RESUMEN
PURPOSE: To provide evidence-based recommendations for prevention and management of salivary gland hypofunction and xerostomia induced by nonsurgical cancer therapies. METHODS: Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials published between January 2009 and June 2020. The guideline also incorporated two previous systematic reviews conducted by MASCC/ISOO, which included studies published from 1990 through 2008. RESULTS: A total of 58 publications were identified: 46 addressed preventive interventions and 12 addressed therapeutic interventions. A majority of the evidence focused on the setting of radiation therapy for head and neck cancer. For the prevention of salivary gland hypofunction and/or xerostomia in patients with head and neck cancer, there is high-quality evidence for tissue-sparing radiation modalities. Evidence is weaker or insufficient for other interventions. For the management of salivary gland hypofunction and/or xerostomia, intermediate-quality evidence supports the use of topical mucosal lubricants, saliva substitutes, and agents that stimulate the salivary reflex. RECOMMENDATIONS: For patients who receive radiation therapy for head and neck cancer, tissue-sparing radiation modalities should be used when possible to reduce the risk of salivary gland hypofunction and xerostomia. Other risk-reducing interventions that may be offered during radiation therapy for head and neck cancer include bethanechol and acupuncture. For patients who develop salivary gland hypofunction and/or xerostomia, interventions include topical mucosal lubricants, saliva substitutes, and sugar-free lozenges or chewing gum. For patients with head and neck cancer, oral pilocarpine and oral cevimeline, acupuncture, or transcutaneous electrostimulation may be offered after radiation therapy.Additional information can be found at www.asco.org/supportive-care-guidelines.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioradioterapia/efectos adversos , Neoplasias/terapia , Guías de Práctica Clínica como Asunto/normas , Enfermedades de las Glándulas Salivales/patología , Trasplante de Células Madre/efectos adversos , Xerostomía/patología , Humanos , Neoplasias/patología , Pronóstico , Enfermedades de las Glándulas Salivales/etiología , Enfermedades de las Glándulas Salivales/terapia , Sociedades Médicas , Xerostomía/etiología , Xerostomía/terapiaRESUMEN
BACKGROUND: Gastrointestinal mucosal injury (mucositis), commonly affecting the oral cavity, is a clinically significant yet incompletely understood complication of cancer chemotherapy. Although antineoplastic cytotoxicity constitutes the primary injury trigger, the interaction of oral microbial commensals with mucosal tissues could modify the response. It is not clear, however, whether chemotherapy and its associated treatments affect oral microbial communities disrupting the homeostatic balance between resident microorganisms and the adjacent mucosa and if such alterations are associated with mucositis. To gain knowledge on the pathophysiology of oral mucositis, 49 subjects receiving 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy were evaluated longitudinally during one cycle, assessing clinical outcomes, bacterial and fungal oral microbiome changes, and epithelial transcriptome responses. As a control for microbiome stability, 30 non-cancer subjects were longitudinally assessed. Through complementary in vitro assays, we also evaluated the antibacterial potential of 5-FU on oral microorganisms and the interaction of commensals with oral epithelial tissues. RESULTS: Oral mucositis severity was associated with 5-FU, increased salivary flow, and higher oral granulocyte counts. The oral bacteriome was disrupted during chemotherapy and while antibiotic and acid inhibitor intake contributed to these changes, bacteriome disruptions were also correlated with antineoplastics and independently and strongly associated with oral mucositis severity. Mucositis-associated bacteriome shifts included depletion of common health-associated commensals from the genera Streptococcus, Actinomyces, Gemella, Granulicatella, and Veillonella and enrichment of Gram-negative bacteria such as Fusobacterium nucleatum and Prevotella oris. Shifts could not be explained by a direct antibacterial effect of 5-FU, but rather resembled the inflammation-associated dysbiotic shifts seen in other oral conditions. Epithelial transcriptional responses during chemotherapy included upregulation of genes involved in innate immunity and apoptosis. Using a multilayer epithelial construct, we show mucositis-associated dysbiotic shifts may contribute to aggravate mucosal damage since the mucositis-depleted Streptococcus salivarius was tolerated as a commensal, while the mucositis-enriched F. nucleatum displayed pro-inflammatory and pro-apoptotic capacity. CONCLUSIONS: Altogether, our work reveals that chemotherapy-induced oral mucositis is associated with bacterial dysbiosis and demonstrates the potential for dysbiotic shifts to aggravate antineoplastic-induced epithelial injury. These findings suggest that control of oral bacterial dysbiosis could represent a novel preventive approach to ameliorate oral mucositis.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/microbiología , Disbiosis/etiología , Microbiota/efectos de los fármacos , Mucosa Bucal/microbiología , Mucosa Bucal/patología , Estomatitis/etiología , Antineoplásicos/efectos adversos , Bacterias/efectos de los fármacos , Quimioterapia , Disbiosis/microbiología , Fluorouracilo/efectos adversos , Hongos/efectos de los fármacos , Humanos , Inflamación , Estudios Longitudinales , Boca/microbiología , Mucosa Bucal/efectos de los fármacos , Estudios Prospectivos , Estomatitis/microbiologíaRESUMEN
