Severe oral mucositis relating to pain and worse oral condition among patients with solid tumors undergoing treatment with FOLFIRI and 5-FU: a retrospective study

ABSTRACT BACKGROUND: There is a need for studies that correlate the severity of oral mucositis (OM) with chemotherapy protocols, transient myelosuppression and oral health. OBJECTIVE: To analyze the severity of OM among individuals with solid tumors during hospitalization and its correlation with the type of chemotherapy, myelosuppression and oral health condition. DESIGN AND SETTING: Retrospective study at a public hospital in Bauru, state of São Paulo, Brazil, that is a regional referral center. METHODS: Individuals diagnosed with solid malignant tumors who received chemotherapy during hospitalization for completion of the antineoplastic treatment cycle or who presented complications resulting from this were assessed. RESULTS: Twenty-eight individuals (24.3%) manifested some degree of OM. The most prevalent degrees of OM according to the World Health Organization (WHO) and modified WHO classification were grades 2 (11.3%) and 5 (4.3%), respectively. It was observed that the higher the OM-WHO (P < 0.001; r = 0.306) and modified OM-WHO (P < 0.001; r = 0.295) classifications were, the greater the oral pain reported by the individuals was. Presence of mucositis in the upper lip and buccal mucosa contributed to increased severity of OM and worsening of swallowing during hospitalization. Thus, severe OM was associated with use of the FOLFIRI protocol (folinic acid, fluorouracil and irinotecan). CONCLUSION: Individuals with tumors who presented severe OM had greater severity of oral pain and worse oral health. Use of the FOLFIRI protocol was associated with higher prevalence of severe OM, while use of 5-fluorouracil (5-FU) was correlated with worse oral condition.


INTRODUCTION
Oral mucositis (OM) is an inflammatory process caused by the cytotoxic effect of antineoplastic treatments (AnTs). This adverse effect has a large impact on individuals following certain chemotherapy protocols for treatment of solid tumors, such as cytarabine, 5-fluorouracil  and alkylating and platinum derivatives. 1,2 During these chemotherapy protocols, OM affects both the mouth and the entire gastrointestinal tract. 3 OM occurs mainly in the mucosa and is not keratinized in the form of erythematous lesions and/or ulcers. It may or may not be associated with edema, burning and intense pain. These signs and symptoms significantly impair the quality of life of individuals under hospitalization and affect speech, swallowing and chewing. Therefore, worse nutritional status often indicates enteral or parenteral nutrition, use of systemic analgesics, increased inpatient hospital time and interruption of AnT. 1,4,5 Certain forms of chemotherapy, besides causing OM, lead to transient myelosuppression and blood pancytopenia. Thus, aside from direct health-related problems, these cause decreased leukocyte counts and are associated with a high risk of opportunistic infections and exacerbation of infections. 6,7 In the literature, few studies have correlated the severity of OM with the chemotherapy protocols used, its relationship with transient myelosuppression or the oral health of individuals under hospitalization. 1,[7][8][9] In addition, there is a lack of studies comparing the severity of OM with the use of oral health indicators and pain assessment by means of an OM-related visual analogue scale (VAS).

Data collected and study group characteristics
The following data on demographic and treatment characteristics were collected from the hospital's electronic medical records: age, sex, diagnosis of cancer, evolution of cancer, comorbidities, Individuals with OM were evaluated with regard to the number of oral regions affected, presence of erythema and ulcers, duration of manifested OM and oral pain (assessed using a VAS). 10 OM was classified in accordance with the World Health Organization categories (OM-WHO) and the modified WHO scale (mOM-WHO). 11,12 To assess the oral health involvement of the individuals included in this study, we used the Bedside Oral Examination (BOE), which classifies the oral condition as normal oral condition (score of 8 to 10), moderately impaired oral condition (score of 11 to 14) or very impaired oral condition (score of 15 to 24). 13 All individuals seen by an oncologist were also evaluated with regard to their need for dental evaluation. Through this perception, consultations were requested by the dental team during these patients' hospitalization. All individuals examined by dentists were under dental care during hospitalization and received the same treatment for OM.  Table 1.

Statistical analysis
To analyze the data distribution, the Shapiro-Wilk test was applied.
Descriptive analysis was performed based on the prevalence and

Patients' demographic data and characteristics
A total of 115 medical records were evaluated. These individuals No therapeutic measures that could potentiate OM were used.
Out of the 115 patients, 24 underwent associated radiotherapy treatment. Of these, only one patient underwent radiotherapy in the head and neck region, while the others had indications for the lower respiratory tract, prostate, uterus, breast, pelvis and digestive tract regions.

Oral mucositis
Regarding OM, 28 individuals (24.3%) presented with some clinical manifestations of OM. The most prevalent degrees of OM were degree 2 (11.3%) according to the OM-WHO classification and grades 1 and 5 according to mOM-WHO (4.3%) ( Table 4).
It was observed that the regions most affected by OM ( Table 5) were the tongue, lower lip, upper lip and buccal mucosa in equal proportions (64.3%). Moreover, OM was manifested in these regions primarily when the chemotherapy protocols used were FOLFIRI, FOLFOX, MTX and gemcitabine hydrochloride. Higher degrees of OM-WHO (P = 0.009) and mOM-WHO (P = 0.004) were observed when the FOLFIRI protocol was used for AnT. Figure 1 shows the relationship between chemotherapy protocols and the prevalence of OM.
With regard to the ratio between OM and pain, the higher the degrees of OM-WHO (P < 0.001; r = 0.306) and mOM-WHO were (P < 0.001; r = 0.295), the higher the level of mouth pain reported by individuals was. In addition, manifestation of OM on the upper lip (P < 0.044) and jugal mucosa (P = 0.005) contributed to increased severity of OM-WHO.

