Capecitabine for ER-positive versus ER-negative breast cancer

  • Protocol
  • Intervention

Authors


Abstract

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

To assess the effects of chemotherapy regimens containing capecitabine compared with regimens not containing capecitabine for women with ER-positive versus ER-negative breast cancer.

Background

Description of the condition

Breast cancer is the most common malignancy among women in the world, with an estimated 1.67 million new cases diagnosed in 2012 accounting for 25% of all cancers (Ferlay 2012). Breast cancer is the fifth leading cause of cancer-related death in the world. In more developed regions it is the second leading cause of cancer-related death among women while it is the leading cause in less developed regions (Ferlay 2012).

Five-year survival following a diagnosis with breast cancer has significantly increased over the last 20 years. This is as a consequence of the implementation of population screening as well as improvements in systemic treatment. Newer agents including endocrine therapies, human epidermal growth factor receptor 2 (HER2) targeted therapies and chemotherapeutic drugs such as the taxanes and capecitabine have contributed significantly to the longer survival for women with locally advanced and metastatic breast cancer. The evidence guiding the use of endocrine and HER2 targeted therapies is clear. However, despite the evidence for a substantial difference in chemotherapy sensitivity between endocrine responsive and non-responsive breast cancers, data guiding the selection of chemotherapeutic agents with respect to hormone receptor status are sparse.

Description of the intervention

Capecitabine is an oral prodrug of fluorouracil. Following absorption, capecitabine is metabolised in the liver and in cancerous tissue. The final step in the conversion of capecitabine to fluorouracil is catalysed by thymidine phosphorylase, which is present in high amounts in cancer cells (Miwa 1998). As such, the effect of capecitabine is concentrated within cancer cells. Capecitabine has been used extensively as a single agent and as part of combination regimens for metastatic breast cancer. Its use as part of adjuvant and neo-adjuvant therapy for breast cancer has also been investigated in clinical trials. However, it is currently not licensed for use in this setting in Australia.

Some of the common adverse effects reported in association with capecitabine, in 5% or more of patients, include diarrhoea, stomatitis, nausea and vomiting, hand-foot syndrome (palmar-plantar erythrodysesthesia), dermatitis, fatigue and cytopaenias. Angina pectoris is a less common but clinically important side effect which is reported to affect 0.2% of patients (FDA 2014).

How the intervention might work

A pooled analysis of individual patient data from capecitabine monotherapy clinical trials for locally advanced or metastatic disease demonstrated that patients with hormone receptor-positive breast cancer experienced significantly improved overall response rates, progression-free survival and overall survival compared with patients with hormone receptor-negative disease (Blum 2012). Several retrospective reviews have also identified significantly greater benefits from capecitabine in hormone receptor-positive metastatic breast cancer (Siva 2008; Gluck 2009; Osako 2009).

In the neoadjuvant setting, capecitabine-containing chemotherapy regimens have been associated with greater benefits in hormone receptor-positive breast cancer also. In an unplanned subgroup analysis from the large phase III GeparTrio trial investigating the tumour response guided treatment switch to capecitabine-vinorelbine after two cycles of docetaxel, doxorubicin and cyclophosphamide, patients with hormone receptor-positive breast cancers experienced significantly longer disease-free survival compared with their hormone receptor-negative counterparts (von Minckwitz 2008). A second phase III trial examining the use of neoadjuvant docetaxel-capecitabine (TX) versus doxorubicin-cyclophosphamide (AC) found that TX was associated with a higher rate of pathologic complete response at 17% in hormone receptor-positive breast cancers compared with 3% for AC, suggesting capecitabine may be a more effective treatment than AC in hormone receptor-positive breast cancer (Lee 2008).

