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Base de datos Cochrane de Revisiones Sistemáticas Protocolo - Intervención

Low dose cytarabine monotherapy for acute myeloid leukaemia

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Versión publicada: 07 diciembre 2011 Historial de versiones

https://doi.org/10.1002/14651858.CD009480

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The main objective of this systematic review is to evaluate the efficacy and safety of low dose cytarabine for patients with AML.

Background

Description of the condition

Acute myeloid leukaemia (AML) is a malignant disease of the haematopoietic stem cell. There are two classifications commonly used to categorise haematopoietic malignancies. In general, AML is characterised by a rapid proliferation of non‐functional myeloblasts in the bone marrow. This results in a loss of functioning cells evolved from the myeloid cell line (i.e. granulocytes, monocytes, erythrocytes and thrombocytes). The symptoms of patients with AML are related to the functional pancytopenia with anaemia, neutropenia and thrombocytopenia despite high white blood cell counts. Often patients present symptoms of anaemia such as fatigue, asthenia, dyspnoea, accompanied by infections and bleeding tendency because of neutropenia and thrombocytopenia, respectively (Lowenberg 1999).

There are two systems commonly used to define AML. The French American British (FAB) classification, introduced in 1976, is based on morphological and cytochemical methods (Bennett 1976). It subcategorises AML into eight entities and sets the threshold between high‐grade myelodysplastic syndromes (MDS) and AML ≧ 30% blasts. The World Health Organization (WHO) classification system, introduced in 1999 and revised in 2008, uses morphology and newer prognostic factors such as karyotype and clinical feature to define different entities (Harris 1999; Vardiman 2009). It differentiates between 17 subtypes of AML and lowers the threshold for the diagnosis of AML to > 20% blasts.

AML is a rare disease with an overall incidence of 3.5/100,000 people, while more than 50% are older than 60 years of age at the time of diagnosis (Altekruse 2010). The outcome after treatment of this disease is heterogenous. A number of prognostic factors, such as advanced age, performance status, cytogenetics, white blood cell count and secondary AML, have been described to be predictors of treatment response and overall survival (Wheatley 2009). Of these prognostic factors, patient age at diagnosis, performance status and karyotype are the factors with the strongest direct effect on treatment outcome (Appelbaum 2006; Frohling 2006; Juliusson 2009).

Advanced age, mostly defined as age over 60 years, plays a critical role for this disease. The survival of patients older than 60 years is only half of that of younger patients (Buchner 2009). Even within the group of older patients, the increase of the patient`s age is associated with a higher incidence of death early after induction therapy, a lower rate of complete response and a lower chance for long‐term survival (Appelbaum 2006). The combination of performance status and age at diagnosis can be used to make an estimate of the percentage of patients who will die within the first 30 days of treatment. Appelbaum et al. shows that in most cases age had a modest effect for patients with an excellent performance status (Appelbaum 2006). But for patients with an inferior performance status, age had a dramatic effect: 82% of patients older than 75 years and a performance status of three died within 30 days after the initiation of induction.

Regarding cytogenetic factors and abnormalities, Grimwade et al. developed a molecular systematic to discriminate three cytogenetic risk groups: favourable, intermediate risk and adverse risk (Grimwade 1998; Grimwade 2001; Grimwade 2010). Using these definitions, rates of overall survival at five years were 65%, 41% and 14% for patients with favourable risk, intermediate risk and adverse risk, respectively (Grimwade 1998). Similar stratification systems to that used in older adults with AML showed overall survival rates at five years for the same groups of 38%, 13% and 4%, respectively (Grimwade 2001).

Description of the intervention

As stated above, the age of a patient plays a critical role for this disease and treatment approaches differentiate between patients up to the age of 60 years and older than 60 years of age (Dohner 2010; Fey 2010; Milligan 2006; NCCN 2011).

The standard therapy for patients up to the age of 60 years is a high‐intensive treatment regimen of cytarabine (there are several regimens of high dose cytarabine, one example is 2 to 3 g/m² every 12 hours for three days, one cycle) plus anthracycline, with or without allogeneic stem cell transplantation (Fey 2010; NCCN 2011).

Patients older than 60 years with poor performance status do not benefit from high‐intensive treatment regime approaches because of the high rates of treatment‐related mortality with these intensive regimes (Appelbaum 2006; Kantarjian 2006). For patients older than 60 years of age with good performance status, no significant co‐morbidities, and positive disease features, a treatment with standard dose cytarabine is recommended (there are several regimens of standard dose cytarabine, one example is 100 to 200 mg/m² every 12 hours for seven days, one or two cycles) (Fey 2010; NCCN 2011). In the case that patients older than 60 years have advanced risk factors (complex cytogenetics, aberration chromosome 5, aberration chromosome 7, aberration 11q23, del(5q), abnormal 3q, trisomy 8, t(6;9), t(9;22)) or severe co‐morbidities there are different recommended alternatives:

How the intervention might work

In‐vitro research showed differentiation of leukaemic cells caused by cytarabine when given in low‐dose (Beran 1986; Griffin 1982; Hoelzer 1984). However, cytarabine is a cytidine analogue (Allegra 1997). Cytidine analogues incorporate in the DNA as “false building blocks” and inhibit the DNA synthesis which is the main mechanism of their antileukaemic activity (Allegra 1997).

