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Supportive Care in Cancer

, Volume 27, Issue 10, pp 3933–3948 | Cite as

Development of the MASCC/ISOO clinical practice guidelines for mucositis: an overview of the methods

  • Vinisha RannaEmail author
  • Karis Kin Fong Cheng
  • Daniel A. Castillo
  • Lorraine Porcello
  • Anusha Vaddi
  • Rajesh V. Lalla
  • Paolo Bossi
  • Sharon Elad
  • On behalf of the Mucositis Study group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO)
Special Article

Abstract

New studies and literature continue to emerge on the management of mucositis secondary to cancer therapy. The evidence-based clinical practice guidelines for mucositis were first published in 2004 and updated in 2007 and 2014 by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The existing 2014 guidelines for mucositis are being updated in line with new literature to inform clinical practice. This paper describes the materials and methods employed for the comprehensive updates to the guidelines for managing mucositis.

Keywords

Mucositis Cancer Cancer therapy Guidelines Methods Data management Systematic review 

Introduction

The Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) conducts periodic systematic reviews to update the clinical practice guidelines for the management of mucositis secondary to cancer therapy, first published in 2004 [1, 2]. The guidelines were first updated in 2007 [3] and then in 2014 [4]. Since the last update in 2014 which included literature published until December 2010, numerous studies addressing the management of mucositis have been published, which justified an update of the systematic review and of the MASCC/ISOO clinical practice guidelines for the management of mucositis. This paper describes the process and methods used for systematic review and comprehensive updates to the evidence-based mucositis guideline by the Mucositis Study Group of MASCC/ISOO in 2016–2018. The findings of this review will be published in a series of subsequent articles.

Previous papers [5, 6] published by the group set out the systematic review approach underlying the search strategies, databases used, data synthesis, and criteria for evaluation of scientific evidence and allocating the level of evidence. In the current update, similar methods have been used with some modifications. Specifically, changes are noted in the following sections below: literature searches; considerations related to the effectiveness; allocating a level of evidence and categories used to classify guidelines; logistics of the review process; and platform for online sharing. This enabled coordinating and sharing data to merge previous evidence with newly published data. This process was used to create, modify, support, or rescind clinical practical guidelines.

Approach of the systematic review

The approach of systematic review was critical in designing the methods of the review and thus guidelines updates.

The current review attempted to classify the literature on mucositis using a grading system for different study designs. This included all published studies regardless of study designs. The evidence was stratified and weighed based on the robustness of the study design and was therefore qualitative in nature. Randomized controlled trials (RCTs) had the most significant contribution. Evidence from less robustly designed studies supported or challenged the findings of the RCT. This method ensured that all possible data were considered in the guidelines development process. This was suitable considering that new techniques and interventions continue to be developed for the management of mucositis, many of which are studied in non-RCTs. If a purely quantitative approach was to be used, these studies would be missed. As the aim of the MSG is to provide a graded compilation of the strategies available for the management of mucositis, a qualitative approach was deemed the most suitable for systematic review of literature on management.

Scope of the review

Due to the broad scope of interventions for the management of mucositis, the review was divided into 9 sections, 8 interventional sections, and 1 non-interventional section (pathogenesis) as follows:
  1. 1.

    Basic oral care

     
  2. 2.

    Growth factors and cytokines

     
  3. 3.

    Anti-inflammatory

     
  4. 4.

    Antimicrobials, coating agents, anesthetics, and analgesics

     
  5. 5.

    Natural and miscellaneous agents

     
  6. 6.

    Cryotherapy

     
  7. 7.

    Gastrointestinal

     
  8. 8.

    Laser and other light therapy

     

A ninth section was dedicated to pathogenesis. This section systematically reviewed the literature about the pathogenesis of mucositis.

The GI section includes all type of interventions for GI mucositis, and the remaining sections are specific for interventions for oral mucositis. Similar categories of interventions have also been adopted by the Cochrane Group for their systematic reviews on interventions for oral mucositis.

Within this scope, the literature search followed certain inclusion and exclusion criteria.

Inclusion criteria:
  1. 1.

    Published clinical research papers testing an intervention for mucositis, or meta-analyses of such studies

     
  2. 2.

    English language

     
  3. 3.

    Published in a peer-reviewed journal

     
  4. 4.

    Articles on frequently used medical databases (PubMed (MEDLINE) as a basis) from January 1, 2011 until June 30, 2016

     
  5. 5.

    Human subjects, of all age groups

     
Exclusion criteria:
  1. 1.

    Papers that do not report the effects of an intervention on mucositis or on related outcomes such as mucositis-associated pain

     
  2. 2.

    Animal studies or in vitro studies

     
  3. 3.

    Papers published in a language other than English

     
  4. 4.

    Papers not studying preventive or therapeutic impact on mucositis as a primary outcome (i.e., tumor efficacy or drug reports)

     

Database search strategy

In order to begin the search for papers, keywords from the previous guidelines were used. These were augmented by keywords sent by members of the MSG. In addition, a call for keywords was publicly posted on the MASCC/ISOO website and society newsletters to include contributions from all members. To avoid any potential bias, generic names were requested, and for products described by trade names, the active ingredient was to be mentioned along with the disclosure of any conflict of interest. See Table 1 for the list of keywords used for this guidelines update.
Table 1

List of keywords used for the literature review

Basic oral care/good clinical practice

Growth factors and cytokines

Anti-inflammatory agents

Antimicrobials, coating agents, anesthetics, analgesics

Natural therapies and miscellaneous

Pathogenesis

Lasers

GI

Artificial saliva

ALD518

Amifostine

Acyclovir

Allopurinol

Bayesian network

CO2

AMP-18

Baking soda

Amino acids

Aminosalicylic acid

Adhesive

Aloe

Epigenetics

Diode

Dietary constituents

Bland rinse

ATL 104

Amlexanox

Alfentanil

Aloe vera

Gut-brain axis

GaAlAs

Dietary supplements

Calcium phosphate

Carcinoembryonic antigen cell adhesion molecule 1

Anti-inflammatory

Aluminum hydroxide

Alternative

Immunotherapy

He-Ne

Exercise

Calculus

Colony-stimulating factors

Anti-TNF

Amphotericin B

Azulene

Microarray

Infrared

Ginger

Caphosol

Cytokines

Anti-tumor necrosis factor

Analgesia

Bee

Microbiome sequencing

InGaAlP

Glucagon-like peptide-1

Caregiver education

Epidermal growth factor

Aspirin

Analgesic

Bethanechol

Microbiota

InGaAs

Glucagon-like peptide-2

Chlorhexidine

Erythropoietin

Benadryl

Antiacid

Calcium phosphate

miRNA

Laser

Herbs

Dental

Fibroblast growth factors

Benzydamine

Antibiotic

Cg53135 (fgf-20) (a protein with in vitro mitogenic activity on epithelial and mesenchymal cells)

Model

LED

Inulin

Dental care

Ghrelin

Betamethasone

Anti-infective

Chamomile

mTOR

Light therapy

Laxative

Dental cleaning

Glucagon-like peptide 2

Celecoxib

Aqua oral

Chewing gum

Neuroimmune

Light-emitting diode

Microbiome sequencing

Dental floss

Glutathione

Corticosteroid

Benzocaine

Chinese medicine

Personalized

Low-level laser therapy

Oxycodone-naloxone

Dentist

Granulocyte colony-stimulating factor

Dexamethasone

Buprenorphine

Clonidine

Pharmacogenetics

Low-level laser therapy

Peppermint

Education

Granulocyte-macrophage colony-stimulating factor

Diphenhydramine

Clarithromycin

Complementary

Pharmacogenomics

Photobiomodulation

Prebiotics

Family education

Hepatocyte growth factor

Ethylol

Clonidine

Curcumin

Precision

Phototherapy

Probiotics

Flossing

IL-11

Flurbiprofen

Coating agent

Doxepin

Prediction

Visible light

Resistant starch

Fluoridated

IL-3

Histamine

Diclosan

Emu oil

Risk

 

Rooibos

Fluoride

IL-6

Human placental extract (placentrex) (Kaushal 2001)

Doxepin

Enzyme

Selection

 

Short-chain fatty acids

Hygienist

Immunologic factors

Hydrocortisone

Fentanyl

Folate

SNPs

 

Stool softener

Lip balm

Insulin-like growth factor

Ibuprofen

Film

Folic acid

  

Targin

Mixed medication mouthwashes

Interleukins

Indomethacin

Fluconazole

Folinic acid

  

Teas

Moisturizer

Intestinal trefoil factor

Infliximab

Gelclair

Glutamine

   

Mouthcare

Keratinocyte growth factor

Irsogladine

Hydromorphone

Glycerin

   

