Research ArticleClinical Studies

Risk Factors for Xerostomia Following Radiotherapy of Head-and-Neck Cancers

BRITTA WARWAS, FLORIAN CREMERS, KARSTEN GERULL, ANKE LEICHTLE, KARL L. BRUCHHAGE, SAMER G. HAKIM, STEVEN E. SCHILD and DIRK RADES
Anticancer Research May 2022, 42 (5) 2657-2663; DOI: https://doi.org/10.21873/anticanres.15743

Abstract

Background/Aim: Many head-and-neck cancer patients receive radiotherapy, which may be associated with significant toxicities. Xerostomia is considered one of the most debilitating late adverse events. This study was performed to identify risk factors for xerostomia. Patients and Methods: Several characteristics were investigated for associations with late xerostomia in 159 patients irradiated for head-and-neck cancer including age, sex, tumor site and size, underlying pathology, histologic grading, upfront resection, systemic treatment, and type and dose of radiotherapy. Results: Ninety (57%) and 35 (22%) patients experienced grade ≥2 and ≥3 xerostomia, respectively. Grade ≥2 xerostomia was significantly associated with tumor site (nasopharynx/oropharynx/oral cavity/floor of mouth, p=0.049). Grade ≥3 xerostomia was significantly associated with age ≥61 years (p=0.035); trends were found for tumor site (p=0.088), bilateral nodal involvement (p=0.093), definitive treatment (p=0.082), and systemic treatment (p=0.055). Conclusion: Risk factors for xerostomia following radiotherapy of head-and-neck cancers were identified including older age, unfavorable tumor site, bilateral involvement of lymph nodes, definitive treatment, and addition of systemic therapies. For patients with risk factors, sparing of the salivary glands is particularly important.

Key Words:

Many head-and-neck cancer patients receive radiotherapy, either as definitive treatment or as adjuvant treatment following resection of the primary tumor with or without dissection of the loco-regional lymph nodes (1, 2). Radiotherapy of the head-and-neck region can be associated with significant acute and late toxicities. Acute toxicities such as radiation dermatitis and oral mucositis usually resolve within a few weeks after the end of treatment, whereas late toxicities often persist for years or even life-long (3-9). In the study of Deboni et al., late xerostomia was considered the most debilitating late toxicity following radio-chemotherapy of head-and-neck cancer (3). Moreover, xerostomia can lead to other late complications such as oral infections, oral mucosa discomfort, dental demineralization, and dental loss (6-9). In previous studies, the prevalence of clinically relevant xerostomia ranged between 37% and 73% after conventional or 3-dimensional conformal radiotherapy (3D-CRT) (10-12). Moreover, in a recent study of patients treated with different radiotherapy techniques including 3D-CRT and high-precision techniques such as intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT) and proton therapy, 39.1% of the patients reported moderate to severe xerostomia (13). In 2010, Dijkema et al. calculated complication (xerostomia) probabilities of 17-26% for a mean dose at the parotid glands of 25-30 Gy and 50% for a mean dose of 40 Gy (14). However, little is known about other potential risk factors of late xerostomia beside the radiation dose at the salivary glands (14-16). Older age, female sex, tumor site (particularly oral cavity), more advanced tumor stage, bilateral irradiation, and addition of chemotherapy were reported as risk factors for xerostomia (13, 16-18). However, with the exception of additional chemotherapy, these findings were limited to one or two studies and not consistent. Therefore, additional studies are required to identify risk factors of xerostomia following radiotherapy of head-and-neck cancers. The present study investigated 14 patient- and tumor-related characteristics for potential associations with the occurrence of late xerostomia in a cohort of head-and-neck cancer patients treated with 3D-CRT.

Patients and Methods

This retrospective study investigated risk factors for xerostomia following loco-regional radiotherapy or radio-chemotherapy in a cohort of 159 head-and-neck cancer patients. These patients were treated between 2005 and 2012. The study was approved by the ethics committee of the University of Lübeck (reference 21-108).

Of the entire cohort, 149 patients (94%) received external beam radiation therapy (EBRT) alone and 10 patients (6%) EBRT plus a brachytherapy boost. EBRT was performed as 3D conformal radiotherapy with 6-MV and 18-MV photon beams including a large number of radiation fields (generally more than 10 fields per plan). Brachytherapy was performed with a high-dose rate (HDR) source (Iridium-192) using the afterloading technique. In 138 patients treated with EBRT alone, radiotherapy started with 50 Gy in 2 Gy-fractions over 5 weeks to the primary tumor and regional lymph nodes, followed by boost doses to the primary tumor and to high- and intermediate-risk lymph node areas. Depending on upfront resection, sequential boost doses were 10 Gy (after microscopically complete resection), 14-16 Gy after microscopically incomplete resection and/or extracapsular extension of lymph node metastasis, and 20 Gy after macroscopically incomplete or no resection, resulting in cumulative doses of 60-70 Gy. Eight patients in the EBRT alone group received accelerated fractionation with a concomitant boost. A dose of 30 Gy in 2 Gy-fractions over 3 weeks was followed by 21.6 Gy in 1.8 Gy-fractions to the same areas over 12 treatment days plus two consecutive boost doses (1.5 Gy per fraction) given the same days after an interval of ≥6 hours, resulting in a cumulative dose of 69.6 Gy (19, 20). Three patients received radiotherapy with 30 Gy in 2 Gy-fractions over 3 weeks, followed by hyperfractionated-accelerated irradiation with two daily fractions of 1.4 Gy over 3 weeks, resulting in a cumulative dose of 70.6 Gy (21). In the 10 patients receiving a brachytherapy boost, EBRT doses ranged between 50-60 Gy to the primary tumor and 50-66 Gy to the lymph node areas. The doses of the brachytherapy boost, which was administered mainly to the primary tumor, ranged between 10 and 20 Gy and were given with two daily fractions of 2.5 Gy and an interval between these fractions of ≥6 hours.

