SCC ACA HN C -(C )RT 4 1 W ilt fa ng e t a l ( 20 03 ) 34 53 54 .2 [34-78 ] 48 :5 SCC O ra l ca vi ty U IC C: 0-IV S, (C )RT 4 24 Fa ng e t a l ( 20 04) 30 77 50 [2 2-7 8] 77: 0 SCC HN C A JC C: III ,IV S, R T 2 24 P: F an g e t a l (20 05 ) 31 A be nd st ei n e t a l (2 00 5) 64 16 7 61 [1 8-86] 11 6: 51 -HN C D ise ase :I-I V S, (C )R T 3 60 P: B jo rd al e t a l (20 01 ) 28 Fa ng e t a l ( 20 05 ) 31 14 9 53 [2 5-81] 13 8: 11 SCC HN C A JC C: III ,IV (C )RT 2 12 N ord gren e t a l( 20 05 ) 32 60 G ro up 1: 5 6 G ro up 2: 57 -HN C T: 2-4 N : 0 ,+ A JC C: III ,IV (C )R T 3 1 G ro up 1: 72 G y, 6w k Gr ou p2 :8 0. 4 G y, 7w k U rd an iz e t a l ( 20 05 ) 37 89 60 68 :21 -Ph ar yn x D ise ase :I-I V S, (C )RT 4 60 P: B jo rd al e t a l (20 01 ) 28 B or gg re ve n e t a l (2 00 7) 65 80 58 [2 3-7 4] 47: 33 SCC O ra l c av ity , O ro ph ar yn x T:2 -4 , N :0 -3 S, RT 3 12 O at es e t a l ( 20 07 ) 20 14 -N as op ha ry nx T: 1-4 N : 0 -3 (C )R T 5 24 B oz ec e t a l ( 20 08) 66 65 61 .2 (9 .3) [4 0-85 ] 49 :16 -HN C T: 2 -4 N :0 -3 S, RT 3 12 B oz ec e t a l ( 20 09 ) 67 41 62 .3 ( 9 .6 ) [43 -8 5] 33: 8 SCC O ra l c av ity , O ro ph ar yn x T:2 -4 N :0 -3 A JCC :II -I V S, (C )R T 3 12 P: B oz ec e t a l (20 09 ) 67 R iz vi e t a l ( 20 09 ) 68 37 51. 8 ( 9. 6) 18: 19 -HN C T: 3, 4 N :1, 2 S, RT 4 6 Verg eer e t a l ( 20 09 ) 35 241 G ro up 1: ≤65 y( n= 95 ),> 65 y (n =5 5) Gr ou p2 :≤ 65 y(n = 68 ),> 65 y(n =2 3) G ro up 1: 10 4: 46 Gr ou p2 : 51 :4 0 SCC HN C T: 0-4 N :0 -3 , U ICC :I-IV S, (C ) RT 5 12 G ro up 1: 3 D -R T G ro up 2 : I M RT

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106 Ta bl e 1 . (C on tin ue d) A ut ho r ( ye ar) Samp le si ze (n) Ag e M ea n (S D ) O R M ed ia n [r an ge ] R at io M al e: Fe m al e H is tolo gy Tum our lo ca liz at io n St ag e Tr ea tm en t m oda lit y * #m ea su re s † FU ‡ R em ar ks Yo sh im ur a e t a l (2 00 9) 69 56 63 [25 -8 8] 46 :10 SCC O ra l ca vi ty T: 1-3 LD R-B T 4 12 Ch an e t a l ( 201 2) 36 18 5 50 .2 (11 .4 ) [2 4-81] 151 :3 4 Re cu rr ent N as op ha ry nx -S,( C )R T 2 6 Al -M am gan i e t al (2 01 3) 70 20 7 < 65 y ( n= 14 2) , ≥ 65 y ( n= 65 ) 143 :6 4 -O ro ph ar yn x T: 1-4 N :0 -3 A JCC :I-IV (C )RT 5 18 K um ar e t a l ( 201 3) 74 60 G ro up 1: 55 [33 -6 5] Gr ou p2 : 51 [3 1-65 ] G ro up 1: 25: 3 Gr ou p2 : 29 :3 SCC HN C T: 1-3 N :0 -2 b A JCC : I -I V RT 6 24 G ro up 1: 3 D -R T G ro up 2: IMR T R at ho d e t a l ( 201 3) 71 83 G ro up 1: 5 2. 0 [2 2-81] Gr ou p2 : 5 3. 4 [2 8-76] G ro up 1: 28 :15 Gr ou p2 : 27: 13 -N as op ha ry nx T: 4 N :3 U IC C:2 -4 (C )R T 5 24 G ro up 1: C RT + E RF Gr ou p2 : C RT Zh ao e t a l (2 01 4) 72 40 56 [2 0-65 ] 33 :7 -HN C St ag e: I-IVA S, (C )RT 3 3 A rs la n e t a l ( 201 5) 73 111 Gr ou p1 : 5 5. 3 ( 12 .4 ) G ro up 2: 5 3. 4 ( 11 .2) G ro up 1: 47: 8 Gr ou p2 : 49 :7 SCC HN C St ag e: 3-4b (C )RT 3 6 La nd st ro m e t a l (2 015 ) 75 19 56 .6 12 :7 SCC ACA HN C T: 1, 2 (C )R T 2 12 R ao e t a l ( 201 6) 19 42 1 ≤5 5y ( n= 19 1) , > 55 y ( n= 23 0) 34 5: 76 SCC Ph ar yn x, La ry nx T: 1-4 N :0 -3 A JCC : I I-IV (C )R T 12 M ed 33 D zi ob a e t a l ( 201 7) 76 117 58 .2 (1 3. 3) 71 :4 6 SCC Ton gue (or al ca vi ty ) T: 1-4 A JC C: I-IVA S, (C )R T 4 12 G ao e t a l ( 201 8) 77 77 < 60 y ( n= 48 ), ≥6 0y (n =2 9) 41 :3 6 SCC ACC Ton gue -S 3 12 Tr ib iu s e t a l ( 201 8) 46 161 60. 4 ( 10. 4) 11 0: 51 HN C U IC C T :1 -4 N :0 -3 RT 3 24 BL= AT

