Table 1 Current data and ongoing trials focusing on metronomic chemotherapy in metastatic breast cancer.
| Chemotherapy drug | Study | Phase | Number of Patients | Study design | Results |
|---|---|---|---|---|---|
| Abbreviations: AE: adverse event, PFS: progression-free survival, OS: overall survival, TTP: time to progression, CBR: clinical benefit rate, CR: complete response, PR: partial response, SD: stable disease, ORR: overall response rate, CTX: cyclophosphamide, MTX: methotrexate, CAPE: capecitabine, NPLD: non-pegylated liposomal doxorubicin | |||||
| Capecitabine (CAPE) | Stockler et al. 12 | III | 323 | Standard intermittent CAPE (1 000 mg/m2 bid days 1–14 q3w, dose escalation to 1 250 mg/m2 possible)vs.continuous metronomic CAPE (650 mg/m2 bid)vs.classical CMF (oral CTX 100 mg/m2 daily days 1–14 + MTX 40 mg/m2 + 5-FU 600 mg/m2 day 1 and 8 q4w) as first-line treatment in MBC patients unsuitable for more aggressive regimens | Survival: OS significantly longer in CAPE-group than CMF-arm (22 vs. 18 months). No difference between standard and metronomic CAPE with regard to OS/PFS Toxicity: significantly more serious AEs in CMF than CAPE (35 vs. 21 %). Toxicity similar in both CAPE arms. |
| Saura et al. 2014 32 | I/II | 72 | Oral neratinib 240 mg daily + CAPE 1 500 mg/m2 daily in trastuzumab-pretreated HER2-positive MBC | Survival: ORR 64 % in patients with no prior lapatinib exposure and 57 % in patients previously treated with lapatinib, median PFS 40.3 and 35.9 weeks, respectively Toxicity: diarrhea (88 %), hand-foot syndrome (48 %) | |
| Ozdemir et al. 2013 19 | II | 64 | CAPE (1 000 mg/m2 days 1–14) + cisplatin (60 mg/m2) q3w, followed by CAPE maintenance therapy in patients with HER2-negative MBC pretreated with anthracycline and taxane | Survival: median TTP 7 months, median OS 17 months Toxicity: The most frequent grade 3–4 events were neutropenia (8 %), nausea/vomiting (8 %) and thrombocytopenia (6 %). | |
| Fedele et al. 2012 44 | II | 60 | Continuous CAPE monotherapy 1 500 mg daily in heavily pretreated patients | Survival: median TTP 7 months, median OS 17 months Toxicity: Grade 3–4 uncommon; haematologic toxicity 5 % | |
| Schwartzberg et al. 2014 36 | II | 41 | Oral CAPE 1 500 or 2 000 mg daily + fulvestrant in pretreated hormone receptor positive HER-negative patients | Survival: median PFS 15 months, median TTP 27 months, median OS 29 months, CBR 58 % Toxicity: Hand-foot-syndrome was the most common AE (grade 3: 7 %, grade 4: 0 %), discontinuation due to AE: 5 %. | |
| Taguchi et al. 2010 45 | II | 33 | Oral CAPE 825 mg/m2 bid days 1–21 q4w as first-line chemotherapy | Survival: response rate 18 %, SD for ≥ 6 months 24 %, median PFS 6.9 months, median OS 24.8 months Toxicity: The only grade 3 AEs were neutropenia (6 %) and hand-foot syndrome (15 %). | |
| CAMELLIA (NCT01917279) | III | Ongoing | Maintenance therapy with oral CAPE: metronomic schedule (500 mg/m2 three times daily without interruptions) vs. standard schedule (1 000 mg/m2 bid days 1–14 q3w) after first-line CAPE + docetaxel chemotherapy in HER2-negative metastatic BC | Ongoing trial; no results yet available | |
| Capecitabine/Taxane | KBCSG-0609 trial 46 | II | 43 | Oral CAPE (828 mg/m2 bid days 1–21) + paclitaxel (80 mg/m2 i. v. days 1, 8, 15) q4w as first- or second-line chemotherapy | Survival: ORR 46.5 %, PFS 8.3 months, OS 22.9 months Toxicity: the most frequent grade 3/4 AE was neutropenia (28 %), leukopenia (12 %), hand-foot syndrome (9 %) and fatigue (7 %) |
