Toremifene in the treatment of breast cancer

Table 1 Randomized controlled clinical trials

Ref.	Type	Pts	Diagnosis	Receptor status	Follow-up	Treatment	Results
Nomura et al[39], 1993	DB	114 women	Advanced or recurrent breast cancer	NS	NS		RR	Time to onset of CR	Duration of efficacy
						TOR 40 mg	26.3%	91 d	155 d
						TAM 20 mg	28.1%	169 d (P < 0.05)	154.5 d
Hayes et al[29], 1995	OL	648 post- or peri-menopausal women	Metastatic breast cancer	Positive or unknown	NS		Overall RR	CR + PR	PFS
						TOR 60 mg	50%	21%	5.6 mo
						TOR 200 mg	48%	23%	5.6 mo
						TAM 20 mg	44% (ns)	19% (ns)	5.8 mo (ns)
Gershanovich et al[31], 1997	OL	463 post-menopausal women	Advanced breast cancer	Positive or unknown	Median 20.5 mo		RR		PFS
						TOR 60 mg	20.4%		49
						TOR 240 mg	28.7%		61
						TAM 40 mg	20.8%		50
Pyrhönen et al[32], 1997	DB	415 post-menopausal women	Advanced breast cancer	Negative or unknown	Median 20.5 mo		CR+PR	TTF	TTP	Median OS
						TOR 60 mg	31.3%	6.3 mo	7.3 mo	33 mo
						TAM 40 mg	37.3%	8.5 mo	10.2 mo	38.7 mo
Holli et al[33], 2000	OL	899 post-menopausal women	Early invasive breast cancer (adjuvant treatment)	Any	Median 3.4 yr		Time to recurrence	Overall recurrence rate	Recurrence rate	Died during follow-up
						TOR 40 mg	21.6 mo	23.1%	20.3%	18.5%
						TAM 20 mg	23.5 mo	26.1%	24.3%	20.7%
Milla-Santos et al[34], 2001	DB	217 women	Advanced breast cancer	Positive	NS		CR (mo)	PR (mo)	SD (mo)	Median TTP (mo)	Median survival (mo)
						TOR 60 mg	12.2	25.4	26.4	11.9	15.4
						TAM 40 mg	8.1	24.3	19.6	9.2 (ns)	12.3 (ns)
Pagani et al[35], 2004	OL	1035 peri- or post- menopausal women	Lymph node positive breast cancer (adjuvant treatment)	ER positive	5.5 yr		5-yr DFS		5-yr OS
						TOR 60 mg	72%		85%
						TAM 40 mg	69%		81%
Zejnalov et al[30], 2006	OL	541 post-menopausal women	Disseminated breast cancer	Positive	NS		CR + PR		Median duration of remission
						TAM 20 mg	25.6% (P < 0.05 compared with three other treatments		9.2 mo
						TOR 60 mg	33.0%		11.3 mo
						TOR 240 mg	41.5%		14.5 mo
						LTZ 2.5 mg	35.4%		13.1 mo
Lewis et al[36], 2010	OL	1813 peri- or post- menopausal women	Stage I or II Early primary invasive breast cancer (adjuvant treatment)	Positive	Median 59 mo		5-Yr DFS
						TOR 60 mg	91.2%
						TAM 20 mg	91.2%
Kimura et al[37], 2012	OL	253 post-menopausal women	Early phase breast cancer (adjuvant treatment)	Positive or unknown	Median 66.5 mo		5-yr survival	Cumulative OS	Cumulative DFS
						TOR 40 mg	97%	97.5%	88.4%
						TAM 20 mg	96.7%	97.3%	90.6%
Yamamoto et al[38], 2013	OL	91 post-menopausal women	Advanced, Non-steroidal aromatase inhibitor resistant in metastatic breast cancer	Positive	Median 16.9 mo		CB	ORR	PFS	OS
						TOR 120 mg	41.3%	10.80%	7.3 mo	32.3 mo
						Exemestane 25 mg	26.7% (ns)	2.2% (ns)	3.7 mo (P = 0.045)	12.9 mo (ns)

DB: Double blind; CR: Complete response; PR: Partial response; SD: Stable disease; LSD: Long stable disease; TOR: Toremifene; TAM: Tamoxifen; DFS: Disease-free survival; OS: Overall survival; (O)RR: (Objective) response rate; CB: Clinical benefit; DFS: Disease-free survival; PFS: Progression-free survival; R: Randomized; OL: Open label; UC: Uncontrolled; RA: Retrospective analysis; CC: Case control; Pr: Prospective; CS: Cohort study; AIU: Aromatase inhibitor; TTP: Time to progression.

