Taxanes for adjuvant treatment of early breast cancer

Thomas Ferguson; Nicholas Wilcken; Rosemary Vagg; Davina Ghersi; Anna K Nowak

doi:10.1002/14651858.CD004421.pub2

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Analysis 1.1

Comparison 1 Overall Effect of Taxanes, Outcome 1 Overall Survival ‐ all studies.

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Analysis 1.2

Comparison 1 Overall Effect of Taxanes, Outcome 2 Disease Free Survival ‐ all studies.

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Analysis 2.1

Comparison 2 Type of Taxane, Outcome 1 Overall Survival.

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Analysis 2.2

Comparison 2 Type of Taxane, Outcome 2 Disease Free Survival.

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Analysis 3.1

Comparison 3 Sequential or Concurrent Anthracycline/Taxane, Outcome 1 Overall Survival.

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Analysis 3.2

Comparison 3 Sequential or Concurrent Anthracycline/Taxane, Outcome 2 Disease free survival.

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Analysis 4.1

Comparison 4 Addition or Substitution of Taxane, Outcome 1 Overall Survival.

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Analysis 4.2

Comparison 4 Addition or Substitution of Taxane, Outcome 2 Disease free survival.

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Analysis 5.1

Comparison 5 Lymph node status, Outcome 1 Overall Survival.

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Analysis 5.2

Comparison 5 Lymph node status, Outcome 2 Disease free survival.

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Analysis 6.1

Comparison 6 Duration of chemotherapy, Outcome 1 Overall Survival.

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Analysis 6.2

Comparison 6 Duration of chemotherapy, Outcome 2 Disease free survival.

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Analysis 7.1

Comparison 7 Publication status, Outcome 1 Overall survival.

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Analysis 7.2

Comparison 7 Publication status, Outcome 2 Disease free survival.

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Analysis 8.1

Comparison 8 Number of Cycles of Taxane‐containig Chemotherapy, Outcome 1 Overall Survival.

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Analysis 8.2

Comparison 8 Number of Cycles of Taxane‐containig Chemotherapy, Outcome 2 Disease free survial.

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Analysis 9.1

Comparison 9 Toxicities, Outcome 1 Cardiotoxicity (includes grade 3/4 and symptomatic CCF).

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Analysis 9.2

Comparison 9 Toxicities, Outcome 2 Febrile neutropaenia.

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Analysis 9.3

Comparison 9 Toxicities, Outcome 3 Grade 3/4 nausea and/or vomiting.

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Analysis 9.4

Comparison 9 Toxicities, Outcome 4 Secondary leukaemia/myelodysplasia.

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Analysis 9.5

Comparison 9 Toxicities, Outcome 5 Grade 3/4 Fatigue.

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Analysis 9.6

Comparison 9 Toxicities, Outcome 6 Grade 3/4 Stomatitis.

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Analysis 9.7

Comparison 9 Toxicities, Outcome 7 Treatment related deaths.

