Effectiveness of taxanes over anthracyclines in neoadjuvant setting: A systematic-review and meta-analysis

Table 1 Population, intervention, comparison and outcome characteristics of included studies

Study	Accrual	Population	Regimen Comparison	Outcomes
ABDREEN[9], 2002	104	Locally advanced breast cancer patients in which only responders of previous four cycles of CVAP	Anthracycline Arm: CVAP chemotherapy, comprised of cyclophosphamide (C) 1000 mg/m2, doxorubicin (A) 50 mg/m2, vincristine (V) 1.5 mg/m2 (I.V.), and prednisone 40 mg/d p.o. for 5 d; Taxane Arm: 4 cycles of Docetaxel (D) 100 mg/m2 was given as an I.V. infusion over 1 h and repeated at 21-d intervals. In addition, these patients received prednisone 100 mg for 5 d, beginning 24 h prior to docetaxel administration.	pCR1, pCR2, OR, cCR, OS
ACCOG[24], 2010	363	Patients with primary tumour>3 cm, inflammatory or locally advanced non-metastatic breast cancer patients	Anthracycline Arm: Six cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) both administered every 3 wk (6xAC); Taxane Arm: Six cycles of doxorubicin (50 mg/m2) and docetaxel (75 mg/m2) administered as a 1-h I.V., with both drugs being given every 3 wk (6xAD).	pCR1, pCR2, pCR3, OR, cCR, BCS; Toxicity, OS, DFS, LRR, DM
Amsterdam trial[25], 2005	57	Invasive breast cancer greater than 3 cm and/or at least one tumor-positive auxiliary lymph node	Anthracycline Arm: Six cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 administered every 3 ws (6xAC); Taxane Arm: Six cycles of doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 (6xAD) 3 wk.	pCR2,
EORCT BIG-01[26], 2011	1856	Invasive breast cancer <71 years with large operable/inflammatory breast cancer patients suitable for neoadjuvant chemotherapy	Anthracycline Arm: Six cycles of iv FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) or tailored FEC (F600, E75, C900) starting on day 1 and then every 21 d with GCF (6xFEC); Taxane Arm: Three cycles of docetaxel 100 mg/m2 iv, followed by 3 cycles of epirubicin 90 mg/m2 and docetaxel 75 mg/m2 on day 1 every 21 d, without GCF.	pCR2, cCR, BCS; Toxicity
NSABP FB-9[8], 2015	50	HER2 negative breast cancer patients with palpable mass of ≥ 2cm in breast or axilla or inflammatory breast cancer patients	Anthracycline Arm: 4 cycles of Eribuline 1.4 mg/m2 on days 1 and 8 of a 21-d cycle followed by A60 C600, every 21 d for 4 cycles; Taxane Arm: Weekly Paclitaxel 80 mg/m2 for 12 doses followed by standard A60C600 every 21 d for 4 cycles.	pCR1, OR, cCR, BCS, Toxicity
Madrid trial[20], 2011	211	Female breast cancer patients aged 18-78 years of clinical stage IIB, IIIA or IIIB and with palpable breast cancer not amenable to BCS	Anthracycline Arm: Four cycles of doxorubicin (75 mg/m2 body surface area); Taxane Arm: Four cycles docetaxel 100 mg/m2 with G-CSF support every 3 wk.	pCR1
Saura et al[4], 2013	295	Breast cancer patients of stage T2-3N0-3M0	Pretreatment: patients received four cycles of doxorubicin (60mg/m2 iv) and cyclophosphamide (600 mg/m2 iv) every 3 wk; Anthracycline Arm: Ixabepilone (40 mg/m2, 3-h infusion) every 3 wk for 4 cycles; Taxane Arm: paclitaxel (80 mg/m2, 1-h infusion) weekly for 12 wk.	pCR1, pCR3, OR, cCR, BCS, Toxicity
