Taxanes for adjuvant treatment of early breast cancer
Appendices
Appendix 1. CENTRAL
#1 MeSH descriptor: [Breast Neoplasms] explode all trees
#2 (early breast cancer* or early breast neoplas* or early breast carcinoma* or early breast tumour* or early breast tumor*):ti,ab,kw
#3 (locally advanced breast cancer* or locally advanced breast neoplas* or locally advanced breast carcinoma* or locally advanced breast tumour* or locally advanced breast tumor*):ti,ab,kw
#4 #1 or #2 or #3
#5 (taxane containing regimen* or taxane containing chemotherapy regimen* or non‐taxane containing regimen* or non‐taxane containing chemotherapy regimen* or taxoid* or paclitaxel or docetaxel or texane* or taxol* or taxotere* or paxene* or anzatax or nsc‐125973 or 4alpha or 7‐epi‐taxol):ti,ab,kw
#6 MeSH descriptor: [Paclitaxel] explode all trees
#7 MeSH descriptor: [Taxoids] explode all trees
#8 #5 or #6 or #7
#9 #4 and #8
Appendix 2. MEDLINE
1. randomised controlled trial.pt.
2. randomized controlled trial.pt.
3. controlled clinical trial.pt.
4. randomized.ab.
5. randomised.ab
6. placebo.ab.
7. randomly.ab.
8. trial.ab.
9. groups.ab.
10.1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9
11.exp Breast Neoplasms/
12.(early adj6 breast adj6 cancer$).mp.
13.(early adj6 breast adj6 neoplasm$).mp.
14.(early adj6 breast adj6 carcinoma$).mp.
15.(early adj6 breast adj6 tumour$).mp.
16.(early adj6 breast adj6 tumor$).mp.
17.11 or 12 or 13 or 14 or 15 or 16
18.taxane containing regimens.mp
19.taxane containing chemotherapy regimens.mp
20.(taxane$ adj6 contain$ adj6 regimen$).mp
21.(taxane$ adj6 contain$ adj6 chemotherap$ adj6 regimen$).mp
22.non‐taxane containing regimens.mp
23.non‐taxane containing chemotherapy regimens.mp
24.(non adj3 taxane$ adj6 contain$ adj6 regimen$).mp
25.(non adj3 taxane$ adj6 contain$ adj6 chemotherap$ adj6 regimen$).mp
26.exp Taxoids/
27.exp Paclitaxel/
28.docetaxel.mp
29.taxane$.mp
30.taxol$.mp
31.taxotere.mp
32.paxene.mp
33.nsc‐125973.mp
34.anzatax.mp
35.4alpha.mp
36.7‐epi‐taxol.mp
37.18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36
38.10 and 17 and 37
39. Animals/
40. Humans/
41. 39 not 40
42. 38 not 41
Appendix 3. Embase
#1
random* OR factorial* OR crossover* OR cross NEXT/1 over* OR placebo* OR (doubl* AND blind*) OR (singl* AND blind*) OR assign* OR allocat* OR volunteer*OR 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'randomized controlled trial'/exp OR 'single blind procedure'/exp
#2
'early breast cancer'
#3
'early breast neoplasm'
#4
'early breast carcinoma'
#5
'early breast tumour'
#6
'early breast tumor'
#7
(early OR 'early stage') NEAR/5 ('breast cancer' OR 'breast carcinoma' OR 'breast neoplasm' OR 'breast tumour' OR 'breast tumor')
#8
'locally advanced breast cancer'
#9
'locally advanced breast neoplasm'
#10
'locally advanced breast carcinoma'
#11
'locally advanced breast tumour'
#12
'locally advanced breast tumor'
#13
'locally advanced' NEAR/5 ('breast cancer' OR 'breast carcinoma' OR 'breast neoplasm' OR 'breast tumour' OR 'breast tumor')
#14
#2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13
#15
'taxane containing regimens'
#16
'taxane containing regimen'
#17
'taxane containing chemotherapy regimens'
#18
'taxane containing chemotherapy regimen'
#19
taxoid*
#20
'paclitaxel'/exp OR paclitaxel
#21
'docetaxel'/exp OR docetaxel
#22
taxane*
#23
'taxol'/exp OR taxol
#24
'taxoid'/exp OR taxoid
#25
'taxotere'/exp OR taxotere
#26
'paxene'/exp OR paxene
#27
taxotere*
#28
paxene*
#29
'nsc 125973'/exp OR 'nsc 125973'
#30
'anzatax'/exp OR anzatax
#31
4alpha
#32
'7 epi taxol'
#33
'non‐taxane containing regimen'
#34
'non‐taxane containing regimens'
#35
'non‐taxane containing chemotherapy regimen'
#36
'non‐taxane containing chemotherapy regimens'
#37
#15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR#35 OR #36
#38
#1 AND #14 AND #37
#39
#38 NOT ([animals]/lim NOT [humans]/lim)
#40
#39 AND [embase]/lim
Appendix 4. WHO ICTRP
Basic Searches:
1. early breast cancer AND taxane containing regimen
2. early breast cancer AND taxane containing regimens
3. early breast cancer AND non taxane containing regimen
4. early breast cancer AND non taxane containing regimens
5. early stage breast cancer AND taxane
6. early stage breast cancer AND non taxane
Advanced Searches:
1. Title: Taxanes for adjuvant treatment of early breast cancer
Recruitment Status: All
2. Condition: early breast cancer*
Intervention: chemotherapy AND taxane containing regimen*
Recruitment Status: All
3. Condition: early breast cancer*
Intervention: chemotherapy AND non taxane containing regimen*
Recruitment Status: All
4. Title: chemotherapy AND taxane containing regimen*
Condition: early breast cancer*
Recruitment Status: All
5. Title: chemotherapy AND non taxane containing regimen*
Condition: early breast cancer*
Recruitment Status: All
6. Condition: early breast cancer*
Intervention: taxane OR taxol OR taxotere OR paclitaxel OR paxene OR nsc‐125973 OR docetaxel OR anzatax OR taxanes OR taxane containing regimen OR taxane containing regimens OR non taxane containing regimen OR non taxane containing regimens
Recruitment Status: All
7. Condition: early stage breast cancer*
