Introduction
Oral mucositis is one of the most frequent side-effects
of head and neck radiotherapy.[] Mucosal inflammation and ulceration cause pain and swallowing difficulties
during radiotherapy and may have a detrimental
effect on treatment, causing prolongation with unintended
interruptions.[,] Several strategies to reduce the severity and frequency of mucositis are described
in the literature, but none of them are completely effective
or strongly recommended.[-] The total radiation
dose for oral mucosa is one of the most important
factors in mucositis. Therefore, a severe side-effect is
inevitable during definitive radiotherapy.[] Mucositis-
induced pain may adversely affect nutritional status,
especially the oral health-related quality of life of
patients receiving curative treatment.[,]
In this prospective single-arm study, we aimed to
maintain the barrier function against mucositis-induced
pain with an oral gel containing glycyrrhetinic
acid, hyaluronic acid and polyvinylpyrrolidone in head
and neck cancer patients during radiotherapy.[,]
This oral gel has previously been described as effective
in reducing pain during chemotherapy, and in a few radiotherapy
studies.[-] In this study, our goal is to
maintain nutritional status and quality of life by maintaining
the mucosal barrier function and reducing oral
pain.
Methods
Ethical Considerations
Ethics approval for this study was obtained from Marmara
University School of Medicine Ethical Committee
with the number 7037436-050.06.04-140018640.
All volunteers signed consent forms after a full explanation
of this clinical study.
Patients and Settings
Thirty patients diagnosed with head and neck cancer
were included in this study. However, one patient died
due to disease progression in the third week of radiotherapy.
Thus, 29 volunteers were included in the analysis
(loss rate: 3.3%). The characteristics of the study
group are summarized in Table 1. All patients were
examined by a dentist experienced in head and neck
radiotherapy (KBK) for oral hygiene evaluation and
periodontal and dental treatment was carried out if
necessary, before radiotherapy. None of the volunteers
reported any alcohol or tobacco usage during radiotherapy.
Table 1: Demographics of the patients and treatments
characteristics
Radiotherapy was applied in a linear accelerator
with 6 MV photon energy using the volumetric arch
technique to patients with curative intent in a median
six weeks, with a mean dose of 66 Gy (range, 60 to 70
Gy). Each patient received the treatment with intensity-
modulated radiotherapy planning (IMRT). Most
of the patients received concurrent weekly cisplatinbased
chemotherapy (83.3%). Oral mucosa for each patient was countered by a radiation oncologist for
organs at risk, including the teeth and buccal mucosa.
The mean volume of oral mucosa was revealed with a
3D radiotherapy planning system (Eclipse v11.0) and it
was 132.69 cc (SD 24.94; range, 81.9 to 201.37 cc). The
percentage of the mean volume received radiation dose
(in Gy) by oral mucosa (V10 to V50) was 40.19% (SD
23.72%; range, 3.1 to 100%) (Table 1).
Oral mucositis was measured and graded weekly
from the beginning to the end of radiotherapy. The
prevalence of severe oral mucositis was documented by
Common Toxicity Criteria v3.0.[] A grade of three
or higher indicates the prevalence of severe mucositis.
All patients were assessed weekly for other sideeffects
by a radiation oncologist (BMA), and for oral
and dental care (physical changes in mucosa, gingiva
and teeth) by a dentist (KBK), and for nutritional status
and treatment by a dietitian (BD) using the subjective
global assessment test (SGA).[] The oral gel
containing glycyrrhetinic acid, hyaluronic acid and
polyvinylpyrrolidone (GelClair®) was provided from Helsinn Pharmaceutical Company without any charge.
The oral gel was used to coat the ulcerated oral mucosa
surface and to reduce mucositis-induced pain
during eating. The application of oral gel was started
at the 12 Gy of radiotherapy when the clinical symptoms
biologically start.[] Therefore, patients used
oral gel before every meal, at least three times a day.
They used oral gel for one minute for each administration
and performed self-measurement using a sand
timer. Regular usage was checked weekly via patients
and/or caregivers" paper-based reports. The self-assessment
visual analog score (VAS) was used for assessing
oral pain weekly during radiotherapy.[] Pain scores
ranging from 0 to 10 on a continuous scale were measured
(0=no pain to 10=very painful). There was no restriction
for painkiller usage, and patients did not use
any other strategy to reduce the mucositis. Oral healthrelated
quality of life was assessed using the EORTC
QoL-HN35 questionnaire at the beginning and at the
end of radiotherapy.[]
Statistical Analysis
For descriptive purposes, numerical variables were
summarized using means and standard deviations, or
medians and interquartile ranges according to the distribution.
The distribution of the continuous variables
was investigated using the Shapiro Wilks test, QQ, PP
plots, skewness and kurtosis values. Patients" mucositisrelated
symptoms were measured each week of radiotherapy.
