Types of studies

We will consider all prospective, randomized controlled trials (RCTs) of methotrexate versus mycophenolate mofetil utilizing a parallel study design for inclusion in this systematic review. We will exclude all other study designs.

Types of participants

We will include all participants who are undergoing allo‐HCT and at risk of developing GVHD. Participants with an existing diagnosis of acute or chronic GVHD will be excluded. There will be no restriction on patient gender, ethnic group, or age. We will describe the disease type and stage of the included patients.

Types of interventions

Included studies must report on the direct comparison of any mycophenolate mofetil‐based regimen versus any methotrexate‐based regimen administered as prophylaxis for acute GVHD in patients undergoing allo‐HCT. Specifically, we will consider a regimen to be used as prophylaxis for acute GVHD if (1) the investigators specifically state mycophenolate mofetil or methotrexate is used as prophylaxis for acute GVHD or (2) if the study inclusion/exclusion criteria exclude patients with an existing diagnosis of acute or chronic GVHD. Supportive care and other GVHD prophylaxis/therapies, if any, should be similar in both arms. Additionally, since mycophenolate mofetil and methotrexate are commonly administered in combination with a calcineurin inhibitor (e.g. cyclosporine or tacrolimus), we will include all regimens containing mycophenolate mofetil versus all those containing methotrexate, regardless of co‐therapies, in the review. We will conduct a subgroup analysis based on different co‐therapies as they are identified.

Types of outcome measures

Electronic searches

We will conduct an electronic search of Cochrane Renal Group (CRG) Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library) using search strategy in (Appendix 1) and MEDLINE using search strategy in (Appendix 2) from inception to the present. No date or language limits will be used.

Searching other resources

In order to identify any recently completed studies which have not yet been published in full, we will conduct a handsearch of conference abstracts from the last two meetings of the American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH), European Group of Blood and Marrow Transplantation (EBMT), and BMT tandem meetings of the American Society of Blood and Marrow Transplantation (ASABM), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Hematology Association (EHA). We will also handsearch references of all identified review articles and included studies. Finally, in order to identify unpublished or ongoing studies, we will search ClinicalTrials.gov, Novartis clinical trials registry, Roche clinical trial protocol registry, and the Metaregister of controlled trials.

Selection of studies

Two authors will review all titles, abstracts, and full‐text reports independently. Studies which meet the following criteria will be included in this review.

1. Prospective clinical trial

2. Parallel study design

3. Patients randomized to prophylaxis with mycophenolate mofetil versus methotrexate

4. Patients undergoing allo‐HCT

We will match references on author names, location and setting, specific intervention details, and participants to avoid inclusion of duplicate publications. Any disagreements which occur during study selection will be resolved by consensus with a third author.

Data extraction and management

Two authors will independently extract data according to Chapter 7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using a standardized data extraction form containing the following items.

• General information: study title, authors, source

• Study characteristics: study design, setting, duration of follow‐up

• Patient characteristics: number of patients enrolled, number of patients included in the analysis, specific disease diagnosis, donor status (related or unrelated donor), HLA‐mismatch, patient age

• Interventions: name, dose, route, administration schedule, and associated therapies

• Outcomes: incidence of acute GVHD (grades II to IV and III to IV GVHD), overall survival, median days to ANC engraftment, median days to platelet engraftment, relapse rate, incidence of chronic GVHD, grade III or IV adverse events, non‐relapse mortality (any death occurring without disease relapse/recurrence), pain

• Risk of bias

For studies which have multiple publications, we will use the publication with longest follow‐up for extracting data on outcomes. We may use earlier publications to extract data on methodology and baseline characteristics. In cases where the method of analysis is not specified by the investigators and only the number of events is reported, we will use number randomized as the denominator. That is, we will record results according to intention‐to‐treat (ITT) analysis.

Assessment of risk of bias in included studies

Two review authors will independently assess the risk of bias in the included studies using The Cochrane Collaboration's tool for assessing the risk of bias as outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a) based on extracted information. Any disagreement between the two authors will be resolved by a third author. In addition to risk of bias, we will evaluate the risk of random error by extracting data on the investigator's pre‐determined effect difference, alpha, power, and sample size.

Specifically, for assessment of risk of bias, we will grade each component of methodological quality low, high, or unclear. We will evaluate selection bias by assessing the investigators' description of method of randomization and allocation concealment. We will consider the method of randomization to be:

• low risk if the investigators describe a random component in the sequence generation process (i.e. refer to a random number table, use a computer random number generator, coin toss);

• high risk if the investigators describe a non‐random component in the sequence generation process (sequence generated by odd or even date of birth, some rule based on date (or day) of admission, or some rule based on hospital or clinic record number); and

• unclear risk if there is insufficient information about the sequence generation process to permit judgment of ‘low risk’ or ‘high risk’.

We will consider allocation concealment to be:

• low risk if participants and investigators enrolling participants could not foresee assignment (i.e. use of central allocation, sequentially numbered identical drug containers or sequentially numbered, opaque, sealed envelopes);

• high risk if participants or investigators enrolling participants could possibly foresee assignments (allocation based on date of birth, case record number, using an open random allocation schedule); and

• unclear risk if there is insufficient information to permit judgment of ‘low risk’ or ‘high risk’.

We will evaluate performance bias by assessing the investigators' description of blinding of patients and investigators. We will consider this to be:

• low risk if no blinding was used, but the outcome is not likely to be influenced by lack of blinding or participants and key study personnel were blinded;

• high risk if no blinding or incomplete blinding was used, and the outcome is likely to be influenced by lack of blinding; and

• unclear risk if there is insufficient information to permit judgment of ‘low risk’ or ‘high risk’.