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Taxane‐containing chemotherapy compared to any chemotherapy without taxanes for early breast cancer (operable, stages I to IIIA)
Patient or population: patients with early breast cancer (operable, stages I to IIIA) Settings: outpatient Intervention: any chemotherapy including a taxane¹ Comparison: any chemotherapy without taxanes
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	any chemotherapy without taxanes	any chemotherapy including a taxane
Mortality (follow‐up: 5 year survival)	Low risk population		HR 0.81 (0.75 to 0.88)	18304 (11)	⊕⊕⊕⊕ high	Analysis showed equivalent efficacy across subgroups including treatment duration, scheduling, doses, specific taxane, node positive and negative groups.
	60 per 1000	49 per 1000 (45 to 53)
	High risk population
	260 per 1000	216 per 1000 (202 to 233)
Risk of recurrence (follow‐up: 5 year survival)	Low risk population		HR 0.81 (0.77 to 0.86	19943 (11)	⊕⊕⊕⊕ high	As above.
	140 per 1000	115 per 1000 (110 to 122)
	High risk population
	360 per 1000	303 per 1000 (291 to 319)
Quality of life² (follow‐up: 24 to 62 months)	See comment	See comment	Not estimable²	‐	See comment	2 studies no significant differences reported
Cardiotoxicity (follow‐up: 43 to 69 months)	12 per 1000	11 per 1000 (6 to 18)	RR 0.9 (0.53 to 1.54)³	11577 (6)	⊕⊕⊕⊝ moderate³	Risk of cardiotoxicity reduced with lower planned dose of anthracycline.
Febrile neutropaenia (follow‐up: 36‐62 months)	56 per 1000	130 per 1000 (62 to 251)	RR 2.32 (1.1 to 4.49)	10224 (7)	⊕⊕⊕⊝ moderate⁴
Nausea and/or vomiting (follow‐up: 36 to 62 months)	114 per 1000	66 per 1000 (48 to 90)	RR 0.58 (0.42 to 0.79)	6087 (5)	⊕⊕⊕⊕ high
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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). CI: Confidence interval; RR: Risk Ratio; HR: Hazard Ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Taxanes are highly active chemotherapy agent in metastic breast cancer. Their incorporation into adjuvant regimens for early breast cancer has increased. Two taxanes, paclitaxel and docetaxel, were included in these studies. In these studies, taxanes were compared to no taxanes in the same or different regimens, and compared to other drugs in the same regimen. Chemotherapy regimens were provided after surgery and in some studies endocrine therapy or radiotherapy were given. ² Different instruments used to measure QOL and not fully reported in full publication. ³ The confidence interval crosses no difference and does not rule out a small increase ⁴ Significant heterogeneity across studies

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Table 1. Grouping of toxicity outcomes and description of individual study definitions

TRIAL	Cardiotoxicity	Febrile Neutropenia	Nausea and Vomiting	Fatigue	Stomatitis
BCIRG 001	Overall congestive heart failure	Reported as "febrile neutropenia" : Protocol definition ‐ Fever of grade 2 or more concomitant with grade 4 neutropaenia requiring IV antibiotics, hospitalisation or both	Grade 3/4 or severe nausea : NCI CTC (version 2)	Grade 3/4 asthenia : NCI CTC (version 2)	Grade 3/4 stomatitis : NCI CTC (version 2)
BIG 2‐98
CALGB 9344	Congestive heart failure during treatment or post‐treatment follow‐up
E2197		Reported as "febrile neutropenia" : toxicity criteria not specified
ECTO	Symptomatic cardiac failure
FINHER		Reported as "neutropenic fever" : 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)
GEICAM 9906		Reported as "febrile neutropenia" : toxicity criteria not specified			Grade 3 mucositis : toxicity criteria not specified
HeCOG		Reported as "febrile neutropenia" : WHO toxicity criteria	Grade 3/4 nausea and/or vomiting : WHO toxicity criteria	Grade 3/4 fatigue : WHO toxicity criteria
NSABP B‐28	Grade 3 or higher cardiac dysfunction
PACS 01	Any serious adverse cardiac event	Reported as "febrile neutropenia" : WHO toxicity criteria	Grade 3/4 nausea and/or vomiting : WHO toxicity criteria		Grade 3/4 stomatitis : WHO toxicity criteria
Taxit 216
US Oncology	Death due to cardiac event	Reported as "fever and neutropenia" : NCI CTC (version 1)	Grade 3/4 nausea : NCI CTC (version 1)	Grade 3/4 asthenia : NCI CTC (version 1)	Grade 3/4 stomatitis : NCI CTC (version 1)

Table 1. Grouping of toxicity outcomes and description of individual study definitions

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Table 2. Combined toxicities (assessable or randomised patients)

