Oral Oncology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Mouth opening in patients irradiated for head and neck cancer: A prospective repeated measures study J.I. Kamstra a,⇑, P.U. Dijkstra a,b, M. van Leeuwen a, J.L.N. Roodenburg a, J.A. Langendijk c a
University of Groningen, University Medical Center Groningen, Department of Oral and Maxillofacial Surgery, The Netherlands University of Groningen, University Medical Center Groningen, Department of Rehabilitation, The Netherlands c University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, The Netherlands b
a r t i c l e
i n f o
Article history: Received 3 October 2014 Received in revised form 26 January 2015 Accepted 28 January 2015 Available online xxxx Keywords: Head and neck cancer Radiotherapy Trismus Range of motion Mandible
s u m m a r y Objectives: Aims of this prospective cohort study were (1) to analyze the course of mouth opening up to 48 months post-radiotherapy (RT), (2) to assess risk factors predicting decrease in mouth opening, and (3) to develop a multivariable prediction model for change in mouth opening in a large sample of patients irradiated for head and neck cancer. Materials and methods: Mouth opening was measured prior to RT (baseline) and at 6, 12, 18, 24, 36, and 48 months post-RT. The primary outcome variable was mouth opening. Potential risk factors were entered into a linear mixed model analysis (manual backward-stepwise elimination) to create a multivariable prediction model. The interaction terms between time and risk factors that were significantly related to mouth opening were explored. Results: The study population consisted of 641 patients: 70.4% male, mean age at baseline 62.3 years (sd 12.5). Primary tumors were predominantly located in the oro- and nasopharynx (25.3%) and oral cavity (20.6%). Mean mouth opening at baseline was 38.7 mm (sd 10.8). Six months post-RT, mean mouth opening was smallest, 36.7 mm (sd 10.0). In the linear mixed model analysis, mouth opening was statistically predicted by the location of the tumor, natural logarithm of time post-RT in months (Ln (months)), gender, baseline mouth opening, and baseline age. All main effects interacted with Ln (months). Conclusion: The mean mouth opening decreased slightly over time. Mouth opening was predicted by tumor location, time, gender, baseline mouth opening, and age. The model can be used to predict mouth opening. Ó 2015 Elsevier Ltd. All rights reserved.
Introduction Decreased mouth opening, a trismus, is a well-known side effect of treatment of head and neck cancer, including of radiotherapy (RT) [1–6]. The prevalence of trismus following RT ranges from 25% to 46% [4–6]. Trismus has a negative impact on function and quality of life [1,7–11]. It impairs eating, speech, oral hygiene, dental treatment, airway clearance, and oncological follow-up [1,5,12]. Trismus is often progressive, hard to treat, and once established, only a limited increase in mouth opening can be achieved [13,14]. Therefore, the focus should be on prevention. Trismus is most likely to develop if RT includes the masticatory muscles and region of the temporomandibular joint, particularly,
⇑ Corresponding author at: University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700RB Groningen, The Netherlands. Tel.: +31 50 3613860. E-mail address: [email protected] (J.I. Kamstra).
when RT is combined with chemotherapy, in case of larger tumors, or when trismus is induced by the tumor itself [4,6,10,15–17]. Fibrosis and atrophy of irradiated tissues contribute to trismus, which is likely to develop between 1 month and 1 year post-RT [10,18,19]. A progressive decrease in mouth opening can be observed even years after finishing RT [19]. Dosages higher than 50 Gy are associated with trismus [4,10,20–22]. Higher incidences of trismus have been observed after external beam RT than after interstitial RT [4,20]. The main limitations of previous studies that aimed at identifying risk factors for trismus were their retrospective design and relatively small sample sizes. The longitudinal course of mouth opening up to 1 year following surgery and/or RT (with or without chemotherapy) has been described in 4 prospective studies with 17 to 143 patients. The main limitations of these studies were the small sample sizes, limited primary tumor sites, or the lack of RT as part of the treatment modalities [17,19,23,24]. Consequently, when several risk factors are present, it has been
http://dx.doi.org/10.1016/j.oraloncology.2015.01.016 1368-8375/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kamstra JI et al. Mouth opening in patients irradiated for head and neck cancer: A prospective repeated measures study. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.01.016
2
J.I. Kamstra et al. / Oral Oncology xxx (2015) xxx–xxx
impossible to statistically predict the longitudinal course of mouth opening of head and neck cancer patients after RT. The aims of our prospective cohort study were (1) to analyze the longitudinal course of mouth opening up to 48 months post-RT, (2) to assess risk factors predicting decrease in mouth opening, and (3) to develop a multivariable prediction model for change in mouth opening based on a large sample size of patients undergoing RT for head and neck cancer. Materials and methods Study design and setting This prospective longitudinal cohort study was conducted between March 2007 and June 2011 at the Department of Radiation Oncology of the University Medical Center Groningen, the Netherlands. The study was carried out according to the regulations of our institute. Participants All patients who underwent definitive or postoperative external beam RT for head and neck cancer, either alone or in combination with chemotherapy or cetuximab, were included. Patients were excluded if their primary tumor was located outside the head and neck region, intracranially, or if it originated from the nasal vestibule or the skin. Patients were also excluded if no data was collected regarding their mouth opening, or if the patient died during RT or within the first 6 months after the start of RT. Tumor classification was based on the Union for International Union Against Cancer (UICC) recommendation TN classification (2009).
