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Citation: Ottaviani, G.; Targato, G.;
Rupel, K.; Gobbo, M.; Generali, D.;
Guglielmi, A.; Dicorato, A.; Adamo,
D.; Canfora, F.; Di Lenarda, R.; et al.
Oral Problems in Oncology Patients
Undergoing Chemotherapy for Solid
Tumors: A Prospective Observational
Study. Cancers 2024,16, 176. https://
doi.org/10.3390/cancers16010176
Academic Editor: Miguel Angel
González Moles
Received: 14 November 2023
Revised: 23 December 2023
Accepted: 27 December 2023
Published: 29 December 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
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4.0/).
cancers
Article
Oral Problems in Oncology Patients Undergoing Chemotherapy
for Solid Tumors: A Prospective Observational Study
Giulia Ottaviani 1, *,† , Giada Targato 2,3 ,† , Katia Rupel 1, Margherita Gobbo 4, Daniele Generali 1,
Alessandra Guglielmi 5, Angela Dicorato 5, Daniela Adamo 6, Federica Canfora 6, Roberto Di Lenarda 1
and Matteo Biasotto 1
1Department of Medical, Surgical and Health Sciences, University of Trieste, Strada di Fiume 447,
34149 Trieste, Italy
2Department od Medicine (DAME), University of Udine, 33100 Udine, Italy
3
Department of Oncology, Udine Academic Hospital, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC),
33100 Udine, Italy
4Unit of Oral and Maxillofacial Surgery, Ca’ Foncello Hospital, 31100 Treviso, Italy
5Department of Oncology, Maggiore Hospital, Piazza dell’Ospitale 1, 34125 Trieste, Italy
6Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, 5 Via
Pansini, 80131 Naples, Italy
*Correspondence: gottaviani@units.it; Tel.: +39-040-3992102
†These authors contributed equally to this work.
Simple Summary: Several oral problems occurring during cancer treatment can lead to the discon-
tinuation or interruption of the scheduled treatment, with a negative impact on patient’s overall
survival. Very few studies focused on patients’ self-reported oral problems during chemotherapy
treatment for solid tumors. Through the administration of a dedicated questionnaire, we aim at
correlating the presence of oral complications to demographic and medical information. Metastatic
disease represented a risk factor for the onset of oral mucositis and salivary gland hypofunction, while
specific chemotherapy regimens increased the risk to develop a subjective reduction in the salivary
flow and difficulty in swallowing. Most of the participants were informed by the oncologist about the
possibility of oral problems arising during oncological therapies. It is of paramount importance to
collect observational data on oral problems from the patients’ perspective in order to plan information
and prevention campaigns to inform patients about their possible occurrence by providing useful
tools for prevention and management.
Abstract: PURPOSE: Oral problems in a group of oncological patients undergoing chemotherapy (CT)
for solid tumors have been examined. Incidence and severity of patients’ self-reported oral problems
have been evaluated along their interaction with age, gender, tumor diagnosis and stage, presence of
mestastasis, CT agent type, and number of CT cycle. We also analyzed the presence of paraesthesia
and anaesthesia and their predisposing factors associated with clinical and treatment-related variables.
METHODS: Patients were asked to fill in a questionnaire to evaluate the onset and the intensity of oral
and perioral pain, oral mucositis, salivary gland hypofunction, dysgeusia, dysphagia, dysphonia, and
sensitivity neuropathy (paraesthesia or dysaesthesia) since the last CT infusion. We also investigated
which types of medications have possibly been used and who recommended it, as well as patients’
degree of awareness about the possibility of oral problems arising during CT. RESULTS: We recruited
194 patients and obtained 491 questionnaires. We found that a metastatic disease was a risk factor
for OM (OR 2.02, p= 0.026) and salivary gland hypofunction (OR 1.66, p= 0.042) and that platinum
agents, compared to mitotic inhibitors, increased the risk of developing salivary gland hypofunction
(OR 2.16, p= 0.013), dysphagia (OR 3.26, p= 0.001), and anaesthesia (OR 5.16, p= 0.041). Young age
was a slight protective factor for most symptoms. The 80% of enrolled patients were informed by the
oncologist about possible oral problems arising during CT. CONCLUSIONS: Our study highlighted
the importance of collecting observational data from the patients’ perspective on oral problems
arising during the routine oncology practice, across a range of solid tumors and CT regimens. The
Cancers 2024,16, 176. https://doi.org/10.3390/cancers16010176 https://www.mdpi.com/journal/cancers
Cancers 2024,16, 176 2 of 16
relevance of these findings focused on the key role of the multidisciplinary team in advising the
patients on the possible occurrence of oral problems, also by recommending their management.
Keywords: chemotherapy; solid tumors; oral problems; stomatotoxicity; numb chin syndrome
1. Introduction
Patients with solid tumors may suffer from oral problems during their oncological
treatment. The great part of these disorders is due to drug stomatotoxicity, but they could
also be related to the tumor progression itself. Despite the advances in cancer treatment,
chemotherapy (CT) is still widely used alone or in combination with surgery, radiotherapy
(RT), targeted therapy, hormone therapy, or immunotherapy. The main side effect of
CT is the lack of selectivity, inducing the damage not only for the neoplasm but also
for the healthy cells characterized by high proliferation. With specific regard to the oral
cavity mucosal cells [
1
], according to the MASCC/ISOO evidence-based guidance [
2
], oral
problems in patients with cancer can manifest, among others, as oral pain and/or oral
mucositis (OM) often associated with oral infections with possible systemic dissemination,
salivary gland hypofunction, taste disturbance (dysgeusia), dysphagia, and difficulty in
speaking (dysphonia) [3–5].