Mucositis was classified as being severe (2 and
3) or not severe (0 and 1). This reasoning warranted the
decision to dichotomize the outcomes, as well as the
choice of threshold. The proportion of severe mucositis
was tested using the Cochran-Armitage test for trend.
A longitudinal study design, with repeated measures,
was used. Changes in VAS scores over time were assessed.
Patients" oral mucosa and VAS were assessed
at six-time points. Generalized estimating equations
(GEE) were used to analyze the predictive factors of
VAS scores. Patients were also analyzed after being divided
according to malnutrition. Thus, the Wilcoxon signed-rank test was used to examine the differences in
the prevalence of oral mucositis related symptoms (revealed
by the EORTC QoLHN35 questionnaire), such
as pain, swallowing, speech, social eating, communication
and altered taste) within groups across different
time-points. It was also of interest, given patients"
pain status (no/yes) at the beginning of the therapy, to
see whether oral mucositis related symptoms changed
concerning time was investigated. The McNemar test
was used to detect whether the nutritional assessment
test SGA (no risk=SGA A/under risk=SGA B or C)
proportion changed between the beginning and the
end of this study. Another analysis was also carried out
looking at weight loss. The mean percentage of weight
loss was 5%, and groups were split by weight loss <5%
vs. ?5%. These statistical tests were performed with R
3.5.3 (R Core Team [2019]; R: A language and environment
for statistical computing; R Foundation for
Statistical Computing, Vienna Austria; URL http://
www.R-project.org/). A p-value of <0.05 was considered
statistically significant.
Results
Mucositis and Pain
The prevalence and proportion of severe oral mucositis
increased from week one to week five, peaked at week
five, then decreased until the end of radiotherapy, as expected.
A significant linear increasing trend for severe
oral mucositis was found by the Cochran-Armitage
linear trend test (p<0.001) (Table 2). Meanwhile, oral
mucositis-induced pain increased each week from the
beginning to the end of radiotherapy (p<0.001). The
only significant predictor for changes in VAS scores
was the cumulative radiation doses of radiotherapy
(p<0.001) (Table 3).
Table 2: Frequencies and prevalence of the severe oral mucositis concerning weeks of radiotherapy
Table 3: Predictors for the changes in VAS scores
Nutritional Status and Quality of Life
There was a significant increase in the prevalence of
patients" mucositis (64.3%) who become at risk (SGA
B or C) at the end of radiotherapy (p<0.001) (Table 4).
Table 4: Changes of the prevalence of malnutrition at
the beginning and end of this study according
to SGA
The mean percentage of weight loss was 4.95%. There
was no difference concerning the severity of mucositis,
cumulative radiation doses or mean dose of oral
mucosa between patients <5% and ?5% weight loss
or SGA A and SGA B and C. On the other hand, the
VAS score was worse in the SGA B and C group of
patients (Fig. 1).
Fig 1: VAS scores according to the weight-loss proportion
in weeks.
Oral health-related quality of life parameters worsened
at the end of radiotherapy in all patients. Although
analysis showed that pain (p=0.01 vs p=0.02), mouth
pain (p=0.123 vs p=0.07), talking difficulties (p=0.06 vs
p=0.001), swallowing difficulties (p=0.09 vs p=0.001),
social eating difficulties (p=0.176 vs p=0.006), communication
(p=0.549 vs p=0.049), taste altering (p=0.004
vs p=0.000) and dry mouth (p=0.05 vs p=0.04) were
significantly worse in patients with ?5% weight loss
(SGA B or C) (Table 5).
Table 5: Comparisons of the EORTC QoLHN35 oral health-related parameters between the beginning and the end of the
radiotherapy
Patients were split according to the mean percentage
of weight loss (≥5%). The severity of mucositis was
not different between groups according to V40, V50
of the oral mucosa. However, VAS scores were lower
in the well-nourished group of patients. Quality of life
parameters was also significantly better in this group of
patients (Table 6).
Table 6: Severity of mucositis, VAS and oral health-related quality of life parameters changes during treatment split by
percentage of weight-loss
Discussion
Mucositis is a dose-limiting and common side-effect
of head and neck radiotherapy.[-] It is not possible
to maintain the integrity of the mucosa before the end
of treatment. There are mainly two ways to reduce the
effects of mucositis during head and neck radiotherapy.
