Circulating tumor DNA-guided adjuvant therapy in locally advanced colon cancer: the randomized phase 2/3 DYNAMIC-III trial
- Study type
- Clinical trial
- Study name
- DYNAMIC-III
- Phase
- Phase 2/3
- Design
- Multicentre randomised trial (1:1 randomisation) of ctDNA-guided versus standard management (AGITG and CCTG); registration: ACTRN12617001566325
- Sample size
- 968 evaluable patients (702, 72.5%, ctDNA-negative)
- Source
- Nat Med · 2025
In plain words
In stage 3 bowel cancer, chemotherapy after surgery is standard. This study looked at whether the ctDNA blood test can be used to adjust how intensive treatment is. About three-quarters of patients were ctDNA-negative and had a good outlook; lighter treatment in them meant fewer side effects and hospital stays, but the rate of staying free of the cancer coming back was slightly lower than with usual treatment, so reducing treatment cannot yet be recommended routinely. In ctDNA-positive patients, more intensive chemotherapy did not help, and these patients need new treatments.
Key results
Treatment arms and regimens
Before randomisation, the physician specified their standard regimen (no chemotherapy, single-agent fluoropyrimidine or fluoropyrimidine + oxaliplatin), and treatment was de-escalated or escalated according to the postoperative ctDNA result (week 5 to 6 sample):
- "No chemotherapy" chosen: ctDNA-negative no treatment; ctDNA-positive 3 months of single-agent fluoropyrimidine.
- "6 months of fluoropyrimidine" chosen: ctDNA-negative no treatment or 3 months of fluoropyrimidine; ctDNA-positive 6 months of fluoropyrimidine + oxaliplatin.
- "3 months of fluoropyrimidine + oxaliplatin" chosen: ctDNA-negative fluoropyrimidine; ctDNA-positive 6 months of fluoropyrimidine + oxaliplatin or FOLFOXIRI for 6 cycles, then further treatment at the physician's discretion.
- "6 months of fluoropyrimidine + oxaliplatin" chosen: ctDNA-negative fluoropyrimidine alone or 3 months of fluoropyrimidine + oxaliplatin; ctDNA-positive FOLFOXIRI for 6 cycles, then further treatment at the physician's discretion.
Recommended regimens (duration 3 or 6 months and dose modification at the physician's discretion, unless stated otherwise):
- Modified de Gramont every 2 weeks: leucovorin 50 mg IV, fluorouracil 400 mg/m² IV and 2400 mg/m² continuous IV infusion by pump over 46 hours.
- Modified QUASAR weekly: leucovorin 50 mg IV and fluorouracil 375 to 450 mg/m² IV (per centre standard).
- Modified Roswell Park weekly (6 weeks and 2 weeks' rest): leucovorin 50 mg IV and fluorouracil 500 mg/m² IV.
- Capecitabine: orally on days 1 to 14 every 21 days (dose per centre standard).
- mFOLFOX6 every 2 weeks (12 or 24 weeks): oxaliplatin 85 mg/m² IV, leucovorin 50 mg IV, fluorouracil 400 mg/m² IV and 2400 mg/m² continuous infusion over 46 hours.
- CAPOX every 3 weeks (12 or 24 weeks): oxaliplatin 130 mg/m² and capecitabine 1000 mg/m² twice daily orally on days 1 to 14 every 21 days.
- FOLFOXIRI every 2 weeks (12 to 24 weeks; at least 6 cycles when escalating from an oxaliplatin-based regimen): irinotecan 165 mg/m² IV, oxaliplatin 85 mg/m² IV, leucovorin 50 mg IV and fluorouracil 3200 mg/m² continuous infusion over 46 hours.
The standard regimen the physician had specified before randomisation (no adjuvant chemotherapy, single-agent fluoropyrimidine or fluoropyrimidine + oxaliplatin) with the same recommended regimens and doses; patient and physician were blinded to the ctDNA result.
Source of the regimen details: ANZCTR trial registration (ACTRN12617001566325, intervention description section: regimens, doses and the de-escalation/escalation algorithm); the full text of the Nature Medicine paper was not openly accessible to us
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
Patients aged 18 years or older with stage III colon cancer (any T, N1 or N2, M0) after resection with curative intent; rectal cancer patients were eligible unless they had received preoperative chemoradiotherapy or were planned for postoperative chemoradiotherapy; suitable for at least 3 months of fluoropyrimidine-based adjuvant chemotherapy; ECOG 0 to 2; ctDNA blood sample at weeks 5 to 6 after surgery. Exclusion criteria: another primary cancer in the previous 3 years, multiple primary colorectal cancers, GFR below 30 mL/min, neutrophils below 1.0 × 109/L, platelets below 75 × 109/L, haemoglobin below 80 g/L or AST/ALT more than 2.5 times the upper limit of normal. Stratification by centre and clinical risk group (low risk T1-3N1; high risk T4 and/or N2) (ANZCTR).
Endpoints
Primary endpoints: 3-year recurrence-free survival (RFS) in ctDNA-negative patients (non-inferiority) and 2-year RFS in ctDNA-positive patients.
Secondary endpoints: treatment-related hospitalisation and ctDNA clearance.
Safety and side effects
No unexpected toxicity was observed. In ctDNA-negative patients, de-escalation reduced hospitalisation (8.5% versus 13.2%).
Clinical significance and place in guidelines
DYNAMIC-III confirmed the strong prognostic value of ctDNA in stage 3 disease, but de-escalation in ctDNA-negative patients did not meet the non-inferiority criterion, and escalation of chemotherapy in ctDNA-positive patients gave no benefit. Changing standard stage 3 treatment based on ctDNA is therefore not yet recommended, and this study underlines the need for trials of novel therapies in ctDNA-positive disease.
Limitations
Standard, de-escalated and escalated regimens were varied and chosen by the physician; the ctDNA-positive part was exploratory and smaller; follow-up for overall survival is still limited.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.