Why MCT?
MCT involves frequent, repetitive oral administration of low-dose chemotherapeutic agents without prolonged breaks. Unlike high-dose chemotherapy, which relies on its direct antitumour effect, MCT exerts both direct and indirect actions, including immune modulation and angiogenesis inhibition. “Compared with traditional regimens, MCT may produce less dramatic but more sustained responses,” Cheung noted. [Oncol Res Treat 2022;45:12-17; Cancer Lett 2017:400:252-258]
“Because doses are significantly lower, MCT is associated with fewer side effects from dose accumulation, making it suitable for long-term use,” Cheung explained. “Cyclophosphamide, methotrexate, capecitabine, and vinorelbine are commonly prescribed alone or in combinations as MCT.”
“Candidates for MCT are typically patients without targetable mutations, who have failed second- or third-line treatments, are older, have comorbidities, or prefer not to have intravenous chemotherapy. MCT is often suitable for patients with HR+, HER2-, ET-resistant ABC, with or without prior use of CDK4/6 inhibitors, who do not require rapid tumour response and prioritize quality of life,” highlighted Cheung.
Single-agent metronomic vinorelbine: Efficacy and tolerability
The phase II TEMPO trial was the first randomized study evaluating single-agent metronomic vinorelbine (NVB) as first-line chemotherapy in HR+, HER2- ABC after ET. Patients (n=163) were randomized to receive NVB in metronomic (50 mg three times weekly) or weekly schedule (60 mg/m2 in cycle 1, increasing to 80 mg/m2 if well tolerated). [Breast 2024:74:103681]
Results demonstrated notable efficacy, with most adverse events (AEs) being mild or moderate (grade ≤2), and a trend favouring tolerability in the metronomic group. (Table)
“While the TEMPO study was noncomparative, single-agent oral NVB — whether in metronomic or weekly schedule — is effective and can be a viable first-line chemotherapy option following ET and CDK4/6 inhibitor failure,” Cheung remarked.
Multiagent metronomic regimen: Prolonged benefit, low toxicity
A study involving 67 patients with ABC, of whom 88 percent had HR+ and HER2-metastatic disease, found that NVB at 30 or 40 mg three times weekly, cyclophosphamide at 50 mg QD, and capecitabine at 500 mg TID achieved an objective response rate of 49 percent, with a median duration of response of 14 months after the first year. The estimated progression-free survival (PFS) rates at 3 and 4 years were 25.4 and 18.5 percent, respectively. [Anticancer Drugs 2022;33:e628-e634]
While 37 percent of patients required dose reductions, only 7 percent experienced grade 3 hand-foot syndrome, indicating manageable toxicity over prolonged treatment. “In practice, dose tailoring can optimize disease control while minimizing toxicity and maintaining quality of life,” Cheung noted.
Combining MCT with immunotherapy: Promising outlook
In a phase II clinical trial, 97 patients with metastatic HER2- ABC who had received ≤1 prior line of chemotherapy were randomized into five groups: 1) NVB monotherapy; 2) NVB plus toripalimab (immune checkpoint inhibitor); 3) NVB, bevacizumab plus toripalimab; 4) cisplatin, NVB and toripalimab; or 5) metronomic cyclophosphamide, capecitabine, NVB and toripalimab (VEX). [Nat Med 2024;30:2528-2539]
Disease control rates were highest in the VEX (69.7 percent) and cisplatin (73.7 percent) groups. Median PFS was longest in the VEX group (6.6 months), followed by the bevacizumab (4.0 months) and cisplatin (3.5 months) groups. All regimens were well tolerated, with nausea and neutropenia being the most common AEs.
“The findings suggest that metronomic VEX with immune checkpoint blockade holds promise as an effective future treatment for ABC,” Cheung commented.
