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©The Author(s) 2017.
World J Clin Oncol. Dec 10, 2017; 8(6): 437-446
Published online Dec 10, 2017. doi: 10.5306/wjco.v8.i6.437
Published online Dec 10, 2017. doi: 10.5306/wjco.v8.i6.437
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 |
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 |
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% |
- Citation: Rabanal C, Ruiz R, Neciosup S, Gomez H. Metronomic chemotherapy for non-metastatic triple negative breast cancer: Selection is the key. World J Clin Oncol 2017; 8(6): 437-446
- URL: https://www.wjgnet.com/2218-4333/full/v8/i6/437.htm
- DOI: https://dx.doi.org/10.5306/wjco.v8.i6.437