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Annals of Oncology 21 (Supplement 5): v261–v265, 2010 Management of oral and gastrointestinal mucositis:ESMO Clinical Practice Guidelines D. E. Peterson1, R.-J. Bensadoun2 & F. Roila3On behalf of the ESMO Guidelines Working Group*1Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, Program in Head and Neck Cancer and Oral Oncology, Neag Comprehensive CancerCenter, University of Connecticut Health Center, Farmington, USA; 2Service d’Oncologie Radiothe´rapique, Poˆle Re´gional de Cance´rologie, CHU de Poitiers, Poitiers, France; 3Department of Medical Oncology, S. Maria Hospital, Terni, Italy Combination therapy (e.g. head and neck radiation withconcurrent chemotherapy) may increase the severity of oral Oral and gastrointestinal mucositis due to cancer therapies such as high-dose chemotherapy and/or radiation continues to While this modelling continues to be valid, there appear to be an important clinical problem. Fortunately, there have been be additional risk factors (e.g. genetic polymorphisms) in some strategic advances over the past decade relative to understanding cohorts that account for degree of clinical expression. This the molecular basis of the injury, opportunities for development latter component of the risk paradigm is under current of drugs and devices to prevent or treat the toxicity, and clinical investigation and is addressed in the ‘Future directions’ section guideline development. The following text addresses this of this report. Further study of these more recently defined paradigm, with focus on evidence-based guidelines as developed factors will likely strategically advance the pathobiological by the Multinational Association of Supportive Care in Cancer model in relation to clinical expression of the toxicity.
(MASCC) in collaboration with the International Society of OralOncology (ISOO).
A variety of assessment scales exist for the measurement of oral mucositis. Most of the scales that are utilized for clinical care Mucositis is defined as inflammatory and/or ulcerative lesions incorporate the collective measurement of oral symptoms, signs of the oral and/or gastrointestinal tract usually caused by cancer and functional disturbances. By comparison, some scales are primarily centred in clinician-based observation of mucosal Alimentary tract mucositis refers to the expression of tissue injury (e.g. erythema, ulceration). These latter scales have mucosal injury across the continuum of oral and particular value in clinical trial-based assessment of oral gastrointestinal mucosa, from the mouth to the anus.
In contrast, there is a limited number of instruments available for assessment of gastrointestinal mucositis. Thesescales typically measure indirect outcomes of mucosal injury, Risk of mucositis has classically been directly associated with including diarrhoea. However, interpretation of such data can modality, intensity and route of delivery of the cancer therapy.
be confounded by other clinical conditions and interventionsthat also contribute to the event being measured. New *Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.
technologies, as described in ‘Future directions’, may lead to Taddei 4, CH-6962 Viganello-Lugano, Switzerland; enhanced assessment strategies for gastrointestinal mucositis.
Approved by the ESMO Guidelines Working Group: January 2008, last update December 2009. This publication supercedes the previously published version—Ann Oncol 2009; 20 (Suppl 4): iv174–iv177.
Conflict of interest: Professor Peterson has reported that he is Principal Investigator on an NIH R13 Conference Grant that provided partial support for the symposium ‘Oral incidence of oral mucositis in patients receiving Complications of Emerging Cancer Therapies’, 14–15 April 2009, Bethesda, MD, USA.
Production of a JNCI Monograph for the conference publications is being supported via an unrestricted educational grant from Biovitrum, which currently owns palifermin. He Incidence of World Health Organization (WHO) grade 3 or 4 has also reported that he is a member of the Scientific Advisory Board and a paid oral mucositis in patients receiving high-dose head and neck consultant for The GI Co., Inc. This company has been responsible for development of radiation to the oral cavity approaches 85%, but all treated recombinant intestinal trefoil factor, for which the Phase II study is cited in the Literature patients have some degree of oral mucositis. Mucositis is one of section (reference 18, J Clin Oncol 2009). Professor Bensadoun and Dr Roila have the prime limiting factors of chemoradiation for advanced head ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected] and neck carcinoma. The oral pain associated with the lesion Patient-controlled analgesia with morphine is recommended frequently leads to the need for enteral nutritional support with as the treatment of choice for oral mucositis pain in patients or without use of a feeding tube or gastrostomy, as well as use undergoing HSCT [I, A]. Regular oral pain assessment using of morphinomimetics, with the objective of maintaining dose validated instruments for self-reporting is essential.
intensity throughout the entire radiation regimen.
In addition to evidence-based recommendations and suggestions published by the MASCC/ISOO, it is relevant to incidence of oral and gastrointestinal mucositis in note that topical anaesthetics can provide short-term pain relief patients undergoing haematopoietic stem-cell for oral mucositis on an empirical basis.
