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Background: In a previous Cochrane Review, we found that for women with metastatic breast cancer unselected for triple-negative disease, there is little or no survival benefit and excess toxicity from platinum-based regimens. In subgroup analyses, however, we found preliminary low-quality evidence of a survival benefit from platinum-based regimens for women with metastatic triple-negative breast cancer (mTNBC). This review updates the evidence from the mTNBC subgroup analyses in the previous Cochrane Review., Objectives: To assess the effects of platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with mTNBC., Search Methods: We obtained relevant studies published prior to 2015 and their extracted results from the mTNBC subgroup analysis in the previous Cochrane Review. We searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov between 2015 and 27 September 2019. We identified further potentially relevant studies from previous trial reports, systematic reviews, and meta-analyses., Selection Criteria: Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with mTNBC. Individual trials could compare one or more platinum-based regimens to one or more non-platinum regimens; hence there could be more 'treatment-comparisons' (i.e. platinum regimen versus non-platinum regimen comparison) than trials. Trial participants may have been purposely selected for mTNBC or inadvertently selected as a subgroup., Data Collection and Analysis: At least two independent reviewers assessed studies for eligibility and quality, and extracted all relevant data from each study. We derived hazard ratios (HRs) for time-to-event outcomes, where possible, and used fixed-effect models for meta-analyses. We analysed objective tumour response rates (OTRRs) and toxicities as binary (dichotomous) outcomes with risk ratios (RRs) used as measures of effects. We extracted quality of life data, if available. We used GRADE to rate the quality of evidence for time-to-event and tumour response outcomes., Main Results: This review includes 13 treatment-comparisons involving 1349 women from 10 studies. Twelve of the 13 treatment-comparisons were included in one or more meta-analyses. Of the 13 treatment-comparisons, six and eight had published or provided time-to-event data on overall survival (OS) or progression-free survival/time to progression (PFS/TTP), respectively, that could be included in meta-analyses. Ten treatment-comparisons published or provided OTRR data that could be included in meta-analyses. Eight of the 13 treatment-comparisons were from studies that selected participants on the basis of mTNBC status, while the other five treatment-comparisons were from studies that reported mTNBC results as part of subgroup analyses. Analysis of six treatment-comparisons indicated that platinum-containing regimens may have provided a small survival benefit to mTNBC patients (HR 0.85, 95% CI 0.73 to 1.00; 958 women; moderate-quality evidence) with no evidence of heterogeneity (P = 0.41; I 2 = 1%). Data from eight treatment-comparisons showed that platinum regimens may improve PFS/TTP (HR 0.77, 95% CI 0.68 to 0.88; 1077 women; very low-quality evidence). There was marked evidence of heterogeneity (P < 0.0001; I 2 = 80%). There was also low-quality evidence of better tumour response for platinum recipients (RR 1.40, 95% CI 1.22 to 1.59; 1205 women) with some evidence of heterogeneity (P = 0.01; I 2 = 58%). The observed heterogeneity for the PFS/TTP and OTRR outcomes may reflect between-study differences and general difficulties in assessing tumour response, as well as the varying potencies of the comparators. Compared with women receiving non-platinum regimens: rates of grade 3 and 4 nausea/vomiting were higher for platinum recipients (RR 4.77, 95% CI 1.93 to 11.81; 655 women; low-quality evidence) and rates of grade 3 and 4 anaemia were higher for platinum recipients (RR 3.80, 95% CI 2.25 to 6.42; 843 women; low-quality evidence). In general, however, relatively few intervention-comparisons could be included in meta-analyses for adverse events. None of the studies reported quality of life., Authors' Conclusions: For women with mTNBC, there was moderate-quality evidence of a small survival benefit from platinum-based regimens compared to non-platinum regimens. This finding is consistent with findings of a PFS/TTP benefit and improved tumour response from platinum-based regimens. These potential benefits, however, should be weighed against previously identified excess toxicities from platinum-based regimens, particularly regimens containing cisplatin. Further randomised trials of platinum-based regimens among women with mTNBC are required., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Adjuvant chemotherapy improves survival in premenopausal and postmenopausal women with early breast cancer. Taxanes are highly active chemotherapy agents used in metastatic breast cancer. Review authors examined their role in early breast cancer. This review is an update of a Cochrane Review first published in 2007., Objectives: To assess the effects of taxane-containing adjuvant chemotherapy regimens for treatment of women with operable early breast cancer., Search Methods: For this review update, we searched the Specialised Register of the Cochrane Breast Cancer Group, MEDLINE, Embase, CENTRAL (2018, Issue 6), the WHO International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov on 16 July 2018, using key words such as 'early breast cancer' and 'taxanes'. We screened reference lists of other related literature reviews and articles, contacted trial authors, and applied no language restrictions., Selection Criteria: Randomised trials comparing taxane-containing regimens versus non-taxane-containing regimens in women with operable breast cancer were included. Studies of women receiving neoadjuvant chemotherapy were excluded., Data Collection and Analysis: Two review authors independently extracted data and assessed risk of bias and quality of the evidence using the GRADE approach. Hazard ratios (HRs) were derived for time-to-event outcomes, and meta-analysis was performed using a fixed-effect model. The primary outcome measure was overall survival (OS); disease-free survival (DFS) was a secondary outcome measure. Toxicity was represented as odds ratios (ORs), and quality of life (QoL) data were extracted when present., Main Results: This review included 29 studies (27 full-text publications and 2 abstracts or online theses). The updated analysis included 41,911 randomised women; the original review included 21,191 women. Taxane-containing regimens improved OS (HR 0.87, 95% confidence interval (CI) 0.83 to 0.92; high-certainty evidence; 27 studies; 39,180 women; 6501 deaths) and DFS (HR, 0.88, 95% CI 0.85 to 0.92; high-certainty evidence; 29 studies; 41,909 women; 10,271 reported events) compared to chemotherapy without a taxane. There was moderate to substantial heterogeneity across studies for OS and DFS (respectively).When a taxane-containing regimen was compared with the same regimen without a taxane, the beneficial effects of taxanes persisted for OS (HR 0.84, 95% CI 0.77 to 0.92; P < 0.001; 7 studies; 10,842 women) and for DFS (HR 0.84, 95% CI 0.78 to 0.90; P < 0.001; 7 studies; 10,842 women). When a taxane-containing regimen was compared with the same regimen with another drug or drugs that were substituted for the taxane, a beneficial effect was observed for OS and DFS with the taxane-containing regimen (OS: HR 0.80, 95% CI 0.74 to 0.86; P < 0.001; 13 studies; 16,196 women; DFS: HR 0.83, 95% CI 0.78 to 0.88; P < 0.001; 14 studies; 16,823 women). Preliminary subgroup analysis by lymph node status showed a survival benefit with taxane-containing regimens in studies of women with lymph node-positive disease only (HR 0.83, 95% CI 0.78 to 0.88; P < 0.001; 17 studies; 22,055 women) but less benefit in studies of women both with and without lymph node metastases or with no lymph node metastases. Taxane-containing regimens also improved DFS in women with lymph node-positive disease (HR 0.84, 95% CI 0.80 to 0.88; P < 0.001; 17 studies; 22,055 women), although the benefit was marginal in studies of women both with and without lymph node-positive disease (HR 0.95, 95% CI 0.88 to 1.02; 9 studies; 12,998 women) and was not apparent in studies of women with lymph node-negative disease (HR 0.99, 95% CI 0.86 to 1.14; 3 studies; 6856 women).Taxanes probably result in a small increase in risk of febrile neutropenia (odds ratio (OR) 1.55, 95% CI 0.96 to 2.49; moderate-certainty evidence; 24 studies; 33,763 women) and likely lead to a large increase in grade 3/4 neuropathy (OR 6.89, 95% CI 3.23 to 14.71; P < 0.001; moderate-certainty evidence; 22 studies; 31,033 women). Taxanes probably cause little or no difference in cardiotoxicity compared to regimens without a taxane (OR 0.87, 95% CI 0.56 to 1.33; moderate-certainty evidence; 23 studies; 32,894 women). Seven studies reported low-quality evidence for QoL; overall, taxanes may make little or no difference in QoL compared to chemotherapy without a taxane during the follow-up period; however, the duration of follow-up differed across studies. Only one study, which was conducted in Europe, provided cost-effectiveness data., Authors' Conclusions: This review of studies supports the use of taxane-containing adjuvant chemotherapy regimens, with improvement in overall survival and disease-free survival for women with operable early breast cancer. This benefit persisted when analyses strictly compared a taxane-containing regimen versus the same regimen without a taxane or the same regimen with another drug that was substituted for the taxane. Preliminary evidence suggests that taxanes are more effective for women with lymph node-positive disease than for those with lymph node-negative disease. Considerable heterogeneity across studies probably reflects the varying efficacy of the chemotherapy backbones of the comparator regimens used in these studies. This review update reports results that are remarkably consistent with those of the original review, and it is highly unlikely that this review will be updated, as new trials are assessing treatments based on more detailed breast cancer biology.

