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Mascc/isoo clinical practice guidelines for the management of mucositis secondary to cancer therapyMASCC=ISOO Clinical Practice Guidelines for the Management of Mucositis Secondary to Cancer Therapy Rajesh V. Lalla, DDS, PhD1; Joanne Bowen, PhD2; Andrei Barasch, DMD, MDSc3; Linda Elting, PhD4; Joel Epstein, DMD, MSD5; Dorothy M. Keefe, MD2; Deborah B. McGuire, PhD, RN6; Cesar Migliorati, DDS, MS, PhD7; Ourania Nicolatou-Galitis, DDS, MSc, DrDent8; Douglas E. Peterson, DMD, PhD1; Judith E. Raber-Durlacher, DDS, PhD9; Stephen T. Sonis, DMD, DMSc10; Sharon Elad, DMD, MSc11; and The Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC=ISOO).
BACKGROUND: Mucositis is a highly significant, and sometimes dose-limiting, toxicity of cancer therapy. The goal of this system- atic 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 vari- ous 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 second- ary to cancer therapy. Cancer 2014;120:1453–61. V 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of Ameri- can Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non- commercial and no modifications or adaptations are made.
KEYWORDS: mucositis, stomatitis, oral, gastrointestinal, guidelines, Multinational Association of Supportive Care in Cancer and Inter-national Society of Oral Oncology (MASCC=ISOO).
Corresponding author: Rajesh V. Lalla, DDS, PhD, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030-1605; Fax: (860)679-4760;Lalla@uchc.edu 1University of Connecticut, Farmington, Connecticut; 2University of Adelaide, Adelaide, South Australia, Australia; 3Winthrop University Hospital, Mineola, NewYork; 4The University of Texas MD Anderson Cancer Center, Houston, Texas; 5City of Hope Medical Center, Duarte, California; 6Virginia Commonwealth University,Richmond, Virginia; 7University of Tennessee Health Science Center, Memphis, Tennessee; 8University of Athens, Athens, Greece; 9Academic Medical Center-Am-sterdam, Amsterdam, the Netherlands; 10Brigham and Women's Hospital, Boston, Massachusetts; 11University of Rochester, Rochester, New York Additional supporting information may be found in the online version of this article.
Other members of the Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral On-cology (MASCC=ISOO) are: Noor Al-Dasooqi, PhD; Michael Brennan, DDS, MHS; Rachel Gibson, PhD; Janet Fulton, PhD, RN; Ian Hewson, BDS; Siri B. Jensen, DDS,PhD; Richard Logan, BDS, MDS, PhD; Kerstin E.O. € Ohrn, PhD, RDH; Triantafyllia Sarri, DDS, MSc; Deborah Saunders, DDS; Inger von B€ owen, DDS, PhD; and Noam Yarom, DMD.
Other contributors to the guidelines update included Justin Allemano, Abdul Rahman Al-Azri, Heliton Spindola Antunes, Anura Ariyawardana, Emma Bateman,Nicole Blijlevens, Christine B. Boers-Doets, Paolo Bossi, Carlton G. Brown, Yu-Chia Chang, Karis K. Cheng, Catherine Cooksley, Elvira P. Correa, Kristopher Dennis,Mario Di Palma, Scott Drucker, June Eilers, Carmen Escalante, Cherry L. Estilo, Hele Everaus, Margot Fijlstra, Monica Fliedner, Annette Freidank, Erich Gerber, FaithGibson, Jes us Garcia Gomez, Josiah Halm, Guido Hita, Ronald D. Hutchins, Brian Hodgson, Allan Hovan, Virginia Jarvis, Emily E. King, Vassilios E. Kouloulias, Marie C. Latortue, Judith Lees, Nilza Nelly Fontana Lopes, Charles Loprinzi, Marisol Michelet, Takehiko Mori, Raj G. Nair, Pasquale Niscola, Loree K. Oberle-Edwards, An-thony Osaguona, Pratibha Parelkar, Jumin Park, Ira Parker, Bo G. Pettersson, Carin Potting, Nikhil G. Rao, Dorothea Riesenbeck, Tanya Rouleau, Mark M. Schubert,Sol Silverman Jr, Yoshihiko Soga, Fred K.L. Spijkervet, Monique Stokman, Andrea M. Stringer, Wim J.E. Tissing, Walter J.F.M. van der Velden, Marianne D. van deWetering, Madhuri Vithala, Dianna S. Weikel, Roger Yazbeck, Eric Yeoh, and Yehuda Zadik.
Disclaimer: The Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC=ISOO) Mucositis Guidelines are devel-oped to facilitate the evidence-based management of mucositis. However, clinicians should also use their own judgment in making treatment decisions for indi-vidual patients. The guideline authors and the MASCC=ISOO do not guarantee or take responsibility for clinical outcomes in individual patients.
