Herceptin® (trastuzumab) in HER2-positive early breast cancer: a systematic review and cumulative network meta-analysis

Wilson, Florence R.; Coombes, Megan E.; Brezden-Masley, Christine; Yurchenko, Mariya; Wylie, Quinlan; Douma, Reuben; Varu, Abhishek; Hutton, Brian; Skidmore, Becky; Cameron, Chris

doi:10.1186/s13643-018-0854-y

Systematic Reviews

Table 2 Summary of study and patient characteristics from RCTs with overall survival results

From: Herceptin® (trastuzumab) in HER2-positive early breast cancer: a systematic review and cumulative network meta-analysis

Study (primary publication)	Treatments	Node name in network	Median follow-up (months)	N total	Median age (years)	Tumor Size > 2 cm (%)	Node + (%)	HR+ (%)	HER2+ (%)
RCTs with 100% HER2+ early breast cancer patients
ALTTO (Piccart-Gebhart 2016) [66]	Anthracycline and/or taxane → trastuzumab IV (52 weeks)	AC-TH_52 weeks	54	2097	51	49	51	57	100
	Anthracycline and/or taxane → lapatinib (52 weeks)	AC-TL_52 weeks	54	2100	51	51	52	57	100
	Anthracycline and/or taxane → trastuzumab IV (12 weeks) → lapatinib (34 weeks)	AC-TL_34 weeks-H_12 weeks	54	2091	51	50	52	58	100
	Anthracycline and/or taxane → trastuzumab IV (52 weeks) + lapatinib (52 weeks)	AC-TL_52 weeks-H_52 weeks	54	2093	51	50	51	57	100
BCIRG 006 (Slamon 2011) [44]	Doxorubicin + cyclophosphamide → docetaxel	AC-T	65	1073	NR	59	71	54	100
	Doxorubicin + cyclophosphamide → docetaxel + trastuzumab IV (52 weeks)	AC-TH_52 weeks	65	1074	NR	62	71	54	100
	Docetaxel + carboplatin + trastuzumab IV (52 weeks)	TCH_52 weeks	65	1075	NR	59	72	54	100
FNCLCC-PACS 04 (Spielmann 2009) [67]	FEC or ED (epirubicin + docetaxel) → trastuzumab IV (52 weeks)	AC-TH_52 weeks	47	260	48	59·1	100	58	100
FNCLCC-PACS 04 (Spielmann 2009) [67]	FEC or ED (epirubicin + docetaxel)	AC-T	47	268	49	50·6	100	61	100
HannaH (Jackisch 2016) [68]	Docetaxel → FEC + trastuzumab IV → trastuzumab IV (52 weeks)	AC-TH_52 weeks	40·6	297	50	NR	79·1	49·8	100
HannaH (Jackisch 2016) [68]	Docetaxel → FEC + trastuzumab SC → trastuzumab SC (52 weeks)	AC-TH_SC,52 weeks	40·3	294	50	NR	75·8	52·4	100
HERA (Goldhirsch 2013) [64]	Anthracycline or taxane → trastuzumab IV (104 weeks)	AC-TH_104 weeks	96	1700	NR	49·5	56·5	51·4	100
	Anthracycline or taxane → trastuzumab IV (52 weeks)	AC-TH_52 weeks	96	1702	49	48·4	56·4	50·9	100
	Anthracycline or taxane	AC-T	96	1697	49	NR	NR	NR	100
HORG (Mavroudis 2015) [70]	FEC → docetaxel + trastuzumab IV (52 weeks)	AC-TH_52 weeks	47	241	54	NR	74·7	64·7	100
HORG (Mavroudis 2015) [70]	FEC → docetaxel + trastuzumab IV (26 weeks)	AC-TH_26 weeks	51	240	56	NR	83·3	68·8	100
NCCTG N9831 and NSABP B-31 (Perez 2014) [51]	Doxorubicin + cyclophosphamide → paclitaxel	AC-T	99·6	2018	~ 50	59·2	92·6	54·8	100
NCCTG N9831 and NSABP B-31 (Perez 2014) [51]	Doxorubicin + cyclophosphamide → paclitaxel + trastuzumab IV (52 weeks)	AC-TH_52 weeks	100·8	2028	~ 50	61.8	93·4	54·7	100
NeoALTTO (de Azambuja 2014) [72]	Paclitaxel → FEC → lapatinib (52 weeks)	AC-TL_52 weeks	45	154	50	100	> 16·2	51·9	100
	Paclitaxel → FEC → trastuzumab IV (52 weeks)	AC-TH_52 weeks	45	149	49	100	> 15·4	50·3	100
	Paclitaxel + → FEC → lapatinib (52 weeks) + trastuzumab IV (52 weeks)	AC-TL_52 weeks-H_52 weeks	45	152	50	100	> 15·8	50·7	100
NOAH (Gianni 2014) [20]	Paclitaxel + doxorubicin → paclitaxel → CMF	AC-T	64·8	118	NR	NR	84	36	100
NOAH (Gianni 2014) [20]	[Paclitaxel + doxorubicin → paclitaxel → CMF → trastuzumab IV (52 weeks)	AC-TH_52 weeks	64·8	117	NR	NR	86	36	100
NSABP B-41 (Robidoux 2013^b) [94]	Doxorubicin + cyclophosphamide → paclitaxel → trastuzumab IV (52 weeks)	AC-TH_52 weeks	22·8	181	NR	100	51	67	100
	Doxorubicin + cyclophosphamide → paclitaxel + lapatinib (12 weeks) → trastuzumab IV (34 weeks)	AC → T-L_12 weeks-H_34 weeks	22·8	174	NR	100	52	58	100
	Doxorubicin + cyclophosphamide → paclitaxel + lapatinib (12 weeks) + trastuzumab IV → trastuzumab IV (52 weeks)	AC → T-L_12 weeks-H_52 weeks	22·8	174	NR	100	49	62	100
PHARE (Pivot 2013) [75]	Anthracycline + taxane + trastuzumab IV → trastuzumab IV (52 weeks)	AC-TH_52 weeks	42·5	1690	54	45.3	44·6	60·4	100
PHARE (Pivot 2013) [75]	Anthracycline + taxane + trastuzumab IV → trastuzumab IV (26 weeks)	AC-TH_26 weeks	42·5	1690	55	47·6	45.3	61·5	100
RCTs with subgroup data of HER2+ early breast cancer patients
