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Supportive Care in Cancer

, Volume 21, Issue 1, pp 303–308 | Cite as

Methodology for the MASCC/ISOO Mucositis Clinical Practice Guidelines Update

  • J. M. BowenEmail author
  • S. Elad
  • R. D. Hutchins
  • R. V. Lalla
  • For the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO)
Special Article

Abstract

Members of the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) recently completed the process of updating the MASCC/ISOO Clinical Practice Guidelines for the prevention and treatment of mucositis. These guidelines, originally published in 2004, and last updated in 2007, provide clinicians with objective, evidence-based recommendations for the management of mucositis secondary to cancer therapy. This brief paper describes the methodology used to conduct the most recent systematic review in 2011, and develop new guidelines, providing the basis for the update. The overriding aims of the process were to assess evidence of effectiveness of interventions for the prevention and treatment of mucositis and to produce clinical practice guidelines for the management of mucositis using best available evidence.

Keywords

Mucositis MASCC/ISOO Methodology 

Introduction

Members of the Mucositis Study Group (MSG) of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) recently completed the process of updating the MASCC/ISOO Clinical Practice Guidelines for the prevention and treatment of mucositis. These guidelines, originally published in 2004 [1], and then updated in 2007 [2], provide clinicians with objective, evidence-based recommendations for the management of mucositis secondary to cancer therapy.

This brief paper describes the methodology used to conduct the most recent systematic review in 2011, and develop new guidelines, providing the basis for the update. A paper describing the detailed considerations and rationale behind our methodology is presented later in this issue. The overriding aims of the process were to assess evidence of effectiveness of interventions for the prevention and treatment of mucositis and to produce clinical practice guidelines for the management of mucositis using best available evidence.

Committee organisation

The MASCC/ISOO MSG was formed in 1998. One of its major goals and activities is the development of clinical practice guidelines for the management of mucositis [3]. In 2010, all academic members of the MSG were invited to participate in the present update. Two independent observers and a research librarian were also invited to participate in the update process. Additional personnel were recruited to retrieve and organise the large number of research papers needing review. All together, almost 100 people were involved in the effort. To provide structure to the large committee, it was organised hierarchically to include an organiser, co-organisers, section heads, co-section heads and reviewers. Each section consisted of a section head, one or two co-section heads and five to ten reviewers.

The role of the organiser was to oversee the whole process and ultimately translate the aims into action by the sections. The co-organisers were responsible for managing the sections (allocated half each) and providing day to day communication between the tiers. The section heads were allocated to one section each, according to previous guidelines experience and research interest, and were invited to name section co-heads. The role of the section head was to allocate papers to each reviewer in their group, collect and cross check reviews, provide summaries of the results and generate provisional guidelines, while the co-section head provided assistance in this role. The role of the reviewers was to conduct quality reviews of all papers allocated to them, and complete the standardised review form, before returning these to their section head. The two independent observers were present at the Guidelines Update Meeting to provide input and ensure transparency and consistency during development of guidelines. The research librarian constructed the literature searches and conducted the database searches with input from the organiser and co-organisers.

Definition of sections

Because of the vast scope of the literature and the large size of the panel, the topic was subdivided into clinical sections, which were assigned to working groups as per previous efforts. The clinical sections for the 2006 published update were as follows: (1) growth factors and cytokines; (2) alternative and natural agents, cryotherapy and laser; (3) basic oral care and good clinical practice; (4) anti-inflammatory agents; (5) amifostine and (6) antimicrobials, mucosal coating agents, anaesthetics, analgesics and nutritional supplements. The organisers made the decision to further separate disparate classes of intervention into new clinical sections to streamline the process. The clinical sections decided upon for the current update therefore included: (1) basic oral care/good clinical practice; (2) growth factors and cytokines; (3) anti-inflammatory agents; (4) antimicrobials, coating agents, anaesthetics and analgesics; (5) laser and other light therapy; (6) cryotherapy; (7) natural and miscellaneous agents and (8) gastrointestinal mucositis. These sections were chosen based on experience with the previous guidelines and, additionally, in recognition of emergence of additional studies in specific areas. Interventions for mucositis were allocated to a section based on the nature of the intervention. Decisions on allocation of interventions that could fall within more than one section were made by the organisers, in consultation with section heads and co-section heads.

