Intensity-modulated versus conventional radiotherapy for breast cancer

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To examine the effect of intensity-modulated radiotherapy (IMRT) for women with breast cancer treated with conservative surgery and post-operative radiation therapy.

Background

Description of the condition

Breast cancer is the most common cancer in women worldwide (Parkin 2005). In the United States of America it has been estimated that there will be 40,000 deaths annually from the disease and 210,000 new cases of invasive breast tumor diagnosed in 2010 (Jemal 2010). Developing countries present lower incidence rates when compared to developed countries (Parkin 2005). These differences might be related to societal features such as risk factors involved in cancerization (Berry 2005) and the availability of screening programmes (Parkin 2005; Ravdin 2007). Risk factors that have been associated with breast cancer include age and gender (Peto 2000), race and ethnicity (Jatoi 2007), benign breast disease (Degnim 2007), personal history of breast cancer (Kelsey 1981), lifestyle and dietary factors (Bernstein 2005; Lahmann 2004), reproductive and hormonal factors (Hsieh 1990), family history and genetic factors (Lichtenstein 2000), previous exposure to ionizing radiation (Henderson 2010), and environmental factors (Lipworth 2009).

For early-stage breast cancer, the standard treatment is breast-conserving surgery followed by radiation therapy. This approach is an effective alternative to mastectomy and leads to high local control rates with good cosmesis (i.e. breast appearance; Bartelink 2001; Fisher 2002). This conservative treatment of breast cancer is based on the surgical excision of the tumor, axillary management and conventional radiotherapy and once the pathological staging and biological markers are known, patients may undergo systemic (whole body) treatments as well (EBCTCG 2005a).

Radiation therapy has been used in patients with breast cancer who have undergone either radical mastectomy or breast-conserving treatments to assure better local control and survival (NCCN 2011; Recht 2001; Veronesi 2002). The effectiveness of conventional radiotherapy was demonstrated in randomized trials comparing radical mastectomy with breast-conserving surgery, showing equivalent overall survival and local control rates (Fisher 2002; Veronesi 2002). After conventional radiotherapy, about 30% of women develop high-grade acute skin toxicity (i.e. breast pain, erythema (redness), desquamation (peeling skin) and edema (swelling)) that is associated with a decrease in their quality of life (Al-Ghazal 1999). This toxicity may, therefore, influence both physician’s and patient’s decision regarding the use of conservative breast surgery and appropriate adjuvant (add on) therapy (Fernando 1996; Fisher 2002; NCCN 2011). The main risk factors of acute radiation-induced toxicity after conventional irradiation are large breast size and non-uniformities of dose (i.e. inhomogeneities) within tissues that receive up to 10% of the prescribed dose (Fernando 1996). Nevertheless, most historical publications use conventional radiation therapy without reference to any acceptable quality assurance standards. Since women with breast cancer usually have good prognoses and long life-expectancy, minimizing toxicities, even when mild, should be a goal of treatment.

Description of the intervention

The aim of radiation therapy is to treat the target volume (i.e. tissue that is to be irradiated to a specific dose) with a uniform (homogeneous) dose while minimizing radiation to surrounding normal tissues. In conventional radiotherapy, planning is based on two dimensions (using planar images such as X-ray) and the dose distribution calculation is made from a single plane (outline) of the patient. Using this technique, the dose range outside this boundary is not considered i.e. there is no exact dose/volume measurement for the entire breast, only information from a single axial plane. This means that other critical structures such as the lungs, heart, spinal cord and esophagus are often included in the treatment field, which may significantly contribute to the toxicity.

Since the 1980s, there have been considerable improvements in the hardware and treatment planning systems used in radiation therapy. These have included developments in three-dimensional conformal radiotherapy (3DCRT) which corrects non-conformities (i.e. the treated volume of tissue concurs with what was planned) and takes into account the patient's chest contour at different levels. With this method, however, the actual dose delivered is practically the same as in conventional radiotherapy, i.e. the non-uniformity in dose (inhomogeneity) remains the same. It is important to note that the dose prescriptions should meet some limits of acceptance such as those outlined by the International Commission on Radiation Units and Measurements (ICRU 62). In breast cancer, these recommendations are not always respected.

