Introduction

Head and neck cancer (HNC) and its treatment often leaves survivors with multiple morbidities that impact quality of life (QOL). QOL among survivors can vary based on involved cancer site, treatment rendered (surgery, radiation therapy [RT] and chemotherapy [CT]), lifestyle factors, and other sociodemographic characteristics [1]. Questionnaires specific to HNC QOL are important to capture the patient experience of how their life is changed by disease and/or treatment related toxicity. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-HNC specific module-35 items (H&N35) scale is generally considered the most used and validated instrument for these assessments [2,3,4]. It has been shown to be reliable and sensitive across different cancer patient and treatment groups in many countries [5].

RT is a primary definitive treatment modality for HNC. RT may be delivered alone, with or without surgery, and with or without CT [6]. Recognition of long-term sequela of inadvertent exposure of radiosensitive salivary gland tissue lying in proximity to tumors and nodal beds has led to efforts to alter radiation technique to help preserve salivary gland function [7]. With gradual advances in HNC RT techniques from two-dimensional RT (2DRT), to three-dimensional conformal RT (3D-CRT), and finally to intensity modulated RT (IMRT), HNC patients have had better outcomes in swallowing, senses (taste/smell), teeth complications, mouth opening, dry mouth and sticky saliva [7]. With technological advances in RT beyond traditional photon therapy, use of proton therapy [8] and functional magnetic resonance imaging (MRI)-guided biologically adapted proton therapy [9] are new options for treatment to avoid nearby critical structures, such as salivary glands.

This analysis reports changes in oral health QOL (OH-QOL) responses over the first 2 years after curative intent RT in the multicenter Clinical Registry of Dental Outcomes in Head and Neck Cancer Patients (OraRad) cohort.

Subjects and Methods

Subjects

The prospective, longitudinal, multicenter clinical registry of dental outcomes in HNC patients (OraRad study) has been previously described, [10]. Institutional Review Board approval was obtained at all sites. From April 2014 to October 2018, 572 participants were enrolled before initiating curative-intent (definitive or postoperative) head and neck RT and were followed at 6-month intervals until 24-months post-RT. Eligibility requirements included: age 18 or older; diagnosed with head and neck squamous cell carcinoma (SCC) or a salivary gland cancer (SGC), or with a non-SCC, non-SGC malignancy of the head and neck region; planned to receive at least 4500 cGy RT to the head and neck region; and had no prior RT to the head and neck region. The first (baseline) study assessments occurred after the pre-radiation dental evaluation and any required extractions and before the first radiation treatment session.

Demographic, tumor and treatment variables

The clinical protocol and variable definition and collection timepoints have been previously reported [10]. Tumor and treatment data were obtained by health record review. Primary tumor site was classified 5 domains: oropharynx (base of tongue, tonsil, oropharynx, and soft palate); oral cavity (oral tongue, oral cavity, gingival/alveolar ridge, mandible, buccal/labial mucosa, floor of mouth, maxilla, retromolar trigone, hard palate, and lip); larynx/hypopharynx (larynx, hypopharynx, and epiglottis); salivary gland (submandibular gland, parotid, and sublingual gland); and other (neck, nasopharynx, pharynx, maxillary sinus, nasal cavity and other sites).

OH-QOL variables

Patient-reported symptoms important to OH-QOL were assessed at each study visit: baseline prior to RT and at 6, 12, 18, and 24-months post-RT, using selected single item questions and composite scales from the EORTC QLQ -H&N35 scale [2, 3]. Ten individual question items were scored on a four-point scale (1 = not at all; 2 = a little; 3 = quite a bit; 4 = very much). These items included patient experience in the past week of problems swallowing liquids, pureed food, and solid foods and choking when swallowing, problems with sense of smell and taste, problems with teeth, opening mouth, dry mouth, and sticky saliva. Two composite scales were assessed: problems with swallowing (which summarizes the problems swallowing liquids, pureed food, and solid foods and choking when swallowing items), and senses problems (which summarizes the problems with sense of smell and taste items). Prior to analysis the ten 4-point scale items and two composite scales were transformed into 1-to-100 scales, with higher scores representing higher level of symptoms. These scales were treated as continuous in all analyses. A 10 unit or more change on a 1–100 scale of variations in mean scores over time for items and scales has been rated as clinically meaningful [2]. Problem severity is demonstrated by percentage of patients who reported mean scores over 50, which corresponds to responses “quite a bit” or “very much” on single items.