Toxicity	Number of trials	Taxane events (pts)	Control events (pts)	OR (95% CI)
CARDIOTOXICITY ‐ Total planned dose of anthracycline the same in both taxane‐ and non‐taxane‐containing arms	3 (a, b, c)	59/3845	47/3816	1.25 (0.85‐1.84)
CARDIOTOXICITY ‐ Total planned dose of anthracycline reduced in the taxane‐containing arm	2 (d, e)	6/1452	16/1448	0.37 (0.14‐0.95)
CARDIOTOXICITY ‐ Taxane replacing anthracycline	1 (f)	2/506	5/510	0.40 (0.08‐2.08)
CARDIOTOXICITY ‐ all studies	6 (a, b, c, d, e, f)	67/5803	68/5774	0.98 (0.70‐1.37)
FEBRILE NEUTROPENIA ‐ Sequential anthracycline and taxane treatment	4(e, g, h, i)	269/2413	167/2426	1.69 (1.38‐2.06)
FEBRILE NEUTROPENIA ‐ Concurrent anthracycline and taxane treatment	2 (a, j)	458/2188	105/2181	5.19 (4.16‐6.47)
FEBRILE NEUTROPENIA ‐ Taxane replacing anthracycline	1 (f)	25/506	13/510	1.99 (1.00‐3.93)
FEBRILE NEUTROPENIA ‐ all studies	7 (a, e, f, g, h, i)	752/5107	285/5117	2.90 (2.52‐3.34)
GRADE 3 OR 4 NAUSEA and/or VOMITING	5 (a, e, f, g, i)	193/3049	345/3038	0.52 (0.43‐0.62)
SECONDARY LEUKAEMIA/MYELODYSPLASIA	7 (a, b, c, e, f, i, j)	25/7093	23/7056	1.08 (0.62‐1.89)
GRADE 3 OR 4 FATIGUE	4 (a, f, g, i)	140/2048	80/2043	1.81 (1.37‐2.41)
GRADE 3 OR 4 STOMATITIS	5 (a, e, f, g, h)	143/3366	99/3382	1.47 (1.13‐2.41)
a	BCIRG 001
b	CALGB 9344
c	NSABP B‐28
d	ECTO
e	PACS 01
f	US Oncology
g	FinHer
h	GEICAM 9906
i	HeCOG
j	E2197

Table 2. Combined toxicities (assessable or randomised patients)

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Table 3. Quality of life

Trial ID	Instruments used	Summary of findings
HeCOG	Patients completed EORTC QLQ‐C30 at baseline and on completion of chemotherapy	No differences were found between the two treatment arms either 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 while emotional functioning and pain significantly improved in the control arm.
BCIRG 001	Patients completed EORTC QLQ‐C30 and the breast‐cancer‐specific QLQ‐BR23 at baseline, before cycles 3 and 5, 3‐4 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. The reduction in QoL score was greater in the TAC arm (mean score 72 to 62) than the FAC arm (mean score 72 to 62).

Table 3. Quality of life

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Table 4. Definition of "Disease Free Survival"

Study	Description	Definition
BCIRG 001	DFS	Time from randomization to date of clinical relapse (histological or radiological evidence), a second cancer (except skin cancer other than melanoma or carcinoma insitu of breast or cervix), or death
CALGB 9344	DFS	Time from randomization to date of first locoregional reccurence, first distant metastasis, or death any cause
FinHer	Recurrence‐free Survival	Time from randomization to date of detection of local or distant relapse (histological or radiological evidence) or contralateral invasive breast cancer or death
HeCOG	DFS	Time from randomization until local recurrence, distant relapse or death (without relapse)
NSABP B‐28	DFS	Time from randomization until local, regional or distant treatment failures, contralateral breast cancers, non‐breast second primary cancers or death
PACS 01	DFS	Time from randomization until time to first relapse (local, regional or distant), contralateral breast cancer or death from any cause
BIG 2‐98	Event‐free Survival	Not published
E2197	DFS	Not published
ECTO	Freedom From Progression	Not published
Jones SE	DFS	Not published
Taxit 216	DFS	Not published
GEICAM 9906	DFS	Not published

Table 4. Definition of "Disease Free Survival"

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Comparison 1. Overall Effect of Taxanes

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall Survival ‐ all studies Show forest plot	11	18304	Peto Odds Ratio (95% CI)	0.81 [0.75, 0.88]

1.1 All studies	11	18304	Peto Odds Ratio (95% CI)	0.81 [0.75, 0.88]
2 Disease Free Survival ‐ all studies Show forest plot	11	19943	Peto Odds Ratio (95% CI)	0.81 [0.77, 0.86]

2.1 All studies	11	19943	Peto Odds Ratio (95% CI)	0.81 [0.77, 0.86]

Comparison 1. Overall Effect of Taxanes

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Comparison 2. Type of Taxane

