Supragingival and subgingival microbiota from patients with poor oral hygiene submitted to radiotherapy for head and neck cancer treatment

ObjectiveThis case-control study aimed to evaluate the effects of conventional radiotherapy (RT) on the prevalence and populations of oral microorganisms in head and neck cancer patients who did not receive adequate preventive dental care. It was hypothesized that side effects of radiotherapy could be associated with radiation dose, microbiological aspects, and socioeconomic conditions of the patients.DesignTwenty-eight dentate patients with head and neck cancer submitted to RT were included in the study. Radiation dose received varied from 4320 to 7020 cGy. Patients with the same demographic and health conditions, but no history of cancer or antineoplastic treatment were used as controls. Clinical examinations were carried out before RT, 15–22 days after starting RT, immediately after and 6 months after RT. Supra and subgingival biofilms were collected and cultivated onto selective and non-selective media. Isolates were identified by biochemical and physiological characteristics. Stimulated and unstimulated salivary flow rate and saliva buffer capacity were also determined.ResultsMucositis, dermatitis, xerostomia, dysgeusia, dysphagia and candidiasis were common after starting RT and during the treatment period. Xerostomia was followed by a decrease in salivary pH and buffer capacity, which showed association with the increase of cariogenic cocci and yeast populations, which were also associated with deterioration of hygiene. Candida and family Enterobacteriaceae showed increased prevalence with RT, and were associated with the occurrence of mucositis and xerostomia.ConclusionsModifications in oral biofilms of irradiated patients showed association with xerostomia and hygiene conditions, which reinforces the necessity of improving patient compliance to oral health care programs.     

A review on the role of salivary MUC5B in oral health

BackgroundThe salivary glycoprotein MUC5B plays a versatile role in maintaining oral health. It contributes to lubrication, pellicle formation, antimicrobial defense, and water retention, and its glycans are an important nutrient for oral bacteria. This review aimed to describe the role of MUC5B in oral health and examine changes in its levels and composition in cases of hyposalivation and xerostomia.HighlightIn cases of hyposalivation, the reduction of total salivary MUC5B levels and MUC5B glycosylation patterns due to Sjögren's syndrome (SS) and medication intake appeared insignificantly limited. In patients with SS, xerostomia was related to reduced MUC5B levels at the anterior tongue. In cases of xerostomia, MUC5B glycosylation might be reduced, yet other factors such as total protein concentration, MUC7 levels and glycosylation, and salivary spinnbarkeit are involved. In contrast to SS- and medication-induced hyposalivation, radiotherapy in the head and neck region leads to a bona fide reduction in salivary MUC5B levels.ConclusionOur findings suggest that MUC5B levels are clearly impaired in hyposalivation and xerostomia related to radiotherapy in the head and neck region versus those related to SS and medication intake. A reduction in glycosylation in the case of dry mouth appears associated with MUC5B and MUC7 as well as other factors.     

Involvement of E2f1 deficiency in salivary gland hypofunction: A review of studies of E2f1-deficient NOD/SCID mice

BackgroundSaliva is essential for the preservation of oral health, and disorders of salivary physiology are associated with numerous oral problems. Hyposecretion of saliva, and consequent xerostomia, leads to severe dental caries, periodontal disease, and mucosal infections, which reduce a patient׳s quality of life. Sjögren׳s syndrome, the use of drugs with anticholinergic effects, and radiotherapy for the treatment of head and neck cancers are the most common causes of xerostomia. However, the pathophysiological features of xerostomia are not yet clear.HighlightRecently, we established E2f1-deficient non-obese diabetic/severe combined immunodeficiency disease (NOD/SCID) mice. The mutant mice demonstrated a reduction of salivary fluid secretion following stimulation with a cholinergic agonist, and xerostomia behavior under physiological conditions. In this article, we review the pathophysiology of xerostomia in E2f1-deficient NOD/SCID mice and discuss the involvement of the E2f1 deficiency in salivary gland hypofunction.ConclusionIn E2f1-deficient NOD/SCID mice, the number of duct cells increased while the number of acinar cells decreased. The water channel aquaporin 5, a marker of acinar cells, demonstrated diffuse localization, ubiquitination, and decreased expression in E2f1-deficient NOD/SCID mice. These events seem to trigger salivary gland hypofunction in E2f1-deficient NOD/SCID mice, which suggest that E2f1 is a key factor in the development of xerostomia.     