Statistical Methods

Linear mixed-effects models with subject specific random intercepts were used to evaluate change in QOL measures across study time points. Associations between covariates and change in QOL measures were evaluated by testing interaction terms between study visits (treated as categorical) and the covariate. Results for covariates that were statistically associated (p-value < 0.05) with a clinically meaningful (≥ 10 unit) change in at least one QOL measure are further described in the text. Trends were visualized using locally estimated scatterplot smoothing (loess) lines [11]. The supplementary appendix gives results for all risk factors considered. Analyses were conducted using R version 4.2.0 [12] using versions 1.1.29, 3.1.3, and 1.7.4.1 of the “lme4” [13], “lmerTest” [14], and “emmeans” [15] packages, respectively. All p-values are two-sided and have not been adjusted for multiple comparisons.

Results

The study enrolled 572 participants with a mean age of 58 (range 21–97) years (Table 1). Males and whites comprised the majority (76.9% and 82.9%, respectively). Most (72.0%) had education beyond high school, were former (51.4%) or current (4.9%) smokers, and (62.7%) currently drink alcohol. Approximately half of primary tumors were in the oropharynx and of those 87.4% were HPV-positive tumors. Regional lymph nodes were involved in 75% of patients. Most (93.2%) received either chemotherapy and/or surgery as additional therapies besides RT. Most RT was delivered by IMRT. The total RT dose to the primary tumor was a mean (sd) of 6572.8 (662.6) cGy, with 42.2% receiving over 7000 cGy and 6% under 6000 cGy.

Table 1 Baseline clinical and demographic characteristics of the OraRad cohort (N = 572)
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OH-QOL trends over time

OH-QOL, as assessed by the 10 single QOL items and 2 combined scales, demonstrated variable levels of change over the 2-year period (Table 2). All items except problems with teeth significantly changed (p-values < 0.01), with senses problems (including problems with taste), sticky saliva, and dry mouth having clinically meaningful (≥ 10 unit) changes.

Table 2 Quality of Life Measures at each time-point and comparison of change from pre-RT. Visit specific model estimated mean (95% CI) for EORTC measures are presented. EORTC scale scores range from 0 to 100 with higher scores representing decreased quality of life
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The senses problems scale significantly increased from average scores of 11.5 (95% CI 9.5 to 13.4) at baseline to a peak of 33.4 (95% CI: 31.3 to 35.4) at 6-months. Scores decreased to 27.3 (95% CI: 25.2 to 29.4) at 12-months but continued to remain elevated compared to baseline at the 18-month and 24-month visits. The problems with sense of taste subscale increased from an average score of 14.8 (95% CI: 12.3 to 17.3) at baseline to 48.6 (95% CI: 45.9 to 51.3) at 6-months. Scores slightly improved to 39.6 (95% CI: 36.8 to 42.4) at 12-months but were still significantly elevated compared to baseline at the 18- and 24-month visits.

Average self-reported dry mouth scores increased from 21.1 (95% CI: 18.5 to 23.7) at baseline to 65.4 (95% CI: 62.7 to 68.2) at 6-months, decreased slightly to 58.3 (95% CI: 55.5 to 61.1) at 12-months, but continued to remain significantly elevated compared to baseline at the 18- and 24-month visits. The sticky saliva scale followed similar trends as the dry mouth scale with an increase from baseline (16.3, 95% CI: 13.7 to 18.8) to 6-months (45, 95% CI: 42.3 to 47.7), slight improvement at 12-months (36.5, 95% CI: 33.6 to 39.3), and continued elevation at 18- and 24- months compared to baseline.

Relationship between patient characteristics and OH-QOL measures

Sex, Age, Race, Ethnicity

Men experienced significantly and clinically meaningful (≥ 10 point) greater increases in problems with sticky saliva from baseline to 12-months and dry mouth from baseline to 6- and 12-months compared to women (Table 3).

Table 3 Difference in change in selected EORTC measures from baseline to each visit based on demographics. Only models with a significant (p < 0.05) relationship between demographic and change in EORTC item are presented. See Supplementary Table S1 for full results. Estimate (95%); p-values are presented
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Individuals older than 65 years experienced a greater increase in dry mouth from baseline to 18-months compared to individuals < 50 years. The oldest age group (over 65 years) also experienced a greater increase in senses problems from baseline to all subsequent visits compared to individuals aged < 50 years. Results followed similar trends but were more pronounced for the sense of taste subscale.

