Abstract
Background/Aim: Radiotherapy of head-and-neck cancers can cause xerostomia. This study investigated potential prognostic factors for complete recovery from this complication. Patients and Methods: Eighty head-and-neck cancer patients with radiation-induced xerostomia were retrospectively evaluated. Thirteen characteristics were analyzed for complete recovery (to grade 0) from xerostomia including age, sex, tumor site and stage, nodal stage, upfront surgery, mean dose to ipsilateral, contralateral and both parotid glands, chemotherapy, radiation type and dose, and initial grade of xerostomia. Results: Fifteen patients (18.8%) experienced complete recovery of xerostomia. Significant associations with complete recovery were found for initial grade 1 xerostomia (p<0.001), mean dose to contralateral parotid gland of <20 Gy (p=0.034), and radiation treatment without chemotherapy (p=0.047). Conclusion: Almost every fifth patient experienced complete recovery of xerostomia. Prognostic factors were identified that can guide radiation oncologists during the process of treatment planning.
Radiotherapy is frequently used to treat head-and-neck cancers and is associated with significant side-effects (1). An important and debilitating late toxicity is radiation-induced xerostomia, which can even lead to additional complications including oral infections and dental loss (2-5). Several studies have evaluated the prevalence and risk factors of post-radiotherapy xerostomia. After 2-dimensional radiotherapy (2D-RT) or 3-dimensional conformal radiotherapy (3D-CRT) for cancers or lymphomas of the head-and-neck, xerostomia occurred in a considerable number of patients (6-10). In another study, where patients received modern precision techniques including intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy, and proton therapy, the prevalence of moderate to severe xerostomia was 39.1% (11).
An important question, particularly for the affected patients, is whether xerostomia will remain, improve, or deteriorate following their treatment. Several studies investigated the course of xerostomia after radiotherapy for head-and-neck cancers (12-22). Most of these studies found at least moderate improvement of xerostomia or salivary gland function over time in some patients. However, in other studies, no improvement of xerostomia was observed after higher mean doses to the parotid gland(s) (10, 12, 19). Moreover, in a randomized trial, improvement of xerostomia patients was not observed in patients treated with 2-dimensional conventional radiotherapy (18). In a retrospective study of 251 patients with cancer of the nasopharynx, xerostomia was consistent over time (21, 22). Data regarding complete recovery of xerostomia are scarce. In a study of patients with cancer of the nasopharynx, stimulated parotid saliva flow reached or exceeded pre-radiotherapy levels in 14 of 32 patients (44%) (16).
In most studies investigating potential prognostic factors for improvement of radiation-induced xerostomia or salivary gland function, the mean dose to the salivary glands was the only significant predictor (10, 12, 15, 17, 19, 22). In an earlier study, xerostomia prior to radiotherapy and time since radiotherapy were additional independent predictors of improvement (13). However, no studies have investigated potential prognostic factors for complete recovery of radiation-induced xerostomia in patients with head-and-neck cancers. The present study investigated 13 characteristics for associations with complete recovery of xerostomia after radiotherapy in a cohort of these patients.
Patients and Methods
A total of 80 patients experiencing xerostomia after radiotherapy for head-and-neck cancer with available follow-up data and a minimum follow-up time of 12 months following radiotherapy were included in this retrospective study. The study was approved by the Ethics Committee of the University of Lübeck (AZ 21-108). The radiation was delivered between 2005 and 2012. Seventy-six patients were treated with external beam radiation therapy (EBRT: 3D-conformal irradiation with 6 and 18 MV photon beams including more than ten fields) alone, and four patients received EBRT combined with a sequential brachytherapy boost (iridium-192 source). Total doses of EBRT alone ranged between 60 and 70.6 Gy (median dose=60 Gy). In all but four patients, the dose per fraction was 2.0 Gy given on five consecutive days per week (conventional fractionation). Of the other four patients, three received an accelerated regimen with a concomitant boost. Three weeks of conventional fractionation (30 Gy in 15 fractions) were followed by 21.6 Gy (1.8 Gy per fraction in the morning on 12 treatment days) plus two consecutive boosts of 9 Gy each (1.5 Gy per fraction in the afternoon after at least 6 hours on the same treatment day), which resulted in a cumulative total dose of 69.6 Gy (23, 24). One patient received conventionally fractionated radiotherapy over 3 weeks (30 Gy in 15 fractions), followed by 40.6 Gy of hyperfractionated-accelerated radiotherapy (1.4 Gy per fraction) over 3 weeks, resulting in a cumulative total dose of 70.6 Gy (25). Patients treated with combined radiotherapy (EBRT plus sequential brachytherapy) received 50-66 Gy of conventionally fractionated EBRT plus 10-15 Gy (two fractions of 2.5 Gy per day and an interfraction interval of ≤6 hours) of brachytherapy.