Why it is important to do this review

At diagnosis, approximately 70% of breast cancers are hormone receptor-positive (Mao 2012). However, presently there is little collated evidence to guide the selection of chemotherapeutic agents for oestrogen receptor-positive (ER+) versus oestrogen receptor-negative (ER-) tumours. The information gained from the completion of this review may help to inform the selection of chemotherapeutic agents for patients based on ER status. Additionally, this review may guide the development of randomised trials in more targeted populations in the adjuvant and neoadjuvant setting and may inform a review of the regulations regarding the prescription of capecitabine in the metastatic setting.

Objectives

To assess the effects of chemotherapy regimens containing capecitabine compared with regimens not containing capecitabine for women with ER-positive versus ER-negative breast cancer.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) looking at chemotherapy regimens containing capecitabine alone or in combination versus a control arm employing a similar regimen without capecitabine for the treatment of breast cancer.

It is anticipated that three or greater RCTs will be found for each section of this review. However, if fewer than three RCTs are found for any of the three sections of this review, well-designed non-randomised controlled trials will be considered.

Types of participants

Women who have been histologically diagnosed with breast adenocarcinoma.

We will include trials where:

  • > 75% of study participants have a defined hormone receptor status;

  • breast cancer may be of any stage.

Types of interventions

Intervention: chemotherapy regimens containing capecitabine alone or as part of combination therapy in ER-positive and ER-negative breast cancer.

Comparator: similar chemotherapy regimens not containing capecitabine in ER-positive and ER-negative breast cancer. The comparator can include: (a) the same chemotherapy regimen without capecitabine, (b) a different chemotherapy regimen without capecitabine, and (c) the same chemotherapy regimen with another drug or drugs substituting for capecitabine.

Comparisons will include:

  • capecitabine-containing regimen versus non-capecitabine containing regimen in ER-positive breast cancer, and

  • capecitabine-containing regimen versus non-capecitabine containing regimen in ER-negative breast cancer.

We will also include studies of strategies that may be:

  • chemotherapy given as neoadjuvant, adjuvant or palliative treatment;

  • inclusive of biologic agents such as trastuzumab and bevacizumab if relevant and provided identical biologics are included in capecitabine-containing and non-capecitabine containing arms;

  • chemotherapy given as first or subsequent line of treatment in the context of metastatic disease.

Types of outcome measures

Primary outcomes
Neoadjuvant chemotherapy
  • Pathologic complete response rate (pCR)

Adjuvant chemotherapy
  • Overall survival (OS)

Palliative chemotherapy
  • OS

Secondary outcomes
Neoadjuvant chemotherapy
  • Disease-free survival (DFS)

  • Recurrence-free survival (RFS)

  • OS

Adjuvant chemotherapy
  • RFS

  • DFS

  • Breast cancer specific survival (BCSS)

Palliative chemotherapy
  • Overall response rate (ORR)

  • Progression-free survival (PFS)

  • Clinical benefit rate (CBR)

Specific information on adverse events will be collected from studies in each of the neoadjuvant, adjuvant and palliative chemotherapy groups. The total number of grade III and IV adverse events along with the total number of participants at risk in each trial will be summed to calculate a single odds ratio. For the following specific toxicities of interest, we will calculate the total number of toxic events:

  • cytopaenias;

  • hand-foot syndrome;

  • mucositis and stomatitis;

  • diarrhoea;

  • ischaemic cardiac disease.

The following outcome definitions will apply.

  1. RFS is defined as the time from randomisation to the date of diagnosis of invasive breast cancer recurrence or death if the patient died before the recurrence of cancer.

  2. If time to progression or time to treatment failure are recorded as endpoints rather than PFS, these can be used in place of PFS.

  3. DFS is defined as the time from randomisation to the time of identification of recurrent or metastatic cancer or death from any cause.

  4. OS is defined as the time from randomisation to death.

  5. BCSS is defined as the time from randomisation to death due to breast cancer.

  6. Response rate is defined using Response Evaluation Criteria In Solid Tumours (RECIST) (Eisenhauer 2009): the overall response is defined as the sum of complete response and partial response, representing the best response of each patient.

