Abstract
Objective:
To compare salivary flow rates between females and males, before and after radiation therapy (RT) for head and neck cancer (HNC).
Methods:
Prospective observational multicenter cohort study (OraRad). Stimulated whole salivary flow was measured before RT and at 6 and 18 months after RT.
Results:
Mean (95% confidence interval) salivary flow in g/min before RT was 0.81 (0.71, 0.90) in females (n = 107) and 1.20 (1.15, 1.25) in males (n = 391) (p < 0.001); at 6 months was 0.34 (0.24, 0.44) in females and 0.50 (0.44, 0.55) in males (p = 0.01); at 18 months was 0.49 (0.38, 0.59) in females and 0.70 (0.64, 0.75) in males (p < 0.001). Median nadir salivary flow after RT was 0.22 in females and 0.35 in males (p < 0.001). A lower nadir salivary flow in females, but not males, was associated with an increased risk for tooth failure (p = 0.02).
Conclusions:
Females with HNC have lower stimulated whole salivary flow than males, before and after RT. Low salivary flow after RT may be a risk factor for tooth failure among females. The lower pre-RT salivary flow rates in females, combined with prior literature in other populations, indicates that, in general, females have lower stimulated salivary flow than males.
Keywords: head and neck neoplasms, radiotherapy, saliva, sex, tooth loss, xerostomia
1 |. INTRODUCTION
Saliva serves several important functions including in mastication, swallowing, taste, and speech. Reduced salivary flow (hyposalivation) is often associated with impairments in these functions, a subjective complaint of dry mouth (xerostomia), and an increased risk for oral disease including dental caries. This is especially true in patients who have received high doses of radiation therapy (RT) for treatment of head and neck cancer (HNC). Most such patients have significant long-term hyposalivation, which leads to increased risk for dental caries, tooth loss, osteoradionecrosis, and impairment of quality of life (Brennan et al., 2022, 2023; Lalla et al., 2023; Lin et al., 2022; Patton et al., 2023; Treister et al., 2022).
Objective assessment of the presence and degree of hyposalivation is important for risk assessment and to guide management strategies (Purdie et al., 2023). This is typically done by measuring stimulated and/or unstimulated whole saliva production over a defined period of time. The standard normal value for unstimulated whole saliva is over 0.1–2 mL/min, while normal stimulated whole salivary flow is 0.7 mL/min or higher (Navazesh & Kumar, 2008). In clinical practice and many research studies, these normal values are applied for both males and females. However, some studies (Galvão-Moreira et al., 2018; Heintze et al., 1983; Li-Hui et al., 2016) have suggested that females normally have a lower salivary flow than males, although this difference has not been well-appreciated by the clinical and research communities.
The aim of this study was to compare objectively measured stimulated whole salivary flow rates between females and males before and after RT for HNC, and to assess the potential impacts of variation between the sexes on the risks for adverse dental/oral outcomes after RT.
2 |. METHODS
2.1 |. Study design
The OraRad study is a prospective observational cohort study of patients receiving RT for HNC (Lalla et al., 2017). Patients were enrolled at six US sites. Institutional Review Board approval was obtained at all sites and all participants provided written informed consent. Patients were eligible if: age 18 years or older; had at least one natural tooth present, diagnosed with head and neck squamous cell carcinoma (SCC) or a salivary gland cancer (SGC), or with a non-SCC, non-SGC malignancy and to receive at least 4500 cGy radiotherapy to the head and neck region. Patients receiving palliative RT or with a history of prior curative RT for HNC were excluded. A total of 572 participants were enrolled between April 2014 and October 2018. The sample size was based on power analyses for the primary outcome of tooth loss (Lalla et al., 2017).
2.2 |. Demographic and treatment data
Information about demographic variables, including the patient’s sex, was collected by self-report. Data on cancer treatments received was collected from the medical record.
2.3 |. Measurement of salivary flow
The stimulated whole salivary flow rate was measured at baseline (prior to RT), and at 6 and 18 months after the start of RT (Lin et al., 2022). Individuals who missed their salivary flow measure-ments at the 6-month or 18-month visit were allowed to make up the measurement at the next subsequent visit: 12 months (n = 30) or 24 months (n = 40), respectively. Participants were provided with unflavored paraffin gum base, a digital timer, and two 50 mL test tubes. To standardize the technique and stabilize the flow rate, participants were initially instructed to chew the gum base for 2 min, and to expectorate saliva into one of the test tubes. Following this, the same chewing/expectorating method was then used for 5 min for the actual flow rate assessment. The amount of saliva collected in 5 min was weighed and recorded, after adjusting for the pre-recorded weight of the paraffin gum base and test tube.
