Table V.

Meta-analyses on efficacy and safety of trastuzumab with chemotherapy for HER-2 positive breast cancer.

Author, year	Object	Studies	Patients	Outcomes	Effect	Major findings	(Refs.)
Valachis et al, 2011a	BC	5	515	pCR rate, BCS rate, neutropenia, neutropenic fever, cardiac AEs	RR	The probability to achieve pCR was higher for trastuzumab group. No significant difference in terms of BCS rate. The addition of trastuzumab did not increase the incidence of neutropenia, neutropenic fever, and cardiac AEs.	(14)
Yin et al, 2011	Early stage BC	6	12,877	DFS, OS, recurrence of locoregional, distant, contralateral BC and CNS	OR	Patients in trastuzumab group derived benefit in DFS, OS, locoregional and distant recurrence, but did worse in CNS recurrence. Concomitant use of trastuzumab lowered the risk of death but bore a higher CNS recurrence risk, OS and CNS recurrence had no difference between the sequential and observation groups.	(16)
Bria et al, 2008	Early stage BC	5	1,186	DFS & OS	RR	DFS and OS were significantly prolonged in trastuzumab group with a higher incidence of CHF, LFEV reduction and BM.	(19)
				Cardio toxicity & BM	RR
Olson et al, 2013	BC	4	9,020	CNS recurrence	RR	Adjuvant trastuzumab was associated with a significant increased risk of CNS metastases as the site of first recurrence in BC patients.	(47)
Brollo et al, 2013	BC ≥60 years	5	1,084	DFS	HR	Compared with chemotherapy alone, 47% relative risk reduction was observed in trastuzumab group. Proportion of cardiac events in older patients treated with trastuzumab was 5%.	(48)
				Cardio toxicity	RR
Petrelli et al, 2012b	Early stage BC	6	13,331	DFS, OS	HR	In concomitant analysis, DFS and OS were longer, but risk of severe cardiac events had no increased in the trastuzumab group; In sequential analysis, DFS was longer but not OS, risk of severe cardiac events was increased in trastuzumab group.	(49)
				Cardiac events	RR
Liao et al, 2011	Advanced stage BC	4	815	OS	HR	Addition of trastuzumab provided substantial benefit in terms of ORR, CR, and OS. The incidence of neutropenia, grade 3–4 neutropenia, overall anemia and cardiac toxicity were significantly higher in trastuzumab group.	(50)
				ORR & CR	RR
				Cardio toxicity, neutropenia, anemia	OR
Dahabreh et al, 2008	Early stage BC	5	13,493	DFS, mortality, locoregional recurrence, distant recurrence	RR	Superiority was observed for patients receiving trastuzumab with respect to DFS, mortality, locoregional recurrence, and distant recurrence. Patients in trastuzumab group had a higher risk for CHF, LVEF, and CNS metastasis.	(51)
				Cardio toxicity, CNS recurrence	RR
Zhu et al, 2013c	Metastatic BC	5	1,043	OS, TTP	HR	The addition of trastuzumab to chemotherapy improved OS, while to hormone therapy did not. All trastuzumab-containing regimens increased cardiac toxicity and grade 3–4 AEs.	(11)
				ORR, clinical benefit ratio	RR
				Cardiac toxicity, grade 3–4 AEs	RR
Moja et al, 2012	Early stage BC	8	11,991	OS, DFS	HR	Adjuvant trastuzumab improved survival with increased risk of cardiac toxicity. Also, studies with concurrent administration showed similar efficacy and toxicity results to sequential studies.	(52)
				Cardiac toxicity	RR

HR, hazard ratio; RR, risk ratio; OR, odds ratio; BC, breast cancer patient; DFS, disease free survival; OS, overall survival; CHF, congestive heart failure; LVEF, left ventricular ejection fraction; BM, brain metastases; CNS, central nervous system; ORR, overall response rate; CR, complete response; pCR, pathologic complete response; TTP, time to progression; AEs, adverse events.

^aNeoadjuvant setting

^bConcomitant and sequential use of trastuzumab

^cTwo trials were trastuzumab in combination with hormone therapy and 3 were with chemotherapy.