Managing xerostomia and salivary gland hypofunction: Executive summary of a report from the American Dental Association Council on Scientific Affairs

Background and OverviewXerostomia, also known as “dry mouth,” is a common but frequently overlooked condition that is typically associated with salivary gland hypofunction, which is the objective measurement of reduced salivary flow. Patients with dry mouth exhibit symptoms of variable severity that are commonly attributed to medication use, chronic disease and medical treatment, such as radiotherapy to the head and neck region. Chronic xerostomia significantly increases the risk of experiencing dental caries, demineralization, tooth sensitivity, candidiasis and other oral diseases that may affect quality of life negatively. This article presents a multidisciplinary approach to the clinical management of xerostomia, consistent with the findings of published systematic reviews on this key clinical issue.Conclusions and Practice ImplicationsInitial evaluation of patients with dry mouth should include a detailed health history to facilitate early detection and identify underlying causes. Comprehensive evaluation, diagnostic testing and periodic assessment of salivary flow, followed by corrective actions, may help prevent significant oral disease. A systematic approach to xerostomia management can facilitate interdisciplinary patient care, including collaboration with physicians regarding systemic conditions and medication use. Comprehensive management of xerostomia and hyposalivation should emphasize patient education and lifestyle modifications. It also should focus on various palliative and preventive measures, including pharmacological treatment with salivary stimulants, topical fluoride interventions and the use of sugar-free chewing gum to relieve dry-mouth symptoms and improve the patient's quality of life.     

Validation of a Portuguese version of the Groningen radiotherapy-induced xerostomia questionnaire

Background The aim of this study was to validate and determine at pretest level the reliability of the Portuguese version of the Groningen radiotherapy-induced xerostomia questionnaire.Material and Methods This study employed 37 head and neck cancer patients. Each patient signed an informed consent and responded to the Portuguese version of the questionnaire in the form of an interview. This was repeated again after 2 weeks. A standard single question provided a validity check. Data were analyzed using Cronbach’s α to test its reliability and total and interitem correlation, and intraclass correlation to determine its internal consistency and test-retest reliability. Construct validity supported by objective measurements as salivary secretion was also investigated. Significance was set at .05.Results Cronbach’s α was 0.91 and 0.89 for the first and second test administrations, respectively, which indicates that the internal consistency was excellent. The intraclass correlation coefficient value for the test-retest reliability was 0.70. The correlation between the total score of the questionnaire and standard single dry mouth question was 0.72 for the first round, indicating a good correlation.Conclusions Demonstrating very good psychometric properties, the Portuguese version of the Groningen radiotherapy-induced xerostomia questionnaire is a valid tool and can be considered a reliable instrument to measure xerostomia in head and neck cancer patients. Key words:Xerostomia, quality of life, xerostomia questionnaire, transcultural validation, head and neck cancer, radiotherapy, saliva.     

Laser phototherapy as a treatment for radiotherapy-induced oral mucositis

Oral mucositis is a harmful side effect of radiotherapy (RT) on the head and neck region. There are encouraging reports on the beneficial aspects of the use of laser light on the treatment of oral mucositis. This paper reports the efficacy of laser phototherapy (LPT) on the treatment of oral mucositis in a patient undergoing RT after surgical removal of a squamous cell carcinoma with osseous invasion of the maxilla. Palatal and commissural lesions were treated with λ660 nm, 40 mW, ?=4 mm(2), in contact mode, 5 x 2.4 J/cm(2) per point, 14.4 J/cm(2) per session. For treating the lesion on the patient's nasal mucosa, LPT (?=4 mm(2), λ780 nm, 70 mW, 3 x 2.1 J/cm(2) per point, 6.3 J/cm(2) per session, contact mode) was used on the external area of the nose. A single dose (2.4 J/cm(2)) with the λ660 nm laser, as described before, was applied on the entrance of each nostril. LPT was used 3 times/week during 4 weeks. Treatment results indicate that the use of LPT on oral mucositis was effective and allowed the patient to carry on the RT without interruption. However, long-term and controlled clinical trials are necessary to establish both preventive and curative protocols using LPT.     