Sixty-one of the 80 patients (76.3%) received upfront resection of the primary tumor, in all but one patient with dissection of locoregional lymph nodes. Extent of resection was complete (R0) in 53, microscopically incomplete (R1) in four, macroscopically incomplete (R2) in one, and unclear (Rx) in three of these patients, respectively. In addition to radiotherapy, 45 patients (56.3%) received chemotherapy, which most commonly included cisplatin alone (n=34) or cisplatin-based regimens (n=7).
All patients developed xerostomia within 6 months following radiotherapy, which was grade 1 in 36, grade 2 in 25, grade ≥3 in 19 patients, respectively, according to the subjective (patient reported) criteria of the Late Effects of Normal Tissues (LENT)/Subjective, Objective, Management, Analytic (SOMA) scoring system regarding dryness of mouth: grade 0=no dryness; grade 1=occasional; grade 2=partial but persistent; grade 3=complete, non-debilitating; grade 4=complete, debilitating (26, 27). Thirteen patient and tumor related characteristics (Table I) were analyzed for associations with complete recovery of xerostomia during the further course of follow up. Since pre-radiotherapy xerostomia grades were not available for a considerable number of patients, complete recovery of xerostomia was defined as decrease of xerostomia to grade 0 (26, 27).
Distribution of patient and tumor characteristics.
These characteristics included age at start of EBRT (≤60 vs. >60 years, median=60 years), sex (female vs. male), tumor site (nasopharynx, oropharynx, oral cavity/floor of mouth vs. hypopharynx/larynx), primary tumor stage (T1-2 vs. T3-4), nodal stage (N0 vs. N+), upfront surgery (no vs. yes), mean dose to the ipsilateral parotid gland [≤31 vs. >31 Gy (10)], mean dose to the contralateral parotid gland [<20 vs. ≥20 Gy (28)], median dose to both parotid glands (<29 vs. ≥29 Gy, median=28.9 Gy), chemotherapy in addition to radiotherapy (no vs. yes), type of radiotherapy (EBRT vs. EBRT + brachytherapy), dose of EBRT alone (60 Gy vs. >60 Gy), and maximum initial (within 6 months after radiotherapy) grade of xerostomia (1 vs. ≥2).
For the analyses, the highest grade of xerostomia within 6 months following radiotherapy was considered the baseline xerostomia. For the statistical analyses regarding associations between potential prognostic factors and complete recovery xerostomia (yes vs. no), the Chi-square test was used or (in case of less than five patients in one group) the Fisher’s exact test. p-Values <0.05 were considered significant.
Results
Median follow-up in the entire cohort was 37 months (range=12-67 months) following radiotherapy. Fifteen patients (18.8%) experienced complete recovery of their xerostomia. Complete recovery was identified after a median of 18 months (range=12-49 months). Significant associations were found between complete recovery of xerostomia and grade 1 xerostomia (maximum grade) during the first 6 months following radiotherapy (p<0.001), a mean dose to the contralateral parotid gland <20 Gy (p=0.034) and radiotherapy alone without chemotherapy (p=0.047) (Table II).
Associations between potential prognostic factors and complete recovery of xerostomia.