Intervention: taxane OR taxol OR taxotere OR paclitaxel OR paxene OR nsc‐125973 OR docetaxel OR anzatax OR taxanes OR taxane containing regimen OR taxane containing regimens OR non taxane containing regimen OR non taxane containing regimens
Recruitment Status: All
Appendix 5. ClinicalTrials.gov
Basic Searches:
1. taxanes for adjuvant treatment of early breast cancer
2. early breast cancer AND taxane containing regimen
3. early breast cancer AND non taxane containing regimen
4. early breast cancer AND (chemotherapy AND taxane containing regimen)
5. early breast cancer AND (chemotherapy AND non taxane containing regimen)
6. early stage breast cancer AND taxane containing regimen
7. early stage breast cancer AND non taxane containing regimen
8. early stage breast cancer AND (chemotherapy AND taxane containing regimen)
9. early stage breast cancer AND (chemotherapy AND non taxane containing regimen)
10. operable breast cancer AND taxane containing regimen
11. operable breast cancer AND non taxane containing regimen
12. operable breast cancer AND (chemotherapy AND taxane containing regimen)
13. operable breast cancer AND (chemotherapy AND non taxane containing regimen)
Advanced Searches:
1. Search Terms: Taxanes for adjuvant treatment of early breast cancer
Recruitment: All studies
Study Results: All studies
Study Type: All studies
2. Conditions: early breast cancer
Interventions: taxane OR taxol OR taxotere OR paclitaxel OR paxene OR nsc‐125973 OR docetaxel OR anzatax OR taxanes OR taxane containing regimen OR taxane containing regimens OR non taxane containing regimen OR non taxane containing regimens
Recruitment: All studies
Study Results: All studies
Study Type: All studies
3. Conditions: early stage breast cancer
Interventions: taxane OR taxol OR taxotere OR paclitaxel OR paxene OR nsc‐125973 OR docetaxel OR anzatax OR taxanes OR taxane containing regimen OR taxane containing regimens OR non taxane containing regimen OR non taxane containing regimens
Recruitment: All studies
Study Results: All studies
Study Type: All studies
4. Conditions: operable breast cancer
Interventions: taxane OR taxol OR taxotere OR paclitaxel OR paxene OR nsc‐125973 OR docetaxel OR anzatax OR taxanes OR taxane containing regimen OR taxane containing regimens OR non taxane containing regimen OR non taxane containing regimens
Recruitment: All studies
Study Results: All studies
Study Type: All studies
Review update: study flow diagram.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Overall effect of taxanes, outcome: 1.1 Overall survival ‐ all studies.
Forest plot of comparison: 1 Overall effect of taxanes, outcome: 1.2 Disease‐free survival: all studies.
Funnel plot of comparison: 1 Overall effect of taxanes, outcome: 1.1 Overall survival ‐ all studies.
Forest plot of comparison: 11 Toxicities, outcome: 11.1 Febrile neutropenia by sequential or concurrent anthracycline/taxane.
Comparison 1 Overall effect of taxanes, Outcome 1 Overall survival ‐ all studies.
Comparison 1 Overall effect of taxanes, Outcome 2 Disease‐free survival: all studies.
Comparison 1 Overall effect of taxanes, Outcome 3 Disease‐free survival: as defined in Cochrane protocol.
Comparison 2 Type of taxane, Outcome 1 Overall survival.
Comparison 2 Type of taxane, Outcome 2 Disease‐free survival.
Comparison 3 Weekly or three‐weekly paclitaxel, Outcome 1 Overall survival.
Comparison 3 Weekly or three‐weekly paclitaxel, Outcome 2 Disease‐free survival.
Comparison 4 Sequential or concurrent anthracycline/taxane, Outcome 1 Overall survival.
Comparison 4 Sequential or concurrent anthracycline/taxane, Outcome 2 Disease‐free survival.
Comparison 5 Addition or substitution of taxane, Outcome 1 Overall survival.
Comparison 5 Addition or substitution of taxane, Outcome 2 Disease‐free survival.
Comparison 6 Duration of chemotherapy, Outcome 1 Overall survival.
Comparison 6 Duration of chemotherapy, Outcome 2 Disease‐free survival.
Comparison 7 Number of cycles of taxane‐containing chemotherapy, Outcome 1 Overall survival.
Comparison 7 Number of cycles of taxane‐containing chemotherapy, Outcome 2 Disease‐free survival.
Comparison 8 Lymph node status, Outcome 1 Overall survival.
Comparison 8 Lymph node status, Outcome 2 Disease‐free survival.
Comparison 9 Hormone receptor status, Outcome 1 Overall survival.
Comparison 9 Hormone receptor status, Outcome 2 Disease‐free survival.
Comparison 10 Publication status, Outcome 1 Overall survival.
Comparison 10 Publication status, Outcome 2 Disease‐free survival.
Comparison 11 Toxicities, Outcome 1 Febrile neutropenia by sequential or concurrent anthracycline/taxane.
Comparison 11 Toxicities, Outcome 2 Febrile neutropenia by type of taxane.
Comparison 11 Toxicities, Outcome 3 Neuropathy (grade 3/4).
Comparison 11 Toxicities, Outcome 4 Neuropathy (grade 3/4) by type of taxane.
Comparison 11 Toxicities, Outcome 5 Fatigue (grade 3/4).
Comparison 11 Toxicities, Outcome 6 Stomatitis (grade 3/4).
Comparison 11 Toxicities, Outcome 7 Cardiotoxicity (includes grade 3/4 and symptomatic CCF).
Comparison 11 Toxicities, Outcome 8 Nausea and/or vomiting (grade 3/4).
Comparison 11 Toxicities, Outcome 9 Secondary leukaemia/myelodysplasia.
Comparison 11 Toxicities, Outcome 10 Treatment‐related deaths.
