Adjuvant Chemotherapy May Be Manageable in the Elderly and Frail Colon Adenocarcinoma Population

Despite the notion that patients aged 70 years or older with colon adenocarcinoma cannot tolerate standard chemotherapy, the ADAGE study has shown that in both young and older patients, the use of adjuvant chemotherapy is manageable.

In ADAGE (NCT02355379), 491 patients with colon adenocarcinoma were enrolled and of those patients, 378 were 70 years or older but considered fit for chemotherapy (group 1), and the remaining 113 patients were deemed frail (group 2). Males made up 57% of the fit cohort and 59% of the frail cohort, and the median age in each group respectively was 76years and 83 years. The majority of patients in both groups had an ECOG performance status of 0.

Toxicity was available from 434 patients. Among those in group 1 who received either fluorouracil (5-FU) capecitabine, the most common adverse events (AEs) were grade 1/2 asthenia occurring in 59% of patients and diarrhea occurring in 42%. Those treated with the combination of folinic acid leucovorin, 5-FU, and oxaliplatin (FOLFOX) most commonly experienced grade 1/2 neurologic AEs (87%) followed by grade 1/2 asthenia in 64%.

Finally, of the patients who received 5-FU or capecitabine in group 2 (n = 30), the most common grade 1/2 AE was asthenia (49%) followed by diarrhea in 40%.

In an interview with Targeted Oncology™, Thomas Aparico of l’hôpital Saint Louis à Paris, challenged the question of whether elderly and frail patients can tolerate chemotherapy in the adjuvant setting and noted the importance of their inclusion in future clinical trials.

TARGETED ONCOLOGY ™: Can you discuss the efficacy observed with oxaliplatin-based adjuvant chemotherapy in colon adenocarcinoma?

Aparico: Oxaliplatin is a standard treatment in the adjuvant treatment of colon adenocarcinoma stage 3, and some stage 2. But we have some concerns about the efficacy and tolerance of oxaliplatin in older patients. That's the reason that we launched this randomized trial phase 3 trial to assess the efficacy and tolerance of oxaliplatin in patients over 70.

What exactly is the debate about the use of this therapy in older patients with colon adenocarcinoma?

The premise that we observed is that oxaliplatin is more toxic, and in the previous trial that we performed in small subsets of young and older patients, we didn't find any benefit of intensifying the chemotherapy. That's why we want to perform a specific trial for all the patients to eventually find the subgroup of patients that would benefit from oxaliplatin and the other subgroup that won’t benefit from oxaliplatin.

Can you provide a detailed description of the patient population being evaluated?

We had 2 distinct groups of patients, because older patients could be fit and really have a good tolerance of chemotherapy and some other older patients are unfit, and so it's more difficult to treat them. We randomized these patients to 5-FU or capecitabine-based adjuvant chemotherapy, which is the known standard after resection of current cancer. In one arm there is monotherapy of 5-FU and in the second arm, it’s oxaliplatin 5-FU or capecitabine. These patients are in group 1 and we have our main end point is survival without progression. Also, in group 1, we have a plan to enroll 756 patients and we currently have more than half of the patients enrolled.

In the second part of the study, we enroll patients that are unfit for chemotherapy. So, in these frail patients, the question is should we have not performed chemotherapy. So, randomization is about the observational value for selection. We expect that the difference that we observe between these 2 arms will be greater than the oxaliplatin versus5-FU, so there are a number of patients we will enroll will be lower. We are planning to enroll 226 patients.

What is important to note about the results that have been reported to date?

The purpose of my ESMO presentation was to share a preliminary analysis of tolerance on chemotherapy in both groups from the trial.

The first point I’ll make about the results is that we have more capecitabine given to the patient in group 2 because as a monotherapy, it is easier to give capsules that don’t need perfusion. The second point is that there was an early stoppage of treatment more frequently in group 2 than group 1. So, in the frailer patients, 38% of patients stopped adjuvant treatment earl compared with 17% of the patients in group 1.

Relating to toxicity, which was the main aim of this presentation, we observed that in all toxicity or serious adverse events related to treatment, the rate is quite low at around 10% in both groups. But there is a difference as we have naturally more neurologic toxicity in patients receiving oxaliplatin because it is the normal toxicity associated with these drugs. We have more accumulated grade 3 and 5 toxicities in patients receiving oxaliplatin. It's a 58% of cumulative grade 3 and 5 events.

This is not the final study analysis. We e can see that there is a bit more depth in group 2 in the observation arm. There are 9 patients that are in the observation arm, and there is less in the group that’s treated with oxaliplatin

So, in conclusion of the first preliminary analysis, the toxicity of adjuvant chemotherapy is manageable in both groups where we have more early treatment in group 2 than in group 1. We have submitted this result to an independent steering committee, that's a given for a little advice to pursue the end of the enrollment of the trial. So now we have more than 100 patients enrolled, and we expect to finish their enrollment at the end of 2022.

What should oncologists take away from this research?

In France, the recommendation is to treat patients only with 5-FU when the patient is older than 70. We are keeping these guidelines as we don’t have the full results of this trial.

I think that this trial shows that you can perform large trials on older patients. And this is very important because this population is important to treat. After all, it's a large number of patients and they are excluded of the registry trial. So, it's important to perform specific trials in this population to produce evidence-based medicine.

_Reference:

_{Aparicio T, Bouche O, Etienne PL, et al. 394P Preliminary tolerance analysis of adjuvant chemotherapy in older patients after resection of stage III colon adenocarcinoma from PRODIGE 34-FFCD 1402-ADAGE randomized phase III trial. Ann Oncol. 2021;32(5):535. doi: 10.1016/j.annonc.2021.08.916}