Cancer treatment with hormone therapy and its relationship with xerostomia and hyposalivation

Background: The appearance of new drugs for cancer treatment has increased patient survival but it has also brought adverse effects, such as the sensation of dry mouth and hyposalivation. Objective: To assess the relationship of using hormone therapy in breast and prostate cancer patients and the occurrence of xerostomia and hyposalivation. Method: Cross-sectional study with 114 patients diagnosed with cancer and treated with hormone therapy (anastrozole or bicalutamide). Age, type of neoplasia, sex, presence of xerostomia (yes or no), and type of medication were obtained with a questionnaire. The researcher collected resting and stimulated salivary ows in the morning. The descriptive statistic analysis, chi-square test (p<0.005), and t-test (<0.005) were performed using the Statistical Package for Social Science™ (SSPS), version 21, for different variables of hyposalivation and hormone therapy. Results: The results showed that 67 (55.8%) patients using hormone therapy drugs presented hyposalivation and 73 (64%) patients presented xerostomia. Conclusion: According to the results of this study, there is a positive association between stimulated hyposalivation and the use of hormone therapy drugs (p = 0.015). There was also a positive association between hyposalivation and xerostomia and the use of hormone therapy drugs (p = 0.049 and p = 0.001).


Background
Cancer treatment should start from the moment the patient receives a con rmed diagnosis and it involves a series of multi-professional interventions including surgery, radiotherapy, chemotherapy, hormone therapy, and target therapy. For cases treated with hormone therapy, the main drugs used to treat breast cancer are tamoxifen (TMXO), when there are estrogen receptors in the tumor mass that inhibit its production; and anastrozole, an aromatase inhibitor (AI) that also works on estrogen in postmenopausal women. For the condition of prostate cancer, the hormone therapy drug bicalutamide works by inhibiting androgenic hormones [1,2,3]. Choosing one medication over another is determined, among other factors, by the type and stage of the tumor. While using tamoxifen is recommended to premenopausal women, postmenopausal women may use both tamoxifen and anastrozole [2]. Bicalutamide has been indicated by the FDA for the metastatic treatment of prostate cancer [3]. When administered orally, its action may be affected by the concomitant use of other drugs and cause adverse effects in the oral cavity.
Studies have shown that estrogen is important for the maintenance of bone and soft tissues in the oral cavity. Thus, drugs that affect the production and prevent or complicate the connection of estrogen to its receptors, such as anastrozole, may affect bone and soft tissues in the oral cavity, increase the risk of periodontal disease, change the taste, decrease salivary ow, and cause xerostomia [2,4].
Xerostomia is characterized by the sensation of dry mouth and it may be primary or secondary. Primary xerostomia is characterized by the decrease in resting or stimulated saliva production, and secondary xerostomia is characterized by the dryness of the mouth with the absence of changes in salivary ow.
Xerostomia and changed salivary ow may occur from changes in saliva composition, radiation in the head and neck region, smoking habit, alcoholism, and excess coffee intake, which are among the local factors that may lead to xerostomia [5,6,7,8,9].
Patients with xerostomia may nd it di cult to eat and/or speak and present a burning sensation, halitosis, and change in taste. Lip dryness, oral candidosis, and dental caries may also be present even if the patient has good oral hygiene. Identifying the etiological factor early and consequently determining the diagnosis, either primary or secondary, will allow introducing a better and more effective treatment plan aiming at control and comfort, especially to women older than 60 years [5,7,8].
The literature is scarce on the relationship between xerostomia and/or hyposalivation and the use of hormone therapy drugs. As for the use of bicalutamide for patients with prostate cancer, there are no studies available. The studies related to the use of anastrozole are not speci c for this condition. They assess changes in the oral cavity as a whole and do not determine in what treatment phase it is more frequently found [2,6,10].
In the speci c case of estrogen receptors, studies have evidenced that the presence of this hormone in the oral mucosa and salivary glands, as well as an antagonist action to this hormone, may be responsible for the sensation of dry mouth [2,11,12]. Preliminary results of a pilot study performed by Taichman et al. [2] did not show differences between the perception of dry mouth or decreased salivary ow of patients using aromatase inhibitors and patients without the medication. However, a longitudinal study performed by the same authors [12], published in 2016, warns about the long-term decrease in salivary ow due to the use of aromatase inhibitors, highlighting that further studies should be performed aiming at these patients with a higher need for oral health care.
Therefore, this research hypothesizes that anastrozole and bicalutamide used in the treatment of breast and prostate cancers, respectively, cause changes in salivary ow and the presence of xerostomia. This study aimed to assess the relationship of xerostomia and hyposalivation with the use of hormone therapy drugs in patients subjected to oncological treatment, by measuring salivary ow.
The inclusion criteria were patients aged 18 years or older, subjected to hormone therapy with anastrozole or bicalutamide to treat breast or prostate cancers, respectively, at the Oncology Outpatient Unit of the Nossa Senhora da Conceição Hospital (Tubarão, Santa Catarina, Brazil). The participants were invited to participate in the study and accepted the Informed Consent Form. The procedure of random sampling by convenience was used. The data were collected from July to October 2016. Sociodemographic data such as age, sex, type of cancer, therapy used, and other medications used were obtained with a self-lled questionnaire. The patients also answered (yes or no) to questions on the sensation of dry mouth, lip dryness, and amount of saliva they believed having (a lot or little). The salivary ow was assessed with the methodology proposed by Sreebny and Valdini [13]. Saliva was collected at two moments: resting and stimulated. To collect resting saliva, the patient was asked to sit comfortably and expel saliva in a plastic cup for six continuous minutes. Stimulated saliva was collected by chewing a piece of sterile latex with 3 mm of thickness and 1 cm of length, tied by a dental oss to avoid swallowing. The saliva produced was deposited in another plastic cup also for six minutes. After a resting period to reduce the interference of foam, aided by a disposable 10-mL syringe, the salivary ow was quanti ed in millimeters and divided by six to obtain values in mL/min, considering resting hyposalivation values ≤ 0.1 mL/min and ≤ 0.7 mL/min when stimulated. The values were written down on their respective questionnaires.
The data collected were inserted in the Statistical Package for Social Science™ (SSPS), version 15.0, for the descriptive analysis of data normality and statistical inference to determine the mean, standard deviation, and mean standard error. The chi-square test was used to verify the association of variables and the Student's t-test was performed to identify the difference of means between the different groups. The results were considered statistically signi cant at p-value < 0.05.