These guidelines refer to the use of the listed agents for the specific indication listed (ie, the prevention or treatment of mucositis or related symptoms). Theseguidelines do not apply to the use of the listed agents for other indications. For example, although it is suggested that chlorhexidine mouthwash not be usedto prevent oral mucositis in patients receiving head and neck radiation therapy, clinicians may choose to use this agent for other indications in this or otherpopulations.
DOI: 10.1002/cncr.28592, Received: September 12, 2013; Revised: November 21, 2013; Accepted: December 20, 2013, Published online February 25, 2014 inWiley Online Library (wileyonlinelibrary.com) 2007.15 Over the last decade, other organizations have also Mucositis refers to mucosal damage secondary to cancer published guidelines for mucositis. The guidelines published therapy occurring in the oral cavity; pharyngeal, laryngeal, by the European Society for Medical Oncology are a direct and esophageal regions; and other areas of the gastrointes- adoption of the MASCC=ISOO guidelines.16 The guide- tinal tract. Mucositis can be caused by chemotherapy lines published by the US National Comprehensive Cancer and=or radiation therapy. It occurs in approximately 20% Network are an adaptation of the MASCC=ISOO guide- to 40% of patients receiving conventional chemotherapy, lines, combined with expert opinion.17 Thus, the 80% of patients receiving high-dose chemotherapy as MASCC=ISOO mucositis guidelines are the leading clinical conditioning for hematopoietic stem cell transplantation practice guidelines for this toxicity. Due to the large volume (HSCT), and nearly all patients receiving head and neck of additional literature published since the last update, we radiation therapy (H&NRT).1-3 Oral mucositis presents undertook the second revision of these guidelines, which is as erythema and=or ulceration of the oral mucosa. In presented here.
addition, the pharyngeal, laryngeal, and esophageal mu-cosa are also at risk for mucositis, particularly in patients MATERIALS AND METHODS undergoing H&NRT. It is typically very painful, requir- Our methods and the underlying considerations have ing opioid analgesics, and impairs nutritional intake and been described in detail in 2 recent publications.18,19 In quality of life.4,5 Gastrointestinal mucositis presents with brief, we developed evidence-based guidelines based on debilitating symptoms such as pain, nausea=vomiting, systematic reviews of the evidence for various interven- and diarrhea.6 Severe mucositis can necessitate a reduction tions. A research librarian constructed search strategies in the chemotherapy dose or a treatment break in RT, and conducted literature searches through the OVID which can negatively influence prognosis.7,8 In addition, interface to Medline. Inclusion criteria were English lan- mucositis has a considerable economic impact, due to guage publications reporting testing of an intervention for costs associated with symptom management, nutritional mucositis in humans, published in a peer-reviewed jour- support, management of secondary infection, and hospi- nal, and indexed in Medline on or before December 31, talization.7,9 Thus, mucositis is a highly significant, and 2010. We excluded articles that did not report the effects sometimes dose-limiting, toxicity of cancer therapy.
of an intervention on mucositis or mucositis-related out- Although direct cell damage from chemotherapy comes (such as pain), animal or in vitro studies, and litera- and=or RT initiates the process, evidence suggests that the ture reviews. Due to the large number and diverse range pathogenesis of mucositis is more complex.10 A 5-stage of interventions, the reviewers and articles were organized model has been proposed.11 Reactive oxygen species, sec- into 8 clinical sections. One section focused on gastroin- ond messengers, proinflammatory cytokines and pathways, testinal mucositis and 7 sections examined the following and metabolic byproducts of colonizing microorganisms classes of interventions for oral mucositis: 1) basic oral are all believed to play a role in amplifying the tissue care; 2) growth factors and cytokines; 3) antiinflammatory injury.12 As a result, a large number of diverse interventions agents; 4) antimicrobials, coating agents, anesthetics, and have been tested for mucositis. Although many of these analgesics; 5) laser and other light therapy; 6) cryotherapy; interventions are available over the counter or for off-label and 7) natural and miscellaneous agents. Each of the 8 sec- use or marketed as devices, to the best of our knowledge tions had a section head, 1 co-section heads, and 5 to only 1 agent to date has been approved by the US Food 10 reviewers. All participants were calibrated to ensure and Drug Administration as a drug for mucositis, albeit in consistency in the application of the review criteria. In a relatively restricted population. Studies of many interven- addition, reviewers and section heads were provided with tions range widely in quality, sometimes with conflicting role-specific written instructions and a manual detailing results. Therefore, there is a need for evidence-based clinical the procedures. Each article was independently reviewed practice guidelines for mucositis to guide clinicians on by 2 reviewers. Each reviewer extracted and entered up to which interventions are truly effective.