Comparison 12 Risk of Bias, Outcome 1 Overall survival.
Comparison 12 Risk of Bias, Outcome 2 Disease‐free survival.
| Taxane‐containing chemotherapy compared to any chemotherapy without taxane for early breast cancer | ||||||
| Patient or population: women with early breast cancer (operable, stages I to IIIA) | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with any chemotherapy without taxanes | Risk with taxane‐containing chemotherapy | |||||
| Overall survival | Low risk of death | HR 0.87 | 39,180 | ⊕⊕⊕⊕ | Additional analyses (including specific taxane, scheduling, treatment duration, doses, node positive, and risk of bias) showed equivalent efficacy | |
| 80 per 1000* | 70 per 1000 | |||||
| High risk of death | ||||||
| 200 per 1000* | 176 per 1000 | |||||
| Disease‐free progression | Low risk of recurrence | HR 0.88 | 41,909 | ⊕⊕⊕⊕ | As above for overall survival | |
| 140 per 1000* | 124 per 1000 | |||||
| High risk of recurrence | ||||||
| 320 per 1000* | 288 per 1000 | |||||
| Quality of life | Not estimable. In general, there did not seem to be differences in quality of life scores between groups at long‐term follow‐up | ‐ | (7 studies) | ⊕⊕⊝⊝ | Studies used the validated EORTC‐C30 questionnaire and measures were patient‐reported | |
| Febrile neutropenia | Study population | OR 1.43 | 34,154 | ⊕⊕⊕⊝ | There was a higher incidence of febrile neutropenia with docetaxel‐containing regimens | |
| 56 per 1000 | 78 per 1000 | |||||
| Neuropathy (including grade 3/4 sensory or motor neuropathy, or both) | Study population | OR 6.89 (3.23 to 14.71) | 31,033 | ⊕⊕⊕⊝ | A test for subgroup differences by taxane type was not significant | |
| 6 per 1000 | 37 per 1,000 | |||||
| Cardiotoxicity (including grade 3/4 and congestive cardiac failure) | Study population | OR 0.87 | 32,894 | ⊕⊕⊕⊝ | Risk of cardiotoxicity was reduced with lower planned dose of anthracycline | |
| 9 per 1000 | 8 per 1000 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aHeterogeneity was detected (I² = 59%) mainly due to variations in chemotherapy backbones. The quality of evidence was not downgraded as variations in chemotherapy are likely to occur in clinical practice. | ||||||
| Study | Description | Definition |
| DFS | Revised to iDFS (in 2016) in line with Standardized Definitions for Efficacy End Points (STEEP), where DFS referred to all invasive ipsilateral, regional, contralateral, and distant disease recurrences, second primary tumours, and death from any cause as events, and all non‐invasive in situ cancer events were excluded | |
| DFS | Time from randomisation to date of clinical relapse (histological or radiological evidence), a second cancer (except skin cancer other than melanoma or carcinoma in situ of breast or cervix), or death | |
| DFS | Time from randomisation until first date of local, regional, or distant relapse; diagnosis of a second primary cancer, including contralateral invasive breast cancer; or death from any cause | |
| RFS | Time from date of random assignment to date of locoregional and/or distant release | |
| RFS | Time from study entry until local recurrence, distant relapse, or death without relapse, whichever occurred first | |
| DFS | Time from randomisation to date of first locoregional recurrence, first distant metastasis, or death from any cause | |
| DFS | Time from date of randomisation to locoregional recurrence, distant recurrence, new primary breast cancer, or death | |
| Freedom from progression | Not reported in trial publication | |
| DFS | Interval between randomisation and locoregional or distant relapse or contralateral invasive breast cancer or second primary invasive non‐breast cancer or ipsilateral or contralateral in situ ductal carcinoma or death without cancer, whichever occurred first | |
| DFS | Time from date of random assignment to date of invasive breast cancer recurrence, invasive contralateral breast cancer, or death from any cause | |
| Recurrence‐free survival | Time from randomisation to date of detection of local or distant relapse (histological or radiological evidence) or contralateral invasive breast cancer or death without recurrence | |
| DFS | Time from random assignment to date of local, regional, or metastatic relapse; date of a second primary malignancy; or death form any cause, whichever occurred first | |
| DFS | Time from date of randomisation to date of local, regional, or metastatic relapse; diagnosis of second primary cancer or death from any cause | |
| DFS | According to the definition of invasive disease‐free survival (IDFS) in the STEEP system | |
| DFS | Time from randomisation to first relapse (local, regional, distant), contralateral breast cancer, or death from any cause | |
| EFS | Time from date of randomisation to date of local recurrence, distant metastases, contralateral breast cancer, second primary malignancy, or death from any cause, whichever occurred first | |