BCIRG 001 (Mackey 2013) [76]	Docetaxel + doxorubicin + cyclophosphamide	AC-T	124	745	49	61	100	76·1	21
BCIRG 001 (Mackey 2013) [76]	Fluorouracil + doxorubicin + cyclophosphamide	AC	123	746	49	57	100	75·7	22
Boccardo 2010 [77]	Epirubicin → cyclophosphamide + methotrexate + fluorouracil	AC	102	122	53·0	47·5	100	79·5	31·1
Boccardo 2010 [77]	Paclitaxel → epirubicin + vinorelbine	T → AV	102	122	54·5	64.8	100	79·5	28·7
BR9601 and NEAT (Earl 2012) [78]	Epirubicin → CMF	AC	88·8	1189	NR	56	72	≥59	21
BR9601 and NEAT (Earl 2012) [78]	Cyclophosphamide + methotrexate + fluorouracil	CMF	88·8	1202	NR	56	72	≥59	20
Colozza 2005 [79]	Cyclophosphamide + methotrexate + fluorouracil	CMF	96	133	NR	51	80	≥63	69
Colozza 2005 [79]	Epirubicin	E	96	133	NR	48	78	≥63	77
Del Mastro 2015 [80]	Epirubicin + cyclophosphamide → paclitaxel (q3w)	AC-T	84	545	51	48	100	77	23
	FEC → paclitaxel (q3w)	AC-T	84	544	53	52	100	81	24
	Epirubicin + cyclophosphamide → paclitaxel (q2w)	Dose dense	84	502	53	48	100	81	21
	FEC → paclitaxel (q2w)	Dose dense	84	500	51	49	100	80	24
E1199 (Sparano 2015^c) [95]	Doxorubicin + cyclophosphamide → paclitaxel (weekly)	Dose dense	145·2	1232	51	63.8	87.8	70·2	19·2
E1199 (Sparano 2015^c) [95]	Doxorubicin + cyclophosphamide → paclitaxel (q3w)	AC-T	145·2	1253	51	60.7	87.8	71·0	20·6
E2198 (Schneider 2015) [82]	Paclitaxel + trastuzumab IV (10 weeks) → doxorubicin + cyclophosphamide	AC-TH_{9–10 weeks}	77	115	49	NR	100	60	53
E2198 (Schneider 2015) [82]	Paclitaxel + trastuzumab IV (10 weeks) → doxorubicin + cyclophosphamide + trastuzumab IV (52 weeks total)	AC-TH_52 weeks	77	112	48	NR	100	63	53
FinHer (Joensuu 2009) [83]	Docetaxel → FEC	AC-T	62	58	49·9	70	78	≥44	100^a
	Docetaxel + trastuzumab IV (9 weeks) → FEC	AC-TH_{9–10 weeks}	62	54	51·4	59	90	≥50	100^a
	Vinorelbine → FEC	AC-V	62	58	49·9	70	78	≥44	100^a
	Vinorelbine + trastuzumab IV (9 weeks) → FEC	AC-VH_9 weeks	62	62	51·4	59	90	≥50	100^a
FinXX (Joensuu 2014) [84]	Capecitabine + docetaxel → cyclophosphamide + epirubicin + capecitabine → trastuzumab IV (52 weeks); or docetaxel → FEC → trastuzumab IV (52 weeks)	AC-TH_52 weeks	80·4	176	52·2	NR	84·6	60·2	100^a
FinXX (Joensuu 2014) [84]	Capecitabine + docetaxel → cyclophosphamide + epirubicin + capecitabine; or docetaxel → FEC	AC-T	80·4	108	50·5	NR	81·4	51·9	100^a
GeparTrio (von Minckwitz 2013) [85]	Docetaxel + doxorubicin + cyclophosphamide → vinorelbine + capecitabine (in non-responders)	AC-T → VX	62	987	NR	NR	54·7	65·6	29·1
GeparTrio (von Minckwitz 2013) [85]	Docetaxel + doxorubicin + cyclophosphamide	AC-T	62	1025	NR	NR	55·3	63·2	30·5
GONO-MIG-1 (Del Mastro 2005) [86]	FEC (q3w)	AC	80·4	53	54	NR	61·2	≥27·2	100^a
GONO-MIG-1 (Del Mastro 2005) [86]	FEC (q2w)	Dose dense	80·4	50	54	NR	61·2	≥27·2	100^a
Miles 1999 [87]	Cyclophosphamide + methotrexate + fluorouracil	CMF	159·6	129	NR	78	100	≥77·5	30
Miles 1999 [87]	No treatment	No Tx	159.6	145	NR	78	100	≥77·5	30
Rocca 2014 [88]	Epirubicin → CMF, or CMF → epirubicin	AC	69	545	53	NR	48·3	≥64·0	34·1
Rocca 2014 [88]	Cyclophosphamide + methotrexate + fluorouracil	CMF	69	160	51	NR	47·5	≥56·9	30·0
TEACH (Goss 2013) [89]	Lapatinib (52 weeks) + anthracycline/taxane	AC-TL_52 weeks	47.4	1571	51	NR	54	59	78
TEACH (Goss 2013) [89]	Placebo (52 weeks) + anthracycline/taxane	AC-T	48·3	1576	52	NR	54	59	80
UNICANCER-PACS01 (Coudert 2012) [90]	FEC	AC	92·8	996	NR	57·8	100	78	9·4
UNICANCER-PACS01 (Coudert 2012) [90]	FEC → docetaxel	AC-T	92·8	1003	NR	57·8	100	78	9·4
Non-randomized studies with 100% HER2+ early breast cancer patients
Bayraktar 2012 [91]	Paclitaxel + trastuzumab → FEC + trastuzumab (52 weeks)	AC-TH_52 weeks	29	235	49	NR	81·5	≥53·8	100
Bayraktar 2012 [91]	Docetaxel + carboplatin + trastuzumab (52 weeks)	TCH_52 weeks	18	65	53	NR	80.0	≥55·6	100
Gonzalez-Angulo 2015 [92]	Adjuvant trastuzumab: paclitaxel + trastuzumab → FEC + trastuzumab (52 weeks)	AC-TH_52 weeks	45	480	~ 50	NR	19·4	61·1	100
Gonzalez-Angulo 2015 [92]	No adjuvant trastuzumab: paclitaxel + trastuzumab (26 weeks) → FEC	AC-TH_26 weeks	45	109	~ 50	NR	15·6	53·2	100
Seferina 2015 [93]	Anthracycline/taxane-containing chemotherapy + trastuzumab (52 weeks)	AC-TH_52 weeks	60	230	51	> 56	56·0	62	100
Seferina 2015 [93]	Endocrine therapy and radiotherapy, no chemotherapy	No chemo	60	246	65	NR	NR	NR	100