Search methods for identification of studies

Electronic searches

We will search the following databases.

(a) The Cochrane Breast Cancer Group (CBCG) Specialised Register. Details of the search strategies used by the CBCG 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). Trials with the key words 'breast neoplasm; breast cancer; breast carcinoma; breast adenocarcinoma; breast tumour/tumor; capecitabine and xeloda' will be extracted and considered for inclusion in the review.
(b) MEDLINE (via OvidSP). See Appendix 1.
(c) EMBASE (via EMBASE.com). See Appendix 2.
(d) CENTRAL. See Appendix 3.
(e) The WHO International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/Default.aspx) for all prospectively registered and ongoing trials. See Appendix 4.
(f) Clinicaltrials.gov (http://clinicaltrials.gov/). See Appendix 5.

Searching other resources

(a) Bibliographic searching

We aim to identify further studies from reference lists of identified relevant trials or reviews. A copy of the full article for each reference reporting a potentially eligible trial will be obtained. Where this is not possible, attempts will be made to contact authors to provide additional information.

(b) Gray literature searching

We will search the conference proceedings of the following conferences from 1996 through to the present for relevant abstracts:

  • American Society of Clinical Oncology Annual Scientific Meeting;

  • San Antonio Breast Cancer Symposium;

  • American Society of Clinical Oncology Breast Cancer Symposium;

  • European Society of Medical Oncology Annual Scientific Meeting;

  • European Breast Cancer Conference.

Data collection and analysis

Selection of studies

The selection criteria will be applied to each reference identified independently by two authors (AW and PL).

With regard to the selection of studies:

  • neither review author will be blinded to the study title, authors or publication details;

  • any disagreements regarding the selection of a study will be resolved by a third author (AR or MB);

  • neither AW nor PL are content experts, although both are knowledgeable in the field;

  • AR is a content expert, MB is a expert in statistics;

  • all relevant studies are to be included and if required, studies will be translated;

  • significant excluded studies will be recorded in the 'Characteristics of excluded studies' table (references will not be included in this table if they obviously do not fulfil the inclusion criteria).

Data extraction and management

Data will be extracted from each publication or abstract independently by two authors (AW and PL).

With regard to the extraction of data, data will be extracted using standard electronic extraction forms (see Appendix 6). Individual data extraction forms will be required for each of the three treatment types studied: neoadjuvant, adjuvant and palliative treatment. The study, participant and treatment information is common to all three forms while information on outcomes, data and analysis will vary between the forms. Aggregate data will be extracted in the first instance, however if there are insufficient data then the trial co-ordinators will be contacted for more information. Individual patient data will be sought if necessary.

Any disagreements regarding the extraction of quantitative data will be resolved by a third author (AR or MB). For studies with more than one publication, data from each publication will be collated utilising a single data collection form or multiple data collection forms depending on the type of publication.

Assessment of risk of bias in included studies

The risk of bias will be assessed using the Cochrane Collaboration's risk of bias assessment tool in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 8.5 (Higgins 2011). Bias will be independently assessed by two authors (AW and PL) with any disagreements to be resolved by a third author (AR or MB). The areas of bias which will be assessed include:

  • selection bias;

  • performance bias;

  • detection bias;

  • attrition bias;

  • reporting bias;

  • other biases

    • recruitment bias - recruitment based on differential response,

    • use of interim results.

The important sources of bias in our review are likely to be selection bias, attrition bias and reporting bias. While all sources of bias will be reported on, these three areas of bias will be prioritised. The assessment of bias will be reported in this review using a 'risk of bias summary' figure. We will present multiple (stratified) analyses to incorporate the findings of our risk of bias assessment with a stratified forest plot.

Measures of treatment effect

Neoadjuvant trials

The primary outcome for neoadjuvant trials is the pathologic complete response rate (pCR). In most trials this is measured using the Modified Regression Scale (von Minckwitz 2008) where the response is graded as follows.