Background: Anthracyclines and taxanes are chemotherapeutic agents widely used in a sequential regimen in the adjuvant and neoadjuvant treatment of early breast cancer to reduce the risk of cancer recurrence. Standard practice is to administer anthracycline-based chemotherapy followed by a taxane. Anthracyclines tend to be administered first as they were established before taxanes for treatment of early breast cancer., Objectives: To assess whether the sequence in which anthracyclines and taxanes are administered affects outcomes for people with early breast cancer receiving adjuvant or neoadjuvant therapy., Search Methods: We searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 1 February 2018., Selection Criteria: Randomised controlled trials comparing administering a taxane prior to an anthracycline with taxane following anthracycline to people with early breast cancer receiving chemotherapy. The studies needed to have reported on at least one of our outcomes of interest, which included overall survival, disease-free survival, pathological response, treatment adherence, toxicity and quality of life., Data Collection and Analysis: Two review authors independently extracted data, assessed risk of bias and quality of the evidence. The primary outcome measure was overall survival. Secondary outcomes included disease-free survival, pathological response (in the neoadjuvant setting only), adverse events, treatment adherence and quality of life. For time-to-event outcomes of overall survival and disease-free survival, we derived hazard ratios (HRs) with 95% confidence intervals (CI) where possible. For dichotomous outcomes of pathological complete response, treatment adherence and adverse events, we reported the treatment effect as a risk ratio (RR) with 95% CI where possible. We used GRADE to assess the certainty of the evidence separately for the neoadjuvant and adjuvant settings., Main Results: There were 1415 participants in five neoadjuvant studies and 280 participants in four adjuvant studies involving five treatment comparisons. Four of the five neoadjuvant studies collected data for the primary outcome (overall survival) and two studies had data available; one of the four adjuvant studies collected overall survival data.The neoadjuvant studies suggested that the administration of taxanes first probably resulted in little to no difference in overall survival (HR 0.80, 95% CI 0.60 to 1.08; 947 participants; 2 studies; moderate-certainty evidence) and disease-free survival (HR 0.84, 95% CI 0.65 to 1.09; 828 participants; 1 study; moderate-certainty evidence). Administration of taxanes first also resulted in little to no difference in pathological complete response (absence of cancer in the breast and axilla: RR 1.15, 95% CI 0.96 to 1.38; 1280 participants; 4 studies; high-certainty evidence). However, there appeared to be a trend in favour of taxanes first. Studies reported treatment adherence using a range of measures. Administration of taxanes first probably did not increase the likelihood of requiring dose reductions compared to administration of anthracyclines first (RR 0.81, 95% CI 0.59 to 1.11; 280 participants; 1 study; moderate-certainty evidence). There was probably little to no difference in the risk of grade 3/4 neutropenia (RR 1.25, 95% CI 0.86 to 1.82; 280 participants, 1 study; moderate-certainty evidence) or grade 3/4 neurotoxicity (RR 0.95, 95% CI 0.55 to 1.65; 1108 participants; 2 studies; low-certainty evidence) when taxanes were given first. There were no data on quality of life.Only one adjuvant study collected data on overall survival and disease-free survival but did not report data. Administration of taxanes first reduced the risk of grade 3/4 neutropenia (RR 0.62, 95% CI 0.40 to 0.97; 279 participants; 4 studies, 5 treatment comparisons; high-certainty evidence) and appeared to result in little to no difference in grade 3/4 neurotoxicity (RR 0.78, 95% CI 0.25 to 2.46; 162 participants; 3 studies; low-certainty evidence). There was probably little to no difference in the proportions experiencing dose delays when taxanes are given first compared to anthracyclines given first (RR 0.76, 95% CI 0.52 to 1.12; 238 participants; 3 studies, 4 treatment comparisons; moderate-certainty evidence). One study reported on quality of life and indicated that scores (using the Functional Assessment of Cancer Therapy - Breast Cancer (FACT-B) validated questionnaire) were similar in both groups though did not provide numerical data., Authors' Conclusions: In the neoadjuvant setting, there is high- to low-certainty evidence of equivalent outcomes for the sequence in which taxanes are delivered. In the adjuvant setting, none of the studies reported on overall survival or disease-free survival. In most institutions, standard practice would be to deliver anthracycline followed by taxane, and currently available data do not support a change in this practice. We wait for the full-text publication of a relevant neoadjuvant study for women with HER2-negative breast cancer for inclusion in an update of this review.