66 fields of data per article into an electronic reviewer In 2004, the Mucositis Study Group of the Multina- form. The quality of the reviewed literature was assessed tional Association of Supportive Care in Cancer and Inter- by identifying major and minor flaws as per the criteria national Society of Oral Oncology (MASCC=ISOO) published by Hadorn et al (see online supporting infor- published what to our knowledge were the first evidence- mation).20 These criteria specify major and minor flaws based clinical practice guidelines for mucositis.13,14 The for 8 study design variables: selection of patients, alloca- first update of these guidelines was published in Cancer in tion to groups, therapeutic regimen, study administration, MASCC=ISOO Mucositis Guidelines/Lalla et al withdrawals, blinding, outcome measurement, and statis- TABLE 2. Criteria for Each Guideline Category tical analysis. The section heads finalized the reviews of Reserved for guidelines that are based on level I or each article and adjudicated discrepancies between the 2 level II evidence.
Used for guidelines that are based on level III, level reviewers. Then the overall body of evidence for each IV, and level V evidence; this implies panel intervention, in each treatment setting, was evaluated and consensus regarding the interpretation of this assigned a level of evidence, based on criteria published by Used when there is insufficient evidence on which Somerfield et al (Table 1).21 These criteria allocate levels to base a guideline; this implies 1) that there is of evidence based on the type of study and according to little or no evidence regarding the practice inquestion, or 2) that the panel lacks consensus whether a study is well designed. To minimize subjectiv- on the interpretation of existing evidence.
ity, we defined a "well-designed study" as a study with no Adapted from Somerfield MR, Padberg JR, Pfister DG, et al. ASCO clinical major flaws, as per the criteria of Hadorn et al.20 The level practice guidelines: process, progress, pitfalls, and prospects. Class Pap of evidence for each intervention was then translated into Curr Comments. 2000;4:881-886.21 a provisional guideline, based on criteria published by Hadorn et al.20 Summary results for each section are pre- Somerfield et al (Table 2).21 There were 3 possible catego- sented below and in Tables 3 and 4, which also list the ries: "recommendation," "suggestion," or "no guideline specifics of each guideline (whether for the prevention or possible." Level I or II evidence was required to support a treatment of mucositis and the specific patient population recommendation, which could only be achieved by 1 it applies to). For more detailed results of each section, randomized controlled trials without any major flaws. A including tables listing the details of every article suggestion was possible for lower-level evidence but only reviewed, please refer to the recently published articles with consistent evidence from multiple studies and panel from the individual sections.22-31 consensus on the interpretation of this evidence. Whenadequate evidence demonstrated the lack of efficacy of an Gastrointestinal Mucositis (Not Including the agent, a guideline "against" the use of that agent was developed. The provisional guidelines were discussed and The previous version of the MASCC=ISOO guidelines finalized at a full-day, in-person guidelines meeting for gastrointestinal mucositis included guidelines in favor attended by > 60 members of the panel and 2 independ- of amifostine, octreotide, sucralfate enemas, and sulfasala- ent observers.
zine in specific treatment settings (Table 3). In addition,it included guidelines against the use of 5-acetyl salicylicacid and related compounds and oral sucralfate. Based on the present systematic review, these prior guidelines were The literature search identified 8279 articles, 1032 of able to be continued with no changes. One previous which were retrieved for detailed evaluation based on titles guideline, which was against the use of systemic glutamine and abstracts; of these, 570 articles qualified for final for the prevention of gastrointestinal mucositis in patients inclusion in the systematic reviews (see online supporting receiving standard-dose and high-dose chemotherapy, was information). Less than 5% of all studies reviewed were changed to "No guideline possible," based on the incorpo- determined to have no major flaws, as per the criteria of ration of newer evidence. In addition, 3 new guidelineswere developed:1) a suggestion in favor of hyperbaric oxy- TABLE 1. Criteria for Each Level of Evidence gen to treat radiation-induced proctitis; 2) a suggestion Evidence obtained from meta-analysis of multiple, well-designed, for probiotic agents containing Lactobacillus species for controlled studies; randomized trials with low false-positive and the prevention of chemotherapy and radiation-induced false-negative errors (high power).
Evidence obtained from at least 1 well-designed experimental diarrhea in patients with pelvic malignancy; and 3) a rec- study; randomized trials with high false-positive and/or false- ommendation against the use of misoprostol suppositories negative errors (low power).
Evidence obtained from well-designed, quasi-experimental studies for the prevention of acute radiation-induced proctitis such as nonrandomized, controlled single-group, pretest-postt- (Table 3).22 Due to inadequate and=or conflicting evi- est comparison, cohort, time, or matched case-control series.
