Stage II CRC: ctDNA guidance reduces adjuvant chemo use, does not increase recurrence

Using circulating tumour DNA (ctDNA) analysis to guide adjuvant treatment of stage II colorectal cancer (CRC) reduces adjuvant chemotherapy use without compromising recurrence-free survival (RFS) compared with standard management guided by clinicopathological criteria, results of a phase II randomized controlled trial have shown.

The multicentre trial included 455 patients (median age, 64 years; Eastern Cooperative Oncology Group performance status 0–1, 99 percent) with histologically confirmed stage II colon or rectal adenocarcinoma with negative resection margins. The patients were randomized 2:1 to receive ctDNA-guided management (n=302) or standard management according to clinicopathological criteria (n=153). In the ctDNA-guided management group, a positive ctDNA result at week 4 or 7 after surgery prompted the use of adjuvant oxaliplatin-based or single-agent fluoropyrimidine chemotherapy (chosen by clinician’s discretion), while patients with negative ctNDA results at both weeks 4 and 7 were not treated with adjuvant chemotherapy. [N Engl J Med 2022;386:2261-2272]

After a median follow-up of 37 months in the ctDNA-guided management group and 38 months in the standard management group, the primary endpoint of recurrence-free survival at 2 years was achieved by 93.5 percent vs 92.4 percent of patients in the respective groups (absolute difference, 1.1 percent; 95 percent confidence interval [CI], -4.1–6.2; noninferiority margin, -8.5 percent), demonstrating noninferiority of ctDNA-guided adjuvant chemotherapy vs the standard approach. At 3 years, recurrence-free survival was also similar between the two groups (91.7 percent vs 92.4 percent).

The comparable recurrence-free survival between the two groups yielded a hazard ratio (HR) of 0.96 (95 percent CI, 0.51–1.82), with generally similar results shown in prespecified subgroup analyses.

In the ctDNA-guided group, 3-year recurrence-free survival rate was 92.5 percent among ctDNA-negative patients and 86 percent among ctDNA-positive patients (HR, 1.83; 95 percent CI, 0.79–4.27). Recurrence rate at 3 years was 7 percent and 14 percent, respectively (HR, 2.45; 95 percent CI, 1.00–5.99).

Fewer patients in the ctDNA-guided vs standard management group received adjuvant chemotherapy (15 percent vs 28 percent; relative risk [RR], 1.82; 95 percent CI, 1.25–2.65). “This [between-group] difference was observed across almost all patient subgroups, with the exception of patients with a lymph node yield of less than 12 and patients older than 70 years of age,” the researchers reported. “The most notable difference was seen in patients with T4 tumours [RR, 2.57; 95 percent CI, 1.46–4.50] and those with poorly differentiated tumours [RR, 5.06; 95 percent CI, 1.02–25.10].”

“For patients with high-risk clinicopathological features, the likelihood of receiving adjuvant chemotherapy was 2.14 times as high [95 percent CI, 1.43–3.21] in the standard vs ctDNA-guided management group,” they added.

“Our results suggest that ctDNA-positive patients with stage II colon cancer appeared to derive considerable benefit from adjuvant chemotherapy, given the low rate of recurrence in this trial as compared with previously reported high recurrence rates in this subgroup of patients when no adjuvant chemotherapy was administered,” the researchers noted. [Sci Transl Med 2016;8:346ra92; Gut 2019;68:663-71] “The results also confirmed the very low risk of recurrence in untreated ctDNA-negative patients.”