Mouthcare protocol/regimen

Lactoferrin

Lactermin

Ib-367

Gum

   

Mouthwash

Macrophage colony-stimulating factor

Lactoferrin

Iseganan

Herbal

   

Multidisciplinary

Milk-derived growth factor extract

Mesalazine

Kefir

Homeopathic

   

Non-medicated rinse

Milk-derived protein

Misoprostol

Keopectate

Honey

   

Nurse

Palifermin

N-Acetyl cysteine

Ketamine

Hydrolytic enzyme

   

Nursing

Platelet-derived growth factor

Non-steroidal anti-inflammatory agents

Lidocaine

Intestinal trefoil factor

   

Nursing oral care/oral hygiene/mouthcare protocol/regimen

PV701

NSAIDS

Local anesthetic

Jelly

   

Oral bandage

Repifermin

Orgotein

“Magic” or “miracle” rinses

Lactoferrin

   

Oral care

Somatomedins

Prednisone

Magnesium hydroxide

L-glutamine

   

Oral care protocol/regimen

Teduglutide

Prostaglandin

Methadone

Licorice

   

Oral decontamination

TGF-b

RK-02-02

Midline mucosa sparing blocks

Mf 5232 (mucotrol), a concentrated oral polyherbal gel wafer formulation

   

Oral hygiene

Thrombopoietin

Salicylic acid

Morphine

Milk

   

Oral hygiene protocol/regimen

TNF

Steroid

Mouth rinse or mouthwash

Milk growth factors

   

Oral rinse

TNF alpha

Thalidomide

Mucoadhesive

Milk-derived protein extract

   

Oral/mouth/mucositis assessment

Transforming growth factors

TNF antibody

MuGard

Multivitamin

   

Oral/mouth/mucositis examination

Vascular endothelial growth factor

TNF inhibitor

Neuropathic

Natural

   

Patient education

Velafermin

Tumor necrosis factor/TNF

Nociceptive

Payayor

   

Plaque

Whey protein

 

Patient controlled

Pentoxifylline

   

Provider education

  

Polymyxin

Pilocarpine

   

Saline

  

Polyvinylpyrrolidone

Polaprezinc

   

Scaling

  

Povidone-iodine

Propantheline anticholinergic

   

Sodium bicarbonate

  

Protegrin

Propolis

   

Staff education

  

Sucralfate

PV-701

   

Superoxide dismutase (SOD)

  

Systemic medications

Radiation: morning versus evening

   

Toothbrush

  

Tetracaine

Reduction of mtx in anti-gvhd prophylactic protocol before hsct

   

Toothbrushing

  

Tetracycline

Retinoid

   

Toothpaste

  

Tobramycin

Rose

   

Water

  

Topical

Shenqi-fanghou

   
   

Ulcerease

Sodium hyaluronate

   
   

Xylocaine

Suction cups

   
   

Zilactin

Tetrachlorodecaoxide (tcdo) (oxoferin)

   
   

Zinc*

Traumeel

   
    

Tretinoin

   
    

Vitamin

   
    

Wax

   
    

Xanthan

   
    

Yangygin-humo decoctalion

   
    

Yeast

   

Zinc was moved to the natural and misc. section during the paper review process

Cryotherapy keywords are listed in Table 2 due to the small number of keywords

Literature searches

Literature search strategies were developed with assistance from two medical research librarians.

The medical librarians developed an initial PubMed scoping search strategy for each section, which was shared with the section heads who identified additional articles not captured within the search. Using the Yale MeSH Analyzer, the librarians identified additional keywords that they sent to the section heads for consideration [7]. Once the keyword lists were confirmed, the librarians developed the final PubMed search strategy for each section. Each search strategy included similar keywords for cancer, oral anatomy, and mucositis, using a “modular” strategy to ensure that each search was conducted consistently for each section. Limits were applied to each section according to the inclusion and excluding criteria listed above.

Following this, the librarians translated the PubMed search strategy for all sections into searches appropriate for Web of Science (WoS). The Natural and Miscellaneous was the section producing the largest number of papers from the PubMed and WoS searches. We therefore piloted the search strategy for EMBASE with this section. No additional relevant papers were identified in the EMBASE search for Natural and Miscellaneous Remedies section. Therefore, it was decided that the EMBASE search would not be conducted for this project.

See Table 2 for the full PubMed strategy. Tables 3 and 4 contain the final search statements used in PubMed and WoS, respectively (available online).
Table 2

Modules used for the search algorithm

 

Statement

Search strategy

Module

Anatomical—all sections on oral mucositis

(oral OR oropharyngeal OR oropharynx OR mouth)

Anatomical—GI section

(GI OR Gastrointestinal OR (mucous membrane*) OR mucosa*)

Anatomical—pathogenesis

(oral OR oropharyngeal OR oropharynx OR mouth OR GI OR Gastrointestinal OR (mucous membrane*) OR mucosa*)

Cancer

cancer[sb]

Mucositis—all sections on oral mucositis

(mucositis OR stomatitis OR oral mucous membrane OR oral mucosa* OR oral ulcer* OR oropharyngitis)

Mucositis—GI section

(mucositis OR (mucosal injury) OR colitis OR enteritis OR ileitis OR enterocolitis OR esophagitis OR gastritis OR proctitis)

Filter 1

((“2011/01/01”[PDat]: “2016/06/30”[PDat]) AND English[lang])

Filter 2

NOT (case report OR Review[publication type])

Filter 3

NOT (“Animals”[Mesh] NOT (“Animals”[Mesh] AND “Humans”[Mesh]))

Section: antimicrobials, coating agents, anesthetics, and analgesics

((Magic rinse) OR (Miracle rinse) OR Acyclovir OR Adhesive OR Alfentanil OR (aluminum hydroxide) OR (amphotericin B) OR analgesia OR Analgesic OR Antiacid OR antibiotic OR (anti-infective) OR (aqua oral) OR benzocaine OR buprenorphine OR clarithromycin OR clonidine OR coating agent OR Diclosan OR Doxepin OR Fentanyl OR Film OR fluconazole OR Gelclair OR Hydromorphone OR (IB-367) OR Iseganan OR Kefir OR Kaopectate OR Ketamine OR lidocaine OR (Local anesthetic) OR (Magnesium hydroxide) OR Methadone OR Morphine OR Mouthrinse OR Mouthwash OR mucoadhesive OR MuGard OR (Patient controlled) OR polymyxin OR Polyvinylpyrrolidone OR (povidone-iodine) OR Protegrin OR sucralfate OR Tetracaine OR tetracycline OR tobramycin OR Topical OR (Ulcer ease) OR xylocaine OR zilactin OR Zinc)

Section: anti-inflammatories

(Anti-inflammatory Agents OR Aminosalicylic acid OR Amlexanox OR Anti-inflammatory OR antiinflammatory OR Anti-TNF OR Anti-tumor necrosis factor OR Aspirin OR Benadryl OR Benzydamine OR Betamethasone OR Celecoxib OR Corticosteroid OR Dexamethasone OR Diphenhydramine OR Ethylol OR Flurbiprofen OR Histamine OR Human placental extract OR Hydrocortisone OR Ibuprofen OR Indomethacin OR Infliximab OR Irsogladine OR Lactermin OR Lactoferrin OR Mesalazine OR Misoprostol OR N-Acetyl cysteine OR Non-steroidal anti-inflammatory OR NSAIDS OR Orgotein OR placentrex OR Prednisone OR Prostaglandin OR RK-02-02 OR Salicylic acid OR Steroid OR Thalidomide OR TNF OR TNF antibody OR anti-TNF therapy OR TNF inhibitor OR Tumor necrosis factor)

Section: basic oral care

((Basic oral care) OR (Oral Care) OR (Artificial Saliva) OR Assessment OR (Baking soda) OR (Bland Rinse) OR Brush* OR (Calcium Phosphate) OR Calculus OR Caphosol OR (Caregiver education) OR Chlorhexidine OR Dental OR (dental care) OR (Dental cleaning) OR (Dental Floss) OR Dentist OR Education OR Examination OR (Family education) OR Floss* OR Fluorid* OR Hygiene OR Hygienist OR (Lip balm) OR (Mixed Medication Mouthwash*) OR Moisturizer OR Mouthcare OR (Mouth Care) OR Mouthwash OR Multidisciplinary OR (Non-medicated rinse) OR Nurs* OR (Oral bandag*) OR (Oral Care) OR (Oral Care Regimen) OR (Oral decontamination) OR (Oral Hygiene) OR (Patient education) OR Plaque OR (Provider education) OR Rinse OR Saline OR Scaling OR (Sodium bicarbonate) OR (Staff education) OR (Superoxide dismutase) OR Toothbrush OR Toothbrush* OR Toothpast* OR Water)