Intensity-modulated radiation therapy (IMRT) is a method that delivers highly conformal radiation with improved dose homogeneity and reduces the radiation dose to the normal, surrounding tissues. IMRT employs an inverse planning algorithm that produces dose distributions that are superior to conventional radiotherapy or 3DCRT. IMRT also allows higher doses to be delivered to the target volume (Webb 2003). In women with breast cancer, IMRT may reduce long-term complications by minimizing undesired radiation to organs-at-risk (such as the heart, lungs, spinal cord, ribs and skin). As a result, IMRT may improve quality of life and, perhaps, even overall survival.

How the intervention might work

The search for improvements in dose uniformity (i.e. homogeneity) is important in order to avoid over-treating areas inside the breast and surrounding tissues. The prescribed radiation dose to the target volume is at the level of 50 Gray (Gy) but there might be areas receiving 30% to 40% more radiation.

For breast cancer, IMRT provides optimal dose homogeneity. Its impact is in reducing both acute, and late, skin and connective tissue toxicities, and improving tolerance and quality of life (Barnett 2011; Donovan 2007; Pignol 2008). For those patients who present with a complex anatomy (i.e. pectus excavatum and flat chest) or need comprehensive nodal treatment, IMRT could represent a useful way to achieve safe delivery of radiation treatment by: (a) improving dose homogeneity, (b) sparing the contralateral breast and nearby organs at risk, such as the lung and heart (McCormick 2011), and (c) diminishing the likelihood of toxicities and secondary-malignancies over time. Reducing the dose of radiation to the heart is particularly desirable, as it would reduce subsequent ischemic heart disease (IHD) and treatment-related deaths from radiation therapy (IHD deaths dilute the survival benefit from post-operative radiation therapy; EBCTCG 2005b; Roychoudhuri 2007).

Some groups have been studying these new technologies in order to assess their potential benefits. Currently, there are three published randomized trials that we know of for women with breast cancer in which IMRT was compared with conventional techniques (Barnett 2011; Donovan 2007; Pignol 2008). In all of these trials, the focus was on the therapy of early-stage disease.The trials showed that IMRT increased radiation dose homogeneity, which was associated with a reduction in skin dermatitis and an improvement in breast cosmesis. These results highlight the potential advantages in minimizing toxicity outcomes, however, even with the reasonable availability of IMRT, the higher costs and complexity of this technology have meant that clinicians do not use it as part of routine clinical practice (Smith 2011).

Why it is important to do this review

To date there are no systematic reviews addressing the efficacy and safety of IMRT for breast cancer. Furthermore, there is still a lack of research on the toxicities related to radiation. Thus, the aim of this systematic review is to assess whether or not the safety and efficacy of IMRT are equivalent to conventional breast cancer radiotherapies.

Objectives

To examine the effect of intensity-modulated radiotherapy (IMRT) for women with breast cancer treated with conservative surgery and post-operative radiation therapy.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) comparing IMRT with any modality of conventional radiotherapy for women with breast cancer.

We will exclude quasi-randomized and non-randomized studies.

Types of participants

Women with ductal carcinoma in situ (DCIS) and early invasive breast cancer who have undergone conservative treatment, comprising:

  1. breast surgery: wide local excision or quadrantectomy;

  2. axillary management: axillary dissection, axillary sampling, sentinel node biopsy plus or minus axillary dissection;

  3. radiotherapy of the entire remaining breast.

The indication for radiotherapy for the following areas is made based on the status of axillary lymph node metastases, and will be considered for analysis:

  1. radiotherapy of the supraclavicular lymph nodes, delivered in conventional fractionation;

  2. radiotherapy of the axillary levels, delivered in conventional fractionation;

  3. radiotherapy of the internal mammary chain, delivered in conventional fractionation.

Types of interventions

Experimental intervention: any type of intensity-modulated radiotherapy (IMRT), defined as inverse-planning IMRT using conventional linear accelerators (sliding window, modulated blocks, and step-and-shoot facility), tomotherapy, volumetric modulated arc therapy (VMAT) and field-in-field technique. Novel techniques will be included for analysis in future studies, but they should meet IMRT characteristics.

Control group: only conventional external beam radiotherapy using 3DCRT delivered at 1.8 to 2.0 Gy per fraction will be eligible.

Treatments that use integrated boost as well as those using sequential boost (electron-beam, brachytherapy, and photon-beam delivery) will be included in the data collection.