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall Survival Show forest plot	11	18304	Peto Odds Ratio (95% CI)	0.81 [0.75, 0.88]

1.1 Docetaxel	6	9377	Peto Odds Ratio (95% CI)	0.76 [0.67, 0.86]
1.2 Paclitaxel	5	8927	Peto Odds Ratio (95% CI)	0.85 [0.76, 0.94]
2 Disease Free Survival Show forest plot	11	19943	Peto Odds Ratio (95% CI)	0.81 [0.77, 0.86]

2.1 Docetaxel	7	12264	Peto Odds Ratio (95% CI)	0.80 [0.74, 0.87]
2.2 Paclitaxel	4	7679	Peto Odds Ratio (95% CI)	0.82 [0.76, 0.89]

Comparison 2. Type of Taxane

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Comparison 3. Sequential or Concurrent Anthracycline/Taxane

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall Survival Show forest plot	10	17288	Peto Odds Ratio (95% CI)	0.81 [0.75, 0.88]

1.1 Concurrent Antracycline/Taxane	3	5284	Peto Odds Ratio (95% CI)	0.79 [0.66, 0.94]
1.2 Sequential Anthracycline/Taxane	7	12004	Peto Odds Ratio (95% CI)	0.82 [0.75, 0.90]
2 Disease free survival Show forest plot	9	16040	Peto Odds Ratio (95% CI)	0.81 [0.76, 0.86]

2.1 Concurrent Anthracycline/Taxane	3	5284	Peto Odds Ratio (95% CI)	0.79 [0.70, 0.90]
2.2 Sequential Anthracycline/Taxane	6	10756	Peto Odds Ratio (95% CI)	0.81 [0.76, 0.88]

Comparison 3. Sequential or Concurrent Anthracycline/Taxane

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Comparison 4. Addition or Substitution of Taxane

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall Survival Show forest plot	11	18304	Peto Odds Ratio (95% CI)	0.81 [0.75, 0.88]

1.1 Addition of taxane	5	8651	Peto Odds Ratio (95% CI)	0.84 [0.76, 0.93]
1.2 Substitution of taxane	6	9653	Peto Odds Ratio (95% CI)	0.76 [0.67, 0.87]
2 Disease free survival Show forest plot	10	17056	Peto Odds Ratio (95% CI)	0.80 [0.76, 0.86]

2.1 Addition of taxane	5	8651	Peto Odds Ratio (95% CI)	0.82 [0.76, 0.89]
2.2 Substitution of taxane	5	8405	Peto Odds Ratio (95% CI)	0.78 [0.71, 0.86]

Comparison 4. Addition or Substitution of Taxane

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Comparison 5. Lymph node status

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall Survival Show forest plot	11	18304	Peto Odds Ratio (95% CI)	0.81 [0.75, 0.88]

1.1 Node positive only studies	6	11890	Peto Odds Ratio (95% CI)	0.81 [0.74, 0.89]
1.2 Node positive or negative studies	5	6414	Peto Odds Ratio (95% CI)	0.81 [0.69, 0.95]
2 Disease free survival Show forest plot	11	19943	Peto Odds Ratio (95% CI)	0.81 [0.77, 0.86]

2.1 Node positive only studies	6	13529	Peto Odds Ratio (95% CI)	0.81 [0.76, 0.87]
2.2 Node positive or negative studies	5	6414	Peto Odds Ratio (95% CI)	0.80 [0.71, 0.91]

Comparison 5. Lymph node status

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Comparison 6. Duration of chemotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall Survival Show forest plot	11	18304	Peto Odds Ratio (95% CI)	0.81 [0.75, 0.88]

1.1 Taxane containing arm longer duration than control arm	4	7747	Peto Odds Ratio (95% CI)	0.85 [0.77, 0.94]
1.2 Taxane containing arm same duration as control arm	7	10557	Peto Odds Ratio (95% CI)	0.76 [0.67, 0.86]
2 Disease free survival Show forest plot	10	17056	Peto Odds Ratio (95% CI)	0.80 [0.76, 0.86]