    • Grade 5 - no microscopic evidence of residual tumour cells in the breast or axillary nodes.

    • Grade 4 - no microscopic evidence of residual tumour cells in the breast, but involved axillary nodes.

    • Grade 3 - residual non-invasive tumour cells in the breast.

    • Grade 2 - residual focal invasive tumours cells in the breast of ≤ 5 mm.

    • Grade 0-1 - all remaining scenarios including the presence of new invasive tumour.

Grade 4 and 5 are considered to represent pCR. This is a small ordinal scale where the event of pCR will be considered as a dichotomous outcome with Grade 4 and 5 representing pCR and all other grades representing no pCR. This outcome will be presented as a risk ratio (RR) with a 95% confidence interval (CI). The outcome will be reported for randomised and assessable patients. We will report the ratio of treatment effect for response so that a RR of less than 1.0 favours the non-capecitabine containing regimen and a RR of greater than 1.0 favours the capecitabine-containing regimen. Care will be required in the context of neoadjuvant pCRs as these are typically significantly higher in ER-negative cancers relative to ER-positive cancers. As such, in the ER-positive disease an absolute difference of 5% or greater for capecitabine-containing regimens compared with non-capecitabine containing regimens will be a relevant clinical difference.

The secondary outcomes for neoadjuvant trials are disease-free survival (DFS), recurrence-free survival (RFS) and overall survival (OS). These will be analysed as time-to-event outcomes and expressed as hazard ratios (HRs). We will use the HR provided in each study or estimate the HR indirectly using methods described by Tierney et al and Parmar et al (Parmar 1998; Tierney 2007). For meta-analytic pooling, we will use the generic-inverse variance method as described in the Cochrane Handbook for Systematic Reviews for Interventions, Chapters 7.7.6 and 9.4.9 (Higgins 2011).

Adjuvant trials

The primary outcome for adjuvant trials is overall survival (OS), which will be analysed as a time-to-event outcome and expressed as a HR. We will use the HR provided in each study or estimate the HR indirectly using methods described by Tierney et al and Parmar et al (Parmar 1998; Tierney 2007). For meta-analytic pooling, we will use the generic-inverse variance method as described in the Cochrane Handbook of Systematic Reviews for Interventions, Chapters 7.7.6 and 9.4.9.

The secondary outcomes for adjuvant trials are RFS, DFS and breast cancer specific survival. These will be analysed as time-to-event outcomes and expressed as HRs. We will use the HR provided in each trial publication or estimate the HR indirectly using methods described by Tierney et al and Parmar et al (Parmar 1998; Tierney 2007). For meta-analytic pooling, we will use the generic-inverse variance method as described in the Cochrane Handbook of Systematic Reviews for Interventions, Chapters 7.7.6 and 9.4.9.

In the adjuvant setting, an absolute improvement of 5% or greater in the RFS for capecitabine-containing regimens compared with non-capecitabine containing regimens will be considered as a relevant clinical difference for ER-positive disease.

Palliative trials

The primary outcome for palliative intent trials is OS, which will be analysed as a time-to-event outcome and expressed as a HR. We will use the HR provided in each study or estimate the HR indirectly using methods described by Tierney et al and Parmar et al (Parmar 1998; Tierney 2007). For meta-analytic pooling, we will use the generic-inverse variance method as described in the Cochrane Handbook of Systematic Reviews for Interventions, Chapters 7.7.6 and 9.4.9.

The secondary outcomes for palliative intent trials are overall response rate (ORR), progression-free survival (PFS) and clinical benefit rate (CBR). ORR is considered a small ordinal scale which will be expressed as a dichotomous outcome with complete response (CR) and partial response (PR) representing overall response and stable disease (SD) and progressive disease (PD) representing no response. This outcome will be presented as a RR with 95% CI and will be reported for randomised and assessable patients. We will report the ratio of treatment effect for response so that a RR of less than 1.0 favours the non-capecitabine containing regimens and a RR of greater than 1.0 favours the capecitabine containing regimens. CBR will also be considered a small ordinal scale and expressed as a dichotomous outcome with CR, PR and SD representing clinical benefit and PD representing no benefit. The outcome will be presented as a RR with 95% CI as per the ORR above. PFS will be analysed as a time-to-event outcome as above.