Small non‐randomised studies of low‐dose cytarabine in heterogeneous populations with AML and MDS patients suggest that between 10% and 20% of these patients will achieve complete remission (CR) (Powell 1989; Winter 1985) with a median survival of three months. A RCT examining low‐dose cytarabine in AML patients that were ineligible for intensive treatment showed similar results of 18% CR. The median survival was three months for patients that did not response and 80 months for those who reached CR (Burnett 2007). The median disease‐free survival in patients with CR was eight months (Burnett 2007).

Why it is important to do this review

The effect of low‐dose cytarabine in the therapy of AML for patients older than 60 years of age is not clear. The main issue is that it is important to do this review since there is no good solution for elderly patients with AML. There are several therapeutic options and low dose cytarabine is one of them. Its role in this frustrating population of AML patients should be evaluated.

So far, there is no systematic review assessing the efficacy and safety of low‐dose cytarabine in the therapy of AML. This Cochrane Review will provide comprehensive evidence to clarify the impact of this agent.

Objectives

The main objective of this systematic review is to evaluate the efficacy and safety of low dose cytarabine for patients with AML.

Methods

Criteria for considering studies for this review

Types of studies

We will consider only randomised controlled trials (RCTs) as primary studies in this review and meta‐analysis. We will include both full text and abstract publications. We will not include cross‐over studies or quasi‐randomised trials.

Types of participants

We will include only newly diagnosed adult participants, i.e. at least 18 years of age, diagnosed with AML. If trials include mixed populations (i.e. patients with different haematological malignancies) we will use data from the subgroup of patients with AML. If subgroup data for AML patients are not available (after contacting the authors of the trial), we will include the trial if at least 80% of patients have AML. Furthermore, we will assess the definition of AML used by the investigators. We will evaluate effects of different definitions of AML (i.e. > 20% blasts versus ≧ 30% blasts) by subgroup analyses.

Types of interventions

We will analyse RCTs assessing low dose cytarabine given as monotherapy in patients that are not eligible for allogeneic stem cell transplantation. We will assess the following comparisons.

1) Low‐dose cytarabine plus best supportive care (intervention) versus best supportive care alone (control)

2) Low‐dose cytarabine (intervention) versus other chemotherapy regimens (control)

Furthermore we will assess different dose and time schedules of low dose cytarabine.

We will include all trials that proclaim to assess "low dose" cytarabine. In the case that the authors did not otherwise specify the examined cytarabine regimen, we will consider doses dose between 5 mg/m2 to 20 mg/m2 every 12 hours as low‐dose cytarabine treatment, corresponding to definitions of the term “low dose” in relevant publications many trials (Di Febo 2007; Faderl 2008; Hagenbeek 1983; Hellstrom 1990; Rossi 2002; Winter 1985; Yamada 1995).

We will not include RCTs examining low‐dose cytarabine compared to allogeneic stem cell therapy or trials assessing low‐dose cytarabine given subsequent to intensive therapy.

Types of outcome measures

Primary outcomes

Overall survival (OS) will be the primary outcome due to its relevance to patients with AML and its importance as an indicator of the benefits of an intervention. We will define OS as the time interval from random treatment assignment or entry onto study to death from any cause or to last follow‐up.

Secondary outcomes

  1. Overall survival at 1 year

  2. Progression‐free survival (PFS) will be defined as the time interval from random treatment assignment or entry onto study to first confirmed progression or relapse, death from any cause or the last follow‐up

  3. Complete response (CR)

  4. Adverse events

  5. Treatment‐related mortality

  6. Quality of Life ( We will only assess information on Quality of Life, if it was analysed using a standardised validated questionnaire. In the case that different questionnaires were used, we will review the concept of measurement of these instruments to compare and if possible meta‐analyse their content.)

Search methods for identification of studies

Electronic searches

We have adapted search strategies from those suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011). We will not apply language restriction to reduce the language bias.

We will search the following databases of medical literature:

Searching other resources

We will search the following conference proceedings from 2000 up to the present, if they are not included in CENTRAL.

  1. American Society of Hematology (ASH)

  2. American Society of Clinical Oncology (ASCO)

  3. European Hematology Association (EHA)

  4. European Society of Medical Oncology (ESMO)

In addition, we will also search the conference proceeding of ASH from the year 1977 up to 2000.

We will electronically search in the database of ongoing trials:

  • Metaregister of controlled trials: http://www.controlled‐trials.com/mrct/.

Furthermore, we will search web sites of pharmaceutical companies and will also check reference lists of RCTs and other systematic reviews to identify eligible trials.

Data collection and analysis

Selection of studies

After the first review of all titles and abstracts of the identified studies from the above sources, two review authors (FH, KB) will independently reject all studies that are clearly ineligible. We will assess selected studies by using an eligibility form regarding study design and compliance with inclusion criteria. The forms will contain the following questions:

  1. Is the study described as randomised?

  2. Were the patients diagnosed with acute myeloid leukaemia?

  3. Were the patients in the intervention group treated with low‐dose cytarabine?

In case of doubt we will include full text analysis and discuss eligibility with both review authors to finalise a decision (preferably including studies rather than losing relevant data). According to PRISMA we will use a flow diagram to show numbers of identified records, excluded articles and included studies (Moher 2009).

