Circulating tumor DNA based adjuvant chemotherapy in stage II colon cancer patients: the MEDOCC-CrEATE trial

Colon cancer (CC) is worldwide a major cause of cancer related mortality.
Patients with early stage disease (stage I and II) have a good chance of
survival, however 15-20% of patients with stage II CC will experience disease
recurrence. Indication for adjuvant chemotherapy (ACT) in stage II CC is not
well established. Currently, only stage II patients with a pT4 lesion are
recommended to receive ACT, but this biomarker lacks sensitivity and
specificity. Circulating tumor DNA (ctDNA) is an emerging biomarker that
recently demonstrated strong prognostic value for disease recurrence in stage
II CC. Detection of ctDNA in the postoperative time period identifies patients
with the highest risk for disease recurrence. Therefore ctDNA-based adjuvant
treatment may lead to a decreased recurrence rate in stage II CC.

Primary objective: to investigate how many patients with detectable ctDNA after
surgery start with adjuvant chemotherapy
Secondary objective: to reduce recurrence rate by ctDNA based adjuvant
chemotherapy (ACT) in stage II colon cancer (CC) patients after primary tumor
resection.

The proposed study is conducted within the cohort study PLCRC and follows the
TwiCs design (i.e. a randomized controlled trial within a prospective cohort).
Within PLCRC, patients that gave informed consent for additional blood
withdrawals (at time of regular withdrawals) are participating in the
observational substudy PLCRC-MEDOCC. In this substudy, blood samples are
collected before and after surgery in stage II and stage III colon cancer
patients for future ctDNA analysis. Patients and doctors are not informed about
results in this observational trial. Patients with a histologically confirmed
stage II colon cancer that are not considered for adjuvant chemotherapy, will
be included in the MEDOCC-CrEATE study. Patients included in MEDOCC-CrEATE will
be randomized 1:1 to the intervention versus control group. Intervention group
: Patients will be asked informed consent (IC) for immediate testing of ctDNA
after surgery. Patients with detectable ctDNA (estimated proportion ~5%) are
considered high risk and will be offered ACT and can subsequently decide
whether they are willing to receive this adjuvant treatment with CAPOX. Control
group : Patients have given IC for randomization to a control group within
PLCRC and participate in PLCRC-MEDOCC. They will get the treatment and
follow-up according to current standard of care and will not get extra
information about this trial (no consequences for this group). At all follow-up
time points in the first 3 years after surgery, blood will be collected for
ctDNA analysis in the observational PLCRC-MEDOCC study. This analysis will be
performed after completion of accrual or during the trial with an interval of
at least 12 weeks after surgery.

Patients will be asked informed consent to immediately analyse their
post-surgery sample for ctDNA. Patients with detectable ctDNA are seen as high
risk and will be offered adjuvant chemotherapy.

Adjuvant chemotherapy is not part of the intervention, but preferably consists
of four 3-weekly cycles with capecitabine and oxaliplatin (CAPOX) for a total
treatment duration of 12 weeks (3 months).

Participation in the MEDOCC-CrEATE study (intervention group) will not pose a
risk to the majority of patients (no detectable ctDNA), but in the small group
(~5% of 660 patients in the intervention group, therefore ~30 patients) with
detectable ctDNA after surgery the expected high risk of disease recurrence
will be communicated by the treating physician and counselling will take place
about adjuvant chemotherapy. The combination chemotherapy schedule of a
fluoropyrimidine and oxaliplatin is part of the standard of care in the
adjuvant colon cancer setting since the beginning of this century. Therefore
the risks and toxicity of the used ACT are well-known. The majority of
side-effects are manageable and transient.
The risk of the withdrawal of extra tubes of blood during regular blood
withdrawal in all study participants is negligible.