OM implies an inflammation of the oral mucosa with an estimated incidence of 40–50%
in patients receiving CT and in almost all patients (80–100%) undergoing head and neck
RT [
6
]. Usually, the OM presents with oedema and erythema associated with pain and a
burning sensation with potential difficulty in swallowing. In addition, the interruption of
the continuity of the mucosal barrier and the CT-induced neutropenia can increase the risk
of local infections or, rarely but dramatically, of systemic spread [7].
The stomatotoxic effect of CT may also involve the major and minor salivary glands,
compromising the quality and quantity of saliva. Hyposalivation may occur following CT,
radioactive iodine treatment, hematopoietic stem cell transplantation (HSCT), head and
neck RT, targeted therapy, and immunotherapy. Moreover, it may be related to medications
used to support the cancer patient (e.g., opioid analgesics, centrally acting pain medications)
and with dehydration [
8
]. Hyposalivation leads to a reduction in mucosal protective factors
and antimicrobial substances contained in saliva, with consequent increased risk of oral
infections and tooth decay [
9
]. Hyposalivation may also lead to difficulties in the formation
of food bolus causing pain in swallowing, promoting the development of oral lesions [
10
].
During anticancer treatments, patients may also develop dysphagia, characterized
by pain and swallowing difficulties, whose general prevalence in oncological patients is
estimated to be around 15.4% [
11
]. During RT or combined CT-RT for head and neck
cancers (HNC), patients are at increased risk of developing dysphagia, directly related to
treatment volumes, thus leading to pain and swallowing difficulties. Dysphagia may be
related to changes in neuromusculoskeletal structure and function, anatomical alterations
of the head and neck area, saliva alterations, and/or odynophagia [
11
]. There is a strong
relationship between OM, salivary gland hypofunction, and dysphagia.
An additional oral problem is represented by dysgeusia, a taste disorder due to
neurological damage, the number of receptor cells, and alterations of the cell structure, in
which a persistent gustatory sensation arises in the absence of taste stimulants, or distorted
gustatory perception [
12
]. The gustatory perception could, rarely, be completely (ageusia)
or, more often, partially reduced in its intensity (hypogeusia). The prevalence of dysgeusia
depends on the cancer treatment: if it is exclusively related to CT, the prevalence is 56.3%;
to head and neck RT, it is 66.5%; while with CT-RT, it rises up to 76%. A permanent taste
alteration may affect about 15% of the patients [13].
Hyposalivation—OM of the palate and laryngeal tissues, fibrosis, edema and atrophy
of vocal folds, and laryngeal/pharyngeal tissues—could lead to voice and/or speech
Cancers 2024,16, 176 3 of 16
alterations [
14
]. The pathophysiology of dysphonia may also include neuromuscular
weakness due to tumor invasion.
In addition to oral problems related to anticancer therapies, the numb chin syndrome
(NCS), a rare form of sensitivity neuropathy manifesting as a sensation of dysaesthesia or
anesthesia in the head and neck regions, specifically in the perioral zone [
15
,
16
], could be
associated to metastatic dissemination rather than CT neurotoxicity itself. This condition is
caused by tumoral infiltration or compression of the mandibular nerve or its distal branches
like the inferior alveolar nerve or the mental nerve [
17
]. In most cases, it is due to the
presence of bone metastases in the mandibular body, but it can also be caused by metastases
of the cranial base or by leptomeningeal dissemination [
18
]. The typical presentation of
NCS is with unilateral sensitivity alterations as dysaesthesia, paraesthesia, or anaesthesia
and involves the labial and chin regions [19].
Oral problems could be responsible for dose reduction or discontinuation of anticancer
therapies, often associated to patients’ reduced survival rates [
19
]. Side effects of CT, includ-
ing oral problems, have been widely collected and analyzed in clinical trials [
20
]. However,
possible biases arising from trials compared to routine care include the exclusion of patients
where complications are more expected or a more accurate monitoring of complications.
Finally, in clinical trials, oral problems are typically assessed and scored by clinicians, not
by patients, often underestimating the number and severity of toxicities experienced by
patients [
21
]. All these considerations lead to the need of collecting observational data in
routine clinical practice. Recent data reporting CT-related oral problems examined only spe-
cific CT regimens [
22
,
23
], tumors [
24
,
25
], or toxicities [
26
,
27
]. The lack of information from
the patients’ perspective on oral problems arising during the routine oncology practice [
28
],
across a range of solid tumors and CT regimens, represented open questions which would
be addressed through our prospective observational study.
2. Materials and Methods
The prospective observational study was conducted in collaboration between the
Department of Oncology (Maggiore Hospital, Trieste, Italy) and the Oral Medicine and
Pathology Unit (Maxillofacial Surgery and Odontostomatology Clinic, Maggiore Hospital,
Trieste, Italy).
Patients, meeting the following inclusion and exclusion criteria, were consecutively
recruited at the day hospital of the Department of Oncology.
Inclusion criteria include the following:
- Male and female genders;
- Age ≥18 years;
- Diagnosis of any solid tumor;
- Outpatients receiving second or subsequent CT cycle;
- Signature of written informed consent.
Exclusion criteria include the following:
- Age < 18 years;
- Haematological cancer;
- Hospitalized patients;
- Patients at first CT infusion or not currently receiving CT;
- Concomitant or previous head and neck RT;
- Patients that refused to sign the written informed consent;
- Patients incapable of understanding and/or wanting.
A specific and anonymous questionnaire in the Italian language, validated by the
regional ethics committee, was elaborated by our multidisciplinary team (Annex S1). For
the entire duration of the study (1-year observation) and for each patient treated with CT in
the observation period, the questionnaire was completed during each CT cycle, excluding
patients undergoing the first CT cycle.