NCC Korea[21], 2008	209	Previously untreated stage II/III breast cancer patients with auxiliary lymph node involvement of age ≥ 18 years, ECOG performance status ≤ 1	Anthracycline Arm: doxorubicin 60 mg/m2 IV on day 1 plus cyclophosphamide 600 mg/m2 IV on day 1 every 3 wk for four cycles; Taxane Arm: docetaxel 75 mg/m2 1-h infusion on day 1 plus capecitabine 1000 mg/m2 orally twice daily on days 1-14 every 3 wk for four cycles.	pCR3, OR, cCR, Toxicity, OS, DFS
Norwagian trial[22], 2012	223	Primary stage III breast cancer patients	Anthracycline Arm: 4x Epirubicin 90 mg/m2 administered at 3 wk interval; Taxane Arm: four cycles of paclitaxel 200 mg/m2 administered at 3 wk intervals.	OR, cCR, BCS, OS
Learn et al[27], 2005	144	Invasive breast carcinoma with clinical staging T1c-T3, N0M0 or T1-3, N1M0	Anthracycline Arm: 4 cycles of doxorubicin and cyclophosphamide (A60 C600) every 21 as well as tamoxifen 20 mg per day for 5 yr as NACT; Taxane Arm: 4 cycles of A60 C600 every 21 d further 4 cycles of docetaxel at 100 mg/m2 every 21 d as NACT; Arm 3 (Docetaxel as ACT): 4x AC as ACT (not part of the current study).	pCR1; OR
Diéras et al[5], 2004	240	Breast cancer patients of stage T2-3N0-1M0, who were not assessable for breast conserving surgery	Anthracycline Arm: 4 cycles of A60 C600 i.v. every 21 d; Taxane Arm: doxorubicin 60 mg/m2 as (IV) bolus during 5 to 15 min immediately followed by paclitaxel 200 mg/m2 as a 3-h infusion every 21 d for 4 cycles.	pCR3, OR, cCR, cPR, BCS; Toxicity, OS, DFS, LRR, DM
Tabchy et al[28], 2010	273	Breast cancer patients with clinical stage I to III	Anthracycline Arm: six courses of 5-fluorouracil (500 mg/m2), doxorubicin50/epirubicine100, and cyclophosphamide (500 mg/m2) all on day 1 repeated in 21-d cycles; Taxane Arm: 12 courses of weekly paclitaxel (80 mg/m2/wk) followed four cycles of anthracycline chemotherapy all on day 1 repeated in 21-d cycles.	pCR1; BCS
NSABP-27[6], 2006	2411	Primary operable breast cancer patients with palpable tumor of stage T1c-3, N0-1 M0.	Arm1- 4 cycles of Doxorubicin 60 mg/m2 Cyclophosphamide 600 mg/m2 every 3 wk; Arm 2-Doxorubicin 60 mg/m2 Cyclophosphamide 600 mg/m2 every 3 wk × 4 followed by Docetaxel 100 mg/m2 every 3 wk × 4 followed by surgery; Arm3 (ACT arm)- Doxorubicin 60 mg/m2 Cyclophosphamide 600 mg/m2 every 3 wk × 4 followed by surgey--> Docetaxel 100 mg/m2 every 3 wk × 4	pCR2, pCR3, OR, cCR, BCS; Toxicity, OPS, DFS, LRR, DM
Buzdar et al[23], 1999	174	Invasive, but non-inflammatory, breast cancer with stage II to IIIA disease	Anthracycline Arm: 4 × FAC (fluorouracil 500, cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2) every 3 wk interval; Taxane Arm: Paclitaxel 250 mg/m2 as a 24-h continuous infusion at 3-wk intervals for four cycles.	pCR3, OR, cCR, BCS; Toxicity, DFS
Cortés-Flores et al[30], 2008	41	Stage IIB and IIIA, locally advanced breast cancer patients	Anthracycline Arm: 5-fluorouracil epirubicine cyclophosphamide; Taxane Arm: docetaxel and epirubicine.	pCR2
Sivasanker et al[29],2017	101	Locally advanced breast cancer patients’ candidates for NACT	Anthracycline Arm: Cyclophosphamide 500 mg/m2, Doxorubicin 50 mg/m2 and 5-FU 500/m2 as IV infusion repeated every 21 d; Taxane Group: Paclitaxel 175 mg/m2 as a 3 h IV infusion, Doxorubicin 50 mg/m2 as IV infusion.	pCR1, pCR2, OR, cCR, BCS