Care will also need to be taken in the context of metastatic disease when comparing both response rates and overall survivals as ER-negative disease may natively carry higher response rates in general whereas ER-positive disease is known to carry a longer median survival than ER-negative disease regardless of the treatment parameters. In this setting, an absolute 10% or greater improvement in ORR in ER-positive disease for capecitabine-containing regimens compared with non-capecitabine containing regimens will be a relevant clinical difference.

Adverse events

All grade III and IV adverse events, along with the total number of participants at risk, will be recorded from each trial. Where possible, data on adverse events will be collected for the treated population rather than the intention-to-treat population. A pooled odds ratio (OR) with 95% CI will be calculated for each toxicity where it is reported in two or more studies. The total number of the following specific adverse events will be recorded in this review: cytopaenias; hand-foot syndrome; mucositis; diarrhoea; and ischaemic cardiac disease.

Unit of analysis issues

Cross-over trials will not be included in this systematic review.

There will not be issues of multiple events per participant or cluster-randomised trials in this review.

Included studies may include those with multiple intervention groups. Specialist statistical advice will be sought regarding the manner in which the multiple intervention groups will be dealt with. Each study utilising multiple groups will need to be considered independently with multiple groups handled either by combining intervention groups or dividing the control group to enable pair-wise comparisons and to ensure that no unit of analysis issues arise.

Dealing with missing data

In this systematic review, missing data will be of significance as it is anticipated that many of the studies meeting eligibility criteria for inclusion may not report the study outcomes based on the hormone receptor status of the participants. This will mean that analysis of the study for inclusion in the systematic review is not possible.

The original investigators will be contacted by written correspondence to gain information regarding the hormone receptor status of participants in order to enable analysis for review. Studies for which this information is unable to be obtained will be included in the review, and the impact of the missing data for these studies will be discussed in the 'Discussion' section of the review.

With regard to studies in which other data are missing, for example participants who are lost to follow up or data for study objectives which are not reported:

  • the original investigators will be contacted by written correspondence where possible;

  • analysis will be by intention to treat, with a sensitivity analysis to consider the impact of the missing results;

  • missing data will not be imputed;

  • if individual patient data are obtained from the original investigators, we will be able to use multiple imputation methods if less than 20% of the patient data are missing;

  • the impact of missing data will be discussed in the 'Discussion' section of the review with regard to the assessment of risk of bias.

Assessment of heterogeneity

Clinical heterogeneity will be assessed using:

  • visual inspection of the forest plots;

  • the Chi2 test, with a cut-off point of P = 0.1;

  • the I2 statistic.

A random-effects model will likely be used to address heterogeneity, depending on evidence of statistical heterogeneity and the exploration of sources of heterogeneity. Statistician advice will be sought for the analysis of heterogeneity.

Assessment of reporting biases

Funnel plots will be used to detect publication bias in this review. Separate funnel plots will be used for each of the areas examined, including neoadjuvant, adjuvant and palliative-intent treatment.

Funnel plot asymmetry may be caused by:

  • publication bias;

  • differences in methodological quality between studies;

  • true heterogeneity between studies;

  • chance.

There are instances in which publication bias may not lead to asymmetry in the funnel plot. Furthermore, visual inspection of the funnel plot for asymmetry alone is subjective and may lead to failure to detect publication bias. As such, funnel plot asymmetry is limited with respect to determination of publication bias. Contour-enhanced funnel plots will be used to assist in the differentiation of publication bias from other causes of funnel plot asymmetry.