compared to those with T1, T2, or T3 tumors. For the clinical interpretation, age was centered at 60 years. The potential risk factors were selected based on the assumed risk to influence mouth opening: location of the tumor (oral cavity, oro- and nasopharynx, salivary glands and ear, hypo- and supraglottic larynx, glottic- and supraglottic larynx, nasal cavity and maxillary sinus, and lymph node metastases from an unknown primary (primary unknown)), squamous cell carcinoma (yes, no), time modeled as the natural logarithm of time in post-RT in months (Ln (months)), gender (male, female), baseline mouth opening (millimeters), stage T4 (yes, no), baseline age (years), total dose of irradiation (Gy), fraction dose of irradiation (Gy), target volume on primary tumor (yes, RT on primary tumor; no, RT on metastasis in head and neck region), RT neck (yes, RT on neck area; no, RT only on primary tumor), re-irradiation in locoregional area (yes, no), surgery on the primary tumor (yes, no), neck dissection (yes, no), and chemotherapy (yes, no). All potential risk factors were entered in a linear mixed model analysis and successively eliminated (manual backward-stepwise elimination) to create a multivariable prediction model (SPSS 22.0 for Windows software (SPPS Inc., Chicago, IL, USA)). A risk factor was eliminated if the significance of the regression coefficient was larger than 0.05 and the model fit (2log likelihood criterion) did not decrease significantly. In addition, interaction terms between time and risk factors significantly related to mouth opening, were explored. An interaction term remained in the model if the model fit increased significantly (2log likelihood criterion). To verify post hoc if missing data may have influenced the results of the linear mixed model analysis, we performed the same analysis with patients with complete data. Because 59 patients had complete data up to 48 months follow-up, we did this analysis with the cohort with complete data up to 36 months, consisting of 104 patients.
Radiotherapy Patients were treated with external beam RT using linear accelerators at the Department of Radiation Oncology according to the standard of care protocols. Details on RT have been described in detail previously [25]. Data At the outpatient clinic of the Department of Radiation Oncology, mouth opening was prospectively measured prior to RT (baseline) and at regular follow-up appointments at 6, 12, 18, 24, 36, and 48 months post-RT. During these visits, patients were asked to open their mouth completely, and mouth opening was measured as maximal interincisal distance in millimeters, using a slide caliper. In case patients were edentulous and not wearing a dental prosthesis, mouth opening was measured from the alveolar ridge. Trismus was defined as a mouth opening of 35 mm or less [2]. Data on tumor and treatment were also prospectively collected. Missing and biologically implausible data were verified and retrieved from medical records. Statistical analysis The primary outcome variable was mouth opening at different time points (baseline, 6, 12, 18, 24, 36 and 48 months post-RT). Prior to data analysis, the association between time and mouth opening was explored. Time was modeled as a linear function, as a squared function, and as a logarithmic function. The model fit was best using a logarithmic function for time. Hence, Ln (months) was used in the analysis. The T stage of the tumor was dichotomized into stage T4 (yes, no) because plots showed that mouth opening over time was different in patients with T4 tumors
Results We initially included 788 head and neck cancer patients who were being treated with any form of RT We excluded 98 patients for the following reasons: primary tumor located outside the head and neck region, no data regarding mouth opening, and/or and deceased during or within the first 6 months post-RT. Patients with tumors originating from the nasal vestibule (n = 11), skin (n = 33), and intracranial (n = 3) were also excluded. For statistical reasons, patients (n = 2) with rare type of tumors (myxofibrosarcoma neck and epitheloid angio-sarcoma) were excluded as well. The study population therefore consisted of 641 consecutive patients (81.3% of the initial sample). Descriptive data The patient, tumor, and treatment characteristics of the study population (n = 641) and the cohort of patients with complete data at 36 months post-RT (n = 104) are shown in Tables 1 and 2. The majority of the patients were male (70.4%) and the mean age at baseline was 62.3 years (sd 12.5). Primary tumors were mostly located in the oro- or nasopharynx (25.3%) and oral cavity (20.6%). Course of mouth opening The mean mouth opening was 38.7 mm (sd 10.8) at baseline, 36.7 mm (sd 10.0) at 6 months post-RT, and 38.2 mm (sd 11.5) at 48 months post-RT. At baseline, 35% of the patients had trismus, which increased to 37% at 48 months post-RT. The highest percentage of patients with trismus was found at 6 months post-RT (42.9%) (Table 3). The course of mouth opening over time differed per tumor location (Fig. 1).
