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

Table 1 Comparing maximum tolerated dose chemotherapy vs metronomic chemotherapy

	Maximum tolerated dose chemotherapy (conventional)	Metronomic chemotherapy
Dose	High doses	Low doses or biologic optimal doses
Administration	Administered at defined intervals (3 weekly, weekly) determined by the recovery of bone marrow	Dosing frequency is continuous (weekly, every other day, daily)
Plasma concentration	Rise and fall of the plasma concentration of the drug	Sustained plasma concentration of the drug
Target	Proliferating tumor cells	Endothelial cells in the growing vasculature of the tumor
Toxicity	Acute and cumulative toxicity is a concern	Acute toxicity is rare. Cumulative toxicity is unknown, except for etoposide (related to leukemia)

Table 2 Neoadjuvant metronomic chemotherapy in triple negative breast cancer

	Ref.	Type of study	n	Patient characteristic	Regimens	pCR	Adverse events
Only MC	Hildebrand et al[34]	Single arm phase II	18	TNBC, ≥ T2	Part 1 (12 wk)	47.60%	Neutropenia G3-G4: 62%
	2016			T4: 5 patients	Weekly DX 24 mg/m2 IV		Febrile neutropenia: 24%
				Node +: 12 patients	Daily CTX 60 mg/m2 PO
				EC II: 47.4%	Followed by Part 2 (12 wk)
				EC III: 28.6%	Weekly PTX 80 mg/m2 IV
					Weekly C 2AUC IV
	Tiley et al[35]	Single arm phase II	17	TNBC, T2-T4, N0-N1	Part 1 (12 wk)	46.60%	Thrombocytopenia G3: 5%
	2012			Median age: 45 yr (25-83) Inflammatory breast cancer: 3	Weekly DX 24 mg/m2 IV		Neutropenia G4: 29%
					Daily CTX 60 mg/m2 PO		Neuropathy G3: 5%
					Followed by Part 2 (12 wk)
					Weekly PTX 80 mg/m2 IV
					Weekly C 2AUC IV
	Ignatova et al[36]	Single arm phase II	40	TNBC cТ2-4, N2-3, M0	Part 1 (9 wk)	60%	Neutropenia G3-4: 22.2%
	2016			Median age: 50 yr (27-69)	Weekly PTX 60 mg/mm2 IV		Mucositis 8.3%
				Histologic grade 3: 33.3%	Weekly C 2AUC IV		Hand-foot syndrome G3: 5.6%
				Ki67 > 20%: 100%	Then followed by Part 2 (9 wk)
					Weekly DX 25 mg/m2 IV
					Daily CTX 50 mg bid PO
					Daily X 500 mg tid PO
Hybrid	Masuda et al[37]	Single arm phase II	40	ER < 10%, T2-T4, N0-N1	Part 1 ( 4 Cycles every 21 d)	47.50%	Neutropenia G3-4: 35%
	2014			Median age 52 yr (33-69)	Day 1, 7, 14 PTX 80 mg/m2 IV		Hand foot syndrome G3-4: 8%
				N1: 40%	Daily CTX 50 mg PO
				ER < 10%: 17.5%	Daily X 1200 mg PO
				EC I: 12.5%	Followed by Part 2 (4 Cycles every 21 d)
				EC II: 77.5%	Day 1 5-FU 500 mg/m2 IV
				EC IIIA: 10%	Day 1 E 100 mg/m2 IV
					Day 1 CTX 500 mg/m2 IV
	Cancello et al[38]	Single arm phase II	34	ER ≤ 10%, PR ≤ 10%, Her2-Median age: 45 yr (31-64)	Part 1 (4 cycles every 21 d)	56%	Neutropenia G3-4: 38%
	2015			Premenopausal: 73%	Day 1 5-FU 200 mg/m2 per day continuous		Anemia G3-4: 3%
				EC II: 35%	Day 1, 2 E 25 mg/m2 IV
				EC III: 67%	Day 1, P 60 mg/m2 IV
				Histologic grade 3: 82%	Followed by Part 2 (three cycles every 28 d)
					Day 1, 7, 14 PTX 90 mg/m2
					Daily CTX 50 mg/d

EC: Clinical stage; ER: Estrogen receptor; DX: Doxorubicin; CTX: Cyclophosphamide; PTX: Paclitaxel; C: Carboplatin; X: Capecitabine; 5-FU: 5-fluoracil; E: Epirubicin; P: Cisplatin; pCR: Pathologic response; TNBC: Triple negative breast cancer; MC: Metronomic chemotherapy.

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.

Table 4 Maintenance for triple negative breast cancer

	IBCSG Trial 22, Oct. 2016	CREATE-X trial, 2015
Study design	Phase III	Phase III
Accrual time	2000-2012	2007-2012
Number of patients	N: 1086 CM: 542 Obs: 539	N: 910 X: 455 Obs: 455
Setting	Prior adjuvant ± RT	Prior neoadyuvant ± RT
Study population	TNBC: 75% HER2+: 19%	Luminal or TNBC No pCR o node positive
Previous treatment	A + CMF: 60% CMF: 16% AT sequential + CMF: 26% H: 59% (of HER2+)	A: 4.1% AT sequential: 81% AT concurrently: 13.6% TC: 5%
Study treatment	C 50 mg/d PO Daily M 2.5 mg bid PO Days 1-2 vs Observation	X 1250 mg/m2 twice/d PO Day 1-14 Observation
Time of treatment	Every week for 1 yr	Every 3 wk for 8 cycles (6 mo)
DFS	5 yr DFS: CM: 78.1% Obs: 74% HR = 0.84 (95%CI: 0.66 to 1.06; P = 0.14) TNBC: n = 814; HR = 0.80; 95%CI: 0.60-1.06 TNBC, node-positive disease: n = 340; HR = 0.72; 95%CI: 0.49-1.05	5 yr DFS: X: 74.1% Obs: 67.7% HR (95%CI): 0.70 (0.53-0.93); P = 0.00524 30% reduction in risk
OS	No results	5 yr OS X: 89.2% Obs: 83.9%, P < 0.01
Adverse events	Hipertransaminasemia G3-G4: 7% Leukopenia: 2%	X: HFS G3: 10.9% Neutropenia G3: 6.6% Diarrhea G3: 3% Obs: Neutropenia 1.6% Diarrhea: 0.4%

C: Cyclophosmide; M: Methotrexate; X: Capecitabine; ER: Estrogen receptor; PR: Progesterone receptor; A: Anthracycline; F: 5Fluoracil; T: Taxane; TNBC: Triple negative breast cancer; H: Herceptin.