Effect of low level laser therapy in the reduction of oral complications in patients with cancer of the head and neck submitted to radiotherapy

The aim of this study was to assess the effect of low level laser therapy on reducing the occurrence and severity of oral complications in patients with head and neck cancer undergoing radiotherapy. Sixty head and neck cancer outpatients from a cancer hospital receiving radiotherapy were selected and randomly assigned into two groups. The laser group was irradiated with an InGaAlP laser and the control received sham laser. The assessment of complications (oral mucositis, pain) was carried out one week after starting radiotherapy, and at the fifteenth and thirtieth sessions of radiotherapy. All patients from both groups showed some degree of oral mucositis. Better outcomes were observed in the laser group when compared with the control in the follow‐up sessions, indicating lower degrees of oral mucositis, pain and higher salivary flow (p < .05). These findings support the use of laser therapy as an adjuvant treatment for the control of oral complications.     

Oral complications of multimodality therapy for advanced squamous cell carcinoma of head and neck

Investigational treatment of advanced localized stage III or stage IV squamous cell carcinoma of the head and neck may include chemotherapy in addition to radiotherapy and surgery. Such therapy, while effective in eradicating local tumors, often produces considerable oral toxicity. In this study we reviewed the oral complications of 22 patients receiving multimodality cancer treatment. The addition of chemotherapy to the treatment regimen did not increase the incidence of complications (osteoradionecrosis, mucositis, xerostomia, radiation caries, or infection) when compared with historical controls receiving radiotherapy alone. Pretreatment dental evaluation and close follow-up of these patients are encouraged.     

Acupuncture for the prevention of radiation-induced xerostomia in patients with head and neck cancer

The aim of this study was to evaluate the effectiveness of acupuncture in minimizing the severity of radiation-induced xerostomia in patients with head and neck cancer. A total of 24 consecutive patients receiving > 5000 cGy radiotherapy (RT) involving the major salivary glands bilaterally were assigned to either the preventive acupuncture group (PA, n = 12), treated with acupuncture before and during RT, or the control group (CT, n = 12), treated with RT and not receiving acupuncture. After RT completion, clinical response was assessed in all patients by syalometry, measuring the resting (RSFR) and stimulated (SSFR) salivary flow rates, and by the visual analogue scale (VAS) regarding dry mouth-related symptoms. Statistical analyses were performed with repeated-measures using a mixed-effect modeling procedure and analysis of variance. An alpha level of 0.05 was accepted for statistical significance. Although all patients exhibited some degree of impairment in salivary gland functioning after RT, significant differences were found between the groups. Patients in the PA group showed improved salivary flow rates (RSFR, SSFR; p < 0.001) and decreased xerostomia-related symptoms (VAS, p < 0.05) compared with patients in the CT group. Although PA treatment did not prevent the oral sequelae of RT completely, it significantly minimized the severity of radiation-induced xerostomia. The results suggest that acupuncture focused in a preventive approach can be a useful therapy in the management of patients with head and neck cancer undergoing RT.     

The role of dentistry in head and neck radiation therapy

In the adult patient, oral complications of cancer radiotherapy stem from the deleterious effects of radiation on salivary glands, oral mucosa, mandibular musculature and alveolar bone. Clinical consequences of such treatment include xerostomia, rampant dental decay, mucositis, taste loss, osteoradionecrosis, infection, trismus, and nutritional stomatitis. These alterations to the normal state occur both during and after completion of head and neck radiation. Fig. 1 outlines the time frame involved in the development of each particular problem. In the past 20 years, many changes have occurred in the management of patients receiving radiation therapy. The traditional regimen of dental care in these patients was one of extracting all teeth encompassed by the radiation field. However, 15 years ago, this concept was questioned due to the incidence of post radiation caries (PRC) outside the zone of irradiation. The purpose of this paper is to review the major consequences of radiation treatment to the head and neck as well as outline the role of the dentist in the management of these patients.     

