Types of studies

We will consider only randomised controlled trials (RCTs), in which randomisation was conducted according to ESA and/or iron status. We will include both full‐text and abstract publications if sufficient information is available on study design, characteristics of participants and interventions provided.

Types of participants

We will include trials on patients of any age with solid cancer and/or haematological malignancy undergoing chemotherapy, radiotherapy or no anti‐cancer therapy. We will apply no gender or ethnicity restrictions. We will only include studies in which participants are anaemic or at risk for anaemia from chemotherapy, radiotherapy or combination therapy, or the underlying malignant disease.

Studies including patients suffering from anaemia as a result of surgery will be excluded, as well as patients suffering from anaemia due to haemolysis.

Types of interventions

Included trials will address one or multiple of the following interventions:

• ESA + IV iron;

• ESA + oral iron;

• ESA + no iron;

• ESA + iron unclear;

• ESA + iron, unclear application;

• no ESA + IV iron;

• no ESA + oral iron;

• no ESA + iron unclear;

• no ESA + iron, application unclear;

• no treatment ‐ defined as baseline therapy excluding the addition of ESAs, or iron supplementation; and

• placebo.

All interventions will be compared to each other using a network meta‐analysis (Figure 1). We assume that any patient that meets the inclusion criteria is, in principle, equally likely to be randomised to any of the eligible interventions. We plan to group interventions by merging doses according to the product characteristics.

Figure 1

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Types of outcome measures

We will estimate the relative ranking of the competing interventions according to the following outcomes:

• on‐study mortality (deaths occurring up to 30 days after the active study period);

• number of red blood cell (RBC) transfusions;

• haematological response (proportion of participants with an increase in haemoglobin (Hb) level of 2 g/dL or more, or increase in haematocrit of six percentage points or more, unrelated to transfusion);

• overall survival (longest follow‐up available); and

• adverse events (AEs).

Electronic searches

We will search the following databases and sources:

• databases of medical literature:

  • MEDLINE (Ovid) (1950 to present) (Appendix 1);

  • the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, latest issue) (Appendix 2);

• conference proceedings of annual meetings of the following societies for abstracts, if not included in CENTRAL (2010 to present):

  • American Society of Hematology;

  • American Society of Clinical Oncology;

  • European Hematology Association;

• databases of ongoing trials:

  • register of controlled trials: www.controlled‐trials.com;

  • EU clinical trials register: www.clinicaltrialsregister.eu/ctr‐search/search;

  • clinicaltrials.gov: www.clinicaltrials.gov; and

• databases and websites of relevant institutions, and organisations (e.g. pharmaceutical industries).

Searching other resources

• Handsearching of references:

  • references of all identified trials and relevant review articles; current treatment guidelines as further literature.

We will use the following sources to identify the studies for this network meta‐analysis:

• previous Cochrane reviews on the effect of ESAs on cancer patients with anaemia, as well as patients with CIA (Tonia 2012; Mhaskar 2016); and

• reference lists of other systematic reviews and meta‐analyses.

Selection of studies

Two review authors will independently screen results of search strategies for eligibility for this review by reading all abstracts. In cases of disagreement, we will obtain the full‐text publication. If no consensus can be reached, we will ask a third review author (Higgins 2011a).

We will document the process of study selection in a flow chart, as recommended by the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement (Moher 2009), showing total numbers of retrieved references and numbers of included and excluded studies.

Data extraction and management

Two review authors will independently extract data according to Chapter Seven of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will contact authors of individual studies to ask for additional information, if required. We will use a standardised data extraction form containing the following items:

• general information:

  • author, title, source, publication date, country, language, duplicate publications;

• quality assessment:

  • allocation concealment, blinding (participants, personnel, outcome assessors), incomplete outcome data, selective outcome reporting, other sources of bias;

• study characteristics:

  • trial design, aims, setting and dates, source of participants, inclusion/exclusion criteria, subgroup analysis, treatment cross‐overs, compliance with assigned treatment, length of follow‐up;

• participant characteristics:

  • patient's age, gender, number of participants recruited/allocated/evaluated, participants lost to follow‐up, type of treatment, underlying disease, newly diagnosed or relapsed;

• interventions:

  • placebo use, ESA‐dose, iron‐dose, dosing regimen, duration, route of administration, RBC transfusion trigger, co‐medications with dose, co‐treatment, route and timing; and

• outcomes:

  • on‐study mortality, haematological response, overall survival, AEs, number of RBC transfusions.

Assessment of risk of bias in included studies

Two review authors will independently assess risk of bias for each study using the following criteria, as outlined in Chapter Eight of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b):

• sequence generation;

• allocation concealment;

• blinding (participants, personnel, outcome assessors);

• incomplete outcome data;

• selective outcome reporting; and

• other sources of bias.

We will make a judgement for each criterion, using one of the following categories:

• 'Low risk': if the criterion is adequately fulfilled in the study (i.e. the study is at low risk of bias for the given criterion);

• 'High risk': if the criterion is not fulfilled in the study (i.e. the study is at high risk of bias for the given criterion); and

• 'Unclear': if the study report does not provide sufficient information to allow a clear judgement, or if risk of bias is unknown for one of the criteria listed above.

Measures of treatment effect

We will use intention‐to‐treat data. For binary outcomes, we will use risk ratios (RRs) with 95% confidence intervals (CIs) as the measure of treatment effect. For time‐to‐event outcomes, we will use hazard ratios (HRs) and their 95% CIs. Data will be extracted from publications according to Parmar 1998 and Tierney 2007. We will calculate continuous outcomes as mean differences (MDs) with 95% CIs. We do not expect continuous outcomes assessed with different instruments, so standardised MD is not required.

Unit of analysis issues

Dealing with missing data

As suggested in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we will take the following steps to deal with missing data.

Whenever possible, we will contact the original investigators to request relevant missing data. If the number of patients evaluated for a given outcome is not reported, we will use the number of patients randomised per treatment arm as denominator. If only percentages but no absolute number of events are reported for binary outcomes, we will calculate numerators using percentages. If estimates for mean and standard deviations are missing, we will calculate these statistics from reported data whenever possible, using approaches described in Chapter 7.7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). If standard deviations are missing and we are not able to calculate them from reported data, we will calculate values according to a validated imputation method (Furukwa 2006). If data are not reported in a numerical but graphical format, we will estimate missing data from figures. We will perform sensitivity analyses to assess how sensitive results are to imputing data in some way. We will address in the Discussion section the potential impact of missing data on findings of the review.

Assessment of heterogeneity

Assessment of reporting biases

In pair‐wise comparisons with at least 10 trials, we will examine the presence of small‐study effects graphically by generating funnel plots. We will use linear regression tests (Egger 1997) to test for funnel plot asymmetry. A P value less than 0.1 will be considered significant for this test (Sterne 2011). We will examine the presence of small‐study effects for the primary outcome only.

Data synthesis

Subgroup analysis and investigation of heterogeneity

The following subgroup analysis will be conducted, if appropriate:

• type of iron (iron dextran, ferrous gluconate, ferrous sulphate, etc.);

• route of iron administration (IV versus oral);

• type of ESA (epoetin versus darbepoetin);

• type of anti‐cancer therapy (chemotherapy, radiotherapy, no treatment);

• cancer type; and

• duration of follow‐up.

Sensitivity analysis

To test the robustness of the results, we will conduct fixed‐effect pair‐wise and network meta‐analyses. We will report the estimates of the fixed‐effect only if they show a difference to the random‐effects model. We will explore the influence of quality components with regard to low and high risk of bias.