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Acute xerostomia in head and neck radiotherapy

Head and neck cancer is the eighth common cancer in Western countries. The incidence of head and neck tumors in Iraq is <2% of all cancers, which are mostly squamous cell carcinomas arising from the mucosa of the upper aero digestive tract. 1,2 Radiation has securely part of head and neck treatment since the 1960s because of lead to cure when used alone or in combination with surgery. The development of concurrent chemotherapy and radiation schedules be one of the greatest advances in oncology. 3 During a course of H and N radiation therapy, there are many side effects including fatigue, loss of taste acuity, radiation dermatitis, and xerostomia. 4 Xerostomia, is caused by salivary gland dysfunction as a result of damage in the field of radiation. 5 There are three major paired salivary glands (parotid, submandibular, and sublingual) producing the majority of the saliva. The remaining saliva is produced from more than 600 minor simple encapsulated tubule-alveolar glands, located throughout the upper aero digestive tract mucosa. 6


INTRODUCTION
Head and neck cancer is the eighth common cancer in Western countries. The incidence of head and neck tumors in Iraq is <2% of all cancers, which are mostly squamous cell carcinomas arising from the mucosa of the upper aero digestive tract. 1,2 Radiation has securely part of head and neck treatment since the 1960s because of lead to cure when used alone or in combination with surgery. The development of concurrent chemotherapy and radiation schedules be one of the greatest advances in oncology. 3 During a course of H and N radiation therapy, there are many side effects including fatigue, loss of taste acuity, radiation dermatitis, and xerostomia. 4 Xerostomia, is caused by salivary gland dysfunction as a result of damage in the field of radiation. 5 There are three major paired salivary glands (parotid, submandibular, and sublingual) producing the majority of the saliva. The remaining saliva is produced from more than 600 minor simple encapsulated tubule-alveolar glands, located throughout the upper aero digestive tract mucosa. 6 Decreased salivation can lead to dental caries, periodontal diseases, a shift of oral flora, poor tolerability to dental prosthesis and inflammation, atrophy and ulceration of mucosa. As a result, radiation-induced xerostomia has a debilitating impact on health and overall quality of life. 5

Study design, setting and data collection
A prospective observational study conducted in the Oncology Teaching Center/Radiation Therapy Department at the Medical City Complex, Baghdad, Iraq. In a period of six months from November 2017 to April 2018.

Study patients and sample size
Total number of 100, all of them diagnosed with HNC as proofed by clinical and histopathological examination and treated by External Beam Radiotherapy (EBRT). All patients subjected to complete evaluation for proper staging with full history, physical examination, and radiological investigations. The HNC was primary in all the patients. The data collection done through daily visits and selected randomly.

Procedure
The dose of external beam radiotherapy used for the treatment of different patients was (30-70 Gray), with a standard fractionation. Each fraction is two GY and five fractions per week. Some patients treated with radiation only, while some others treated with chemotherapy, prior to or concurrent with the Radiotherapy. Radiation delivered for all patients with 3D conformal technique, using Elekta infinity, and Elekta synergy machines.

Partitions
The patients assessed for symptoms and signs of xerostomia according to subjective experience of dry mouth and patients classified by xerostomia grades into the following: 1. Mild symptomatic (dry or thick saliva) without significant dietary alteration.
2. Moderate symptomatic and significant oral intake alteration (eg, copious water, other lubricants, diet limited to purees and/or soft moist foods).
3. Severe symptoms leading to inability to adequately aliment orally; IV fluids, tube feedings, or parenteral nutrition indicate.

Statistical analysis
The data analysed using Statistical Package for Social Sciences (SPSS) version 25. The data presented as mean, standard deviation and ranges. Categorical data presented by frequencies and percentages. Pearson's Chi-square test used to assess statistical association between certain variables and outcome. A level of p-value less than 0.05 considered significant.

Ethical approval
All patients verbally informed about the study and they asked the permission to be a part of the study. All personal information kept anonymous. Data exclusively used for the sake of this study.

Age and gender
Study patient's age ranging from 13-78 years with a mean 51.69±13.7 years. The highest proportion found in age group 40-59 years (52%), Figure 1. Figure 2 shown the distribution of gender, males higher than females (67% versus 33%) with male to female ratio of 2:1.

Past medical history and social habits
Most of patients were non-drinker and had no past medical history (91% and 80% respectively). Concerning smoking, the highest proportion of study patients were former smokers (54%) ( Table 2).

Dose of radiotherapy
Study patient's dose of radiotherapy was ranging from 30 to 70 GY with a mean of 63.2 GY and SD of ±9.65 GY. About half of patients (49%) received dose of radiotherapy ≥70 GY ( Table 2). Figure 3 shown the distribution by prior and concurrent chemotherapy. Most of the patients didn't take chemotherapy during radiotherapy (90%), while 68% of them were previously received chemotherapy.