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107 Ta bl e 1 . (C on tin ue d) A ut ho r ( ye ar) Samp le si ze (n) Ag e M ea n (S D ) O R M ed ia n [r an ge ] R at io M al e: Fe m al e H is tolo gy Tum our lo ca liz at io n St ag e Tr ea tm en t m oda lit y * #m ea su re s † FU ‡ R em ar ks Ve lu th at ti l e t a l (2 01 9) 45 25 ≤6 0y ( n= 21 ), > 60 y ( n= 4) 11 :14 SCC O ra l ca vi ty St ag e: 4A -4 C RT 2 2 *: t he t ex t i n b ol d i nd ic at es t ha t a ll t he p at ie nt s i n t hi s s tu dy r ec ei ve d t ha t p ar tic ul ar t re at m en t m od al ity . †: n um ber o f m ea su rem en t po in ts repo rt ed ‡: f ol lo w -u p p er io d ( in m on th s a ft er t re at m en t) §: c al cu la te d f ro m d at a r ep or te d. A bbr ev ia tion s: H is to lo gy ; S CC : s qu am ou s c el l c ar ci no m a, A CA : a de no ca rc in om a, A CC : a de no id c ys tic c ar ci no m a. Tu m ou r l oc al iz at io n; H N C: h ea d a nd n ec k c an ce r, U A D T: u pp er a er o-di ge st iv e t ra ct . St ag e: T : T um ou r c la ss ifi ca tio n, N : n od es cl as si fic at io n, U IC C: s ta ge a cc or di ng t o U ni on f or I nt er na tio na l C an ce r C on tr ol , I N CA : s ta ge a cc or di ng t o I ns tit ut o N ac io na l d e C ân ce r ( N at io na l I ns tit ut e o f C an ce r B ra zi l), A JC C: s ta ge a cc or di ng t o A m er ic an J oi nt C om m itt ee o n C an ce r. Tr ea tm en t m od al ity ; S: s ur ge ry , RT : r ad io th er ap y, C : c he m ot he ra py , ( C) RT : c he m or ad io th er ap y, L D R-BT : l ow -d os e-ra te i nt er st iti al b ra ch yt he ra py . Re m ar ks ; P : p ar tia l o ve rla p of s tu dy po pu la tio n, T: To ta l o ve rla p o f s tu dy p op ul at io n, A I: af te r in te rv en tio n, G y: G ra y of r ad ia tio n, w k: w ee k, 3D -R T: th re e-di m en si on al ra di ot her ap y, IM RT : i nt en si ty m od ul at ed ra di ot her ap y, E RF : e xt ra co rpo re al ra di of re qu en cy .

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Risk of bias assessment

The overall Cohen’s Kappa bias assessment score was 0.310 (52% agreement). The source or study population was not described (adequately) in the majority of the studies. These studies were scored with “N/A” on the study participation domain (n=32; 60%) (Table

2).5,13,16,18,20,28,30,32,36,37,43,45-47,51-58,60,61,64,65,68,69,72,73,75,77_{Eleven studies (21%) did not report attrition}

rate.13,19,33,35,51,55,61,70,72,73,77_{Some did not report the attrition rate because only the patients}

with complete data were included. Four studies (8%) were scored with “N/A” on the

outcome measurement domain14,16,55,60_{: two studies did not describe the measurement}

method 55,60_{and two studies used a non-validated measurement method (extra-oral}

measurements) 14,16_{. The majority of the studies were scored with a high risk of bias}

concerning the statistical analysis and reporting domain (n=42; 79%) because they lacked

a multivariate analysis.5,13,14,17,18,20,28-37,43,45-47,51,52,54-58,60-68,70,72-75,77

Distinguishing the outcome measurements

A distinction was made between objective (e.g., using a ruler or calliper) or subjective (e.g., using a patient’ questionnaire) assessments of restricted mouth opening. An additional distinction was made between the objective studies, namely using a restricted mouth opening

as a cut-off point (n=6)13,14,47-50_{or a decrease in MMO measured in millimetres (n=16).}15,16,43,51-63

The subjective analyses assessed the perception of a restricted mouth opening either

using the EORTC QLQ H&N35 (n=29)17,18,20,28-37,45,46,64-77_{or an addendum similar to the}

EORTC QLQ H&N35 (n=1)5_{or Common Terminology Criteria for Adverse Events (CTCAE)}

(n=1).19_{The Gothenburg Trismus Questionnaire (GTQ) (n=3) was used as a secondary}

endpoint to assess trismus.48,49,63

Univariate analyses

In 16 studies, a single prognostic factor for a decrease in MMO and the patients’ perception

of difficulties with opening the mouth was analysed over time (Table 3).

