Clinical TrialOxaliplatin plus fluoropyrimidines as adjuvant therapy for colon cancer in older patients: A subgroup analysis from the TOSCA trial
Introduction
Colorectal cancer is one of the most diagnosed cancers in the world, regardless of the geographical area [1]. The increase in average life expectancy, due to improved eating habits and reduced mortality from heart disease, as well as other non–cancer-related causes, has resulted in a higher incidence of this tumour in the older patients, at about 5% in the seventh decade of life [2].
Nonetheless, older patients have always been largely underrepresented in randomised trials that have demonstrated the usefulness of adjuvant chemotherapy for stage III colon cancer (CC) [[3], [4], [5], [6]]. The consideration that older people constitute a largely heterogeneous population makes it even more difficult to interpret these data and transfer them to everyday practice.
Pooled analyses of 5-Fluorouracil (5-FU) reported improved recurrence-free survival and overall survival (OS) in the chemotherapy arm compared with surgery alone, and the benefit was the same in both younger (<70 years old) and older patients [p = 0.33 for time to tumour recurrence (TTR) and p = 0.61 for OS], with no significant differences in toxicity, excluding neutropenia [7].
Instead, there are conflicting data regarding the additional benefit of oxaliplatin in older patients with stage III CC. A pooled analysis of adjuvant chemotherapy (e.g., CAPOX/FOLFOX) reported disease-free survival (DFS) and OS benefits versus 5-FU in all age groups and in patients with comorbidities, although the efficacy was attenuated for those aged ≥ 70 [8]. Another analysis of the newer regimens from the ACCENT database showed that TTR, DFS and OS were not significantly better than 5-FU/LV in patients aged ≥70 years [9].
However, as a significant number of patients report neuropathy for years after the cessation of oxaliplatin chemotherapy, several studies have recently assessed whether its reduced administration over time (3 vs 6 months) could give the same benefits with diminished toxicity. Findings from the International Duration Evaluation of Adjuvant Chemotherapy pooled analysis of 12,834 patients with stage III CC, from six randomised trials (SCOT, PRODIGE, CALGB/SWOG C80702, TOSCA, HORG, and ACHIEVE), demonstrated that three months of therapy was non-inferior to six months in lower risk patients (T1-3 and N1), especially with CAPOX, whereas in patients with T4 and/or N2 disease, six months of chemotherapy was superior to three months [10].
The purpose of this study is to evaluate the effect of age (<70 vs ≥ 70 years old) on the efficacy of an adjuvant treatment with oxaliplatin and fluoropyrimidines in terms of TTR, DFS, OS, and cancer-specific survival (CSS) in the subgroup of patients with stage III CC and randomised in TOSCA [11].
Section snippets
Study population and objectives of the study
This is a post-hoc analysis of the TOSCA (clinicaltrials.gov NCT0064660), an open-label, phase III, multicentre, non-inferiority trial in which randomised patients with high-risk stage II or stage III CC received 3 or 6 months of FOLFOX-4/CAPOX adjuvant chemotherapy. The trial failed to demonstrate a formal non-inferiority of 3 months vs 6 months of treatment. TTR was defined as time between randomisation and disease recurrence. DFS was defined as the time between randomisation and disease
Results
Of 3614 patients from 127 centres included in the per-protocol population defined in the TOSCA trial, 2360 patients (1667 young and 693 older) from 124 centres were included in this analysis, whereas 1254 were excluded because they had stage II CC. Patient and tumour characteristics of young and older patients are summarised in Table 1. Statistically significant differences were found in terms of the ECOG PS equal to 1 [55 (3.3%) young and 73 (10.5%) older patients, p < 0.001] and of
Discussion
As far as we are aware, this is the first study to look at the relevance of patient age in relation to the efficacy of adjuvant chemotherapy, also as a function of its duration (3 or 6 months) and treatment (CAPOX or FOLFOX). Because the results were not affected by either the treatment arm or the type of chemotherapy, we therefore combined the two treatment duration arms and compared the overall outcome of therapy between older and younger patients. We found that older patients have a higher
Author contributions
G.R., S.L., M.D.B., M.R., M.G.Z., M.B., A.Z., F.P., D.F., V.M., A.M., L.C., C.C., P.B., D.A., A.M.B., L.F., D.C., D.B., A.D.S. and R.L. enrolled and followed up patients. G.R., S.L., M.G.Z., S.B., C.C., V.P., R.L. and S.K.G. analysed data. Fa.G., and Fr.G. performed statistical analysis. G.R., A.P. and Fr.G. wrote, edited and discussed the manuscript.
Funding
This work was supported by AIFA (Agenzia Italiana del Farmaco) [grant no. FARM5RWTWZ].
Conflict of interest statement
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.
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