Section: cryotherapy

(Cryotherapy OR Cryotherap* OR Cold OR (Cold Therap*) OR (Cold Temperature*) OR (Cold Water*) OR Freeze OR Freezing OR Froze OR Frozen OR Ice OR (ice water*) OR Icy)

Section: growth factors and cytokines

((ATL 104) OR (Colony-Stimulating Factors) OR (Cytokines) OR (Epidermal Growth Factor) OR (Fibroblast Growth Factors) OR (Glucagon-like Peptide 2) OR (Granulocyte Colony-Stimulating Factor) OR (Granulocyte-Macrophage Colony-Stimulating Factor) OR (IL-11) OR (IL-3) OR (Insulin-like Growth Factor) OR (Interleukins) OR (Keratinocyte Growth Factor) OR (Lactoferrin) OR (Macrophage Colony-Stimulating Factor) OR (Palifermin) OR (Repifermin) OR (TGF-b) OR (TNF) OR (TNF Alpha) OR (Transforming Growth Factors) OR (Velafermin) OR (Whey Protein) OR (Erythropoietin) OR (Thrombopoietin) OR (Carcinoembryonic Antigen Cell Adhesion Molecule 1) OR (Ghrelin) OR (Glutathione) OR (Hepatocyte Growth Factor) OR (Intestinal Trefoil Factor) OR (Milk-derived Growth Factor Extract) OR (Milk-derived Protein) OR (Platelet-derived Growth Factor) OR (PV701) OR (Somatomedins) OR (Teduglutide) OR (Vascular Endothelial Growth Factor) OR (Amino Acids) OR (Immunologic Factors) OR (ALD518 IL-6))

Section: lasers

(Lasers OR Laser OR LLLT OR (Low level laser therapy) OR (Light therapy) OR Phototherapy OR (Low-level laser) OR LED OR (Light-emitting diode) OR Diode OR (Visible light) OR (He-Ne) OR InGaAlP OR GaAlAs OR InGaAs OR CO2 OR (Infra-red) OR Photobiomodulation))

Section: natural and miscellaneous remedies

(natural remedies OR natural remedy OR natural therapeutic OR natural therapies OR natural therapy OR allopurinol OR aloe OR aloe vera OR alternative OR azelastine hydrochloride OR azulene OR bee OR beta carotene OR bethanechol OR calcium phosphate OR capsaicin OR fgf 20 OR cg53135 OR chamomile OR chewing gum OR chinese medicine OR chitosan OR clonidine OR colchicine OR complementary OR curcumin OR doxepin OR dyclonine OR emu oil OR enzyme OR folate OR folic acid OR folinic acid OR gabapentin OR glutamine OR glycerin OR gum OR herbal OR homeopathic OR honey OR human placental extract OR placentrex OR humidification OR hydrolytic enzyme OR hyperbaric oxygen OR intestinal trefoil factor OR jelly OR lactobacillus OR lactoferrin OR l glutamine OR licorice OR aluminum hydroxide OR magnesium hydroxide OR manuka oil OR anuka OR milk OR mucotrol OR multivitamin OR natural OR payayor OR pentoxifylline OR pilocarpine OR polaprezinc OR propantheline OR propolis OR pv 701 OR radiation OR retinoid OR rhodiola algida OR rose OR shenqi OR collagen OR amino acid OR amino acids OR sodium hyaluronate OR suction cups OR tetrachlorodecaoxide OR tcdo OR oxoferin OR traumeel OR tretinoin OR vitamin OR vitamin a OR vitamin e OR wax OR wobe mugos OR wobe mugos e OR xathan OR yeast)

Section: gastrotintestinal (GI)

((Glucagon-like peptide-1) OR (Glucagon-like peptide-2) OR (Short chain fatty acids) OR (microbiome sequencing) OR Inulin OR Prebiotics OR Probiotics OR (Resistant starch) OR (Dietary constituents) OR (Dietary supplements) OR Ginger OR Peppermint OR Teas OR Rooibos OR Herbs OR Exercise OR (Stool softener) OR Laxative OR (Oxycodone-naloxone) OR Targin OR (AMP-18) OR (Short chain fatty acids) OR diarrhea)

Pathogenesis—oral

(Prediction OR Microbiota OR Personalised OR Precision OR Pharmacogenomics OR Prediction OR Selection OR Immunotherapy OR mTOR OR Gut-brain axis OR Epigenetics OR miRNA OR Microbiome OR Sequencing OR Risk OR Microarray OR (Bayesian network) OR SNPs OR Pharmacogenetics OR Model OR Neuroimmune)

Pathogenesis—GI

(Microbiota OR Immunotherapy OR mTOR OR Gut-brain axis OR Epigenetics OR miRNA OR Microbiome OR Sequencing OR Microarray OR Model OR Neuroimmune)

Complete section statement included a combination of the following modules

Antimicrobials, coating agents, anesthetics, and analgesics

• Anatomical—all sections on oral mucositis

• Cancer

• Mucositis—all sections on oral mucositis

• Filter 1 + 2 + 3

• Section: antimicrobials, coating agents, anesthetics, and analgesics

Anti-inflammatories

• Anatomical—all sections on oral mucositis

• Cancer

• Mucositis—all sections on oral mucositis

• Filter 1 + 2 + 3

• Section: anti-inflammatories

Basic oral care

• Anatomical—all sections on oral mucositis

• Cancer

• Mucositis—all sections on oral mucositis

• Filter 1 + 2 + 3

• Section: basic oral care

Cryotherapy

• Anatomical—all sections on oral mucositis

• Cancer

• Mucositis—all sections on oral mucositis

• Filter 1 + 2 + 3

• Section: cryotherapy

Growth factors and cytokines

• Anatomical—all sections on oral mucositis

• Cancer

• Mucositis—all sections on oral mucositis

• Filter 1 + 2 + 3

• Section: growth factors and cytokines

Lasers

• Anatomical—all sections on oral mucositis

• Cancer

• Mucositis—all sections on oral mucositis

• Filter 1 + 2 + 3

• Section: lasers

Natural and miscellaneous remedies

• Anatomical—all sections on oral mucositis

• Cancer

• Mucositis—all sections on oral mucositis

• Filter 1 + 2 + 3

• Section: natural and miscellaneous remedies

Gastrotintestinal (GI)

• Anatomical—GI section

• Cancer

• Mucositis—GI section

• Filter 1 + 2 + 3

• Section: gastrointestinal (GI)

Pathogenesis

• Anatomical—all sections on oral mucositis

• Cancer

• Mucositis—all sections on oral mucositis

• Filter 1 + 2 + 3

• Section: pathogenesis—GI

• Section: pathogenesis—oral

Table 3

Complete section statement PubMed

Section

PubMed statement

Antimicrobials, coating agents, anesthetics, and analgesics

(mucositis OR stomatitis OR oral mucous membrane OR oral mucosa* OR oral ulcer* OR oropharyngitis) AND cancer[sb] AND (oral OR oropharyngeal OR oropharynx OR mouth) AND ((Magic rinse) OR (Miracle rinse) OR Acyclovir OR Adhesive OR Alfentanil OR (aluminum hydroxide) OR (amphotericin B) OR analgesia OR Analgesic OR Antiacid OR antibiotic OR (anti-infective) OR (aqua oral) OR benzocaine OR buprenorphine OR clarithromycin OR clonidine OR coating agent OR Diclosan OR Doxepin OR Fentanyl OR Film OR fluconazole OR Gelclair OR Hydromorphone OR (IB-367) OR Iseganan OR Kefir OR Kaopectate OR Ketamine OR lidocaine OR (Local anesthetic) OR (Magnesium hydroxide) OR Methadone OR Morphine OR Mouthrinse OR Mouthwash OR mucoadhesive OR MuGard OR (Patient controlled) OR polymyxin OR Polyvinylpyrrolidone OR (povidone-iodine) OR Protegrin OR sucralfate OR Tetracaine OR tetracycline OR tobramycin OR Topical OR (Ulcer ease) OR xylocaine OR zilactin OR Zinc) NOT (case report OR Review[publication type]) NOT (“Animals”[Mesh] NOT (“Animals”[Mesh] AND “Humans”[Mesh])) AND ((“2011/01/01”[PDat]: “2016/06/30”[PDat]) AND English[lang])