Evidence obtained from well-designed, nonexperimental studies, dence, no guideline was possible for several agents such as comparative and correlational descriptive and case reviewed, including activated charcoal, balasalazide, bude- sonide, cefixime, celecoxib, cholestyramine=levofloxacin, Evidence obtained from case reports and clinical examples.
chrysin, circadian rhythm, formalin, heater probes, leu- Adapted from Somerfield MR, Padberg JR, Pfister DG, et al. ASCO clinical covorin, metronidazole, neomycin, palifermin, physical practice guidelines: process, progress, pitfalls, and prospects. Class PapCurr Comments. 2000;4:881-886.21 activity, and sodium butyrate.
TABLE 3. MASCC/ISOO Clinical Practice Guidelines for Gastrointestinal Mucositis (Not Including the OralCavity)a RECOMMENDATIONS IN FAVOR OF AN INTERVENTION (ie, strong evidence supports effectiveness in the treatment setting listed):1. The panel recommends that intravenous amifostine be used, at a dose of 340 mg/m2, to prevent radiation proctitis in patients receiving radiation therapy (II).
2. The panel recommends that octreotide, at a dose of 100 lg subcutaneously twice daily, be used to treat diarrhea induced by standard- or high- dose chemotherapy associated with HSCT, if loperamide is ineffective (II).
SUGGESTIONS IN FAVOR OF AN INTERVENTION (ie, weaker evidence supports effectiveness in the treatment setting listed):1. The panel suggests that intravenous amifostine be used to prevent esophagitis induced by concomitant chemotherapy and radiation therapy in patients with non-small cell lung carcinoma (III).
2. The panel suggests that sucralfate enemas be used to treat chronic radiation-induced proctitis in patients with rectal bleeding (III).
3. The panel suggests that systemic sulfasalazine, at a dose of 500 mg administered orally twice a day, be used to prevent radiation-induced enteropathy in patients receiving radiation therapy to the pelvis (II).
4. The panel suggests that probiotics containing Lactobacillus species be used to prevent diarrhea in patients receiving chemotherapy and/or radiation therapy for a pelvic malignancy (III).
5. The panel suggests that hyperbaric oxygen be used to treat radiation-induced proctitis in patients receiving radiation therapy for a solid tumor (IV).
RECOMMENDATIONS AGAINST AN INTERVENTION (ie, strong evidence indicates lack of effectiveness in the treatment setting listed):1. The panel recommends that systemic sucralfate, administered orally, not be used to treat gastrointestinal mucositis in patients receiving radiation ther- apy for a solid tumor (I).
2. The panel recommends that 5-acetyl salicylic acid (ASA), and the related compounds mesalazine and olsalazine, administered orally, not be used to prevent acute radiation-induced diarrhea in patients receiving radiation therapy for a pelvic malignancy (I).
3. The panel recommends that misoprostol suppositories not be used to prevent acute radiation-induced proctitis in patients receiving radiation therapy for prostate cancer (I).
SUGGESTIONS AGAINST AN INTERVENTION (ie, weaker evidence indicates lack of effectiveness in the treatment setting listed):None Abbreviations: HSCT, hematopoietic stem cell transplantation; MASCC/ISOO, Multinational Association of Supportive Care in Cancer and International Societyof Oral Oncology.
a Level of evidence for each guideline is in brackets following the guideline statement.
version of the MASCC=ISOO guidelines for oral mucosi- tis included a recommendation in favor of this agent for The results of the current systematic review indicated that the prevention of oral mucositis in patients receiving most studies examining the use of oral care protocols for the high-dose chemotherapy and total body irradiation fol- prevention of oral mucositis reported a beneficial effect.
lowed by autologous stem cell transplantation for hemato- These protocols typically included a combination of tooth- logical malignancies. Based on the current systematic brushing, flossing, and 1 mouth rinses to maintain oral review, this recommendation was continued with no hygiene. Although the evidence was not strong enough to change in the target population (Table 4). The evidence support a recommendation, there was adequate positive evi- reviewed also continued to support a suggestion against the dence to support a suggestion in favor of using oral care pro- use of granulocyte-macrophage–colony-stimulating factor tocols for the prevention of oral mucositis across all cancer mouthwash for the prevention of oral mucositis in patients treatment modalities (Table 4). The evidence also sup- undergoing autologous or allogeneic HSCT. Furthermore, ported a suggestion against the use of chlorhexidine mouth- the use of granulocyte–colony-stimulating factor during wash for the prevention of oral mucositis in patients H&NRT has been associated with reduced local tumor con- receiving H&NRT. No guideline was possible regarding trol.33 Due to inadequate and=or conflicting evidence, no the use of oral care protocols for the treatment of oral muco- guideline was possible for the following agents reviewed: pal- sitis. In addition, no guideline was possible related to the individual use of the following mouth rinses: saline, sodium factor in treatment settings other than that listed above, bicarbonate, mixed medication mouthwashes, calcium fibroblast growth factor-20, keratinocyte growth factor-2, phosphate, and chlorhexidine in patients receiving chemo- therapy, due to inadequate and=or conflicting evidence.31 growth factor-b, epidermal growth factor, milk-derivedgrowth factor extract, interleukin-11, ATL-104, and Growth factors and cytokines recombinant human intestinal trefoil factor.23 To the best of our knowledge, palifermin (keratinocytegrowth factor-1) is the only agent that has been approved Antiinflammatory agents as a drug by the US Food and Drug Administration and Benzydamine hydrochloride is a nonsteroidal antiin- the European Medicines Agency for oral mucositis. Evi- flammatory drug that can inhibit the production of dence included a large, well-designed, randomized con- proinflammatory cytokines such as tumor necrosis trolled trial and other supporting studies.32 The previous factor-a and interleukin-1b. The previous version of MASCC=ISOO Mucositis Guidelines/Lalla et al TABLE 4. MASCC/ISOO Clinical Practice Guidelines for Oral Mucositisa RECOMMENDATIONS IN FAVOR OF AN INTERVENTION (ie, strong evidence supports effectiveness in the treatment setting listed):1. The panel recommends that 30 min of oral cryotherapy be used to prevent oral mucositis in patients receiving bolus 5-fluorouracil chemotherapy (II).
