Oral mucositis in patients undergoing radiotherapy for head and neck cancer : An observational cross-sectional study

Radiotherapy (RT) is indispensable in the treatment of head Background: and neck cancer (HNC). Oral mucositis (OM) is a complication in HNC patients undergoing RT. This study aimed to identify the incidence, distribution of OM, and its effect on treatment breaks in a section of HNC in patients in Iraq. This is an observational, descriptive cross-sectional study. In Methods: total, 50 patients with primary HNC, treated with external beam RT, from 30th April to 10th September 2017 at  Baghdad Radiation Oncology and Nuclear Medicine Center were included in the study. Cases of OM were graded according to the World Health Organization scale. 80% of patients were below 65 years, and the male/female ratio Results: was 2.6:1. Tumor sub-sites were nasopharynx (36%), larynx (22%), parotid (14%) and tongue (12%). 74% were smokers during or before starting RT. 86% were in stages III or IV. Incidence of OM was 72%; 16% grade I, 40% grade II, and 16% grade III. OM occurred in 93% females and 64% males, and 79% received concurrent regimens. OM occurred in HNC treated by RT, more in females, who Conclusions: received chemotherapy plus RT, and those with tumors of the oral cavity and nasopharynx. OM-related unplanned breaks may interrupt treatment schedule. HNC imposes a double burden in Iraq as it attacks a productive age group, and the vast majority of the patients included in this study were diagnosed in advanced stages.


Introduction
Globally, head and neck cancer (HNC) accounts for 550,000 cases and 380,000 deaths, annually 1 . In the US, HNC accounts for 3% of cancers 2 , and in Europe, it was estimated to be 4% in 2012 3 . Men are affected more than women with a ratio of 2:1 and 4:1 for US and Europe, respectively. In Iraq, the incidence of HNC is <2% 4 . The primary causes of HNC are tobacco and alcohol, and viral infections including Epstein-Barr virus and hepatitis virus 5-7 . Radiotherapy (RT) plays a central and evolving role in the treatment of HNC 8 and is used with or without chemotherapy (CT) as a definitive or adjuvant treatment 8 . The oral cavity is susceptible to direct and indirect toxic effects of cancer CT and RT 9 . This risk reflects high rates of cellular turnover for the lining mucosa, a diverse and complex micro-flora, and trauma to oral tissues during normal oral function 10-12 . Oral mucositis (OM) is a debilitating side effect of RT 13 and is exacerbated by concomitant CT 14 , which can begin 1-2 weeks after initiation of RT as asymptomatic erythema often progressing to erosion and ulceration. The ulcers are painful, covered by a white fibrinous pseudo-membrane, associated with dysphagia and decreased oral intake 15,16 .
Radiation therapy is an important method used in the treatment of head and neck cancers and, like all other methods used in treatment, it is not without the side effects of treatment. The injuries that occur to mucous membranes of the oral cavity are only part of those effects, which we can avoid and reduce them before and during and after treatment by adhering to the recommendations of the treating physician and the work of therapeutic planning. This study aimed to identify the incidence, distribution of OM, and its effect on treatment breaks in a section of HNC in patients in Iraq.

Study design and setting
This is an observational, cross-sectional study for HNC treated by external beam radiation therapy (EBRT), which included patients 50 patients, who were patients from 30th April to 10th September 2017.
The study was conducted at Baghdad radiation Oncology and Nuclear Medicine center, Bagdad, Iraq.

Participants
Patients who fit the eligibility criteria during the study dates who were scheduled for treatment were included in the study.
Dose of EBRT: 50-70 Gray, with a standard fractionation. Each fraction is 2Gy and 5 fractions per week. Radiation delivered with 3D conformal technique, using Elekta infinity, and Elekta synergy machines.
Eligibility criteria of patients was: primary HNC; T3 or T4 disease; positive nodes; residual disease; positive margins; perineural invasion; lymphovascular infiltration; extracapsular extension; treatment as described above.
Patients were excluded who had comorbid conditions, were treated in a palliative way, and those with metastasis or with a bad performance status.

Data collection
We conditionally collected data from patient files when they attended follow-up at the in-patient or/and out-patient clinic, or when these patients made visits to our center.
Variables collected: Variables collected included: patient's gender, age and smoking status; tumor histopathology, stage, grade, subsites, and primary or metastases; radiotherapy dose, fractions, interpretations and oral mucositis onset.
Assessment by World Health Organization's scale of OM was performed as follows: Grade 0, no OM; Grade I, soreness; Grade II, erythema, ulcers, able to eat solids; Grade III, Ulcers, liquid diet only; Grade IV, alimentation not possible.

Statistical analysis
The collected data was categorized and analyzed by T-test to identify the incidence of OM and its distribution. SPSS IBM version 22 was used.

Ethical considerations
Written informed consent was obtained from the patients for the publication of their data in this article, and the study was conducted according to the ethical standards established by the 1964 Declaration of Helsinki. The Medical Ethical Committee of Baghdad University approved this study (code:611) on 18/04/2017.