In the entire cohort, 118 patients (74%) received upfront resection of the primary tumor. In 100 patients, a microscopically complete (R0) resection was achieved. Resection status was microscopically incomplete (R1) in 11 patients, macroscopically incomplete (R2) in two patients, and unclear (Rx) in five patients, respectively. A neck dissection of lymph nodes was performed in all but one patient, and was unilateral in 44 patients and bilateral in 73 patients, respectively. A total of 91 patients (57%) received systemic treatment in addition to radiotherapy. In 86 patients, systemic treatment was given concurrent systemic treatment with cisplatin alone (n=57), cisplatin plus other agents (n=14), or other regimens mainly including cetuximab and/or taxanes (n=15). Moreover, six patients received induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) followed by concurrent radio-chemotherapy with cisplatin.

Fourteen potential risk factors for post-treatment xerostomia (Table I) were investigated including age (≤60 vs. ≥61 years, median=60 years), sex (female vs. male), tumor site (nasopharynx/oropharynx/oral cavity/floor of mouth vs. hypopharynx/larynx), primary tumor size (T1-3 vs. T4), nodal stage (N0-1 vs. N2a-2b vs. N2c-3), bilateral nodal involvement (no vs. yes), underlying pathology (squamous cell carcinoma vs. other), histologic grading (G1-2 vs. G3), upfront resection (no vs. yes), systemic treatment (no vs. yes), type of radiotherapy (EBRT alone vs. EBRT + brachytherapy boost), and total dose of EBRT (60 Gy vs. >60 Gy).

View this table:
Table I.

Distribution of the potential risk factors.

Late xerostomia was defined as occurring after 6 weeks or later following radiotherapy and graded according to the subjective criteria of the Late Effects of Normal Tissues (LENT)/Subjective, Objective, Management, Analytic (SOMA) scoring system: 0 no dryness of mouth; 1 occasional dryness; 2 partial but persistent dryness; 3 complete dryness, non-debilitating; 4 complete dryness, debilitating (22, 23). For the analyses, the highest grade of xerostomia that a patient experienced between 6 weeks and 24 months following radiotherapy was used. Potential risk factors were separately evaluated with respect to grade ≥2 and grade ≥3 xerostomia. Statistical analyses regarding associations between the investigated potential risk factors and late xerostomia were performed with the Chi-square test or, in case of less than five patients in one group, with the Fisher’s exact test.

Results

Ninety patients (57%) experienced grade ≥2 late xerostomia following radiotherapy. Grade ≥2 xerostomia (Table II) was significantly associated with tumor sites, namely nasopharynx, oropharynx, oral cavity, or floor of mouth (p=0.049). Grade ≥3 late xerostomia was observed in 35 patients (22%). The occurrence of grade ≥3 xerostomia (Table III) was significantly associated with age ≥61 years (p=0.035). In addition, trends for associations with grade ≥3 xerostomia were found for tumor sites (p=0.088), bilateral nodal involvement (p=0.093), definitive treatment (p=0.082), and systemic treatment in addition to radiotherapy (p=0.055).

View this table:
Table II.

Associations between potential risk factors and grade ≥2 xerostomia after radiotherapy.

View this table:
Table III.

Associations between potential risk factors and grade ≥3 xerostomia after radiotherapy.