Literature searches

Literature search strategies were developed by initially creating lists of known interventions for oral and gastrointestinal mucositis. The organisers produced the lists and received feedback from the section heads regarding intervention coverage. The research librarian then created search statements which linked the intervention keywords together with keywords related to cancer, its treatment and mucosal injury. Searches were then conducted through the OVID interface to MEDLINE and limited to human research published in English. For mucositis clinical interventions, all papers indexed in MEDLINE before 31 December 2010 were included in the review. This approach identified over 8,000 articles. In addition to database searches, the reference lists of previous guidelines papers and Cochrane meta-analyses were searched for any additional studies. Access to specific section searches is available on request from the authors.

The output of the search strategies were exported into Endnote libraries. An Endnote library containing the articles identified was sent to each section head to select papers for retrieval. Section heads removed articles which did not meet specified inclusion criteria and returned the updated libraries to the organisers. Standard flow charts were provided to control numbers of included and excluded studies as suggested in the “PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration” [4]. The workflow for the review is shown in Fig. 1. Inclusion and exclusion criteria were as follows:
Fig. 1

Review flow diagram. Title and abstract of all articles identified by database searches were assessed for relevance to review before retrieval. Papers were then excluded based on failure to meet inclusion criteria. The remaining articles were assessed for methodological quality and underwent data extraction concurrently

Inclusion criteria
  1. 1.

    Published clinical research papers testing an intervention (prevention or treatment) for mucositis or meta-analyses of such studies.

     
  2. 2.

    English language

     
  3. 3.

    Published in a peer-reviewed journal (note, online publication on the journal’s website is adequate for inclusion)

     
  4. 4.

    Indexed in Medline on or before 31 December 2010.

     
  5. 5.

    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.

    Literature reviews

     
  4. 4.

    Papers published in a language other than English

     

Selected papers were retrieved and made accessible to reviewers through a password-protected online database.

Forms and calibration

To ensure consistency in data extraction, quality assessment and data synthesis, a series of manuals and instructions files were developed and delivered to all involved. These included an overall instructions manual, and separate instructions for reviewers, and instructions for section heads. Forms developed for this process included an Excel review form for individual reviewers, and a separate Excel form for the section heads to complete.

Each reviewer and section head/co-head also underwent calibration. The calibration consisted of blinded review of the paper by Silva et al. (2010), a randomised controlled trial (RCT) investigating low-level laser therapy for prevention of oral mucositis [5], before receiving the calibration key with standardised responses. According to this key, the reviewers were able to adjust future reviews. In addition, calibration teleconferences were conducted to discuss and ensure correct usage of the electronic review forms.

Data extraction and synthesis

Each paper was independently reviewed by two reviewers. Each reviewer extracted up to 66 fields of data per paper and entered them in the reviewer form. The section head received two separate review forms for each paper. The section head then combined the two reviews into one final review in the section heads Excel form. Discrepancies in any field between the two reviewers were resolved by the section head, by reference to the publication and/or discussion with reviewers, as appropriate. In another sheet of the section head form, data from all the different papers for each intervention were put together so that the overall data for each intervention could be evaluated. In yet another sheet of the section head form, the most critical fields needed for guideline development were entered. Interventions were separated based on (1) the aim of the intervention: prevention or treatment of mucositis; (2) the treatment setting: radiotherapy, chemotherapy, chemoradiotherapy or high-dose conditioning therapy for hematopoietic stem cell transplant and (3) the route of administration of the intervention.

Criteria used to evaluate literature

The quality of the reviewed literature was assessed by identifying flaws in study design and methods as part of the data extraction process. Identification of flaws in study design and reporting followed the guidelines published by Hadorn et al. [6]. This allowed reviewers to assign major and minor flaws to each study (Table 1). As part of the data extraction process, each reviewer identified major and minor flaws in the reviewed papers. In case of discrepancy between the two reviewers, the respective section head/co-head made the final decision on the list of major and minor flaws for each study. Less than 5 % of all studies reviewed were found to have no major flaws.
Table 1

Study design flaws

Study design variable

Major flaws

Minor flaws

1. Selection of patients

a. Diagnostic criteria for mucositis not described

a. Diagnostic criteria for mucositis inadequately described

b. Inclusion and exclusion criteria not specified

b. Inclusion and exclusion criteria inadequately described

c. Decision regarding inclusion or exclusion from study made after treatment initiated

c. Patients were excluded from participation but no reasons given

d. Study population not representative of majority of patients

e. Cohort studies—groups not treated concurrently

 

2. Allocation of patients to treatment groups

For randomised clinical trials only:

For randomised clinical trials only:

a. Appears patients were not randomly assigned to groups

a. Patients were not allocated to groups in a truly randomised fashion

b. Known prognostic factors or confounders for mucositis were not measured at baseline or no comparison of the values for these variables

For cohort or registry studies only:

c. Known prognostic factors or confounders for mucositis were not measured at baseline

3. Therapeutic regimen

None

a. Mean daily dose taken by patients not recorded

b. Actual dosing schedule not described, only total daily dose given

c. Titration end points not described

d. Other therapeutic manoeuvres not described adequately enough to be able to repeat study

4. Study administration

a. Patients were crossed over into the other group outside of the study design

a. In a multicentre study—methods of diagnosis, treatment, or outcome measurement were not identical among participating centres

b. Medications were used that were not part of the study design and could confound the results

c. Other significant breaks in study protocol occurred

5. Withdrawals from study

a. Reasons for patient withdrawals not listed

a. Excessive number of withdrawals regardless of reasons (>10 % for studies lasting <3 months, >15 % for studies lasting >3 months)

b. Sensitivity analysis shows that the number of withdrawals with unlisted/unknown outcomes could significantly bias results

6. Patient blinding (Randomised Controlled Trials Only)

a. A placebo was not used in the control group

a. For studies that used mortality as an endpoint, a study that claimed to be placebo controlled gave no description of how placebo was administered

b. For studies with patient reported health status or symptoms as the primary end point: A study that claimed to be placebo controlled but gave no description of how it was administered

b. For studies with patient reported health status or symptoms as end point: Physical characteristics, side effects or method of administration of placebo differed from that of the active drug so that it was possible for the patient to discern the treatment assignment

7. Outcome measurement

a. For studies that require investigators to rate patient clinical status or measure clinical parameters (such as scoring mucositis): Double blind method was not used

a. For studies that measure mortality—double blind methodology was not used

b. For studies that require investigators to rate patient clinical status or measure clinical parameters (such as scoring mucositis): Double blind method was attempted but suffered from serious flaws

b. For studies that measured mortality—double blind method was attempted but suffered from serious flaws

8. Statistical analysis

a. The analytical techniques described are incorrect and there is inadequate information to perform a correct analysis

a. Analytical techniques described are incorrect, but there is adequate information to perform correct analysis

b. A significant difference was found in one or more baseline characteristics that are known prognostic factors or confounders, but this was not adjusted for in the analysis

b. Means and tests for statistical significance are presented without measure of variance

c. Results are presented in graphical form and tests for significance are presented without giving the actual mean values to create the graph

d. Withdrawals are not handled properly

e. Post-hoc subgroup analyses are performed

f .One-sided tests are inappropriately used for testing statistical significance

Table adapted from Hadorn et al. [6]

Assignment of a level of evidence

Once the major and minor flaws in each paper were identified, the overall body of evidence for a given intervention was assessed. Based on this, the section head assigned a level of evidence for each paper and for each intervention for each specific indication (prevention or treatment of mucositis) and route of administration, in each population. The assigning of a level of evidence was based on criteria published by Somerfield et al. (Table 2) [7]. These criteria allocate levels of evidence based on the type of study and according to whether or not a study is “well-designed”. In order to minimise subjectivity in determining whether a study is well-designed or not, we defined a “well-designed study” as a study with no major flaws, per the Hadorn criteria. If a study did not meet this definition of well-designed, it was assigned a level of evidence one level below what it would have received if it had no major flaws. For example, a single randomised controlled trial with no major flaws was assigned level II; however, if it had one or more major flaws, it was assigned level III. The overall body of evidence for an intervention was assigned with the level of evidence of the highest-ranking individual paper available for that intervention. For example, if there were three papers for a given intervention, one RCT with major flaws (level III) and two case–control studies with major flaws (level IV), an overall level of evidence of III was assigned for that intervention. An exception to this rule was the rare situation in which there were two or more well-designed RCTs (level II) for an intervention. In this case, an overall level of evidence of I was assigned for the intervention.
Table 2