One is to reduce the volume of the high dose area
of the mucosa, and another is to use medication, such
as protective agents, anti-inflammatory agents and
painkillers.[-] Due to the primary tumor side and
treatment protocols, and despite modern techniques,
it is not always possible to reduce the mucosal volume
receiving high doses. Moreover, none of the recommendations
for the medication fully work for severe
mucositis. The Multinational Society for Supportive
Care in Cancer (MASCC) recommends benzydamine
for high-level treatment of mucositis to reduce and
improve radiotherapy related mucositis.[,,] We
aimed to use an oral gel that coats the damaged mucosal
area to decrease the severity of mucositis and the pain it causes. Oral mucositis becomes worse in
the later weeks of radiotherapy. In our study, we observed
mucositis severity and frequency as expected
in high-dose radiotherapy. The goals of this study are
to reduce mucositis-induced pain, to protect against
weight-loss and improve quality of life with oral gel. In
the literature, there are a couple of randomized control
studies to test the barrier function against mucositis.
Two prospective trials found no difference in mucositis
incidence comparing standard care.[,] In their
randomized study, Barber et al.[] found that the
barrier function is not more effective than Sucralfate
and Mucaine in relieving the pain associated with radiotherapy-
induced oral mucositis. However, Hadjieva
et al.[] found a positive effect of the gel on mucositis in their randomized study. Our results showed that the
coating agent itself could not decrease the frequency
and severity of radiation-induced mucositis against a
definitive high dose of radiotherapy (≥60 Gy).
It is difficult to assess pain as a symptom due to its
subjective nature.[] Therefore, we used a self-assessment
method of VAS to measure pain in our patients.
[] Mucositis-induced pain increased week by week,
and the difference between the initial period and the
end of radiotherapy was significant (p<0.001). This result
may reflect inadequate pain relief. We found that
concurrent chemotherapy, the mucosal volume of high
doses, oral mucosa volume and oral pain at the beginning
of radiotherapy has no impact on VAS scores expect
cumulative radiation dose (p<0.001).
There is not a single type of pain in radiotherapy for
head and neck cancer patients.[] Therefore, we asked
about previous pain experience before radiotherapy
and used the oral health-related QoL parameters of the
EORTC HN35 questionnaire.[] Pain (Q1-Q4), mouth
pain, talking difficulties, swallowing difficulties, social
eating difficulties, communication, altered taste and
dry mouth all got significantly worse et the end of radiotherapy.
Furthermore, more than 60% of the patients
became at risk of malnutrition. What is interesting is
that there was no difference according to the cumulative
radiation dose (V40 and V50) of the oral mucosa or mucosal
severity between patients according to nutritional
status. However, the VAS score was lower in well-nourished
patients (Table 6, Fig. 1). All parameters except altered
taste were significantly worse in the malnutrition
group. Hence, we think that the key point is to reduce
mucositis-induced pain to maintain quality of life and
nutritional status in head and neck radiotherapy.
In this study, we followed a multidisciplinary approach
for the evaluation of mucositis-induced pain
by radiation using an oncologist, dentist and dietitian.
However, there are some limitations to this study. This
had no control group to compare the standard of care,
and a lack of long-term follow-up to observe late toxicities.
Conclusion
Severe mucositis incidence and frequency cannot be reduced
in high definitive doses of radiotherapy. Mucositis-
induced pain may have a direct effect on malnutrition
risk and quality of life during radiotherapy. Therefore, it
is crucial to find effective solutions against mucositis-induced
pain concerning maintaining the nutritional status
and quality of life of head neck cancer patients.
Acknowledgement: We thank Miss Nargül Türkmen, the
assistant manager, for her support to complete this study. We
also thank to Helsinn Pharmaceutical Company which provided
the oral gel without any charge.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: Marmara University School
of Medicine Ethical Committee with the number 7037436-
050.06.04-140018640.
Financial Support: None declared.
Authorship contributions: Concept - B.M.A.; Design -
B.M.A., K.B.K.; Supervision - B.M.A., K.B.K., B.D.; Funding - None; Materials - B.M.A., K.B.K., B.D., E.A.; Data
collection and/or processing - B.M.A., K.B.K., B.D., E.A.;
Data analysis and/or interpretation - B.M.A., K.B.K., B.D.,
E.A.; Literature search - B.M.A., K.B.K., B.D., E.A.; Writing
- B.M.A., B.D.; Critical review - B.M.A., K.B.K., B.D., E.A.
References
Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ,
Gwede CK, et al. Mucositis incidence, severity and
associated outcomes in patients with head and neck
cancer receiving radiotherapy with or without chemotherapy:
a systematic literature review. Radiother Oncol
2003;66(3):253-62.
Bese NS, Hendry J, Jeremic B. Effects of prolongation
of overall treatment time due to unplanned interruptions
during radiotherapy of different tumor sites and
practical methods for compensation. Int J Radiat Oncol
Biol Phys 2007;68(3):654-61.
Russo G, Haddad R, Posner M, Machtay M. Radiation
treatment breaks and ulcerative mucositis in head and
neck cancer. Oncologist 2008;13(8):886-98.
