In this narrative synthesis of 18 randomised controlled trials, neoadjuvant taxane chemotherapy was found to be efficacious and safe in women with non-metastatic breast cancer when compared with other neoadjuvant therapy or with adjuvant taxane therapy. Differences between the intervention regimens, participant characteristics and the study outcomes suggest that the findings should be interpreted with caution.

To determine the effectiveness and safety of neoadjuvant taxane chemotherapy in women with non-metastatic breast cancer.

Computerised searches of MEDLINE and EMBASE (to September 2004) and the Cochrane Library (Issue 3, 2004) were performed; the strategies for the MEDLINE and EMBASE searches were reported. Searches of online conference proceedings of the American Society of Clinical Oncology (1999 to 2004) and the San Antonio Breast Cancer Symposium (2001 to 2003) were also conducted. Personal files and the bibliographies of identified trials were also searched. Studies reported in full and in abstract form were eligible for inclusion in the review; those published in languages other than English were excluded. Some of the included studies were ongoing and interim results were included in the review.

Study designs of evaluations included in the review

Randomised controlled trials (RCTs), systematic reviews and meta-analyses were eligible for inclusion. All of the included studies were RCTs (either phase II or III), with durations of follow-up (where reported) ranging from 8.3 to 105 months.

Specific interventions included in the review

Studies that compared a neoadjuvant taxane-containing chemotherapy regimen with any other neoadjuvant chemotherapy were eligible for inclusion. The taxane-containing regimens included were paclitaxel and docetaxel. Intervention regimens were compared with other neoadjuvant regimens, adjuvant taxane regimens, and alternative taxane dose and/or treatment schedules. Details of the treatments, dosages and schedules used were reported.

Participants included in the review

Studies of women with non-metastatic breast cancer were eligible for inclusion. The participant inclusion and exclusion criteria used by the individual primary studies varied. The majority of the participants included in the review were stage II or III, but a range of participants according to TNM (Tumour, Nodes, Metastasis) criteria were included. No details of the age of the included participants were given. Two trials randomised participants according to their initial response to chemotherapy.

Outcomes assessed in the review

Studies that reported rates of clinical response, pathological response, breast conservation, disease-free survival or overall survival were eligible for inclusion. The definitions of clinical and pathological response varied between the included trials and were reported in the review. Adverse events were also reported.

How were decisions on the relevance of primary studies made?

Three reviewers assessed studies for inclusion. No mention was made of how any disagreements were resolved.

It was unclear whether a formal assessment of study quality was performed. However, a narrative summary of the quality of the individual studies was provided. The authors commented on quality factors such as sample size, methods of randomisation or controlling for confounding, allocation concealment, blinding, p-value adjustment to account for multiple testing, and the use of intention-to-treat analysis.

The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. Response and survival data were reported as percentages.

How were the studies combined?

The studies were combined in a narrative.

How were differences between studies investigated?

Some differences between the studies were evident from the text and tables of the review. The studies were grouped according to the interventions compared: neoadjuvant taxane regimens versus other neoadjuvant regimens; neoadjuvant taxane regimens versus adjuvant taxane regimens; and taxane dose and/or schedule comparison.

Eighteen RCTs (7 phase II and 11 phase III) were identified (6,205 patients).

Neoadjuvant taxane regimens versus other neoadjuvant regimens (10 trials, 3,873 patients).

Seven trials were reported in abstract form only. Of the other three, two did not report the method of randomisation and none were blinded.

Paclitaxel was associated with a statistically significant improvement in pathological complete response (25% versus 0%), but no difference in pathological partial response in one small study. Neoadjuvant paclitaxel was associated with higher rates of breast conserving therapy in 2 studies, but no information was available on whether these differences were statistically significant.

Docetaxel was associated with a significant improvement in pathological complete response in one of 3 studies (26% versus 13%, p<0.001); with improved clinical overall response in one study (85% versus 64%, p=0.001); and with higher rates of node-negative disease at surgery (58% versus 51%, p<0.001) in one study. Three studies found that neoadjuvant docetaxel was associated with higher rates of breast conservation, but the statistical significance of these findings was unclear.

One study found that neoadjuvant docetaxel was associated with better overall survival (97% versus 84%, p=0.02) and disease-free survival (93% versus 78%, p=0.04) at 38 and 65 months, respectively, whereas another 2 studies found no significant difference in disease-free survival at 32 months or in the median length of progression-free survival.

Neoadjuvant taxane regimens versus adjuvant taxane regimens (1 trial, 892 patients).

The study was reported in abstract form, thus its quality could not be determined.

Compared with those who received no neoadjuvant chemotherapy, patients who received neoadjuvant taxanes were significantly more likely to be node-negative at surgery (61% versus 38%, p=0.0001) and to have breast conservation (71% versus 35%, p<0.0001).

Taxane dose and/or schedule comparisons (7 trials, 2,492 patients).

Four trials were reported in abstract form only. The remaining trials suffered from poor reporting of the method of randomisation and the use of blinding.

Significantly higher numbers of pathological complete responses were reported for one study of 12 versus 4 cycles of neoadjuvant paclitaxel combination chemotherapy (16% versus 4%, p=0.03); for one study of weekly versus 3-weekly paclitaxel (29% versus 14%, p<0.01); for one study of six versus three cycles of epirubicin and docetaxel (19% versus 8%, p=0.0045); and for one study of dose-dense sequential docetaxel compared with standard therapy (18% versus 10%, p=0.03). Another study found higher pathological complete response in patients treated with six cycles as opposed to four cycles of doxorubicin and paclitaxel; however, the significance of these findings was not reported.

One trial reported a higher rate of breast conservation in women who received dose-dense compared with standard epirubicin and paclitaxel (66% versus 55%, p=0.016).

One trial reported higher rates of node-negative disease at surgery in women who received combination compared with sequential doxorubicin and docetaxel (53% versus 19%; 2.17 versus 4.81 positive nodes, p=0.037).

Adverse effects of taxanes.

Rates of adverse events were inconsistent and p-values were rarely reported. However, in general, haematological toxicity (neutropenia and febrile neutropenia) was more frequently associated with taxane-containing regimens. There was some evidence that neurotoxicity may be associated with neoadjuvant paclitaxel and hand-foot syndrome with neoadjuvant docetaxel. There was little evidence to suggest other adverse events were more commonly associated with neoadjuvant taxanes.

Neoadjuvant taxane chemotherapy appeared from the preliminary results of RCTs to be efficacious and safe. There was no evidence to indicate that one taxane was more beneficial than another in the neoadjuvant setting.

This review answered a clear research question supported by clearly defined inclusion criteria. The search strategy appeared adequate and included trials databases, conference abstracts and contact with experts. Details of the search strategy were provided and attempts were made to reduce the risk of publication bias through the inclusion of abstracts as well as full articles, although language bias could have affected the results since the search was restricted to trials published in English. It was not clear whether the reviewers attempted to minimise the risk of error and bias during the validity assessment and data extraction processes. Although it was unclear whether a formal validity assessment was carried out, the authors did consider individual study quality when synthesising the data.

Few details of the patients in the included trials were given, thus limiting the reader's ability to judge the external generalisability of the results. Given the differences between the studies, intervention regimens, participants and the reporting of study outcome measures, the use of a narrative synthesis was reasonable. In light of the aforementioned differences, the findings of the review should be interpreted cautiously.

Practice: The authors did not state any implications for practice.

Research: The authors stated that their findings were based on preliminary data, implying that further trials comparing different neoadjuvants and comparing neoadjuvants with other treatments are required. Such trials should also assess the level of adverse events associated with the various treatment comparisons.

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.