Anti-inflammatories

(mucositis OR stomatitis OR oral mucous membrane OR oral mucosa* OR oral ulcer* OR oropharyngitis) AND cancer[sb] AND (oral OR oropharyngeal OR oropharynx OR mouth) AND (Anti-inflammatory Agents OR Aminosalicylic acid OR Amlexanox OR Anti-inflammatory OR antiinflammatory OR Anti-TNF OR Anti-tumor necrosis factor OR Aspirin OR Benadryl OR Benzydamine OR Betamethasone OR Celecoxib OR Corticosteroid OR Dexamethasone OR Diphenhydramine OR Ethylol OR Flurbiprofen OR Histamine OR Human placental extract OR Hydrocortisone OR Ibuprofen OR Indomethacin OR Infliximab OR Irsogladine OR Lactermin OR Lactoferrin OR Mesalazine OR Misoprostol OR N-Acetyl cysteine OR Non-steroidal anti-inflammatory OR NSAIDS OR Orgotein OR placentrex OR Prednisone OR Prostaglandin OR RK-02-02 OR Salicylic acid OR Steroid OR Thalidomide OR TNF OR TNF antibody OR anti-TNF therapy OR TNF inhibitor OR Tumor necrosis factor) NOT (case report OR Review[publication type]) NOT (“Animals”[Mesh] NOT (“Animals”[Mesh] AND “Humans”[Mesh])) AND ((“2011/01/01”[PDat]: “2016/06/30”[PDat]) AND English[lang])

Basic oral care

(mucositis OR stomatitis OR oral mucous membrane OR oral mucosa* OR oral ulcer* OR oropharyngitis) AND cancer[sb] AND (oral OR oropharyngeal OR oropharynx OR mouth) AND ((Basic oral care) OR (Oral Care) OR (Artificial Saliva) OR Assessment OR (Baking soda) OR (Bland Rinse) OR Brush* OR (Calcium Phosphate) OR Calculus OR Caphosol OR (Caregiver education) OR Chlorhexidine OR Dental OR (dental care) OR (Dental cleaning) OR (Dental Floss) OR Dentist OR Education OR Examination OR (Family education) OR Floss* OR Fluorid* OR Hygiene OR Hygienist OR (Lip balm) OR (Mixed Medication Mouthwash*) OR Moisturizer OR Mouthcare OR (Mouth Care) OR Mouthwash OR Multidisciplinary OR (Non-medicated rinse) OR Nurs* OR (Oral bandag*) OR (Oral Care) OR (Oral Care Regimen) OR (Oral decontamination) OR (Oral Hygiene) OR (Patient education) OR Plaque OR (Provider education) OR Rinse OR Saline OR Scaling OR (Sodium bicarbonate) OR (Staff education) OR (Superoxide dismutase) OR Toothbrush OR Toothbrush* OR Toothpast* OR Water) NOT (case report OR Review[publication type]) NOT (“Animals”[Mesh] NOT (“Animals”[Mesh] AND “Humans”[Mesh])) AND ((“2011/01/01”[PDat]: “2016/06/30”[PDat]) AND English[lang])

Cryotherapy

(mucositis OR stomatitis OR oral mucous membrane OR oral mucosa* OR oral ulcer* OR oropharyngitis) AND cancer[sb] AND (oral OR oropharyngeal OR oropharynx OR mouth) AND (Cryotherapy OR Cryotherap* OR Cold OR (Cold Therap*) OR (Cold Temperature*) OR (Cold Water*) OR Freeze OR Freezing OR Froze OR Frozen OR Ice OR (ice water*) OR Icy) NOT (case report OR Review[publication type]) NOT (“Animals”[Mesh] NOT (“Animals”[Mesh] AND “Humans”[Mesh])) AND ((“2011/01/01”[PDat]: “2016/06/30”[PDat]) AND English[lang])

Growth factors and cytokines

(mucositis OR stomatitis OR oral mucous membrane OR oral mucosa* OR oral ulcer* OR oropharyngitis) AND cancer[sb] AND (oral OR oropharyngeal OR oropharynx OR mouth) AND ((ATL 104) OR (Colony-Stimulating Factors) OR (Cytokines) OR (Epidermal Growth Factor) OR (Fibroblast Growth Factors) OR (Glucagon-like Peptide 2) OR (Granulocyte Colony-Stimulating Factor) OR (Granulocyte-Macrophage Colony-Stimulating Factor) OR (IL-11) OR (IL-3) OR (Insulin-like Growth Factor) OR (Interleukins) OR (Keratinocyte Growth Factor) OR (Lactoferrin) OR (Macrophage Colony-Stimulating Factor) OR (Palifermin) OR (Repifermin) OR (TGF-b) OR (TNF) OR (TNF Alpha) OR (Transforming Growth Factors) OR (Velafermin) OR (Whey Protein) OR (Erythropoietin) OR (Thrombopoietin) OR (Carcinoembryonic Antigen Cell Adhesion Molecule 1) OR (Ghrelin) OR (Glutathione) OR (Hepatocyte Growth Factor) OR (Intestinal Trefoil Factor) OR (Milk-derived Growth Factor Extract) OR (Milk-derived Protein) OR (Platelet-derived Growth Factor) OR (PV701) OR (Somatomedins) OR (Teduglutide) OR (Vascular Endothelial Growth Factor) OR (Amino Acids) OR (Immunologic Factors) OR (ALD518 IL-6)) NOT (case report OR Review[publication type]) NOT (“Animals”[Mesh] NOT (“Animals”[Mesh] AND “Humans”[Mesh])) AND ((“2011/01/01”[PDat]: “2016/06/30”[PDat]) AND English[lang]) Sort by: PublicationDate

Lasers

(mucositis OR stomatitis OR oral mucous membrane OR oral mucosa* OR oral ulcer* OR oropharyngitis) AND cancer[sb] AND (oral OR oropharyngeal OR oropharynx OR mouth) AND (Lasers OR Laser OR LLLT OR (Low level laser therapy) OR (Light therapy) OR Phototherapy OR (Low-level laser) OR LED OR (Light-emitting diode) OR Diode OR (Visible light) OR (He-Ne) OR InGaAlP OR GaAlAs OR InGaAs OR CO2 OR (Infra-red) OR Photobiomodulation) NOT (case report OR Review[publication type]) NOT (“Animals”[Mesh] NOT (“Animals”[Mesh] AND “Humans”[Mesh])) AND ((“2011/01/01”[PDat]: “2016/06/30”[PDat]) AND English[lang]) Sort by: PublicationDate

Natural and miscellaneous remedies

(mucositis OR stomatitis OR oral mucous membrane OR oral mucosa* OR oral ulcer* OR oropharyngitis) AND cancer[sb] AND (oral OR oropharyngeal OR oropharynx OR mouth) AND (natural remedies OR natural remedy OR natural therapeutic OR natural therapies OR natural therapy OR allopurinol OR aloe OR aloe vera OR alternative OR azelastine hydrochloride OR azulene OR bee OR beta carotene OR bethanechol OR calcium phosphate OR capsaicin OR fgf 20 OR cg53135 OR chamomile OR chewing gum OR chinese medicine OR chitosan OR clonidine OR colchicine OR complementary OR curcumin OR doxepin OR dyclonine OR emu oil OR enzyme OR folate OR folic acid OR folinic acid OR gabapentin OR glutamine OR glycerin OR gum OR herbal OR homeopathic OR honey OR human placental extract OR placentrex OR humidification OR hydrolytic enzyme OR hyperbaric oxygen OR intestinal trefoil factor OR jelly OR lactobacillus OR lactoferrin OR l glutamine OR licorice OR aluminum hydroxide OR magnesium hydroxide OR manuka oil OR anuka OR milk OR mucotrol OR multivitamin OR natural OR payayor OR pentoxifylline OR pilocarpine OR polaprezinc OR propantheline OR propolis OR pv 701 OR radiation OR retinoid OR rhodiola algida OR rose OR shenqi OR collagen OR amino acid OR amino acids OR sodium hyaluronate OR suction cups OR tetrachlorodecaoxide OR tcdo OR oxoferin OR traumeel OR tretinoin OR vitamin OR vitamin a OR vitamin e OR wax OR wobe mugos OR wobe mugos e OR xathan OR yeast) NOT (case report OR Review[publication type]) NOT (“Animals”[Mesh] NOT (“Animals”[Mesh] AND “Humans”[Mesh])) Filters: Publication date from 2011/01/01 to 2016/06/30; English Sort by: PublicationDate

Gastrotintestinal (GI)

(mucositis OR (mucosal injury) OR colitis OR enteritis OR ileitis OR enterocolitis OR esophagitis OR gastritis OR proctitis) AND cancer[sb] AND (GI OR Gastrointestinal OR (mucous membrane*) OR mucosa*) AND ((Glucagon-like peptide-1) OR (Glucagon-like peptide-2) OR (Short chain fatty acids) OR (microbiome sequencing) OR Inulin OR Prebiotics OR Probiotics OR (Resistant starch) OR (Dietary constituents) OR (Dietary supplements) OR Ginger OR Peppermint OR Teas OR Rooibos OR Herbs OR Exercise OR (Stool softener) OR Laxative OR (Oxycodone-naloxone) OR Targin OR (AMP-18) OR (Short chain fatty acids) OR diarrhea) NOT (case report OR Review[publication type]) NOT (“Animals”[Mesh] NOT (“Animals”[Mesh] AND “Humans”[Mesh])) AND ((“2011/01/01”[PDat]: “2016/06/30”[PDat]) AND English[lang]) Sort by: PublicationDate