Incidence of WHO grade 3 or 4 oral mucositis can be as high as75% in patients undergoing haematopoietic stem-cell  Use of midline radiation blocks and three-dimensional transplantation (HSCT), depending on the intensity of the radiation treatment to reduce mucosal injury is conditioning regimen used and the use of methotrexate prophylactically to prevent graft-versus-host disease.
 Benzydamine oral rinse for prevention of radiation-induced Management of oral and gastrointestinal mucositis is one of the mucositis in patients with head and neck cancer receiving main challenges during the period of aplasia, with risk of sepsis moderate-dose radiation therapy is recommended [I, A].
related to the degree of mucosal barrier breakdown and depth  Chlorhexidine is not recommended for prevention of oral mucositis in patients with solid tumours of the head and neck and who are undergoing radiotherapy [II, B].
incidence of mucositis associated with standard  Antimicrobial lozenges are not recommended for prevention of radiation-induced oral mucositis [II, B].
radiotherapy) for non-Hodgkin’s lymphoma and Data relative to the risk of developing grade 3 or 4 oral  Sucralfate is not recommended for treatment of radiation- mucositis and diarrhoea are presented in Table 1. For all tumour sites, chemotherapy with 5-fluorouracil (5-FU),capecitabine or tegafur leads to a high rate (e.g. 20%–50%) of alimentary tract mucositis. Recently reported phase I modelling  Oral cryotherapy (30 min) is recommended for prevention of of drug dose and sequence may be of benefit to future patients oral mucositis in patients receiving bolus 5-FU in this regard. Chemotherapy with methotrexate and other antimetabolites leads to a 20%–60% rate of alimentary tract  Oral cryotherapy (20–30 min) is suggested to decrease mucositis according to the drug’s given dose per cycle. As mucositis in patients treated with bolus doses of edatrexate described in ‘Future directions’, recent advances in cancerpatient management, including utilization of molecularly targeted cancer therapies, are anticipated to strategically  Acyclovir and its analogues are not recommended to redefine cure rates and adverse event profiles in the coming prevent mucositis caused by standard-dose chemotherapy years. The impact of these agents on the risk of mucosal damage and diarrhoea has yet to be described.
In addition to the MASCC/ISOO guidelines published inMarch 2007, a study published after the literature reviews were completed suggested that keratinocyte growth factor-1(palifermin) may be useful in a dose of 40 lg/kg/day for 3 days Oral and gastrointestinal mucositis management guidelines, as for prevention of oral mucositis in patients receiving bolus developed by the Mucositis Study Group of MASCC/ISOO, are  Chlorhexidine is not recommended to treat established oral basic oral care and good clinical practice. Multidisciplinary development and evaluation of oral care protocols that includefrequent use of non-medicated oral rinses (e.g. saline mouth high-dose chemotherapy with or without total body irradiation rinses 4–6 times/day) is recommended. Patient and staff education in the use of such protocols is recommended forreduction of the severity of oral mucositis from chemotherapy  Palifermin is recommended in a dose of 60 lg/kg/day for 3 days before conditioning treatment and for 3 days post- Interdisciplinary development of systematic oral care transplant for the prevention of oral mucositis in patients protocols is suggested. As part of the protocols, the use of a soft with haematological malignancies receiving high-dose toothbrush that is replaced on a regular basis is also suggested chemotherapy and total body irradiation with autologous consistent with good clinical practice.
Table 1. Risk of grade 3–4 oral mucositis and diarrhoea by chemotherapy regimen CHOP-14: cyclophosphamide + doxorubicin + CHOP-DI-14: cyclophosphamide + doxorubicin + vincristine + prednisone, dose-intensified CHOEP-14: cyclophosphamide + doxorubicin + CEOP/IMVP-Dexa: cyclophosphamide + etoposide + vincristine + prednisone/ifosfamide +methotrexate- dexamethasone A/T/C, doxorubicin taxane, cyclophosphamide AC/T doxorubicin + cyclophosphamide, taxane A/CT doxorubicin, cyclophosphamide + taxane A/T doxorubicin, taxane administered sequentially FAC (weekly): 5-FU + doxorubicin + cyclophosphamide AC (weekly): doxorubicin + cyclophosphamide TAC: docetaxel + doxorubicin + cyclophosphamide Lung ALL (no XRT) (continued)Gemcitabine + platinum Taxane is paclitaxel or docetaxel.
From Keefe DM, Schubert MM, Elting LS et al. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 2007; 109:820–831.
