Metronomic chemotherapy has been described as the chronic administration of low doses of chemotherapy agents without extended rest periods, most of them given orally. This modality of treatment has gained ground since 2002 after the first clinical trial conducted by Dr. Marco Colleoni in advanced breast cancer. The clinical benefit in many patients with no toxicity obtained and the very good cost effectiveness ratio, were amazing.
In this article published in the Journal of Clinical Oncology in June 2016, Colleoni et al present the results of a two arms, open label, randomised phase III trial, developed to evaluate the efficacy and safety of 12 months of metronomic cyclophosphamide plus methotrexate as maintenance after adjuvant treatment. Random assignment was 1:1. The experimental arm consisted of oral cyclophosphamide 50 mg/day continuously and oral methotrexate 2.5 mg twice/day, on days 1 and 2 of every week for 1 year. Primary treatment included: Total mastectomy with axillary clearance and optional radiotherapy, or a lesser procedure (quadrantectomy or lumpectomy) with required radiotherapy and either axillary lymph node dissection or sentinel lymph node biopsy. The eligible patients were those with any nodal status, T1-3 disease, or pT4 with minimal dermal invasion and no detectable metastatic disease; histologically proven ER-negative and progesterone–negative (<10% positive cells by immunohistochemistry) early breast cancer with any HER2 status. Adjuvant trastuzumab was administered according to national guidelines to patients with HER2-positive tumours.
The primary endpoint was DSF (defined as the time from random assignment to the first appearance of one of the following: invasive recurrence of breast cancer (local, regional, or distant), invasive contralateral breast cancer, second (non breast) invasive cancer, or death without recurrence or second invasive cancer; the secondary end point were breast cancer-free interval, distant recurrence-free interval, and overall survival.
This trial enrolled 1086 patients from 32 centres (n= 542 in the experimental arm; 539 in the observational arm). Overall, 458 patients (42%) had lymph node–positive disease; 204 (19%) had HER2-positive disease (106 [52%] of whom received trastuzumab); and 814 (75%) had Triple negative (TN) disease.
The results showed that after 7 years of follow up, there were non-significant differences in DFS for both groups. Moreover, the risk of relapse was not reduced. Even the TN subgroup (node negative and node positive) did not show significant differences in DFS.
Regarding the toxicity, 64 patients (14%) experienced grade 3 or 4 treatment-related adverse events (reversible elevated ALT in 7% and leukopenia in 2%). There were no occurrences of myelodysplasia.
This trial did not reach the primary endpoint, so we could consider it as a negative trial (with all the implications that the “negative” word has).
Personally I think that the inclusion of low risk patients was the main reason for the failure. Metronomic chemotherapy is an anti-angiogenic therapy, and the angiogenesis mechanisms are more expressed in larger tumours, with high duplication rate, and larger areas of hypoxia. Also, the inclusion of patients with HER2+ who received trastuzumab, is another factor that could have interfered in the results.
HER2 is the mainly driven pathway in HER2-positive tumours, and blocking this pathway is associated with a superior overall survival, and metronomic maintenance do not provide any benefit after adjuvant trastuzumab, based on that TN node positive subgroup analysis did showed potential risk reduction.
Last but not least, yes, this trial is a negative one. But that’s not the end of metronomic as a maintenance treatment; on the contrary, additional studies on maintenance approaches in high-risk patients with TN disease are highly encouraged. It is important to underline the good cost/effectiveness balance of this treatment modality, in a moment where “mabs” and “inibs” are filling the market of cancer treatment, some of them with really good results, many of them with questionable results, all of them extremely expensive.
Should metronomic chemotherapy as a maintenance strategy be explored further either in early stage breast cancer in general or in particular subtypes such as triple negative disease?
The author has no actual, potential, real or apparent interest to declare and has no involvement that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated.