Types of studies

We will include randomised controlled trials of adults in which at least 90% are diagnosed with histologically proven mycosis fungoides (classical "Alibert‐Bazin" type).

We will exclude quasi‐randomised studies (e.g. alternate treatment allocation or by date of birth), as we consider this study design to be of poor quality and likely to lead to unreliable study results.

Types of participants

We will include studies of adults (aged 18 years or more) diagnosed with histologically confirmed mycosis fungoides of the classical "Alibert‐Bazin" type.

We will exclude studies from this review that include more than 10% of participants with variants and subtypes of mycosis fungoides like folliculotropic mycosis fungoides, pagetoid reticulosis, or granulomatous slack skin.

Types of interventions

We will be interested in comparisons of any local or systemic therapy with either another local or systemic therapy or with placebo. Types of interventions include:

• topical therapies;

• skin‐directed phototherapies;

• total skin electron beam;

• radiotherapy;

• chemotherapy;

• extracorporeal photochemotherapy;

• biological response modifiers;

• combination therapies;

• newer skin‐directed treatment approaches; and

• newer systemic treatment approaches.

Comparisons shall be made according to stage of disease, whereas the TNMB classification shall be used primarily under consideration of applicability of the interventions in a certain disease stage.

Types of outcome measures

With mycosis fungoides being a slowly progressive disease we shall investigate improvement and clearance as well as relapses separately.

Electronic searches

We will search the following databases for randomised controlled trials:

• The Cochrane Skin Group Specialised Register;

• The Cochrane Central Register of Controlled Trials (Clinical Trials) in The Cochrane Library;

• MEDLINE (from 2005 to the present);

• EMBASE (from 2007 to the present); and

• LILACS (Latin American and Caribbean Health Science Information database) (from inception to the present).

The UK Cochrane Centre (UKCC) has an ongoing project to systematically search MEDLINE and EMBASE for reports of trials which are then included in the Cochrane Central Register of Controlled Trials (Clinical Trials). Searching has currently been completed in MEDLINE to 2004 and in EMBASE to 2006. The Cochrane Skin Group will undertake further searching for this review to cover the years that have not been searched by the UKCC.

We have devised a draft search strategy to find randomised controlled trials (RCTs) in MEDLINE (OVID) which is displayed in Appendix 1. We will modify this to include additional search terms where necessary and will use it as the basis for search strategies for the other databases listed.

Searching other resources

Selection of studies

We will assess studies that seem to meet the inclusion criteria by screening for eligibility using an eligibility form. This eligibility form will contain the following questions:

• Is the study described as randomised?

• Did at least 90% of the participants in the study have biopsy‐proven classical mycosis fungoides?

• Is the stage of the mycosis fungoides given?

• Are the participants under investigation 18 years of age or older?

To be eligible, studies will have to meet all of the criteria stated above. If there is insufficient information to judge eligibility, we will try to contact the first author of the report for clarification. We will solve any disagreements between the two review authors (TW and PR) by discussion. We will identify any duplicate reports. We will obtain full text versions of all eligible studies for quality assessment and data collection. At every stage of searching and screening of the literature we will document the overall number of studies identified, excluded and included, with reasons, in a flow diagram as suggested by the Preferred Reporting Items of Systematic Reviews and Meta‐Analyses (PRISMA) (Moher 2009).

We will resolve disagreements by discussion and consensus with a third party (AB).

Data extraction and management

Two authors (TW and PR) will independently screen titles and abstracts of studies identified from the above sources for the eligibility criteria stated previously. If this cannot be done satisfactorily from the title and abstract, we will obtain a full text version for assessment. We will look for:

• Information about treatment and outcome for each participant:

• • Diagnosis and stage of mycosis fungoides

  • Received treatment

  • Additional therapy

  • Remission/improvement

  • Duration of remission

  • Toxicity and adverse events

• Potentially significant participant‐related prognostic factors:

• • Age (birth date)

  • Sex

• Potentially significant tumour‐related prognostic factors:

• • Histologic subtype

  • Clinical stage (patch, plaque, tumour)

  • Blood tumor burden: atypical T lymphocytes (Lutzner cells)

  • Elevated eosinophilic cells

  • Systemic involvement (lymph nodes, bone marrow, internal organs)

We will try to obtain any missing data from the trial authors where possible. We will develop a data collection form and pilot it in order to summarise the trials.

Assessment of risk of bias in included studies

Two authors (TW and PR) will assess quality by doing a 'Risk of bias' assessment using the new features of Review Manager 5 and as described in Table 8.5c of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). The same authors will assess the domains which will include:

(a) sequence generation;

(b) allocation concealment;

(c) blinding;

(d) whether incomplete outcome data were addressed;

(e) whether the study was free of selective reporting; and

(f) whether the study was free of other bias.

We will discuss any disagreements until consensus is obtained. We will assess quality using an assessment form designed for the topic of this review (sources used: Hollis 1999; Jüni 2001; Moher 1995; Verhagen 1998).

Measures of treatment effect

The effect measure of choice will be the risk ratio (RR). For continuous effect measures we shall use the standardised mean difference. For combining continuous effect measures presented on different scales we shall use the standardised mean difference instead. We shall combine time‐to‐event effect measures using the hazard ratio. For all measures of effect we will report 95% confidence intervals and corresponding P values.

Dealing with missing data

We will attempt to obtain data that were not reported directly from the original researchers. If data on adverse outcomes is missing, we will use the "rule of three" to calculate (Hanley 1983). The rule of three states that if none of n participants showed the event, we can be 95% confident that the chance of this event is at most 3/n.

We will deal with missing data by contacting the corresponding author of the paper with missing data and asking him or her to provide this data. If the corresponding author does not reply within four weeks or does not provide the requested data, we will impute missing data using the last observation carried forward method and we will test the effect of this. As part of our sensitivity analysis, we will also compute missing data to create a worst and a best case scenario to explore the robustness of our findings.

Assessment of heterogeneity

In order to address clinical heterogeneity, we will tabulate the included studies in terms of study characteristics and outcomes and then carefully examine them for quality, similarities, and differences. We will address statistical heterogeneity using I² statistic. Substantial heterogeneity will be defined as an I² statistic with a value greater than 50%. If extreme levels of heterogeneity exist between the studies (I² statistic > 80%) we will report the results of the studies individually, and explore heterogeneity using subgroup analyses.

Assessment of reporting biases

In order to assess for possible reporting bias, we will examine a funnel plot for asymmetry where feasible (e.g. more than 10 studies for an outcome). If asymmetry is detected, we will explore possible reasons including selection biases, poor methodological quality of smaller studies, true heterogeneity, artefact, and chance.

Data synthesis

Where possible, we will conduct a meta‐analysis of trials and subgroups, or both, using random‐effects models. We will present data in the form of forest plots.

Subgroup analysis and investigation of heterogeneity

We will explore potential causes of heterogeneity by performing subgroup analysis: stage of mycosis fungoides (patch, plaque, or tumour) and different interventions. In addition, analysis of the interventions will be carried out depending upon the stage of mycosis fungoides. Furthermore, we will conduct subgroup analysis according to potentially significant participant‐related prognostic factors (age and gender) or potentially significant tumour‐related prognostic factors, as described above.

Sensitivity analysis

We will perform sensitivity analyses to explore the influence of the following factors on effect size.

1. Study quality as in allocation concealment.

2. Largest trials in the review.

3. Excluding studies using the following filters (language of publication, funding sources, etc).

4. Investigation of the origin (individual participant data or publication) of the data/information.