Compared to White individuals, Black individuals had a greater increase in difficulty opening mouth wide from baseline to 6-, 12- and 24-months. Similarly, individuals of other/unknown races had a greater increase in difficulty opening mouth wide scores from baseline to 6-, 18- and 24-months, compared to White individuals.

Non-Hispanic individuals experienced a greater increase in difficulty swallowing solid foods from baseline to 6-months compared to Hispanic individuals. However, Hispanic individuals experienced a greater increase in difficulty opening mouth wide from baseline to 12-, 18-, and 24-months.

Tumor site

Figure 1 presents QOL trends by tumor site. Tumor site was associated with changes in difficulty swallowing solid food (p = 0.037), choking while swallowing (p = 0.038), dry mouth (p < 0.001), and sticky saliva (p = 0.026; Supplementary Table S2).

Fig. 1
figure 1

Relationship between tumor site and OH-QOL measures. Loess curve for EORTC scale by primary site of RT. Visit month has been jittered for visualization purposes. Statistical comparisons between sites are provided in Supplementary Tables S1-S2

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Oropharynx tumors were associated with a significant and clinically meaningful increase in difficulty swallowing solid food from baseline to 12-, 18- and 24-months compared to oral cavity and from baseline to 18- and 24-months compared to larynx/hypopharynx. Individuals with tumors in “other” sites had an increase in difficulty swallowing solid food from baseline to 6-, 12-, and 24-months compared to oral cavity and from baseline to 24-months compared to larynx/hypopharynx.

Larynx/hypopharynx tumors were associated with a decrease in choking while swallowing from baseline to 12- and 18-months compared to oral cavity and oropharynx; from baseline to 12- and 18-months compared to “other” sites.

Oropharynx tumors were associated with increased dry mouth from baseline to 6-, 12-, and 24-months compared to larynx/hypopharynx; baseline to 6- and 12- months compared to oral cavity, baseline to 6- and 18 months compared to “other” sites; and baseline to all subsequent visits compared to salivary gland. A primary site of salivary gland was associated with less of an increase in dry mouth from baseline to 6-months compared to larynx/hypopharynx; baseline to all subsequent visits compared to oral cavity; and baseline to 6-, 12-, and 24-months compared to “other” sites. A primary site of larynx/hypopharynx was associated with less of an increase in dry mouth from baseline to 24-months compared to oral cavity and “other” sites.

Oropharynx tumors were associated with an increase in sticky saliva from baseline to 6-months compared to oral cavity and from baseline to 6-, 12-, and 18-months compared to salivary gland. A primary site of larynx/hypopharynx was associated with an increase in sticky saliva from baseline to 6-months compared to salivary gland tumors.

Tumor stage

Nodal involvement was associated with an increase in dry mouth from baseline to all subsequent visits (p-values < 0.001). In addition, individuals with nodal involvement had an increase in sticky saliva from baseline to 6- and 24-months compared to individuals without nodal involvement (Table 4).

Table 4 Difference in change in selected EORTC measures from baseline to each visit based on AJCC (7th edition) classification and total RT dose to primary site. Only models with a significant (p < 0.05) relationship between classification and change in EORTC item are presented. See supplementary Table S1 for full results. Estimate for specified category or dose (95% CI); p-values are presented
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Radiation dose

Total RT dose to the primary site was associated with an increase in the swallowing scale (p = 0.001), problems swallowing solid foods (p < 0.001), the senses problems scale (p < 0.001), problems with sense of smell (p = 0.031) and taste (p < 0.001), problems opening mouth (p < 0.003), dry mouth (p < 0.001), and sticky saliva (p < 0.001; Table 4). A 1000 cGy difference in dose (the interquartile range in this population) was associated with a clinically meaningful (≥ 10 point) increase in difficulty swallowing solid food, dry mouth, sticky saliva, sense of taste, and the senses problems scale from baseline to 6-months and dry mouth from baseline to 6- and 12-months.

Impact of Treatment Modalities Used

Treatment modality was associated with change in the swallowing scale (p < 0.001); problems swallowing liquids (p < 0.001), pureed foods (p = 0.009), and solid foods (p < 0.001); problems opening mouth wide (p = 0.003); dry mouth (p < 0.001); sticky saliva (p < 0.001); problems with teeth (p = 0.007), senses (p = 0.034), and taste (p = 0.036) (Supplementary Table S3; Fig. 2).