BACKGROUND: Mucositis is a highly significant, and sometimes dose-limiting, toxicity of cancer therapy. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for mucositis. METHODS: A literature search was conducted to identify eligible published articles, based on predefined inclusion/exclusion criteria. Each article was independently reviewed by 2 reviewers. Studies were rated according to the presence of major and minor flaws as per previously published criteria. The body of evidence for each intervention, in each treatment setting, was assigned a level of evidence, based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible. RESULTS: The literature search identified 8279 papers, 1032 of which were retrieved for detailed evaluation based on titles and abstracts. Of these, 570 qualified for final inclusion in the systematic reviews. Sixteen new guidelines were developed for or against the use of various interventions in specific treatment settings. In total, the MASCC/ISOO Mucositis Guidelines now include 32 guidelines: 22 for oral mucositis and 10 for gastrointestinal mucositis. This article describes these updated guidelines. CONCLUSIONS: The updated MASCC/ISOO Clinical Practice Guidelines for mucositis will help clinicians provide evidence-based management of mucositis secondary to cancer therapy.
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Antineoplásicos/efectos adversos , Esofagitis/terapia , Mucositis/etiología , Mucositis/terapia , Higiene Bucal , Proctitis/terapia , Sustancias Protectoras/uso terapéutico , Radioterapia/efectos adversos , Estomatitis/etiología , Estomatitis/terapia , Amifostina/uso terapéutico , Analgésicos/uso terapéutico , Antiinfecciosos/uso terapéutico , Antiinflamatorios/uso terapéutico , Antiulcerosos/administración & dosificación , Antineoplásicos/administración & dosificación , Crioterapia , Citocinas/administración & dosificación , Esofagitis/etiología , Esofagitis/prevención & control , Medicina Basada en la Evidencia , Humanos , Oxigenoterapia Hiperbárica , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Terapia por Luz de Baja Intensidad , Mucositis/inducido químicamente , Mucositis/prevención & control , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Fototerapia , Proctitis/etiología , Proctitis/prevención & control , Protectores contra Radiación/uso terapéutico , Estomatitis/inducido químicamente , Estomatitis/prevención & control , Sucralfato/administración & dosificaciónRESUMEN
GOALS: Oral mucositis can be a significant and dose-limiting complication of high-dose cancer therapy. Mucositis is a particularly severe problem in patients receiving myeloablative chemotherapy prior to bone marrow or hematopoetic stem cell transplant (HSCT). The cyclooxygenase (COX) pathway mediates tissue injury and pain through upregulation of pro-inflammatory prostaglandins, including prostaglandin E2 (PGE2) and prostacyclin (PGI2). The objective of this small (n = 3) pilot study was to examine the role of the COX pathway in causing mucosal injury and pain in chemotherapy-induced oral mucositis. MATERIALS AND METHODS: We collected blood, saliva, and oral mucosal biopsy specimens from three autologous HSCT patients at the following time-points before and after administration of conditioning chemotherapy: Day -10, +10, +28, and +100, where day 0 is day of transplant. RNA extracted from full-thickness tissue samples was measured by RT-PCR for the following: COX-1, COX-2, microsomal prostaglandin E synthase (mPGES), IL-1beta, and TNF-alpha. Blood and saliva samples were measured by ELISA for PGE2 and PGI2, which are markers of COX activity. Severity of oral mucositis was determined using the Oral Mucositis Index. Severity of pain due to oral mucositis was measured using a Visual Analog Scale. Relationships between the different variables were examined using Spearman rank correlation coefficients. MAIN RESULTS: Mean mucositis and pain scores increased significantly after administration of chemotherapy and then gradually declined. The correlation between changes in mucositis and pain scores was strong and statistically significant. The following additional correlations were statistically significant: between tissue COX-1 and pain; between tissue mPGES and pain; between salivary PGE1 and pain; between salivary PGI2 and pain. Other relationships were not statistically significant. CONCLUSIONS: Our finding of significant associations of pain scores with tissue COX-1 and mPGES, as well as salivary prostaglandins, is suggestive of a role for the cyclooxygenase pathway in mucositis, possibly via upregulation of pro-inflammatory prostaglandins. However, our small sample size may have contributed to the lack of significant associations between COX-2 and other inflammatory mediators with mucosal injury and pain. Thus, additional studies with larger numbers of subjects are warranted to confirm the involvement of the cyclooxygenase pathway in chemotherapy-induced mucositis.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Mediadores de Inflamación/análisis , Oxidorreductasas Intramoleculares/análisis , Mucosa Bucal/química , Prostaglandina-Endoperóxido Sintasas/metabolismo , Saliva/química , Estomatitis/inducido químicamente , Biomarcadores/análisis , Biopsia , Ensayo de Inmunoadsorción Enzimática , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Mucosa Bucal/metabolismo , Dimensión del Dolor , Proyectos Piloto , Prostaglandina-E Sintasas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estomatitis/sangreRESUMEN