Pathogenesis—oral

(mucositis OR stomatitis OR oral mucous membrane OR oral mucosa* OR oral ulcer*) AND cancer[sb] AND (oral OR oropharyngeal OR oropharynx OR mouth) AND (Prediction OR Microbiota OR Personalised OR Precision OR Pharmacogenomics OR Prediction OR Selection OR Immunotherapy OR mTOR OR Gut-brain axis OR Epigenetics OR miRNA OR Microbiome OR Sequencing OR Risk OR Microarray OR (Bayesian network) OR SNPs OR Pharmacogenetics OR Model OR Neuroimmune) NOT (case report OR Review [Publication Type]) AND ((“2011/01/01”[PDat]: “2016/06/30”[PDat]) AND English[lang]) Sort by: PublicationDate

Pathogenesis—GI

(mucositis OR (mucosal injury) OR colitis OR enteritis OR ileitis OR enterocolitis OR esophagitis OR gastritis OR proctitis) AND cancer[sb] AND (GI OR Gastrointestinal OR (mucous membrane*) OR mucosa*) AND (Prediction OR Microbiota OR Personalised OR Precision OR Pharmacogenomics OR Prediction OR Selection OR Immunotherapy OR mTOR OR Gut-brain axis OR Epigenetics OR miRNA OR Microbiome OR Sequencing OR Risk OR Microarray OR (Bayesian network) OR SNPs OR Pharmacogenetics OR Model OR Neuroimmune) NOT (case report OR Review [Publication Type]) AND ((“2011/01/01”[PDat]: “2016/06/30”[PDat]) AND English[lang]) Sort by: PublicationDate

Table 4

Complete section statement Web of Science

Section

Web of Science statement

Antimicrobials, coating agents, anesthetics, and analgesics

TS=((Mucosit* OR Stomatit* OR Oromucosit* OR Oropharyngit* OR Mucosa* OR Ulcer* OR (muco$s* NEAR/2 membran*) OR (mucosa* NEAR/2 barrier)) AND ((bone marrow NEAR/2 transplant*) OR (condition* NEAR/2 regimen*) OR (Hemato NEAR/2 Oncolog*) OR (hematopoietic NEAR/2 stem cell* NEAR/2 transplant*) OR antineoplastic* OR biochemotherap* OR Cancer* OR Carcin* OR carcinogen* OR chemotherap* OR cytotoxic* OR Hematolo* OR Hematooncological OR Hemato-Oncological OR leuk$emia* OR lymphoma* OR Malignan* OR Neoplasm* OR Oncolog* OR radiotherap* OR tumo$r*) AND (Mouth OR Oral* OR buccal* OR Oropharyn* OR (Oris NEAR/2 Cavitas) OR (Vestibule NEAR/2 Oris)) AND ((Magic rinse) OR (Miracle rinse) OR Acyclovir OR Adhesive OR Alfentanil OR (aluminum hydroxide) OR (amphotericin B) OR analgesia OR Analgesic OR Antiacid OR antibiotic OR (anti-infective) OR (aqua oral) OR benzocaine OR buprenorphine OR clarithromycin OR clonidine OR coating agent OR Diclosan OR Doxepin OR Fentanyl OR Film OR fluconazole OR Gelclair OR Hydromorphone OR (IB-367) OR Iseganan OR Kefir OR Kaopectate OR Ketamine OR lidocaine OR (Local anesthetic) OR (Magnesium hydroxide) OR Methadone OR Morphine OR Mouthrinse OR Mouthwash OR mucoadhesive OR MuGard OR (Patient controlled) OR polymyxin OR Polyvinylpyrrolidone OR (povidone-iodine) OR Protegrin OR sucralfate OR Tetracaine OR tetracycline OR tobramycin OR Topical OR (Ulcer ease) OR xylocaine OR zilactin OR Zinc)) NOT TI=(rat* OR mouse OR mice OR rabbit* OR dog* OR murine OR “animal model” OR “in vivo” OR “in vitro”) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article OR Letter OR Proceedings Paper) Indexes=SCI-EXPANDED, ESCI Timespan=2011-2016

Anti-inflammatories

TS=((Anti-inflammatory Agents) OR anti-inflammator* OR antiinflammator* OR (Aminosalicylic acid) OR “Aminosalicylic Acid” OR Amlexanox OR Anti-inflammatory OR antiinflammatory OR (Anti-TNF) OR AntiTNF OR (Anti-tumor necrosis factor) OR “Anti-tumo$R necrosis factor” OR “Antitumo$R necrosis factor” OR Aspirin OR Benadryl OR Benzydamine OR Betamethasone OR Celecoxib OR Corticosteroid OR Dexamethasone OR Diphenhydramine OR Ethylol OR Flurbiprofen OR Histamine OR (Human placental extract) OR (Human NEAR/2 placent* NEAR/2 extract*) OR Hydrocortisone OR Ibuprofen OR Indomethacin OR Infliximab OR Irsogladine OR Lactermin OR Lactoferrin OR Mesalazine OR Misoprostol OR (N-Acetyl cysteine) OR “N-Acetyl cysteine” OR “NAcetyl cysteine” OR (Non-steroidal anti-inflammatory) OR NSAIDS OR NSAID* OR Orgotein OR placentrex OR Prednisone OR Prostaglandin OR (RK-02-02) OR “RK-02-02” OR (Salicylic acid) OR “Salicylic acid” OR Steroid OR Thalidomide OR TNF OR (TNF antibody) OR (TNF NEAR/2 (antibod* OR inhibitor*)) OR (anti-TNF therapy) OR (TNF inhibitor) OR (Tumor necrosis factor) OR (Tumo$r NEAR/2 necrosis NEAR/2 factor*)) AND (TS= (Mouth OR Oral* OR buccal* OR Oropharyn* OR (Oris NEAR/2 Cavitas) OR (Vestibule NEAR/2 Oris))) AND (TS=((bone marrow NEAR/2 transplant*) OR (condition* NEAR/2 regimen*) OR (Hemato NEAR/2 Oncolog*) OR (hematopoietic NEAR/2 stem cell* NEAR/2 transplant*) OR antineoplastic* OR biochemotherap* OR Cancer* OR Carcin* OR carcinogen* OR chemotherap* OR cytotoxic* OR Hematolo* OR Hematooncological OR Hemato-Oncological OR leuk$emia* OR lymphoma* OR Malignan* OR Neoplasm* OR Oncolog* OR radiotherap* OR tumo$r*)) AND (TS= (Mucosit* OR Stomatit* OR Oromucosit* OR Oropharyngit* OR Mucosa* OR Ulcer* OR (muco$s* NEAR/2 membran*) OR (mucosa* NEAR/2 barrier))) NOT TI=(rat* OR mouse OR mice OR rabbit* OR dog* OR murine OR “animal model” OR “in vivo” OR “in vitro”) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article OR Letter OR Proceedings Paper)