Data extraction and management

Two review authors (FH, KB) will independently extract data according to Chapter 7 of the Handbook (Higgins 2011a) by using a standardised data extraction form containing the following items.

  • General information: author, title, source, publication date, country, language, duplicate publications

  • Quality assessment: sequence generation, 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, comparability of groups, subgroup analysis, statistical methods, power calculations, treatment cross‐overs, compliance with assigned treatment, length of follow‐up, time point of randomisation

  • Participant characteristics: age, gender, number of participants recruited/allocated/evaluated, participants lost to follow‐up

  • Interventions: setting, dose and duration of low‐dose cytarabine treatment, type of additional or comparator chemotherapy, supportive treatment, type of treatment (first‐line treatment, pretreated patients), additional treatment

  • Outcomes: OS, PFS, CR, quality of life, adverse events, treatment‐related mortality

Assessment of risk of bias in included studies

To assess the methodological quality and the risk of bias we will use a questionnaire according to the recommendations in Chapter 8 of the Handbook for the following criteria (Higgins 2011b).

  • Sequence generation

  • Allocation concealment

  • Blinding (participants, personnel, outcome assessors)

  • Incomplete outcome data

  • Selective outcome reporting

  • Other sources of bias

Measures of treatment effect

For binary outcomes we will calculate risk ratios (RR) with 95% confidence intervals (CI) for each trial. We will calculate continuous outcomes as standardised mean difference (SMD). For time‐to‐event outcomes we will extract the hazard ratio (HR) from published data according to Parmar 1998 and Tierney 2007.

Dealing with missing data

As suggested in Chapter 16 of the Handbook (Higgins 2011), there are many potential sources of missing data which are to be taken into account: at study level; at outcome level; at summary data level; at individual level; at study‐level characteristics (e.g. for subgroups analysis). Firstly, it is important to make the difference between "missing at random" and "not missing at random".

If we assume data to be missing at random, we will analyse the only the available data (i.e. ignoring the missing data).

In the case we assume data not to be missing at random, we will input the missing data with replacement values, and treat these as if they were observed (e.g. last observation carried forward, imputing an assumed outcome such as assuming all were poor outcomes, imputing the mean, imputing based on predicted values from a regression analysis).

Assessment of heterogeneity

We will assess heterogeneity of treatment effects between trials by using a Chi² test with a significance level at P < 0.1. We will use the I² statistic to quantify possible heterogeneity (30% < I² < 75%: moderate heterogeneity, I² > 75 % considerable heterogeneity) (Deeks 2011).

We will use the tests for interaction to test for differences between subgroup results.

Assessment of reporting biases

In meta‐analyses with at least 10 trials, we will explore potential publication bias by generating a funnel plot and we will statistically test by means of a linear regression test. We will consider P < 0.1 as significant for this test (Sterne 2011).

Data synthesis

We will perform analyses according to the recommendations of Chapter 9 of the Handbook (Deeks 2011). We will use aggregated data for analysis. For statistical analysis, we will analyse data using the Cochrane software Review Manager (RevMan 2011). One review author will input data into software and a second review author will check it for accuracy. We will perform meta‐analyses using a fixed‐effect model (for example the generic inverse variance method for survival data outcomes and Mantel‐Haenszel method for dichotomous data outcomes). We will perform meta‐analyses only if we can identify at least two trials that assess similar comparisons, e.g. low‐dose cytarabine plus best supportive care versus best supportive care alone or low‐dose cytarabine versus other chemotherapy regimens. In the case of different trials of low‐dose cytarabine versus other chemotherapy regimens, we will include only similar controls in one meta‐analysis. We will use the random‐effects model in terms of sensitivity analyses.

If appropriate, we will calculate the number needed to treat to benefit and the number needed to treat to harm for the primary outcome.

Subgroup analysis and investigation of heterogeneity

We will assess heterogeneity of treatment effects between trials by using a Chi² test with a significance level at P < 0.1. We will use the I² statistic to quantify possible heterogeneity. On the following characteristics we will consider performing subgroup analyses, if appropriate.

  1. Different types of AML (de novo AML versus MDS related AML)

  2. Different types of low‐dose definition (e.g. 5 mg/m2 every 12 hours versus 20 mg/m2 every 12 hours)

  3. Different types of definitions of AML (i.e. > 20% blasts versus ≧ 30% blasts)

Sensitivity analysis

  • Quality components, including full‐text publications versus abstracts, preliminary results versus mature results, published versus unpublished data.

  • Random‐effects modelling.

  • In the case that the trial includes only MDS and AML patients and less than 80% of the patients have AML, we will use the trial for sensitivity analysis.

  • Based on risk of bias, i.e. we will perform a analysis of all moderate and low risk of bias by omitting studies that we judge to be of high risk of bias. We will provide a justification of our individual judgement within the review.