Testing for funnel plot asymmetry in this review may be limited by the number of studies included for each of the primary outcome measures. It is likely that there will be fewer than 10 studies for each of the three arms for this review. However, if there are a sufficient number of studies, funnel plot asymmetry may be tested using the methods listed in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 10.4.3) together with the assistance of our statistician.

If evidence of small-study effects are found as part of the assessment of reporting bias, a sensitivity analysis will be performed in which the fixed-effect and random-effects model estimates will be compared.

Other possible sources of publication bias include duplicate or multiple publication bias; location bias; citation bias; language bias; and outcome reporting bias, all of which may affect this review. We will endeavour to detect multiple publications of the same study, although we appreciate the difficulties in doing this. We will be searching numerous electronic databases, including trial registries, to minimise location biases and we have not limited our inclusion criteria by language. Where possible, we will be contacting corresponding authors to obtain information regarding study outcomes to reduce the risk of outcome reporting bias.

Data synthesis

Dichotomous outcomes will be pooled using the Mantel-Haenszel fixed-effect model method.

Time-to-event outcomes will be pooled using the generic inverse-variance method, allowing a mixture of log-rank and Cox model estimates to be obtained from studies.

The RevMan software will be used to perform the analysis.

A summary of findings table using GRADEprofiler will be used to summarise the findings of the review.

Subgroup analysis and investigation of heterogeneity

Subgroups to be examined in this review include:

  • HER2 overexpression in each of neoadjuvant, adjuvant and palliative-intent treatment groups;

  • capecitabine as first or subsequent line of therapy in palliative intent treatment.

A subgroup analysis will be performed to assess for heterogeneity for each of the subgroups identified above.

Sensitivity analysis

If there are adequate data, sensitivity analyses will be performed to assess the robustness of results. It is difficult to predetermine the likely sensitivity analyses that will be performed. Likely sensitivity analyses to be included are exclusion of studies with high risk of bias and unpublished studies.

Acknowledgements

None

Appendices

Appendix 1. MEDLINE

1Case-Control Studies/
2Control Groups/
3Matched-Pair Analysis/
4Retrospective Studies/
5((case* adj5 control*) or (case adj3 comparison*) or control group*).ti,ab.
6or/1-5
7Cohort Studies/
8Longitudinal Studies/
9Follow-Up Studies/
10Prospective Studies/
11Retrospective Studies/
12cohort.ti,ab.
13longitudinal.ti,ab.
14prospective.ti,ab.
15retrospective.ti,ab.
16or/7-15
17randomized controlled trial.pt.
18controlled clinical trial.pt.
19randomized.ab.
20placebo.ab.
21Clinical Trials as Topic/
22randomly.ab.
23trial.ti.
24(crossover or cross-over).tw.
25Pragmatic Clinical Trials as Topic/
26pragmatic clinical trial.pt.
27or/17-26
28exp Breast Neoplasms/
29(breast adj6 cancer$).tw.
30(breast adj6 neoplasm$).tw.
31(breast adj6 carcinoma$).tw.
32(breast adj6 tumo?r$).tw.
33or/28-32
34Capecitabine.tw.
35xeloda.tw.
36or/34-35
37and/33,36
38exp animals/ not humans/
3937 not 38
406 and 39
4116 and 39
4227 and 39

Appendix 2. EMBASE

  1. 'case control study'/syn OR 'case control study' OR ('case control' OR 'case base' OR 'case matched' OR retrospective) NEXT/3 (analys* OR design* OR evaluation* OR research OR stud* OR survey* OR trial*)

  2. (cohort OR concurrent OR incidence OR longitudinal OR followup OR 'follow up' OR prospective OR retrospective) NEXT/1 (analys* OR design* OR evaluation* OR research OR stud* OR survey* OR trial*) OR 'prospective method'/exp OR 'prospective method' OR 'retrospective study'/syn OR 'retrospective study'

