Increased risk of adverse drug events secondary to bevacizumab treatment in patients with advanced or metastatic breast cancer: a meta-analysis of randomized controlled trials

Figures & data

Figure 1 Study flow diagram.

Figure 2 Risk of bias assessment.

Notes: + refers to low risk of bias; ? refers to unclear risk of bias; − refers to high risk of bias.

Table 1 Characteristics of the included randomized controlled trials

Study	Trial phase	Evaluated patients (n)	Treatment arms (n)	Median PFS (months)	Median OS (months)	Bevacizumab dose	Median follow-up duration (months)	ER and/or PR + (%)	Her2+/Her2− (%)
Brufsky et al^Citation8	3	684	CHE + PLA (225) CHE + BEV (459)	5.1 7.2	16.4 18.0	– 10–15 mg/kg every 2–3 wks	15	73 72	0/85 0/84
Diéras et al^Citation16	2	185	ONA + BEV + PAC (63) ONA + PLA + PAC (60) PLA + BEV + PAC (62)	7.3 5.4 7.2	14.7 13.4 17.4	10 mg/kg every 2 wks – 10 mg/kg every 2 wks	NA	0	0/100
Diéras et al^Citation17	2	228	TRE (10 mg/kg per wk) + PAC + BEV (56) TRE (3 mg/kg per wk) + PAC + BEV (57) PLA + PAC + BEV (58) TRE (10 mg/kg per wk) + PAC (57)	11.3 9.2 12.2 10.0	NA	10 mg/kg every 2 wks 10 mg/kg every 2 wks 10 mg/kg every 2 wks –	15.5	80 82 78 65	0/98 0/100 0/100 0/100
Gianni et al^Citation9	3	424	DOC + TRA (208) DOC + TRA + BEV (216)	13.7 16.5	NA	– 15 mg/kg every 3 wks	25.8 26.0	51 53	71/7 71/9
Martin et al^Citation10	2	282	PAC + MOT (91) PAC + PLA (94) PAC + BEV (97)	9.5 9.0 11.5	NA	– – 10 mg/kg every 2 wks	NA	73 75 78	0/100
Martín et al^Citation18	3	374	ET (184) ET + BEV (190)	14.4 19.3	51.8 52.1	– 15 mg/kg every 3 wks	23.7	100	0/100
Miles et al^Citation4	3	736	DOC + PLA (241) DOC + BEV (7.5 mg/kg every 3 wks) (248) DOC + BEV (15 mg/kg every 3 wks) (247)	8.1 9.0 10.0	31.9 30.8 30.2	– 7.5 mg/kg every 3 wks 15 mg/kg every 3 wks	10.2	78 78 76	0/100
Miles et al^Citation19	3	481	PAC + PLA (242) PAC + BEV (239)	8.8 11.0	25.8 NA	– 10 mg/kg every 2 wks	14.8 15.0	84 84	0/100
Miller et al^Citation11	3	462	CAP (230) CAP + BEV (232)	4.2 4.9	14.5 15.1	– 15 mg/kg every 3 wks	14.8	52 42	20/NA 26/NA
Miller et al^Citation3	3	673	PAC + BEV (326) PAC (347)	11.8 5.9	26.7 25.2	10 mg/kg every 2 wks –	25.9	60/45* 63/45*	1/93 1/90
Robert et al^Citation5	3	1,237	CAP + PLA (206) CAP + BEV (409) TAX/anthra + PLA (207) TAX/anthra + BEV (415)	5.7 8.6 8.0 9.2	NA	– 15 mg/kg every 3 wks – 15 mg/kg every 3 wks	15.6	74 77 77 76	0/95 0/96 0/99 0/99
							19.2
von Minckwitz et al^Citation20	3	494	CHE (247) CHE + BEV (247)	4.2 6.3	NA	– 15 mg/kg every 3 wks or 10 mg/kg every 2 wks	15.9 16.1	76 80	0/100

Note:

* Values shown as ER+ patients/PR + patients.