pCR1: Pathological complete response to breast as well as axilla; pCR2: Pathological complete response to breast regardless of axilla; pCR3: Pathological complete response to breast allowing for ductal carcinoma in situ; NACT: Neoadjuvant Chemotherapy; OR: Overall response; cCR: Clinical complete response; BCS: Breast conserving surgery; OS: Overall survival; DFS: Disease free survival; LRR: Loco-regional recurrence; DM: Distant metastasis.

Table 2 Subgroup as well as overall meta-analysis for all considered outcomes

Outcome	Sub-Group	Number of studies	Events taxane	Events anthracycline	Egger’s test P-value	I2 Statistic	Risk Ratio(95%CI)	Grade
pCR (BA)	Taxane v/s Anthracycline	2	21/125	24/128	-	38.3	0.74 (0.23-2.39)	High
	Taxane + Anthracyline v/s Anthracycline	6	106/562	103/627	0.110	41.9	1.23 (0.86-1.76)	High1
	Overall	8	127/687	127/755	0.573	34.4	1.14 (0.84-1.55)	High1
pCR (B)	Taxane v/s Anthracycline	1	16/47	8/50	-	-	2.13 (1.01-4.50)	Moderate2
	Taxane + Anthracyline v/s Anthracycline	6	443/1951	329/1959	0.475	72.6	1.48 (1.04-2.12)	Moderate1, 3
	Overall	7	459/1998	337/2009	0.331	69.6	1.54 (1.11-2.15)	Moderate1, 3
pCR (DCIS)	Taxane v/s Anthracycline	2	29/189	24/186	-	85.4	1.06 (0.25-4.47)	Moderate1, 3
	Taxane + Anthracyline v/s Anthracycline	4	761/1679	183/683	0.339	71.4	1.23 (0.86-1.75)	Moderate1, 3
	Overall	6	790/1868	207/869	0.277	71.7	1.20 (0.84 -1.70)	Moderate1, 3
Overall response	Taxane v/s Anthracycline	4	249/356	221/349	0.956	66.2	1.12 (0.94-1.33)	Low3, 4
	Taxane + Anthracyline v/s Anthracycline	7	1098/1348	1024/1345	0.045	71.4	1.14 (1.02-1.27)	Low3, 4
	Overall	11	1347/1704	1245/1694	0.031	69.1	1.13 (1.04-1.24)	Low3, 4
Complete clinical response	Taxane v/s Anthracycline	4	62/356	45/349	0.908	00.0	1.40 (1.01-1.93)	Moderate4
	Taxane + Anthracyline v/s Anthracycline	7	548/2231	511/2176	0.273	60.1	1.13 (0.88-1.43)	Low3, 4
	Overall	11	610/2587	556/2525	0.106	49.5	1.18 (0.97-1.44)	Moderate4
Breast conserving surgery	Taxane v/s Anthracycline	1	40/86	30/85	-	-	1.32 (0.91-1.90)	Moderate2
	Taxane + Anthracyline v/s Anthracycline	8	1040/2206	1007/2199	0.633	00.0	1.03 (0.97-1.09)	High1
	Overall	9	1080/2292	1037/2284	0.406	01.1	1.04 (0.98-1.10)	High1
Overall survival	Taxane v/s Anthracycline	3	18/255	31/251	0.002	74.9	0.41 (0.13-1.31)	Low1, 35
	Taxane + Anthracyline v/s Anthracycline	4	424/2026	456/1960	0.899	0.0	0.91 (0.79-1.05)	High1
	Overall	7	442/2281	487/2211	0.059	37.4	0.86 (0.70-1.05)	High1
Disease free survival	Taxane v/s Anthracycline	3	71/285	84/289	0.144	0.00	0.92 (0.63-1.36)	High1
	Taxane + Anthracyline v/s Anthracycline	4	722/2026	772/1958	0.685	0.00	0.89 (0.80-0.99)	High1
	Overall	7	793/2311	856/2247	0.791	0.00	0.89 (0.80-0.99)	High1
Loco-regional recurrence	Overall	4	120/2026	161/1960	0.808	0.00	0.74 (0.59-0.94)	High
Distant metastasis	Overall	4	426/2026	441/1960	0.264	0.00	0.94 (0.82-1.07)	High

¹Involves non-blinded RCT(s) but objective measurement will not change the drawn evidences.

²Evidence is based on few sample (Imprecise).

³Imprecision because of higher heterogeneity (I²).

⁴Involves non-blinded RCTs which may change the drawn evidence.

⁵Publication Bias.pCR: Pathological complete response; DCIS: Ductal carcinoma in situ.

Table 3 Pooled effect estimates for various toxicity in taxanes in comparison to anthracyclines

Toxicity	Number of studies	RR (95%CI)
Hematological toxicity
Neutropenia	7	1.00 (0.78-1.29)
Febrile neutropenia	4	2.67 (2.33-3.07)
Leucopenia	4	0.72 (0.36-1.45)
Anemia	3	0.75 (0.12-4.53)
Thrombocytopenia	4	0.07 (0.03-0.19)
Thrombosis	2	1.07 (0.59-1.96)
Cardiac and nervous system toxicity
Neuropathy	2	1.01 (0.35-2.93)
Sensory neuropathy	3	18.26 (5.87-56.80)
Cardiac left ventricular function	1	0.33 (0.01-8.14)
Cardiovascular toxicity	1	2.74 (0.88-8.57)
Dermatological toxicities
Hand foot syndrome	2	27.43 (3.75-200.84)
Rash	1	8.96 (0.48-166.20)
Dermatological toxicity	2	3.71 (1.18-11.67)
Alopecia	1	0.78 (0.73-0.83)
Diarrhea	5	1.90 (0.97-3.73)
Gastro	1	4.23 (1.43-12.53)
constipation	1	3.49 (0.73-16.73)
Oral toxicities
Stomatitis	6	1.89 (1.23-2.91)
Musculoskeletal pain	1	1.01 (0.06-15.95)
General toxicity
Nausea	7	0.33 (0.24-0.44)
Fatigue	5	1.29 (0.96-1.73)
Infection	4	2.53 (2.00-3.19)
Other	6	1.12 (0.61-2.06)
Vomiting	4	0.23 (0.16-0.33)
Allergic reaction	3	21.25 (2.74-164.67)
Myalgia	3	1.99 (0.36-11.01)
Serious adverse event	1	0.65 (0.29-1.45)
edema	1	6.97 (0.36-134.74)
Fever	1	15.85 (0.96-260.89)
Hypotension	1	6.97 (0.36-134.74)
Pulmonary	1	3.54 (0.92-13.65)
Arthelgia	3	0.02 (0.01-0.04)
Bone pain	1	0.07 (0.00-1.17)