14,16,35,43,46,53-58,62,65,71,72,74_{Regarding patient related factors, a significant effect was found in relation to}

gender (in one study in the period between before and after treatment)14_{and the -509}

genotype.56_{Patients with a homozygous T allele (TT) in the -509 genotype had a greater}

reduction in MMO than those with a homozygous C allele (CC) or heterozygous C allele (CT). Tumour related factors included large reductions in MMO when the tumour was

located near the oral cavity or oropharynx.53,54_{Less reduction was found in other areas,}

such as the nasopharynx, hypopharynx, larynx, or lymph drainage areas.53,54_{No significant}

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109 also resulted in a reduction in MMO, with the most occurring after chemoradiotherapy

and the least after surgery.14_{The MMO decreased directly after surgery but increased}

in the six months thereafter. When patients received (chemo) radiotherapy, the MMO decreased directly after the treatment, but did not increase in the six months thereafter.

The MMO decreased even more with an increase in radiation dose.54

Patients who were given conventional three-dimensional radiotherapy, instead of

intensity modulated radiotherapy, perceived more difficulties opening the mouth.35,71

Also, patients who underwent chemotherapy without the addition of extracorporeal radiofrequency perceived more difficulties with opening the mouth compared with

those who received additional extracorporeal radiofrequency.72_{Regarding the remaining}

factors, a greater reduction in MMO was found when mucositis was present compared

to when mucositis was not present.53_{MMO was not significantly reduced in relation to}

alcohol consumption and smoking factors.16_{Patients with a lower social economic status}

perceived more difficulties with opening the mouth than patients with a middle or high

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110

Table 2. Quality assessment using the QUIPS tool.

Author (year) Study partici-pation

Study

Attrition Prognostic Factor Measure-ment Outcome measure-ment Study Con-fouding Statistical Analysis and Reporting Overall risk of bias

Objective measurements – cut- off point for trismus

Yan et al (2003) 13 _N/A _N/A _L _L _H _H _H

Scott et al (2011) 14 _H _H _L _N/A* _L _H _H

Lee et al (2012)47 _N/A _H _L _L _M _H _H

Pauli et al (2013)48 _M _L _L _L _L _M _H

Pauli et al (2016)49 _L _M _M _L _M _M _H

van der Geer et al (2016)50 _M _H _L _L _M _L _H Objective measurements - maximal mouth opening measurements

Goldstein et al (1999) 51 _N/A _N/A _L _L _M _H _H

Wang et al (2005) 52 _N/A _M _L _L _H _H _H

Bragante et al (2012) 54 _N/A _M _L _L _M _H _H

Mucke et al (2012)55 _N/A _N/A _L _N/A _H _H _H

Lyons et al (2013)56 _N/A _M _L _M _L _H _H

Lazarus et al (2014) 57 _N/A _M _L _L _H _H _H

Safdar et al (2014) 58 _N/A _L _L _L _H _H _H

Wetzels et al (2014) 16 _N/A _M _L _N/A* _L _L _H

Bragante et al (2015) 53 _N/A _L _L _L _L _L _L

Fong et al (2015) 59 _H _M _L _L _H _M _H

Kamstra et al (2015)15 _L _H _L _M _M _L _H

Manaktala et al(2015) 60 _N/A _L _L _N/A _H _H _H

Nayar et al (2016)61 _N/A _N/A _L _L _H _H _H

Al-Saleh et al (2017) 43 _N/A _H _L _M _H _H _H

Lalla et al (2017) 62 _H _H _L _M _H _H _H

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111

Table 2. (Continued)

Author (year) Study

partici-pation

Study

Attrition Prognostic Factor Measure-ment Outcome measure-ment Study Con-fouding Statistical Analysis and Reporting Overall risk of bias Subjective measurements De Graeff et al (1999)17 _L _M _L _L _H _H _H De Graeff et al (2000) 29 _L _M _L _L _M _H _H Epstein et al (2000) 5 _N/A _H _L _L _M _H _H Bjordal et al (2001)28 _N/A _L _L _L _H _H _H Hammerlid et al 2001) 18 _N/A _L _L _M _L _H _H Ohrn et al (2001) 33 _M _N/A _L _L _H _H _H Wiltfang et al (2003) 34 _L _M _L _L _H _H _H Fang et al (2004) 30 _N/A _M _L _L _H _H _H Abendstein et al (2005)64 _N/A _L _L _L _M _H _H Fang et al (2005) 31 _L _L _L _L _H _H _H

Nordgren et al(2005) 32 _N/A _M _L _L _M _H _H

Urdaniz et al (2005)37 _N/A _L _L _L _M _H _H Borggreven et al (2007) 65 _N/A _L _L _L _M _H _H Oates et al (2007)20 _N/A _L _L _L _H _H _H Bozec et al (2008) 66 _L _H _L _L _L _H _H Bozec et al (2009) 67 _L _M _L _L _L _H _H Rizvi et al (2009) 68 _N/A _L _L _M _H _H _H Vergeer et al (2009) 35 _M _N/A _L _L _H _H _H Yoshimura et al (2009)69 _N/A _M _M _L _L _M _H Chan et al (2012) 36 _N/A _L _L _L _H _H _H Al-Mamgani et al (2013) 70 _L _N/A _L _L _M _H _H Rathod et al (2013) 71 _L _H _L _L _L _L _L