  3. random* OR factorial* OR crossover* OR cross NEXT/1 over* OR placebo* OR (doubl* AND blind*) OR (singl* AND blind*) OR assign* OR allocat* OR volunteer* OR 'crossover procedure'/exp OR 'crossover procedure' OR 'double blind procedure'/exp OR 'double blind procedure' OR 'randomized controlled trial'/exp OR 'randomized controlled trial' OR 'single blind procedure'/exp OR 'single blind procedure'

  4. 'breast'/exp OR 'breast' OR 'breast disease'/exp OR 'breast disease' AND ('neoplasm'/exp OR 'neoplasm') OR 'breast tumor'/exp OR 'breast tumor' OR (breast* NEAR/6 neoplas*):ab,ti OR (breast* NEAR/6 cancer*):ab,ti OR (breast* NEAR/6 carcin*):ab,ti OR (breast* NEAR/6 tumo*):ab,ti OR (breast* NEAR/6 metasta*):ab,ti OR (breast* NEAR/6 malig*):ab,ti

  5. 'breast cancer'/exp OR 'breast cancer' OR 'breast neoplasm' OR 'breast carcinoma'/exp OR 'breast carcinoma' OR 'breast tumour' OR 'breast tumor'/exp OR 'breast tumor'

  6. #4 OR #5

  7. 'capecitabine' OR 'capecitabine'/exp OR capecitabine

  8. 'xeloda' OR 'xeloda'/exp OR xeloda

  9. #7 OR #8

  10. #6 AND #9

  11. #10 NOT ([animals]/lim NOT [humans]/lim)

  12. #1 AND #11

  13. #2 AND #11

  14. #3 AND #11

  15. #12 AND [embase]/lim

  16. #13 AND [embase]/lim

  17. #14 AND [embase]/lim

Appendix 3. CENTRAL

#1 MeSH descriptor: [Breast Neoplasms] explode all trees
#2 breast near cancer*
#3 breast near neoplasm*
#4 breast near carcinoma*
#5 breast near tumour*
#6 breast near tumor*
#7 #1 or #2 or #3 or #4 or #5 or #6
#8 capecitabine
#9 xeloda
#10 #8 or #9
#11 #7 and #10

Appendix 4. WHO ICTRP

Advanced search:
Title: breast cancer AND capecitabine

Appendix 5. ClinicalTrials.gov

Advanced search:
Title: breast cancer AND capecitabine

Appendix 6. Data extraction form template

  • SOURCE

    • Study ID

    • Report ID

    • Review author ID

    • Citation and contact details

  • ELIGIBILITY

    • Confirm eligibility

    • Reason for exclusion

  • METHODS

    • Study design

    • Total study duration

    • Sample size considerations

    • Sequence generation

    • Allocation sequence concealment

    • Blinding

    • Other concerns RE bias

  • PARTICIPANTS

    • Total number

    • Diagnostic criteria including measurement of hormone receptor status (immunohistochemistry diagnostic criteria)

    • Age

    • Country

    • Co-morbidities

    • Breast cancer stage

    • Hormone Receptor Status (%)

      • ER and PgR positive (%)

      • ER positive/PgR negative or unknown (%)

      • ER negative or unknown/PgR positive (%)

      • ER and PgR negative (%)

      • Not assessed or unknown (%)

    • Her 2 Status (%) (Defined by IHC 3+ and/or ISH positive)

    • Breast cancer molecular subtype

    • For palliative treatment trials, percentage of non-capecitabine patients who subsequently crossed over to receive capecitabine following trial completion

    • For palliative treatment trials, receipt of endocrine and other targeted therapies prior to commencement of trial

    • For palliative treatment trials, receipt of chemotherapy prior to commencement of trial

  • INTERVENTION AND COMPARATOR GROUPS

    • Total number of groups

    • Chemotherapy regimen, including dose

    • Co-interventions including endocrine therapy, biologic agents, radiotherapy

    • Adherence

    • Exposure

  • OUTCOME MEASURES

    • The outcome measure for each of neoadjuvant, adjuvant and palliative-intent treatment chemotherapy regimens containing capecitabine compared with regimens not containing capecitabine for women with ER-positive breast cancer