Table 2 Non-randomized clinical trials (case reports or series with fewer than 10 patients excluded)

Ref.	Pts	Studytype	Diagnosis	Treatment	Results
Asaishi et al[68], 1993	51 women	Not stated	Advanced breast cancer refractory to TAM		CR + PR	SD > 6 mo	Median duration of response	Median duration of SD > 6 mo
				TOR 120 mg	11.8%	15.7%	127 d	238.5 d
Gams et al[69], 2002	102 women peri- or post-menopausal women	Pr	Advanced breast cancer refractory to TAM		OR		SD
				TOR 200 mg	5%		23%
					(TTF 10.9 mo)		(TTF 7.8 mo)
Pyrhönen et al[70], 1994	50 Women	Pr	Advanced breast cancer refractory to TAM		RR	Mixed response	SD
				TOR 240 mg	4%	6%	18% < 5 mo 26% > 5 mo
					Hietanne et al[71], 1997	73 post-menopausal women	Pr	Advanced breast cancer		OR (CR + PR)	NC	PD
TOR 240 mg	59%	29%	12%
Yamamoto et al[72], 2005	10 Women	RA	Metastatic breast cancer		OR	CB	Media TTP	Median OS
				TOR 120 mg	30%	70%	9 mo	21.5 mo
Ohtake et al[73], 2009	12 post-menopausal women who had failed AI therapy	RA	Advanced/recurrent breast cancer		CR	CB	Mean TTP
				TOR 120 mg	16.70%	58.30%	33.8 wk
Okita et al[74], 2009	15 women	Pr	Metastatic breast cancer		CR	PR	No change	Stable > 6 mo	PD	Mean TTF
				TOR 120 mg	0%	6.7%	66.7%,	26.7%	26.7%	2.7 mo
				Paclitaxel 80 mg/m2 on 5 d
Koyama et al[75], 2011	19 postmenopausal women	RA	Advanced or metastatic breast cancer		OR	CB
				TOR 120 mg	36.8% (1 CR, 6 PR 6)	47.4%
Gu et al[40], 2012	810 pre-menopausal women	RA	Early invasive breast cancer (adjuvant treatment)		5-yr OS	DFS
				TOR 60 mg	100%	97.2%
				TAM 20 mg	98.4 (ns)%	90.4% (P = 0.022)
Sawaki et al[76], 2012	13 post-menopausal women	Pr	Adjuvant aromatase inhibitor resistant metastatic breast cancer		CR	SD	PD	CB	PFS
				TOR 120 mg	7.7%	53.8%	38.5%	46.2%	5.9 mo
Tokura et al[77], 2012	18 women	Pr	Advanced/recurrent breast cancer		CB	PD	Media PFS
				TOR 120 mg	58%	22%	5.5 mo
					(5 PR, 5 long SD)
Koike et al[78], 2013	21	Pr	Recurrent or metastatic breast cancer		CR	PR/SD
					(12 wk)	(12 wk)
				TOR 120 mg	0%	21.1%/47.4%
Ogata et al[79], 2013	23 women	Pr	Recurrent breast cancer who were receiving or had received adjuvant aromatase inhibitor therapy		PR	SD	CB	Median TTP
				TOR 120 mg	13%	62%	78.30%	8.1 mo
Qin et al[41], 2013	1847 pre-menopausal women	RA	Operable breast cancer (adjuvant treatment)		DFS	5-Yr DFS	5-Yr OS
				TOR 60 mg	10.3 yr	87%	94.3%
				TAM 20 mg	10.3 yr	85%	93.5%

DB: Double blind; CR: Complete response; PR: Partial response; SD: Stable disease; LSD: Long stable disease; TOR: Toremifene; TAM: Tamoxifen; DFS: Disease-free survival; OS: Overall survival; (O)RR: (Objective) response rate; CB: Clinical benefit; DFS: Disease-free survival; PFS: Progression-free survival; R: Randomized; OL: Open label; UC: Uncontrolled; RA: Retrospective analysis; CC: Case control; Pr: Prospective; CS: Cohort study; AIU: Aromatase inhibitor; TTP: Time to progression.