Background: Studies have reported high tumour response rates for platinum-containing regimens in the treatment of women with metastatic breast cancer. Most of these studies were conducted prior to the 'intrinsic subtype' era, and did not specifically focus on metastatic triple-negative breast cancers (mTNBCs)., Objectives: To identify and review the evidence from randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with metastatic breast cancer., Search Methods: For this review update, we searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov on 28 May 2015. We identified further potentially relevant studies from handsearching references of previous trials, systematic reviews, and meta-analyses. Prior to this review update, the most recent search for studies was conducted in May 2003 for the original 2004 review., Selection Criteria: Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with metastatic breast cancer., Data Collection and Analysis: At least two independent reviewers assessed studies for eligibility and quality, and extracted all relevant data from each study. Hazard ratios (HRs) were derived for time-to-event outcomes, where possible, and fixed-effect models were used for meta-analyses. Objective tumour response rates (OTRRs) and toxicities were analysed as binary (dichotomous) outcomes with risk ratios (RRs) used as measures of effects. Quality of life data were extracted where available. GRADE was used to rate the quality of evidence for survival and tumour response outcomes at the level of subgroups selected and unselected for mTNBC, and for toxicity outcomes based on combining data from selected and unselected populations., Main Results: This update includes 15 new eligible treatment-comparisons from 12 studies. In total, 28 treatment-comparisons, involving 4418 women, from 24 studies are now included in one or more meta-analyses. Of the 28 treatment-comparisons, 19 and 16 had published or provided extractable time-to-event data on overall survival (OS) or progression-free survival/time to progression (PFS/TTP), respectively. All 28 treatment-comparisons provided OTRR data that could be included in meta-analyses. Most women recruited to the studies were not selected on the basis of mTNBC status.In a subgroup of three treatment-comparisons assessing women with mTNBC, platinum-containing regimens may have provided a survival benefit (HR 0.75, 95% CI 0.57 to 1.00; low-quality evidence). In women unselected for intrinsic subtypes such as mTNBC, there was little or no effect on survival (HR 1.01, 95% CI 0.92 to 1.12; high-quality evidence). This effect was similar to the combined analysis of survival data for both populations (HR 0.98, 95% CI 0.89 to 1.07; I 2 =39%, 1868 deaths, 2922 women; 19 trials). The difference in treatment effects between mTNBC women compared with unselected women was of borderline statistical significance (P = 0.05).Data from three treatment-comparisons with mTNBC participants showed that platinum regimens may improve PFS/TTP (HR 0.59, 95% CI 0.49 to 0.72; low-quality evidence). Thirteen treatment-comparisons of unselected metastatic participants showed that there was probably a small PFS/TTP benefit for platinum recipients, although the confidence interval included no difference (HR 0.92, 95% CI 0.84 to 1.01; moderate-quality evidence). Combined analysis of data from an estimated 1772 women who progressed or died out of 2136 women selected or unselected for mTNBC indicated that platinum-containing regimens improved PFS/TTP (HR 0.85, 95% CI 0.78 to 0.93). There was marked evidence of heterogeneity (P = 0.0004; I 2 = 63%). The larger treatment benefit in mTNBC women compared with unselected women was statistically significant (P < 0.0001).There was low-quality evidence of better tumour response in both subgroups of women with mTNBC and unselected women (RR 1.33, 95% CI 1.13 to 1.56; RR 1.11, 95% CI 1.04 to 1.19, respectively). Combined analysis of both populations was closer to the effect in unselected women (RR 1.15, 95% CI 1.08 to 1.22; 4130 women). There was considerable evidence of heterogeneity (P < 0.0001; I 2 = 64%), which may reflect between-study differences and general difficulties in assessing response, as well as the varying potencies of the comparators.Compared with women receiving non-platinum regimens: rates of grade 3 and 4 nausea/vomiting were probably higher among women receiving cisplatin- (RR 2.65, 95% CI 2.10 to 3.34; 1731 women; moderate-quality evidence) but the effect from carboplatin-containing regimens was less certain (RR 0.77, 95% CI 0.47 to 1.26; 1441 women; moderate-quality evidence); rates of grade 3 and 4 anaemia were higher among women receiving cisplatin- (RR 3.72, 95% CI 2.36 to 5.88; 1644 women; high-quality evidence) and carboplatin-containing regimens (RR 1.72, 95% CI 1.10 to 2.70; 1441 women; high-quality evidence); rates of grade 3 and 4 hair loss (RR 1.41, 95% CI 1.26 to 1.58; 1452 women; high-quality evidence) and leukopenia (RR 1.38, 95% CI 1.21 to 1.57; 3176 women; moderate-quality evidence) were higher among women receiving platinum-containing regimens (regardless of platinum agent)., Authors' Conclusions: In women with metastatic breast cancer who do not have triple-negative disease, there is high-quality evidence of little or no survival benefit and excess toxicity from platinum-based regimens. There is preliminary low-quality evidence of a moderate survival benefit from platinum-based regimens for women with mTNBC. Further randomised trials of platinum-based regimens in this subpopulation of women with metastatic breast cancer are required.

Background: Fulvestrant is a selective oestrogen receptor down-regulator (SERD), which by blocking proliferation of breast cancer cells, is an effective endocrine treatment for women with hormone-sensitive advanced breast cancer. The goal of such systemic therapy in this setting is to reduce symptoms, improve quality of life, and increase survival time., Objectives: To assess the efficacy and safety of fulvestrant for hormone-sensitive locally advanced or metastatic breast cancer in postmenopausal women, as compared to other standard endocrine agents., Search Methods: We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 7 July 2015. We also searched major conference proceedings (American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer Symposium) and practice guidelines from major oncology groups (ASCO, European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network, and Cancer Care Ontario). We handsearched reference lists from relevant studies., Selection Criteria: We included for analyses randomised controlled trials that enrolled postmenopausal women with hormone-sensitive advanced breast cancer (TNM classifications: stages IIIA, IIIB, and IIIC) or metastatic breast cancer (TNM classification: stage IV) with an intervention group treated with fulvestrant with or without other standard anticancer therapy., Data Collection and Analysis: Two review authors independently extracted data from trials identified in the searches, conducted 'Risk of bias' assessments of the included studies, and assessed the overall quality of the evidence using the GRADE approach. Outcome data extracted from these trials for our analyses and review included progression-free survival (PFS) or time to progression (TTP) or time to treatment failure, overall survival, clinical benefit rate, toxicity, and quality of life. We used the fixed-effect model for meta-analysis where possible., Main Results: We included nine studies randomising 4514 women for meta-analysis and review. Overall results for the primary endpoint of PFS indicated that women receiving fulvestrant did at least as well as the control groups (hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.89 to 1.02; P = 0.18, I 2 = 56%, 4258 women, 9 studies, high-quality evidence). In the one high-quality study that tested fulvestrant at the currently approved and now standard dose of 500 mg against anastrozole, women treated with fulvestrant 500 mg did better than anastrozole, with a HR for TTP of 0.66 (95% CI 0.47 to 0.93; 205 women) and a HR for overall survival of 0.70 (95% CI 0.50 to 0.98; 205 women). There was no difference in PFS whether fulvestrant was used in combination with another endocrine therapy or in the first- or second-line setting, when compared to control treatments: for monotherapy HR 0.97 (95% CI 0.90 to 1.04) versus HR 0.87 (95% CI 0.77 to 0.99) for combination therapy when compared to control, and HR 0.93 (95% CI 0.84 to 1.03) in the first-line setting and HR 0.96 (95% CI 0.88 to 1.04) in the second-line setting.Overall, there was no difference between fulvestrant and control treatments in clinical benefit rate (risk ratio (RR) 1.03, 95% CI 0.97 to 1.10; P = 0.29, I 2 = 24%, 4105 women, 9 studies, high-quality evidence) or overall survival (HR 0.97, 95% CI 0.87 to 1.09, P = 0.62, I 2 = 66%, 2480 women, 5 studies, high-quality evidence). There was no significant difference in vasomotor toxicity (RR 1.02, 95% CI 0.89 to 1.18, 3544 women, 8 studies, high-quality evidence), arthralgia (RR 0.96, 95% CI 0.86 to 1.09, 3244 women, 7 studies, high-quality evidence), and gynaecological toxicities (RR 1.22, 95% CI 0.94 to 1.57, 2848 women, 6 studies, high-quality evidence). Four studies reported quality of life, none of which reported a difference between the fulvestrant and control arms, though specific data were not presented., Authors' Conclusions: For postmenopausal women with advanced hormone-sensitive breast cancer, fulvestrant is at least as effective and safe as the comparator endocrine therapies in the included studies. However, fulvestrant may be potentially more effective than current therapies when given at 500 mg, though this higher dosage was used in only one of the nine studies included in the review. We saw no advantage with combination therapy, and fulvestrant was equally as effective as control therapies in both the first- and second-line setting. Our review demonstrates that fulvestrant is a safe and effective systemic therapy and can be considered as a valid option in the sequence of treatments for postmenopausal women with hormone-sensitive advanced breast cancer.