Discussion

Xerostomia is considered a very burdensome late toxicity following radiotherapy for head-and-neck cancers that can also lead to significant additional complications (3, 6-9). An important factor significantly associated with the occurrence of xerostomia is the radiation dose at the parotid glands (14-16). Therefore, it is very important to spare the parotid glands during the process of radiation treatment planning whenever reasonably possible. In addition to the radiation dose at the salivary glands, other factors were reported to be associated with xerostomia. In the study of Beetz et al., the risk of xerostomia increased with age (p=0.014, multivariate logistic regression model) (16). On univariate analyses, xerostomia was associated with the addition of chemotherapy (p=0.02) and bilateral neck irradiation (p<0.01) but not with sex (p=0.046) and age (p=0.54). In the study of Teguh et al., dry mouth was associated with age (p<0.05), female sex (p<0.05), tumor site (oral cavity followed by oropharynx, hypopharynx and nasopharynx, p<0.05), more advanced nodal stage (p<0.05), and addition of chemotherapy (p<0.05) on univariate analyses (17). A trend was observed for bilateral neck irradiation (p=0.056). Owosho et al. identified only additional chemotherapy (p<0.05) and cancer of unknown primary (p=0.03), which was not included in the present study, as risk factors for xerostomia in addition to the radiation dose at the parotid glands (18). In the most recent study, Aggarwal et al. identified female sex (p=0.006), T4-tumors (p=0.027), and current cigarette smoking at the time of the questionnaire (p=0.04) as significant risk factors for xerostomia in long-term survivors after radiotherapy or radio-chemotherapy for oropharynx cancer (13). Upfront resection showed a trend for an inverse correlation with the occurrence of xerostomia (p=0.063). The addition of chemotherapy was non-significantly associated with xerostomia (p=0.10). When looking at the inconsistent findings from the previous studies, it becomes obvious that additional studies are needed to properly identify risk factors of xerostomia in addition to the radiation dose at the salivary glands. Therefore, several patients- and tumor-related factors were analyzed for associations with late xerostomia in the present study. According to its results, tumor site was significantly associated with grade ≥2 xerostomia and age ≥61 years with grade ≥3 xerostomia. Moreover, trends were also seen for associations between tumor site, bilateral nodal involvement, no upfront, and addition of systemic treatment (mainly chemotherapy). These results are mainly in line with those of previous studies. The fact that xerostomia was less common after treatment for larynx and hypopharynx cancers can be explained by the greater distance of these tumors to the parotid glands when compared to other tumors, particularly to cancers of the oropharynx and oral cavity. Older age is a risk factor, since the function of the salivary glands like other organ functions decrease with age (16, 24). Moreover, it is well recognized that the addition of chemotherapy significantly increases radiation toxicities (24, 25). Since bilateral nodal involvement requires higher doses to both sides of the neck, the function of bilateral salivary glands is more likely to be impaired, resulting in a higher risk of damage to the glands and significant xerostomia (13, 15, 17). Patients who do not receive upfront resection likely have more advanced unresectable tumors and/or significant comorbidities that do not allow anesthesia and surgery. Since more advanced tumors require larger radiation fields and, if unresectable, higher total doses, it is more likely that the salivary glands receive higher doses associated with a greater risk of xerostomia (14-16).

Several options have been investigated in order to reduce the risk of xerostomia following radiotherapy of head-and-neck cancers including the use of modern precision radiotherapy techniques and protective agents. Radiotherapy techniques included IMRT, VMAT, and proton beams. In a prospective study of 56 patients with cancer of the oropharynx, a decrease of the parotid flow rate to less than 25% of the pre-radiotherapy rate was found significantly less often after IMRT than after conventional radiotherapy (27). In a retrospective study from 2007 including 148 head-and-neck cancer patients, IMRT was associated with a significantly lower incidence of xerostomia than 3D-CRT and conventional radiotherapy (17% vs. 63% vs. 73%, p=0.037). In two more recent studies, IMRT techniques were also significantly superior to 3D-CRT with respect to prevention of xerostomia (13, 28). Xerostomia rates may be further improved with the use of proton therapy. In a study comparing IMRT and intensity-modulated proton therapy (IMPT), moderate to severe xerostomia occurred significantly less often in the IMPT group (29). In addition to modern radiotherapy techniques, several agents have been investigated regarding their potential to reduce xerostomia (7, 30-34). According to a current multidisciplinary guideline, several interventions may be offered in addition to tissue-sparing radiotherapy techniques, including bethanechol and acupuncture during the course of radiotherapy, topical mucosal lubricants, saliva substitutes, and sugar-free lozenges or chewing gum for patients developing salivary gland hypofunction and/or xerostomia, and oral pilocarpine, oral cevimeline, acupuncture, or transcutaneous electrostimulation following radiotherapy (7).

In conclusion, risk factors for xerostomia following radiotherapy of head-and-neck cancers were identified including tumor site (nasopharynx/oropharynx/oral cavity/floor of mouth), age ≥61 years, bilateral nodal involvement, definitive treatment, and addition of systemic treatment. In the literature, female sex, advanced tumor stage, and bilateral irradiation were also reported to be associated with the development of xerostomia. For patients with one or more of these risk factors, sparing of the salivary glands is particularly important and should be performed whenever reasonably possible.

Footnotes

  • Authors’ Contributions

    The study was designed by all Authors. B.W. provided the data that were analyzed by D.R. Interpretation of the data was performed by all Authors. B.W., S.E.S. and D.R. 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 3, 2022.
  • Revision received March 21, 2022.
  • Accepted March 22, 2022.

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Risk Factors for Xerostomia Following Radiotherapy of Head-and-Neck Cancers
BRITTA WARWAS, FLORIAN CREMERS, KARSTEN GERULL, ANKE LEICHTLE, KARL L. BRUCHHAGE, SAMER G. HAKIM, STEVEN E. SCHILD, DIRK RADES
Anticancer Research May 2022, 42 (5) 2657-2663; DOI: 10.21873/anticanres.15743
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