2. The panel recommends that recombinant human keratinocyte growth factor-1 (KGF-1/palifermin) be used to prevent oral mucositis (at a dose of 60 lg/kg per day for 3 days prior to conditioning treatment and for 3 days after transplant) in patients receiving high-dose chemotherapy and total bodyirradiation, followed by autologous stem cell transplantation, for a hematological malignancy (II).
3. The panel recommends that low-level laser therapy (wavelength at 650 nm, power of 40 mW, and each square centimeter treated with the required time to a tissue energy dose of 2 J/cm2), be used to prevent oral mucositis in patients receiving HSCT conditioned with high-dose chemotherapy, withor without total body irradiation (II).
4. The panel recommends that patient-controlled analgesia with morphine be used to treat pain due to oral mucositis in patients undergoing HSCT (II).
5. The panel recommends that benzydamine mouthwash be used to prevent oral mucositis in patients with head and neck cancer receiving moderate dose radiation therapy (up to 50 Gy), without concomitant chemotherapy (I).
SUGGESTIONS IN FAVOR OF AN INTERVENTION (ie, weaker evidence supports effectiveness in the treatment setting listed):1. The panel suggests that oral care protocols be used to prevent oral mucositis in all age groups and across all cancer treatment modalities (III).
2. The panel suggests that oral cryotherapy be used to prevent oral mucositis in patients receiving high-dose melphalan, with or without total body irradi- ation, as conditioning for HSCT (III).
3. The panel suggests that low-level laser therapy (wavelength around 632.8 nm) be used to prevent oral mucositis in patients undergoing radiotherapy, without concomitant chemotherapy, for head and neck cancer (III).
4. The panel suggests that transdermal fentanyl may be effective to treat pain due to oral mucositis in patients receiving conventional or high-dose chemotherapy, with or without total body irradiation (III).
5. The panel suggests that 2% morphine mouthwash may be effective to treat pain due to oral mucositis in patients receiving chemoradiation for head and neck cancer (III).
6. The panel suggests that 0.5% doxepin mouthwash may be effective to treat pain due to oral mucositis (IV).
7. The panel suggests that systemic zinc supplements administered orally may be of benefit to prevent oral mucositis in oral cancer patients receiving radiation therapy or chemoradiation (III).
RECOMMENDATIONS AGAINST AN INTERVENTION (ie, strong evidence indicates lack of effectiveness in the treatment setting listed):1. The panel recommends that PTA (polymyxin, tobramycin, amphotericin B) and BCoG (bacitracin, clotrimazole, gentamicin) antimicrobial lozenges and PTA paste not be used to prevent oral mucositis in patients receiving radiation therapy for head and neck cancer (II).
2. The panel recommends that iseganan antimicrobial mouthwash not be used to prevent oral mucositis in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (II), or in patients receiving radiation therapy or concomitant chemoradiation for head and neck cancer(II).
3. The panel recommends that sucralfate mouthwash not be used to prevent oral mucositis in patients receiving chemotherapy for cancer (I), or in patients receiving radiation therapy (I) or concomitant chemoradiation (II) for head and neck cancer.
4. The panel recommends that sucralfate mouthwash not be used to treat oral mucositis in patients receiving chemotherapy for cancer (I), or in patients receiving radiation therapy (II) for head and neck cancer.
5. The panel recommends that intravenous glutamine not be used to prevent oral mucositis in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (II).
SUGGESTIONS AGAINST AN INTERVENTION (ie, weaker evidence indicates lack of effectiveness in the treatment setting listed):1. The panel suggests that chlorhexidine mouthwash not be used to prevent oral mucositis in patients receiving radiation therapy for head and neck can- 2. The panel suggests that granulocyte-macrophage-colony-stimulating factor mouthwash not be used to prevent oral mucositis in patients receiving high-dose chemotherapy, for autologous or allogeneic stem cell transplantation (II).