Background: It is generally accepted that taxanes are among the most active chemotherapy agents in the management of metastatic breast cancer. This is an update of a Cochrane review first published in 2003., Objectives: The objective of this review was to compare taxane-containing chemotherapy regimens with regimens not containing a taxane in the management of women with metastatic breast cancer., Search Methods: In this review update, we searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE, EMBASE, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 14 February 2013 using keywords such as 'advanced breast cancer' and 'chemotherapy'. We searched reference lists of articles, contacted study authors, and did not apply any language restrictions., Selection Criteria: Randomised controlled trials comparing taxane-containing chemotherapy regimens to regimens without taxanes in women with metastatic breast cancer. We included published and unpublished studies., Data Collection and Analysis: Two review authors independently assessed trial quality and extracted data. We derived hazard ratios (HRs) for overall survival, time to progression, and time to treatment failure where possible, and used a fixed-effect model for meta-analysis. We represented objective tumour response rates and toxicity as risk ratios (RRs). We extracted quality of life data where present., Main Results: This review included 28 studies. The updated analysis included 6871 randomised women, while the original review had 3643 women. Of the 28 included studies, we considered 19 studies to be at low risk of bias overall; however, some studies failed to report details on allocation concealment and methods of outcome assessment for those outcomes that are more likely to be influenced by a lack of blinding (for example tumour response rate). Studies varied in the taxane-containing chemotherapy backbone, and the comparator arms and were categorised into three groups: Regimen A plus taxane versus Regimen A (2 studies); Regimen A plus taxane versus Regimen B (14 studies); and single-agent taxane versus Regimen C (13 studies). Thirteen studies used paclitaxel, 14 studies used docetaxel, and 1 study allowed the investigator to decide on the type of taxane; the majority of studies delivered a taxane every 3 weeks. Twenty studies administered taxanes as first-line treatment, and 21 studies involved anthracycline naïve women in the metastatic setting. The combined HR for overall survival and time to progression favoured the taxane-containing regimens (HR 0.93, 95% confidence interval (CI) 0.88 to 0.99, P = 0.002, deaths = 4477; and HR 0.92, 95% CI 0.87 to 0.97, P = 0.002, estimated 5122 events, respectively) with moderate to substantial heterogeneity across trials. If the analyses were restricted to studies of first-line chemotherapy, this effect persisted for overall survival (HR 0.93, 95% CI 0.87 to 0.99, P = 0.03) but not for time to progression (HR 0.96, 95% CI 0.90 to 1.02, P = 0.22). Tumour response rates appeared to be better with taxane-containing chemotherapy in assessable women (RR 1.20, 95% CI 1.14 to 1.27, P < 0.00001) with substantial heterogeneity across studies. Taxanes were associated with an increased risk of neurotoxicity (RR 4.84, 95% CI 3.18 to 7.35, P < 0.00001, 24 studies) and hair loss (RR 2.37, 95% CI 1.45 to 3.87, P = 0.0006, 11 studies) but less nausea/vomiting compared to non-taxane-containing regimens (RR 0.62, 95% CI 0.46 to 0.83, P = 0.001, 26 studies). Leukopaenia and treatment-related death did not differ between the two groups (RR 1.07, 95% CI 0.97 to 1.17, P = 0.16, 28 studies; and RR 1.00, 95% CI 0.63 to 1.57, P = 0.99, 23 studies, respectively). For quality of life measures, none of the individual studies reported a difference in overall or any of quality of life subscales between taxane-containing and non-taxane chemotherapy regimens., Authors' Conclusions: Taxane-containing regimens appear to improve overall survival, time to progression, and tumour response rate in women with metastatic breast cancer. Taxanes are also associated with an increased risk of neurotoxicity but less nausea and vomiting compared to non-taxane-containing regimens. The considerable heterogeneity encountered across studies probably reflects the varying efficacy of the comparator regimens used in these studies and indicates that taxane-containing regimens are more effective than some, but not all, non-taxane-containing regimens.

Background: Combination chemotherapy can cause greater tumour cell kill if the drug dose is not compromised, while sequential single agent chemotherapy may allow for greater dose intensity and treatment time, potentially meaning greater benefit from each single agent. In addition, sequentially using single agents might cause less toxicity and impairment of quality of life, but it is not known whether this might compromise survival time., Objectives: To assess the effect of combination chemotherapy compared to the same drugs given sequentially in women with metastatic breast cancer., Search Methods: We searched the Cochrane Breast Cancer Group Specialised Register, using the search terms "advanced breast cancer" and "chemotherapy", MEDLINE and EMBASE on 31 October 2013. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were also searched (22 March 2012)., Selection Criteria: Randomised controlled trials of combination chemotherapy compared to the same drugs used sequentially in women with metastatic breast cancer in the first-, second- or third-line setting., Data Collection and Analysis: Two authors independently extracted data from published trials. Hazard ratios (HR) were derived from time-to-event outcomes where possible, and a fixed-effect model was used for meta-analysis. Response rates were analysed as dichotomous variables (risk ratios (RR)), and toxicity and quality of life data were extracted where available., Main Results: Twelve trials reporting on nine treatment comparisons (2317 patients randomised) were identified. The majority of trials (10 trials) had an unclear or high risk of bias. Time-to-event data were collected for nine trials for overall survival and eight trials for progression-free survival. All 12 trials reported results for tumour response. In the 12 trials there were 1023 deaths in 2317 women randomised. There was no difference in overall survival, with an overall HR of 1.04 (95% confidence interval (CI) 0.93 to 1.16; P = 0.45), and no significant heterogeneity. This result was consistent in the four subgroups analysed (risk of bias, line of chemotherapy, type of schema of chemotherapy, and relative dose intensity). In particular, there was no difference in survival according to the type of schema of chemotherapy, that is whether chemotherapy was given on disease progression or after a set number of cycles. In the eight trials that reported progression-free survival, 678 women progressed out of the 886 women randomised. The combination arm had a higher risk of progression than the sequential arm (HR 1.16; 95% CI 1.03 to 1.31; P = 0.01) with no significant heterogeneity. This result was consistent in all subgroups. Overall tumour response rates were higher in the combination arm (RR 1.13; 95% CI 1.03 to 1.24; P = 0.008) but there was significant heterogeneity for this outcome across the trials. In the seven trials that reported treatment-related deaths, there was no significant difference between the two arms, although the CIs were very wide due to the small number of events (RR 1.53; 95% CI 0.71 to 3.29; P = 0.28). The risk of febrile neutropenia was higher in the combination arm (RR 1.32; 95% CI 1.06 to 1.65; P = 0.01). There was no statistically significant difference in the risk of neutropenia, nausea and vomiting, or treatment-related deaths. Overall quality of life showed no difference between the two groups, but only three trials reported this outcome., Authors' Conclusions: Sequential single agent chemotherapy has a positive effect on progression-free survival, whereas combination chemotherapy has a higher response rate and a higher risk of febrile neutropenia in metastatic breast cancer. There is no difference in overall survival time between these treatment strategies, both overall and in the subgroups analysed. In particular, there was no difference in survival according to the schema of chemotherapy (giving chemotherapy on disease progression or after a set number of cycles) or according to the line of chemotherapy (first-line versus second- or third-line). Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression.