Zhao et al (2014)72 _N/A _N/A _L _L _H _H _H

Arslan et al (2015) 73 _N/A _N/A _L _L _H _H _H

Kumar et al (2013) 74 _L _L _L _L _H _H _H

Landstrom et al (2015)75 _N/A _L _L _L _H _H _H

Rao et al (2016) 19 _H _N/A _L _M _L _L _H

Dzioba et al (2017)76 _L _H _L _L _M _M _H

Gao et al (2018) 77 _N/A _N/A _L _L _H _H _H

Tribius et al (2018) 46 _N/A _L _N/A _L _H _H _H

Veluthattil et al (2019) 45 _N/A _M _L _L _H _H _H

*:extra-oral measurement N/A: not applicable L: low risk of bias M: moderate risk of bias H: high risk of bias

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112 Ta bl e 3 . O ve rv ie w of p at ie nt , t um ou r, t re at m en t, a nd o th er ch ar ac te ris tic s a s p ro gn os tic f ac to rs f or de cr ea se i n m ax im al m ou th o pe ni ng ( ob je ct iv e) a nd p at ie nt s’ p er ce pt io n of d iff ic ul tie s o pe ni ng t he m ou th ( su bj ec tiv e) . Pa ti en t ch ar act er is ti cs Ti m e po in ts o f an al ys is Ag e Gen der De nt al s ta tu s -5 09 G en ot ype Ob je ct iv e m ea su re s <5 5 55 -6 4 65+ Ma le Fe m al e D ent ate Ed en tu lo us Sc ot t e t a l (2 01 1) 14 AT -B T -1 1[ -2 1; -2 ] -4 [-1 3; -1 ] -3 [-1 2; 1] -8 [-1 6; -2 ] a -2 [-1 1; 1] a -6 [-1 4; -2 ] -9 [-22 ;0] 6M -BT -6 [-1 1; 1] -4 [-1 0; 3] -5 [-] -5 [-1 1;2] -1 [-1 0; 3] -4 [-1 0; 3] -1 0[ -2 3; 0] CC -50 9 ge no ty pe CT -50 9 ge no ty pe TT -50 9 ge no ty pe Ly on s e t a l (2 01 3) 56 AT -B T -8 .5 [-4. 5; -1 3. 0] b -1 7. 0 [-8. 0; -2 6. 0] b -2 6.5 [-33 .0 ;-15 .0 ] b Ma le Fe m al e D ent ate Ed en tu lo us W et ze ls e t a l (2 01 4) 16 AT -B T -1 4. 3 ( -) A -1 4. 9 ( -) A -1 3. 8 ( -) A -1 4. 5( -) A 6M -BT -9. 0 ( -) A -9. 2( -) A -8 .1 (-) A -9. 3( -) A 12M -B T -8 .7( -) A -8 .5 (-) A -8 .1 (-) A -8 .5 (-) A Ma le Fe m al e La lla e t a l (2 01 7) 62 6M -BT -3 .3 (-) A -3 .0 (-) A

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113 Ta bl e 3 . (C on tin ue d) Tum our ch ar act er is ti cs Ti m e po in ts o f an al ys is Lo ca liz at io n St ag e Ob je ct iv e m ea su re s O ral O ro ph ar yn x T-st ag e 1 ,2 T-st ag e 3 ,4 N-st ag e 0 N-st ag e + Sc ot t e t a l (2 01 1) 14 AT -B T -7 [-1 4; -2 ] -5 [-1 6; -1 ] -5 [-1 4; -1 ] -9 [-1 8; -1 ] -5 [-1 4; -1 ] -8 [-1 6; -1 ] 6M -BT -4[ -1 0;2] -9 [-] -3 [-1 0; 3] -9 [-1 6; 1] -3 [-1 0; 3] -8 [-1 3; 1] M ou th O ro ph ar yn x Hy po - phar yn x La ry nx D ra in ag e ar ea St ag e I St ag e I I St ag e III St ag e I VA St ag e I VB B ra ga nt e e t a l (2 01 2) 54 AT -B T -1 1. 0( 1. 7) b -1 1. 5( 7. 8) b -2 .0 (0 .0) b -5 .3 (6 .3 ) b -2 .8 (4 .5 ) b -8 .0 (-) -0 .8 ( 1. 5) -7. 8 ( 5. 9) -4 .5 ( 5. 9) -6. 3 ( 6. 9) O ro ph ar yn x O th er s A JC C 1-3 A JCC 4 La za ru s e t a l (2 01 4) 57 3M -BT -4 .1 (-) A -5 .0 (-) A -3 .5 (-) A -4 .8 (-) A 6M -BT -3 .8 (-) A -6. 2 (-) A -4 .1 (-) A -5 .0 (-) A Ma xi lla M an di ble Ton gue an d f lo or o f mou th T1 T2 T3 T4 W et ze ls e t a l (2 01 4) 16 AT -B T -1 9. 1( -) a, A -1 5. 5( -) a, A -1 0. 7( -) a, A -1 2. 0( -) A -1 6. 7( -) A -1 7. 3( -) A -1 5. 0( -) A 6M -BT -1 5. 1( -) a, A -9. 6( -) a, A -5 .0 (-) a, A -5 .7( -) A -1 0. 4( -) A -1 4. 5( -) A -1 3. 8( -) A 12M -B T -1 1. 8( -) a, A -8 .1 (-) a, A -7. 5( -) a, A -7. 1( -) A -9. 4( -) A -1 0. 8( -) A -1 2. 0( -) A O ra l Ca vi ty a nd O ro ph ar yn x r Na so - phar yn x H yp o- ph ar yn x a nd La ry nx r B ra ga nt e e t a l (2 015 ) 53 AT -B T -5. 64 (6 .4 2) a -1 .6 8 ( 6. 27 ) a