We will judge detection bias due to knowledge of the allocated interventions by outcome assessors to be:

• low risk if no blinding of outcome assessment was used, but the outcome measurement is not likely to be influenced by lack of blinding or blinding of outcome assessment was ensured;

• high risk if there was no blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; and

• unclear risk if there is insufficient information to permit judgment of ‘low risk’ or ‘high risk’. 

We will judge attrition bias due to the amount, nature, or handling of incomplete outcome data to be:

• low risk if there are no missing outcome data, reasons for missing outcome data are unlikely to be related to true outcome, or missing outcome data are balanced in numbers across intervention groups, with similar reasons for missing data across groups. For continuous outcome data, a plausible effect size (difference in means or standardized difference in means) among missing outcomes is not enough to have a clinically relevant impact on observed effect size, and missing data have been imputed using appropriate methods;

• high risk if the reasons for missing outcome data are likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups. For dichotomous outcome data, the proportion of missing outcomes compared with the observed event risk is enough to induce clinically relevant bias in the intervention effect estimate, and for continuous outcome data, a plausible effect size (difference in means or standardized difference in means) among missing outcomes is enough to induce clinically relevant bias in the observed effect size, or uses ‘as‐treated’ analysis with substantial departure of the intervention received from that assigned at randomization or uses potentially inappropriate application of simple imputation;

• unclear risk if there is insufficient reporting of attrition/exclusions to permit judgment of ‘low risk’ or ‘high risk’ (e.g. number randomized not stated, no reasons for missing data provided).

We will consider reporting bias due to selective outcome reporting to be:

• low risk if the study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way or the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified;

• high risk if the study’s pre‐specified primary outcomes have not been reported, primary outcomes are reported using measurements that were not pre‐specified, primary outcomes were not pre‐specified, outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis, or the study report fails to include results for a key outcome that would be expected to have been reported for such a study; and

• unclear if there is insufficient information to permit judgment of ‘low risk’ or ‘high risk’.

For the evaluation of risk or random error, we will capture whether investigators report pre‐determined effect difference, alpha, power, and sample size calculation (yes/no and reported values) and if they were able to enroll the pre‐specified number of patients (pre‐specified sample size versus total number enrolled per arm).

Measures of treatment effect

Unit of analysis issues

The unit of analysis for this review will be the individual study. Since we only plan to include prospective clinical trials with a parallel study design, we do not expect unit of analysis issues associated with cluster‐randomized trials or cross‐over studies. In the case of repeated follow‐up (e.g. reporting of survival at three months and six months), we will use the longest follow‐up from each study. We will treat recurring events (e.g. adverse events) as a single event occurring in one patient (e.g. four instances of grade III nausea in one patient will be considered as one patient with grade III nausea). Given the nature of the disease and the two regimens, we do not expect unit of analysis issues associated with multiple treatment attempts or use of multiple body parts. In the case of multiple intervention arms, we will combine arms together to create a single pair‐wise comparison. If one or more arms does not contain mycophenolate mofetil or methotrexate, it/they will not be included in the analysis.

Dealing with missing data

As suggested in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b), in the case of missing data, we will make an attempt to contact the principal investigator, corresponding author (or both) of the study. If the corresponding author does not provide the missing data, the study will be included in the systematic review but excluded from the meta‐analysis for the outcome with missing data. We will conduct a sensitivity analysis to evaluate the robustness of findings despite missing data and we will disclose any potential impacts of the missing data in the Discussion.

Assessment of heterogeneity

To evaluate heterogeneity between pooled studies,we will calculate Chi² and I² statistics Higgins 2011c). We will consider an I² > 50% or a Chi² test with a significance level at P < 0.1 to indicate statistically significant heterogeneity. We will assess potential sources of heterogeneity by conducting a sensitivity analysis on all aspects of study quality. Using the same methods we will also calculate heterogeneity (test of interaction) between subgroups while performing sensitivity or subgroup analysis.

Assessment of reporting biases

We will assess publication bias using a funnel plot (Egger 1997; Higgins 2011d) if more than 10 studies are included in the review. We will evaluate selective reporting of outcomes within studies by comparing outcomes reported with outcomes specified in protocols, if available.

Data synthesis

We will perform pooled analysis using RevMan 5 software (RevMan 2011) (version 5.1.6). We will employ a random‐effects model using the DerSimonian‐Laird approach to pool studies for all analyses (DerSimonian 1986).

We will construct a 'Summary of findings' table using the most clinically and patient‐relevant outcomes (Guyatt 2011). These outcomes will include: (1) overall survival; (2) incidence of grade III to IV acute GVHD; (3) incidence of grade II to IV acute GVHD; (4) incidence of chronic GVHD; (5) non‐relapse mortality; (6) incidence of any grade III to IV adverse events. Additionally, we will evaluate and report the quality of evidence for each outcome according to GRADE guidelines (Balshem 2011; Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e).

Subgroup analysis and investigation of heterogeneity

We plan to conduct a subgroup analysis on prognostically relevant factors including gender, age (adult versus child), stage, previous treatment, differences in therapy regimen (co‐therapies), remission status prior to conditioning (complete remission), and type of donor (sibling versus unrelated).

Sensitivity analysis

In order to assess the robustness of the pooled results and explore possible reasons for heterogeneity, we will conduct a sensitivity analysis on all aspects of methodological quality. We will conduct additional sensitivity analyses on any differences observed in patient population, intervention, or control treatment.