Cancers 2024,16, 176 4 of 16
The questionnaire collected patients’ general information and medical history such as
age, gender, tumor diagnosis and stage, presence of metastasis, CT agent type (antimetabo-
lites, mitotic inhibitors, topoisomerase II inhibitors, platinum agents, anti-tumor antibiotics,
alkylating agents, multiple CT-based combination), and number of CT cycles.
The questionnaire was planned in relation to the criteria for patients’ subjective as-
sessment and perception of oral problems, in agreement with the MASCC/ISOO evidence-
based guidance [
2
]. Specifically, through the administration of the questionnaire, the
following items were assessed: presence of oral and perioral pain, OM, salivary gland
hypofunction, dysgeusia, dysphagia, dysphonia, and sensitivity neuropathy (paraesthesia
or dysaesthesia). Patients were also asked about frequency and duration, since last CT
infusion, of the reported oral problems and about their intensity using the numerical rating
scale—an 11 pt numerical scale with boxes (0–10) for each response—since this format
proved to have good feasibility, reliability, and convergent validity [29,30].
When patients reported in the questionnaire the onset of oral problems, we investi-
gated which types of medications have been used and who recommended them. Eventually,
we investigated the degree of awareness of the patients about the possibility of oral prob-
lems arising during CT.
2.1. Questionnaire Face and Content Validity
The face validity of the questionnaire, including questions appropriateness, logical
sequence, and comprehensibility was administered and examined by 10 patients before
the beginning of the study. The impact score (IS) of each item was calculated using a
five-point Likert appropriateness scale ranging from 1 (not appropriate at all) to 5 (highly
appropriate) and items scoring < 1.5 were removed from the questionnaire [
31
]. Moreover,
content validity was assessed using the content validity ratio (CVR) and content validity
index (CVI). Items were classified as not necessary, useful but not essential, or essential,
and CVR values, according to Lawshe’s formula [
32
], lower than 0.62 were removed from
the questionnaire. The relevance of each item was defined according to a four-point Likert
scale and items with CVI < 0.80 were removed from the final questionnaire [33].
2.2. Statistical Analysis
IBM SPSS software version 29.0 for Windows (Armonk, NY, USA) was used to perform
the statistical analyses.
Patients’ demographic and medical information were summarized by calculating de-
scriptive statistics, comprising means, standard deviations (SDs), medians, and interquartile
ranges (IQRs). After assessing the normality of distribution of data using the Kolmogorov–
Smirnov test, a Student’s t-test was employed to evaluate any significant differences in
patients’ age distribution. The chi-squared test was used to analyze the significance of the
differences in categorical variables (tumor diagnosis, presence of metastasis, CT agent type,
and number of CT cycles) between genders.
Then, a multiple backward logistic regression model, using backward variable selec-
tion, was conducted exploring the considered variables as predictors for oral problems.
In particular, the onset of oral problems was considered as the dependent variables (oral
and perioral pain, OM, salivary gland hypofunction, dysgeusia, dysphagia, dysphonia,
sensitivity neuropathy), while the explanatory variables (categories) entered in each model
were age, gender, tumor diagnosis, presence of metastasis, CT agent type, number of CT
cycle, and medications to manage oral problems. The cut-off levels of significance were 0.05
and 0.10 for entry and removal, respectively. For each significant association of variables,
odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. A p-value < 0.05 was
considered statistically significant.
Cancers 2024,16, 176 5 of 16
3. Results
3.1. Descriptive Analysis
A total of 194 patients were recruited, 89 males and 105 females. Female mean age
was 63.5
±
11.2, median age 65 (range 32–85), while males mean age was 67
±
11 years,
median age 69 (range 26–83). Any statistically significant difference between groups’ age
were found.
A total of 491 questionnaires were collected, with an average of 2.5 questionnaires per
person. Female patients filled in 55.6% of the questionnaires, while male patients filled
in 44.4%.
Table 1shows the prevalence of tumor diagnosis and stage, metastasis, CT agent type,
and number of CT cycles according to patients’ gender distribution.
Table 1. Distribution of tumor diagnosis and stage, presence of metastasis, CT agent type, and number
of CT cycles according to gender (chi-squared Test). ** Significance p≤0.01. NS—not significative.
Female Male Diff.
Frequency
(Total 105)
Percentage
(Total 100%)
Frequency
(Total 89)
Percentage
(Total 100%)
Tumor diagnosis
p< 0.0001 **
Lung and pleura 13 12.4% 32 36.0%
Gastrointestinal 30 28.6% 35 39.3%
Pancreas and hepatobiliary 12 11.4% 10 11.2%
Prostate 0 0.0% 1 1.1%
Breast 28 26.7% 0 0.0%
Ovarian 13 12.4% 0 0.0%
Uterus 3 2.9% 0 0.0%
Testis 0 0.0% 4 4.5%
Kidney and urinary tract 2 1.9% 2 2.3%
Melanoma 0 0.0% 2 2.3%
Soft tissue 1 0.9% 1 1.1%
Central nervous system 1 0.9% 1 1.1%
Unknown origin 2 1.9% 1 1.1%
Tumor stage NS
Stage I 5 4.76% 6 6.74%
Stage II 7 6.67% 8 8.99%
Stage IIII 24 22.86% 23 25.84%
Stage IV 69 65.71% 52 58.43%
Metastasis NS
Yes 69 65.7% 52 58.4% 69
No 36 34.3% 37 41.6% 36
CT agent type NS
Antimetabolites 17 16.2% 9 10.1% 17
Mitotic inhibitors 18 17.1% 7 7.9% 18
Topoisomerase II inhibitors
1 0.95% 0 0.0% 1
Platinum agents 4 3.8% 0 0.0% 4
Anti-tumor antibiotics 2 1.9% 1 1.1% 2
Cancers 2024,16, 176 6 of 16
Table 1. Cont.