Please cite this article in press as: Kamstra JI et al. Mouth opening in patients irradiated for head and neck cancer: A prospective repeated measures study. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.01.016
3
J.I. Kamstra et al. / Oral Oncology xxx (2015) xxx–xxx Table 1 Patient, tumor, and treatment characteristics. Study population (n = 641) Variable
N (%)
Patient characteristics Male gender Baseline age (years) Deceased Months between start RT and death Dental state Dentulous Fully edentulous Partially edentulous Not known Baseline mouth opening (millimeters) Exercise therapy for trismus
Cohort of patients with complete data (n = 104) Mean (sd)
N (%)
451 (70.4)
Mean (sd)
64 (61.5) 62.3 (12.5)
59.7 (13.0)
199 (31.0)
1 (1.0) 17.8 (10.6)
55 ()
241 (37.6) 319 (49.8) 77 (12.0) 4 (0.6)
45 (43.3) 49 (47.1) 8 (7.7) 2 (1.9) 38.7 (10.8)
39.5 (10.4)
17 (2.7)
6 (5.8)
Tumor characteristics Squamous cell carcinoma Stage T4
512 (79.9) 183 (28.5)
76 (73.1) 19 (18.3)
Location of the primary tumor (categorized by beam configuration) Oral cavity Oro- and nasopharynx Salivary glands and ear Hypo- and supraglottic larynx Glottic- and subglottic larynx Nasal cavity and maxillary sinus Unknown primary
132 (20.6) 162 (25.3) 66 (10.3) 115 (17.9) 116 (18.1) 24 (3.7) 26 (4.1)
26 (25.0) 19 (18.3) 12 (11.5) 16 (15.4) 23 (22.1) 4 (3.8) 4 (3.8)
248 216 176 610 490
50 41 18 98 72
Treatment characteristics Surgery primary tumor Neck dissection Chemotherapy Target volume on primary tumor RT neck area Total dose of irradiation Fraction dose of irradiation Duration of RT in months Re-irradiation in locoregional area
(38.7) (33.7) (27.5) (95.2) (76.4)
(48.1) (39.4) (17.3) (94.2) (69.2)
65.2 (7.1) 2.0 (0.2) 1.3 (0.2)
65.9 (5.5) 2.0 (0.1) 1.4 (0.2)
32 (5)
–
Table 2 TN classification.
Outcome linear mixed model analysis
N0
N1
N2a
N2b
N2c
N2 (nasopharynx)
N3
Total
T0 T1 T2 T3 T4 Unknown
2 62 109 36 64 8
1 13 24 17 18 8
0 4 7 0 3 7
1 24 24 17 31 11
2 7 17 27 60 0
0 0 3 1 0 0
0 2 7 1 6 4
6 112 191 99 182 38
Total
281
81
21
108
113
4
20
628a
a
Of 50 patients, T classification was missing: TN classification was reported (n = 38) or no classification was applicable (n = 12; in example, for a non-malignant pleiomorf adenoma). Of 13 patients, no N classification was reported.
In the linear mixed model analysis, mouth opening was statistically predicted by the location of the tumor, Ln (months), gender, baseline mouth opening, tumor stage T4, baseline age, and target volume on primary tumor. All main effects interacted with Ln (months) (Table 4). The results of the linear mixed model analysis can predict mouth opening post-RT statistically. For example, for a 70-yearold male with a T2 carcinoma in the oral cavity who received target volume on the primary tumor only, with a mouth opening of 40 mm at baseline, mouth opening can be estimated at 36 months post-RT by using the following equation:
Table 3 Mouth opening and numbers of patients with trismus. Months post-RT
N patients per point of time (deceased before follow-up)
N cumulative deceased patients
Mean mouth opening (sd)
Mean mouth opening (sd)a
N patients with trismus (%)
N patients with trismus (%)a
Baseline 6 months 12 months 18 months 24 months 36 months 48 months
566 473 425 392 368 230 131
0 18 87 131 163 184 196
38.7 36.7 37.3 37.3 38.0 38.0 38.2
39.5 38.7 39.1 37.9 38.3 37.2 –
196 (34.6) 203 (42.9) 161 (37.9) 160 (40.8) 139 (37.8) 83 (36.1) 48 (36.6)
33 29 33 43 40 39 –
(18) (69) (44) (32) (21) (12)
(10.8) (10.0) (10.3) (10.6) (10.7) (10.6) (11.5)
(10.4) (9.6) (11.1) (10.8) (10.7) (10.7)
(31.7) (27.9) (31.7) (41.3) (38.5) (37.5)
a Cohort of patients (n = 104) with complete data up to 36 months post-RT. There were 59 patients with complete data up to 48 months post-RT, however, for statistical reasons the cohort up to 36 months was used.