Indexes=SCI-EXPANDED, ESCI Timespan=2011-2016

Basic oral care

TS=((Basic oral care) OR (oral care AND (basic* OR decontaminat* OR hygien* OR regimen*)) OR (Oral Care) OR (Artificial Saliva) OR (artificial NEAR/3 saliva) OR Assessment OR (Baking soda) OR (Bland Rinse) OR Brush* OR (Calcium Phosphate) OR Calculus OR Caphosol OR (Caregiver education) OR ((Caregiv* OR Famil*) AND educat*) OR Chlorhexidine OR Dental OR (dental care) OR (Dental cleaning) OR (Dental Floss) OR (Dental AND (car* OR clean* OR floss*)) OR Dentist OR Education OR Educat* OR Examination OR Exam* OR (Family education) OR (educat* AND (caregiv* OR famil* OR patient* OR provider* OR staff)) OR Floss* OR Fluorid* OR Hygiene OR Hygienist OR Hygien* OR (Lip balm) OR (Mixed Medication Mouthwash*) OR (Mixed Medication AND (mouthwash* OR mouth wash*)) OR Moisturizer OR Moisturiz* OR Mouthcare OR (Mouth Care) OR mouthcare* OR (mouth care*) OR Mouthwash OR Multidisciplinary OR Multidisciplin* OR (Non-medicated rinse) OR ((Non-medicat* OR Nonmedicat*) AND rins*) OR Nurs* OR (Oral bandag*) OR (Oral Care) OR (Oral Care Regimen) OR (Oral decontamination) OR (Oral Hygiene) OR (Patient education) OR Plaque OR (Provider education) OR Rinse rins* OR Saline OR saline OR Scaling OR scaler OR (Sodium bicarbonate) OR (Staff education) OR (Superoxide dismutase) OR Toothbrush OR Toothbrush* OR t*th brush* OR toothbrush* OR Toothpast* OR t*th past* OR toothpast* OR Water) AND TS= (Mouth OR Oral* OR buccal* OR Oropharyn* OR (Oris NEAR/2 Cavitas) OR (Vestibule NEAR/2 Oris)) AND TS=((bone marrow NEAR/2 transplant*) OR (condition* NEAR/2 regimen*) OR (Hemato NEAR/2 Oncolog*) OR (hematopoietic NEAR/2 stem cell* NEAR/2 transplant*) OR antineoplastic* OR biochemotherap* OR Cancer* OR Carcin* OR carcinogen* OR chemotherap* OR cytotoxic* OR Hematolo* OR Hematooncological OR Hemato-Oncological OR leuk$emia* OR lymphoma* OR Malignan* OR Neoplasm* OR Oncolog* OR radiotherap* OR tumo$r*) AND TS= (Mucosit* OR Stomatit* OR Oromucosit* OR Oropharyngit* OR Mucosa* OR Ulcer* OR (muco$s* NEAR/2 membran*) OR (mucosa* NEAR/2 barrier)) NOT TI=(rat* OR mouse OR mice OR rabbit* OR dog* OR murine OR “animal model” OR “in vivo” OR “in vitro”) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article OR Letter OR Proceedings Paper)

Indexes=SCI-EXPANDED, ESCI Timespan=2011-2016

Cryotherapy

TS=((Mucosit* OR Stomatit* OR Oromucosit* OR Oropharyngit* OR Mucosa* OR Ulcer* OR (muco$s* NEAR/2 membran*) OR (mucosa* NEAR/2 barrier)) AND ((bone marrow NEAR/2 transplant*) OR (condition* NEAR/2 regimen*) OR (Hemato NEAR/2 Oncolog*) OR (hematopoietic NEAR/2 stem cell* NEAR/2 transplant*) OR antineoplastic* OR biochemotherap* OR Cancer* OR Carcin* OR carcinogen* OR chemotherap* OR cytotoxic* OR Hematolo* OR Hematooncological OR Hemato-Oncological OR leuk$emia* OR lymphoma* OR Malignan* OR Neoplasm* OR Oncolog* OR radiotherap* OR tumo$r*) AND (Mouth OR Oral* OR buccal* OR Oropharyn* OR (Oris NEAR/2 Cavitas) OR (Vestibule NEAR/2 Oris)) AND (Cryotherapy OR Cryotherap* OR Cold OR (Cold Therap*) OR (Cold Temperature*) OR (Cold Water*) OR Freeze OR Freezing OR Froze OR Frozen OR Ice OR (ice water*) OR Icy)) NOT TI=(rat* OR mouse OR mice OR rabbit* OR dog* OR murine OR “animal model” OR “in vivo” OR “in vitro”) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article OR Letter OR Proceedings Paper) Indexes=SCI-EXPANDED, ESCI Timespan=2011-2016

Growth factors and cytokines

TS= (Mucosit* OR Stomatit* OR Oromucosit* OR Oropharyngit* OR Mucosa* OR Ulcer* OR (muco$s* NEAR/2 membran*) OR (mucosa* NEAR/2 barrier)) AND TS=((bone marrow NEAR/2 transplant*) OR (condition* NEAR/2 regimen*) OR (Hemato NEAR/2 Oncolog*) OR (hematopoietic NEAR/2 stem cell* NEAR/2 transplant*) OR antineoplastic* OR biochemotherap* OR Cancer* OR Carcin* OR carcinogen* OR chemotherap* OR cytotoxic* OR Hematolo* OR Hematooncological OR Hemato-Oncological OR leuk$emia* OR lymphoma* OR Malignan* OR Neoplasm* OR Oncolog* OR radiotherap* OR tumo$r*) AND TS= (Mouth OR Oral* OR buccal* OR Oropharyn* OR (Oris NEAR/2 Cavitas) OR (Vestibule NEAR/2 Oris)) AND TS=((ATL 104) OR “ATL 104” OR (Colony-Stimulating Factors) OR Cytokines OR Cytokine* OR (Epidermal Growth Factor) OR (Fibroblast Growth Factors) OR (Glucagon-like Peptide 2) OR “Glucagon-like Peptide-2” OR (Granulocyte Colony-Stimulating Factor) OR (Granulocyte-Macrophage Colony-Stimulating Factor) OR ((Granulocyte* OR Macrophage* OR “Granulocyte-Macrophage*”) NEAR/2 “Colony-Stimulating Factor*”) OR (IL-11) OR “IL-11” OR (IL-3) OR “IL-3” OR (Insulin-like Growth Factor) OR Interleukins OR Interleukin* OR (Keratinocyte Growth Factor) OR Lactoferrin OR Lactoferrin* OR (Macrophage Colony-Stimulating Factor) OR “Colony-Stimulating Factor*” OR Palifermin OR Palifermin* OR Repifermin OR Repifermin* OR (TGF-b) OR “TGF-b” OR TNF OR (TNF Alpha) OR “TNF Alpha” OR (Transforming Growth Factors) OR Velafermin OR Velafermin* OR (Whey Protein) OR (Whey NEAR/2 Protein*) OR Erythropoietin OR Erythropoietin* OR Thrombopoietin OR Thrombopoietin* OR (Carcinoembryonic Antigen Cell Adhesion Molecule 1) OR “Carcinoembryonic Antigen Cell Adhesion Molecule-1” OR Ghrelin OR Ghrelin* OR Glutathione OR Glutathione* OR (Hepatocyte Growth Factor) OR (Intestinal Trefoil Factor) OR “Intestinal Trefoil Factor*” OR (Milk-derived Growth Factor Extract) OR (Milk-derived Protein) OR “Milk-derived Protein*” OR “Milk-derive*” OR (Platelet-derived Growth Factor) OR PV701 OR Somatomedins OR Somatomedin* OR Teduglutide OR Teduglutide* OR (Vascular Endothelial Growth Factor) OR ((Epidermal* OR Fibroblast* OR “Insulin-like” OR Keratinocyte* OR Transform* OR Hepatocyte* OR “Platelet-derive*” OR “Vascular Endothelial”) NEAR/2 “Growth Factor*”) OR (Amino Acids) OR “Amino Acid*” OR (Immunologic Factors) OR “Immunologic Factor*” OR (ALD518 IL-6) OR “ALD518” OR “IL-6”)) NOT (TI=(rat* OR mouse OR mice OR rabbit* OR dog* OR murine OR “animal model” OR in vivo OR in vitro) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article OR Letter OR Proceedings Paper) Indexes=SCI-EXPANDED, ESCI Timespan=2011-2016

Lasers

TS=((Mucosit* OR Stomatit* OR Oromucosit* OR Oropharyngit* OR Mucosa* OR Ulcer* OR (muco$s* NEAR/2 membran*) OR (mucosa* NEAR/2 barrier)) AND ((bone marrow NEAR/2 transplant*) OR (condition* NEAR/2 regimen*) OR (Hemato NEAR/2 Oncolog*) OR (hematopoietic NEAR/2 stem cell* NEAR/2 transplant*) OR antineoplastic* OR biochemotherap* OR Cancer* OR Carcin* OR carcinogen* OR chemotherap* OR cytotoxic* OR Hematolo* OR Hematooncological OR Hemato-Oncological OR leuk$emia* OR lymphoma* OR Malignan* OR Neoplasm* OR Oncolog* OR radiotherap* OR tumo$r*) AND (Mouth OR Oral* OR buccal* OR Oropharyn* OR (Oris NEAR/2 Cavitas) OR (Vestibule NEAR/2 Oris)) AND (Lasers OR Laser OR LLLT OR (Low level laser therapy) OR (Light therapy) OR Phototherapy OR (Low-level laser) OR LED OR (Light-emitting diode) OR Diode OR (Visible light) OR (He-Ne) OR InGaAlP OR GaAlAs OR InGaAs OR CO2 OR (Infra-red) OR Photobiomodulation)) NOT TI=(rat* OR mouse OR mice OR rabbit* OR dog* OR murine OR “animal model” OR “in vivo” OR “in vitro”) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article OR Letter OR Proceedings Paper) Indexes=SCI-EXPANDED, ESCI Timespan=2011-2016