Fig. 2
figure 2

Relationship between cancer treatment modalities and OH-QOL measures. Loess curve for EORTC scale by treatment modality. Visit month has been jittered for visualization purposes. Statistical comparisons are provided in Supplementary Tables S1 and S3

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RT + CT was associated with a greater increase from baseline in problems swallowing solid food compared to surgery + RT (all visits), surgery + RT + CT (all visits), and RT alone (6-months); problems swallowing liquids compared to surgery + RT + CT (6-months) and RT alone (6-months); and problems swallowing pureed food compared to RT alone (6-months). RT alone was associated with a greater increase in problems swallowing solids from baseline to 24-months compared to surgery + RT + CT, and surgery + RT.

RT + CT was associated with a greater increase from baseline in difficulty opening mouth compared to surgery + RT (12- and 24-months) and RT alone (12-months). Surgery + RT + CT was associated with a greater increase from baseline in difficulty opening mouth compared to surgery + RT (12- and 24-months) and RT only (12-months).

RT + CT was associated with a greater increase from baseline in dry mouth compared to surgery + RT (all visits), surgery + RT + CT (6- and 12-months), and RT alone (6-months). Surgery + RT + CT was associated with a greater increase in dry mouth from baseline to 6-, 12-, and 18-months compared to surgery + RT. RT alone was associated with a greater increase in dry mouth from baseline to all visits compared to surgery + RT. RT + CT had an increase in sticky saliva from baseline to 6-months compared to all other modalities.

RT only was associated with a greater increase in problems with teeth from baseline to 12-months compared to all other modalities and baseline to 24-months compared to surgery + RT + CT and surgery + RT.

RT + CT was associated with an increase from baseline in problems with senses (6-months) and problems with taste (6- and 12-months) compared to surgery + RT. RT alone was associated with an increase in problems with taste from baseline to 12-months compared to surgery + RT.

Discussion

Curative intent treatment involving multimodality therapy for HNC contributes to treatment-related toxicities that impact survivor QOL. Improved understanding of OH-QOL, as reported by survivors, can better prepare the cancer care team to develop and select individual treatment plans that not only improve local control and achieve cancer remission, but lessen the long-term burden of treatment toxicities. Mitigation of treatment toxicities can improve the chance of leaving survivors with higher quality years remaining. This is increasingly important because HNC epidemiology is changing to reflect more HPV-positive tumors, that generally result in longer survivorship, [16] extending the interest and focus on enjoying life. Despite technological advances in photon-based RT, including IMRT, the impact of RT dose on salivary glands creates burden for HNC survivors. Our study agrees with a systematic review and meta-analysis [17] that treatment of oropharyngeal tumors results in marked sequelae of dry mouth and sticky saliva.

Numerous retrospective and prospective studies have documented short and long-term functional deficits using patient-reported outcomes from various HNC radiation techniques in single center studies, identifying salivary and swallowing challenges [18,19,20]. Few studies have documented OH-QOL changes among HNC patients after treatment including RT out to 2 years or beyond focusing on impact of IMRT [21, 22]. We previously reported that in the OraRad cohort, salivary flow reduced to 37% of pre-RT level at 6-months, with partial recovery to 59% of pre-RT dose at 18-months and subjective changes in swallowing, mouth opening, dry mouth, and sticky saliva were significantly associated with salivary flow changes [23]. This is consistent with the Likhterov et al. [20] finding of among patients receiving RT, salivary weight declines and improves over 36 months, creating correlated changes in EROTC scores for dry mouth (strongest association), sticky saliva and senses in a prospective study of HNC patients at Mt Sinai Beth Israel Hospital in New York. Although designed to test the validity, reliability and sensitivity of the EORTC questionnaires only up to 1-year post-RT, Bjordal et al. [2] found in their 500 Norwegian, Swedish and Dutch patient cohort (86% received RT; 43% surgery and 14% CT) that dry mouth was the only item in the original study with a mean score post-treatment over 50, indicating severity of symptom report, consistent with our finding.

Adding CT to RT for HNC treatment increases survival [24] and creates higher local toxicity risk [25] thus making CT + RT impact on muscles of mastication and salivary dysfunction more detrimental than RT alone, as suggested in this study. The OraRad study enrolled patients at academic medical centers during a time of multiple trials of de-escalation therapy for HPV-positive oropharyngeal tumors and did not exclude these trial patients from enrollment. De-escalation approaches to HNC treatment are intended to reduce acute and chronic toxicity of therapy without compromising survival by omitting, modifying, or reducing CT or RT dose and volume [26]. While only 6% of our patients received less than 6000 cGy, it is unlikely the OraRad cohort is able to demonstrate any impact of these de-escalation protocols on lowering oral toxicities and thus reducing OH-QOL variables of interest.