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114 Ta bl e 3 . (C on tin ue d) Su bj ect iv e m ea su re s O ra l ca vi ty O ro ph ar yn x T2 T3 ,4 B org gre ven e t al (2 00 7) 65 6M -BT 10.6( -) 24 .2 (-) 23 .5 (-) 14 .3 (-) 12M -6 M 5. 6( -) -1 1. 5( -) -1 1. 1( -) 3. 3( -) Tre at m en t ch ar act er is ti cs Tre at m en t m oda lit y R econ st ruc ti on R ad ia ti on do se Ob je ct iv e m ea su re s N o R T RT CR T N o f re e-fla p So ft -fr ee _flap Co m pos ite fr ee fl ap Sc ot t e t a l (2 01 1) 14 AT -B T -8 [-1 4; -2 ] -5[ -1 3; 1] -9 [-] -2 [-9; -1 ] -6 [-1 6; -2 ] -1 1[ -1 2; 0] 6M -BT -1 [-9; 4] a -7 [-1 5; 0] a -7 [-] a -1 [-1 0; 4] -5 [-1 1; 1] -4 [-] RT CR T To tal dos e B ra ga nt e e t a l (2 01 2) 54 AT -B T -5 .5 (6. 0) -4 .4 ( 5. 5) R= -0 .1 64 a S o nl y S+R T S+ RT+ _ORN M uc ke e t a l (2 01 2) 55 AT -B T -2 2. 5% b -49 .2 % b -49 .0 % b Pla ty sm a f la p Su bm en ta l fla p Sa fd ar e t a l (2 01 4) 58 6M -BT -3 .7 (-1 .8 ) a,B -4 .7 (-1. 6) a,B S o nl y S+R T RT N o s ur ge ry Lo cal fl ap My oc ut an eo us or f re e f la p Bo ne g ra ft / fla p W et ze ls e t a l (2 01 4) 16 AT -B T -1 3. 4( -) a, A -1 8. 2( -) a, A -7. 1( -) a, A -1 1. 1( -) A -2 2. 9( -) A -1 7. 9( -) A -1 7. 4( -) A 6M -BT -4 .5 (-) a, A -1 5. 0( -) a, A -8 .2 (-) a, A -5 .5 (-) A -2 0. 9( -) A -1 2. 9( -) A -1 2. 7( -) A 12M -B T -4 .6 (-) a, A -13 .9 (-) a, A -8 .0 (-) a, A -5 .9 (-) A -1 4. 6( -) A -1 1. 9( -) A -9. 8( -) A M an dib u-lo to m y su rg er y Tra ns ora l sur ge ry A l-Sa le h e t a l (2 01 7) 43 1. 5-2A T-B T 11 .7 (-) a, A 5. 4 ( -) a, A

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115 Ta bl e 3 . (C on tin ue d) Su bj ect iv e m ea su re s 3D -R T IM RT Verg eer e t a l (2 00 9) 35 6W-BT 8. 8( -) b, A -7. 4( -) b, A 6M -BT 11 .9 (-) b, A 1. 3( -) b, A RT CR T K um ar e t a l (2 01 3) 74 1M -B T -3 .7( -) a, A -1 2. 3( -) a, A 6M -BT 0. 0( -) a, A -1 7. 06 (-) a, A 3D -R T IM RT R at ho d e t a l (2 01 3) 71 3M -BT 6( -) b, A -4 (-) b, A 6M -BT 16 (-) b, A -3 (-) b, A 12M -B T -2 (-) b, A -2 (-) b, A 18M-BT 2( -) b, A -4 (-) b, A 24 M -B T 8( -) b, A -9 (-) b, A CR T+ E RF CR T Zh ao e t a l (2 01 4) 72 6M -AT -3 .5 (-) a, A 17. 1 (-) a, A 12 M -AT -2 .6 (-) a, A 18 .2 (-) a, A 18M-AT -6 .6 (-) a, A 20 .4 (-) a, A 24 M -AT -6 .4 (-) a, A 19 .0 (-) a, A