Female Male Diff.
Frequency
(Total 105)
Percentage
(Total 100%)
Frequency
(Total 89)
Percentage
(Total 100%)
Tumor diagnosis
p< 0.0001 **
Alkylating agents 1 0.95% 2 2.2% 1
Multiple CT-based
combination 62 59.1% 70 78.7% 62
CT cycle NS
Equal or less than 5 84 80% 70 78.7% 84
More than 5 21 20% 19 21.3% 21
The 80% of enrolled patients were informed by the oncologist about possible oral
problems arising during CT. We considered the answer given at the first questionnaire
compilation, in case the patient filled in more than one questionnaire.
3.2. Oral Problems
Patients’ oral problems and their frequency over the last month are presented in
Tables 2and 3, respectively. Among the considered oral problems, none led to the necessity
of suspending, delaying, or modifying the oncological treatment schedules.
Table 2. Frequencies of answers to the questionnaire and distribution of answers according to gender
(Pearson chi-square test). * Significance 0.01 < p
≤
0.05. ** Significance p
≤
0.01. NS—not significative.
Overall Sample Female Male Diff.
Frequency
(Total 491)
Percentage
(Total 100%)
Frequency
(Total 273)
Percentage
(Total 100%)
Frequency
(Total 218)
Percentage
(Total 100%)
Oral pain No 385 78.4% 206 53.5% 179 46.5% NS
Yes 106 21.6% 67 63.2% 38 36.8%
Oral
mucositis No 415 84.5% 221 53.3% 194 46.7% p= 0.014 *
Yes 76 15.5% 52 68.4% 24 31.6%
Salivary
gland hy-
pofunction
No 274 55.8% 142 51.8% 132 48.2% NS
Yes 217 44.2% 131 60.4% 86 39.6%
Dysphagia No 397 80.9% 224 56.4% 173 43.6% NS
Yes 94 19.1% 49 52.1% 45 47.9%
For
solids 18 19.2% 8 44.4% 10 55.6%
For
liquids 19 20.2% 9 47.4% 10 52.6%
For both 57 60.6% 32 56.1% 25 43.9%
Cancers 2024,16, 176 7 of 16
Table 2. Cont.
Overall Sample Female Male Diff.
Frequency
(Total 491)
Percentage
(Total 100%)
Frequency
(Total 273)
Percentage
(Total 100%)
Frequency
(Total 218)
Percentage
(Total 100%)
Dysphonia No 332 67.6% 189 56.9% 143 43.1% NS
Yes 159 32.4% 84 52.8% 75 47.2%
Low
and/or
hoarse
voice
139 87.4% 68 48.9% 71 51.1%
Pain
during
phona-
tion
20 12.6% 16 80.0% 4 20.0%
Labial
pain No 306 62.3% 150 49.0% 156 51.0% p= 0.000 **
Yes 185 37.7% 123 66.5% 62 33.5%
Dryness 173 93.5% 113 65.3% 60 34.7%
Ulcers 12 6.5% 10 83.3% 2 16.7%
Paraesthesia
No 458 93.3% 255 55.7% 203 44.3% NS
Yes 33 6.7% 18 54.5% 15 45.5%
Unilateral
4 12.1% 1 25.0% 3 75.0%
Bilateral 29 87.9% 17 58.6% 12 41.4%
Anaesthesia
No 471 95.9% 261 55.4% 210 44.6% NS
Yes 20 4.1% 12 60.0% 8 40.0%
Unilateral
5 25.0% 1 20.0% 4 80.0%
Bilateral 15 75.0% 11 73.3% 4 26.7%
Table 3. Frequency of oral problems over the last month.
Oral
Pain
Oral
Mucositis
Salivary Gland
Hypofunction Dysphagia Dysphonia Labial
Pain
Paraesthesia
and/or
Anaesthesia
No. % No. % No. % No. % No. % No. % No. %
Always
present 24 22.6% 18 23.7% 116 53.5% 16 17.0% 46 28.9% 113 61.1% 10 24.4%
3 weeks 3 2.8% 0 0.0% 7 3.2% 0 0.0% 6 3.8% 3 1.6% 1 2.4%
2 weeks 1 0.9% 1 1.3% 26 12.0% 5 5.3% 25 15.7% 14 7.6% 3 7.3%
1 week 4 3.8% 3 3.9% 10 4.6% 7 7.45% 13 8.2% 10 5.4% 0 0.0%
Twice/month
22 20.8% 7 9.2% 25 11.5% 23 24.5% 35 22.0% 15 8.1% 5 12.2%
Once/month
40 37.7% 24 31.6% 30 13.8% 36 38.3% 28 17.6% 21 11.3% 18 43.9%
Rarely 12 11.4% 23 30.3% 3 1.4% 7 7.45% 6 3.8% 9 4.9% 4 9.8%
Total 106 100% 76 100% 217 100% 94 100% 159 100% 185 100% 41 100%
Where assessable, the intensities of the oral problems referred to by patients have been
assessed through the NRS. Results are summarized in Table 4. Any statistically significant
differences among intensity of referred the oral problems were found.
Cancers 2024,16, 176 8 of 16
Table 4. Intensity of oral problems (11 pt numerical rating scale from 0 to 10).