Ranna V, Cheng KKF, Castillo DA, Porcello L, Vaddi
A, Lalla RV, et al; Mucositis Study group of the Multinational
Association of Supportive Care in Cancer/
International Society for Oral Oncology (MASCC/
ISOO). Development of the MASCC/ISOO clinical
practice guidelines for mucositis: an overview of the
methods. Support Care Cancer 2019;27(10):3933-48.
Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe
DM, et al; Mucositis Guidelines Leadership Group of
the Multinational Association of Supportive Care in
Cancer and International Society of Oral Oncology
(MASCC/ISOO). MASCC/ISOO clinical practice
guidelines for the management of mucositis secondary
to cancer therapy. Cancer 2014;120(10):1453-61.
De Sanctis V, Bossi P, Sanguineti G, Trippa F, Ferrari
D, Bacigalupo A, et al. Mucositis in head and neck
cancer patients treated with radiotherapy and systemic
therapies: Literature review and consensus statements.
Crit Rev Oncol Hematol 2016;100:147-66.
Chung YL, Pui NNM. Confounding factors associated
with oral mucositis assessment in patients receiving
chemoradiotherapy for head and neck cancer. Support
Care Cancer 2017;25(9):2743-51.
Lee SC, Wang TJ, Chu PY. Predictors of weight loss
during and after radiotherapy in patients with head
and neck cancer: A longitudinal study. Eur J Oncol
Nurs 2019;39:98-104.
Jung YS, Park EY, Sohn HO. Oral Health Status and
Oral Health-related Quality of Life According to
Presence or Absence of Mucositis in Head and Neck
Cancer Patients. J Cancer Prev 2019;24(1):43-7.
Buchsel PC. Polyvinylpyrrolidone-sodium hyaluronate
gel (Gelclair): a bioadherent oral gel for the treatment
of oral mucositis and other painful oral lesions. Expert
Opin Drug Metab Toxicol 2008;4(11):1449-54.
Barber C, Powell R, Ellis A, Hewett J. Comparing
pain control and ability to eat and drink with standard
therapy vs Gelclair: a preliminary, double centre,
randomised controlled trial on patients with radiotherapy-
induced oral mucositis. Support Care Cancer
2007;15(4):427-40.
Innocenti M, Moscatelli G, Lopez S. Efficacy of gelclair
in reducing pain in palliative care patients with oral
lesions: preliminary findings from an open pilot study.
J Pain Symptom Manage 2002;24(5):456-7.
Hadjieva T, Cavallin-Ståhl E, Linden M, Tiberg F.
Treatment of oral mucositis pain following radiation
therapy for head-and-neck cancer using a bioadhesive
barrier-forming lipid solution. Support Care Cancer
2014;22(6):1557-62.
National Cancer Institude. Common Terminology
Criteria for Adverse Events v3.0 (CTCAE). Available
from: https://ctep.cancer.gov/protocolDevelopment/
electronic_applications/docs/ctcaev3.pdf. Accessed,
January 2, 2020.
Detsky AS, McLaughlin JR, Baker JP, Johnston N,
Whittaker S, Mendelson RA, et al. What is subjective
global assessment of nutritional status? JPEN J Parenter
Enteral Nutr 1987;11(1):8-13.
Bentzen SM, Saunders MI, Dische S, Bond SJ. Radiotherapy-
related early morbidity in head and neck cancer:
quantitative clinical radiobiology as deduced from
the CHART trial. Radiother Oncol 2001;60(2):123-35.
Price DD, McGrath PA, Rafii A, Buckingham B. The
validation of visual analogue scales as ratio scale
measures for chronic and experimental pain. Pain
1983;17(1):45-56.
Sherman AC, Simonton S, Adams DC, Vural E, Owens
B, Hanna E. Assessing quality of life in patients with
head and neck cancer: cross-validation of the European
Organization for Research and Treatment of
Cancer (EORTC) Quality of Life Head and Neck module
(QLQ-H&N35). Arch Otolaryngol Head Neck
Surg 2000;126(4):459-67.
Zadik Y, Arany PR, Fregnani ER, Bossi P, Antunes
HS, Bensadoun RJ, et al; Mucositis Study Group of
the Multinational Association of Supportive Care
in Cancer/International Society of Oral Oncology
(MASCC/ISOO). Systematic review of photobiomodulation
for the management of oral mucositis in cancer
patients and clinical practice guidelines. Support Care
Cancer 2019;27(10):3969-83.
Flook C, Calman F, Mant M, Subramanian R, O"Connell
M. GELCLAIR® vs benzydamine in a randomised
controlled study in patients with oral mucositis due
to radical radiotherapy. Abstracts of the 17th MASCC
International Symposium. Support Care Cancer
2005;13(6):401-83.
Bossi P, Giusti R, Tarsitano A, Airoldi M, De Sanctis V,
Caspiani O, et al. The point of pain in head and neck
cancer. Crit Rev Oncol Hematol 2019;138:51-9.