| BOOG 2006–06 trial 11 (EUDRA-CT 2006–006058-83) | II Randomized | 312 | 6 × paclitaxel (90 mg/m2) days 1, 8, and 15 + bevacizumab (10 mg/kg) days 1 and 15 q4w, followed by bevacizumab (15 mg/kg) q3wvs.8 × paclitaxel (90 mg/m2) days 1, 8 + bevacizumab (15 mg/kg) + oral CAPE (825 mg/m2 bid days 1–14) q3w, followed by bevacizumab + CAPE q3w in HER2-negative metastatic or locally recurrent BC | Survival: PFS significantly longer in the CAPE arm (11.2 vs. 8.4 months); higher ORR (69 vs. 51 %; p = 0.01) and longer duration of response (6.8 vs. 5.4 months) in the CAPE arm; no difference in OS (24.2 vs. 23.1 months) Toxicity: increased rate of grade 3–4 AEs in the CAPE arm (HFS: 34 vs. 0 % and neutropenia: 20 vs. 12 %) | |
| CHAT trial 13 | II Randomized | 222 | Trastuzumab + docetaxel (100 mg/m2) q3wvs.trastuzumab + docetaxel (75 mg/m2) + CAPE (950 mg/m2 bid days 1–14) q3w as first-line therapy in HER2-positive MBC | Survival: PFS significantly longer in CAPE arm (17.9 vs. 12.8 months); 2-year-survival higher in CAPE arm (75 vs. 66 %), OS data not mature yet Toxicity: higher in CAPE arm (febrile neutropenia: 27 vs. 15 %; grade 3/4 neutropenia: 77 vs. 54 %; grade 3 HFS: 17 vs. 1 %; grade 3/4 diarrhea: 11 vs. 4 %) | |
| Mavroudis et al. 2009 14 | III | 272 | Docetaxel (75 mg/m2) + epirubicin (75 mg/m2) q3wvs.docetaxel (75 mg/m2) + CAPE (950 mg/m2 bid days 1–14) q3w as first-line therapy | Survival: similar in both arms (median TTP 11 months) Toxicity: more hematological toxicity in epirubicin arm, more HFS in CAPE arm | |
| Young et al. 2012 43 | II | 47 | Docetaxel (15 mg/m2 weekly) + oral CAPE (1 250 mg/m2 daily) + oral celecoxib (200 mg bid) | Survival: CBR 42 %, median TTP 3.6 months | |
| Cyclophosphamide (CTX)/Methotrexate (MTX) | Colleoni et al. 2006 27 | IIRandomized | 171 | Two arms: oral CTX (50 mg daily) and MTX (5 mg twice-weekly) ± thalidomide 200 mg daily | Survival: addition of thalidomide did not improve response rate Toxicity: mild; higher neurological toxicity (2 vs. 60 %; p < 0.0001) and constipation (8 vs. 51 %; p < 0.0001) in thalidomide arm |
| Colleoni et al. 2002 47 | II | 63 | Oral CTX (50 mg daily) + MTX (5 mg twice-weekly) | Survival: CBR 32 %, CR 3 % Toxicity: low except for elevation of liver transaminases and 2 % grade ≥ 3 leukopenia | |
| Miscoria et al. 2012 48 | II | 62 | Oral CTX + MTX in pretreated advanced BC patients | Survival: median OS 7.1 months, median PFS 2.6 months | |
| Gebbia et al. 2012 49 | Retrospective | 61 | Oral CTX 50 mg daily ± MTX 2.5 mg twice a week as second or third line of chemotherapy in endocrine therapy resistant metastatic patients | Survival: TTP 5.2 months in CTX arm, 6.2 months in the combination arm; median OS 12.8 and 14 months, respectively Toxicity: both regimens well tolerated | |
| Salem et al. 2008 50 | II | 42 | Oral CTX (50 mg daily) + MTX (5 mg twice-weekly) in heavily pretreated patients (≥ 2 lines of prior chemotherapy) | Survival: CBR 31 %, PR 17 %, CR 0 % Toxicity: mild; the most common non-hematological toxicity was elevation in transaminases level (40 %); the only grade 4 AE was neutropenia (2.4 %) | |
| Wong et al. 2010 51 | I/II | 41 | Daily dalteparin and oral CTX (50 mg daily), MTX (5 mg twice-weekly), and daily prednisone (5 mg) | Survival: OS 48 weeks, TTP 10 weeks Toxicity: minimal, transient grade 3 elevation of liver transaminases: 27 %, grade 3 vomiting: 2 % | |
| Aurilio et al. 2012 37 | Retrospective | 32 | Oral CTX 50 mg daily + MTX 5 mg twice-weekly + fulvestrant 250 mg q4w | Survival: CBR 56 %, OS 44 months | |
