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Use of capecitabine in state IV breast cancer: an evidence summary |
Tomiak E, Verma S, Levine M, Pritchard K, Sawka C, Breast Cancer Disease Site Group |
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Authors' objectives To determine the role of capecitabine in the treatment of stage IV breast cancer.
Searching MEDLINE (from 1995 to 2002), the Cochrane Library (Issue 2, 2002) and Cancerlit (from 1995 to 1999) were searched without language restriction. The searches were conducted from 1995 to 1999 using the MeSH term 'exp breast neoplasms' along with the textwords 'capecitabine', 'xeloda', 'breast', 'mammary', 'cancer' and 'neoplasm'. Updated searches (from 2000 to 2002) combined disease- specific terms and treatment-specific terms with the search-specific terms 'meta-analysis', 'randomized controlled trial(s)' or 'random' (see website for details). PubMed was searched for articles not yet listed on MEDLINE. In addition, Proceedings of the American Society for Clinical Oncology (1998 to 2002) and the San Antonio Breast Cancer Symposia (23rd and 24th) were examined, as were bibliographies from articles and personal files. Unpublished data were sought from the US Food and Drug Administration website and Hoffmann-La Roche Ltd. Ongoing trials were identified through the PDQ database and the CentreWatch Clinical Trials Listing Service websites.
Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs) were of primary interest. Uncontrolled phase II studies and retrospective analyses were also included.
Specific interventions included in the reviewStudies of capecitabine, single-agent or in combination with other agents, were eligible for inclusion. The studies included in the review tested first-line or second-, third- or fourth-line treatment. The majority of the patients included received 2,510 mg/m2 on days 1 to 14 in 3-week cycles. The comparators in the included studies were cyclophosphamide methotrexate fluorouracil (CMF), paclitaxel and docetaxel.
Participants included in the reviewStudies in women with stage IV metastatic breast cancer were eligible for inclusion. The participants in the included studies were women receiving first-line treatment, women for whom anthracycline treatment had failed, and heavily pre-treated women whose cancer was refractory to paclitaxel. Age was reported for only one included study (greater than 55 years).
Outcomes assessed in the reviewStudies that reported tumour response rate and time to tumour progression were eligible for inclusion. The other outcomes reported were quality of life, survival, response duration and adverse effects.
How were decisions on the relevance of primary studies made?The studies were selected by two members of the Cancer Care Ontario Practice Guidelines Initiative Breast Cancer Disease Site Group and methodologists. No further details were given.
Assessment of study quality The authors did not state that they assessed validity.
Data extraction The authors did not state how the data were extracted for the review, or how many of the reviewers performed the data extraction. The data extracted included the capecitabine dose and regimen, number of patients, complete and partial response rates, time to progression and survival.
Methods of synthesis How were the studies combined?Data from the included studies were not pooled because of differences in the patient populations. A narrative synthesis was undertaken and an interpretive summary provided.
How were differences between studies investigated?The studies were grouped separately as first-line therapy, combination therapy or second-, third- or fourth-line therapy. The studies were differentiated according to previous treatments received. Evidence from RCTs was set apart from non-randomised study data.
Results of the review One RCT (n=95) of first-line therapy and one RCT (n=511) of combination therapy were included. The assessment of second-, third- or fourth-line therapy included one RCT (n=44) and one phase II study (n=135). Two retrospective analyses (n=570 and n=107) were also included in the assessment of toxicity.
First-line therapy.
In one RCT (n=95) that compared capecitabine to CMF in women aged 55 years and over, the tumour response rates were 25% (95% confidence interval, CI: 14, 37) and 16 (95% CI: 5, 33), respectively. The median time to progression was 132 days (95% CI: 91, 213) with capecitabine and 94 days (95% CI: 74, 147) with CMF. Clinical adverse events of grade 3 and 4 were more common with capecitabine, whereas haematological adverse effects were more common with CMF.
Second-, third- or fourth-line therapy. One RCT (n=44) of capecitabine versus paclitaxel in women for whom anthracycline treatment had failed was stopped early because the patients' treatment preferences impeded randomisation. No difference was shown in the response rate or median time to progression. Adverse effects were more common with paclitaxel. One phase II study (n=163) of capecitabine in heavily pre-treated women showed a tumour response in 27 of 135 evaluable women (20%, 95% CI: 14, 28). The response rate in women (n=42) resistant to both anthracycline and paclitaxel was 29%. The median duration of response was 8.1 months and median survival was 12.8 months. Grade 3 and 4 adverse effects included diarrhoea, hand-foot syndrome, fatigue, stomatitis, nausea and vomiting. Neutropenia occurred in 3% of the patients; no alopecia was reported. Quality of life (pain intensity, analgesic consumption and performance status) was incorporated in a Clinical Benefit Response rate evaluated for 147 women. Twenty per cent had a positive response with improvements lasting over 18 weeks, and 31% were stable. Combination therapy. One RCT (n=511) of capecitabine-docetaxel versus docetaxel in women with locally advanced or metastatic breast cancer, who had previously received an anthracycline, showed a significantly higher response rate with combination therapy: 42 versus 30% (p=0.006). The median survival after 15 months' follow-up was 14.5 months with combination therapy versus 11.5 months with docetaxel alone. The hazard ratio (HR) for mortality was 0.775 (95% CI: 0.63, 0.95, p=0.0126). Time to progression was significantly longer with combination therapy (HR 0.652, 95% CI: 0.54, 0.77, p=0.0001). Combination therapy was associated with more grade 3 or 4 stomatitis, diarrhoea and hand-foot syndrome, while tolerance was noted to decrease in women over the age of 60. Quality of life was measured for 454 women. No significant differences were found over 48 weeks.
