Table 1 Current data and ongoing trials focusing on metronomic chemotherapy in non-metastatic breast cancer (BC).
| Metronomic chemotherapy drug | Study | Phase setting | Number of patients | Study design | Results |
|---|---|---|---|---|---|
| Abbreviations: AE: adverse event, BC: breast cancer, DFS: disease-free survival, RFS: relapse-free survival, OS: overall survival, CTX: cyclophosphamide, MTX: methotrexate, CAPE: capecitabine, PLD: pegylated liposomal doxorubicin, UFT: tegafur-uracil | |||||
| Capecitabine (CAPE) | GBG GeparQuattro trial 21 | IIIneoadjuvant | 1 495 | 4 × EC (epirubicin 90 mg/m2 + cyclophosphamide 600 mg/m2 q3w), followed by one of three arms:1) 4 × docetaxel 100 mg/m2 q3w (EC-T)2) 4 × docetaxel 75 mg/m2 q3w + CAPE 900 mg/m2 bid days 1–14 q3w (EC-TX)3) 4 × docetaxel 75 mg/m2 q3w, followed by 4 × CAPE 900 mg/m2 bid days 1–14 q3w (EC-T-X) | Survival: No significant differences in DFS/OS or pathological complete response rate between arms |
| SYSUCC-001 (NCT01112826) | IIIadjuvant maintenance | Ongoing | Adjuvant therapy followed by one year of CAPE 650 mg/m2 bid vs. adjuvant therapy alone | Ongoing trial; no results yet available | |
| MACRO (NCT02012634) | IIIadjuvant maintenance | Ongoing | Adjuvant chemotherapy followed by one year of oral CAPE 900 mg/m2 bid days 1–14 q3w vs. no maintenance in triple-negative patients | Ongoing trial; no results yet available | |
| Alagizy et al. 2014 9 | IIadjuvant maintenance | 41 | One-arm trial: 500 mg CAPE twice daily for 6 months following adjuvant chemotherapy in patients with non-metastatic triple-negative BC | Survival: Estimated mean DFS42 months (median not reached); estimated meanOS44 months Toxicity: Therapy was well tolerated with no grade 2 toxicities | |
| Shawky et al. 2014 10 | IIadjuvant maintenance | 19 | One-arm trial: one year CAPE 650 mg/m2 bid after adjuvant chemotherapy | Survival: Median DFS42 months; median OS not reached after median follow-up of 30 months Toxicity: All patients completed one year of capecitabine, no dose reductions due to adverse events were required.5 %: grade 3/4 HFS; 5 %: grade 3 diarrhea | |
| Capecitabine/cyclophosphamide (CTX) | Masuda et al. 2014 14 | IIneoadjuvant | 40 | One-arm trial:12 × paclitaxel (80 mg/m2) weekly + CTX (50 mg daily) + CAPE (1 200 mg/m2 daily), followed by 4 × FEC q3w in triple-negative BC | Survival: pCR: 47.5 %; survival data not published yet Toxicity: Grade 3–4 adverse events included neutropenia (35 %), leukopenia (25 %), and HFS (8 %) |
| Cyclophosphamide | SWOG0012 19 | IIIneoadjuvant | 372 | Standard chemotherapy (5 × doxorubicin 60 mg/m2 + CTX 600 mg/m2 q3w) followed by paclitaxel weeklyvs.15 × doxorubicin 24 mg/m2 weekly + oral CTX (60 mg/m2 daily) followed by paclitaxel weekly in patients with locally advanced or inflammatory BC | Survival: pCR significantly higher after metronomic therapy in inflammatory BC (27.3 vs. 12.5 %), no differences in locally advanced BC; no significant differences in OS and DFS Toxicity: more grade 3/4 hematological AEs in the standard arm; more stomatitis/pharyngitis and HFS in the metronomic arm |
| Bottini et al. 2006 16 | IIrandomizedneoadjuvant | 114 | Letrozole (2.5 mg daily for 6 months) vs. letrozole + oral CTX (50 mg daily for 6 months) in elderly patients | Survival: ORR 72 % (letrozol mono) vs. 88 % (combination). The proportion of patients alive and disease-free after 2 years was 83.5 % in the combination group and 82.0 % in the letrozole mono group. No long-term survival data published yet. Toxicity: No interruptions/delays of treatment in the letrozole group. In the combination group one interruption of cyclophosphamide because of grade 3 cystitis, and one delay of cyclophosphamide because of grade 4 thrombocytopenia | |