Oral pseudomembranous candidiasis, herpes simplex virus-1 infection, and oral mucositis in head and neck cancer patients receiving radiotherapy and granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwash

Oral pseudomembranous candidiasis (OPC) was evaluated in 61 patients receiving head and neck radiotherapy (RT). Herpes simplex virus-1 (HSV-1) reactivation was also investigated in 14 patients. According to the agreed protocol, granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwash was administered in 46 patients with radiation-induced ulcers. Candidiasis was diagnosed in 31 patients. Candida albicans was the most frequent isolate. Multiple Candida species were isolated from the lesions of four patients. Concurrent candidiasis and radiation-induced ulcers were observed in 17 patients. Viral culture and the polymerase chain reaction disclosed the presence of HSV-1 in five patients. Twenty of the 46 patients, with initial mucositis grade II and grade III, completed RT with mucositis grade I, indicating a beneficial effect of GMCSF mouthwash, although further controlled studies are necessary to verify that. In conclusion, OPC was an important infection in patients undergoing radiotherapy. The role of HSV-1 in oral mucositis during head and neck radiotherapy needs additional study.     

Evaluation of some oral postradiotherapy sequelae in patients treated for head and neck tumors

The aim of this study was to evaluate the oral sequelae of radiotherapy in patients treated between 1999 and 2003 for head and neck tumors. One-hundred patients (24 women, 76 men) ranging in age from 30 to 83 years (mean 59.2 years) were examined. Time since radiotherapy ranged from 1 to 72 months (mean 28 months). The total mean radiation dose received by the patients was 5,955 cGy. The evaluation protocol included anamnesis, intraoral and extraoral examination, measurement of stimulated salivary flow and salivary pH. Symptoms reported by the patients included dry mouth (68%), dysphagia (38%), and dysgeusia (30%). In 64% of the patients, the mean stimulated salivary flow rate was less than 0.7 ml/min. The mean salivary pH was 6.97 (+/- 0.714). Stimulated salivary flow increased with increasing postradiotherapy time (p < 0.05). The prevalence of mucositis was associated with higher radiation doses (p < 0.05), and the prevalence of atrophic candidiasis was related to a longer post-treatment period (p < 0.05). Two cases of recurrence of the primary tumor were detected during the study. The main effect of radiotheraphy in the head and neck region was a reduction of the salivary flow rate, even though our study demonstrated that there was a modest late improvement of the salivary flow.     

头颈部恶性肿瘤患者放疗前外周血淋巴细胞核内γ-H2AX焦点数与放疗后急性放射性损伤程度相关性研究

目的 探讨头颈部恶性肿瘤患者放疗前外周血淋巴细胞核内γ-H2AX焦点数与放疗后急性放射性黏膜和皮肤反应程度的相关性。方法 选择2010年12月至2012年3月湖北三峡职业技术学院附属医院收治的34例头颈部恶性肿瘤初诊患者,采集其外周血进行1Gy的6MV-X线照射,通过细胞免疫荧光技术检测淋巴细胞核内γ-H2AX焦点数;同时追踪观察所有患者放疗后出现急性放射性黏膜和皮肤反应的情况,探寻其与外周血淋巴细胞核内γ-H2AX焦点数之间的相关性。结果 34例患者中,出现急性放射性黏膜反应Ⅰ级6例（占17.65%）,Ⅱ级19例（占55.88%）,Ⅲ级8例（占23.53%）,Ⅳ级1例（占2.94%）;出现急性放射性皮肤损伤Ⅰ级9例（占26.47%）,Ⅱ级12例（占35.29%）,Ⅲ级13例（占38.24%）。急性放射性黏膜和皮肤反应程度与患者外周血淋巴细胞核内γ-H2AX焦点数的水平均呈正相关（r = 0.815,P < 0.05;r = 0.888,P < 0.05）。结论 头颈部恶性肿瘤患者放疗前检测外周血淋巴细胞核内γ-H2AX焦点数的水平可作为预测放疗后急性放射性黏膜和皮肤反应发生风险大小及严重程度的客观生物学指标。     

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??Abstract??Objective To study the relativity of nuclear γ-H2AX foci number of peripheral blood lymphocytes with acute radiation injury after chemotherapy in patients with head and neck malignancies. Methods Totally 34 patients with head and neck malignancies were selected in this study. The blood samples were collected and given 1Gy dose of radiation immediately?? γ-H2AX foci number of peripheral blood lymphocytes was detected after 3 hours by immunofluorescence. Acute mucositis and dermatitis of patients were observed after receiving radiotherapy. Results In 34 patients??6 cases??17.65%?? acute radiation mucositis grade I??19 cases??55.85%??grade ?? 8 cases??23.53%??grade ?? ??and 1 case ??2.92%??grade ????9 cases??26.47%?? acute radiation dermatitis grade ?? ??12 cases??35.29%??grade ?? ??13 cases??38.24%??grade III.The presence of acute mucositis and dermatitis correlated significantly with γ-H2AX foci detection in peripheral blood lymphocytes??r = 0.815?? P < 0.05?? r = 0.888?? P < 0.05??. Conclusion γ-H2AX foci number of peripheral blood lymphocytes is expected to become a powerful tool to predict radiation-induced mucositis and dermatitis.     

