Metronomic chemotherapy for non-metastatic triple negative breast cancer: Selection is the key

Table 3 Adjuvant metronomic chemotherapy in triple negative breast cancer

	Ref.	Study design	n	Regimens	Characteristics	Outcome	Adverse events
MTD plus MC	Nars et al[40] 2015	Phase III	: 158	Arm A:	Median age: 46 yr	Median DFS = 2	Arm A
			A: 78	Part 1 (3 cycles)	TNBC	Arm A: 28 mo	Neutropenia G3: 19%
				Day 1 5FU 500 mg/m2 PO	Stages II-III	Arm B: 24 mo	Neutropenia G4: 1.9%
				Day 1 E 100 mg/m2	Tumor size > 1.0 cm	P = 0.05	Febril neutropenia G3: 12%
				Day 1 CTX 500 mg/m2	Positive or negative axillary lymph nodes;		Nausea, vomiting G3: 12%
				Day 1-2 MTX 2.5 mg twice/d PO	ECOG < 2	OS :
				Part 2 (3 cycles)		Arm A: 37 mo
				Day 1 T 80 mg/m2		Arm B: 29 mo
				Day 1 Ca 5AUC		P = 0.04
				Followed by MC × 1 yr			Arm B:
				Daily CTX 50 mg/d PO			Neutropenia G3: 17%
			B: 80	Arm B:			Febril Neutropenia G3: 9%
				Part 1 (3 cycles)
				Day 1 5FU 500 mg/m2 PO
				Day 1 E 100 mg/m2
				Day 1 CTX 500 mg/m2
				Part 2 (3 cycles)
				Day 1 T 80 mg/m2
	FIN XX et al[41] 2011	Phase III	A: 753	Arm A :	Median age: 52 yr	DFS 5 yr (P = 0.087)	6 deaths related to treatment
				Part 1 - every 3 wk for 3 cycles	Luminal, TNBC, Her2	A: 86.6%	Arm A: 4 patients
				Day 1 T 60 mg/m2 IV	T1: 46%, T2: 47%	B: 84.1%	Arm B: 2 patients
				Day 1-15 X 900 mg/m2 twice/d PO	1-3 positive axillary nodes: 62%
				Followed	> 3 positive axillary nodes: 28%	Subgroup:	Discontinued treatment
				Part 2 -every 3 wk for 3 cycles	Grade 3: 42%	TNBC > 3 axillary nodes:	Arm A: 24%
				Day 1 CTX 600 mg/m2 IV	ER negative: 24%	HR, 0.64; 95%CI: 0.44 to 0.95	Arm B: 3%
				Day 1 E 75 mg/m2 IV	Her 2 +: 19%	(P = 0.027)
			B: 747	Day 1-15 X 900 mg/m2 twice/d PO
				Arm B:
				Part 1 ( every 3 wk x 3 cycles)
				Day 1 T 80 mg/m2 IV
				Part 2 ( every 3 wk x 3 cycles)
				Day 1 CTX 600 mg/m2 IV
				Day 1 E 75 mg/m2 IV
				Day 1 5FU 600 mg/m2 IV
Main- tenance	IBCSG Trial 22	Phase III	n: 1086	Arm A: (every week for 1 yr)	Median age: 51 yr	6.9 yr OS:	Arm A
	Oct. 2016[42]		A: 542	Daily CTX 50 mg/d PO	TNBS, Her 2	HR 0.84; 95%CI, 0.66 to 1.06; P = 0.14);	Grade 3-4 treatment related AE: 14% patients
				Day 1-2 MTX 2.5 mg twice/d PO on	Premenopausal: 45%	TNBC: (n = 814; HR = 0.80; 95%CI: 0.60 to 1.06)
					Node positive disease 42%		Hypertransaminasemia G3 G4: 7%
			B: 539	Arm B:	Her2 +: 19%, only 52% received trastuzumab	TNBC, node-positive disease: n = 340
				Observation	TNBC: 75%	HR = 0.72; (95%CI: 0.49 to 1.05)	Leukopenia G3-G4 : 2%
					Tumor > 2 cm: 54%
					Grade 3: 84%		2 patients with AML
					1-3 node +: 25%
					> 3 node +: 16%
					Prior anthracycline: 60%
					Prior anthracycline + taxane: 26.1%
	CREATE-X trial	Phase III	n: 455	Arm A: (every 3 wk for 8 cycles)	Luminal TBNC patients	5 yr DFS: (P = 0.00524).	Arm A:
	2015[43]			Day 1-14 X 1250 mg/m2 twice/d	Prior: Neoadyuvant no pCR or node positive	A: 74.1%	HFS G3: 10.9%
				Arm B:	Anthracycline and/or taxane: 80%	B: 67.7%
				Observation	5FU regimen: 60%	30% reduction in risk
					Six cycles completed: 58%
					Eight cycles completed: 38%	5 yr OS P < 0.01
						A: 89.2%
						B: 83.9%
Ongoing	CIBOMA/2004-01/GEICAM 2003-11 trial	Phase III	A: 207	Arm A: every 3 wk for 8 cycles	Median age: 51 yr	Ongoing	Arm A:
	2010[45]			Day 1–14 X 1000 mg/m2 per twice day PO	TNBC		HFS G3: 17.4%
			B: 193	Arm B:	Caucasian: 63.9%		Diarrhea: 2.9%
				Observation	Postmenopausal: 68.2%		Fatigue: 1.9%
					Basal phenotype: 82%
					Neoadjuvant: 9.7%
					Adjuvant: 86.4%
					Complete 8 cycles: 77.3%
	ECOG – ACRIN Cancer Research Group EA 1131 trial[46]	Phase III	Expected 562	Arm A: observation	TNBC	Ongoing	Ongoing
				Arm B: Carboplatin / Cisplatin day 1 IV every 3 wk for 4 cycles	Stage II-III
				Arm C: Capecitabine twice daily on days 1-14 every every 3 wk for 6 courses	Residual basal like disease after neoadjuvant chemotherapy

5FU: 5-Fluoracil; E: Epirubicin, Ca: Carboplatin; T: Docetaxel; CTX: Cyclophosphamide; MTX: Methotrexate; X: Capecitabine; AT: Anthracycline/taxane regimen; HFS: Hand-foot syndrome.