2.4 |. Assessment of missing and hopeless teeth
A tooth was recorded as “missing” if no part of the tooth was clinically visible in the oral cavity at the study visit. A tooth was recorded as “hopeless” if it was present and met one or more of the following criteria: non-restorable due to fracture or extensive caries, amputated crown with root remaining, persistent or uncontrolled odontogenic or periodontal infection. “Tooth failure” was defined as a tooth that was either newly missing or declared hopeless since the last study visit (Brennan et al., 2022).
2.5 |. Assessment of exposed bone
Exposed bone was clinically assessed as visible exposed bone in the mouth, with loss of the overlying soft tissue. The location of exposed bone was recorded using the tooth numbers of teeth present or normally present in that location and allowed for locations covering the region of third molars (Treister et al., 2022).
2.6 |. Statistical analyses
Continuous values were summarized using medians and ranges and compared using Mann–Whitney U tests. Categorical variables were summarized using proportions and compared using Fisher’s exact tests.
Linear mixed-effects models with subject-specific random intercepts were used to evaluate change in salivary flow. Association between sex and change in salivary flow was evaluated by testing interaction terms between study visits (treated as categorical) and sex (treated as binary). Additional analyses adjusted for changes in salivary flow associated with chemotherapy and surgery by including the interaction between study visits and chemotherapy/surgery categories. To test whether salivary flow changed proportionally between males and females, it was log-transformed. Salivary flow values of zero were imputed at half of the minimum non-zero value prior to log-transformation.
Cox proportional hazards models with Breslow’s methods for ties were used to test the relationship between salivary flow measures and sex on time to first study visit at which a tooth failure event was recorded. Participants were censored at last visit attended. Two measures of salivary flow were evaluated: baseline salivary flow classified into above or below the sex-specific median baseline salivary flow rate, and nadir salivary flow which was defined as the lowest salivary flow experienced by an individual during follow-up.
Given the low frequency of exposed bone events, permutation tests were used to evaluate the interaction between sex and salivary flow measures on the odds of exposed bone during follow-up. The permutation was conducted such that only the relationship between salivary flow and sex was permuted across 10,000 iterations while keeping the relationship between sex and exposed bone and salivary flow measures and exposed bone constant. The test statistic for the permutation tests was the logratio of odds ratio statistic generated from logistic regression models.
Analyses were conducted using R version 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria). All p-values are two-sided and have not been adjusted for multiple comparisons.
3 |. RESULTS
There were 518 individuals (113 females and 405 males) who had stimulated salivary flow measured during the study and had follow-up information on exposed bone or tooth failure (Table 1). Stimulated whole salivary flow was measured at baseline (pre-RT), and at 6-month and 18-month post-RT visits for 498 (107 females and 391 males), 481 (104 females and 377 males) and 422 participants (87 females and 335 males), respectively. Reasons for non-participation at each stage and a flow diagram have been published (Brennan et al., 2022). Female participants were significantly less likely to be white, former or current smokers, or to receive chemotherapy as an additional therapy. Females were significantly more likely to receive surgery (including parotid gland surgery), have a primary site of oral cavity or SGC, and to receive a lower total RT dose to the primary site.
TABLE 1.
Comparison of baseline clinical and demographic characteristics between sexes. Median (range) or N (%) are presented.