Please cite this article in press as: Kamstra JI et al. Mouth opening in patients irradiated for head and neck cancer: A prospective repeated measures study. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.01.016
4
J.I. Kamstra et al. / Oral Oncology xxx (2015) xxx–xxx
Fig. 1. Course of mouth opening per tumor location. Note: Y-axis starts at 30 mm.
Mouth opening ¼ 12:88 þ ½1:57 ðoral cavityÞ þ ½4:00 3:58ðLnðmonthsÞÞ þ ½1:10ðmale genderÞ þ ½0:69 40ðbaseline mouth openingÞ þ ½0:05 10ðbaseline age centered at 60 yearsÞ
post-RT (Table 4 and Fig. 2). The longitudinal course of mouth opening differed between primary tumor locations (Figs. 1 and 2).
Interpretation
þ ½4:76ðtarget volume on primary tumorÞ þ ½0:69 3:58ðoral cavity LnðmonthsÞ þ ½0:32 3:58ðmale gender LnðmonthsÞ þ ½0:10 40 3:58ðbaseline mouth opening LnðmonthsÞ þ ½0:01 10 3:58ðbaseline age centered at 60 years LnðmonthsÞ þ ½1:69 3:58ðtarget volume on primary tumor LnðmonthsÞ ¼ 35; 1 mmðNote Lnð36monthsÞ ¼ 3:58:Þ Mean predicted mouth opening according the multivariable prediction model differed per tumor location (Fig. 2). Mouth opening of patients with tumors of all included locations decreased in the first 6 months post-RT, except when the tumor was located in the salivary glands or ears. When patients had a lymph node metastasis from an unknown primary, mouth opening did not decrease in these first 6 months either. The linear mixed model analysis was repeated for the cohort of patients with complete data (n = 104) (Appendix 1). The differences in regression coefficients were largest for the interactions between Ln (months) and location of the primary tumor.
Discussion Key results The mean mouth opening of the study population changed marginally over time. The results of our study showed that mouth opening can be predicted statistically by a variety of risk factors and their interactions. Based on the multivariable prediction model, the longitudinal course of mouth opening can be predicted statistically. We found that mean mouth opening decreased the first 6 months post-RT and gradually recovered up to 48 months
The consequences of trismus are severe, and trismus secondary to head and neck cancer is hard to treat. If the multivariable prediction model presented in our study indicates high risk of trismus, preventive measures can be taken to prevent deterioration of mouth opening. For example, patients who perform exercises during RT experience a smaller decrease in mouth opening compared to those who do not exercise [16,26,27]. Additionally, a larger increase in mouth opening is expected when exercises are started early [28]. However, such preventive programs can be a burden to patients, especially during the course of RT. These programs should therefore be limited to those with the highest risks. The interactions between location of the tumor and Ln (months) indicate that the change over time depends on the location of the tumor. The results of our study showed on average only a small decrease in mouth opening over time, with the highest percentage of patients with trismus at 6 months post-RT. The percentage of patients with trismus at 48 months post-RT was nearly the same as the percentage at baseline. The largest change in mouth opening occurred during the first 6 months post-RT, in both the course of mouth opening (Fig. 1) and the predicted mouth opening according the multivariable prediction model (Fig. 2). The interaction term between Ln (months) and mouth opening prior to RT indicates that a larger mouth opening prior to RT will result in a greater loss of mouth opening post-RT. About 30% of the study population died, most likely the patients with T4 tumors and those who underwent more intensive treatment. Such patients are more likely to develop trismus. The dropout of these patients could explain the recovery of mouth opening over time. Up to 48 months post-RT, only 59 patients had complete data. However, to verify the model in a cohort of patients with complete data, a larger sample was preferred. Therefore, we decided to use
Please cite this article in press as: Kamstra JI et al. Mouth opening in patients irradiated for head and neck cancer: A prospective repeated measures study. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.01.016
5
J.I. Kamstra et al. / Oral Oncology xxx (2015) xxx–xxx Table 4 Results of the linear mixed model analysis to predict mouth opening post-RT of the study population (n = 641). Risk factors
b
Se (b)
p
95% CI lower bound
95% CI upper bound
Intercept Tumor location Oral cavity Oro- and nasopharynx Salivary glands and ear Hypo- and supraglottic larynx Glottic- and subglottic larynx Nasal cavity and maxillary sinus Unknown primary Ln (months) Male gender Baseline mouth opening Stage T4 Baseline age centered at 60 years Target volume on primary tumor
12.88
1.47
10.00
15.77
1.57 1.04 2.56 3.56 4.40 1.26 – 4.00 1.10 .69 1.14 .05 4.76
2.58 2.62 2.61 2.63 2.63 2.68 – .32 .50 .02 .52 .02 2.34
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Mouth opening in patients irradiated for head and neck cancer: A prospective repeated measures study J.I. Kamstra a,⇑, P.U. Dijkstra a,b, M. van Leeuwen a, J.L.N. Roodenburg a, J.A. Langendijk c a
University of Groningen, University Medical Center Groningen, Department of Oral and Maxillofacial Surgery, The Netherlands University of Groningen, University Medical Center Groningen, Department of Rehabilitation, The Netherlands c University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, The Netherlands b
a r t i c l e
i n f o
