CEA increase as a marker of disease progression after first-line induction therapy in metastatic colorectal cancer patients. A pooled analysis of TRIBE and TRIBE2 studies

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The upfront treatment of unresectable metastatic colorectal cancer (mCRC) usually involves a combination of chemotherapeutic agents (fluoropyrimidines, oxaliplatin and irinotecan) and monoclonal antibodies targeting angiogenesis pathway (bevacizumab) or, in tumours not bearing RAS mutations, epidermal growth factor receptor (EGFR; cetuximab and panitumumab). Usually, the period of combination therapy, named induction phase, is followed after 4-6 months by a maintenance treatment consisting of a fluoropyrimidine and a biological agent, or a treatment break[1].
During the treatment, disease is re-assessed by radiological imaging every 2 - 3 months. The radiological assessment allows monitoring response to systemic therapy, evaluating early tumour shrinkage and depth of response[2], parameters able to affect subsequent treatment choices including the possibility to perform locoregional treatments, as well as the choice to administer maintenance therapy or to recommend a treatment holiday. After the induction phase, no major improvement in tumour shrinkage is expected and the most relevant information with regard to disease assessment is the occurrence of disease progression (PD) or not. In this phase the availability of a simple and cheap serum marker able to predict disease control status would be useful to avoid unnecessary and relatively expensive imaging assessments. In this scenario, carcinoembryonic antigen (CEA) that is elevated in approximately two-thirds of mCRC and usually adopted to monitor response to systemic therapies together with radiological imaging, seems to be the best candidate to this purpose. However, evidence is not enough to routinely use CEA serum levels as an alternative to imaging and no specific data are available regarding the adoption of a threshold of CEA percent increase from nadir able to predict disease control after the end of the induction therapy[3].

In our analysis, we assessed the role of CEA in predicting PD after induction therapy in mCRC patients pooling data from two phase III randomised trials by Gruppo Oncologico del Nord Ovest, TRIBE[4] and TRIBE2[5], that compared FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) plus bevacizumab with FOLFIRI (5-fluorouracil, leucovorin and irinotecan) or FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) plus bevacizumab, as first-line treatment. In both studies, a maintenance therapy with 5-fluorouracil and bevacizumab was planned following the upfront combination therapy. The primary aim was to identify a threshold for percent increase in CEA from nadir able to predict PD and therefore to reduce the need of radiological imaging. Only patients with a baseline value of CEA ≥10ng/mL prior to the beginning of the induction treatment, not progressing during induction therapy, and with at least one paired radiological evaluation and CEA assessment after the end of the induction therapy were included in the present analysis. Overall, 1178 paired CEA and radiological assessments from 434 patients were analyzed. According to the optimal cut-off determined by ROC analysis, a CEA increase of at least 120% from nadir differentiated between PD and no-PD with a sensitivity of 74% and a specificity of 78%, excluding PD in the 92% of radiological assessments and allowing to avoid the 67% of imaging. Due to the low positive predictive value of 48%, the PD detected by CEA variation needs confirmation with a radiological assessment. The main limitation is that CEA cut-off of 120% was not able to detect PD in the 26% of cases. In order to mitigate this issue, a different clinically relevant threshold was evaluated based on the best sensitivity cut-off. Therefore, using any CEA increase from nadir as threshold, the sensitivity grew to 93% and only in the 7% of cases the radiological PD was not detected. However, the specificity decreased to 35% and radiological imaging could be avoided only in 29% of cases when adopting this criterion.

Waterfall plots of CEA variation from nadir showing observed and predicted disease control using a CEA cut-off of 120% (Panel A and B) and any CEA increase (Panel C and D)

Therefore, the threshold of 120% CEA increase from nadir could be used during follow-up in most patients not candidate to metastases resection after the end of induction chemotherapy thus sparing a relevant amount of radiological assessments. The adoption of any increase of CEA as cut-off should be especially evaluated when missing PD may cause immediate deterioration of patients’ conditions due to high risk of disease-related symptoms (i.e. liver failure due to multiple liver metastases, intestinal occlusion due to peritoneal carcinomatosis, uncontrolled pain due to pelvic relapse).

Waiting for novel tumour monitoring approaches, including circulating tumour DNA, currently under investigation, present data require confirmation before being translated into clinical practice.

 References

  1. Van Cutsem E, Cervantes A, Adam R et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016; 27(8):1386–1422.
  2. Heinemann V, Stintzing S, Modest DP et al. Early tumour shrinkage (ETS) and depth of response (DpR) in the treatment of patients with metastatic colorectal cancer (mCRC). Eur J Cancer 2015; 51(14):1927–1936.
  3. Locker GY, Hamilton S, Harris J et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 2006; 24(33):5313–5327.
  4. Loupakis F, Cremolini C, Masi G et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014; 371(17):1609–1618.
  5. Cremolini C, Antoniotti C, Rossini D et al. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 2020; 21(4):497–507.

Roberto Moretto

MD, Azienda Ospadaliero-Universitaria Pisana