Levels of evidence

I

Evidence obtained from meta-analysis of multiple, well-designed, controlled studies; randomised trials with low false-positive and false-negative errors (high power)

II

Evidence obtained from at least one well-designed experimental study; randomised trials with high false-positive and/or false-negative errors (low power)

III

Evidence obtained from well-designed, quasi-experimental studies, such as nonrandomised, controlled single-group, pretest–posttest comparison, cohort, time or matched case–control series

IV

Evidence obtained from well-designed, non-experimental studies, such as comparative and correlational descriptive and case studies

V

Evidence obtained from case reports and clinical examples

Table adapted from Somerfield et al. [7]

Development of guidelines

The evidence level for each intervention facilitated guideline development. Based on the methodology described in Somerfield et al. (Table 3) [7], guidelines were assigned to one of three possible categories: Recommendation, Suggestion or No Guideline Possible. Specifically, level I or II evidence was required to form a recommendation, which could only be achieved by one or more RCTs without any major flaws. A suggestion could be formed using level III or lower evidence. However, in practice, a suggestion was only created when more than one study existed for the intervention in the specific setting. If only one study existed, or if there was no panel consensus on the interpretation of the literature, no suggestion was possible. Furthermore, any intervention that showed evidence in the literature of worsening mucositis or inducing severe side effects was noted specifically by the section head and the risk–benefit ratio was discussed by the wider group. In practice, this could be one of the reasons for the development of a guideline against the use of an agent. Directions for clinical practice were specified based on the aim, setting and administration for each intervention. The provisional guidelines were discussed at a Guidelines Update Meeting attended by over 60 members of the committee and two independent observers. Committee consensus was achieved before finalising guidelines. A summary of the entire process is shown in Fig. 2.
Table 3

Categories used to classify agents

Recommendation

Reserved for guidelines that are based on level I or level II evidence

Suggestion

Used for guidelines that are based on level III, level IV and level V evidence; this implies panel consensus on the interpretation of this evidence

No guideline possible

Used when there is insufficient evidence on which to base a guideline; this implies (1) that there is little or no evidence regarding the practice in question or (2) that the panel lacks consensus on the interpretation of existing evidence

Table adapted from: Somerfield et al. [7]

Fig. 2

Guideline development process. Literature searches were conducted, with studies then selected based on inclusion and exclusion criteria. Each study was reviewed by two independent reviewers, with findings assimilated and summarised by the section head. Levels of evidence (LOE) were then allocated to each intervention in each setting. The provisional guidelines were confirmed or modified upon consensus at the Mucositis Guidelines Workshop meeting

Summary

This guidelines update process assembled a large panel of mucositis experts to assess the current state of the evidence and develop clinical practice guidelines for mucositis management. The results generated are presented in a series of manuscripts based on class of intervention and provide a structured approach to deliver the best possible supportive care.

Notes

Acknowledgments

The authors thank Drs. Ira Parker and Sol Silverman, Jr, for acting as independent observers.

Conflict of interest

The Mucositis Guidelines Update was sponsored by Helsinn Healthcare S.A., Switzerland and BioAlliance Pharma, France. Per MASCC policy, no industry representatives had any role in the development of the guidelines. No author has a financial relationship with the sponsoring organisations. All review data are available for review upon request.

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • J. M. Bowen
    • 1
    Email author
  • S. Elad
    • 2
  • R. D. Hutchins
    • 3
  • R. V. Lalla
    • 4
  • For the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO)
  1. 1.School of Medical SciencesThe University of AdelaideAdelaideAustralia
  2. 2.Division of Oral Medicine, Eastman Institute for Oral HealthUniversity of Rochester Medical CenterRochesterUSA
  3. 3.Research Medical LibraryU. T. M. D Anderson Cancer CenterHoustonUSA
  4. 4.Section of Oral Medicine and Neag Comprehensive Cancer CenterUniversity of Connecticut Health CenterFarmingtonUSA

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