| DFS | Time from randomisation until local recurrence, distant relapse, or death (without relapse) | |
| DFS | Time from randomisation to date of breast cancer recurrence (local, regional, or distant), invasive contralateral breast cancer, non‐breast second primary cancer, or death from any cause | |
| iDFS and DDFS | Any local invasive or distant recurrence of breast cancer, any contralateral breast cancer, any second malignancy, and any death irrespective of its cause for iDFS | |
| RFS | Time from random assignment to time of recurrence of the primary breast cancer (local, nodal, metastatic). Patients with contralateral breast cancer, second malignancy, non‐disease‐related death were censored | |
| RFS | Time from random assignment to time of recurrence of the primary breast cancer (local, nodal, metastatic). Patients with contralateral breast cancer, second malignancy, non‐disease‐related death were censored | |
| DFS | Time from randomisation until local, regional, or distant treatment failure, contralateral breast cancer, non‐breast second primary cancer, or death | |
| DFS | Time from randomisation until first relapse (local, regional, or distant), contralateral breast cancer, or death from any cause | |
| TTR | Time to locoregional relapse, contralateral breast cancer, or distant metastasis, whichever occurs first | |
| DFS | Time from study entry to first local recurrence or distant metastasis, or death as a result of any cause | |
| DFS | Time from randomisation until first relapse (locoregional or distant), contralateral breast cancer, or death from any cause | |
| DFS | Time from randomisation to first invasive relapse, new primary breast cancer (ipsilateral or contralateral), or death form any cause | |
| DFS | Time from date of randomisation to local or distant recurrence or contralateral breast cancer or second primary malignancy or death from any case, whichever occurred first | |
| DFS | Time between randomisation and date of first documented disease recurrence or death from any cause | |
| DFS | Time from first dose of chemotherapy until date of any recurrence of breast cancer, a new second breast cancer or any other type of cancer, death due to any cause without relapse or recurrence of breast cancer, or date of last patient contact | |
| DFS: disease‐free survival | ||
| Trial | Cardiotoxicity | Febrile neutropenia | Neuropathy | Nausea/vomiting | Fatigue | Stomatitis |
| Grade 3/4 cardiac symptoms: NCI CTC (version 2) | Reported as "febrile neutropenia": NCI CTC (version 2) | Grade 3/4 neurological symptoms: NCI CTC (version 2) | Grade 3/4 vomiting: NCI CTC (version 2) | NR | Grade 3/4 mucositis: NCI CTC (version 2) | |
| Congestive heart failure (cardiac function grade 3 or 4) | Reported as "febrile neutropenia": Protocol definition ‐ fever of grade 2 or more concomitant with grade 4 neutropenia requiring IV antibiotics, hospitalisation, or both | Grade 3/4 neurosensory effects: NCI CTC (version 1) | Grade 3/4 or severe vomiting: NCI CTC (version 2) | Grade 3/4 asthenia: NCI CTC (version 2) | Grade 3/4 stomatitis: NCI CTC (version 2) | |
| Grade 3/4 cardiac function toxicity | Reported as "febrile neutropenia": protocol defined grade 4 neutropenia, fever with > 38 degrees Celsius, NCI CTC (version 1) | Grade 3/4 neurosensory effects: NCI CTC (version 1) | Grade 3/4 or severe vomiting: NCI CTC (version 1) | Grade 3 or higher asthenia: NCI CTC (version 1) | Grade 3 or higher stomatitis: NCI CTC (version 1) | |
| Grade 3/4 cardiotoxicity: WHO toxicity criteria | NR | Grade 3/4 peripheral neuropathy: WHO toxicity criteria | Grade 3/4 nausea and/or vomiting: WHO toxicity criteria | NR | Grade 3/4 stomatitis: WHO toxicity criteria | |
| Grade 3 or higher cardiotoxicity (left ventricular systolic dysfunction, restrictive cardiomyopathy, general cardiac, cardiac deaths attributed to protocol treatment ‐ myocardial infarction and left ventricular dysfunction) | Reported as grade 3/4 febrile neutropenia: NCI CTC (version 2) | Grade 3/4 neuropathy (reported both sensory and motor): NCI CTC (version 2) | Grade 3/4 vomiting: NCI CTC (version 2) | Grade 3/4 fatigue: NCI CTC (version 2) | NR | |
| Congestive heart failure during treatment or post treatment follow‐up | NR | NR | NR | NR | NR | |
| Diagnosed congestive cardiac failure | Grade 3/4 febrile neutropenia: NCI CTC (version 2) | Grade 3/4 peripheral neuropathy: NCI CTC (version 2) | Grade 3/4 nausea and/or vomiting: NCI CTC (version 2) | NR | Grade 3/4 stomatitis: NCI CTC (version 2) | |
| Grade 3/4 congestive heart failure | Reported as "febrile neutropenia": toxicity criteria not specified | Grade 3/4 neuropathy (reported both sensory and motor) | Grade 3 or higher vomiting: toxicity criteria not specified | Grade 3 or higher fatigue: toxicity criteria not specified | Grade 3 or higher stomatitis: toxicity criteria not specified | |
| Symptomatic cardiac failure | NR | Grade 3 neuropathy reported only: NCI CTC (no version provided) | NR | NR | NR | |
