ReviewOral mucositis
Introduction
By virtue of their rapid mitotic rate, mucosal cells are natural targets of cancer cytotoxic regimens. This collateral damage affects treatment delivery and is often a dose-limiting toxicity, particularly for (chemo)radiation for head and neck cancers, and conditioning regimens for haematopoietic stem cell transplantation (HSCT). Newer targeted agents such as cetuximab may enhance toxicity of radiotherapy.1 Similarly, rapamycin (mTOR) inhibitors have been reported to cause mouth ulcers.[2], [3] Thus, while other toxicities may be declining, mucosal damage remains an area of concern.
Oral mucositis is defined as inflammation of oral mucosa resulting from cancer therapy typically manifesting as atrophy, swelling, erythema and ulceration. The condition may be exacerbated by local factors, such as trauma from teeth, or microbial colonization. The term stomatitis refers to any inflammatory condition of oral tissue, including mucosa, dentition/periapices, and periodontium. Stomatitis thus defines a broader range of pathoses of oral tissues, including mucositis.
A number of instruments to evaluate the observable, subjective and functional dimensions of oral mucositis are available.4 In addition, patient-reported outcomes of mouth and throat soreness have been developed.[5], [6]
Traditionally, mucosal toxicities have been separated by site of occurrence and studied accordingly. However, new insights have led to the realization that cancer treatment-induced mucosal damage affects the entire alimentary tract. Therefore, terminology has been introduced to describe this cancer therapy-associated mucosal injury, such as alimentary mucositis and mucosal barrier injury.[7], [8]
Section snippets
Pathobiology
Significant progress has been made in understanding the pathobiology of mucositis. A biological model for chemotherapy- and radiotherapy-induced oral mucositis proposed by Sonis,9 appeared to be more generally applicable to alimentary mucositis.[4], [10] What was once thought to be a simple reflection of direct epithelial damage induced by cytotoxic therapy is now considered to be a complex phenomenon that also affects the connective tissue. The model includes events that have been described in
Chemotherapy-induced versus radiation-induced mucositis
While there is similarity in the cellular events of chemotherapy- and radiation-induced mucositis, the biological pathways may be slightly different.11 Chemotherapy is administered systemically, whereas radiation therapy affects a specific body area. In addition, there are differences in the kinetics of treatment, affecting the clinical course (Fig. 1).[12], [13] Chemotherapy may be delivered over a short time, in which case the injury to mucosal tissues tends to be acute. Chemotherapy-induced
Prevalence and risk factors
Development of mucositis depends on a number of factors, related to both therapy and patient characteristics. Some potential risk factors have been identified, while others remain obscure.14 Treatment variables that may affect the prevalence and the severity of mucositis include the type, dose, and schedule of systemic cytotoxic medications, radiation dose and field, and concomitant use of chemotherapy and radiation. The majority of patients treated for head and neck cancers or those receiving
The impact of mucositis
A significant number of patients report oral mucositis as the most debilitating and troublesome adverse effect of cancer therapy.[21], [22] Prospective studies indicate that virtually all patients treated for head and neck cancer developed mouth and throat soreness of such severity that it reduced quality of life.[23], [24] Opioid analgesics did not always adequately palliate mucosal pain, and may lead to other problems such as dry mouth and constipation. In addition to its significant
Oral ulceration with a non-mucositis etiology
Other oral lesions may develop in the cancer patient that can complicate the diagnosis of mucositis. For correct diagnosis it is mandatory to have information about stomatotoxic therapies and prophylactic medications, peripheral blood counts and the time of onset as well as the location of the lesions. Frequent oral inspection to detect lesions at an early stage is helpful for diagnosis and successful management. Fungal and viral infections are the most common, but other microbial culprits may
Management
As mucositis became increasingly a dose-limiting toxicity, attempts to prevent and treat it gained momentum in the scientific and clinical environments. Unfortunately, most studies to date have had significant limitations and the available prophylactic and therapeutic strategies are limited. Systematic reviews of the literature have led to the publication of clinical practice guidelines.[37], [38], [39], [40], [41], [42], [43]
Selected interventions have met some success and these include
Concluding remarks
International collaboration between multidisciplinary basic researchers and clinicians has been crucial to a better understanding of mucositis and has led to a joint approach towards improving patient management.[4], [37], [38] Nevertheless, what we currently have to offer to patients to manage mucositis and oropharyngeal pain is still inadequate.[48], [23] Ongoing research into patient-reported outcomes is important and new techniques to detect mucositis at a subclinical stage are promising.49
Conflict of interest statement
Judith E. Raber-Durlacher occasionally lectures for EUSA Pharma. None of the other authors has any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work.