Systemic treatments such as hormones, chemotherapy, or monoclonal antibodies are permitted, as long as they are applied equally to each arm of the trial.

Hypofractionated radiotherapy (i.e. more than 2 Gy per fraction) will be excluded.

Partial breast radiotherapy will be excluded.

Types of outcome measures

Primary outcomes
  1. Local control, considered separately for DCIS and early breast cancer, defined as the time (from randomization) until the development of any local recurrence during follow-up (time-to-event outcome). We define local recurrence as including recurrence in the ipsilateral breast (i.e. the breast in which cancer had been diagnosed), the skin and parenchyma.

  2. Acute toxicity related to radiotherapy, i.e. any toxic events occurring in the breast, skin, lung and heart within three months of completion of radiotherapy. Acute toxicity will be classified according to the scales used by authors, otherwise we will use the score from the National Cancer Institute Common Toxicity Criteria (NCI-CTC; http: ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcsv20_4-30-992.pdf (accessed 21 February 2011)).

Secondary outcomes
  1. Overall survival, considered separately for DCIS and early breast cancer, defined as the time from randomization to any-cause death during follow-up.

  2. Disease-free survival, considered separately for DCIS and early breast cancer, defined as the time from randomization to relapse during follow-up.

  3. Late toxicity related to radiotherapy, i.e. any toxic events occurring more than six months after radiotherapy. These will be classified according to the scales used by the authors, otherwise we will consider grade 3 or 4 toxic events according to the National Cancer Institute Common Toxicity Criteria (http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf (accessed 21 February 2011)).

  4. Cosmesis, classified according to the scales used by authors, otherwise we will use scores from the Harvard/Radiation Therapy Oncology Group (RTOG)/National Surgical Adjuvant Breast and Bowel Project (NSABP) criteria (Harris 1979).

  5. Quality of life, classified according to the scales used by authors, or current scores (European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and BR-23, Global Health Score, and Arm Symptoms Score (BRAS)).

  6. Mastectomy rate.

  7. Secondary malignancy rate.

  8. Treatment costs.

Search methods for identification of studies

See: Breast Cancer Group methods used in reviews.

Electronic searches

We will search the following databases.

  1. The Cochrane Breast Cancer Group (CBCG) Specialised Register. The CBCG will search their Specialised Register. Details of the search strategies used by the Group for the identification of studies and the procedure used to code references are outlined in the Group's module (http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/BREASTCA/frame.html). We will extract trials coded with the key words 'early breast cancer', 'locally advanced breast cancer', 'radiotherapy', and 'intensity modulated radiotherapy'.

  2. The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), refer to Appendix 1.

  3. MEDLINE (via Ovid SP), refer to Appendix 2.

  4. EMBASE (via EMBASE.com), refer to Appendix 3.

  5. The WHO International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/AdvSearch.aspx) for all prospectively registered and ongoing trials. See Appendix 4.

  6. ClinicalTrials.gov (http://www.clinicaltrials.gov/). See Appendix 5.

  7. The LILACS database (http://bases.bireme.br/cgi-bin/wxislind.exe/iah/online/?IsisScript=iah/iah.xis&base=LILACS&lang=p). This database contains bibliographic references of health publications from Latin America and Caribbean countries from 1982 onwards. It includes 605 health journals with more than 290,000 references. See Appendix 6.

Searching other resources

We will also conduct the following.

  1. A manual search of reference lists from the retrieved studies.

  2. Contact experts in the field for information about ongoing or non-published studies.

Data collection and analysis

Selection of studies

Independently, two authors (GNM and SAH) will check the titles and abstracts of studies obtained in the search for potentially relevant trials. From this first evaluation, full versions of all potentially relevant articles will be obtained. Any disagreements will be resolved by a third author (RR).

Excluded trials will be recorded in the 'Characteristics of excluded studies' table with reasons for their exclusion.

Data extraction and management

Data will be extracted and recorded on data extraction forms. Forms will be developed and piloted independently by two authors (GNM and SAH). Full data extraction will be conducted independently by these two authors, and disagreements will be resolved by a third author (RR). We will try to obtain unpublished data of interest from authors by email.

The following information from the eligible primary studies will be inserted on data extraction forms:

  • Publication details (i.e. year, country, authors).