3. The panel suggests that misoprostol mouthwash not be used to prevent oral mucositis in patients receiving radiation therapy for head and neck can- 4. The panel suggests that systemic pentoxifylline, administered orally, not be used to prevent oral mucositis in patients undergoing bone marrow trans- plantation (III).
5. The panel suggests that systemic pilocarpine, administered orally, not be used to prevent oral mucositis in patients receiving radiation therapy for head and neck cancer (III), or in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (II).
Abbreviations: Gy, grays; HSCT, hematopoietic stem cell transplantation; MASCC/ISOO, Multinational Association of Supportive Care in Cancer and Interna-tional Society of Oral Oncology; mW, milliwatt; nm, nanometers.
a Level of evidence for each guideline is in brackets after the guideline statement.
the MASCC=ISOO mucositis guidelines included a tion. A new suggestion was developed against the use recommendation for the use of benzydamine mouth- of misoprostol mouth rinse for the prevention of oral wash to prevent oral mucositis in patients with head mucositis in patients receiving H&NRT (Table 4).
and neck cancer who were receiving moderate-dose RT Although we reviewed 30 studies related to amifostine based on evidence from studies indicating a benefit in use for the prevention of oral mucositis in various set- radiation doses up to 50 grays in patients not receiving tings, no guideline was possible due to conflicting evi- concomitant chemotherapy. For the present systematic dence.24 Additional agents reviewed for which no review, the entire body of evidence, including 2 addi- guideline was possible included diphenhydramine, pros- tional studies in this patient population, was reviewed.
taglandin E2, immunoglobulins, corticosteroids, indo- These studies did not allow the extension of this rec- ommendation to patients receiving > 50 grays of radia- flurbiprofen, histamine, colchicine, and Placentrex.25 Antimicrobials, coating agents, anesthetics, and prevention of oral mucositis in patients receiving bolus dosing of 5-fluorouracil. A suggestion for the use of Several topical antimicrobial agents have been examined cryotherapy in patients receiving high-dose melphalan for the treatment of oral mucositis with either negative or as conditioning for HSCT was revised to clarify that mixed results. The evidence reviewed supported the con- this applies regardless of the use of concomitant total tinuation of a recommendation against the use of lozenges body irradiation. No guidelines related to cryotherapy containing polymyxin, tobramycin, and amphotericin were possible in other treatment settings due to inad- and bacitracin, clotrimazole, and gentamicin as well as equate evidence.28 polymyxin, tobramycin, and amphotericin paste for theprevention of oral mucositis in patients receiving Natural and miscellaneous agents H&NRT. A new recommendation was developed against Zinc is an essential trace element that is required for some the use of iseganan mouthwash in patients receiving tissue repair processes. Zinc also has an antioxidant effect.
HSCT or H&NRT. We reviewed 20 studies examining We reviewed 3 discrete studies testing zinc supplementa- the use of the mucosal coating agent sucralfate in various tion in patients receiving H&NRT, all of which found a settings. The evidence supported recommendations positive effect. A new suggestion was developed in favor of against the use of sucralfate for the prevention or treat- zinc in patients with oral cancer undergoing RT or che- ment of oral mucositis in patients receiving chemotherapy moradiation.36,37 However, there is some evidence indi- and also in patients receiving H&NRT. No guideline was cating that the use of antioxidants in smokers during possible for any anesthetic agent reviewed due to inad- H&NRT may reduce the efficacy of the RT.38 The evi- equate evidence. Guidelines were developed in favor of dence reviewed supported the continuation of a recom- the use of patient-controlled analgesia with morphine, mendation against the use of intravenous glutamine for transdermal fentanyl, morphine mouth rinse, and doxe- the prevention of oral mucositis in patients receiving pin mouth rinse for the management of oral mucositis high-dose chemotherapy for HSCT (Table 4). Due to pain in specific treatment settings (Table 4). Agents for inadequate and=or conflicting evidence, no guideline was which no guideline was possible included acyclovir, clari- possible in relation to other agents of natural origin thromycin, nystatin, kefir, povidone-iodine, fluconazole, reviewed, including glutamine in other treatment settings, sodium hyaluronate topical, tetracaine, dyclonine, MGI- the antioxidants vitamin A and E, honey, aloe vera, cha- 209 (with benzocaine), cocaine, amethocaine, capsaicin, momile, Kamillosan, Chinese herbals, indigowood root, methadone, ketamine, nortryptyline, and gabapentin.26 manuka and kanuka oils, oral gel wafers, Rhodiola algida,traumeel S, and Wobe-Mugos E.29 Laser and other light therapy Pilocarpine is a cholinergic agonist that stimulates We reviewed 24 studies evaluating the effects of laser or salivary secretion. The present systematic review sup- other light therapy on