头颈癌术后调强放疗后口干症的综合评价

目的:对头颈癌术后调强和常规放疗后的口干症行前瞻性评估,以确定调强放疗预防口干症的效果.方法:82例头颈癌患者(口腔癌71例、口咽癌11例)分别行调强放疗(40例)和常规放疗(42例).在放疗前、后5个时间点,对口干进行综合评估.应用SPSS13.0软件包对数据进行统计学处理.结果:调强组腮腺平均放射剂量(22.21±5.02)Gy显著低于常规放疗组的(50.22±5.86)Gy(P<0.01);调强和常规组在放疗后6个月的中重度田干发生率,分别为RTOG评分法30%和92.9%,上海九院评分法25%和90.5%;口干问卷法15%和83.3%;调强组放疗后6个月时的静态和刺激唾液流为放疗前的51.0%和72.5%,常规组仅为放疗前的3.6%和8.2%(P<0.01);九院口干评分法结果与2种唾液流率均显著相关(r=0.79和0.78,19<0.01).结论:调强放疗后口干症明显减少,推荐上海九院评分法用于口干症评估.     

口腔定位支架预防头颈部放疗患者口腔并发症作用的Meta分析

目的    评价口腔定位支架对头颈部放疗患者口腔并发症的预防作用。方法    计算机检索PubMed、Embase、Cochrane library、中国知网、万方、VIP维普等数据库,查找口腔定位支架在头颈部肿瘤放疗中运用的相关研究,检索时间截至2021年1月。对方法学相似的研究合并使用RevMan5.3软件进行Meta分析,其余研究结果进行描述性分析。结果    最终纳入5项随机对照研究、2项回顾性队列研究、1项前瞻性观察研究。Meta分析结果显示,使用口腔定位支架进行头颈部放疗患者的中重度黏膜炎及严重味觉障碍的发生率显著小于不使用口腔定位支架的患者（均P < 0.001）;使用口腔定位支架有减轻口干症的趋势。结论    口腔定位支架在头颈部放疗中对口腔正常组织有一定的保护作用。     

Efficacy of pilocarpine lozenge for post-radiation xerostomia in patients with head and neck cancer

BACKGROUND: Patients with radiation-induced xerostomia produce little or no saliva. Several studies have demonstrated the efficacy of systemic administration of pilocarpine hydrochloride in individuals with post-radiation xerostomia. However, analysis of pilocarpine lozenges for treatment of post-radiation xerostomia in patients with head and neck cancer has not been reported. METHODS: The aim of this study was to quantify improvement in clinical symptoms and salivary function after treatment of post-radiation xerostomia with pilocarpine lozenges. In a double-blinded, placebo-controlled trial, 33 head and neck cancer patients were assigned randomly to receive Salagen tablet, pilocarpine hydrochloride lozenge (3 or 5 mg) or placebo lozenge every 10 days. At each visit, a subjective evaluation was undertaken through the use of visual analog scales before and at 180 minutes after treatment. Whole resting saliva was collected before and at 0, 30, 60, 90, 120, 150 and 180 minutes after treatment. RESULTS: The percentage of patients with decreased feeling of oral dryness, sore mouth or speaking difficulties after taking 5-mg pilocarpine lozenge was greater than Salagen or placebo. There were statistically significant increases in salivary production in pilocarpine treatment groups vs. placebo (P < 0.05). CONCLUSION: The 5-mg pilocarpine lozenge produced the best clinical results, but further investigation with a larger group of patients is required.     