Acknowledgment
We want to acknowledge the significant contribution of Professor S.T. Sonis to this review paper. The Multinational Association for Supportive Care in Cancer provided a travel stipendium to J.E.R.-D to present this paper.
References (49)
- et al.
Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer
Radiother Oncol
(2009) Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity
Oral Oncol
(1998)The pathobiology of mucositis
Semin Oncol Nurs
(2004)- et al.
Risk factors for ulcerative oral mucositis in cancer patients: unanswered questions
Oral Oncol
(2003) Advances in understanding of toxicities of treatment for head and neck cancer
Oral Oncol
(2009)- et al.
Mucositis-related morbidity and resource utilization in head and neck cancer patients receiving radiation therapy with or without chemotherapy
J Pain Symptom Manage
(2009) The impact, biology and therapeutic opportunities of oral mucositis
Oral Oncol
(2009)- et al.
Use of sidestream dark-field (SDF) imaging for assessing the effects of high-dose melphalan and autologous stem cell transplantation on oral mucosal microcirculation in myeloma patients
Oral Surg Oral Med Oral Pathol Oral Radiol Endod
(2010) - et al.
Experiences and practical conclusions concerning temsirolimus and adverse event management in advanced renal cell carcinoma within a compassionate use program in Germany
Cancer Chemother Pharmacol
(2009) - et al.
Preliminary characterization of oral lesions associated with inhibitors of mammalian target of ripamycin in cancer patients
Cancer
(2010)
Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients
Cancer
Reliability and validity of a patient self-administered daily questionnaire to assess impact of oral mucositis (OM) on pain and daily functioning in patients undergoing autologous bone marrow transplantation (HSCT)
Bone Marrow Transplant
Longitudinal evaluation of the oral mucositis weekly questionnaire-head and neck cancer, a patient-reported outcomes questionnaire
Cancer
Alimentary tract mucositis in cancer patients: impact on terminology and assessment on research and clinical practice
Support Care Cancer
Mucosal barrier injury: biology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview
Bone Marrow Transplant
Oral mucositis: a challenging complication of radiotherapy, chemotherapy, and radiochemotherapy. Part 1, pathogenesis and prophylaxis of mucositis
Head Neck
Prevention and treatment of the consequences of head and neck radiotherapy
Crit Rev Oral Biol Med
A biological approach to mucositis
J Support Oncol
Regimen-related gastrointestinal toxicities in cancer patients
Curr Opin Support Palliative Care
Oral mucositis in patients receiving reduced-intensity regimens for allogeneic hematopoietic cell transplantation: comparison with conventional regimen
Support Care Cancer
Predictors of oral mucositis in patients receiving hematopoietic stem cell transplants for chronic myelogenous leukemia
J Clin Oncol
TNF polymorphisms are associated with toxic, but not with aGVHD complications in the recipients of allogeneic sibling haematopoietic stem cell transplantation
Bone Marrow Transplant
Prospective oral mucositis audit: oral mucositis in patients receiving high-dose melphalan or BEAM conditioning chemotherapy – European Blood and Marrow Transplantation Mucositis Advisory Group
J Clin Oncol
Patient reports of complications of bone marrow transplantation
Support Care Cancer
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