oral mucositis. The evidence sup- ported 2 new suggestions against the use of systemic pilo- ported the development of 2 new guidelines: a recom- carpine specifically for the prevention of oral mucositis: mendation in favor of low-level laser therapy (LLLT) for during H&NRT and in patients receiving high-dose the prevention of oral mucositis in patients receiving chemotherapy, with or without total body irradiation, high-dose chemotherapy for HSCT with or without before HSCT (Table 4). It should be noted that these total body irradiation,34 and a suggestion for LLLT in guidelines apply only to the use of pilocarpine for the pre- the prevention of oral mucositis in patients receiving vention of mucositis. Pilocarpine can be beneficial to H&NRT without concomitant chemotherapy (Table increase salivary flow, particularly in patients treated with 4).35 No guideline was possible related to the use of H&NRT who are experiencing hyposalivation. The evi- LLLT in any other treatment setting, or related to the dence also supported the continuation of a suggestion use of other emerging light modalities such as light- against the use of the phosphodiesterase inhibitor pentoxi- emitting diodes and visible light.27 fylline for the prevention of oral mucositis in patientsundergoing bone marrow transplantation. Due to inad- equate and=or conflicting evidence, no guideline was pos- A total of 22 eligible studies examined the placement sible in relation to other miscellaneous agents=modalities of ice chips in the mouth during the delivery of chem- reviewed including allopurinol, midline mucosa-sparing otherapy. The evidence supported the continuation of radiation blocks, payayor, timing of RT, bethanechol, a recommendation for the use of cryotherapy for the chewing gum, propantheline, and tetrachlorodecaoxide.30 MASCC=ISOO Mucositis Guidelines/Lalla et al a protective coating can protect the exposed nerve endings To ensure consistency in the application of review criteria and thus reduce pain, the data regarding sucralfate did not and guideline development, we reviewed the entire body provide support for such a beneficial effect. Recently, of evidence for each intervention, not just the new publi- several proprietary mucosal coating agents have been mar- cations since the last guidelines update. Our methodology keted as devices for oral mucositis. Our literature search provides confidence that the evaluation of the literature identified only 1 eligible published study of one of these and subsequent guidelines development across various agents, on the basis of which no guideline was possible.
interventions are based on uniform and transparent crite- The goal of such clinical practice guidelines is to ria. The present systematic review resulted in the develop- improve clinical outcomes by facilitating evidence-based ment of 16 new guidelines for or against the use of various care. To achieve this, it is important for the guidelines to interventions in specific treatment settings. Thus, the clin- be widely disseminated and, most importantly, adopted ical usefulness of these guidelines should continue to into routine practice. Strategies to facilitate guidelines increase. However, it is recognized that there are many uptake can include open-access publication of the clinical situations faced by the practitioner that are not guidelines-related articles and translations into other lan- addressed by these guidelines, due to inadequate and=or guages, as well as online resources, including a version conflicting evidence. This constitutes a limitation of such suitable for viewing on a smartphone. MASCC=ISOO is strictly evidence-based guidelines. Therefore, symptom also in discussions with relevant organizations to determine management (such as pain control and nutritional sup- how we can work together to minimize duplication of port) continues to be an important part of any mucositis effort and promote the clinical use of supportive care guide- lines. The motto of the MASCC=ISOO is "Supportive An important new guideline developed in the pres- care makes excellent cancer care possible." In keeping with ent update is the new recommendation (based on level II this, MASCC=ISOO is committed to enhancing the sup- evidence) in favor of LLLT for the prevention of oral portive care of oncology patients, with the goal of improv- mucositis in patients receiving HSCT conditioned with ing the patient experience and allowing for the delivery of high-dose chemotherapy. In addition, a new suggestion optimal cancer treatment.
(based on level III evidence) was developed in favor ofLLLT for the prevention of oral mucositis in patients undergoing H&NRT, without concomitant chemother- The Guidelines Update Meeting was supported by BioAlliance apy. However, patients now typically receive H&NRT Pharma and Helsinn Healthcare, SA. No honorarium or travel sup- with concomitant chemotherapy, and no guideline was port was provided to the reviewers for participation in the guide- possible in that population due to inadequate evidence.
lines update effort. No industry representatives attended the Although the majority of studies of LLLT demonstrate a guidelines update meeting or participated in the guidelines updateeffort in any way.