2.1 Taxane containing arm longer duration than control arm	4	7747	Peto Odds Ratio (95% CI)	0.83 [0.77, 0.90]
2.2 Taxane containing arm same duration as control arm	6	9309	Peto Odds Ratio (95% CI)	0.77 [0.70, 0.85]

Comparison 6. Duration of chemotherapy

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Comparison 7. Publication status

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	11	18304	Peto Odds Ratio (95% CI)	0.81 [0.75, 0.88]

1.1 Studies with published efficacy paper	7	12291	Peto Odds Ratio (95% CI)	0.81 [0.74, 0.89]
1.2 Studies published in abstract form only	4	6013	Peto Odds Ratio (95% CI)	0.80 [0.67, 0.96]
2 Disease free survival Show forest plot	11	19943	Peto Odds Ratio (95% CI)	0.81 [0.77, 0.86]

2.1 Studies with published efficacy paper	7	12291	Peto Odds Ratio (95% CI)	0.80 [0.75, 0.86]
2.2 Studies published in abstract form only	4	7652	Peto Odds Ratio (95% CI)	0.84 [0.76, 0.93]

Comparison 7. Publication status

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Comparison 8. Number of Cycles of Taxane‐containig Chemotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall Survival Show forest plot	10	17056	Peto Odds Ratio (95% CI)	0.81 [0.75, 0.88]

1.1 Three cycles of Taxane	3	3604	Peto Odds Ratio (95% CI)	0.74 [0.61, 0.91]
1.2 Four or more cycles of Taxane	7	13452	Peto Odds Ratio (95% CI)	0.83 [0.76, 0.90]
2 Disease free survial Show forest plot	10	17056	Peto Odds Ratio (95% CI)	0.80 [0.76, 0.86]

2.1 Three cycles of Taxane	3	3604	Peto Odds Ratio (95% CI)	0.79 [0.68, 0.91]
2.2 Four or more cycles of Taxane	7	13452	Peto Odds Ratio (95% CI)	0.81 [0.75, 0.87]

Comparison 8. Number of Cycles of Taxane‐containig Chemotherapy

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Comparison 9. Toxicities

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cardiotoxicity (includes grade 3/4 and symptomatic CCF) Show forest plot	6	11577	Odds Ratio (M‐H, Random, 95% CI)	0.90 [0.53, 1.55]

1.1 Total planned dose of anthracycline the same in both taxane‐ and non‐taxane‐containing arms	3	7661	Odds Ratio (M‐H, Random, 95% CI)	1.24 [0.83, 1.86]
1.2 Total planned dose of anthracycline reduced in the taxane‐containing arm	2	2900	Odds Ratio (M‐H, Random, 95% CI)	0.38 [0.15, 0.98]
1.3 Taxane replacing anthracycline	1	1016	Odds Ratio (M‐H, Random, 95% CI)	0.40 [0.08, 2.08]
2 Febrile neutropaenia Show forest plot	7	10224	Odds Ratio (M‐H, Random, 95% CI)	2.51 [1.11, 5.66]

2.1 Sequential anthracycline and taxane treatment	4	4839	Odds Ratio (M‐H, Random, 95% CI)	1.57 [0.48, 5.17]
2.2 Concurrent anthracycline and taxane treatment	2	4369	Odds Ratio (M‐H, Random, 95% CI)	6.80 [1.91, 24.15]
2.3 Taxane replacing anthracycline	1	1016	Odds Ratio (M‐H, Random, 95% CI)	1.99 [1.00, 3.93]
3 Grade 3/4 nausea and/or vomiting Show forest plot	5	6087	Odds Ratio (M‐H, Random, 95% CI)	0.55 [0.39, 0.77]

4 Secondary leukaemia/myelodysplasia Show forest plot	7	14149	Odds Ratio (M‐H, Random, 95% CI)	1.06 [0.59, 1.89]

5 Grade 3/4 Fatigue Show forest plot	4	4091	Odds Ratio (M‐H, Random, 95% CI)	1.55 [0.83, 2.89]

6 Grade 3/4 Stomatitis Show forest plot	5	6748	Odds Ratio (M‐H, Random, 95% CI)	1.38 [0.50, 3.82]

7 Treatment related deaths Show forest plot	6	11260	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.33, 3.04]

Comparison 9. Toxicities

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