Results
In the total patient population 72% were men, while 28% were women; male/female ratio was 2.5:1. The mean age was 53.3±11 years, and majority (38%) were between the ages of 55 and 64 years. Patients aged 65 years or more composed 20% of the total population (Table 1). In total, 76% received CT before or concurrent with RT. The vast majority (86%) had advanced stages III or IV of cancer. 74% were smokers, during or before starting RT ( Table 1); 86% of these were men, while 43% were women. Seven sub-sites were observed. The highest was the nasopharynx, followed by the larynx, parotid, and then the tongue ( Figure 1).
In total 72% of patients had an incidence of OM, with no patients with grade IV; 40% were grade II, and grades I and III appeared in 16% of patients ( Figure 2). OM occurred in 100% of young patients, below 35 years, 50% among 45-54 years old, and 90% in patients ≥ 65 years. 93% of women developed OM compared to 64% of men (Table 2). OM appeared in 50% of patients treated    (Table 2). In this study, the majority of OM cases (47%) came from nasopharynx tumors (Table 2).
In total, 20% of patients had single breaks in their treatment schedule; the total break days was 20 days, giving an average of 2 days per break (Figure 3). Unplanned breaks were observed more in men, those who smoke, those with both RT and CT treatment, those with stage IV cancer, and those with grade III OM (Table 3).

Discussion
In most countries around the world, HNC is most common in men, and the male/female ratio ranges from 2:1 to 4:1 7,17 ; in the UK, the ratio of male/female was 2.7:1, and in Australia it was 2 , smokers (30%), those who were treated with CT plus RT (30%), those with stage IV (44%), and those with grade III OM (50%). In this study, two patients had breaks before the end of the 3rd week, and four had unplanned breaks at the 6th and 7th weeks, so a total of six patients (12%) had breaks at a critical treatment time. However, the break durations were only 1-3 days, but it is important to mention that in most of the times, the break is decided by patients themselves (subjective). It is convenient to mention here the conclusion of Bonomi et al., that OM is not only painful but also decreases the patient's willingness to continue treatment 24 .

Conclusions
OM is an ongoing toxicity of RT, yet it still represents an important clinical challenge and causes burden to patients and caregivers. Most patients with HNC treated by radiation develop OM. The sub-site of the tumor is a main risk for development of OM. It was observed that young and old ages, combined RT plus CT, and advanced stage of tumor are associated with high incidence and severe OM. Patients with OM are at high risk of unplanned breaks in radiation. HNC in Iraq attack young and middle age people, which may lead to increases on its social and economic burden.

Recommendations
1. Using a multidisciplinary approach for oral management of HNC, before, during and after treatment.
2. Provision of psychological care and support services for these types of patients.
3. Education of patients and families regarding oral care.
4. Encouragement and support of multi-center studies and researches.
5. Raising competency of dentists, primary health care physicians and dermatologists to ensure early detection of HNC.
Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Grant information
The author(s) declared that no grants were involved in supporting this work.
The authors mentioned different primary causes for HNC, yet, they investigated smoking only. Are other variables investigated for the study population?
The last paragraph of the introduction section should be reformatted and attached to references.
The methods section: The authors did not mention surgery as a treatment modality for HNC patients. This should be addressed and included at the study statistics.
The authors selected variables: Please, state "tumor stage" instead of "stage" Please, state "OM grade" instead of "grade".
Did you show any data for OM onset?
Did you investigate viral infections as well?
Treatment unplanned breaks issue needs to be discussed in detail and data sorted as well. Who decided the break? Which treatment was interrupted in "CT plus RT" group? And, for how long was it? Were the breaks caused by OM only?
Please, discuss why there was no significant difference in all groups (Table 3).
I would recommend reformatting the recommendation section to reflect the study results and conclusion. Table 1: please, adjust clearly the P-value (done for which groups) and mention in the text.    In total, the article English language should be improved. I suggest to it be reviewed by a native English speaker.

Is the work clearly and accurately presented and does it cite the current literature?
Yes Data collection: it is not clear how they collect data (they asked patients to fill in a questionnaire, they extract data from medical records, …).    Table 3: are the authors sure that the only reason to break treatment is OM? In the Discussion they reported: "that in most of the times the break is decided by patients themselves". This aspect needs to be more detailed: how many times does it happen? In which way did they break the treatment?
Was OM the only reason for breaking the treatment? All differences by sub groups are not significant (add a comment in the text).
Recommendations: are not related with results reported in the article (especially for n. 2 and 3).
In general, the English needs to be revised.

Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound? Partly

If applicable, is the statistical analysis and its interpretation appropriate? Partly
Are all the source data underlying the results available to ensure full reproducibility? Partly

Are the conclusions drawn adequately supported by the results? Partly
No competing interests were disclosed.

4.
Minor points: In the introduction part, the authors described Human Hepatitis Virus as a risk factor, but in the cited references, it looks like Human Papilloma Virus should be the risk factor. Figure 1: The presentation of the pie chart looks unsuitable. Improvement of the colour usage (it's not necessarily in colour figure) is recommended.

If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Yes

Are the conclusions drawn adequately supported by the results? Partly
No competing interests were disclosed.

Competing Interests:
Reviewer Expertise: Radiation oncology; head and neck cancer; clinical oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
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