| Grade 3/4 heart rhythm toxicity | Reported as "febrile neutropenia": NCT CTC (version 2) | Grade 3/4 neuropathy: NCI CTC (version 2) | Grade 3/4 vomiting: NCI CTC (version 2) | Grade 3/4 fatigue: NCI CTC (version 2) | Grade 3/4 mucositis: NCI CTC (version 2) | |
| NR | Reported as "neutropenic fever": NCI CTC (version 2) | Grade 3/4 neuropathy (reported both sensory and motor): NCI CTC (version 2) | Grade 3/4 vomiting: NCI CTC (version 2) | Grade 3/4 fatigue: NCI CTC (version 2) | Grade 3/4 stomatitis: NCI CTC (version 2) | |
| Grade 3/4 cardiac dysfunction, Grade 4 cardiac ischaemia, Grade 3 arrhythmia | Reported as "febrile neutropenia": NCI CTC (version 2) | Grade 3/4 sensory neuropathy: NCI CTC (version 2) | Grade 3/4 vomiting: NCI CTC (version 2) | Grade 3/4 fatigue: NCI CTC (version 2) | Grade 3/4 mucositis: NCI CTC (version 2) | |
| Grade 3/4 arrhythmia, Grade 3/4 congestive heart failure | Reported as "febrile neutropenia": protocol defined fever Grade 2 or higher with Grade 4 neutropenia requiring intravenous antibiotics, hospitalisation, or both | Grade 3/4 peripheral neuropathy (reported both sensory and motor): NCI CTC (version 2) | Grade 3/4 vomiting: NCI CTC (version 2) | Grade 3/4 fatigue: NCI CTC (version 2) | Grade 3/4 stomatitis: NCI CTC (version 2) | |
| NR | Reported as "febrile neutropenia" grade 3/4: NCI CTC (version 1) | Grade 3 peripheral sensory neuropathy: NCI CTC (version 1) | Grade 3/4 nausea and vomiting: NCI CTC (version 1) | Grade 3/4 fatigue: NCI CTC (version 1) | Grade 3/4 mucositis: NCI CTC (version 1) | |
| Reversible cardiotoxicity | Reported as "neutropenic fever" grade 3/4: NCI CTC (version 3) | Grade 3/4 neurotoxicity: NCI CTC (version 3) | Grade 3/4 nausea and/or vomiting: NCI CTC (version 3) | NR | Grade 3/4 mucositis: NCI CTC (version 3) | |
| Grade 3/4 cardiotoxicity: WHO criteria | Reported as "febrile neutropenia" grade 3/4: WHO criteria | Grade 3/4 neurological toxicity: WHO criteria | Grade 3/4 nausea and vomiting: WHO criteria | NR | Grade 3/4 stomatitis: WHO criteria | |
| NR | Reported as "febrile neutropenia": WHO toxicity criteria | Grade 3/4 peripheral neuropathy: WHO toxicity criteria | Grade 3/4 nausea and/or vomiting: WHO toxicity criteria | Grade 3/4 fatigue: WHO toxicity criteria | NR | |
| Grade 3/4 cardiotoxicity | Reported as "febrile neutropenia" grade 3/4: NCI CTC (version 2) | Grade 3/4 neurotoxicity: NCI CTC (version 2) | Grade 3/4 nausea: NCI CTC (version 2) | Grade 3/4 asthenia: NCI CTC (version 2) | Grade 3/4 stomatitis: NCI CTC (version 2) | |
| Grade 3 to 5 congestive heart failure and cardiac ischaemia | Reported as "febrile neutropenia" grade 1 to 5: NCI CTC (version 3) | Grade 3 to 5 sensory neuropathy: NCI CTC version 3 | Grade 3 to 5 vomiting: NCI CTC (version 3) | Grade 3 to 5 fatigue: NCI CTC (version 3) | Grade 3 to 5 mucositis, stomatitis, oesophagitis: NCI CTC (version 3) | |
| Grade 3/4 cardiotoxicity | Reported as "febrile neutropenia" grade 3/4: NCI CTC (version 2) | Grade 3/4 neuropathy (reported both sensory and motor): NCI CTC (version 2) | Grade 3/4 vomiting: NCI CTC (version 2) | NR | Grade 3/4 stomatitis: NCI CTC (version 2) | |
| Grade 3/4 cardiotoxicity | Reported as "febrile neutropenia" grade 3/4: NCI CTC (version 2) | Grade 3/4 neuropathy (reported both sensory and motor): NCI CTC (version 2) | Grade 3/4 vomiting: NCI CTC (version 2) | NR | Grade 3/4 stomatitis: NCI CTC (version 2) | |
| Grade 3 or higher cardiac dysfunction | NR | NR | NR | NR | NR | |
| Any serious adverse cardiac event | Reported as "febrile neutropenia": WHO toxicity criteria | NR | Grade 3/4 nausea and/or vomiting: WHO toxicity criteria | NR | Grade 3/4 stomatitis: WHO toxicity criteria | |
| NR | Reported as "febrile neutropenia" defined as any Grade 3/4 neutropenia plus fever (> 38 degrees) requiring antibiotics: NCI CTC (version 2) | NR | Grade 3/4 nausea and/or vomiting: NCI CTC (version 2) | NR | Grade 3/4 mucositis: NCI CTC (version 2) | |
| Grade 3/4 cardiac event | Reported as "febrile neutropenia" Grade 3/4: WHO toxicity criteria | NR | Grade 3/4 nausea‐vomiting: WHO toxicity criteria | NR | Grade 3/4 stomatitis: WHO toxicity criteria | |
| NR | Reported as "febrile neutropenia" Grade 3/4: NCI CTC (version 2) | Grade 3/4 neuropathy: NCI CTC (version 2) | Grade 3/4 nausea and/or vomiting: NCI CTC (version 2) | Grade 3/4 lethargy: NCI CTC (version 2) | Grade 3/4 stomatitis (mucositis): NCI CTC (version 2) | |
| Cardiac function toxicity | Reported as "febrile neutropenia": NCI CTC (version 2) | Grade 3/4 neuropathy (reported both sensory and motor): NCI CTC (version 2) | Grade 3/4 vomiting: NCI CTC (version 2) | Grade 3/4 asthenia: NCI CTC (version 2) | Grade 3/4 stomatitis: NCI CTC (version 2) | |
| Cardiac events | Reported as "febrile neutropenia": NCI CTC (version 3) | Grade 3/4 peripheral neuropathy: NCI CTC (version 3) | Grade 3/4 nausea (vomiting not reported): NCI CTC (version 3) | Grade 3/4 fatigue: NCI CTC (version 3) | NR | |