Article history: Received 3 October 2014 Received in revised form 26 January 2015 Accepted 28 January 2015 Available online xxxx Keywords: Head and neck cancer Radiotherapy Trismus Range of motion Mandible
s u m m a r y Objectives: Aims of this prospective cohort study were (1) to analyze the course of mouth opening up to 48 months post-radiotherapy (RT), (2) to assess risk factors predicting decrease in mouth opening, and (3) to develop a multivariable prediction model for change in mouth opening in a large sample of patients irradiated for head and neck cancer. Materials and methods: Mouth opening was measured prior to RT (baseline) and at 6, 12, 18, 24, 36, and 48 months post-RT. The primary outcome variable was mouth opening. Potential risk factors were entered into a linear mixed model analysis (manual backward-stepwise elimination) to create a multivariable prediction model. The interaction terms between time and risk factors that were significantly related to mouth opening were explored. Results: The study population consisted of 641 patients: 70.4% male, mean age at baseline 62.3 years (sd 12.5). Primary tumors were predominantly located in the oro- and nasopharynx (25.3%) and oral cavity (20.6%). Mean mouth opening at baseline was 38.7 mm (sd 10.8). Six months post-RT, mean mouth opening was smallest, 36.7 mm (sd 10.0). In the linear mixed model analysis, mouth opening was statistically predicted by the location of the tumor, natural logarithm of time post-RT in months (Ln (months)), gender, baseline mouth opening, and baseline age. All main effects interacted with Ln (months). Conclusion: The mean mouth opening decreased slightly over time. Mouth opening was predicted by tumor location, time, gender, baseline mouth opening, and age. The model can be used to predict mouth opening. Ó 2015 Elsevier Ltd. All rights reserved.
Introduction Decreased mouth opening, a trismus, is a well-known side effect of treatment of head and neck cancer, including of radiotherapy (RT) [1–6]. The prevalence of trismus following RT ranges from 25% to 46% [4–6]. Trismus has a negative impact on function and quality of life [1,7–11]. It impairs eating, speech, oral hygiene, dental treatment, airway clearance, and oncological follow-up [1,5,12]. Trismus is often progressive, hard to treat, and once established, only a limited increase in mouth opening can be achieved [13,14]. Therefore, the focus should be on prevention. Trismus is most likely to develop if RT includes the masticatory muscles and region of the temporomandibular joint, particularly,
⇑ Corresponding author at: University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700RB Groningen, The Netherlands. Tel.: +31 50 3613860. E-mail address: [email protected] (J.I. Kamstra).
when RT is combined with chemotherapy, in case of larger tumors, or when trismus is induced by the tumor itself [4,6,10,15–17]. Fibrosis and atrophy of irradiated tissues contribute to trismus, which is likely to develop between 1 month and 1 year post-RT [10,18,19]. A progressive decrease in mouth opening can be observed even years after finishing RT [19]. Dosages higher than 50 Gy are associated with trismus [4,10,20–22]. Higher incidences of trismus have been observed after external beam RT than after interstitial RT [4,20]. The main limitations of previous studies that aimed at identifying risk factors for trismus were their retrospective design and relatively small sample sizes. The longitudinal course of mouth opening up to 1 year following surgery and/or RT (with or without chemotherapy) has been described in 4 prospective studies with 17 to 143 patients. The main limitations of these studies were the small sample sizes, limited primary tumor sites, or the lack of RT as part of the treatment modalities [17,19,23,24]. Consequently, when several risk factors are present, it has been
http://dx.doi.org/10.1016/j.oraloncology.2015.01.016 1368-8375/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kamstra JI et al. Mouth opening in patients irradiated for head and neck cancer: A prospective repeated measures study. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.01.016
2
J.I. Kamstra et al. / Oral Oncology xxx (2015) xxx–xxx
impossible to statistically predict the longitudinal course of mouth opening of head and neck cancer patients after RT. The aims of our prospective cohort study were (1) to analyze the longitudinal course of mouth opening up to 48 months post-RT, (2) to assess risk factors predicting decrease in mouth opening, and (3) to develop a multivariable prediction model for change in mouth opening based on a large sample size of patients undergoing RT for head and neck cancer. Materials and methods Study design and setting This prospective longitudinal cohort study was conducted between March 2007 and June 2011 at the Department of Radiation Oncology of the University Medical Center Groningen, the Netherlands. The study was carried out according to the regulations of our institute. Participants All patients who underwent definitive or postoperative external beam RT for head and neck cancer, either alone or in combination with chemotherapy or cetuximab, were included. Patients were excluded if their primary tumor was located outside the head and neck region, intracranially, or if it originated from the nasal vestibule or the skin. Patients were also excluded if no data was collected regarding their mouth opening, or if the patient died during RT or within the first 6 months after the start of RT. Tumor classification was based on the Union for International Union Against Cancer (UICC) recommendation TN classification (2009).