Background: The addition of radiotherapy (RT) following breast conserving surgery (BCS) was first shown to reduce the risk of ipsilateral recurrence in the treatment of invasive breast cancer. Ductal carcinoma in situ (DCIS) is a pre-invasive lesion. Recurrence of ipsilateral disease following BCS can be either DCIS or invasive breast cancer. Randomised controlled trials (RCTs) have shown that RT can reduce the risk of recurrence, but assessment of potential long-term complications from addition of RT following BSC for DCIS has not been reported for women participating in RCTs., Objectives: To summarise the data from RCTs testing the addition of RT to BCS for treatment of DCIS to determine the balance between the benefits and harms., Search Methods: We searched the Cochrane Breast Cancer Group Specialised Register (2 June 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 1), MEDLINE (2 June 2011), EMBASE (2 June 2011) and the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP; 2 June 2011). Reference lists of articles and handsearching of ASCO (2007), ESMO (2002 to 2007), and St Gallen (2005 to 2007) conferences were performed., Selection Criteria: RCTs of breast conserving surgery with and without radiotherapy in women at first diagnosis of pure ductal carcinoma in situ (no invasive disease present)., Data Collection and Analysis: Two authors independently assessed each potentially eligible trial for inclusion and its quality. Two authors also independently extracted data from published Kaplan-Meier analysis (survival curves) and reported summary statistics. Data were extracted and pooled for four trials. Data for planned subgroups were extracted and pooled for analysis.There were insufficient data to pool for long-term toxicity from radiotherapy., Main Results: Four RCTs involving 3925 women were identified and included in this review. All were high quality with minimal risk of bias. Three trials compared the addition of RT to BCS. One trial was a two by two factorial design comparing the use of RT and tamoxifen, each separately or together, in which participants were randomised in at least one arm. Analysis confirmed a statistically significant benefit from the addition of radiotherapy on all ipsilateral breast events (hazards ratio (HR) 0.49; 95% CI 0.41 to 0.58, P < 0.00001), ipsilateral invasive recurrence (HR 0.50; 95% CI 0.32 to 0.76, p=0.001) and ipsilateral DCIS recurrence (HR 0.61; 95% CI 0.39 to 0.95, P = 0.03). All the subgroups analysed benefited from addition of radiotherapy. No significant long-term toxicity from radiotherapy was found. No information about short-term toxicity from radiotherapy or quality of life data were reported., Authors' Conclusions: This review confirms the benefit of adding radiotherapy to breast conserving surgery for the treatment of all women diagnosed with DCIS. No long-term toxicity from use of radiotherapy was identified.

Background: The addition of a chemotherapy drug or drugs to an established regimen is one method used to increase the dose and intensity of treatment for metastatic breast cancer., Objectives: To assess the effects of adding one or more chemotherapy drugs to an established regimen in women with metastatic breast cancer., Search Strategy: We searched the Cochrane Breast Cancer Group's Specialised Register (to August 2009) using the codes for "advanced breast cancer" and "chemotherapy". This review is an update of the original Cochrane Review (Issue 3, 2006)., Selection Criteria: Randomised trials with a first line regimen of at least two chemotherapy drugs compared to the same regimen plus the addition of one or more chemotherapy drugs in women with metastatic breast cancer., Data Collection and Analysis: Two authors extracted data independently from published trials. We derived hazard ratios (HR) from time-to-event outcomes where possible, and used a fixed-effect model for meta-analysis. We analysed response rates as dichotomous variables and extracted toxicity data where available., Main Results: We identified 17 trials reporting on 22 treatment comparisons (2674 patients randomised). Fifteen trials (20 treatment comparisons) reported results for tumour response and 11 trials (14 treatment comparisons) published time-to-event data for overall survival. There were 1532 deaths in 2116 women randomised to trials of the addition of a drug to the regimen and control (the regimen alone). There was no detectable difference in overall survival between these patients, with an overall HR of 0.96 (95% confidence interval (CI) 0.87 to 1.07, P = 0.47) and no significant heterogeneity. We found no difference in time to progression between these regimens, with an overall HR of 0.93 (95% CI 0.81 to 1.07, P = 0.31) and no significant heterogeneity. Addition of a drug to the regimen was favourably associated with overall tumour response rates (odds ratio 1.21, 95% CI 1.01 to 1.44, P = 0.04) although we observed significant heterogeneity for this outcome across the trials. Where measured, acute toxicities such as alopecia, nausea and vomiting and leucopenia were more common with the addition of a drug., Authors' Conclusions: The addition of one or more drugs to the regimen shows a statistically significant advantage for tumour response in women with metastatic breast cancer but the results suggest no difference in survival time or time to progression. The positive effect on tumour response was also associated with increased toxicity.

Background: The addition of radiotherapy (RT) following breast conserving surgery (BCS) was first shown to reduce the risk of ipsilateral recurrence in the treatment of invasive breast cancer. Ductal carcinoma in situ (DCIS) is a pre-invasive lesion. Recurrence of ipsilateral disease following BCS can be either DCIS or invasive breast cancer. Randomised controlled trials (RCTs) have shown that RT can reduce the risk of recurrence, but assessment of potential long-term complications from addition of RT following BSC for DCIS has not been reported for women participating in RCTs., Objectives: To summarise the data from RCTs testing the addition of RT to BCS for treatment of DCIS to determine the balance between the benefits and harms., Search Strategy: We searched the Cochrane Breast Cancer Group Specialised Register (January 2008), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 1), MEDLINE (February 2008), and EMBASE (February 2008). Reference lists of articles and handsearching of ASCO (2007), ESMO (2002 to 2007), and St Gallen (2005 to 2007) conferences were performed., Selection Criteria: RCTs of breast conserving surgery with and without radiotherapy in women at first diagnosis of pure ductal carcinoma in situ (no invasive disease present)., Data Collection and Analysis: Two authors independently assessed each potentially eligible trial for inclusion and its quality. Two authors also independently extracted data from published Kaplan-Meier analysis (survival curves) and reported summary statistics. Data were extracted and pooled for four trials. Data for planned subgroups were extracted and pooled for analysis.There were insufficient data to pool for long-term toxicity from radiotherapy., Main Results: Four RCTs involving 3925 women were identified and included in this review. All were high quality with minimal risk of bias. Three trials compared the addition of RT to BCS. One trial was a two by two factorial design comparing the use of RT and tamoxifen, each separately or together, in which participants were randomised in at least one arm. Analysis confirmed a statistically significant benefit from the addition of radiotherapy on all ipsilateral breast events (hazards ratio (HR) 0.49; 95% CI 0.41 to 0.58, P < 0.00001), ipsilateral invasive recurrence (HR 0.50; 95% CI 0.32 to 0.76, p=0.001) and ipsilateral DCIS recurrence (HR 0.61; 95% CI 0.39 to 0.95, P = 0.03). All the subgroups analysed benefited from addition of radiotherapy. No significant long-term toxicity from radiotherapy was found. No information about short-term toxicity from radiotherapy or quality of life data were reported., Authors' Conclusions: This review confirms the benefit of adding radiotherapy to breast conserving surgery for the treatment of all women diagnosed with DCIS. No long-term toxicity from use of radiotherapy was identified.

