2022 ESMO Conference reported data on two clinical trials using biomarkers and imaging to guide treatment decisions and detect recurrence in patients with colorectal cancer (CRC), indicating that circulating tumor DNA (ctDNA) may have a place in patient follow-up. In the future, intensive imaging of CT scans may allow early detection of relapses in resection of phase II-III CRCh patients, resulting in more curative procedures.
·PRODIGE 13 Trial Reporter Professor Come Lepage·
II Phase II DYNAMIC study data provided after preliminary analysis showed that adjuvant chemotherapy was performed in patients with ctDNA-positive resection stage II CRC, while ctDNA-negative patients had an observational follow-up to reduce the use of adjuvant chemotherapy without affecting recurrence-free survival (N Engl J Med. 2022;386:2261–2272). The exploratory analysis presented at the 2022 ESMO Conference found that postoperative ctDNA analysis is more sensitive to predict distant recurrence than local recurrence (Abstract 318MO). It also shows that adjuvant chemotherapy can achieve ctDNA clearance and that this clearance is associated with positive results (2-year recurrence-free survival rate of 97%). Neither CEA levels after surgery nor chemotherapy increased the prognostic value of ctDNA-negative patients.
Figure 1 In the DYNAMIC study, exploratory analysis showed that ctDNA is more sensitive than local recurrence in predicting distant recurrence in patients with stage II colorectal cancer
Figure 2 Adjuvant chemotherapy can achieve ctDNA clearance, and is related to positive results. The second report of the final results of the
Phase III PRODIGE 13 trial showed that when observing the entire study population, intensive follow-up (CT scan and CEA) for resected phase II-III CRC patients lacks survival advantages. However, intensive follow-up of CT scans increased the cure rate of surgical treatment (LBA28). These findings confirm the results presented at the 2020 ESMO Conference (Ann Oncol. 2020;31(Suppl_4):S409–S461; Abstract 398O).
Figure 3 Intensive follow-up of patients with resection of stage II-III CRC did not improve the survival advantage
Professor Julien Taieb of the University of Descartes Paris, France commented on the data from both studies: "Adjuvant chemotherapy after CRC surgery can prevent recurrence and improve survival. However, it only improved the prognosis of about 20% of patients with stage III CRC, which means that 80% of patients experienced the associated toxicity but did not benefit. In stage II CRC, only about 5% of patients benefited from this treatment (Ann Oncol. 2020;31:1291–1305). Therefore, we need to distinguish patients at higher risk of recurrence who may benefit from adjuvant therapy from those at lower risk of recurrence who can undergo surgery alone. "
Professor Taieb also outlined the economic implications of evaluating patients, "Follow-up and adjuvant therapy for postoperative patients are expensive; costs vary by country by country, but data lack of data to support the follow-up treatment required by patients. More intensive follow-up can detect recurrence earlier, which may lead to further metastasis and cure for surgical or ablation treatment. Like CRC, some patients with metastatic disease can be cured, and more intensive follow-up may leave more patients with curative treatment."
Although ctDNA testing can avoid the use of chemotherapy for patients who are unlikely to benefit, Prof Taib warns that more work needs to be done to ensure the reliability of this approach. “The problem is that we don’t know when to use adjuvant chemotherapy in stage II CRC, despite the release of ESMO guidelines (Ann Oncol. 2020;31:1291–1305), but the situation varies between centers. In the DYNAMIC study, the recurrence rate of ctDNA-negative patients with high risk factors cannot be ignored, at about 20%, which is important in this phase II population.
Although ctDNA is helpful, we may miss some patients with ctDNA-negative but at high risk of recurrence, which makes treatment decisions difficult. UK, Netherlands, and Australia Countries such as these use a more pragmatic population-based approach, while the United States and other European countries make decisions based on individual patients and do not believe in population-based data. Data from DYNAMIC show that ctDNA is a good predictive marker of long-term survival and can be used as a new endpoint for clinical trials and to change clinical practice. CEA, a classic marker of CRC, lacks sensitivity and specificity for predicting recurrence in patients and may be replaced by ctDNA in the future, but monitoring frequency needs further study."DYNAMIC is a good prospective study, but we also need to confirm these data in larger studies and further study the best techniques and methods for ctDNA detection. Economic factors are also critical, and the cost of ctDNA monitoring is much higher than that of CEA, so further research on the cost-effectiveness of different methods is needed. Costs may decrease with the widespread use of ctDNA detection. ”
ctDNA detection of microresidual diseases and the ability to determine appropriate patients with chemotherapy will be the most important tool in the field of CRC-assisted treatment in the next 10 years. Data from the DYNAMIC trial complements data published in another study that show the prognostic value of continuous postoperative ctDNA detection. PRODIGE 13 also provides important information on how best to follow up patients after surgery. Intensive monitoring can improve the discovery of recurrence rates of curative surgery and support the value of intensive monitoring of CT scans.
References
1, Tie J, et al. Circulating tumour DNA (ctDNA) dynamics, CEA and sites of recurrence for the randomised dynamic study: Adjuvant chemotherapy (ACT) guided by ctDNA analysis in stage II colon cancer (CC) ESMO Congress 2022, Abstract 318MO
Mini Oral Session 2 – GI, lower dietive, 12.09.2022, h. 14:45 – 15:55, Grenoble Auditorium
2, Lepage C, et al. Prognostic effect of imaging and CEA following-up in reflected colorectal cancer (CRC): Final results and relapse free survival (RFS) - PRODIGE 13 a FFCD phase III trial. ESMO Congress 2022, LBA28
Mini Oral Session 2 – GI, lower dietive, 12.09.2022, h. 14:45 – 15:55, Grenoble Auditorium
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