NRS Oral Pain NRS Oral Mucositis
NRS Salivary Gland
Hypofunction NRS Dysphagia
NRS Paraesthesia
and/or
Anaesthesia
Frequency Percentage Frequency Percentage Frequency Percentage Frequency Percentage Frequency
Percentage
00 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
11 0.9% 0 0.0% 13 6.0% 0 0.0% 1 24%
28 7.5% 3 3.9% 22 10.1% 6 6.4% 5 12.2%
39 8.5% 7 9.2% 27 12.4% 12 12.8% 8 19.5%
410 9.4% 7 9.2% 27 12.4% 16 17.0% 8 19.5%
524 22.6% 12 15.8% 53 24.4% 7 7.4% 4 9.8%
611 10.4% 5 6.6% 20 9.3% 9 9.6% 6 14.6%
713 12.4% 15 19.7% 20 9.3% 16 17.0% 5 12.2%
818 17.0% 13 17.2% 23 10.6% 15 16.0% 2 4.9%
95 4.7% 3 3.9% 2 0.9% 7 7.4% 2 4.9%
10 7 6.6% 11 14.5% 10 4.6% 0 0.0% 0 0.0%
Average
5.8 6.5 4.9 5.9 4.7
The presence of paraestheria and/or anesthesia in labial or chin regions was reported
in 17 questionnaires. Specifically, these patients were undergoing the following antiblastic
treatments: one patient, platinum agents; seven patients, antimetabolites; three patients,
mitotic inhibitors; and six patients, multiple CT-based combinations.
Anaesthesia was highlighted in 12 questionnaires in patients treated with platinum
agents, in 6 questionnaires in patients treated with antimetabolites, and in 2 questionnaires
in patients treated with mitotic inhibitors. Moreover, in 12 out 53 questionnaires (22.6%)
patients reported the presence of both paraesthesia and anaesthesia.
When oral problems were reported, patients were asked whether any medication has
been used and who recommended it for local recovery (Table 5).
Table 5. Medications to manage oral problems.
Frequency
(Total 491)
Percentage
(Total 100%)
Total n. medications 214 43.6%
Bicarbonate and/or antifungal rinses 96 19.5%
Others 181 36.9%
Mouth and/or labial hydration 59 32.6%
Mouthrinses (not specified) 57 31.5%
Mouthrinses with chlorhexidine 27 14.9%
Natural local products 17 9.4%
Specific products for oral mucositis 10 5.5%
Photobiomodulation 5 2.8%
Gel 2 1.1%
Topical antiviral 2 1.1%
Unknown 2 1.1%
Total 181 Total 100%
Cancers 2024,16, 176 9 of 16
With regard to the type of medication used as a symptomatic approach, 277 ques-
tionnaires were considered: in 98 questionnaires (35.4%), the treatment was suggested
by the oncologist and/or by the nurse staff; in 38 questionnaires (13.7%), by the general
practitioner and/or by the dentist; in 27 questionnaires (9.7%), by other health care figures;
and 114 questionnaires (41.2%) consisted of homemade treatments. In this latter category,
medications were self-prescribed (97/114 patients), prescribed by pharmacists or herbalists
(5/114 patients), or suggested by relatives, friends, or other patients (12/114 patients).
3.3. Multivariate Analysis
In the multivariate analysis, 481 questionnaires out 491 were included, since 10 patients
did not specify their tumor stage in the questionnaire; therefore, this missing data could
have generated bias in the data analysis. Multiple backward logistic regression models
were performed to correlate the independent variables (age, gender, tumor diagnosis,
metastasis, CT agent type, CT cycle, and use of medications to manage oral problems) and
oral problems considered in the study (Table 6).
Table 6. Multiple backward logistic regression model predicting oral problems in cancer patients.
OR—odds ratio; CI—confidence interval. * Significance 0.01 < p
≤
0.05. ** Significance p
≤
0.01.
NS—not significative.
Independent
Variables
Oral Pain Oral Mucositis Salivary Gland
Hypofunction Dysphagia
No.
OR (95% CI) Diff. OR (95% CI) Diff. OR (95% CI) Diff. OR (95% CI) Diff.
Age 0.98
(0.96–1.00) 0.014 ** 0.95
(0.93–0.97) 0.000 ** 0.98
(0.96–1.00) 0.013 * 0.96
(0.94–0.98) 0.000 **
Gender
NS NS NS NS NS NS
Female
263
1
Male
218
0.59
(0.34–1.03) NS
Tumor
diagnosis
NS NS NS NS
0.016 *
NS NS
Pancreas and
hepatobiliary 60 1
Miscellaneous
78 0.87
(0.42–1.79)
NS
Breast and
prostate 91 2.68
(1.22–5.90)
0.015 *
Lung and
pleura 83 0.82
(0.39–1.71)
NS
Gastrointestinal 169
0.96
(0.48–1.89)
NS
Metastases
NS NS NS NS
No
169
1 1
Yes
312
2.02
(1.09–3.74) 0.026 * 1.66
(1.02–2.70) 0.042 *
CT agent type
NS NS NS NS
0.017 * 0.008 **
Mitotic
inhibitors
116
1 1
Platinum
agents
198
2.16
(1.17–3.96)
0.013 * 3.26
(1.62–6.56)
0.001 **
Antimetabolites
97 0.98
(0.48–2.00)
NS 2.95
(1.36–6.44)
0.006 **
Multiple
CT-based
combination
70 2.14
(1.06–4.33)
0.035 * 1.97
(0.81–4.78)
NS
Cancers 2024,16, 176 10 of 16
Table 6. Cont.
Independent
Variables
Oral Pain Oral Mucositis Salivary Gland
Hypofunction Dysphagia
No.
OR (95% CI) Diff. OR (95% CI) Diff. OR (95% CI) Diff. OR (95% CI) Diff.
CT cycle NS NS NS NS 0.95
(0.89–1.00) NS NS NS
Medications
NS NS
NS 0.016 * NS
None 74 1 1 1
One class
104
3.27
(1.13–9.49)
0.030 * 0.60
(0.31–1.15)
NS 0.53
(0.26–1.10)
NS
Two or more
classes
303
3.42
(1.25–9.35)
0.017 * 1.25
(0.70–2.23)
NS 0.51
(0.28–0.95)
0.033 *
Independent
Variables
Dysphonia Labial Pain Paresthesia Anaesthesia
No.