Results
Due to technical limitations, the Results section can only be accessed as a download in the supplementary les section.

Discussion
Considering the results found in this study, there is a signi cant change in salivary ow and the presence of xerostomia in patients under cancer treatment.
The high rate of patients using other medications than the ones for cancer treatment re ects the global perspective, which shows a high incidence and prevalence rates of chronic non-transmissible diseases such as cardiovascular diseases and mental disorders, among which are depression and anxiety [6,14].
Johanson and colleagues [15] highlight the xerostomic potential and salivary changes of these medications. Although the salivary ow tests have been performed only once along with the use of hormone therapy drugs, it is not possible to con rm that changes in salivary ow and xerostomia already existed before the antineoplastic treatment or whether they were potentiated by the association of the additional medication. Longitudinal studies are suggested for a better assessment of this association.
The mean resting salivary ow volume found in this study was higher than the value found by Niklander et al. [16] (0.1 ± 0.28 mL/min), which shows no functional changes in salivary glands. The means of stimulated salivary ow volume are similar to the values obtained by Rahnama et al. [17] (0.812 ± 0.095 mL/min). Lago et al. [18] observed that hormone therapy increases salivary ow in 0.52 mL/min, showing an in uence of hormone therapy drugs used by postmenopausal women, especially the ones under estroprogestative therapy. This study did not aim to assess whether women were pre-or postmenopausal, but it allows inferring that these drugs work on the salivary glands and affect salivary ow.
Aromatase inhibitors such as anastrozole have become the hormone therapy drug of choice for the treatment of breast cancer in postmenopausal women because they inhibit the production of estrogen, reducing the growth of cancer and preventing recurrences. Decreased salivary ow is among the side effects, with either stimulus or not [2], which is also evidenced in the present study. Studies such as by Foschin and colleagues, in 2017 [19], showed the presence of estrogen receptors in salivary gland tumors, revealing the presence of this hormone in the mucosa of the glands. The decrease in estrogen production due to hormone therapy drugs may lead to decreased salivary production, resulting in a hyposalivation condition.
A study has evidenced a decrease in androgenic hormone in menopausal women and that this condition is a predisposing factor for Sjögren syndrome [20]. This research is the rst study assessing the association between the use of hormone therapy drugs with antiandrogenic action, hyposalivation, and xerostomia, although it has shown a statistically signi cant result for hyposalivation in the presence of stimulated salivary ow, xerostomia, and hyposalivation. Although prostate cancer is the second most frequently found in men, its incidence and prevalence are lower than breast cancer in women [2].
Moreover, the use of hormone therapy drugs, such as the ones that inhibit the androgenic synthesis, is indicated only in cases of metastasis [3]. Both these conditions may justify the presence of only 16 patients in the sample. The decrease or absence of the androgenic hormone in these patients by the action of hormone therapy drugs may be responsible for the changes found in salivary ow. However, further studies are suggested to better understand this condition.
The sensation of dry mouth in this study was determined by patient self-perception. It is known that the symptom differs from one person to another and the absence of standardization for the responses may have under-or overestimated the results found. This same limitation was also observed in other studies [20,21], which showed a relationship between xerostomia and different oncological diseases, with a strong relationship between head and neck radiotherapy and women older than 60 years [6,7].
Although studies recommend a mean time to collect resting and stimulated saliva of ve minutes, Löfgren et al. [22] addressed, in a systematic review, diagnostic methods of mouth dryness and salivary gland function. The results showed that increasing the time increased the speci city of salivary ow reduction. It also stands out that the methods to assess mouth dryness are scarce and show methodological de ciencies. In this study, the salivary ow was collected for six minutes due to a misguided interpretation of the methodology used, in which the rst minute of each collection was interpreted as a preparation minute and added to the total collection time. To prevent underestimating the salivary volume, this minute was added in the methodology, so the total volume was divided by six minutes in both resting and stimulated salivary ows.
Even with limitations, such as the absence of information on salivary ow and xerostomia before the treatment and during it, absence of a control group, and decreased sample power for not reaching the minimum sample number, the results obtained in this study showed the presence of hyposalivation and xerostomia in patients under hormone therapy and that this condition affects or aggravates the quality of life. The magnitude of this response was approximately four times higher in men than in women. Considering the small sample size and the heterogeneous population, further studies are suggested to better explain the relationship between hyposalivation, xerostomia, and hormone therapy.

Conclusion
The results of this study allow concluding that: Anastrozole and bicalutamide presented a statistically signi cant result for mean stimulated salivary ow volume; p = 0.0001 (CI: -0.70/-0.205).
Anastrozole and bicalutamide cause a statistically signi cant decrease in stimulated hyposalivation (p = 0.049).
Xerostomia is a usual complaint among patients using anastrozole and bicalutamide, showing a statistically signi cant result (p = 0.001).

Consent for publication: Not Applicable
Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests: The authors declare that they have no competing interests.
Funding: Not Applicable