Background: Combination chemotherapy regimens are frequently favoured over single agents for the treatment of metastatic breast cancer, in an attempt to achieve superior tumour response rates. It is not known however whether giving more intensive chemotherapy regimens results in better health outcomes, when both survival and toxicity are considered, and whether better response rates and rates of progression free survival actually translate to better overall survival., Objectives: To compare single agent with combination chemotherapy for the treatment of metastatic breast cancer., Search Strategy: We searched the Cochrane Breast Cancer Group Specialised Register November 2008. Handsearching of recent conference proceedings was also undertaken., Selection Criteria: Randomised trials of single agent chemotherapy compared to combination therapy in metastatic breast cancer., Data Collection and Analysis: Two authors independently assessed trials for eligibility and quality, and extracted data. Hazard ratios were derived for reported time-to-event outcomes.Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present., Main Results: Forty three eligible trials (48 comparisons) were identified. These included 9742 women, 55% of whom were receiving first-line treatment for metastatic disease. For overall survival there was a statistically significant difference in favour of the combination regimens with no heterogeneity (HR 0.88, 95% CI 0.83-0.93, p<0.00001). Results were very similar when trials of first-line treatment were analysed, and for analyses where the single agent was also included in the combination regimen. Combination regimens showed a statistically significant advantage for survival over single agent taxane (HR 0.82; 95% CI 0.75-0.89, p<0.00001), but not anthracycline (HR 0.94.86-1.02, p=0.15).Combination regimens were also associated with significantly better time to progression (HR 0.78, 95% CI 0.74 - 0.82, p<0.00001) and response (RR 1.29, 95% CI 1.14 -1.45, p<0.0001) although heterogeneity was statistically significant in both instances and probably due to clinical diversity of the participants and interventions.Women receiving combination regimens experienced a statistically significant detrimental effect on white cell count, increased alopecia and nausea and vomiting., Authors' Conclusions: Combination chemotherapy regimens show a statistically significant advantage for survival, tumor response and time to progression in women with metastatic breast cancer but they also produce more toxicity. An unresolved question is whether combination regimens are more effective than single agents given sequentially.

Background: Adjuvant chemotherapy improves survival in pre- and post-menopausal women with early breast cancer. Taxanes are highly active chemotherapy agents in metastatic breast cancer. Their role in early breast cancer was examined in this review., Objectives: To review the randomised evidence comparing taxane containing chemotherapy regimens with non-taxane containing chemotherapy regimens as adjuvant treatment of pre- or post-menopausal women with early breast cancer., Search Strategy: The Cochrane Breast Cancer Group Specialised Register was searched on 9th January 2007 using the codes for 'early breast cancer' and keywords for taxanes. Details of the search strategy used to create the register are described in the Group's module in The Cochrane Library. The reference lists of other related literature reviews and articles were also searched., Selection Criteria: Randomised trials comparing taxane containing regimens with non-taxane containing regimens in women with operable breast cancer. Women receiving neoadjuvant chemotherapy were excluded., Data Collection and Analysis: Data were collected from published trials and abstracts. Studies were assessed for eligibility and quality and the data extracted independently by two review authors. Hazard ratios (HR) were derived for time-to-event outcomes, and meta-analysis was performed using a fixed-effect model. The primary outcome measure was overall survival (OS); disease-free survival (DFS) was a secondary outcome measure. Toxicity and quality of life data were extracted when reported., Main Results: We identified 20 studies, 12 of these (7 full publications, 5 abstracts) had sufficient data published for inclusion (11 for OS and 11 for DFS) in the review. The weighted average median follow up was 60.4 months. All studies fulfilled quality criteria either adequately or well. Amongst 18,304 women with 2483 deaths, the HR for OS was 0.81 (95% CI 0.75 to 0.88, P < 0.00001) favouring taxane containing regimens. Amongst 19,943 women with 4800 events, the HR for DFS was 0.81 (95% CI 0.77 to 0.86, P < 0.00001) favouring taxane containing regimens. There was no statistical heterogeneity for either OS or DFS., Authors' Conclusions: This meta-analysis of studies supports the use of taxane containing adjuvant chemotherapy regimens with improvement of overall survival and disease-free survival for women with operable early breast cancer. The review did not identify a subgroup of patients where taxane containing treatment may have been more or less effective. Dosage and scheduling of the taxane drug is not clearly defined and we await results of the next generation of studies to determine the optimal use of taxanes in early breast cancer.

The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.

Background: The addition of a chemotherapy drug or drugs to an established regimen is one method used to increase the dose and intensity of treatment for metastatic breast cancer., Objectives: To identify and review the randomised trial evidence in the first line management of women with metastatic breast cancer that evaluates the addition of one or more chemotherapy drugs to an established regimen., Search Strategy: We searched the specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group on 3rd August 2004 (updated search on 2nd August 2005) using the codes for "advanced breast cancer" and "chemotherapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library., Selection Criteria: Randomised trials that evaluated a first line regimen of at least two chemotherapy drugs, and compared it to that same regimen plus the addition of one or more chemotherapy drugs in women with metastatic breast cancer., Data Collection and Analysis: We collected data from published trials and assessed studies for eligibility and quality. Two reviewers extracted data independently. We derived hazard ratios (HR) from time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. We analysed response rates as dichotomous variables and extracted toxicity data where available., Main Results: We identified 17 trials reporting on 22 treatment comparisons (2674 patients randomised). Fifteen trials (20 treatment comparisons) reported results for tumour response and 11 trials (14 treatment comparisons) published time-to-event data for overall survival. There were 1532 deaths in 2116 women randomised to trials of the addition of a drug to the regimen and control (the regimen alone). There was no detectable difference in overall survival between these patients, with an overall HR of 0.96 (95% CI 0.87 to 1.07, P = 0.47) and no statistically significant heterogeneity. We found no difference in time to progression between these regimens, with an overall HR of 0.93 (95% CI 0.81 to 1.07, P = 0.31) and no statistically significant heterogeneity. Addition of a drug to the regimen was favourably associated with overall tumour response rates (OR 1.21, 95% CI 1.01 to 1.44, P = 0.04) although we observed statistically significant heterogeneity for this outcome across the trials. Where measured, acute toxicities such as alopecia, nausea and vomiting and leukopenia were more common with the addition of a drug., Authors' Conclusions: The addition of one or more drugs to the regimen shows a statistically significant advantage for tumour response in women with metastatic breast cancer but the results suggest no difference in survival time or time to progression. The positive effect on tumour response observed with addition of a drug to the regimen was also associated with increased toxicity.