compared to those with T1, T2, or T3 tumors. For the clinical interpretation, age was centered at 60 years. The potential risk factors were selected based on the assumed risk to influence mouth opening: location of the tumor (oral cavity, oro- and nasopharynx, salivary glands and ear, hypo- and supraglottic larynx, glottic- and supraglottic larynx, nasal cavity and maxillary sinus, and lymph node metastases from an unknown primary (primary unknown)), squamous cell carcinoma (yes, no), time modeled as the natural logarithm of time in post-RT in months (Ln (months)), gender (male, female), baseline mouth opening (millimeters), stage T4 (yes, no), baseline age (years), total dose of irradiation (Gy), fraction dose of irradiation (Gy), target volume on primary tumor (yes, RT on primary tumor; no, RT on metastasis in head and neck region), RT neck (yes, RT on neck area; no, RT only on primary tumor), re-irradiation in locoregional area (yes, no), surgery on the primary tumor (yes, no), neck dissection (yes, no), and chemotherapy (yes, no). All potential risk factors were entered in a linear mixed model analysis and successively eliminated (manual backward-stepwise elimination) to create a multivariable prediction model (SPSS 22.0 for Windows software (SPPS Inc., Chicago, IL, USA)). A risk factor was eliminated if the significance of the regression coefficient was larger than 0.05 and the model fit (2log likelihood criterion) did not decrease significantly. In addition, interaction terms between time and risk factors significantly related to mouth opening, were explored. An interaction term remained in the model if the model fit increased significantly (2log likelihood criterion). To verify post hoc if missing data may have influenced the results of the linear mixed model analysis, we performed the same analysis with patients with complete data. Because 59 patients had complete data up to 48 months follow-up, we did this analysis with the cohort with complete data up to 36 months, consisting of 104 patients.
Radiotherapy Patients were treated with external beam RT using linear accelerators at the Department of Radiation Oncology according to the standard of care protocols. Details on RT have been described in detail previously [25]. Data At the outpatient clinic of the Department of Radiation Oncology, mouth opening was prospectively measured prior to RT (baseline) and at regular follow-up appointments at 6, 12, 18, 24, 36, and 48 months post-RT. During these visits, patients were asked to open their mouth completely, and mouth opening was measured as maximal interincisal distance in millimeters, using a slide caliper. In case patients were edentulous and not wearing a dental prosthesis, mouth opening was measured from the alveolar ridge. Trismus was defined as a mouth opening of 35 mm or less [2]. Data on tumor and treatment were also prospectively collected. Missing and biologically implausible data were verified and retrieved from medical records. Statistical analysis The primary outcome variable was mouth opening at different time points (baseline, 6, 12, 18, 24, 36 and 48 months post-RT). Prior to data analysis, the association between time and mouth opening was explored. Time was modeled as a linear function, as a squared function, and as a logarithmic function. The model fit was best using a logarithmic function for time. Hence, Ln (months) was used in the analysis. The T stage of the tumor was dichotomized into stage T4 (yes, no) because plots showed that mouth opening over time was different in patients with T4 tumors
Results We initially included 788 head and neck cancer patients who were being treated with any form of RT We excluded 98 patients for the following reasons: primary tumor located outside the head and neck region, no data regarding mouth opening, and/or and deceased during or within the first 6 months post-RT. Patients with tumors originating from the nasal vestibule (n = 11), skin (n = 33), and intracranial (n = 3) were also excluded. For statistical reasons, patients (n = 2) with rare type of tumors (myxofibrosarcoma neck and epitheloid angio-sarcoma) were excluded as well. The study population therefore consisted of 641 consecutive patients (81.3% of the initial sample). Descriptive data The patient, tumor, and treatment characteristics of the study population (n = 641) and the cohort of patients with complete data at 36 months post-RT (n = 104) are shown in Tables 1 and 2. The majority of the patients were male (70.4%) and the mean age at baseline was 62.3 years (sd 12.5). Primary tumors were mostly located in the oro- or nasopharynx (25.3%) and oral cavity (20.6%). Course of mouth opening The mean mouth opening was 38.7 mm (sd 10.8) at baseline, 36.7 mm (sd 10.0) at 6 months post-RT, and 38.2 mm (sd 11.5) at 48 months post-RT. At baseline, 35% of the patients had trismus, which increased to 37% at 48 months post-RT. The highest percentage of patients with trismus was found at 6 months post-RT (42.9%) (Table 3). The course of mouth opening over time differed per tumor location (Fig. 1).