| Characteristic | Overall (N = 518) | Male (N = 405) | Female (N = 113) | p-value |
|---|---|---|---|---|
| Age (years) | 58.0 [21.0, 89.0] | 59.0 [21.0, 89.0] | 58.0 [23.0, 88.0] | 0.098 |
| Race | ||||
| White Only | 428 (82.6%) | 353 (87.2%) | 75 (66.4%) | <0.001 |
| Black Only | 39 (7.5%) | 21 (5.2%) | 18 (15.9%) | |
| Other | 51 (9.8%) | 31 (7.7%) | 20 (17.7%) | |
| Educational level | ||||
| ≤High school | 142 (27.5%) | 110 (27.3%) | 32 (28.3%) | 0.738 |
| >High school | 374 (72.5%) | 293 (72.7%) | 81 (71.7%) | |
| Dental insurance | ||||
| Does not have | 185 (35.7%) | 143 (35.3%) | 42 (37.2%) | 0.800 |
| Has | 333 (64.3%) | 262 (64.7%) | 71 (62.8%) | |
| Smoking status | ||||
| Former or current smoker | 281 (54.4%) | 237 (58.7%) | 44 (38.9%) | 0.001 |
| Never used | 236 (45.6%) | 167 (41.3%) | 69 (61.1%) | |
| Type of RT | ||||
| IMRT | 452 (87.3%) | 98 (86.7%) | 354 (87.4%) | 0.557 |
| IMRT with other modality | 22 (4.2%) | 8 (7.1%) | 14 (3.5%) | |
| Proton only | 30 (5.8%) | 5 (4.4%) | 25 (6.2%) | |
| 3-D conformal radiation | 12 (2.3%) | 2 (1.8%) | 10 (2.5%) | |
| Other | 1 (0.2%) | 0 (0.0%) | 1 (0.2%) | |
| Unknown | 1 (0.2%) | 0 (0.0%) | 1 (0.2%) | |
| Primary Site of RT | ||||
| Oropharynx | 244 (47.1%) | 216 (53.3%) | 28 (24.8%) | <0.001 |
| Oral cavity | 66 (12.7%) | 34 (8.4%) | 32 (28.3%) | |
| Salivary gland | 50 (9.7%) | 30 (7.4%) | 20 (17.7%) | |
| Larynx/Hypopharynx | 36 (6.9%) | 31 (7.7%) | 5 (4.4%) | |
| Other | 122 (23.6%) | 94 (23.2%) | 28 (24.8%) | |
| RT treatment to primary site | ||||
| Bilateral | 201 (38.9%) | 159 (39.4%) | 42 (37.2%) | 0.795 |
| Unilateral | 316 (61.1%) | 245 (60.6%) | 71 (62.8%) | |
| Total dose to primary site of RT (cGy) | 6600.0 [636.0, 7639.0] | 6996.0 [636.0, 7639.0] | 6600.0 [4000.0, 7440.0] | 0.002 |
| Mean RT dose to the parotids (cGy) | 2630.5 [0, 6712.5] | 2653.5 [0, 6712.5] | 2531.0 [0, 6167.5] | 0.073 |
| Mean RT dose to the mandible (cGy) | 3691.0 [0, 7180.0] | 3715.0 [0, 7180.0] | 3614.0 [0, 5690.0] | 0.408 |
| Received surgery pre-RT | ||||
| No | 217 (41.9%) | 185 (45.7%) | 32 (28.3%) | 0.001 |
| Yes | 301 (58.1%) | 220 (54.3%) | 81 (71.7%) | |
| Received parotid gland surgery | ||||
| No | 474 (91.5%) | 379 (93.6%) | 95 (84.1%) | 0.003 |
| Yes | 44 (8.5%) | 26 (6.4%) | 18 (15.9%) | |
| Received chemotherapy | ||||
| No | 192 (37.1%) | 135 (33.3%) | 57 (50.4%) | 0.001 |
| Yes | 326 (62.9%) | 270 (66.7%) | 56 (49.6%) | |
Abbreviations: cGy, centiGray; IMRT, intensity modulated radiation therapy; N, number of participants; RT, radiation therapy.
3.1 |. Differences in salivary flow between females and males
The mean (95% confidence interval) stimulated whole salivary flow rate before the start of RT was 0.81 (0.71, 0.90) g/min for females and 1.20 (1.15, 1.25) g/min for males (p < 0.001; Table 2). For both females and males, there was a significant reduction in salivary flow from baseline to 6 months (p < 0.001; Figure 1; Table A1). This was followed by a partial recovery in salivary flow between 6 and 18 months, but flow at 18 months was still lower than baseline (p < 0.001). Mean salivary flow at 6 months was 0.34 (0.24, 0.44) g/min in females and 0.50 (0.44, 0.55) g/min in males (p = 0.01). Mean salivary flow at 18 months was 0.49 (0.38, 0.59) g/min in females and 0.70 (0.64, 0.75) g/min in males (p < 0.001). Although the post-RT changes in salivary flow were proportionally similar between females and males (p = 0.44), females reached significantly lower nadir values than males. Median nadir salivary flow after RT was 0.22 g/min in females and 0.35 g/min in males (p < 0.001; Figure A1).
TABLE 2.