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116 Ta bl e 3 . (C on tin ue d) O th er ch ar act er is ti cs Sm ok in g Alc oh ol (> 1 d ail y) M uco si ti s SE S Ob je ct iv e m ea su re s Ye s N o Ye s N o W et ze ls e t a l (2 01 4) 16 AT -B T -1 2. 9 (-) A -1 5. 4( -) A -1 4. 8( -) A -1 4. 3( -) A 6M -BT -8 .9 (-) A -9. 1( -) A -9. 1( -) A -9. 0( -) A 12M -B T -8 .9 (-) A -8 .2 (-) A -1 0. 5( -) A -7. 6( -) A Ye s N o B ra ga nt e e t a l (2 015 ) 53 AT -B T -5. 9( 6. 6) a -0 .6 (5. 3) a Ob je ct iv e m ea su re s Lo w Mi ddl e H igh Tr ib iu s e t a l (2 01 8) 46 24 M -AT -1 2. 3( -) a, A -3 0. 5( -) a, A -3 0.6( -) a, A N um be r o f d ec im al s a re r ep or te d a s t he a ut ho rs h av e r ep or te d i t. I n c as e t w o o r m or e d ec im al s a re g iv en , 1 d ec im al i s r ep or te d. Fo r t he o bj ec tiv e m ea su re s, a d ec re as e ( a n eg at iv e v al ue ), m ea ns a w or se r es tr ic te d m ou th o pe ni ng . F or t he s ub je ct iv e m ea su re s, a n i nc re as e ( a p os iti ve v al ue ), m ea ns a w or se re st ric te d m out h o pe ni ng. a: s ig nif ic an t b: s ig nif ic an t i n s om e anal ys es A : d iff er en ce b et w ee n m ea n s co re s c al cu la te d B: C on ve rsi on c en tim et er s t o m ill im et er s ** [* *] : m ed ia n[ in te rq ua rt ile ra ng e] ** (* *): m ea n s co re (s ta nd ar d d ev ia tio n) A bb rev ia tio ns : AT : a fte r o nc ol og ic al tr ea tm ent BT : b efor e on co lo gi ca l t rea tm en t (n )W : n um be r o f w ee ks a ft er o nc ol og ic al t re at m en t (n )M : n um be r o f m on th s a ft er o nc ol og ic al t re at m en t (-): n ot r ep or te d A JC C: s ta ge a cc or di ng t o A m er ic an J oi nt C om m itt ee o n C an ce r RT : ra di ot he ra py O RN : os te or ad io ne cr os is CR T: c he mo ra di ot he ra py 3D -R T: thr ee -d im en sio nal ra dio th er ap y IM RT : i nte ns ity m od ula te d r ad io th er ap y ER F: ex tr ac or po rea l r ad io fr eq ue nc y SES : s oc io ec on omi c s tat us

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117

Timing

The highest percentage of patients developed trismus directly after treatment and it continued to increase in the six months thereafter (Figure 2A). The percentage of patients with trismus seemed to stabilize 12 months after treatment. MMO decreased directly after treatment and in the six months thereafter (Figure 2B) and appeared to stabilize 12 months after treatment. Patients’ perception of difficulties with opening the mouth was highly diverse (Figure 2C). The majority of the patients perceived difficulties with opening the mouth directly after treatment, but thereafter the perception varied considerably.

Figure 2. Longitudinal evaluation of percentage of patients with trismus (A), maximal mouth

opening (B), and patient’s quality of life score- domain: difficulties opening the mouth (C). A Time (months) 42 36 30 24 18 12 6 0 EOR TC QLQ H & N 35 - M out h ope ning 60 50 40 30 20 10 0 Gao et al (2018) Dzioba et al (2017) Landstrom et al (2015) Arslan et al (2015) Lazarus et al (2014)* Rathod et al (2013) Pauli et al (2013)* Al-Mamgani et al (2013) Yoshimura et al (2009) Bozec et al (2009) Bozec et al (2008) Oates et al (2007) Borggreven et al (2007) Nordgren et al(2006) Urdaniz et al (2005) Fang et al (2005) Abendstein et al (2005) Fang et al (2004) Ohrn et al (2001) Hammerlid et al (2001) Bjordal et al (2001) De Graeff et al (2000) De Graeff et al (1999)Study Page 1

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118 B Time (months) 48 42 36 30 24 18 12 6 0 Maxi mal mo uth o pen in g (MMO ) 55 50 45 40 35 Thor et al (2017) Lalla et al (2017) Manaktala et al(2015) Kamstra et al (2015) Bragante et al (2015) Wetzels et al (2014) Lazarus et al (2014) Bragante et al (2012)Study Page 1 C Time (months) 48 42 36 30 24 18 12 6 0 Percen tag e tri smu s (%) 100 80 60 40 20 0 Thor et al (2017)* Kamstra et al (2015)* Wetzels et al (2014)* Pauli et al (2013) Lee et al (2012) Scott et al (2011)Study Page 1

*after study name: secondary outcome

Broken lines displays studies that had overlapping data with other studies. The studies that contained the largest sample size are displayed as straight lines.

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119 The figures were based on 29 studies. Other studies were not included because: they did not report data on restricted mouth opening at time points before and after oncological

treatment (n=14)19,34-36,43,46,49,51,55,56,59,61,72,74_{; the trismus scores were reported as a cumulative}

incidence13_{; MMO was reported as a normalized value}52_{; a mean reduction}58_{; or as a}

median score14_{; or the scores of the questionnaires were not transformed into symptom}

scores(n=3)5,44,68_{or were reported as a median score}45,75_{. The data from studies that}

included the same study population as another study were not displayed either.50

Multivariate analyses

Three studies built multivariate prognostic models (Table 4).15,53,76_{Two studies analysed}

factors affecting MMO15,53_{, and one study analysed the factors affecting perceived}

difficulties with opening the mouth76_{. Presence of mucositis, deterioration of overall}

functioning (according to the Karnofsky Performance Status Scale), tumours located near the oral cavity, oro- and nasopharynx, nasal cavity and maxillary sinus, shorter time after radiotherapy, female gender, a small baseline mouth opening, large tumour (T stage 4), higher age, and a great target volume ( radiotherapy) were significantly associated with a decrease in MMO. A combination of oncological treatment modalities (surgery and (chemo) radiotherapy) and shorter time after oncological treatment) were associated with perceived difficulties with opening the mouth.