Numerous studies have documented increased breast cancer risks with hormone replacement therapy (HRT), but these do not give a woman her specific absolute risk for the remainder of her life. This article estimates the magnitude of the effect of HRT on breast cancer incidence in California and calculates a woman's cumulative risk of breast cancer with different formulations and durations of HRT use. The effects of HRT on the underlying breast cancer incidence were estimated using the attributable fraction method, applying HRT prevalence data from the 2001 California Health Interview Survey and published rates of higher relative risk (RR) from HRT use from the Women's Health Initiative (WHI) study and Million Women's Survey (MWS). The annual number of breast cancers potentially attributable to HRT in California was estimated, along with individual cumulative risk of breast cancer for various ages to 79 years according to HRT use, duration, and formulation. Using the WHI data, 829 of 19,000 breast cancers (4.3%) in California may be attributable to HRT. This figure increases to 3401 (17.4%) when the MWS RRs are applied. Use of estrogen-only HRT or short-term (approximately 5 years) use of combined HRT has a minimal effect on the cumulative risk calculated to the age of 79 years; application of the MWS data to a Californian woman commencing HRT at the age of 50 years (no HRT, 8.5%; estrogen only, 8.6%; combined, 9.1%). Prolonged (approximately 10 years) use of combined HRT increases the cumulative risk to 10.3%. This article demonstrates that HRT will generate a small additional risk of breast cancer in an individual. The reduction in perimenopausal symptoms may be considered sufficient to warrant this extra risk. However, this view needs to be balanced because the small increases in individual risk will be magnified, producing a noticeable change in population cancer caseload where HRT use is high.

Background: It is generally accepted that taxanes are among the most active chemotherapy agents in the management of metastatic breast cancer., Objectives: To identify and review the randomised evidence comparing taxane containing chemotherapy regimens with regimens not containing a taxane in the management of women with metastatic breast cancer., Search Strategy: The specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library., Selection Criteria: Randomised trials comparing taxane-containing chemotherapy regimens with regimens not containing taxanes in women with metastatic breast cancer., Data Collection and Analysis: Data were collected from published trials. Studies were assessed for eligibility and quality, and data were extracted, by two independent reviewers. Hazard ratios were derived for time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present., Main Results: Twenty one eligible trials were identified of which 12 have published time-to-event data and 16 have reported response data. The quality of randomisation was generally not described. An estimated 2621 deaths in 3643 randomised women demonstrate a statistically significant difference in favour of taxane-containing regimens with a HR for overall survival of 0.93 (95% CI=0.86-1.00, p=0.05) and no statistically significant heterogeneity. If the analysis is restricted to trials of firstline chemotherapy the HR changes to 0.92 and is no longer statistically significant (95% CI 0.84-1.02, p=0.11). There was also a significant difference in favour of taxanes in relation to time to progression (overall HR 0.92, 95%CI 0.85-0.99, p=0.02) and overall response in assessable women (overall OR 1.34, 95%CI 1.18-1.52, p<0.00001) however there was strong statistical evidence of heterogeneity (P<0.00001), probably reflecting the varying efficacy of the comparator regimens used in the trials., Authors' Conclusions: When all trials are considered, taxane-containing regimens appear to improve overall survival, time to progression and overall response in women with metastatic breast cancer. The degree of heterogeneity encountered indicates that taxane-containing regimens are more effective than some, but not all non-taxane-containing regimens.

Background: It is commonly thought that combining chemotherapy agents for treating women with metastatic breast cancer will result in regimens that are more active, offer superior tumour response rates with more time before progression and improve overall survival. However, it is not known whether giving patients more intensive chemotherapy regimens (judged according to some measure eg dose, dose intensity, response rate, or toxicity) results in better health outcomes. One way to investigate the effect of more versus less-intensive chemotherapy is to compare regimens containing a single drug (and hence possibly less active treatment) with regimens containing a greater number of drugs (and hence possibly more active but more toxic), even when adjustments are made to dosages or schedules to account for toxicity., Objectives: To compare use of single chemotherapy agents with regimens containing a combination of agents for the treatment of metastatic breast cancer., Search Strategy: The Specialised Register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied by the group to create the register, and the procedure used to code references, are described in the group's module on The Cochrane Library., Selection Criteria: Randomised trials comparing single agent chemotherapy with combination therapy in women with metastatic breast cancer., Data Collection and Analysis: Data were collected from published trials. Studies were assessed for eligibility and quality, and data were extracted by two independent reviewers. Hazard ratios were derived for time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present., Main Results: Thirty seven eligible trials were identified of which 28 had published time-to-event data. The quality of randomisation was generally not described. Data, based on an estimated 4220 deaths in 5707 women, show a modest advantage for combination chemotherapy regimens compared with single agents with a hazard ratio (HR) for overall survival of 0.88 (95% CI=0.83-0.94, P<0.0001) and no evident heterogeneity. Results are similar if the analysis is limited to trials in women receiving first-line chemotherapy. Combination regimens are favourably associated with time to progression (overall HR of 0.78 (95% CI=0.73-0.83, P<0.00001) and tumour response rates (OR 1.28, CI=1.15-1.42, P<0.00001) although significant heterogeneity was observed (P=0.002 and P<0.00001 respectively). This probably reflects the varying efficacy of the comparator regimens used in the trials. Women receiving combination regimens experienced a higher toxicity level for leukopenia, hair loss and nausea and vomiting compared with those receiving a single agent, which was statistically significant., Authors' Conclusions: Compared with single-chemotherapy agents, combination regimens show a statistically significant advantage for tumor response and time to progression in women with metastatic breast cancer, a modest improvement in overall survival and significantly worse toxicities.

Background: Antitumour antibiotics are used in the management of metastatic breast cancer. Some of these agents have demonstrated higher tumour response rates than non-antitumour antibiotic regimens, however a survival benefit has not been established in this setting., Objectives: To identify and review the randomised evidence comparing anti-tumour antibiotic containing chemotherapy regimens with regimens not containing an anti-tumour antibiotic in the management of women with metastatic breast cancer., Search Strategy: The specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May, 2003 using the codes for "advanced breast cancer" and "chemotherapy". Details of the search strategy and coding applied by the Group to create the register are described in the Group's module on The Cochrane Library., Selection Criteria: Randomised trials comparing anti-tumour antibiotic containing regimens with regimens not containing anti-tumour antibiotics in women with metastatic breast cancer., Data Collection and Analysis: Data were collected from published trials. Studies were assessed for eligibility and quality, and data were extracted by two independent reviewers. Hazard ratios (HRs) were derived from time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Quality of life and toxicity data were extracted where present. A primary analysis was conducted for all trials and by class of antitumour antibiotic., Main Results: Thirty-three trials reporting on 45 treatment comparisons were identified. All trials published results for tumour response and 26 trials published time-to-event data for overall survival. The observed 4084 deaths in 5284 randomised women did not demonstrate a statistically significant difference in survival between regimens that contained antitumour antibiotics and those that did not (HR 0.97, 95% CI 0.91 to 1.03, P = 0.35) and no significant heterogeneity. Antitumour antibiotic regimens were favourably associated with time-to-progression (HR 0.84, 95% CI 0.77 to 0.91) and tumour response rates (odds ratio (OR) 1.34, 95% CI 1.21 to 1.48) although statistically significant heterogeneity was observed for these outcomes. These associations were consistent when the analysis was restricted to the 29 trials that reported on anthracyclines. Patients receiving anthracycline-containing regimens were also more likely to experience toxic events compared to patients receiving non-antitumour antibiotic regimens. No statistically significant difference was observed in any outcome between mitoxantrone-containing and non-antitumour antibiotic-containing regimens., Reviewers' Conclusions: Compared to regimens without antitumour antibiotics, regimens that contained these agents showed a statistically significant advantage for tumour response and time to progression in women with metastatic breast cancer but were not associated with an improvement in overall survival. The favourable effect on tumour response and time to progression observed in anthracycline-containing regimens was also associated with greater toxicity.