Difference in stimulated whole salivary flow between sexes.
| Male mean flow (g/min) | Female mean flow (g/min) | Unadjusted difference (g/min) | Difference adjusted for chemotherapy and surgery (g/min) | |
|---|---|---|---|---|
| Baseline (pre-RT) | 1.20 (1.15, 1.25) | 0.81 (0.71, 0.9) | 0.40 (0.29, 0.51), p <0.001 | 0.39 (0.28, 0.50), p <0.001 |
| 6 months after RT | 0.50 (0.44, 0.55) | 0.34 (0.24, 0.44) | 0.16 (0.05, 0.27), p = 0.01 | 0.20 (0.09, 0.32), p <0.001 |
| 18 months after RT | 0.70 (0.64, 0.75) | 0.49 (0.38, 0.59) | 0.21 (0.09, 0.32), p <0.001 | 0.24 (0.12, 0.35), p <0.001 |
Note: Means (95% CI), and p-value are presented. Estimates generated from linear mixed-effects model with subject-specific random effects, interaction between study visits and sex, and main effects for study visits and sex. Adjusted model additionally included chemotherapy/surgery categories and the interaction between chemotherapy/surgery categories and study visit.
Abbreviation: RT, radiation therapy.
FIGURE 1.
Stimulated whole salivary flow at each visit by sex. Figure presents means with 95% confidence intervals. See Table 2 and Table A1 for additional details. Visit 0 = Baseline visit (before start of radiation therapy [RT]); Visit 6 = 6 months after start of RT; Visit 18 = 18 months after start of RT. Asterisks denote statistical significance at each time point. ***p ≤ 0.001 at visits 0 and 18. **p ≤ 0.01 at visit 6.
3.2 |. Effect of variation in salivary flow between sexes on risk of tooth failure
During the 2 years after RT, 16 of 113 females (14.2%) and 66 of 405 males (16.3%) experienced tooth failure (had one or more teeth extracted or declared as “hopeless”).
Baseline salivary flow was classified as above or below the sex-specific median salivary flow rate before the start of RT which was 0.81 g/min for females and 1.10 g/min for males. There was no detectable interaction between this measure and sex on the time to first tooth failure (ratio of hazard ratios (HRs): 1.72, 95% CI: 0.52–5.71, p = 0.37). For individuals with baseline salivary flow below their sex-specific median value, there was not a significant difference in the time to first tooth failure between males and females (HR: 0.91, 95% CI: 0.44–1.89, p = 0.81). Similarly, for individuals with baseline salivary flow above their sex-specific median value, there was not a significant difference in the time to first tooth failure between sexes (HR: 1.57, 95% CI: 0.61–4.07, p = 0.35).
There was a significant interaction between sex and nadir salivary flow (p = 0.03) on the time to first tooth failure. For females, a 0.1 g/min lower nadir salivary flow was associated with a 38% increased risk of tooth failure (HR = 0.62, 95% CI: 0.43–0.92, p = 0.02). On the other hand, for males there was not a significant relationship between nadir salivary flow and time to first tooth failure (HR = 0.96, 95% CI: 0.89–1.03, p = 0.28).
3.3 |. Effect of variation in salivary flow between sexes on risk of exposed bone
During the 2 years after RT, 6 of 113 females (5.3%) and 29 of 405 males (7.2%) experienced exposed intraoral bone.
There was a significant interaction between sex and baseline salivary flow classified as above or below the sex-specific median value on the risk of exposed bone (p = 0.03). None (0%) of the 54 females with pre-RT stimulated whole salivary flow above the female median experienced exposed bone post-RT as compared to 5 of 53 (9.4%) females with pre-RT salivary flow below the female median (p = 0.06).
Among males, the occurrence of exposed bone was similar between those whose pre-RT salivary flow was above or below the male median (7.1% vs. 7.2%, respectively, p > 0.99).
The risk of exposed bone among females with pre-RT stimulated whole salivary flow above the female median was significantly lower compared to males with pre-RT salivary flow above the male median (0% vs 7.1%, respectively; p = 0.05). Among individuals with pre-RT stimulated whole salivary flow below their sex-specific median value, the risk of exposed bone was comparable between males and females (7.2% vs 9.4%, respectively, p = 0.56).
There was not a detectable interaction between sex and nadir salivary flow on the risk of experiencing exposed bone (p = 0.71). Nadir salivary flow rates were similar between females who did versus did not experience exposed bone (p = 0.39) and between males who did versus did not experience exposed bone (p = 0.44; Table A2).