Best evidence synthesis

There is moderate evidence that the presence of mucositis and a deterioration of overall functioning (according to the Karnofsky Performance Status Scale) results in a reduction of MMO. There is limited to moderate evidence that target volume, time after treatment, and baseline mouth opening results in a reduction of MMO, and that time after treatment results in higher scores of perceived difficulties opening the mouth. There is conflicting evidence that the factors age localization, age, T classification, reconstruction after surgery, different types of treatment modalities, and gender affect MMO, and that the different types of treatment modalities affect perceived difficulties opening the mouth as well. Conflicting evidence was mainly the result of a different categorization of a particular factor across the studies. For instance, a significant association between factor tumour localisation and MMO was found, if tumour localisation was categorized in the two

categories: “oral cavity and oropharynx” versus “nasopharynx, hypopharynx and larynx”.53

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120

However, no significant association was found between factor tumour localisation and MMO, if tumour localisation was categorized in the two categories “oral cavity”

versus “oropharynx”.14

Significant associations were found between a reduction in MMO and the factors: T classification: if stage 4 was compared to other stages; treatment modalities, if multiple treatment modalities were compared to a single treatment modality or (chemo)radiotherapy was compared to surgery more than six months after treatment; reconstruction, if platysma flap was compared with a submental flap. A significant association between higher scores on perceived difficulties opening the mouth and the factor treatment modality was found, if multiple treatment modalities were compared to one single treatment modality or chemoradiotherapy was compared to radiotherapy alone. The largest reductions on MMO were found for a greater target volume (limited to moderate evidence) and the presence of mucositis after radiotherapy (moderate evidence) (Table 4, estimated effects). The greatest increases for perceived difficulties opening the mouth were found for a combination of treatment modalities given (conflicting evidence) and time after treatment (limited to moderate evidence) (Table 4, estimated effects).

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121 Ta bl e 4 . P ro gn os tic fa ct or m ode ls for re st ric te d m out h op en in g. St ud y O ut com e m ea su re M et ho d f or in cl ud in g f ac to r i n mo de l Pe rf or m ed an al ys is Fa ct or s i n t he f in al mo de l Est im at ed e ff ec t O bj ect iv e m ea su rem en t – m ax im al m ou th o pen in g B ra ga nt e e t a l (2 01 5) 53 Re du ct io n i n ma xi mal m ou th open in g Bi var iat e anal ys is (p< 0. 20 ) Li ne ar r eg re ss io n anal ys is Ente r (p < 0. 05) B 95 % C on fid en ce Inte rv al Ch an ge i n d ie t co ns is te nc y a fte r ra di ot he ra py -0 .29 -4 .2 7; 3. 69 Ra di at io n f ie ld – o ra l ca vit y a nd o ro ph ar yn x -2 .8 3 -6 .6 1; 0. 96 M uc os itis a fte r ra di ot he ra py * -4 .1 9 -7. 62 ;-0 .8 0 D iff er en ce i n K ar no fs ky Pe rf or m an ce S cal e *,† 0.1 2 0. 02 ;0. 24 Di sea se s ta ge : I II/ IV -0 .9 0 -4 .26 ;6 .0 7 K am st ra e t a l (2 015 ) 15 Chan ge in ma xi m al m ou th o pe ni ng Th eo re tic al pl au sa bi lit y Li ne ar m ix ed m od el anal ys is Ba ck w ar d ste pw is e se le ct io n (p < 0. 05) (-lo g lik eli ho od cr ite rion ) B 95 % C on fid en ce Inte rv al Inte rc ep t 12. 88 10 .0 0; 15 .7 7 Lo ca tio n O ra l ca vi ty 1. 57 -3 .5 0; 6. 63 O ro - a nd n as op ha ry nx 1. 04 -4 .0 9; 6.18 Sa liv ar y g la nds a nd e ar 2. 56 -2 .5 7; 7. 68 H yp o- a nd s up ra gl ot tic la ry nx 3. 56 -1 .6 1; 8. 73 G lo tt ic - a nd s ub gl ot tic la ry nx 4. 40 -0 .76 ;9 .5 7