  • Study design.

  • Setting, inclusion and exclusion criteria, randomization method, allocation concealment, blinding.

  • Population data (i.e. age, time of diagnosis).

  • Details of intervention (i.e. doses, regimen, scheme, length, type of radiotherapy).

  • Outcome measures.

  • Withdrawals.

  • Length of follow up.

  • Type of data analyses (e.g. intention-to-treat, modified intention-to-treat).

  • Any potential risks of bias.

Data will be inserted into Review Manager software (RevMan), and, if possible, pooled for meta-analysis.

Assessment of risk of bias in included studies

Critical appraisal of the methodological quality of the included studies will be carried out independently by two authors (GNM and SAH) using the Cochrane Collaboration's risk of bias (RoB) tool as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). For each RoB domain and specific question (detailed below), authors will assign an assessment of either 'high', 'low' or 'unclear'. In accordance with the result from the three main domains (the first three), the studies will be classified as being at 'low, 'moderate' or 'high' risk of bias overall.

  1. Sequence generation: was the allocation sequence adequately generated?

  2. Allocation concealment: was allocation adequately concealed?

  3. Blinding of participants, personnel, and outcome assessors: was knowledge of the allocated interventions adequately prevented during the study?

  4. Incomplete outcome data: were outcome data adequately assessed and accounted for?

  5. Selective outcome reporting: are reports of the study free of suggestion of selective outcome reporting?

  6. Other potential threats to validity: was the study apparently free from other problems that could put it at risk of bias?

Under other biases, we will note whether or not formal quality assurance of radiotherapy was performed. The performance of quality assurance may act as a surrogate measure of the quality of IMRT.

Measures of treatment effect

For each outcome, we will calculate the summary estimates of treatment effect with 95% confidence intervals (CI).

Dichotomous outcomes (i.e. acute and late toxicity, cosmetic assessments, mastectomy rate, and secondary malignancy rate) will be reported as risk ratios (RRs) or, if this is not possible, as risk differences (RDs) with 95% CIs.

Continuous outcomes (i.e. quality of life assessments using validated scores, and treatment costs) will be reported as mean differences (MD) for outcomes measured on the same scale, and standardized mean differences (SMDs) for outcomes measured on different scales, with 95% CIs.

For time-to-event outcomes (i.e. local control, overall survival and disease-free survival), the hazard ratio (HR) will be reported. When possible, the HR and associated variances will be obtained directly from the trial publications. If the HRs are not reported, they will be obtained indirectly using the methods described by Parmar et al using other available summary statistics, or from data extracted from published Kaplan-Meier curves (Parmar 1998). To allow for immature follow up the numbers at risk will be adjusted on the basis of estimated minimum and maximum follow-up times. If these are not reported in any of the reports available, minimum follow up will be estimated using the estimated time taken to complete treatment, and maximum follow up will be estimated using the last event reported in the relevant time-to-event curve.

Unit of analysis issues

The unit of analysis will be the individual patient.

Dealing with missing data

In the case of missing or unavailable data, trial authors will be contacted for detailed information. If the data are missing to the extent that the study cannot be included in the meta-analysis, the results will be presented and discussed in the main text of the review.

Assessment of heterogeneity

The Chi2 test and the I2 statistic will be used to assess the percentage of total variation across studies due to heterogeneity rather than due to chance. An I2 value greater than 50% will be considered to indicate substantial heterogeneity (Higgins 2011b).

Clinical and methodological diversities will be investigated as potential causes of heterogeneity, and then decisions about whether to pool results will be based on the degree of heterogeneity and the clinical diversity of the studies. If data aggregation is not possible, results of individual studies will be presented and discussed in the main text.

The following factors will be investigated as potential causes of heterogeneity:

  • Clinical diversity: the study location and setting, full characteristics of participants, co-morbidity and treatments that participants may be receiving on trial entry. We will consider how outcomes were measured, the definition of outcomes and how they were recorded.

  • Methodological diversity: we will consider the randomization process, study methodological quality and analytical method.

Assessment of reporting biases

Trial authors will be contacted about reasons for the non-reporting of data for some outcomes. We will search for trial protocols and other versions of included trials.

Data synthesis

Data will be synthesized using Review Manager software (RevMan).

