ctDNA-Based Adjuvant Chemotherapy for High-Risk Rectal Cancer

Rationale - Rectal cancer is a worldwide cause of cancer related mortality. The incidence of rectal cancer in the Netherlands is approximately 3500 patients per year. The introduction of combined neoadjuvant (chemo)radiotherapy and total mesorectal excision (TME) has significantly reduced the local recurrence rate, but distant recurrence rates remain around 30%. Recurrences are likely to derive from residual local disease or subclinical metastatic disease (minimal residual disease). These micro metastases are undetectable by the currently used imaging techniques but still present after surgery. Adjuvant chemotherapy might be beneficial for patients at high risk for recurrence. However, there are only a few randomised controlled trials on perioperative chemotherapy available. Studies on adjuvant chemotherapy in rectal cancer yielded conflicting results. As a consequence, treatment with adjuvant chemotherapy in patients with rectal cancer is not evidence based and therefore not standard of care in the Netherlands. Recent studies suggest that preoperative intensive chemotherapy with radiotherapy, compared to standard chemotherapy and radiotherapy, resulted in a prolonged disease-free survival and overall survival. However, this was at the cost of increased toxicity, and whether the observed improvement in overall survival can be attributed to the addition of neo-adjuvant intensive chemotherapy is under debate. Consequently, there is an urgent need for biomarkers to identify those patients at high risk to recur after standard treatment, to select the patients that might benefit the most from adjuvant chemotherapy.

Objective - To investigate disease-free survival in patients with high-risk rectal cancer by treating these patients with adjuvant chemotherapy in case of detectable ctDNA after surgery.

Main trial endpoints - The primary endpoint of the study will be disease-free survival in the intention-to-treat population, calculated from the date of surgery to the date of recurrence or death from any cause of the patient, whichever occurs first.

Secondary trial endpoints - Secondary outcomes will be disease-free survival, carried out as per protocol analysis to analyse pure treatment effect. In addition, overall survival will be calculated measured from the date of surgery to the date of death from any cause. Quality of life will be assessed in both groups by obtaining already completed questionnaires provided by the PLCRC cohort study to compare the effect of adjuvant chemotherapy on quality of life. The robustness of ctDNA as biomarker will be analysed by comparing the disease-free survival of patients with detectable ctDNA who are not treated adjuvant chemotherapy (control group) with patients with undetectable ctDNA. The clearance of ctDNA of the patients who received adjuvant chemotherapy in the experimental group will be compared with the patients in the control group. Lastly, the co-occurrence of ctDNA in peripheral blood at the timing of detection of recurrent disease on imaging will be studied.

Trial design - The proposed study is conducted within the prospective Dutch ColoRectal Cancer (PLCRC) cohort and follows the trial within cohort (TwiCs) design, i.e. a randomised controlled trial within a prospective cohort.

Trial population - Patients ≥ 18 years of age with primary resected rectal cancer that meet the inclusion criteria, participating in the PLCRC cohort with informed consent for randomisation and considered physically fit for adjuvant chemotherapy are eligible.

Interventions - Patients with detectable ctDNA after surgery and randomised to the experimental group will be offered adjuvant chemotherapy within 8 weeks of surgery and no longer than 12 weeks after surgery. Adjuvant chemotherapy consists of 6 cycles of 5FU/folinic acid and oxaliplatin (FOLFOX) every 2 weeks, or 4 cycles of capecitabine and oxaliplatin (CAPOX). Duration of treatment will be 3 months (12 weeks).

Ethical considerations - In current clinical practice there is no indication for adjuvant chemotherapy for patients after surgery for primary rectal cancer. Therefore, all participating patients have no indication for adjuvant chemotherapy. Patients randomised to the experimental group will be offered adjuvant chemotherapy to reduce recurrence. According to routine clinical care, patients receiving adjuvant chemotherapy will undergo blood withdrawals and visit their treating physician before every cycle of chemotherapy. The combination chemotherapy schedule of CAPOX and FOLFOX is commonly administered in the adjuvant setting in current practice for colorectal cancer, therefore the risks and toxicity of the used adjuvant chemotherapy are well-known. The majority of side-effects are manageable and transient. The risk of the withdrawal of extra tubes of blood during regular blood withdrawal in all study participants is negligible. The benefit for participants enrolled in this trial is the potential chance to reduce their risk of recurrence with adjuvant chemotherapy.

• Overall survival, intention-to-treat [Срок оценки: From the date of surgery to the date of death from any cause of the patient, with a median follow-up of 5 years]
• Disease-free survival, per-protocol [Срок оценки: Calculated from the date of surgery to the date of progression (recurrence) or death from any cause of the patient, assessed up to 2 years of follow-up]
• Overall survival, per-protocol [Срок оценки: Calculated from the date of surgery to the date of death from any cause of the patient, with a median follow-up of 5 years]
• The effect of adjuvant chemotherapy on quality of life - EQ-5D-5L [Срок оценки: Questionnaires are obtained within PLCRC at baseline, 3 months, 6 months, 1 year, 1.5 years, 2 years and yearly after, assessed up to 4 years of follow-up]
• The effect of adjuvant chemotherapy on quality of life - QLQ-C30 [Срок оценки: Questionnaires are obtained within PLCRC at baseline, 3 months, 6 months, 1 year, 1.5 years, 2 years and yearly after, assessed up to 4 years of follow-up]
• The effect of adjuvant chemotherapy on quality of life - QLQ-CR29 [Срок оценки: Questionnaires are obtained within PLCRC at baseline, 3 months, 6 months, 1 year, 1.5 years, 2 years and yearly after, assessed up to 4 years of follow-up]
• Comparing disease-free survival of patients with detectable ctDNA but without receiving adjuvant chemotherapy with patients with undetectable ctDNA [Срок оценки: Calculated from the date of surgery to the date of progression (recurrence) or death from any cause of the patient, assessed up to 2 years of follow-up]
• Comparing overall survival of patients with detectable ctDNA but without receiving adjuvant chemotherapy with patients with undetectable ctDNA [Срок оценки: Calculated from the date of surgery to the date of death from any cause of the patient, with a median follow-up of five years]
• To investigate the prognostic value of ctDNA clearance after adjuvant chemotherapy [Срок оценки: Two 10 mL CellSave blood samples will be collected at least 14 days after completion of chemotherapy. ctDNA clearance (yes/no) will be analyzed for correlation with disease-free survival at 2 years and overall survival at 5 years.]
• To investigate the co-occurrence of ctDNA in peripheral blood at the timing of detection of recurrent disease on imaging. [Срок оценки: Up to 2 years after rectal surgery, at the time recurrent disease is detected on imaging and prior to any additional treatments.]