Oxaliplatin-containing chemotherapy appears to be safe with manageable toxicities and to be effective in reducing recurrence rates in a large population of older patients with stage III colon cancer fit for inclusion into clinical trials. Considering the duration of chemotherapy, the same management guidelines would need to apply for this group of patients as for their younger counterparts.
An ACCENT/IDEA pooled analysis of 12 adjuvant trials including more than 17,000 patients is the largest study evaluating the tolerance and efficacy of adjuvant oxaliplatin-containing chemotherapy according to age in patients with stage III colon cancer; 24% of patients were age older than 70 years. Time to recurrence (TTR) may be a more appropriate endpoint for efficacy in this patient population according to Dr. Demetris Papamichael of the Department of Medical Oncology, Bank of Cyprus Oncology Centre in Nicosia, Cyprus and colleagues who published the findings on 28 March 2024 in the JCO.
The authors wrote in the background that the median age at diagnosis of colon cancer is around 70 years in western countries. However, this population has been underrepresented in the adjuvant trials as only 14-20% of patients enrolled in these studies were age >70 years. Whether there is a benefit conferred by the addition of oxaliplatin to fluoropyrimidine for patients older than 70 years with stage III colon cancer remains controversial. Final results of the ongoing ADAGE phase III trial dedicated to adjuvant chemotherapy in older patients are eagerly awaited.
Unlike previous studies which focused on the benefit or not of the addition of oxaliplatin in older patients, in the ACCENT/IDEA pooled analysis published in the JCO, the authors compared patient outcomes, toxicity patterns, and treatment adherence of oxaliplatin-based chemotherapy, between patients ≥70 and patients <70 years. They studied the prognostic impact of age, as well as treatment adherence/ toxicity patterns according to age, in patients with stage III colon cancer who received 3 or 6 months of FOLFOX4, mFOLFOX6 or CAPOX based on data collected from trials from the ACCENT and IDEA databases.
Associations between age and TTR, disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrolment.
TTR was defined as the time from random assignment to colon cancer recurrence; deaths without recurrence were censored at the time of death. DFS was defined as the time from random assignment to recurrence or death from any cause, whichever occurred first. Second primary colon cancers were not counted as events in the DFS and TTR analyses. OS was defined as the time from random assignment to death from any cause. SAR was defined as the time from the first documented recurrence to death from any cause. CSS was defined as the time interval between random assignment and cancer-related death.
A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhoea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% versus 11.2%; p = 0.01 and 12.1% versus 9.6%; p = 0.04).
In multivariable analysis, TTR was not significantly different between patients younger than 70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in patients ≥70 years. The relative dose intensity was somewhat inferior in the older age group with higher rates of early treatment discontinuation.
In this population, patients ≥70 years were more likely to have a poorer performance status, and their tumour was more frequently T4, localised in the proximal colon, and had a sporadic MSI-high phenotype with BRAFV600E consistent with other reports in the recent literature. Other prognostic factors were not statistically different according to age, such as risk-group or lymph-node ratio.
The proportion of patients treated with CAPOX was higher in patients ≥70 years, perhaps partly due to the higher inclusion rate of older patients in the more recent IDEA trials, whereas inclusion rate of these patients was particularly low in older trials that tested a targeted therapy in combination with FOLFOX because of more restrictive inclusion criteria, inducing heterogeneity among trials.
Regarding the efficacy of oxaliplatin-containing chemotherapy according to age, the authors observed no statistically significant difference for TTR between patients ≥70 years and those <70 years after adjusting for known prognostic factors or on the basis of duration of adjuvant chemotherapy. They concluded that oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate endpoint for efficacy in this patient population.
The study was previously presented at ESMO Annual Congress on 12 September 2022 in Paris, France.
It was supported in part by a special ESMO grant given to the ESMO/SIOG Cancer in the Elderly Working Group.
Reference
Gallois C, Shi Q, Pederson LD, et al. Oxaliplatin-Based Adjuvant Chemotherapy in Older Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 12 Trials. JCO; Published online 28 March 2024. DOI: https://doi.org/10.1200/JCO.23.0132