Additional toxicity data.
A safety analysis conducted by Hoffmann-La Roche of 570 cancer (breast and colorectal) patients given capecitabine (2,500 mg/m2 per day in two doses) noted grade 3 or 4 adverse effects including hand-foot syndrome (13%), diarrhoea (12.1%), stomatitis (3.9%), nausea (3.7%), neutropenia (3.7%), vomiting (3.5%) and fatigue (3.5%), but no alopecia. Nine per cent of patients had treatment withdrawn because of adverse effects. Additional Hoffmann-La Roche data led to capecitabine being contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/minute). An independent retrospective analysis of 107 women found much higher rates of hand-foot syndrome (74%), diarrhoea (44%), stomatitis (37%), nausea and vomiting (47%). Adverse events were more common at doses of greater than 2,100 mg/m2.
Authors' conclusions The authors state that the limited data available do not allow a firm clinical recommendation on capecitabine for first-line therapy or following anthracycline treatment failure. Capecitabine shows promise in heavily treated women if third- or fourth-line therapy is to be considered.
CRD commentary This review set out clear questions and stated the inclusion criteria for the participants, intervention and outcomes. The intervention criteria were expanded for updates to include combination as well as single-agent therapy, but the searches do not appear to have been backdated. Since evidence from RCTs is usually limited in areas such as advanced cancer, the inclusion of other study designs was justifiable. However, inclusion does not appear to have been limited to the uncontrolled phase II studies specified. This could indicate that subjective decisions were made regarding the inclusion of non-randomised data. The search for relevant studies was thorough. The search strategy was altered for updates so that it became more specific for randomised studies and meta-analyses. The nature of the evidence base examined, therefore, changed over time. Insufficient details of the study selection process were reported to judge the potential for bias. No validity assessment of the included studies was reported, nor were details of how the data were extracted.
The included studies were described adequately in the text but the tables provided no additional information about them. The tables did, however, present studies of alternative treatments that were not part of the review. It cannot be assumed that those studies were identified or reviewed systematically, and care should be taken when comparing interventions tested in different studies (i.e. indirect comparisons). A narrative synthesis was appropriate given the clinical differences between the studies. The tentative conclusions are appropriate to the limited amount of data available. The review is updated regularly on the web where information about ongoing trials is available.
Implications of the review for practice and research Practice: The authors state that if third- or fourth-line chemotherapy is to be considered, capecitabine appears to be a reasonable option. Capecitabine may be a reasonable alternative to paclitaxel in patients for whom anthracycline treatment has failed. Combination therapy may be more effective than single-agent capecitabine and the associated higher toxicity can be reduced by initiating treatment at a lower dose (75%). They also state that upon further investigation capecitabine might become an attractive option for elderly patients or women wishing to avoid adverse effects associated with CMF.
Research: The authors state that RCTs are needed to compare the drugs available to heavily pre-treated women, and that such trials need to evaluate toxicity, quality of life and cost-effectiveness as well as response rate, time to progression and survival. A large RCT is needed to confirm capecitabine as a reasonable alternative to paclitaxel in anthracycline-resistant patients. Confirmatory studies are also needed before capecitabine can be considered as an option for first-line treatment. All of these trials need to assess quality of life.
Funding Cancer Care Ontario, Ontario Ministry of Health.
Bibliographic details Tomiak E, Verma S, Levine M, Pritchard K, Sawka C, Breast Cancer Disease Site Group. Use of capecitabine in state IV breast cancer: an evidence summary. Current Oncology 2000; 7(2): 84-90 Other publications of related interest This paper is based on a Practice Guideline/Evidence Summary report produced by Cancer Care Ontario Practice Guidelines Initiative. The series is published on the Internet and regularly updated. To ensure that you are viewing the most up to date version, go to the Cancer Care Ontario website at: http://www.cancercare.on.ca/english/toolbox/qualityguidelines/pebc/ This abstract is based on the journal article and web version accessed on 28/03/2003.
Browman GP, Levine MN, Mohide EA, Hayward RS, Pritchard KI, Gafni A, et al. The practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation. J Clin Oncol 1995;13:502-12.
Indexing Status Subject indexing assigned by CRD MeSH Antineoplastic Combined Chemotherapy Protocols /therapeutic use; Breast Neoplasms /drug therapy; Deoxycytidine /therapeutic use AccessionNumber 12002008583 Date bibliographic record published 31/08/2003 Date abstract record published 31/08/2003 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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