Natural and miscellaneous remedies

TS=((natural remedies) OR (natural remedy) OR (natural NEAR/2 (remedy OR remedies)) OR (natural therapeutic) OR (natural therapies) OR (natural therapy) OR (natural NEAR/2 (therapeut* OR therapy OR therapies)) OR (allopurinol) OR aloe OR (aloe vera) OR alternative OR (azelastine hydrochloride) OR “azelastine hydrochloride” OR azulene OR bee OR (beta carotene) OR “beta carotene” OR bethanechol OR (calcium phosphate) OR “calcium phosphate” OR capsaicin OR (fgf 20) OR “fgf 20” OR cg53135 OR chamomile OR (chewing gum) OR “chew* gum*” OR (chinese medicine) OR “chinese medicine” OR chitosan OR clonidine OR colchicine OR complementary OR curcumin OR doxepin OR dyclonine OR emu oil OR “emu oil*” OR enzyme OR folate OR (folic acid) OR “folic acid*” OR (folinic acid) OR “folinic acid*” OR gabapentin OR glutamine OR glycerin OR gum OR herbal OR homeopathic OR Homeopath* OR honey OR (human placental extract) OR “human placent* extract*” OR placentrex OR humidification OR (hydrolytic enzyme) OR “hydrolytic enzyme*” OR (hyperbaric oxygen) OR “hyperbaric oxygen*” OR (intestinal trefoil factor) OR “intestinal trefoil factor*” OR jelly OR lactobacillus OR lactoferrin OR (l glutamine) OR “l glutamine” OR licorice OR Licorice* OR (aluminum hydroxide) OR “aluminum hydroxide” OR (magnesium hydroxide) OR “magnesium hydroxide” OR (manuka oil) OR “manuka oil*” OR anuka OR milk OR mucotrol OR multivitamin OR multivitamin* OR natural OR payayor OR pentoxifylline OR pilocarpine OR polaprezinc OR propantheline OR propolis OR (pv 701) OR “pv 701” OR radiation OR retinoid OR (rhodiola algida) OR “rhodiola algida” OR rose OR rose* OR shenqi OR collagen OR (amino acid) OR (amino acids) OR “amino acid*” OR (sodium hyaluronate) OR “sodium hyaluronate” OR (suction cups) OR “suction cup*” OR tetrachlorodecaoxide OR tcdo OR oxoferin OR traumeel OR tretinoin OR vitamin OR Vitamin* OR vitamin a OR (vitamin e) OR wax OR wax* OR (wobe mugos) OR (wobe mugos e) OR “wobe mugos” OR xathan OR yeast OR Yeast* OR (Hematopoietic NEAR/3 Stem Cell* NEAR/3 Transplant*) OR mouthwash* OR (Transplant* NEAR/4 Condition*)) AND TS= (Mouth OR Oral* OR buccal* OR Oropharyn* OR (Oris NEAR/2 Cavitas) OR (Vestibule NEAR/2 Oris)) AND TS=((bone marrow NEAR/2 transplant*) OR (condition* NEAR/2 regimen*) OR (Hemato NEAR/2 Oncolog*) OR (hematopoietic NEAR/2 stem cell* NEAR/2 transplant*) OR antineoplastic* OR biochemotherap* OR Cancer* OR Carcin* OR carcinogen* OR chemotherap* OR cytotoxic* OR Hematolo* OR Hematooncological OR Hemato-Oncological OR leuk$emia* OR lymphoma* OR Malignan* OR Neoplasm* OR Oncolog* OR radiotherap* OR tumo$r*) AND TS= (Mucosit* OR Stomatit* OR Oromucosit* OR Oropharyngit* OR Mucosa* OR Ulcer* OR (muco$s* NEAR/2 membran*) OR (mucosa* NEAR/2 barrier)) NOT TI=(rat* OR mouse OR mice OR rabbit* OR dog* OR murine OR “animal model” OR “in vivo” OR “in vitro”) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article OR Letter OR Proceedings Paper) Indexes=SCI-EXPANDED, ESCI Timespan=2011-2016

Gastrotintestinal (GI)

TS=((mucositis OR (mucosal injury) OR colitis OR enteritis OR ileitis OR enterocolitis OR esophagitis OR gastritis OR proctitis) AND ((bone marrow NEAR/2 transplant*) OR (condition* NEAR/2 regimen*) OR (Hemato NEAR/2 Oncolog*) OR (hematopoietic NEAR/2 stem cell* NEAR/2 transplant*) OR antineoplastic* OR biochemotherap* OR Cancer* OR Carcin* OR carcinogen* OR chemotherap* OR cytotoxic* OR Hematolo* OR Hematooncological OR Hemato-Oncological OR leuk$emia* OR lymphoma* OR Malignan* OR Neoplasm* OR Oncolog* OR radiotherap* OR tumo$r*) AND (Gastrointestinal OR GI OR (Digestive Tract*) OR (muco$s* NEAR/2 membran*) OR mucosa*) AND ((Glucagon-like peptide-1) OR (Glucagon-like peptide-2) OR (Short chain fatty acids) OR (microbiome sequencing) OR Inulin OR Prebiotics OR Probiotics OR (Resistant starch) OR (Dietary constituents) OR (Dietary supplements) OR Ginger OR Peppermint OR Teas OR Rooibos OR Herbs OR Exercise OR (Stool softener) OR Laxative OR (Oxycodone-naloxone) OR Targin OR (AMP-18) OR (Short chain fatty acids) OR diarrhea)) NOT TI=(rat* OR mouse OR mice OR rabbit* OR dog* OR murine OR “animal model” OR “in vivo” OR “in vitro”) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article OR Letter OR Proceedings Paper) Indexes=SCI-EXPANDED, ESCI Timespan=2011-2016

Pathogenesis—oral

TS=((Mucosit* OR Stomatit* OR Oromucosit* OR Oropharyngit* OR Mucosa* OR Ulcer* OR (muco$s* NEAR/2 membran*) OR (mucosa* NEAR/2 barrier)) AND ((bone marrow NEAR/2 transplant*) OR (condition* NEAR/2 regimen*) OR (Hemato NEAR/2 Oncolog*) OR (hematopoietic NEAR/2 stem cell* NEAR/2 transplant*) OR antineoplastic* OR biochemotherap* OR Cancer* OR Carcin* OR carcinogen* OR chemotherap* OR cytotoxic* OR Hematolo* OR Hematooncological OR Hemato-Oncological OR leuk$emia* OR lymphoma* OR Malignan* OR Neoplasm* OR Oncolog* OR radiotherap* OR tumo$r*) AND (Mouth OR Oral* OR buccal* OR Oropharyn* OR (Oris NEAR/2 Cavitas) OR (Vestibule NEAR/2 Oris)) AND (Prediction OR Microbiota OR Personalised OR Precision OR Pharmacogenomics OR Prediction OR Selection OR Immunotherapy OR mTOR OR Gut-brain axis OR Epigenetics OR miRNA OR Microbiome OR Sequencing OR Risk OR Microarray OR (Bayesian network) OR SNPs OR Pharmacogenetics OR Model OR Neuroimmune)) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article OR Letter OR Proceedings Paper) Indexes=SCI-EXPANDED, ESCI Timespan=2011-2016

Pathogenesis—GI

TS=((mucositis OR (mucosal injury) OR colitis OR enteritis OR ileitis OR enterocolitis OR esophagitis OR gastritis OR proctitis) AND ((bone marrow NEAR/2 transplant*) OR (condition* NEAR/2 regimen*) OR (Hemato NEAR/2 Oncolog*) OR (hematopoietic NEAR/2 stem cell* NEAR/2 transplant*) OR antineoplastic* OR biochemotherap* OR Cancer* OR Carcin* OR carcinogen* OR chemotherap* OR cytotoxic* OR Hematolo* OR Hematooncological OR Hemato-Oncological OR leuk$emia* OR lymphoma* OR Malignan* OR Neoplasm* OR Oncolog* OR radiotherap* OR tumo$r*) AND (Gastrointestinal OR GI OR (Digestive Tract*) OR (muco$s* NEAR/2 membran*) OR mucosa*) AND (Prediction OR Microbiota OR Personalised OR Precision OR Pharmacogenomics OR Prediction OR Selection OR Immunotherapy OR mTOR OR Gut-brain axis OR Epigenetics OR miRNA OR Microbiome OR Sequencing OR Risk OR Microarray OR (Bayesian network) OR SNPs OR Pharmacogenetics OR Model OR Neuroimmune)) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article OR Letter OR Proceedings Paper) Indexes=SCI-EXPANDED, ESCI Timespan=2011-2016

The medical librarians input the search results from each section into EndNote libraries, with separate folders for results from PubMed, Web of Science, and identified duplicate articles. EndNote libraries were shared via email with appropriate section heads, along with spreadsheets of the search strategies.

