Literature

Clinical Pearls & Morning Reports


By Carla Rothaus

Published June 15, 2022

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Did a ctDNA-guided approach as compared with a standard approach reduce the use of adjuvant treatment without compromising the risk of recurrence in the trial by Tie et al.?

Tie et al. conducted a phase 2 trial in which patients with stage II colon cancer were randomly assigned following curative-intent surgery to have their disease managed according to circulating tumor DNA (ctDNA) results or managed by the treating clinician according to standard clinicopathological criteria. Read the NEJM Original Article here.

Clinical Pearls

Q: How often is surgery curative in patients with stage II colon cancer?

A: Colorectal cancer remains common worldwide. The current standard care for nonmetastatic colon cancer is surgery, with histopathological staging informing the use of up to 6 months of adjuvant chemotherapy. Although the benefit of adjuvant chemotherapy has been unequivocally established for patients with stage III colon cancer, its usefulness for patients with stage II disease continues to be debated. Surgery alone can cure more than 80% of patients with stage II colon cancer, and no clear overall survival benefit has been observed in trials of adjuvant therapy.

Q: Who should receive adjuvant therapy after surgery for stage II colon cancer?

A: Guidelines currently recommend that adjuvant chemotherapy be considered for patients who have stage II colon cancer with high-risk clinicopathological features, who may be more likely to benefit from adjuvant treatment. However, the current definitions of “high risk” are inadequate, since many patients who have cancer with high-risk features do not have disease recurrence, whereas some with disease that is deemed low-risk do. Furthermore, the survival benefit conferred by adjuvant chemotherapy remains modest (<5%) even when patients with high-risk disease are selectively treated, and therefore many patients are exposed to unnecessary chemotherapy.

Morning Report Questions 

Q: Describe the basic methodology of the trial by Tie et al.

A: The trial enrolled patients with resected histologically confirmed stage II (T3 or T4, N0, M0) colon or rectal adenocarcinoma with negative resection margins. Patients were randomly assigned in a 2:1 ratio to have their disease managed according to ctDNA results or managed by the treating clinician according to standard clinicopathological criteria. ctDNA analysis is a promising alternative strategy in which peripheral blood (a “liquid biopsy”) is directly evaluated for evidence of minimal residual disease that could ultimately be the source of a later clinical recurrence. The primary efficacy end point of the trial was recurrence-free survival at 2 years. A key secondary end point was treatment with adjuvant chemotherapy. The median follow-up was 37 months.

Q: Did a ctDNA-guided approach as compared with a standard approach reduce the use of adjuvant treatment without compromising the risk of recurrence in the trial by Tie et al.?

A: A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, –4.1 to 6.2 [noninferiority margin, –8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and was 92.5% among ctDNA-negative patients who did not.

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