Please cite this article in press as: Kamstra JI et al. Mouth opening in patients irradiated for head and neck cancer: A prospective repeated measures study. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.01.016
3
J.I. Kamstra et al. / Oral Oncology xxx (2015) xxx–xxx Table 1 Patient, tumor, and treatment characteristics. Study population (n = 641) Variable
N (%)
Patient characteristics Male gender Baseline age (years) Deceased Months between start RT and death Dental state Dentulous Fully edentulous Partially edentulous Not known Baseline mouth opening (millimeters) Exercise therapy for trismus
Cohort of patients with complete data (n = 104) Mean (sd)
N (%)
451 (70.4)
Mean (sd)
64 (61.5) 62.3 (12.5)
59.7 (13.0)
199 (31.0)
1 (1.0) 17.8 (10.6)
55 ()
241 (37.6) 319 (49.8) 77 (12.0) 4 (0.6)
45 (43.3) 49 (47.1) 8 (7.7) 2 (1.9) 38.7 (10.8)
39.5 (10.4)
17 (2.7)
6 (5.8)
Tumor characteristics Squamous cell carcinoma Stage T4
512 (79.9) 183 (28.5)
76 (73.1) 19 (18.3)
Location of the primary tumor (categorized by beam configuration) Oral cavity Oro- and nasopharynx Salivary glands and ear Hypo- and supraglottic larynx Glottic- and subglottic larynx Nasal cavity and maxillary sinus Unknown primary
132 (20.6) 162 (25.3) 66 (10.3) 115 (17.9) 116 (18.1) 24 (3.7) 26 (4.1)
26 (25.0) 19 (18.3) 12 (11.5) 16 (15.4) 23 (22.1) 4 (3.8) 4 (3.8)
248 216 176 610 490
50 41 18 98 72
Treatment characteristics Surgery primary tumor Neck dissection Chemotherapy Target volume on primary tumor RT neck area Total dose of irradiation Fraction dose of irradiation Duration of RT in months Re-irradiation in locoregional area
(38.7) (33.7) (27.5) (95.2) (76.4)
(48.1) (39.4) (17.3) (94.2) (69.2)
65.2 (7.1) 2.0 (0.2) 1.3 (0.2)
65.9 (5.5) 2.0 (0.1) 1.4 (0.2)
32 (5)
–
Table 2 TN classification.
Outcome linear mixed model analysis
N0
N1
N2a
N2b
N2c
N2 (nasopharynx)
N3
Total
T0 T1 T2 T3 T4 Unknown
2 62 109 36 64 8
1 13 24 17 18 8
0 4 7 0 3 7
1 24 24 17 31 11
2 7 17 27 60 0
0 0 3 1 0 0
0 2 7 1 6 4
6 112 191 99 182 38
Total
281
81
21
108
113
4
20
628a
a
Of 50 patients, T classification was missing: TN classification was reported (n = 38) or no classification was applicable (n = 12; in example, for a non-malignant pleiomorf adenoma). Of 13 patients, no N classification was reported.
In the linear mixed model analysis, mouth opening was statistically predicted by the location of the tumor, Ln (months), gender, baseline mouth opening, tumor stage T4, baseline age, and target volume on primary tumor. All main effects interacted with Ln (months) (Table 4). The results of the linear mixed model analysis can predict mouth opening post-RT statistically. For example, for a 70-yearold male with a T2 carcinoma in the oral cavity who received target volume on the primary tumor only, with a mouth opening of 40 mm at baseline, mouth opening can be estimated at 36 months post-RT by using the following equation:
Table 3 Mouth opening and numbers of patients with trismus. Months post-RT
N patients per point of time (deceased before follow-up)
N cumulative deceased patients
Mean mouth opening (sd)
Mean mouth opening (sd)a
N patients with trismus (%)
N patients with trismus (%)a
Baseline 6 months 12 months 18 months 24 months 36 months 48 months
566 473 425 392 368 230 131
0 18 87 131 163 184 196
38.7 36.7 37.3 37.3 38.0 38.0 38.2
39.5 38.7 39.1 37.9 38.3 37.2 –
196 (34.6) 203 (42.9) 161 (37.9) 160 (40.8) 139 (37.8) 83 (36.1) 48 (36.6)
33 29 33 43 40 39 –
(18) (69) (44) (32) (21) (12)
(10.8) (10.0) (10.3) (10.6) (10.7) (10.6) (11.5)
(10.4) (9.6) (11.1) (10.8) (10.7) (10.7)
(31.7) (27.9) (31.7) (41.3) (38.5) (37.5)
a Cohort of patients (n = 104) with complete data up to 36 months post-RT. There were 59 patients with complete data up to 48 months post-RT, however, for statistical reasons the cohort up to 36 months was used.