4 |. DISCUSSION
Measurement of stimulated whole salivary flow is a commonly used method to objectively assess the presence and degree of salivary hypofunction. The saliva produced is usually measured by weighing it. A value lower than 0.7 g/min (sometimes represented as 0.7 mL/min) is considered to indicate salivary hypofunction (Navazesh & Kumar, 2008). However, this cut-off is usually applied to both females and males, without consideration for potential variation between the sexes. Our study demonstrates that prior to the start of RT, female participants had a significantly lower stimulated whole salivary flow as compared to the male participants. At baseline, the mean stimulated whole salivary flow for females (0.81 g/min) was about 33% lower than that for males (1.20 g/min; p < 0.001). Considering the typically used cut-off value of 0.7 g/min, 44% of females were already below this value at baseline compared to 24% of males. As this measurement preceded the start of RT, this difference cannot be attributed to the effects of RT. Although females were less likely to receive chemotherapy, and more likely to receive surgery, including parotid gland surgery, there continued to be a significantly lower baseline salivary flow for females after accounting for these differences (see Table 2). Therefore, this difference in baseline salivary flow can be attributed to a normal variation between the sexes, rather than to any characteristic of the HNC patient population.
Although it has not been well-appreciated, there is prior support in the literature for this variation in normal salivary flow between sexes. Parvinen and Larmas measured stimulated whole salivary flow over 5 min in 326 females and 316 males, all over the age of 30 years. The mean stimulated whole salivary flow was 8.6 mL/5 min for females and 10.1 mL/5 min for males (p < 0.001; Parvinen & Larmas, 1981). Bergdahl measured unstimulated and stimulated whole salivary flow rates in 758 women and 659 men, aged between 20 and 69 years. The mean unstimulated whole salivary flow rate was 0.26 mL/min for women and 0.33 mL/min for men (p < 0.001). The mean stimulated whole salivary flow rate was 2.02 mL/min for women and 2.50 mL/min for men (p < 0.001; Bergdahl, 2000). Kado et al measured stimulated whole salivary flow in 387 females and 232 males, with an overall mean age of 14.6 years. The mean stimulated whole salivary flow rate was 1.21 mL/min for females and 1.35 mL/min for males (p = 0.0048), thus demonstrating that a difference in salivary flow between the sexes is present at younger ages as well (Kado et al., 2021). Percival et al. reported a significantly lower mean unstimulated whole salivary flow rate of 0.33 mL/min in 61 adult females, as compared to 0.50 mL/min in 55 adult males (p < 0.005). Interestingly, they also found a significantly lower stimulated parotid saliva flow rate in females (0.45 mL/min) as compared to males (0.59 mL/min) (p < 0.05) (Percival et al., 1994). Thus, the previous literature supports our finding of lower stimulated whole salivary flow rate in females and indicates that this difference by sex also applies to unstimulated whole salivary flow and to the parotid glands specifically.
The reason for this difference in salivary flow between the sexes has not been extensively studied, but some data suggest that it is principally related to the size of the salivary glands. Ono et al. measured the sizes of the 3 major salivary glands in 28 young adults using magnetic resonance imaging (MRI). They found that the unstimulated whole salivary flow rate was significantly correlated with the size of the parotid (r = 0.50, p = 0.007) and submandibular (r = 0.44, p = 0.02) glands. The size of the parotid glands was also significantly correlated with body weight (r = 0.66, p < 0.001; Ono et al., 2006). Inoue et al. used MRI to measure the size of the parotid and submandibular glands in 26 female and 24 male healthy young adults. They found that the mean size of the parotid and submandibular glands was significantly smaller in females (p < 0.001 for each gland type). Furthermore, the gland sizes in both women and men were significantly correlated with unstimulated whole salivary flow rate, as well as with Body Mass Index (BMI). Therefore, they concluded that the lower mean salivary flow rate in women is due to their smaller salivary glands, which is attributed to the lower BMI of women as a group compared to men (Inoue et al., 2006). Data from the Third National Health and Nutrition Examination Survey (NHANES III) indicate a median BMI of 24.5 for healthy US men as compared to 21.5 for healthy US women (Flegal, 2006).