OR (95% CI) Diff. OR (95% CI) Diff. OR (95% CI) Diff. OR (95% CI) Diff.
Age NS NS 0.98
(0.96–0.99) 0.009 ** 0.97
(0.94–1.00) NS 0.93 (0.90–0.97) 0.000 **
Gender
NS NS NS NS NS NS
Female
263
1
Male
218
0.50
(0.34–0.74) 0.001 **
Tumor
diagnosis
NS NS NS NS
0.021 *
NS NS
Pancreas and
hepatobiliary 60 1
Miscellaneous
78 0.11
(0.01–0.98) 0.048 *
Breast and
prostate 91 0.76
(0.18–3.18) NS
Lung and
pleura 83 0.30
(0.07–1.33) NS
Gastrointestinal 169
1.99
(0.63–6.32) NS
Metastases
NS NS NS NS NS NS
No
169
1
Yes
312
1.64
(1.08–2.49) 0.021 *
CT agent type
0.046 *
NS NS
0.027 * NS
Mitotic
inhibitors
116
1 1 1
Platinum
agents
198
1.06
(0.63–1.79) NS 3.50
(0.83–14.79) NS 5.16 (1.07–24.88) 0.041 *
Antimetabolites
97 1.12
(1.15–3.90) 0.016 * 1.38
(0.27–6.95) NS 2.70 (0.41–17.71) NS
Multiple
CT-based
combination
70 1.48
(0.76–2.89) NS 6.55
(1.48–29.07) 0.013 * NS NS
CT cycle 1.06
(1.00–1.11) 0.041 * NS NS NS NS 1.10 (1.00–1.22) 0.049 *
Medications 0.046 * 0.020 *
NS NS NS NS
None 74 1 1 1
One class
104
0.45
(0.23–0.89) 0.022 * 0.48
(0.25–0.92) 0.026 *
Two or more
classes
303
0.80 (0.46–1.4) NS 0.97
(0.56–1.68) NS
Specifically, OM onset was significantly related to the presence of metastasis
(OR = 2.02, p= 0.026) and led to the use of medications for his management (one class
OR = 3.27, p= 0.030; two or more classes OR = 3.42, p= 0.017). A salivary gland hypo-
function, referred by patients after CT, was more evident in those affected by breast and
prostate tumors (OR = 2.68, p= 0.015) undergoing platinum agents (OR = 2.16, p= 0.013) or
multiple CT-based combinations (OR = 2.14, p= 0.035). Similarly, most patients submitted
Cancers 2024,16, 176 11 of 16
to platinum agents or antimetabolites experienced dysphagia (OR = 3.26, p= 0.001 and
OR = 2.95, p= 0.006, respectively). Despite the presence of swallowing difficulties, pa-
tients were less prone to take two or more classes of medications (OR = 0.51, p= 0.033).
Antimetabolites lead to a slight increase in the presence of dysphonia (OR = 1.12, p= 0.016),
which increased with the number of CT cycles performed (OR = 1.06, p= 0.041). However,
patients with dysphonia and with labial pain were less prone to use one class of medication
to manage this oral problem (OR = 0.45, p= 0.022 and OR = 0.48, p= 0.026, respectively).
The presence of labial pain was less related to male gender (OR = 0.50, p= 0.001) and
mainly to the presence of metastasis (OR = 1.64, p= 0.021). Patients that most referred the
presence of paresthesia and anesthesia were treated with multiple CT-based combinations
(OR = 6.55, p= 0.013) and platinum agents (OR = 5.16, p= 0.041), respectively. As the num-
ber of CT cycles increased, a slight increase in the occurrence of anesthesia was reported by
patients (OR = 1.10, p= 0.049).
4. Discussion
In the present study, we investigated the presence of oral problems arising after CT
regimens in patients affected by solid tumors. Differently from the majority of clinical trials,
where oral problems have been recorded by healthcare professionals [
21
,
22
], we focused
on the impact of these complications from patients’ perspective through the administration
of a dedicated questionnaire.
Most of the oral problems complained by oncological patients undergoing CT are
related to drug stomatotoxicity [
3
–
5
,
34
], as oral pain, OM, salivary gland hypofunction,
dysphagia, dysphonia, labial pain, or, in less cases, to tumor metastatic dissemination
(NCS, 17).
Among the considered oral problems, OM and its oral manifestations can significantly
impact on anticancer therapies, as they can lead to the necessity of suspending, delaying,
or modifying the oncological treatment schedules. OM can be associated to oral pain, oral
ulcers, dysphagia, and dysphonia. The prevalence of OM and oral pain in our survey
was 15.5% (76 questionnaires) and 21.6% (106 questionnaires), respectively. Compared
to the literature data, our study seems slightly to underestimate the prevalence of OM.
This is likely related to an evaluation only reported by patients and not confirmed by any
clinical assessment, unlike of what has been recorded in studies considering the same oral
problem [35,36].