| Mayer et al. 2012 28 | I | 23 | Oral CTX 50 mg daily + MTX 5 mg once/twice-weekly + vandetanib daily in 3 dose-escalation cohorts | Survival: PR 10 %, SD ≥ 24 weeks 15 % | |
| Orlando et al. 2006 31 | II | 22 | Oral CTX 50 mg daily + MTX 5 mg twice-weekly + trastuzumab 6 mg/m2 q3w | Survival: median TTP 6 months, CBR 46 % Toxicity: low, 23 % grade ≥ 2 liver toxicity, 14 % grade ≥ 2 leukopenia | |
| Garcia-Saenz et al. 2008 21 | II | 22 | Oral CTX (50 mg daily) + MTX (1 mg/kg i. v. q2w) + bevacizumab 10 mg/kg i. v. q2w in pretreated BC | Survival: CBR 64 %, CR 0 %, PR 32 %, median PFS 7.5 months, median OS 13.6 months | |
| Soriano et al. 2011 41 | II | 21 | Oral CTX (50 mg daily) + MTX (5 mg twice-weekly) + five bi-weekly vaccinations (aluminum hydroxide-precipitated 1E10 anti-idiotype Mab), followed by reimmunizations q4w in pretreated BC | Survival: median TTP 10 months, median OS 13 months Toxicity: no grade 4 AEs, one grade 3 AE (nausea/vomiting: 5 %) | |
| Cyclophosphamide | Licchetta et al. 2010 38 | II | 29 | Oral CTX (50 mg day 1–21 q28) + fractionated megestrol acetate (80 mg bid) in pretreated postmenopausal patients | Survival: ORR 31 %, disease control rate 41 %, mean TTP 7.4 months, mean OS13.4 months Toxicity: mild |
| Perroud et al. 2013 52 | II | 15 | Oral CTX 50 mg daily + celecoxib 400 mg daily | Survival: overall clinical benefit rate 47 %, median TTP 14 weeks, 1-year-OS 47 % Toxicity: low: gastric grade 1 and hematological grade 1/2, no grade 3/4 | |
| Cyclophosphamide/Thiotepa/Carboplatin | Wang et al. 2015 42 | II | 23 | CTX (3 g/m2) + thiotepa (150 mg/m2) + carboplatin (AUC6) q4w, followed by immunotherapy (3 infusions of DC-CIKs) and maintenance chemotherapy with oral CTX 50 mg daily in triple-neg. pretreated metastatic BC | Survival: PR 13 %, SD 56 %, PD 30 %, median PFS 13.5 months, median OS 15.2 months Toxicity: The most common serious AEs were neutropenia (100 %) and anemia (70 %), no treatment-related deaths. |
| Cyclophosphamide/5-FU/Vincristine/NPLD | Manso et al. 2013 53 | Retrospective | 84 | Oral CTX 50 mg daily + prednisone 20 mg daily + i. v. weekly NPLD 30 mg + 5-FU 500 mg + vincristine 0.25 mg | Survival: median 8.4 months, median OS 21 months Toxicity: most common grade 2–3 hematologic AE: neutropenia (56 %), non-hematologic AE: asthenia (71 %) and mucositis (31 %); asymptomatic decline of the left ventricular EF in 4 % |
| Cyclophosphamide/Capecitabine | SAKK 24/09 15 | III | 147 | Bevacizumab + paclitaxelvs.bevacizumab + metronomic oral CTX (50 mg daily) and CAPE (3 × 500 mg/d) as first-line therapy in HER2-negative advanced BC | Survival: no significant differences between treatment arms Toxicity: Less hair loss in metronomic arm was the only clinically and statistically significant difference. |
| Wang et al. 2012 54 | II | 68 | Oral metronomic CTX 65 mg/m2 days 1–14 + CAPE 1 000 mg/m2 bid days 1–14 q3w in anthracycline/taxane-pretreated patients | Survival: median PFS 5.2 months, OS 16.9 months, overall response rate 30 % Toxicity: hand foot syndrome grade 3: 4.4 %, anorexia grade 3/4: 7.5 % | |
| Yoshimoto et al. 2012 55 | II | 51 | Oral CAPE 828 mg/m2 bid + CTX 33 mg/m2 bid days 1–14 q3w in HER2-negative patients | Survival: median PFS 12.3 months, 1- and 2-year OS rates 86 and 71 %, respectively Toxicity: grade 3 leukopenia 26 %, neutropenia 16 %, no grade 3 hand-foot syndrome | |
| Dellapasqua et al. 2008 22 | II | 46 | Oral CAPE 1 500 mg daily + CTX 50 mg daily + i. v. bevacizumab 10 mg/kg q2w | Survival: overall response rate (CR+PR) of 48 %; median TTP 42 weeks Toxicity: mild, grade 3 or 4 toxicity included hypertension (17 %), leukopenia (4 %), neutropenia (4 %), transaminitis (4 %), proteinuria (2 %), nausea (2 %), vomiting (2 %) | |