| Death due to cardiac event | Reported as "febrile neutropenia" Grade 3/4 : NCI CTC (version 1) | NR | Grade 3/4 vomiting: NCI CTC (version 1) | Grade 3/4 asthenia: NCI CTC (version 1) | Grade 3/4 stomatitis: NCI CTC (version 1) | |
| NCI CTC: National Cancer Institute Common Toxicity Criteria | ||||||
| Trial ID | Instruments used | Summary of findings |
| Patients completed EORTC QLQ‐C30 and the breast cancer‐specific QLQ‐BR23 at baseline, before each course of chemotherapy, and at 4 weeks, 6 weeks, and 6 months after completion of chemotherapy | Both treatment groups had decreased EORTC‐C30 scores for physical, role, emotional, social, and cognitive functioning from baseline to 28 days after chemotherapy. Global health scores also decreased in this time frame for both groups. Changes in symptom scores were generally similar between treatment groups with the exception of nausea/vomiting and pain scores. Nausea/vomiting was worse for the FEC120 group than for the EC‐Doc group (+9.42 above baseline vs +1.88), and pain scores were worse in the EC‐Doc group (+9.18 for EC‐Doc vs ‐1.61 for FEC120). Changes in items on the EORTC BR23 over time were quantitatively and qualitatively similar in the 2 treatment groups | |
| Patients completed EORTC QLQ‐C30 (version 2.0) and the breast cancer‐specific QLQ‐BR23 (version 1.0) questionnaires at baseline, before cycles 3 and 5, at 3 to 4 weeks after completion, and at 6, 12, and 24 months | Both FAC and TAC arms led to a transient and statistically significant reduction in QoL scores, which returned to baseline levels at first follow‐up visit. QoL measures were similar between groups and were similar to baseline measures at 6 months and at the end of 2 years | |
| QoL results designed to study short‐ and long‐term toxicities on quality of life by treatment agent and duration. No further details provided | QoL to be reported in a companion study | |
| Patients completed EORTC QLQ‐C30 and the breast cancer‐specific QLQ‐BR23 in the clinic at baseline and 9 months, 2 years, and 5 years after random assignment | No significant difference in overall QoL or across any of the scales between treatments at 9 months, 2 years, or 5 years | |
| Patients completed EORTC QLQ‐C30 and the breast cancer‐specific QLQ BR23 at baseline, and at the end of the first, second, and third cycles of chemotherapy | No difference reported for QoL global functioning scales and other items. However there was worsening of systemic therapy side effects, future perspective, nausea and vomiting, diarrhoea, appetite loss, and upset by hair loss and body experience with docetaxel compared to CMF at the end of 1 or more cycles | |
| Patients completed EORTC QLQ‐C30 and the breast cancer‐specific QLQ‐BR23 at baseline after each chemotherapy cycle and at 6, 12, and 24 months after completion of chemotherapy | During chemotherapy, QoL decreased and was worse with TAC than with FAC, but this effect resolved by week 44. There were no statistically significant differences in QoL between TAC+G‐CSF and FAC after cycle 6 or during further follow‐up | |
| Trial registry record indicates that QoL will be compared across treatment arms. No further details provided | QoL information not yet reported | |
| Patients completed EORTC QLQ‐C30 questionnaire at baseline and on completion of chemotherapy | Only 23% of participants (72 participants in E‐T‐CMF and 67 participants in E‐CMF) completed baseline and end of chemotherapy questionnaires. There was no difference between the 2 treatment arms at the beginning or at the end of chemotherapy. Significant increase in nausea and vomiting for both groups. Social functioning significantly decreased in the taxane‐containing arm, and emotional functioning and pain significantly improved in the control arm | |
| NCIC‐CTGMA21 (NCIC‐CTG MA21a; NCIC‐CTG MA21b) | Patients completed EORTC QLQ‐C30 and the breast cancer‐specific QLQ‐BR within 7 days before random assignment and afterwards | QoL results will be reported in a separate article |
| Selected centres invited participants to quality of life substudy. These patients completed EORTC QLQ‐C30, QLQ‐BR23, and Hospital Anxiety and Depression Scale (HADS) before randomisation, before fifth and after eighth cycles, and at 9, 12, 18, and 24 months post chemotherapy | FEC‐D was associated with worse global QoL (P = 0.001), physical (P < 0.0001), role (P = 0.002), emotional functioning (P = 0.008), social functioning (P = 0.003), pain (P = 0.001), and fatigue (P = 0.006) compared to control. In contrast, there was more nausea and vomiting in the control group (P = 0.01) than in the FEC‐D group | |
| CMF: cyclophosphamide, methotrexate and fluorouracil | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall survival ‐ all studies Show forest plot | 27 | 39180 | Hazard Ratio (95% CI) | 0.87 [0.83, 0.92] |
| 1.1 All studies | 27 | 39180 | Hazard Ratio (95% CI) | 0.87 [0.83, 0.92] |