Please cite this article in press as: Kamstra JI et al. Mouth opening in patients irradiated for head and neck cancer: A prospective repeated measures study. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.01.016
4
J.I. Kamstra et al. / Oral Oncology xxx (2015) xxx–xxx
Fig. 1. Course of mouth opening per tumor location. Note: Y-axis starts at 30 mm.
Mouth opening ¼ 12:88 þ ½1:57 ðoral cavityÞ þ ½4:00 3:58ðLnðmonthsÞÞ þ ½1:10ðmale genderÞ þ ½0:69 40ðbaseline mouth openingÞ þ ½0:05 10ðbaseline age centered at 60 yearsÞ
post-RT (Table 4 and Fig. 2). The longitudinal course of mouth opening differed between primary tumor locations (Figs. 1 and 2).
Interpretation
þ ½4:76ðtarget volume on primary tumorÞ þ ½0:69 3:58ðoral cavity LnðmonthsÞ þ ½0:32 3:58ðmale gender LnðmonthsÞ þ ½0:10 40 3:58ðbaseline mouth opening LnðmonthsÞ þ ½0:01 10 3:58ðbaseline age centered at 60 years LnðmonthsÞ þ ½1:69 3:58ðtarget volume on primary tumor LnðmonthsÞ ¼ 35; 1 mmðNote Lnð36monthsÞ ¼ 3:58:Þ Mean predicted mouth opening according the multivariable prediction model differed per tumor location (Fig. 2). Mouth opening of patients with tumors of all included locations decreased in the first 6 months post-RT, except when the tumor was located in the salivary glands or ears. When patients had a lymph node metastasis from an unknown primary, mouth opening did not decrease in these first 6 months either. The linear mixed model analysis was repeated for the cohort of patients with complete data (n = 104) (Appendix 1). The differences in regression coefficients were largest for the interactions between Ln (months) and location of the primary tumor.
Discussion Key results The mean mouth opening of the study population changed marginally over time. The results of our study showed that mouth opening can be predicted statistically by a variety of risk factors and their interactions. Based on the multivariable prediction model, the longitudinal course of mouth opening can be predicted statistically. We found that mean mouth opening decreased the first 6 months post-RT and gradually recovered up to 48 months
The consequences of trismus are severe, and trismus secondary to head and neck cancer is hard to treat. If the multivariable prediction model presented in our study indicates high risk of trismus, preventive measures can be taken to prevent deterioration of mouth opening. For example, patients who perform exercises during RT experience a smaller decrease in mouth opening compared to those who do not exercise [16,26,27]. Additionally, a larger increase in mouth opening is expected when exercises are started early [28]. However, such preventive programs can be a burden to patients, especially during the course of RT. These programs should therefore be limited to those with the highest risks. The interactions between location of the tumor and Ln (months) indicate that the change over time depends on the location of the tumor. The results of our study showed on average only a small decrease in mouth opening over time, with the highest percentage of patients with trismus at 6 months post-RT. The percentage of patients with trismus at 48 months post-RT was nearly the same as the percentage at baseline. The largest change in mouth opening occurred during the first 6 months post-RT, in both the course of mouth opening (Fig. 1) and the predicted mouth opening according the multivariable prediction model (Fig. 2). The interaction term between Ln (months) and mouth opening prior to RT indicates that a larger mouth opening prior to RT will result in a greater loss of mouth opening post-RT. About 30% of the study population died, most likely the patients with T4 tumors and those who underwent more intensive treatment. Such patients are more likely to develop trismus. The dropout of these patients could explain the recovery of mouth opening over time. Up to 48 months post-RT, only 59 patients had complete data. However, to verify the model in a cohort of patients with complete data, a larger sample was preferred. Therefore, we decided to use
Please cite this article in press as: Kamstra JI et al. Mouth opening in patients irradiated for head and neck cancer: A prospective repeated measures study. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.01.016
5
J.I. Kamstra et al. / Oral Oncology xxx (2015) xxx–xxx Table 4 Results of the linear mixed model analysis to predict mouth opening post-RT of the study population (n = 641). Risk factors
b
Se (b)
p
95% CI lower bound
95% CI upper bound
Intercept Tumor location Oral cavity Oro- and nasopharynx Salivary glands and ear Hypo- and supraglottic larynx Glottic- and subglottic larynx Nasal cavity and maxillary sinus Unknown primary Ln (months) Male gender Baseline mouth opening Stage T4 Baseline age centered at 60 years Target volume on primary tumor
12.88
1.47
10.00
15.77
1.57 1.04 2.56 3.56 4.40 1.26 – 4.00 1.10 .69 1.14 .05 4.76
2.58 2.62 2.61 2.63 2.63 2.68 – .32 .50 .02 .52 .02 2.34