It is known that oral pain is not always proportionally related to the presence of OM,
but it can be also due to the presence of oral oedema [
7
]. OM can be very disabling for
patients (NRS
≥
7 in 55.3% of enrolled patients), but it is not necessarily present after
every CT cycle, in fact OM was described as sporadic (less than one episode a month) in
30.3% of the questionnaires. In 18–40% of the cases, OM manifests after the first infusional
therapy, but sometimes it appears later due to the cumulative effect of some CT regimens
and the concomitant CT-induced neutropenia [
1
]. However, in our analysis, the number
of CT cycles did not statistically influence the development of oral pain and OM, like in
the cross-sectional study by Wilberg et al. [
37
]. The presence of oral pain and OM was
mostly reported by female (63.2% female vs. 36.8% men for oral pain and 68.4% vs. 31.65%,
p= 0.014, for OM). However, according to the results of the multivariate analysis, the
female gender was not considered a risk factor for the development of oral pain and OM,
similarly to the study by Wilberg et al. [
37
]. On the contrary, the randomized multicentre
study by Vukurka et al. showed an increased risk of OM with more severe lesions in female,
despite they enrolled only oncohaematological patients undergoing CT before bone marrow
transplantation [
38
]. We also observed that age was a protective factor for the development
of both oral pain and OM (OR 0.98, p= 0.014 for oral pain; OR 0.95, p= 0.000 for OM). The
same results were found in relation to salivary gland hypofunction (0.98, p= 0.013) and
labial pain (OR 0.98, p= 0.009). These data are in disagreement with the literature where
OM is usually more frequent and more severe in people older than 50 years, probably
for the concomitant renal failure and the consequent CT dose accumulation [
7
]. We did
Cancers 2024,16, 176 12 of 16
not find a correlation between the development of oral pain and OM and CT agent type,
probably because in each category there were stomatotoxic drugs. Unfortunately, any other
observational study considered this risk factor [
39
,
40
] or, conversely, were considered only
specific schemes or restricted number of molecules [
41
–
43
]. On the contrary, in our study,
the presence of metastatic disease was a risk factor for the development of OM (OR 2.02,
p= 0.026) and salivary gland hypofunction (OR 1.66, p= 0.042), likely related to a worse
performance status and more aggressive CT regimens.
Alteration in salivary production was the most referred symptom in our study group
(44.2%). Similar results were obtained in the cross-sectional study from Frowen et al. [
44
],
where the prevalence of patient-reported xerostomia was 56%. Despite hyposalivation
being referred as always present in 53.5% of the questionnaires, it did not cause a great
discomfort (mean NRS = 4.9), similarly to the results obtained by Mercadante et al. [
39
]
and Chen et al. [
40
]. A correlation was found between these manifestations and the female
gender, to note 60.4% of questionnaires concerning salivary gland hypofunction were sub-
mitted by females, despite with no statistically significant differences. The administration of
platinum agents and multiple CT-based combination represented a risk factor for the devel-
opment of salivary gland hypofunction compared to mitotic inhibitors and antimetabolites
(OR = 2.16, p= 0.013 and OR = 2.14, p= 0.035, respectively).
Furthermore, we found a significative correlation between the presence of dyspha-
gia and the use of platinum agents and antimetabolites compared to mitotic inhibitors
(OR 3.26, p= 0.001 and OR 2.95, p= 0.006, respectively). It is interesting to observe that
47 questionnaires complaining about dysphagia were all related to therapy containing
platinum agents and that platinum agents were the most frequent category related to
dysphagia for solids (9 out 18), liquids (11 out 19), and both (27 out 57). This drug can cause
stomatotoxicity but also neurotoxicity, with dysphagia and pharyngolaryngeal dysaesthe-
sia, mostly related to low temperature exposition, as drinking cold water. In our study,
dysphagia for liquids was platinum-related in 11 questionnaires out of 19. However, we
did not investigate the cold correlation due to the small sample of questionnaires complain-
ing about this disorder, compared to the prospective, multicenter, international study of
Argyriou et al., in which the cold-related pharyngolaryngeal dysaesthesia reached 91.8% of
patients receiving oxaliplatinum [
45
]. Dysphagia was reported by patients as an intermit-
tent symptom, occurring once or twice a month. Dysphagia was referred as very intense
(46.8% questionnaires with NRS
≥
7) or as a slight disturbance (36.0% questionnaires with
NRS
≤
4), with an average of 5.9. Similar results were reported by Mercadante et al.,
where 15% of patients reported dysphagia, with an average intensity of 5.3 related to the
NRS [
39
]. Even Chen et al. found that the difficulty in swallowing in CT-treated patients
was a disorder mostly referred as mild or moderate [40].
The frequency of dysphonia in our study (32.4% of all questionnaires) was very similar
to the one found by Chen et al. (31.5%), even if their sample was smaller [
40
], and by
Frowen et al. [
44
]. Even in the study from Chen et al., the lowering of vocal tonality was
greater than pain in phonation (83.3% vs. 16.7%, 40). The use of antimetabolites increased
the risk of this disorder compared to mitotic inhibitors (OR 1.12, p= 0.016), probably for
the inflammation and oedema of both oral and upper airways mucosa.
Besides oral problems in cancer patients undergoing CT for solid tumors, a dedi-
cated attention has been posed to the NCS, a rare sensitivity neuropathy that usually
expresses itself with unilateral sensitivity alterations in lip and/or chin regions. It is mostly
caused by bone metastases in the mandibular body, which represents less than 1% of all
bone metastases [
46
] and its onset seems to be a negative prognostic factor for patient’s
survival [47].
The presence of paraesthesia and total anaesthesia in these regions were referred to,
respectively, in 33 and 20 questionnaires. Among these, 12 patients referred to a difference
between the left and right sides, where on the one side reported a reduced sensitivity
(paraesthesia) and on the other its complete absence (anaesthesia). Only five patients
referred this symptom as unilateral, so we investigated this symptom in relation to their
Cancers 2024,16, 176 13 of 16
medical history in order to consider the diagnosis of NCS. However, in none of them NCS
was confirmed by instrumental diagnostic examinations (computed tomography, nuclear
magnetic resonance, PET-CT, bone scintigraphy). The absence of diagnosis of NCS is
probably due to the small sample size of patients with bone metastases 26 (13.6%).
