The background is that in metastatic colorectal cancer the prognostic impact of relative dose intensity
of chemotherapy is well known but in localised colon cancer early treatment discontinuation, or ETD,
has been reported in about 30% of patients with a prescription of six months of chemotherapy. But the
prognostic impact of ETD in localised colon cancer isn’t clear. In addition, this data is coming from
retrospective study, not derived from therapeutic trials, and included elderly patients or patients
treated with fluoropyrimidine alone before 2006.

In addition, in these patients we may need to stop oxaliplatin early, mainly due to neuropathy. The
prognostic impact of the relative dose intensity of oxaliplatin is also unclear – we have very few data
on this. So we need more robust data of the prognostic impact of early treatment discontinuation and
early oxaliplatin discontinuation while continuing fluoropyrimidine.

What was the methodology used in this study?

It is a pooled analysis of eleven adjuvant trials from the ACCENT and IDEA databases. The patients
included were patients with stage 3 colon cancer and treated with FOLFOX or CAPOX for six months.
The patients treated with fluoropyrimidine alone or targeted therapy with a duration of chemotherapy
of three months or who stopped chemotherapy due to recurrence were excluded from the analysis.

We defined early treatment discontinuation, or ETD, as a complete stop of all adjuvant
chemotherapies if our patients had received 75% of cycles of chemotherapy, so a maximum of nine
cycles for the FOLFOX regimen and a maximum of six cycles for the CAPOX regimen. In the same
way we defined early oxaliplatin discontinuation, or EOD, as a discontinuation of oxaliplatin only while
continuing fluoropyrimidine before patients had received 75% of oxaliplatin cycles, so a maximum of
nine cycles of oxaliplatin for FOLFOX and a maximum of six cycles of oxaliplatin for CAPOX.

What were the key findings?

For the baseline characteristics, ETD and EOD were associated with female gender, performance
status more than 0, older age, CAPOX regimen and only for ETD with malnutrition defined by BMI.

For the prognostic impact of early treatment discontinuation we found in a multivariate analysis by
adjusting on age, gender, year of enrolment, TNM stage, that ETD was impacting DFS with a three-
year DFS rate of 69% for ETD patients compared to 79% for no ETD patients which is highly
significant. We observed the same results for overall survival. According to risk group and regimen in
subgroup analyses, we observed the same results except for patients treated with CAPOX and with
low risk tumours without significant difference for DFS and OS between ETD and no ETD patients.

For the prognostic impact of early oxaliplatin only discontinuation, by contrast, we found that DFS and
OS were not significantly different between EOD and no EOD patients. We observed the same results
in subgroup analyses according to regimen and risk group. Interestingly, when dividing the population
according to the number of cycles of oxaliplatin received, we found that in patients receiving 100% of
oxaliplatin cycles and in patients receiving at least 50% of oxaliplatin cycles we see no difference for
DFS. Conversely, receiving less than 50% of oxaliplatin cycles was associated with a worse DFS.

How can these results impact the future treatment of colon cancer?

With these results we can say that in patients receiving six months’ adjuvant regimen for stage 3
colon cancer chosen in MTD, maintaining the planned number of cycles of chemotherapy is very
important. If grade 2+ neuropathy occurs at any time point we have to stop oxaliplatin according to
good clinical practice but after three months of treatment if the patient has grade 1 or 2 neuropathy stopping oxaliplatin is likely a valid option, so after three months of both drugs, in order to avoid long-
lasting neuropathy and improve the quality of life of our patients.