Initially, a fixed-effect model will be used for all analysis, however, if significant clinical or methodological heterogeneity exists, we will use a random-effects model. If data aggregation is not feasible, the results will be discussed and presented as tables or graphics.

For dichotomous outcomes, the risk ratio will be calculated. The Mantel-Haenszel method will be used for the fixed-effect model and the inverse variance (DerSimonian and Laird) method will be applied for the random-effects model.

For continuous data outcomes we will use the mean difference for studies that report an outcome using the same scale, otherwise (for studies that use different scales), we will apply the standardized mean difference. The inverse-variance method will be used for the fixed-effect analysis, and the inverse variance (Dersimonian and Laird) method will be used for the random-effects analysis.

We will use the hazard ratio for time-to-event data. The inverse-variance method will be used for a fixed-effect or a random-effects analysis.

Subgroup analysis and investigation of heterogeneity

The following variables will be considered for subgroup analysis:

  • Time from the diagnosis to surgery and radiotherapy.

  • Patient age brackets (under 40 years, 41 to 50 years, 51 to 60 years, 61 to 70 years, 71 to 80 years, and over 80 years).

  • Different surgical modalities of breast surgery (quadrantectomy, lumpectomy, tumorectomy, and partial mastectomy).

  • Radiotherapy issues, such as:

    • Delivered doses: conventional fractionation (i.e. 1.8 to 2.0 Gy/day in 25 to 28 days until 50 to 50.4 Gy) or simultaneously integrated boost fractionation.

    • Boost issues: delivered doses (10 Gy in five fractions), technique (electron-beam, photon-beam, brachytherapy) and treatment context (sequential or integrated to whole-breast irradiation).

    • Conventional techniques (conventional planning, 3DCRT planning).

    • IMRT techniques (step-and-shoot, sliding window, VMAT, tomotherapy, field-in-field among others, biologically equivalent dose).

    • Formal quality assurance of radiotherapy.

Sensitivity analysis

Sensitivity analysis will be carried out by excluding trials of low, or moderate, methodological quality, or both, from the analysis. Moreover, time since publication of studies will be considered for analysis, dividing them as follows: before 1995, 1995 to 2000, 2001 to 2005, 2006 to 2010, 2011 to present. These analyses will be presented and compared with the overall findings.

Acknowledgements

We would like to acknowledge the Brazilian Cochrane Centre, specifically Professor Doctor Alvaro Nagib Atallah, MD, PhD, for his great support.

We also acknowledge the editorial base of the Cochrane Breast Cancer Group for their guidance.

Appendices

Appendix 1. CENTRAL

#1    MeSH descriptor: [Breast Neoplasms] explode all trees

#2    breast and (cancer* or tumour* or tumor* or neoplas*)      

#3    #1 and #2  

#4    MeSH descriptor: [Radiotherapy, Intensity-Modulated] explode all trees 

#5    Intensity-modulated radiotherap*   

#6    IMRT

#7    #4 or #5 or #6   

#8    MeSH descriptor: [Radiotherapy] explode all trees    

#9    conventional radiotherap*    

#10   radiotherap*     

#11   #8 or #9 or #10  

#12   #3 and #7 and #11      

Appendix 2. MEDLINE (via OvidSP)

# ▲Searches
1randomised controlled trial.pt.
2randomized controlled trial.pt.
3controlled clinical trial.pt.
4randomized.ab.
5randomised.ab.
6placebo.ab.
7randomly.ab.
8trial.ab.
9groups.ab.
101 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9
11exp Breast Neoplasms/
12exp Radiotherapy, Intensity-Modulated/
13intensity-modulated radiotherap*.mp.
14intensity modulated radiotherap*.mp.
15IMRT.mp.
1612 or 13 or 14 or 15
1710 and 11 and 16

Appendix 3. EMBASE (via Embase.com)