It is not clearly understood whether this normal variation in salivary flow between the sexes puts women at higher risk for oral disease. Although some studies have demonstrated higher caries experience in women as compared to men, this is not a consistent finding (Bertilsson et al., 2021; Brown et al., 2002; Lukacs, 2011). In theory, if a relatively lower salivary flow in women is in the setting of a smaller oral cavity, then proportionally less saliva may be needed to normally maintain health. However, in situations where salivary flow is reduced, then the lower baseline salivary flow of women may make them more likely to reach critically low levels that increase risk for disease. In the present study, even though the post-RT changes in salivary flow were proportionally similar in women and men, women reached significantly lower levels as a group because of their lower mean baseline levels. The median nadir flow rate was 0.22 g/min for females and 0.35 g/min for males (p < 0.001). Despite partial recovery in flow by 18 months after RT, the median stimulated whole salivary flow rate at 18 months was 0.43 g/min for females and 0.60 g/min for males (p < 0.001). Although a greater proportion of women had oral cancers or had parotid gland surgery, adjusted analyses accounting for these confounders still demonstrated significantly lower salivary flow for women at both 6 and 18 months after RT. Furthermore, women received a slightly lower total RT dose to the primary site and mean RT dose to the parotid glands as compared to men. This persistently lower salivary flow in females appears to impact their risk for post-RT complications. There was a significant relationship between nadir salivary flow and risk of tooth failure in females, which was not seen in males. Furthermore, the risk of exposed bone was significantly lower among females with a pre-RT salivary flow greater than the female median as compared to females with lower salivary flow. Thus, although women as a group overall did not have an increased risk of tooth failure or exposed bone in our study (Brennan et al., 2022; Treister et al., 2022), females with lower salivary flow did demonstrate an increased risk, which was not seen for men with lower salivary flow.
Strengths of this study include its large sample size across six clinical centers, and use of standardized methodology, training, and materials for measurement of salivary flow, as well as for assessment of other outcomes. A centralized Data Coordinating Center reviewed all data entered and identified any missing, incomplete or inconsistent entries for resolution. Limitations of this analysis include the fact that salivary flow was measured at only three time-points over the 2-year study period. Therefore, the nadir values we measured may not have been the true nadir. We also did not measure unstimulated salivary flow rate and BMI, which would have been interesting to compare between men and women.
In conclusion, this study demonstrates that females with HNC have lower stimulated whole salivary flow than males, before and after RT. When considered in the context of the prior literature cited, this difference in salivary flow between the sexes appears to be a general finding that is not limited to the HNC population. Such variations may put women with lower baseline salivary flow at higher risk for oral disease in situations where salivary flow is pathologically reduced.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the contributions of all the study participants and of study personnel at each clinical site and the Data Coordinating Center.
FUNDING INFORMATION
The Observational Study of Dental Outcomes in Head and Neck Cancer Patients (also known as OraRad) is funded by grant U01 DE022939 from the National Institute for Dental and Craniofacial Research (USA) awarded to the study principal investigators Drs. Brennan and Lalla. The sponsor had no role in the preparation of this manuscript.
APPENDIX A
TABLE A1.
Change in salivary flow across visits.
| Visit comparison | Male change in flow (g/min) | Female change in flow (g/min) |
|---|---|---|
| 6 months—baseline (pre-RT) | −0.71 (−0.76, −0.66) | −0.47 (−0.56, −0.37) |
| 18 months—baseline (pre-RT) | −0.51 (−0.56, −0.46) | −0.32 (−0.42, −0.21) |
| 18 months—6 months | 0.20 (0.15, 0.25) | 0.15 (0.05, 0.26) |
Note: Estimated mean change and 95% confidence intervals are presented.
Abbreviation: RT, radiation therapy.
TABLE A2.
Comparison of nadir salivary flow rates between individuals who did versus did not experience exposed bone stratified by sex.
| Did not experience exposed bone | Experienced exposed bone | p-value | |
|---|---|---|---|
| Female | 0.22 (0.11,0.50), N = 101 | 0.22 (0.04,0.47), N = 6 | 0.394 |
| Male | 0.35 (0.20,0.64), N = 366 | 0.31 (0.22,0.51), N = 27 | 0.438 |
Note: Median (interquartile range) and Wilcoxon rank sum p-values are presented.
FIGURE A1.
Distribution of salivary flow by sex at baseline before start of radiation therapy (RT), 6 months after start of RT and 18 months after start of RT. The dot and line represent median and quartiles at each visit.
Footnotes
CONFLICT OF INTEREST STATEMENT
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
DATA AVAIL ABILIT Y STATEMENT
The data required to reproduce these findings will be made available upon request.
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Associated Data
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Data Availability Statement
The data required to reproduce these findings will be made available upon request.