| 2 Disease‐free survival: all studies Show forest plot | 30 | 41909 | Hazard Ratio (95% CI) | 0.88 [0.85, 0.92] |
| 2.1 All studies | 30 | 41909 | Hazard Ratio (95% CI) | 0.88 [0.85, 0.92] |
| 3 Disease‐free survival: as defined in Cochrane protocol Show forest plot | 25 | 35063 | Hazard Ratio (95% CI) | 0.86 [0.82, 0.89] |
| 3.1 DFS ‐ excluding Boccardo, CALGB40101, NCIC‐CTG MA21 & RAPP‐01 | 25 | 35063 | Hazard Ratio (95% CI) | 0.86 [0.82, 0.89] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall survival Show forest plot | 27 | Hazard Ratio (95% CI) | Subtotals only | |
| 1.1 Docetaxel | 15 | 22105 | Hazard Ratio (95% CI) | 0.86 [0.81, 0.92] |
| 1.2 Paclitaxel | 12 | 17075 | Hazard Ratio (95% CI) | 0.89 [0.82, 0.96] |
| 2 Disease‐free survival Show forest plot | 30 | Hazard Ratio (95% CI) | Subtotals only | |
| 2.1 Docetaxel | 16 | 22730 | Hazard Ratio (95% CI) | 0.87 [0.82, 0.91] |
| 2.2 Paclitaxel | 14 | 19179 | Hazard Ratio (95% CI) | 0.91 [0.85, 0.96] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall survival Show forest plot | 10 | Hazard Ratio (95% CI) | Subtotals only | |
| 1.1 Weekly paclitaxel | 4 | 4176 | Hazard Ratio (95% CI) | 0.80 [0.65, 0.98] |
| 1.2 Three‐weekly paclitaxel | 6 | 8433 | Hazard Ratio (95% CI) | 0.86 [0.78, 0.95] |
| 2 Disease‐free survival Show forest plot | 10 | Hazard Ratio (95% CI) | Subtotals only | |
| 2.1 Weekly Paclitaxel | 4 | 4176 | Hazard Ratio (95% CI) | 0.79 [0.67, 0.92] |
| 2.2 Three‐weekly paclitaxel | 6 | 8433 | Hazard Ratio (95% CI) | 0.85 [0.79, 0.92] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall survival Show forest plot | 23 | Hazard Ratio (95% CI) | Subtotals only | |
| 1.1 Sequential anthracycline/taxane | 18 | 24764 | Hazard Ratio (95% CI) | 0.86 [0.81, 0.91] |
| 1.2 Concurrent anthracycline/taxane | 6 | 8839 | Hazard Ratio (95% CI) | 0.86 [0.78, 0.94] |
| 2 Disease‐free survival Show forest plot | 26 | Hazard Ratio (95% CI) | Subtotals only | |
| 2.1 Sequential anthracycline/taxane | 20 | 26866 | Hazard Ratio (95% CI) | 0.86 [0.82, 0.90] |
| 2.2 Concurrent anthracycline/taxane | 7 | 9466 | Hazard Ratio (95% CI) | 0.90 [0.83, 0.97] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall survival Show forest plot | 19 | Hazard Ratio (95% CI) | Subtotals only | |
| 1.1 Addition of taxane ‐ question 1 | 7 | 10842 | Hazard Ratio (95% CI) | 0.84 [0.77, 0.92] |
| 1.2 Substitution of taxane ‐ question 3 | 13 | 16196 | Hazard Ratio (95% CI) | 0.80 [0.74, 0.86] |
| 2 Disease‐free survival Show forest plot | 20 | Hazard Ratio (95% CI) | Subtotals only | |
| 2.1 Addition of taxane ‐ question 1 | 7 | 10842 | Hazard Ratio (95% CI) | 0.84 [0.78, 0.90] |
| 2.2 Substitution of taxane ‐ question 3 | 14 | 16823 | Hazard Ratio (95% CI) | 0.83 [0.78, 0.88] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall survival Show forest plot | 22 | Hazard Ratio (95% CI) | Subtotals only | |
| 1.1 Taxane‐containing arm longer duration than control arm | 9 | 13865 | Hazard Ratio (95% CI) | 0.84 [0.77, 0.91] |
| 1.2 Taxane‐containing arm same duration as control arm | 14 | 18660 | Hazard Ratio (95% CI) | 0.87 [0.81, 0.94] |
| 2 Disease‐free survival Show forest plot | 25 | Hazard Ratio (95% CI) | Subtotals only | |
| 2.1 Taxane‐containing arm longer duration than control arm | 9 | 13865 | Hazard Ratio (95% CI) | 0.83 [0.77, 0.88] |
| 2.2 Taxane‐containing arm same duration as control arm | 17 | 21391 | Hazard Ratio (95% CI) | 0.90 [0.85, 0.96] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall survival Show forest plot | 25 | Hazard Ratio (95% CI) | Subtotals only | |
| 1.1 3 cycles of taxane | 7 | 6551 | Hazard Ratio (95% CI) | 0.77 [0.69, 0.86] |
| 1.2 4 or more cycles of taxane | 19 | 29458 | Hazard Ratio (95% CI) | 0.91 [0.86, 0.96] |
| 2 Disease‐free survival Show forest plot | 28 | Hazard Ratio (95% CI) | Subtotals only | |
| 2.1 3 cycles of taxane | 7 | 6551 | Hazard Ratio (95% CI) | 0.80 [0.73, 0.88] |
| 2.2 4 or more cycles of taxane | 22 | 32187 | Hazard Ratio (95% CI) | 0.91 [0.87, 0.95] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall survival Show forest plot | 27 | Hazard Ratio (95% CI) | Subtotals only | |
| 1.1 Node‐positive‐only studies | 17 | 22055 | Hazard Ratio (95% CI) | 0.83 [0.78, 0.88] |
| 1.2 Node‐positive or ‐negative studies | 7 | 10269 | Hazard Ratio (95% CI) | 0.95 [0.87, 1.04] |
| 1.3 Node‐negative‐only studies | 3 | 6856 | Hazard Ratio (95% CI) | 1.08 [0.89, 1.32] |
| 2 Disease‐free survival Show forest plot | 30 | Hazard Ratio (95% CI) | Subtotals only | |
| 2.1 Node‐positive‐only studies | 17 | 22055 | Hazard Ratio (95% CI) | 0.84 [0.80, 0.88] |
| 2.2 Node‐positive or ‐negative studies | 10 | 12998 | Hazard Ratio (95% CI) | 0.95 [0.88, 1.02] |
| 2.3 Node‐negative‐only studies | 3 | 6856 | Hazard Ratio (95% CI) | 0.99 [0.86, 1.14] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall survival Show forest plot | 5 | Hazard Ratio (Fixed, 95% CI) | Subtotals only | |
