Replik

Dear colleague, thank you for your comments [1] regarding our article [2]. We totally agree that carcinoembryonic antigen (CEA) is frequently used, and its values are sometimes difficult to interpret. As you mentioned, the lack of normalisation of CEA after curative surgery is of great importance. Owing to its half-life of 3–5 days, we expect normalisation from 2 weeks to 1 month after curative surgery. If this is not the case, we actively search for metastasis and early relapse. This is of great value since adjuvant chemotherapy whenever indicated should be initiated within 4–8 weeks for patients with colon cancer. Delayed adjuvant chemotherapy, started after more than 8 weeks, is significantly associated with worse overall survival.

As mentioned, in clinical practice, we often encounter patients without recurrence for whom serum CEA levels do not become negative after surgery, as well as those whose ­serum CEA levels transiently increase after surgery and then subsequently decrease. Currently, determination of better cutoff values according to whether the serum CEA level is negative or positive before surgery would ­enhance diagnostic accuracy for the detection of recurrence during postoperative surveillance. On the other hand, an increase in the cutoff value (10 µg/l) may increase the specificity for detecting recurrence, but at the same time it would decrease the sensitivity. However, CEA needs to be seen as a triage test, where a rise should lead to further investigation rather than initiation of therapy, as it gives no information about the location and extent of recurrence.

We understand you raise the question on whether you can avoid unnecessary or potentially harmful therapies and misguided decisions in end-of-life care due to the lack of robust predictive biomarkers of benefit from conventional cytotoxic chemotherapy.

On the other hand, nowadays we do not treat colon cancer patients with chemotherapy only, we also provide personalised therapy with drugs that target the immune microenvironment, angiogenesis and activated pathways such as EGFR/HER2/BRAF family, resulting in >24 months increased median overall survival for patients with metastatic colo-rectal cancer.

Currently, there is great interest in a novel immunotherapy that redirects T cells independently of their T cell receptor specificity to ­tumour cells expressing the CEA glycoprotein at the cell (cibisatamab) and a phase I trial is ongoing (NCT03866239) [3, 4].