Mouth condition
In the BOE assessment, 58 individuals (50.4%) had a normal oral condition, 53 (46.3%) had a moderately impaired oral condition and only 4 (3.5%) had a very impaired oral condition.
By analyzing the relationship between oral conditions and OM, it was observed that worse oral condition was significantly associated with greater degrees of OM-WHO (P = 0.025; r = 0.208) and mOM-WHO (P < 0.001; r = 0.228).
The oral condition of individuals who received certain types of chemotherapy was significantly correlated with more severe manifestations of OM-WHO (P = 0.025; r = 0.208) and mOM-WHO     Figure 2 shows the relationship between chemotherapy protocols and VAS and BOE.  (Table 6). However, there were no significant correlations between specific chemotherapy protocols and the severity of OM-WHO and mOM-WHO. Nor were there any statistically significant correlations between chemotherapy protocols and myelosuppression reference values (P > 0.05). Figure 3 shows four graphs correlating the chemotherapy protocols with anemia, thrombocytopenia, leukopenia and neutropenia.

Individuals under AnT for solid tumors have risk factors that
contribute to manifestation of severe OM. These factors may be related to systemic conditions, such as certain types of chemotherapy (CT); or to local conditions, such as damage to the oral cavity. In the present study, a relationship was observed between damage to the oral cavity and manifestation of severe OM. 14,15 Due to the intense discomfort, buccal pain and significant worsening of oral condition in relation to OM among individuals under hospitalization for AnT, it is important and necessary to trace individuals who are at higher risk of OM. 16 In this study, OM was observed in 24.3% of the individuals.
This proportion was similar to what was found in other studies that evaluated OM in individuals who underwent certain types of chemotherapy for solid tumors. In one such study, the prevalence of OM was 24% among individuals who underwent a second cycle of certain types of chemotherapy; and in another, it was 31% under the same treatment. 17,18 When 5-FU is used in protocols such as TPF, CAF or FOLFIRI, the incidence rate of OM can reach more than 15%, causing      The use of 5-FU worsens oral health, especially in the lips, tongue and gums, considering that these are the mouth regions most affected. When 5-FU was used, the risk of developing severe OM-WHO was found to be 15% higher, consequently worsening the patients' swallowing capacity. 20 The oral health of patients under 5-FU treatment can become worse because, aside from the oral pain caused by OM, these individuals also experience constant nausea and vomiting. 21 In addition, hyposalivation in individuals under 5-FU treatment increases the incidence of mucositis, which suggests that this is a risk factor for OM. [22][23][24][25] Another important symptom, which was also observed in this study, was oral pain. This is a fundamental issue that interferes with the quality of life of individuals with cancer, and it is directly related to severe OM. 16 It has been observed in other studies that patients on AnT for solid tumors who develop OM have worse quality of

Relationship between chemotherapy and thrombocytopenia
Relationship between chemotherapy and leukopenia life than those without OM, and that this manifestation predisposes them to other side effects such as pain and poor physical and emotional wellbeing, which negatively impacts their quality of life. 17 Understanding the risk factors relating to OM and the oral conditions that can compromise quality of life and interrupt AnT is necessary. Oral condition is directly related to the severity and repair of OM. 15,26 In previous studies, worse oral condition was related to greater severity of OM. However, those studies did not find any significant relationship between dental and prosthetic conditions and the severity of OM, as found in our study. One possible explanation for this is that although the visible plaque index and gingival plaque index are directly related to the incidence of OM, the ratio of lost, decayed or restored teeth was not determined by those authors. 26 There is evidence that neutropenic patients are between three and as much as 7.5 times more likely to develop OM than are patients without neutropenia. 27,28 In our study, we analyzed the correlation between the severity of OM and use of certain chemotherapy protocols and transient myelosuppression, but no significant result was found. In a study on oncopediatric patients under hospitalization, a significant relationship was observed, and this was explained by the degree of neutropenia, which was shown to influence the risk of developing OM, and by the difference in the QT protocols applied. 28 This study brought a lot of relevant information relating to the severity of oral mucositis, with regard to oral pain and chemotherapy protocols for oral health. However, it should be considered that this was a cross-sectional study, consisting of analysis on the medical records of individuals hospitalized under a single cycle, which limited assessment of the cumulative effect of chemotherapy cycles on the severity of oral mucositis. In addition, no data on tumor staging, drug doses used or other drugs used concomitantly that could directly interfere with oral toxicity were collected.
Lastly, other limitations of this study that may have confounded the analysis on the results comprised the small sample, wide age range and heterogeneity of the study group.

CONCLUSIONS
Individuals with solid tumors who presented with severe OM had greater severity of oral pain and worse oral health. Use of the FOLFIRI chemotherapy protocol was associated with higher prevalence of severe OM. Individuals who used 5-FU had worse oral condition, mainly with regard to changes to the lips, tongue and gums. Knowledge of chemotherapy protocols helps identify individuals with a greater chance of developing severe OM or with a worse oral condition through use of certain types of chemotherapy during hospitalization. Through screening, it is possible to reduce morbidity and mortality and provide better quality of life for patients with cancer.