#1'randomised controlled trial'/exp OR 'randomised controlled trial'
#2'randomized controlled trial'/exp OR 'randomized controlled trial'
#3'controlled clinical trial'/exp OR 'controlled clinical trial'
#4randomised AND controlled AND trial             
#5controlled AND clinical AND trial
#6ranomi*ed:ab                
#7placebo:ab
#8randomly:ab
#9trial:ab
#10groups:ab
#11#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10
#12'breast neoplasm'
#13'breast cancer'/exp OR 'breast cancer'
#14'breast tumour'      
#15'breast tumor'/exp OR 'breast tumor'
#16#12 OR #13 OR #14 OR #15
#17'intensity-modulated radiotherapy'/exp OR 'intensity-modulated radiotherapy'
#18'intensity modulated radiotherapy'/exp OR 'intensity modulated radiotherapy'
#19'IMRT'/exp OR IMRT
#20#17 OR #18 OR #19
#21#11 AND #16 AND #20
#22#21 AND [humans]/lim AND [embase]/lim AND [1996-2013]/py

Appendix 4. WHO ICTRP search portal

Basic Searches:

1.     Intensity-modulated versus conventional radiotherapy for breast cancer

2.     breast cancer AND intensity-modulated radiotherapy

 

Advanced Searches:

1.       Title: Intensity-modulated versus conventional radiotherapy for breast cancer

Recruitment Status: ALL

2.       Condition: breast cancer

Intervention: (intensity-modulated radiotherapy OR intensity modulated radiotherapy) AND conventional radiotherapy

Recruitment Status: ALL

Appendix 5. Clinicaltrials.gov

Basic Searches:

1.     Intensity-modulated versus conventional radiotherapy for breast cancer[ft1] 

2.     breast cancer AND ((intensity-modulated radiotherapy OR intensity modulated radiotherapy) AND (conventional radiotherapy))[ft2] 

 

Advanced Searches:

1.       Title: Intensity-modulated versus conventional radiotherapy for breast cancer

Recruitment: All studies

Study Results: All studies

Study Type: All studies

Gender: All studies

2.      Condition: breast cancer

Intervention: (intensity-modulated radiotherapy OR intensity modulated radiotherapy) AND (conventional radiotherapy)

Recruitment: All studies

Study Results: All studies

Study Type: All studies

Gender: All studies

Appendix 6. LILACS

#1 (Breast Neoplasms) OR  (Neoplasias de la Mama) OR (Neoplasias da Mama) OR (Cancer of Breast) OR (Breast Cancer) OR (Breast Tumors))

#2 (Radiotherapy, Intensity-Modulated) OR (Intensity-modulated Radiation Therapy) OR (Intensity-Modulated Radiotherapies) OR (Intensity-Modulated Radiotherapy) OR (Radiotherapies, Intensity-Modulated) OR (Radiotherapy, Intensity Modulated) OR IMRT OR (Radioterapia de Intensidade Modulada) OR (Radioterapia de Intensidad Modulada)

#3 #1 AND #2

#4 "ENSAIO CLINICO" or "ENSAIO CLINICO CONTROLADO" or "ENSAIO  CLINICO CONTROLADO ALEATORIO" or "ENSAIO CLINICO FASE I" or "ENSAIO CLINICO FASE II" or "ENSAIO CLINICO FASE III" or "ENSAIO CLINICO FASE IV" or "METANALISE" or "REVISAO" [Tipo de publicação]

#5 #3 AND #4

Contributions of authors

  1. Drafting the protocol: SAH, GNM and RR.

  2. Study selection: SAH, GNM and RR (arbiter).

  3. Extract data from studies: SAH, GNM and RR (arbiter).

  4. Enter data into RevMan: SAH and GNM.

  5. Carry out the analysis: SAH and GNM.

  6. Interpret the analysis: SAH, GNM, HC, JLFS and ACSDB.

  7. Draft the final review: SAH, GNM, and HC.

  8. Disagreement resolution: RR.

  9. Update the review: SAH, GNM, EM and HC.

Declarations of interest

The following authors declare that they have no conflicts of interest that relate to this review: Samir Abdallah Hanna, Gustavo Nader Marta, Rachel Riera, Heloisa de Andrade Carvalho, Joao Luis Fernandes da Silva, and Alfredo Carlos Dornellas Simoes de Barros.

Sources of support

Internal sources

  • Hospital Sírio-Libanês, São Paulo, Brazil.

    Support

External sources

  • Brazilian Cochrane Centre, Universidade Federal de São Paulo, São Paulo, Brazil, Brazil.

    Support

  • Faculdade de Medicina, Universidade de Sao Paulo and Hospital Sirio Libanes, São Paulo, Brazil, Brazil.

    Support

Ancillary