    • The outcome measure for each of neoadjuvant, adjuvant and palliative-intent treatment chemotherapy regimens containing capecitabine compared with regimens not containing capecitabine for women with ER-negative breast cancer

  • OUTCOME MEASURES - Neoadjuvant Treatment

    • Primary Outcome - pCR

      • Definition of pCR

    • Secondary Outcomes - RFS, DFS, OS

      • Duration of follow up

      • Definition of DFS and RFS

      • Follow up investigations

  • OUTCOME MEASURES - Adjuvant Treatment

    • Primary Outcome - RFS

      • Definition of RFS

      • Duration of follow up

      • Follow up investigations

    • Secondary Outcomes - DFS, OS, BCSS

      • Definition of BCSS and DFS

      • Duration of follow up

      • Follow up investigations

  • OUTCOME MEASURES - Palliative Treatment

    • Primary Outcome - ORR

      • Definition of ORR

      • Timing and nature of response investigations (CT, PET, clinical, other)

    • Secondary Outcomes - OS, PFS, CBR

      • Definition of PFS, CBR

      • Duration of follow up

      • Follow up investigations

  • OUTCOME MEASURES - Adverse events

    • Definition of specific adverse events

    • Methods of monitoring for adverse events including the frequency of examination/investigation and person reporting event (clinician or patient)

  • OUTCOME MEASURES - Palliative Treatment

    • Primary Outcome - ORR

      • Definition of ORR

      • Timing and nature of response investigations (CT, PET, clinical, other)

    • Secondary Outcomes - OS, PFS, CBR

      • Definition of PFS, CBR

      • Duration of follow up

      • Follow up investigations

  • OUTCOME MEASURES - Adverse events

    • Definition of specific adverse events

    • Methods of monitoring for adverse events including the frequency of examination/investigation and person reporting event (clinician or patient)

  • RESULTS - Neoadjuvant Treatment

    • Primary Outcome - pCR

      • Risk ratio (RR) with 95% confidence interval (CI)

    • Secondary Outcomes - DFS, RFS, OS

      • Hazard ratio (HR)

  • RESULTS - Adjuvant Treatment

    • Primary Outcome - RFS

      • HR

    • Secondary Outcomes - DFS, OS, BCSS

      • HR

  • RESULTS - Palliative Treatment

    • Primary Outcome - ORR

      • RR with 95% CI

    • Secondary Outcomes - OS, PFS, CBR

      • HR for OS, PFS

      • RR with 95% CI for CBR

  • RESULTS - Adverse Events

    • Cytopaenias

    • Hand-foot syndrome

    • Mucositis

    • Diarrhoea

    • Ischaemic cardiac disease

  • MISCELLANEOUS

    • Funding source

    • Ethical approval

    • Single or multicentre

    • Correspondence required

    • Author conclusions

    • Author conflicts of interest

Contributions of authors

  1. Draft the protocol: AW

  2. Study selection: AW, PL, MB

  3. Extract data from studies: AW, PL, MB

  4. Enter data into RevMan: AW, PL, MB

  5. Carry out the analysis: AW, PL, MB

  6. Interpret the analysis: AW, PL, AR, MB

  7. Draft the final review: AW, PL, MB, AR

  8. Disagreement resolution: AR, MB

  9. Update the review: AR

Declarations of interest

AW, PL and AR are all salaried medical officers in the Medical Oncology Department at Royal Perth Hospital.

MB is a professor of biostatistics at the University of Notre Dame.

AR is a member of the Roche Advisory Board.

Sources of support

Internal sources

  • Royal Perth Hospital, Australia.

    Salary

  • Royal Perth Hospital, Cancer Research Fellowship, WA Health, Australia.

    Salary

  • University of Notre Dame, Australia.

    Salary

External sources

  • No sources of support supplied

Ancillary