Table 3 Incidence of adverse events among 1847 women with invasive breast cancer treated with tamoxifen or toremifene[41]

	Adverse event incidence (%)
Adverse event	Tamoxifen(n = 1451)	Toremifene(n = 396)	P value
Flushing	480 (33.1)	39 (35.1)	0.450
Sweating	295 (20.3)	82 (20.7)	0.869
Nausea or vomiting	213 (14.7)	57 (14.4)	0.881
Fatigue	74 (5.1)	18 (4.5)	0.653
Insomnia	62 (4.3)	14 (3.5)	0.513
Dizziness	14 (1.0)	6 (1.5)	0.408
Dry eyes	60 (4.1)	17 (4.3)	1
Blurred vision	40 (2.8)	9 (2.3)	0.595
Cataracts	7 (0.5)	2 (0.5)	1
Weight gain	68 (4.7)	17 (4.3)	0.740
Vaginal discharge	241 (16.6)	69 (17.4)	0.701
Irregular menses	145 (10)	25 (6.3)	0.025
Endometrial cancer	1 (0.1)	0 (0)	0.601
Ovarian cyst	20 (1.4)	4 (1.0)	0.631
Thromboembolic events	22 (1.5)	5 (1.3)	0.709
Hypertriglyceridemia	76 (5.2)	19 (4.8)	0.725
Hyper-LDL cholesterolemia	65 (4.5)	16 (4.0)	0.783
Fatty liver	64 (4.4)	13 (3.3)	0.320
Elevated ast	59 (4.1)	15 (3.8)	0.802
Elevated alp	33 (2.3)	7 (1.8)	0.571
Hepatic cyst	29 (2.0)	6 (1.5)	0.550
Bilirubin	27 (1.9)	8 (2.0)	1

Table 4 Frequency of subjective adverse events among 499 patients with invasive breast cancer randomised to adjuvant toremifene or tamoxifen therapy[33]

	Toremifene		Tamoxifen
	Number of patients	%	Number of patients	%
Sweating	247	53.8	225	51.1
Hot flashes	237	51.6	209	47.5
Vaginal discharge	193	42.0	156	35.5
Vaginal dryness	120	26.1	117	26.6
Itching	118	25.7	119	27.0
Depression	112	24.4	119	27.0
Rash	90	19.6	75	17.0
Nausea	78	17.0	85	19.3
Vaginal bleeding	40	8.7	37	8.4
Diarrhea	37	8.1	51	11.6
Weight increase	23	5.0	19	4.3

Table 5 Frequency of serious adverse events among 499 patients with invasive breast cancer randomised to adjuvant toremifene or tamoxifen therapy[33]

	Toremifene		Tamoxifen
	Number ofpatients	%	Number ofpatients	%
Serious adverse events	72	15.7	74	16.8
Cardiac events	9	2.0	6	1.4
Myocardial infarctions	7	1.5	5	1.1
Angina pectoris	2	0.4	1	0.2
Thromboembolic events	16	3.5	26	5.9
Pulmonary embolisms	3	0.7	3	0.7
Deep vein thrombosis	8	1.7	11	2.5
Cerebrovascular events	5	1.1	12	2.7
Endometrial events	17	3.7	19	4.3
Polyps	8	1.7	7	1.6
Hemorrhage	2	0.4	3	0.7
Disorders	7	1.5	9	2.0
Subsequent cancers	12	2.6	8	1.8
Breast	3	0.7	1	0.2
Uterine	-	-	2	0.5
Gastrointestinal	3	0.7	1	0.2
Other	6	1.3	4	0.2
Cataracts	3	0.7	8	1.8
Increased liver enzyme levels	2	0.4	2	0.5
Bone fractures	13	2.8	5	1.1
Osteoporotic	2	0.4	3	0.7