1. The circulating tumour DNA-guided approach was non-inferior to the standard clinicopathological approach in terms of 2-year recurrence-free survival.

2. Less adjuvant chemotherapy was used with the circulating tumour DNA approach.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Cancer recurrence risk after surgery is usually estimated clinicopathologically, whereby adjuvant therapy is recommended if reduction of cancer recurrence has been demonstrated. However, in colorectal cancer stage II, classifications of high and low-risk patients are inadequate since many high-risk patients do not have disease recurrence while some low-risk patients do. This study explored the use of circulating tumour DNA (ctDNA) to predict recurrence risk after surgery of stage II colon cancer patients and accordingly better assess their need for adjuvant chemotherapy. Patients were randomly assigned to have their cancer managed according to their ctDNA results or by the standard clinicopathological criteria. Compared to the standard management group, a lower percentage of patients in the ctDNA group received adjuvant chemotherapy. Reassuringly, the 2-year recurrence-free survival in the ctDNA guided management was non-inferior to standard management. Limitations to this study include the lack of randomization of ctDNA-positive and ctDNA-negative patients in receiving treatment or not. A longer follow up is also needed to determine if chemotherapy in ctDNA-positive patients prevents relapse or simply delays it. The strengths of this study are that it has limited bias given the design and that it provides an accurate alternative to the current clinicopathological management. With this ctDNA approach, certain subgroups can avoid unnecessary chemotherapy, along with the physical and financial costs that that accompany it. Overall, ctDNA is a powerful and useful biomarker that will change the current management of stage II colon cancer and future studies will investigate the role of intensification and de-escalation of treatment based on ctDNA.

Click to read the study in NEJM

Click to read an accompanying editorial in the New England Journal of Medicine

Relevant Reading: Adjuvant chemotherapy for stage II colon cancer

In-Depth [randomized control trial]: This phase II multicenter study in Australia randomly assigned 455 patients in a 2:1 ratio to receive ctDNA guided management or standard clinicopathological management of their stage II colon cancer; 302 were in the ctDNA group and 153 in the standard management group. Patients in the ctDNA group who had a positive result receive physician’s choice of adjuvant chemotherapy, while the standard treatment proceeded to adjuvant systemic therapy based on standard of care risk stratification criteria. Two-year recurrence-free survival was 93.5% and 92.4% for the ctDNA and standard management groups, respectively (95% confidence interval [CI], -4.1 to 6.2; noninferiority margin, -8.5%). In the ctDNA group, 15% of ctDNA positive patients received adjuvant chemotherapy compared to 28% in the standard management group (relative risk, 1.82%; 95% CI, 1.25 to 2.65). Three-year recurrence-free survival for ctDNA-positive patients who received adjuvant chemotherapy and ctDNA-negative patients who did not was 86.4% and 92.5%, respectively (hazard ratio, 1.83; 95% CI, 0.79 to 4.27). Overall, the ctDNA-guided approach in the treatment of stage II colon cancer reduced adjuvant chemotherapy use while not altering recurrence-free survival.

Image: PD

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