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122 Ta bl e 4 . (C on tin ue d) St ud y O ut com e m ea su re M et ho d f or in cl ud in g f ac to r i n mo de l Pe rf or m ed an al ys is Fa ct or s i n t he f in al mo de l Est im at ed e ff ec t N as al c av ity a nd m ax ill ar y sin us 1. 26 -4 .0 0; 6.5 3 Un kn ow n p rim ar y -N /A Ti m e a fte r r ad io th er ap y 4.0 0 3. 38 ;4 .6 3 M al e g en der 1. 10 0.1 1; 2. 08 M out h op en in g b efo re tr ea tm en t 0. 69 0.6 5; 0. 73 Tu m ou r s ta ge : T 4 -1 .1 4 -2.1 6; -0 .1 1 Ag e -0 .05 -0. 08 ;-0. 01 Ta rg et v ol um e o n pr im ar y tu mo ur -4 .76 -9. 36 ;-0 .1 7 O ra l ca vi ty *t im e 0. 69 -0 .4 7; 1. 85 O ro ph ar yn x o r na so phar yn x* tim e 0. 47 -0 .70 ;1 .6 4 Sa liv ar y g la nd s o r ea r* Tim e 0. 91 -0 .26 ;2 .0 8 H yp op ha ry nx or s up ra glo tt ic la ry nx* Ti m e 1. 27 0. 09 ;2 .45 G lo tt ic o r s ub gl ot tic la ry nx* Ti m e 1. 48 0. 30; 2. 66 N as al c av ity o r m ax ill ar y sin us *T im e 0. 62 -0 .5 7; 1. 82 Un kn ow n p rim ar y* Tim e -N /A M out h op en in g b efo re tr ea tm en t* Ti m e -0 .10 -0. 11 ;-0. 09 M al e g en der *T im e 0. 32 0. 11 ;0. 54 Ba se lin e a ge c en te re d at 6 0 y ea rs *T im e -0 .01 -0 .0 2;0 .0 0 Tu mo ur s ta ge T 4* Ti me -0 .27 -0. 50 ;-0. 05 Ta rg et v ol um e o n pr im ar y tu mo ur *T ime -1 .6 9 -2 .7 5; -0 .6 4

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123 Ta bl e 4 . (C on tin ue d) St ud y O ut com e m ea su re M et ho d f or in cl ud in g f ac to r i n mo de l Pe rf or m ed an al ys is Fa ct or s i n t he f in al mo de l Est im at ed e ff ec t Su bj ect iv e m ea su rem en ts D zi ob a e t a l (2 01 7) 76 EO RT C Q LQ H N 35 ‡ M ix ed e ff ec t re gr es sio n anal ys is p> 0. 05 ex cl us io n inte ra ct io n te rm s p> 0. 05 ex cl us io n fo r tr ea tm en t B 95 % C on fid en ce Inte rv al Ba se line 14 .6 5 7. 4; 21 .9 Su rg er y a nd ra di ot he ra py 2. 24 -7. 6; 12 .0 Su rg er y a nd che mo ra di ot he ra py 14 .59 5. 5; 23 .7 1 m on th a ft er tr ea tm en t 12 .42 5. 2; 19 .6 6m ont hs a fte r tr ea tm en t 11 .3 0 3. 7; 18 .9 1 y ea r a ft er t re at m en t 2. 86 -5 .3 ;1 1. 0 a: s ig ni fic an tly c on tr ib ut in g t o t he m od el b: K ar no fs ky P er fo rm an ce S ca le : a n i nd ex u se d t o c la ss ify f un ct io na l i m pa irm en t, u si ng a s ca le o f 0 -1 00 . c: T he E ur op ea n O rg an iz at io n f or R es ea rc h a nd T re at m en t o f C an ce r Q ua lit y o f L ife Q ue st io nn ai re - H ea d a nd N ec k c an ce r M od ul e 3 5: a v al id at ed q ua lit y o f l ife q ue st io nn ai re , sp ec ifi ca lly f or h ea d a nd n ec k c an ce r r el at ed s ym pt om s.

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124

Table 5. Best evidence synthesis of prognostic factors on MMO and on scores for perceived

difficulties opening the mouth.

Prognostic factor Studies Number of patients per study Total number of patients Associa-tions (+,-,+/-) Level of evidence

Maximal mouth opening reduction

Disease stage [54;57;53] 26;29;56 111 - Moderate

Presence of mucositis [53;53] 56 56 + Moderate

Deterioration of overall functioning (Karnofsky

Performance Status Scale*)

[53] 56 56 + Moderate

Diet consistency [53] 56 56 - Moderate

Larger target volume [15] 641 641 + Limited/

Moderate

Shorter time after treatment [15] 641 641 + Limited/

Moderate

Smaller baseline mouth opening [15] 641 641 + Limited/

Moderate

Localization

† Oral cavity (predominantly maxilla) and oropharynx vs. other localizations [16;53;15] 143;56;641 840 + Conflicting† 54 26 26 +/-[14;57;53‡] 64;29;56 149 -Age [15] 641 641 + Conflicting† [14] 64 64 -T classification

† T classification stage 4 versus other stages.

[15] 641 641 + Conflicting†

[14;16] 64;143 207

-Reconstruction

† Platysma flap versus submental flap

[58] 65 65 + Conflicting†

[14;16] 64;143 207

-Treatment modalities

† multiple treatment modalities vs. single treatment modality; † (Chemo) radiotherapy vs. surgery >6months [16;43] 143;16 159 + Conflicting† [14 ;55] 64;96 160 +/-[54] 26 26 -Gender [15] 641 641 + Conflicting [14] 64 64 +/-[16;62] 143;372 515

-Dental status [14;16] 64;143 207 - Limited

Alcohol [16] 143 143 - Limited

Smoking [16] 143 143 - Limited

N classification [14] 64 64 - Limited

-509 genotype [56] 62 62 +/- Limited