Xerostomia
The distribution by diagnosis of xerostomia is shown in Figure 4. We noticed that the highest proportion diagnosed with grade I (37%), while 21% of them free. The association between xerostomia and general characteristics shown in (Table 3), the highest prevalence of xerostomia seen in females (93.9%) with a significant association (p=0.01). Regarding past medical history, the highest prevalence seen in patients who didn't have past medical history (85%) with a significant association (p=0.003). No statistical significant association (p≥0.05) between prevalence of xerostomia and all other variables. Table 3 shown the association between xerostomia and tumor details. All patients diagnosed with oral, nasopharyngeal, and parotid tumor developed xerostomia (100%) with a significant association (p=0.001). It was obvious that there was no significant association (p≥0.05) between prevalence of xerostomia and prior or concurrent chemotherapy. The prevalence of xerostomia increasing as the dose of radiotherapy increased until dose of 70 GY, when it remained about the same level, so the highest prevalence of xerostomia seen radiotherapy dose between 60-69 GY (86.2%), with a significant association (p=0.047). The highest prevalence of xerostomia grade III seen in patients diagnosed with parotid tumor (37.5%) with a significant association (p=0.001). No significant association (p≥0.05) between xerostomia grade and both of tumor stage and radiation dose (Table 4).

DISCUSSION
Radiation-induced xerostomia is a side effect after treatment for oral and oropharyngeal cancers. This may induce swallowing difficulties, compromised oral wellbeing, reduced nutrition intake, or speech deficiencies. The quality of life is often impaired for these patients. 8 In the present study, nasopharyngeal and larynx cancer were the commonest tumors (29% and 28% respectively), and 78% of patients diagnosed with squamous cell carcinoma when 53% of them were in stage III. When compared to results of Iranian study conducted on 63 head and neck cancer in 2012, laryngeal and oropharyngeal tumor had the highest prevalence constituted 31.7% and 26.9% respectively. 9 Another different results observed in USA study conducted in 2006, as the primary tumor sites was in the oropharynx as (68%). 10 An agreement observed in study conducted in Greece (2017) included 60 patients, where half of them had laryngeal/hypopharyngeal cancer (28% and 2% respectively). 11 About half of patients (49%) received radiotherapy ≥70 GY, and concerning the chemotherapy (90%) of the patients didn't take chemotherapy, only 68% previously received chemotherapy. In Iran (2012), 63 head and neck cancer patients, give different results observed when chemoradiation used in 55 patients (87.3%), while RT alone used in 8 patients (12.7%) at doses of at least 25-30 GY with average received radiation doses was 53.9 GY. 10 In Greece (2017), 78.3% of patients with head and neck cancer had undergone chemotherapy in addition to radiotherapy. 11 which disagreed with our study. In 37% of patients had xerostomia grade I and 21% of them free of xerostomia and significantly associated with gender (p=0.01), as xerostomia seen in females in (93.9%), it also significantly associated with past medical history (p=0.003), and in patients who didn't have past medical history (85%). Significant association (p=0.001) found with tumor, as all patients with oral, nasopharyngeal, and parotid tumor had xerostomia. Radiotherapy dose significantly associated with xerostomia (p=0.047), since the highest prevalence found in patients who received radiotherapy dose between 60-69 GY (86.2%), while no significant association found with concurrent chemotherapy (p≥0.05).
Finally, xerostomia grade III found in parotid tumor (37.5%), which is significantly associated with xerostomia (p=0.001). In Iran (2012) the follow up visits conducted two, four, and six weeks later, they found that a significant difference in xerostomia score throughout follow-up period and xerostomia was significantly lower in period prior to the start of radiotherapy, which represented 11% in pre-treatment and reached to 14% and 25% in the following radiotherapy session which was not significantly associated (p=0.13). 9 Another studies showed much higher results, as in Belgium (2008), 75 head and neck cancer patients enrolled in a study yielded results showed that majority of patients (93%) suffered from xerostomia and 65% had moderate to severe xerostomia (grade II to III). 12 Another German study in 2011 included 95 patients who underwent radiotherapy for head and neck cancer and recorded information regarding xerostomia development, they noticed that incidence of xerostomia was significantly higher in patients who received higher radiotherapy doses to the parotid glands (p=0.0195) in comparison to other region with small doses. 13 All these studies, although differed in the percentages and association, but agreed in facts that serious xerostomia easily occurred after a larger exposure dose to the neck, and furthermore, differences in results observed might be attributed to several factors as sample size, dose and type of radiotherapy used, site and grade of tumor for which radiotherapy was used and location of radiotherapy applied. Males were more prevalent than females (67% versus 33%) with male to female ratio of 2:1. Age was ranging from 13 to 78 years with a mean 51.69±13.7 years and the highest proportion was found in age group 40-59 years (52%). Out of 63 Iranian patients participated in a study conducted in 2012, 43 patients (77.8%) were male with male: female ratio was 3.5:1. 10 Finally, higher results observed in Greece in a study conducted on 60 patients with head and neck cancer, as male represented 80% of them (48 patients) with male: female ratio was 4:1. 11

CONCLUSION
Females, negative past medical history, advanced stage of tumor, high dose of radiotherapy and site of tumor (oral, nasopharyngeal, and parotid) were significantly associated factors with incidence of xerostomia. Tumor site was significant factor associated with the grade of xerostomia.

Recommendations
 Delivering the radiation therapy for head and neck cancers with sparing the salivary gland tissue by the use of new radiotherapy techniques, IMRT may help to decrease the intensity of xerostomia.  Maintaining good oral health by educating the patients about dental care before and during radiotherapy in the form of frequent brushing, flossing and use of flouride treatment.  Dietary management by advising patients to drink plenty of fluids to maintain hydration and avoid hot drinks, spicy food, smoking and alcohol.  The use of amifostine during radiation treatment in order to prevent xerostomia and educate patients about the use of artificial saliva, chewing gum and pilocarpine to manage xerostomia.  Further researches and studies about this disturbing side effect are needed to confirm the results of this study and to know more illustrate causes and ways of management.