Background: Studies have reported high tumour response rates for platinum-containing regimens in the treatment of women with metastatic breast cancer., Objectives: To identify and review the evidence from randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with metastatic breast cancer., Search Strategy: The specialised register maintained by the editorial base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied to create the register, and the procedure used to code references, are described in the Cochrane Breast Cancer Group module on The Cochrane Library., Selection Criteria: Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with metastatic breast cancer., Data Collection and Analysis: Studies were assessed for eligibility and quality, and data (from published trials) were extracted by two independent reviewers. Hazard ratios were derived for time-to-event outcomes, where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data (not available) were extracted where present., Main Results: Thirteen eligible trials were identified, of which 12 had published time-to-event data. The quality of randomisation was generally not described.Data, based on an estimated 987 deaths in 1377 women, was unable to show a statistically significant difference in favour of platinum-containing regimens. The hazard ratio (HR) for overall survival was 1.00 (95% confidence interval (CI) 0.88 to 1.15, p=0.96), with minor heterogeneity. Results were similar when the analysis was limited to trials in women receiving first line chemotherapy. There was no statistically significant difference in favour of platinum-containing regimens for time to progression (overall HR of 1.06 (95% CI 0.95 to 1.19, p=0.31) although there was marked evidence of heterogeneity (p< 0.0001). There was a statistically significant difference in overall response in favour of platinum-containing regimens (OR 1.47; 95% CI 1.23 to 1.76, p=0.0001). However, there was strong statistical evidence of heterogeneity (p < 0.00010) probably reflecting the varying efficacy of the comparator regimens used in the trials. Heterogeneity may also reflect the differences, and difficulties, in assessing response. Women receiving platinum-containing regimens experienced statistically significant greater toxicity levels for leukopenia, hair loss, nausea and vomiting and anaemia compared with those receiving non-platinum regimens., Reviewers' Conclusions: In view of the significant excess toxicity, lack of progression or survival benefit and the availability of less toxic active agents it is difficult to justify the use of platinum-containing regimens, particularly as first line treatment for women with metastatic breast cancer in routine clinical practice. Ongoing trials are examining the possibility of synergy between platins and trastuzamab, a monoclonal antibody treatment. No randomised trials containing oxalplatin were identified for the present review.

Background: Both chemotherapy and endocrine therapy can be used as treatments for metastatic breast cancer., Objectives: To review the evidence and determine whether chemotherapy or endocrine therapy has the most beneficial effect on treatment outcomes (survival, response rate, toxicity and quality of life)., Search Strategy: The specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 16th September 2002 using the codes for "advanced breast cancer", "chemotherapy" and "endocrine therapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library., Selection Criteria: Randomised trials comparing the effects of chemotherapy alone with endocrine therapy alone on pre-specified endpoints in metastatic breast cancer., Data Collection and Analysis: Data were collected from published trials. Hazard ratios were derived for survival analysis and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present., Main Results: The primary analysis of overall effect using hazard ratios derived from published survival curves involved six trials (692 women). There was no significant difference seen (HR=0.94, 95%CI 0.79-1.12, p=0.5). A test for heterogeneity was p=0.1. A pooled estimate of reported response rates in eight trials involving 817 women shows a significant advantage for chemotherapy over endocrine therapy with RR=1.25 (1.01-1.54, p=0.04). However the two largest trials showed trends in opposite directions, and a test for heterogeneity was p=0.0018. There was little information available on toxicity and quality of life. Six of the seven fully published trials commented on increased toxicity with chemotherapy, mentioning nausea, vomiting and alopecia. Three of the seven mentioned aspects of quality of life, with differing results. Only one trial formally measured quality of life, concluding that it was better with chemotherapy., Reviewer's Conclusions: In women with metastatic breast cancer and where hormone receptors are present, a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive disease.

Background: It is generally accepted that taxanes are among the most active chemotherapy agents in the management of metastatic breast cancer., Objectives: To identify and review the randomised evidence comparing taxane containing chemotherapy regimens with regimens not containing a taxane in the management of women with metastatic breast cancer., Search Strategy: The specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library., Selection Criteria: Randomised trials comparing taxane-containing chemotherapy regimens with regimens not containing taxanes in women with metastatic breast cancer., Data Collection and Analysis: Data were collected from published trials. Studies were assessed for eligiblity and quality, and data were extracted, by two independent reviewers. Hazard ratios were derived for time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present., Main Results: Twenty eligible trials were identified of which 17 had published at least some results, and 12 had published time-to-event data. The quality of randomisation was generally not described. An estimated 2659 deaths in 3643 randomised women demonstrate a statistically significant difference in favour of taxane-containing regimens with a HR for overall survival of 0.90 (95% CI=0.84-0.97, p=0.009) and no significant heterogeneity. If the analysis is restricted to trials of firstline chemotherapy the HR changes to 0.92 and is no longer statistically significant (95% CI 0.84-1.02, p=0.12). There was also a significant difference in favour of taxanes in relation to time to progression (overall HR 0.87, 95%CI 0.81-0.93, p<0.0001) and overall response (overall OR 1.29, 95%CI 1.13-1.47, p<0.0001) however there was strong statistical evidence of heterogeneity (P<0.00001), probably reflecting the varying efficacy of the comparator regimens used in the trials., Reviewer's Conclusions: When all trials are considered, taxane-containing regimens appear to improve overall survival, time to progression and overall response in women with metastatic breast cancer. The degree of heterogeneity encountered indicates that taxane-containing regimens are more effective than some, but not all non-taxane-containing regimens.

Two female patients with desmoid tumors (aggressive fibromatosis) showed tumor regression after endocrine therapy. In one patient, tumor response to tamoxifen has been maintained over several years of treatment. In the second patient, who had inoperable mesenteric fibromatosis, the tumor progressed on tamoxifen but regressed after treatment with Zoladex (goserelin acetate, ICI, Melbourne, Australia) and medroxyprogesterone acetate (MPA). To the authors' knowledge this is the first report of the use of Zoladex in the treatment of desmoid tumors. This review of the literature reveals that the biology of this disease is related to the endogenous hormonal environment and that estrogen receptors have been documented in desmoid tumors. Thirty-five cases are identified where endocrine agents have been employed, with a response rate of 51%. Furthermore, tumors may respond to second-line hormonal therapy after failing to respond to initial endocrine treatment. Endocrine treatments have also been used in other disorders of fibroblastic origin. The authors recommend that endocrine treatment be employed in inoperable desmoid tumors or where there has been postsurgical recurrence. In addition, the role for endocrine therapy in other soft tissue neoplasms should be determined.