Data were extracted from the most recent full-text publications, when available
^aPatient characteristics were available for the HER2+ subgroup population. Therefore, the percentage of HER2+ patients in the HER2+ subgroup is 100%, even though it is a non-randomized subset of the RCT
^bPatient characteristics for NSABP B-41 were extracted from Robidoux 2013; [94] OS results were extracted from Robidoux 2016. [74]
^cPatient characteristics for E1199 were extracted from Sparano 2015; [95] OS results were extracted from Sparano 2008. [81]
AC anthracycline (doxorubicin, epirubicin) + cyclophosphamide, AV anthracycline + vinorelbine, CMF cyclophosphamide + methotrexate + fluorouracil, Dose dense AC → T, or AC, either weekly or biweekly, E epirubicin, ED epirubicin + docetaxel, ER+ estrogen receptor-positive, FEC fluorouracil + epirubicin + cyclophosphamide, H Herceptin® intravenous (IV), HER2+ human epidermal growth factor receptor 2-positive, HR+ hormone receptor-positive, H_SC Herceptin® subcutaneous (SC), IV intravenous, L lapatinib, No Chemo no chemotherapy (includes endocrine therapy and radiotherapy), No Tx no treatment, NR not reported, OS overall survival, PBO placebo, PgR+ progesterone receptor-positive, q2w once every 2 weeks, q3w once every 3 weeks, RCT randomized controlled trial, T taxane (docetaxel, paclitaxel), TCH docetaxel + carboplatin + Herceptin® IV, V vinorelbine, X capecitabine

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