| Montagna et al. 2012 24 | II | 24 | Oral CAPE 1 500 mg daily + CTX 50 mg daily + i. v. bevacizumab 15 mg/kg q3w + erlotinib 100 mg daily | Survival: CR 4 %, 58 % PR, overall clinical benefit rate 75 %, median TTP 43 weeks Toxicity: grade 3 AEs: diarrhea (4 %), thrombosis (4 %), hypertension (8 %) | |
| Cyclophosphamide/Capecitabine/Vinorelbine | VEX trial (EUDRA-CT 2010–024266-21) | II | Ongoing | Oral CTX + CAPE + VIN | Ongoing trial; no results yet available |
| Saridaki et al. 2012 56 | I | 36 | Escalated doses of oral VIN (starting dose 30 mg) every other day + capecitabine (starting dose 800 mg/m2 bid) days 1–14 q3w | Survival: CR 5.5 %, PR 28 % Toxicity: Main AEs were grade 2–3 neutropenia (17 %), grade 2–3 anemia (16 %), grade 2–4 fatigue (28 %), grade 2–3 nausea/vomiting (11 %), and grade 3–4 diarrhea (8 %), no treatment-related deaths; the recommended MTD doses were VIN 60 mg and capecitabine 1 250 mg/m2. | |
| VICTOR-1 trial 57 | I–II | 12 (phase I), 22 (phase II) | Oral CAPE 1 500 mg daily + VIN 20–40 mg thrice a week | Survival: CBR 58 % Toxicity: The maximum tolerated dose of VIN in phase I was 40 mg thrice a week; grade 3–4 toxicity in 6 % of patients (mostly hematological with spontaneous recovery, one case of grade 3 neuropathy and one case of grade 3 hand-foot-syndrome). | |
| Vinorelbine | Addeo et al. 2010 58 | II | 34 | Oral VIN (70 mg/m2) days 1, 3, 5, for 3 weeks on and 1 week off, q4w, for a maximum of 12 cycles as first-line therapy in elderly patients | Survival: PFS 8 months, OS 16 months, 6 % CR, 32 % PR |
| De Iuliis et al. 2015 59 | II | 32 | Oral VIN 30 mg one day on and one day off without interruptions until progression or unacceptable toxicity in elderly patients | Survival: clinical benefit 50 % Toxicity: no grade 3/4 toxicities | |
| Saloustros et al. 2011 25 | II | 13 | Oral VIN (50 mg thrice weekly) + bevacizumab (10 mg/kg) biweekly in pretreated patients | Survival: PR 8 %, SD 46 %, the study was closed prematurely due to lack of efficacy | |
| Tempo Breast-1 trial (EudraCT 2014-003860-19) 60 | IIRandomized | Ongoing | Oral metronomic VIN (50 mg thrice weekly)vs.Oral weekly VIN (60 mg/m2 weekly, increased to 80 mg/m2 from the second cycle) as first-line chemotherapy in hormone receptor positive HER2-negative patients | Ongoing trial; no results yet available | |
| Vinorelbine/Temozolomide | Addeo et al. 2012 61 | II | 36 | Oral temozolomide (75 mg/m2) + whole-brain radiotherapy, followed by 4 weeks off-therapy, followed by oral VIN (70 mg/m2 thrice weekly) for 3 weeks + temozolomide (75 mg/m2 days 1–21 q4w) for 12 additional cycles in patients with newly diagnosed brain metastasis | Survival: CR 8 %, PR 44 %, median PFS 8 months, median OS 11 months |
| Irinotecan/Tegafur-gimeracil-oteracil potassium | Otsuka et al. 2015 62 | II | 34 | Irinotecan (60 mg/m2 on days 1, 8, and 15 q4w + TS-1 80 mg/m2 orally on days 3–7, 10–14, and 17–21 every 4 weeks in patients with metastatic or recurrent BC | Survival: response rate: 47 %, median PFS 14 months, median OS 26 months Toxicity: grade 3 or 4: neutropenia (15 %), leukopenia (12 %), diarrhea (8 %), and anemia (2 %) |
| 5-FU/Eniluracil | Smith et al. 2000 63 | II | 33 | Oral 5-FU 1 mg/m2 bid + eniluracil 10 mg/m2 bid days 1–28, q35 d as first-line chemotherapy | Survival: partial response in 55 % patients, median response duration 14 months Toxicity: Toxicity-associated delay and dose reduction occurred in 2 and 5 % of courses. |