benefit, the variable quality of the studies and the widevariation in laser parameters used complicates the evalua- CONFLICT OF INTEREST DISCLOSURES tion of the evidence.27 Animal studies indicate that LLLTpromotes wound healing and has an antiinflammatory Dr. Lalla received grants from Evolife Laboratories and BioAl-liance Pharma, as well as personal fees from iNova Pharmaceuti- effect.39,40 Barriers to the acceptance of this technology cals, Sucampo, Cangene, and Ingalpharma outside of the current include the cost of laser equipment and the labor- study. Dr. Elting received a grant from Helsinn Research funding intensiveness of this modality (because many regimens for work outside of the current study. Dr. Epstein received a involve the daily treatment of patients). In addition, a mo- grant from 3M-Riker Canada for participation in a phase 3 study dality such as LLLT can only act on mucosa by direct con- related to the current work. Dr. Keefe received grants from Hel-sinn Healthcare, GlaxoSmithKline, and Nestec for work outside tact. It will not be useful for areas such as pharyngeal, of the current study. Dr. Sonis is an employee of Biomodels laryngeal, or esophageal mucosa, which are also at risk of LLC, has acted as a consultant for Clinical Assistance Programs, mucositis in patients receiving H&NRT, but are difficult acted as a member of the advisory board for Actogenix, acted as to directly access.
an advisor for Avaxia, acted as a biomodels consultant for BioAl- Sucralfate is a generically available mucosal coating liance, acted as a member of the advisory board for Galera, acted agent. We reviewed 20 studies that clearly demonstrated a as a consultant for Izun, acted as an advisor for PolyMedix, actedas a biomodels consultant for Piramal, received fees as a founder- lack of benefit for sucralfate in the prevention or treat- consultant for Inform Genomics, acted as a member of the advi- ment of oral mucositis secondary to chemotherapy or sory boards of Synedgen and Soligenix, acted as a member of the RT.26 Although it appears theoretically feasible that such advisory board of and as a consultant for Pfizer, acted as a member of the advisory board of Reata, acted as a consultant for 18. Bowen JM, Elad S, Hutchins RD, Lalla RV;Mucositis Study Group Access, and acted as a biomodel consultant for Novartis and of the Multinational Association of Supportive Care in Cancer-International Society of Oral Oncology. Methodology for the Merck for work outside of the current study. Dr. Sonis also holds MASCC=ISOO Mucositis Clinical Practice Guidelines Update. Sup- the following patents that are broadly relevant to the current port Care Cancer. 2013;21:303-308.
work: US Patent 6458777, US Patent 6663850, US Patent 19. Elad S, Bowen J, Zadik Y, Lalla RV;Mucositis Study Group of the 6713463, US Patent 6841578B2, and US Patent 7297123.
Multinational Association of Supportive Care in Cancer=Interna-tional MASCC=ISOO Clinical Practice Guidelines for Mucositis: consider- ations underlying the process. Support Care Cancer. 2013;21:309-312.
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21. Somerfield MR, Padberg JR, Pfister DG, et al. ASCO clinical prac- 2. Vera-Llonch M, Oster G, Ford CM, Lu J, Sonis S. Oral mucositis tice guidelines: process, progress, pitfalls, and prospects. Class Pap and outcomes of allogeneic hematopoietic stem-cell transplantation Curr Comments. 2000;4:881-886.
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22. Gibson RJ, Keefe DM, Lalla RV, et al. Systematic review of agents for the management of gastrointestinal mucositis in cancer patients.
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Grochow LB. Patterns of mucositis and pain in patients receiving 24. Nicolatou-Galitis O, Sarri T, Bowen J, et al. Systematic review of preparative chemotherapy and bone marrow transplantation. Oncol amifostine for the management of oral mucositis in cancer patients.
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29. Yarom N, Ariyawardana A, Hovan A, et al. Systematic review of nat- 9. Elting LS, Cooksley CD, Chambers MS, Garden AS. Risk, out- ural agents for the management of oral mucositis in cancer patients.
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31. McGuire DB, Fulton JS, Park J, et al. Systematic review of basic 11. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer. 2004;4: oral care for the management of oral mucositis in cancer patients.
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12. Al-Dasooqi N, Sonis ST, Bowen JM, et al. Emerging evidence on 32. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral muco- the pathobiology of mucositis. Support Care Cancer. 2013;21:2075- sitis after intensive therapy for hematologic cancers. N Engl J Med.
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vitamin supplementation and cigarette smoking during radiation 40. Lopes NN, Plapler H, Lalla RV, et al. Effects of low-level laser therapy therapy in relation to long-term effects on recurrence and mortality: on collagen expression and neutrophil infiltrate in 5-fluorouracil- a randomized trial among head and neck cancer patients. Int J Can- induced oral mucositis in hamsters. Lasers Surg Med. 2010;42:546-
Effects of dietary melatonin supplementation on total serum nitrites and antioxidant capacity of late gestating Holstein heifers B. O. Fleming, K. E. Brockus, C. G. Hart, C. O. Lemley Department of Animal and Dairy Sciences, Mississippi State University The hormone melatonin was first purified from a bovine pineal gland extract in 1958 (Chowdhury et al., 2008). Being a lipophilic molecule, it is able to easily pass through many