A great part of questionnaires (29 out 53), reporting paraesthesia and/or anaesthesia,
referred to the use of platinum agents, which are known for causing acute and chronic
neurotoxicity involving also the perioral area [48]. In addition, 15 out 24 of non-platinum-
related questionnaires came from patients with previous platinum CT scheme. The statis-
tical analysis showed a significative increased risk of anaesthesia in patients undergoing
platinum agents compared to mitotic inhibitors (OR 5.16, p= 0.041). We also observed
a little increased risk of anaesthesia related to the number of CT cycles, probably due to
its cumulative effect (OR 1.10, p= 0.049). Even the prospective study of Argyriou et al.
showed a correlation between the use of platinum agents and the development of perioral
paraesthesia: 95.2% of patients complained about this cold-related disorder [
45
]. How-
ever, their high incidence could be due to the exclusive enrollment of patients undergoing
oxaliplatinum therapy, particularly neurotoxic [
49
]. On the contrary, Rahnma et al., in a
case-control study, considered different CT regimens (oxaliplatinum, cisplatin, doxorubicin,
fluorouracil, docetaxel, and cyclophosphamide) and found the presence of tingling and
numbness in the inferior lip in 22.4% patients [
50
]. Our results highlighted that the multiple
CT-based combination group increased the risk of perioral paraesthesia compared to mitotic
inhibitors (OR 6.55, p= 0.013), probably for the large presence of vinca alkaloids in this
category, known for causing neurotoxicity [
37
]. Moreover, the perioral paraesthesia and/or
anaesthesia were referred as present once or twice a month in the 63% of the questionnaires,
probably related to the infusional CT scheme performed (every 14, 21, or 28 days).
To manage these oral problems, in several questionnaires, patients reported the em-
ployment of medications. This is reasonable if we consider that in 138 questionnaires, no
symptoms were referred to, while in many cases, symptoms were modest or resolved in a
short time. On the contrary, in 96 questionnaires, it was reported that the use of bicarbonate
rinses and/or an antimicotic was routinely recommended by the medical and nursing staff
in our university hospital.
Some interesting data concerns the number of patients (20%) who declared that did
they not receive information about the possibility of an onset of oral problems during
CT and their management. However, our results are much more encouraging than those
reported in the literature. Wilberg et al. showed that 73% of the patients enrolled were
unprepared about possible oral CT-related side effects [37].
Differently from other similar studies [
20
,
21
], where oral problems are typically as-
sessed by clinicians, often underestimating the number and severity of toxicities expe-
rienced by patients, the present study analyzed the patients’ perspective. The obtained
results highlighted the importance of collecting observational data from the patients’ per-
spective on oral problems arising during the routine oncology practice, across a range of
solid tumors and CT regimens. Our data provide guidance for planning an evidence-based
framework for the management of oral problems in oncological patients, although every
patient requires individualized management. This could include the planning of patient-
oriented training sessions (through brochures, videos, or apps). Indeed, the relevance of
our findings focused on the key role of the multidisciplinary team in advising the patients
on the possible occurrence of oral problems, also by recommending their management.
Alongside the clinical relevance of our study, some limitations need to be discussed.
A heterogeneous sample of patients was enrolled, with different ages, tumors diagnoses
(according to site and staging), and consequently different types of CT schemes. Similarly,
patient’s socio-demographic characteristics and local and general conditions could be
implemented (i.e., considering patients’ race, social education, body mass and Karnofsky
indexes, pre-existing co-morbidities, oral hygiene, periodontal disease, etc.).
While patients’ self-reported oral problems represent an unquestionably strong point
of the study, which distinguishes it from already published studies on the same topic, a
Cancers 2024,16, 176 14 of 16
clinical evaluation could be useful to compare subjective and objective differences in the
clinical manifestation of oral problems CT-related. Furthermore, an increase in patients’
sample is essential to identify the NCS, particularly including patients with bone metastases
over a longer follow up.
5. Conclusions
The results of the present study, reporting the patients’ perspective on oral problems
arising during anticancer therapies, underline the importance of monitoring subjective
symptoms during the clinical routine. The relevance of our findings focused on the key
role of the multidisciplinary team in advising patients on the possible occurrence of oral
problems, also by preventing their onset or recommending their management through
awareness campaigns. Future research should assess the effect of self-reporting oral prob-
lems on clinical outcomes and the efficiency for early detection of adverse events related to
anticancer therapies.
Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/cancers16010176/s1, Annex S1: Questionnaire on Oral Problems
in Oncology Patients Undergoing Chemotherapy for Solid Tumors.
Author Contributions: Conceptualization, G.O., G.T., A.G. and M.B.; methodology, G.O., G.T., K.R.
and M.G.; software, G.O. and G.T.; validation, D.G., A.G., R.D.L. and M.B.; formal analysis, D.A. and
F.C.; investigation, G.O., G.T., K.R., M.G. and A.D., and M.B.; resources, A.G., R.D.L. and M.B.; data
curation, G.O., G.T., D.A. and F.C.; writing—original draft preparation, G.O., G.T., K.R. and M.G.;
writing—review and editing, D.G., A.G. and A.D.; visualization, D.A. and F.C.; supervision, R.D.L.
and M.B.; project administration, R.D.L. and M.B.; funding acquisition, not applicable. All authors
have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki, and approved by the Ethic Committee of the Friuli Venezia Giulia Italian Region (protocol
code 20581/CEUR). According to the Ethical Standards, patients were guaranteed the possibility of
leaving the study at any time and for any reason.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Written informed consent has been obtained from the patients to publish this paper.
Data Availability Statement: Data available on request due to privacy restrictions. The data presented
in this study are available on request from the corresponding author.
Conflicts of Interest: The authors declare no conflict of interest.
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