| Cancello et al. 2015 18 | IIneoadjuvant | 34 | One-arm trial:4 × ECF (epirubicin/cisplatin/5-FU q3w, followed by 3 × paclitaxel 90 day 1, 8, and 15 q4w + oral CTX 50 mg daily for 12 weeks in triple-negative BC patients | Survival: pCR 56 %, PD 0 % Toxicity: Grade ≥ 3 hematologic AEs included leukopenia (9 %), neutropenia (38 %), anemia (3 %), nonhematologic Grade ≥ 3 AEs included only stomatitis (3 %) | |
| Dellapasqua et al. 2011 15 | IIneoadjuvant | 29 | One-arm trial:8 × PLD (20 mg/m2) q2w + oral CTX (50 mg daily) | Survival: PR 62 %, breast conserving surgery possible in 44 %; survival data not published yet Toxicity: no grade 4; 10 % grade 3 skin toxicity; 21 % HFS | |
| Cyclophosphamide/methotrexate (MTX) | IBCSG Trial 22-00 11, 26 | IIIadjuvant maintenance | 1 086 | One year of oral CTX (50 mg/d) and MTX (2.5 mg bid days 1 and 2 of every week) vs. no maintenance therapy after adjuvant chemotherapy | Survival: Metronomic maintenance chemotherapy reduced the risk of breast cancer recurrence by 16 % in ER/PR negative patients (statistically not significant); triple-negative and node positive patients had most benefit (statistically not significant); greater benefit from maintenance in patients with higher TILs score 13 Toxicity: 13.5 % of patients in maintenance arm reported grade 3 or 4 toxicity of any kind; 25 % of patients discontinued maintenance treatment because of adverse events |
| ABCDE trial (NCT00925652) | IIadjuvant maintenance | Ongoing | Randomized trial in HER2-negative patients with residual tumor after neoadjuvant chemotherapy: diet ± exercise ± daily oral CTX + MTX bid twice-weekly + bevacizumab q3w for 6 months (then q6w for 1.5 years) | Trial terminated due to slow accrual; no results yet available | |
| CASA-CM trial 24 | IIIadjuvant | 77 | Elderly patients with ER/PR-negative tumors not suitable for standard chemotherapy randomized to PLD 20 mg/m2 q2w vs. oral CTX 50 mg daily + MTX 5 mg twice a week for 16 weeks | Survival: 19 % of patients had a distant or local relapse (median follow-up 42 months); probability of event was similar at 3 years in both groups Toxicity: metronomic regimen was better tolerated than PLD (no interruptions in 83 vs. 68 %, respectively); grade 3 toxicity was observed in 51 % of PLD group and 34 % of metronomic group | |
| Nasr et al. 2015 12 | IIIadjuvant maintenance | 158 | Triple-negative BC stage II–III randomized to FEC/docetaxel (100 mg/m2)vs.FEC/docetaxel (80 mg/m2) + 3 × carboplatin AUC5 + oral metronomic maintenance (CTX 50 mg daily + MTX 5 mg twice a week for one year) | Survival: OS significantly better in the carboplatin/maintenance arm (37 vs. 29 months, p = 0.04) Toxicity: No grade 4 AEs during maintenance treatment; grade 3 AEs: increased transaminases 11 %, leuconeutropenia 2.8 %, anemia 1.5 % | |
| Cyclophosphamide/methotrexate/5-FU (CMF) | Cho et al. 2015 23 | retrospectiveadjuvant | 248 | A retrospective review of all consecutive BC patients treated with 6 months of adjuvant CMF (oral CTX 60 mg/m2 daily + i. v. MTX 15 mg/m2 weekly + 5-FU 300 mg/m2 weekly) as their sole chemotherapy between 2003 and 2013; all patients HER2-negative, 52 % node negative | Survival: RFS and OS at 5 years was 94.5 and 98 %, respectively (follow-up 67 months) Toxicity: 18 % grade 3 neutropenia, one death during therapy from pneumocystis pneumonia in a patient with previously undiagnosed AIDS |
| CMF/tegafur-uracil (UFT) | NSAS-BC01 and CUBC trial (pooled analysis) 27 | IIIadjuvant | 1 057 | Oral UFT(300 mg/m2 daily) for 2 years vs. 6 cycles of CMF | Survival: UFT was non-inferior to CMF in ER-positive patients |