Period of the review

The previous update of the MASCC/ISOO Clinical Practice Guidelines for Mucositis reviewed all the literature available until the end of 2010 [4]. For this review, a significant number of papers had been identified from the searches for the timeframe from January 2011 until June 2016. Because the principles of manuscript reviewing and evidence analysis were similar to the previous guidelines update, this systematic review could focus solely on the data published since 2010 and merge this into the evidence from the previous reviews. Papers published after the timeframe of the review were addressed in the Discussion to indicate future trends and consistency with the current guidelines.

Considerations related to the effectiveness

The effectiveness of the intervention was presented as per patient population (hematological cancer, solid cancer, head and neck cancer), cancer therapy modality (chemotherapy, radiotherapy, radio-chemotherapy, hematopoietic stem cell transplantation), aim of intervention (prevention or treatment), and as detailed as possible in terms of dose and concentration.

Interventions were reviewed for effectiveness, and this was described in terms of mucositis severity, mucositis duration, pain severity, and pain duration. Information about other reported outcome measures was retrieved and integrated to describe the findings on efficacy.

For the purpose of the review, studies conducted in HSCT patient population were classified as hematological cancer studies. The study population may have included patients with a non-cancer diagnosis. This was done as the effect of the HSCT on the oral mucosa is independent of the diagnosis. Evidence regarding the intensity of the conditioning regimen for HSCT or cancer therapy were assessed as they affected the risk for oral mucositis. In regard to the patient age, the results were stratified as intervention for pediatric and adult population. The wording of the guidelines reflects this stratification.

Criteria for evaluation of scientific evidence

Similar to the guidelines update published in 2014, for the current guidelines update, we applied the Hadorn criteria for evaluation of scientific evidence [8]. The Agency for Health Care Policy and Research originally published these criteria when it sponsored the clinical practice guidelines for the management of patients with heart failure due to left ventricular systolic dysfunction [8, 9, 10, 11]. Briefly, the criteria classify flaws in study design as major and minor flaws. These allow for grading the study and determine the scientific contribution of the study findings. These criteria were modified to meet the requirements of mucositis studies, as described in the previous publication [6]. This process was repeated by two independent reviewers and relayed back separately to the section head. The final decision on any discrepant answers was made by the section head.

Allocating a level of evidence and categories used to classify guidelines

The new evidence was merged with the data from the 2011 systematic review. The most significant contribution from the database of publications prior to 2011 came from randomized controlled trials.

The methods used to determine the level of evidence and classification of guidelines described in a previous paper [6] were adapted from Somerfield paper [11] and followed the MASCC Guidelines Policy [12]. Briefly, evidence was defined according to 5 levels (I–V) and this determined the guideline category as recommendation, suggestion, no guideline possible. If a paper was deemed not well designed as per the Hadron criteria, it was downgraded to a lower level of evidence.

Positive guidelines were reserved for situations in which strong evidence indicated effectiveness of the intervention in the treatment setting listed. Negative guidelines were reserved for situations in which strong evidence indicated lack of effectiveness in the treatment settings listed. This does not imply that this is a harmful intervention.

For the current update, it was noted that there was an increase in the number of randomized controlled trials (RCTs). However, many of these had a small sample size often with inconclusive results, which limited the applicability of the findings. Therefore, in order to determine a recommendation-type guideline, we looked for multiple RCTs, at least one of them with no major flaws.

Logistics of the review process

A section head and co-head were appointed for each section. Their roles were to coordinate the transfer of papers and review forms between the reviewers and central data storage platform and assist reviewers in review process. In addition, section heads from the previous update were available as consultants to assist and guide with the review.

A call for reviewers was sent to enlist members for the review process. According to the MASCC policy for guidelines development [12], members were asked to disclose any conflicts of interest and the section they would like to participate in. Only members who met the MASCC criteria participated as reviewers. The allocation of members to each section was done based on the reviewer preference and volume of papers to be reviewed. A manual survey on the number of randomized controlled trials (RCTs) for each section was performed prior to the full literature review in order to obtain an estimate about the expected volume of literature in each section. The number of reviewers for each section was proportional to the number of RCTs identified for the section. Reviewers sent their top 3 preferences for section they would like to be included into. To enable uniformity in the review process among different sections, each section head and reviewer was supplied with a set of tools as follows:
  1. 1.

    Section head guide

     
  2. 2.

    Instructions for section heads/instructions for reviewers

     
  3. 3.

    Section head form/reviewer form

     
  4. 4.

    Article flowchart

     
  5. 5.

    Procedure manual

     
  6. 6.

    Somerfield and Hadorn papers

     
  7. 7.

    Section members—email list

     

Calibration

A demonstration for the use of these tools was created in a PowerPoint format and distributed via email to section heads and co-heads. Online sessions were conducted to review the use of these resources and clarify any questions.

Following this, calibration exercises were carried out using a paper relevant to the topic of this review [13]. Once the exercise was completed, a key was sent to ensure uniformity among the participants of the review. Subsequently, papers were made available to section heads for distribution to reviewers. Periodic online conferences with section heads were conducted for problem-solving and ensuring consistency in the review process.

To enable the pooling of previous and new data, a criteria sheet was developed to extract relevant data from the previous guideline papers. These data were tabulated in a standard format and provided to all sections to ensure uniformity throughout the review process. The compiled data was presented by each section at a MSG guidelines meeting in Washington June 2017, where a preliminary discussion on allocating the level of evidence and recommendations for guidelines took place.

Platform for online sharing

In the previous update, a single Google drive account was used by all members to access publications and data forms. Since the previous review, numerous changes occurred in the Google drive interphase, which required several modifications in the design of our online sharing plan. For the current guidelines, nine google drive accounts, one for each section was created for bilateral communication of reviewer forms. In addition, a single Google drive with publications from all sections was created for unilateral access to papers. This compartmentalized design was intended to optimize account usage to relevant users. One backup account was also created. Many different Google drive designs were considered. However, due to the security features in Google drive requiring recovery email address and phone numbers, users were locked out of their accounts, and multistep verifications were needed to access back their accounts.

In the final architecture, only section heads were provided with access details to the account, and reviewers were emailed copies of the publications and reviewer forms. These were then sent back to the section heads, who uploaded the completed reviewer form to Google drive. The section-specific drive was then used for communication about the compilation of the two reviewer forms into a single section head form.

The advantages of this system were that data transfer was efficient and ensured minimum errors in transmission of data. Also, as a limited number of persons were accessing each account, any security concerns by Google drive could be managed. Unintentional deleting and duplication of files that were noted when multiple users accessed the same account were avoided.

Conclusion

The methods used were critical for converting a large pool of data into a practical clinical set of guidelines while combining the findings of the recent systematic review with the previous review. A detailed set of instructions was provided to the group to ensure consistency. The process of updating existing guidelines requires periodic examination of policy and procedures related to guideline production.

Notes

Compliance with ethical standards

Conflict of interest

Employees of commercial entities were not eligible to serve on this MASCC Guidelines Panel. All authors completed a conflict of interest disclosure form and conflicts are disclosed in the guideline’s publications. The authors disclose no conflict of interest (VR, KC, LP, DC). PB has served an advisory role for Galera Therapeutics. SE reports no conflict in regard to mucositis, and consulting to Falk Pharma as the Medical Expert for a clinical trial about oral chronic graft versus host disease. RVL has served as a consultant for Colgate Oral Pharmaceuticals, Galera Therapeutics, Ingalfarma SA, Monopar Therapeutics, Mundipharma, and Sucampo Pharma; has received research support to his institution from Galera Therapeutics, Novartis, Oragenics, and Sucampo Pharma; and has received stock in Logic Biosciences.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Vinisha Ranna
    • 1
    Email author
  • Karis Kin Fong Cheng
    • 2
  • Daniel A. Castillo
    • 3
  • Lorraine Porcello
    • 4
  • Anusha Vaddi
    • 5
  • Rajesh V. Lalla
    • 6
  • Paolo Bossi
    • 7
  • Sharon Elad
    • 5
  • On behalf of the Mucositis Study group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO)
  1. 1.Department of Oral and Maxillofacial SurgeryThe Mount Sinai HospitalNew YorkUSA
  2. 2.Alice Lee Centre for Nursing Studies, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  3. 3.Edward G. Miner LibraryUniversity of Rochester Medical CenterRochesterUSA
  4. 4.Bibby Dental Library, Eastman Institute for Oral HealthUniversity of Rochester Medical CenterRochesterUSA
  5. 5.Oral Medicine, Eastman Institute for Oral HealthUniversity of Rochester Medical CenterRochesterUSA
  6. 6.Section of Oral MedicineUniversity of Connecticut HealthFarmingtonUSA
  7. 7.Department of Medical and Surgical Specialties, Radiological Sciences and Public Health - Medical OncologyUniversity of BresciaBresciaItaly

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