Abbreviations: PFS, progression-free survival; O S, overall survival; ER, estrogen receptor; PR, progesterone receptor; Her2, human epidermal growth factor receptor 2; CHE, chemotherapy; PLA, placebo; BEV, bevacizumab; ONA, onartuzumab; PAC, paclitaxel; TR E, trebananib; NA, not available; DOC, docetaxel; TRA, trastuzumab; MOT, motesanib; ET, endocrine therapy; CAP, capecitabine; TAX, taxanes; anthra, anthracycline; wk, week.

Figure 3 Forest plot for the meta-analysis of relative risk of hypertension (grade ≥3) with bevacizumab-treated patients.

Abbreviations: OR, odds ratio; M–H, Mantel–Haenszel; CI, confidence interval; PLA, placebo; PAC, paclitaxel; BEV, bevacizumab; TRE, trebananib; MOT, motesanib; DOC, docetaxel; anthra, anthracycline; CAP, capecitabine; TAX, taxanes.

Figure 4 Forest plot for the meta-analysis of relative risk of proteinuria (grade ≥3) with bevacizumab-treated patients.

Abbreviations: OR, odds ratio; M–H, Mantel–Haenszel; CI, confidence interval; DOC, docetaxel; BEV, bevacizumab; PLA, placebo; anthra, anthracycline; CAP, capecitabine; TAX, taxanes.

Figure 5 Forest plot for the meta-analysis of relative risk of bleeding (grade ≥3) with bevacizumab-treated patients.

Abbreviations: OR, odds ratio; M–H, Mantel–Haenszel; CI, confidence interval; NA, not available; PLA, placebo; BEV, bevacizumab; PAC, paclitaxel; ONA, onartuzumab; TRE, trebananib; DOC, docetaxel; anthra, anthracycline; CAP, capecitabine; TAX, taxanes.

Figure 6 Forest plot for the meta-analysis of relative risk of cardiac toxicity (grade ≥3) with bevacizumab-treated patients.

Abbreviations: OR, odds ratio; M–H, Mantel–Haenszel; CI, confidence interval; NA, not available; PAC, paclitaxel; BEV, bevacizumab; MOT, motesanib; PLA, placebo; DOC, docetaxel; anthra, anthracycline; CAP, capecitabine; TAX, taxanes.

Figure 7 Forest plot for the meta-analysis of relative risk of neutropenic fever (grade ≥3) with bevacizumab-treated patients.

Abbreviations: OR, odds ratio; M–H, Mantel–Haenszel; CI, confidence interval; NA, not available; DOC, docetaxel; BEV, bevacizumab; PLA, placebo; anthra, anthracycline; CAP, capecitabine; TAX, taxanes.

Table 2 Summary of studies that assessed the correlation between bevacizumab efficacy and incidence of hypertension

Study	Design	Results
Schneider et al^Citation22	Genotyping study (data extracted from the E2100 trial)	Patients with high-grade hypertension were associated with a superior median OS compared with those with no hypertension (38.7 vs 25.3 months; P=0.002)
Gampenrieder et al^Citation23	Retrospective matched-pair analysis	Patients with hypertension had superior survival outcomes in PFS (13.7 vs 6.6 months, HR 0.34, 95% CI 0.23–0.49; P<0.001) and 2-year OS (78% vs 30%, HR 0.20, 95% CI 0.12–0.35; P<0.001)
Hurwitz et al^Citation24	Retrospective analysis of results from seven Phase III studies	Two of the seven included trials had the underlying malignancy of metastatic breast cancer: the AVADO and RIBBON-1 trials Both trials showed no significant interaction between hypertension and survival outcomes: in the AVADO trial, the HR for PFS was 0.68 (P=0.0823) and for OS was 0.72 (P=0.2800); in the RIBBON-1 trial, the HR for PFS was 0.82 (P=0.2597) and for OS was 0.62 (P=0.0505)
Smith et al^Citation26	Subgroup analysis (data extracted from the ATHENA trial)	No correlation between development of hypertension and OS was detected
Launay-Vacher et al^Citation25	Retrospective cohort study	Hypertension was not predictive of OS in bevacizumab-treated patients with breast cancer

Abbreviations: OS, overall survival; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval.

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