 Cryotherapy is suggested to prevent oral mucositis in patients before HSCT, if the treatment centre is able to support the receiving high-dose melphalan [II, A].
necessary technology and training [II, B].
 Pentoxifylline is not recommended to prevent mucositis in  Granulocyte-macrophage colony stimulating factor (GMCSF) basic bowel care and good clinical practice. In addition to the mouthwashes are not suggested for prevention of oral evidence-based guidelines below, basic bowel care should mucositis in patients undergoing HSCT [II, C].
include maintenance of adequate hydration. In addition,  Low-level laser therapy (LLLT) is suggested to reduce consideration should be given to the potential for transient incidence of oral mucositis and its associated pain, in patients lactose intolerance and the presence of bacterial pathogens.
receiving high-dose chemotherapy or chemoradiotherapy These suggestions are consistent with good clinical practice.
are given in square brackets. Statements without grading wereconsidered justified standard clinical practice by the expert  Use of 500 mg sulfasalazine orally twice daily is suggested to reduce the incidence and severity of radiation-inducedenteropathy in patients receiving external beam radiotherapy  Amifostine is suggested in a dose of at least 340 mg/m2 to The mucositis guidelines reported in this version of the ESMO prevent radiation proctitis in those receiving standard-dose Clinical Practice Guidelines contain few changes in comparison radiotherapy for rectal cancer [III, B].
with the previous two versions as published in Annals of  Oral sucralfate is not recommended to reduce related side-effects Oncology in 2008 and 2009, respectively. The MASCC/ of radiotherapy. It does not prevent acute diarrhoea in patients ISOO Mucositis Study Group has continued to monitor the with pelvic malignancies undergoing external beam literature following publication of its updated mucositis radiotherapy, and compared with placebo it is associated with management guidelines in 2007. At the annual meeting of the more gastrointestinal side-effects, including rectal bleeding [I, A].
MASCC/ISOO Mucositis Study Group in June 2009, it was  5-amino-salicylic acid and its related compounds mesalazine determined that no new guidelines were warranted at the and olsalazine are not recommended to prevent present time, based on the current state of the science as The group also addressed the importance of discussing future guideline development and integration with colleagues in other  Sucralfate enemas are suggested to help manage chronic health professional organizations and who have created radiation-induced proctitis in patients who have rectal guidelines more recently, in order to extend the dissemination and utilization of evidence-based mucositis managementinterventions. Next steps are being planned by the Mucositis standard-dose and high-dose chemotherapy: prevention In addition, there continues to be key progress relative to the  Either ranitidine or omeprazole is recommended for molecular pathobiology, computational biology and clinical prevention of epigastric pain following treatment with impact of mucosal injury in cancer patients that may generate standard-dose cyclophosphamide, methotrexate and 5-FU or strategic research and clinical advances in the future. These treatment with 5-FU with or without folinic acidchemotherapy [II, A].
advances will likely result in revisions in the MASCC/ISOOmucositis guidelines in the next 2–5 years. Examples of novel,  Systemic glutamine is not recommended for the prevention of gastrointestinal mucositis [II, C].
important future opportunities based on the recent advancesinclude the following.
standard-dose and high-dose chemotherapy: treatment  Delineation of predictive models that could enhance the  Octreotide is recommended at a dose of at least 100 lg s.c.
ability of clinicians to prospectively identify which solid twice daily when loperamide fails to control diarrhoea tumour patients are at highest risk for development of induced by standard-dose or high-dose chemotherapy clinically significant oral and/or gastrointestinal mucositis.
Recent research relative to identification of systemic and/ormucosal tissue-based genetic susceptibility for mucositis combined chemotherapy and radiotherapy: prevention represents an important example of this modelling.
 Amifostine is suggested to reduce oesophagitis induced by Enhanced technologies to assess severity of gastrointestinal concomitant chemotherapy and radiotherapy in patients with non-small-cell lung cancer [III, C].
 Utilization of single or combination topical and/or systemic preventive and treatment interventions, once several molecularly targeted therapies for mucositis are approved forclinical use.
The summary presented above is based on work conducted by  Increased clinical recognition of the importance of Grade II members of the Mucositis Study Group of MASCC/ISOO.
oral and/or gastrointestinal mucositis, in the context of Additional guidelines are also available from other health symptom burdens that are experienced by cancer patients.
professional organizations (e.g. The Cochrane Collaboration).
 Potential impact of emerging targeted cancer therapies on the See ‘Future directions’ regarding plans to link the MASCC/ incidence and severity of alimentary tract mucositis.
ISOO mucositis guidelines with guidelines from other healthprofessional organizations over time.
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