The 270 oropharyngeal tumors in our OraRad cohort were mostly (87%) HPV-positive, limiting ability to directly assess HPV-positivity’s impact on OH-QOL changes for this tumor site. However, Korsten et al. [27] reported among 270 oropharyngeal cancer patients, the 29% with HPV-positive tumors had a global QOL pattern that scored better pretreatment, worse during treatment and recovered faster and more fully at 2 years follow-up, than those with HPV-negative tumors, adjusting for sociodemographic, clinical and lifestyle factors, suggesting possible higher adaptability in this often younger population.

HNC treatment may result in long-term challenges with swallowing function. In a study of 228 survivors from 1 month to 40 years post-RT, in a multidisciplinary HNC survivorship clinic at the University of Pittsburgh, 91.2% reported at least one treatment-related impact and 56% reported at least three treatment-related effects impacting their daily life in the last week, with the most important specific outcome occurrence rates being: 51.3% swallowing, 37.3% saliva and 30.3% pain [28]. Choking when swallowing negatively impacted patients’ QOL throughout the 24 months they were followed in the OraRad study. Our finding that swallowing function was most impacted by tumor location in the oropharynx is consistent with Bjordal et al. [2] who report that those with pharyngeal cancer had the highest levels of problems with swallowing. Patients with larger primary tumors also reported greater challenges with swallowing, particularly in the first year post-RT. Radiation approaches have also been attempted to spare dysphagia/aspiration at risk anatomic structures, such as pharyngeal constrictor muscles, involved in post-RT dysphagia and aspiration [29, 30].

Different patient susceptibilities may require different and more patient-specific approaches during pretreatment planning. Considering the assertion of Bjordal et al. [2], that a 10 unit or more change in mean scores over time for items and scales is clinically meaningful to patients, in our study cohort problems with dry mouth, sticky saliva, taste, and senses problems were the assessed OH-QOL aspects of importance as patient reported outcomes at 24-months. RT dose unsurprisingly was most meaningful in a progressive manner at diminishing OH-QOL. Senses of taste and smell were most impacted in older patients. A report of oral and pharyngeal cancer survivor prevalence on January 1, 2022 in the United States (U.S.), estimates 64% being over age 65 years and 63% being alive more than 5 years since their cancer diagnosis [31]. Even in healthy aging, there is a strong inverse influence of age on taste perceptions and preferences [32]. Older patients also experienced greater increases in dry mouth which is consistent with diminished secretory reserve capacity in the aging [33].

The primary outcome of the OraRad study was tooth failure, defined as a tooth being deemed hopeless and/or extracted, by the 24-month post-RT visit. Subjects often had pre-RT oral health assessments and treatment to prevent post-RT dental problems before study enrollment and obtaining baseline assessments. The 2-year estimated fraction of tooth failure was 17.8% and was significantly associated with greater reduction in salivary flow [34]. The OH-QOL question of “during the past week have you had problems with your teeth?” did not show statistically significant changes over the 24-month study period; however, the scores did demonstrate a trend of worsening at each subsequent visit. It is possible that the clinical changes to the dentition and their subsequent impact on OH-QOL is a gradual process over time that will be more impactful for QOL in later years of cancer survivorship. An additional study visit at approximately 7 years after RT is planned for survivors in this OraRad cohort to help answer this question.

There were some limitations to our study including generalizability since OraRad was restricted to HNC patients receiving RT in U.S. academic medical centers, where multidisciplinary cancer management teams including dentists are available for dental care coordination. Time points of assessment of OH-QOL parameters at 6-month intervals may miss more nuanced time-related changes in patient perception. With lack of assessments beyond 24-months after RT we are not able to determine longer term changes in OH-QOL outcomes. QOL measures are subject to recall bias by participants and may be influenced by the Hawthorne effect of participation in a clinical study of oral side effects of RT. Our selected OH-QOL measures could have failed to detect true changes in the patient perception of these outcomes.

Demographic, cancer and treatment variables impacted OH-QOL for HNC patients through the first 24 months after undergoing RT. Despite improving RT techniques designed to limit toxicities, dry mouth, swallowing, and taste impacts of RT remain for at least 2 years, as reminders of the prior cancer treatment, that are made worse by additional use of CT. This work demonstrated toxicity profiles that might be anticipated by various baseline and treatment parameters that should be considered in designing HNC treatment plans and providing patient education about clinical course and duration of OH-QOL-impacting toxicities.