Non-neoplastic salivary gland diseases

A wide range of non neoplastic disorders can affect the salivary glands, although the more common are: mumps, acute suppurative sialadenitis, Sj?gren's syndrome and drug-induced xerostomia. Salivary dysfunction is not a normal consequence of old age, and can be due to systemic diseases, medications or head and neck radiotherapy. Diagnosis of salivary disorders begins with a careful medical history, followed by a cautious examination. While complaints of xerostomia may be indicative of a salivary gland disorder, salivary diseases can present without symptoms. Therefore, routine examination of salivary function must be part of any head, neck, and oral examination. Health-care professionals can play a vital role in identifying patients at risk for developing salivary dysfunction, and should provide appropriate preventive and interventive techniques that will help to preserving a person's health, function, and quality of life. The present work provides an overview of most of the non neoplastic disorders of the salivary glands, in which the general presentation, pathology, and treatments are discussed.     

Oral health status of 207 head and neck cancer patients before, during and after radiotherapy

The aim of this retrospective study was to describe the oral health status of patients before, during, and after radiotherapy (RT) for the treatment of head and neck cancer (HNC). Before RT, the following data was collected: presence of unrecoverable teeth, residual roots, unerupted teeth, use of dentures, periodontal alterations, caries, candidiasis, and xerostomia. Mucositis, candidiasis, and xerostomia were evaluated during RT. Patients continued to be followed after RT for evaluation of mucositis, candidiasis, xerostomia, radiation caries, and osteoradionecrosis. For statistical analysis, 95% confidence intervals (CI) were determined using sample size, population, and percentages. Before RT, 120 (57.9%) patients presented with alterations in the oral cavity namely, 85 (41.0%) with periodontal disease, 44 (21.2%) with residual roots, 25 (12.0%) with caries, 15 (7.2%) with candidiasis, and 12 (5.8%) had an unerupted tooth present. Xerostomia was a complaint of 19 patients (9.1%). Restorations were indicated for 33 patients (15.9%), whereas extraction was indicated for 104 (50.2%) patients. During RT, mucositis was found in 80 (61.7%) patients, candidiasis in 60 (45.8%), and xerostomia was a complaint of 82 patients (62.6%). After RT, mucositis persisted in 21 patients (19.2%), candidiasis was identified in 23 patients (21.1%), and xerostomia was reported by 58 patients (53.2%). Radiation caries developed in 12 patients (11.0%), whereas six patients (5.5%) developed osteoradionecrosis. The demographic profile herein presented will be useful as baseline data to provide additional epidemiological information and to determine future measures for prevention and treatment of RT-induced complications and sequelae.     

Risk factors for oral mucositis during chemotherapy treatment for solid tumors: a retrospective STROBE-guided study

Background This study retrospectively analyzed the risk factors for transchemotherapy oral mucositis (OM).Material and Methods Before each chemotherapy cycle, patients were routinely evaluated for the presence/severity of OM based on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale for adverse effects and graded as follows: However, specific conditions such as mucositis are graded on a five-point scale: 0, absence of mucositis, grade 1 (Asymptomatic or mild), 2 (Presence of pain and moderate ulceration, without interference with food intake), 3 (severe pain with interference with food intake) or 4 (Life-threatening with the need for urgent intervention). Information from 2 years of evaluations was collected and patient medical records were reviewed to obtain data on chemotherapy cycle, sex, age, body mass index, body surface area, primary tumor, chemotherapy protocol, and history of head and neck radiotherapy. The X² test and multinomial logistic regression were used for statistical analysis (SPSS 20.0, p<0.05).Results Among 19,000 total evaluations of 3,529 patients during 5.32±4.7 chemotherapy cycles (CT) the prevalence of OM was 6.3% (n=1,195). Chemotherapy duration (p<0.001), female sex (p=0.001), adjuvant intention (p=0.008) and the use of carboplatin (p=0.001), cisplatin (p=0.029), docetaxel (p<0.001) and bevacizumab (p=0.026) independently increased the risk of mucositis. In head and neck tumors, 2018 year (p=0.017), chemotherapy duration (p=0.018), BMI>30 (p=0.008), radiotherapy (p=0.037) and use of carboplatin (p=0.046) and cyclophosphamide (p=0.010) increased this prevalence.Conclusions Cycles of chemotherapy, sex, cytotoxicity drugs, bevacizumab and head and neck radiotherapy increase the risk of OM in solid tumors. Key words:Mucositis, stomatitis, antineoplastic agentes, neoplasms, antineoplastic combined chemotherapy protocols.