PURPOSE: This study evaluated the safety and efficacy of recombinant human intestinal trefoil factor (rhITF) administered as topical oral spray for prevention and treatment of chemotherapy-induced oral mucositis (OM). PATIENTS AND METHODS: Ninety-nine patients with colorectal cancer who had moderate to severe OM (WHO grade >or= 2) in the first cycle of chemotherapy were randomly assigned to receive either placebo, rhITF 10 mg/mL (ie, low dose), or rhITF 80 mg/mL (ie, high dose) by oral spray (300 microL, eight times each day) for 14 consecutive days in the second chemotherapy cycle. Patients were assessed on days 1, 3, 5, 7, 10, 12, 14, and 21 (+/- 2 days for the last assessment) for safety and for OM incidence and severity. RESULTS: Treatment of patients at high risk for developing OM with low- or high-dose rhITF significantly reduced the amount of incidence (75% to 81%; low-dose rhITF P < .001; high-dose rhITF P = .002). Frequencies of WHO grade >or= 2 OM in the placebo, low-dose rhITF, and high-dose rhITF groups were 48.5%, 9.1%, and 12.1%, respectively. Assessment of the area under the curve revealed statistically significant reductions in OM severity in the rhITF-treated groups versus placebo. Only a minority of patients (6.1%) reported treatment-emergent adverse events (TEAEs), all of which were mild to moderate in intensity and resolved without sequelae. The incidence of TEAEs was not significantly different among treatment groups. CONCLUSION: rhITF oral spray formulation was safe and effective when used for the reduction of chemotherapy-associated OM in patients with colorectal cancer. Patients exhibited high compliance in dosing administration. Future clinical study is planned to develop this drug for use in OM management in patients with cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Péptidos/uso terapéutico , Estomatitis/prevención & control , Dolor Abdominal/inducido químicamente , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Diarrea/inducido químicamente , Método Doble Ciego , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Cefalea/inducido químicamente , Humanos , Hipertensión/inducido químicamente , Mucosa Intestinal/metabolismo , Masculino , Persona de Mediana Edad , Péptidos/efectos adversos , Péptidos/genética , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Estomatitis/inducido químicamente , Resultado del Tratamiento , Factor Trefoil-2Asunto(s)
Atención Dental para Enfermos Crónicos , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Profilaxis Antibiótica , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/radioterapia , Terapia Combinada , Irradiación Craneana , Infección Focal Dental/etiología , Sobrecrecimiento Gingival/inducido químicamente , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Neoplasias de Cabeza y Cuello/radioterapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Oxigenoterapia Hiperbárica , Terapia de Inmunosupresión , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Infecciones/etiología , Enfermedades Maxilomandibulares/etiología , Enfermedades Maxilomandibulares/terapia , Mucositis/inducido químicamente , Higiene Bucal , Osteorradionecrosis/etiología , Osteorradionecrosis/terapia , Estomatitis/inducido químicamente , Trombocitopenia/inducido químicamente , Xerostomía/etiologíaRESUMEN
Oral mucositis can be a significant problem for cancer patients and is frequently seen in the patient population receiving high-dose head and neck radiation therapy (85%-100%), stem cell transplantation (75%-100%), and myelosuppressive chemotherapy for solid tumors (5%-40%). Current guidelines published through the joint efforts of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology recommend strategies for the prevention and treatment of mucositis in the setting of radiation therapy, chemotherapy, and combined chemoradiation therapy. An improved understanding of its pathologic basis has led to the development of targeted agents to combat mucositis. One of these drugs, palifermin, is a keratinocyte growth factor agent approved for patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. Another agent is AES-14, an uptake-enhanced L-glutamine suspension that has shown efficacy in phase III trials in reducing the risk of developing oral mucositis in breast cancer patients receiving chemotherapy. As the understanding of the pathobiology of mucositis improves, clinicians should be able to customize future therapies based on each patients risk for developing the condition.