Discussion
After radiotherapy for head-and-neck cancers, xerostomia is very difficult for patients and entails the risk of serious complications affecting the oral mucosa and teeth (3-5). Depending on the radiation technique, xerostomia can occur in up to 81% of these patients (6-10). Fortunately, improvement of radiation-induced xerostomia is possible. In previous studies evaluating the course of post-radiotherapy xerostomia, improvement was mainly reported after 1 year (8, 12, 16-18) or during the second year (13, 14, 19, 20). In the present study, complete recovery of xerostomia was identified in 18.8% of patients after a median of 18 months. In the study of McMillan et al., an improvement rate of stimulated parotid saliva of 44% was reported (16). However, an improved rate of stimulated parotid saliva may not consequently lead to clinical improvement of xerostomia.
When planning on radiation treatment, it would be helpful if prognostic factors for improvement and complete recovery of xerostomia were available. This information would be important for optimally tailoring the radiation dose to the target volumes and the organs at risk. Prior to this study, no prognostic factors were reported associated with complete recovery of xerostomia after irradiation of head-and-neck cancers.
In the present study, complete recovery was significantly associated with initial maximum xerostomia of grade 1, a mean dose to the ipsilateral parotid gland <20 Gy, and radiotherapy alone (without addition of chemotherapy). The prognostic impact of the initial grade of xerostomia is supported by a study of Eisbruch et al., where xerostomia scores were independently associated with pre-radiotherapy baseline xerostomia scores (13). Associations between the mean dose to one or both parotid glands and improvement of xerostomia were previously found in several studies (10, 12, 15, 17-20, 22). In the study of Kam et al., patients treated with IMRT and 2D-RT had mean parotid doses of 32.2 Gy and 61.5 Gy, respectively (18). A trend of improvement of xerostomia according to patient-reported outcomes was found in the IMRT group but not in the 2D-RT group. Rodrigues et al. observed no improvement (100% persistent xerostomia and 100% sticky saliva) in patients receiving >31 Gy to a least one parotid gland (10). Pan et al. differentiated between the doses to the ipsilateral and the contralateral parotid gland (22). A mean dose of <39 Gy at the ipsilateral and a V30 (volume of the gland receiving 30 Gy) of ≤52% at the contralateral gland were independent predictors of improvement of xerostomia. In addition, other studies found a correlation between the mean dose to one or both parotid glands and parotid function such as the saliva flow rate (12, 15, 17, 19, 20). An association between improvement of xerostomia and the addition of chemotherapy was not previously described. However, chemotherapy was found to be significantly associated with the occurrence of xerostomia in several studies (29-31). In a prospective study of 167 patients treated with 3D-CRT, xerostomia was significantly more common after radio-chemotherapy than after radiotherapy alone (odds ratio=2.53, 95% confidence interval=1.15-5.58, p=0.02) (29). In another study including data from 434 patients treated with different radiotherapy techniques, the addition of chemotherapy to radiotherapy was associated with a higher rate of dry mouth (OR=2.026, 95% confidence interval not stated, p<0.05) (30). Moreover, in a study of 63 patients receiving IMRT, patients with xerostomia had received chemotherapy more frequently than patients without xerostomia (93% vs. 63%, p<0.05) (31).
When interpreting the results of the current study, its limitations should be considered. These include the retrospective design with a risk of hidden selection biases. Since 11 patients (14%) had a follow-up of less than 2 years and maximum improvement of xerostomia can occur during the second year, some complete recoveries might have been missed (13, 14, 19, 20). In addition, since complete recovery was defined as decrease to grade 0, recovery to preradiotherapy grades >0 were not considered. Moreover, the grading of xerostomia was based on subjective (patient reported) information alone (26, 27).
In summary, almost every fifth patient experienced complete recovery of xerostomia. Significant prognostic factors were identified for complete recovery including initial grade 1 xerostomia, mean dose to contralateral parotid gland of <20 Gy, and radiation treatment without chemotherapy. These prognostic factors can guide radiation oncologists during the treatment planning and contribute to the optimization of the dose distributions at the target volumes and organs at risk.
Footnotes
Authors’ Contributions
The study was designed by all Authors. B.W. provided the data that were interpreted by all Authors. D.R. and S.E.S. drafted the manuscript, which was reviewed and finally approved by all Authors.
Conflicts of Interest
On behalf of all Authors, the corresponding Author states that there are no conflicts of interest related to this study.
- Received March 25, 2022.
- Revision received April 20, 2022.
- Accepted April 29, 2022.
- Copyright © 2022 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