| 1.1 Hormone receptor‐positive | 4 | Hazard Ratio (Fixed, 95% CI) | 0.79 [0.70, 0.89] | |
| 1.2 Hormone receptor‐negative | 5 | Hazard Ratio (Fixed, 95% CI) | 0.88 [0.73, 1.05] | |
| 2 Disease‐free survival Show forest plot | 12 | Hazard Ratio (Fixed, 95% CI) | Subtotals only | |
| 2.1 Hormone receptor‐positive | 11 | Hazard Ratio (Fixed, 95% CI) | 0.91 [0.85, 0.97] | |
| 2.2 Hormone receptor‐negative | 12 | Hazard Ratio (Fixed, 95% CI) | 0.80 [0.73, 0.88] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall survival Show forest plot | 27 | Hazard Ratio (95% CI) | Subtotals only | |
| 1.1 Studies with published efficacy paper | 26 | 38208 | Hazard Ratio (95% CI) | 0.88 [0.84, 0.92] |
| 1.2 Studies with results from online thesis | 1 | 972 | Hazard Ratio (95% CI) | 0.67 [0.48, 0.94] |
| 2 Disease‐free survival Show forest plot | 30 | Hazard Ratio (95% CI) | Subtotals only | |
| 2.1 Studies with published efficacy paper | 28 | 40310 | Hazard Ratio (95% CI) | 0.88 [0.85, 0.92] |
| 2.2 Studies with results in abstract format or in online thesis | 2 | 1599 | Hazard Ratio (95% CI) | 0.84 [0.67, 1.04] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Febrile neutropenia by sequential or concurrent anthracycline/taxane Show forest plot | 24 | 33763 | Odds Ratio (M‐H, Random, 95% CI) | 1.55 [0.96, 2.49] |
| 1.1 Sequential anthracycline and taxane treatment | 16 | 20148 | Odds Ratio (M‐H, Random, 95% CI) | 1.31 [0.82, 2.10] |
| 1.2 Concurrent anthracycline and taxane treatment | 6 | 8552 | Odds Ratio (M‐H, Random, 95% CI) | 5.76 [3.36, 9.87] |
| 1.3 Taxane replacing anthracycline | 3 | 5063 | Odds Ratio (M‐H, Random, 95% CI) | 0.22 [0.02, 3.04] |
| 2 Febrile neutropenia by type of taxane Show forest plot | 25 | 34154 | Odds Ratio (M‐H, Random, 95% CI) | 1.43 [0.89, 2.31] |
| 2.1 Docetaxel | 16 | 22596 | Odds Ratio (M‐H, Random, 95% CI) | 2.83 [1.88, 4.27] |
| 2.2 Paclitaxel | 9 | 11558 | Odds Ratio (M‐H, Random, 95% CI) | 0.36 [0.19, 0.67] |
| 3 Neuropathy (grade 3/4) Show forest plot | 23 | 31033 | Odds Ratio (M‐H, Random, 95% CI) | 6.89 [3.23, 14.71] |
| 4 Neuropathy (grade 3/4) by type of taxane Show forest plot | 23 | 31033 | Odds Ratio (M‐H, Random, 95% CI) | 6.89 [3.23, 14.71] |
| 4.1 Docetaxel | 12 | 18355 | Odds Ratio (M‐H, Random, 95% CI) | 3.74 [1.33, 10.53] |
| 4.2 Paclitaxel | 11 | 12678 | Odds Ratio (M‐H, Random, 95% CI) | 11.93 [3.59, 39.70] |
| 5 Fatigue (grade 3/4) Show forest plot | 16 | 25003 | Odds Ratio (M‐H, Random, 95% CI) | 1.81 [1.31, 2.49] |
| 5.1 Docetaxel | 10 | 16503 | Odds Ratio (M‐H, Random, 95% CI) | 2.14 [1.65, 2.78] |
| 5.2 Paclitaxel | 6 | 8500 | Odds Ratio (M‐H, Random, 95% CI) | 1.28 [0.58, 2.84] |
| 6 Stomatitis (grade 3/4) Show forest plot | 23 | 29500 | Odds Ratio (M‐H, Random, 95% CI) | 1.29 [0.93, 1.78] |
| 6.1 Docetaxel | 16 | 22648 | Odds Ratio (M‐H, Random, 95% CI) | 1.73 [1.28, 2.35] |
| 6.2 Paclitaxel | 7 | 6852 | Odds Ratio (M‐H, Random, 95% CI) | 0.64 [0.31, 1.32] |
| 7 Cardiotoxicity (includes grade 3/4 and symptomatic CCF) Show forest plot | 23 | 32894 | Odds Ratio (M‐H, Random, 95% CI) | 0.87 [0.56, 1.33] |
| 7.1 Total planned dose of anthracycline the same in both taxane‐ and non‐taxane‐containing arms | 9 | 14967 | Odds Ratio (M‐H, Random, 95% CI) | 1.27 [0.88, 1.84] |
| 7.2 Total planned dose of anthracycline reduced in the taxane‐containing arm | 10 | 12473 | Odds Ratio (M‐H, Random, 95% CI) | 0.39 [0.18, 0.86] |
| 7.3 Taxane replacing anthracycline | 4 | 5454 | Odds Ratio (M‐H, Random, 95% CI) | 1.01 [0.26, 3.91] |
| 8 Nausea and/or vomiting (grade 3/4) Show forest plot | 26 | 34450 | Odds Ratio (M‐H, Random, 95% CI) | 0.83 [0.67, 1.04] |
| 8.1 Docetaxel | 16 | 22648 | Odds Ratio (M‐H, Random, 95% CI) | 0.80 [0.62, 1.03] |
| 8.2 Paclitaxel | 10 | 11802 | Odds Ratio (M‐H, Random, 95% CI) | 0.89 [0.57, 1.39] |
| 9 Secondary leukaemia/myelodysplasia Show forest plot | 19 | 33225 | Odds Ratio (M‐H, Random, 95% CI) | 0.85 [0.54, 1.33] |
| 9.1 Docetaxel | 13 | 24911 | Odds Ratio (M‐H, Random, 95% CI) | 0.97 [0.60, 1.59] |
| 9.2 Paclitaxel | 6 | 8314 | Odds Ratio (M‐H, Random, 95% CI) | 0.45 [0.15, 1.32] |
| 10 Treatment‐related deaths Show forest plot | 22 | 34882 | Odds Ratio (M‐H, Random, 95% CI) | 1.24 [0.63, 2.47] |
| 10.1 Docetaxel | 15 | 26021 | Odds Ratio (M‐H, Random, 95% CI) | 1.54 [0.76, 3.15] |
| 10.2 Paclitaxel | 7 | 8861 | Odds Ratio (M‐H, Random, 95% CI) | 0.73 [0.14, 3.85] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall survival Show forest plot | 27 | 39180 | Hazard Ratio (95% CI) | 0.87 [0.83, 0.92] |
| 1.1 Low risk of bias | 21 | 33206 | Hazard Ratio (95% CI) | 0.90 [0.86, 0.95] |
| 1.2 Unclear or high risk of bias | 6 | 5974 | Hazard Ratio (95% CI) | 0.74 [0.65, 0.83] |
| 2 Disease‐free survival Show forest plot | 30 | 41909 | Hazard Ratio (95% CI) | 0.88 [0.85, 0.92] |
| 2.1 Low risk of bias | 24 | 35935 | Hazard Ratio (95% CI) | 0.90 [0.87, 0.94] |
| 2.2 Unclear or high risk of bias | 6 | 5974 | Hazard Ratio (95% CI) | 0.76 [0.69, 0.84] |
