Circulating tumor DNA guided adjuvant chemotherapy in stage II colon cancer (MEDOCC-CrEATE): study protocol for a trial within a cohort study

Abstract

Background Accurate detection of patients with minimal residual disease (MRD) after surgery for stage II colon cancer (CC) remains an urgent unmet clinical need to improve selection of patients who might benefit form adjuvant chemotherapy (ACT). Presence of circulating tumor DNA (ctDNA) is indicative for MRD and has high predictive value for recurrent disease. The MEDOCC-CrEATE trial investigates how many stage II CC patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces the risk of recurrence in these patients. Methods/design MEDOCC-CrEATE follows the ‘trial within cohorts’ (TwiCs) design. Patients with colorectal cancer (CRC) are included in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) and give informed consent for collection of clinical data, tissue and blood samples, and consent for future randomization. MEDOCC-CrEATE is a subcohort within PLCRC consisting of 1320 stage II CC patients without indication for ACT according to current guidelines, who are randomized 1:1 into an experimental and a control arm. In the experimental arm, post-surgery blood samples and tissue are analyzed for tissue-informed detection of plasma ctDNA, using the PGDx elio™ platform. Patients with detectable ctDNA will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin while patients without detectable ctDNA and patients in the control group will standard follow-up according to guideline. The primary endpoint is the proportion of patients receiving ACT when ctDNA is detectable after resection. The main secondary outcome is 2-year recurrence rate (RR), but also includes 5-year RR, disease free survival, overall survival, time to recurrence, quality of life and cost-effectiveness. Data will be analyzed by intention to treat. Discussion The MEDOCC-CrEATE trial will provide insight into the willingness of stage II CC patients to be treated with ACT guided by ctDNA biomarker testing and whether ACT will prevent recurrences in a high-risk population. Use of the TwiCs design provides the opportunity to randomize patients before ctDNA measurement, avoiding ethical dilemmas of ctDNA status disclosure in the control group. Trial registration Netherlands Trial Register: NL6281/NTR6455 . Registered 18 May 2017, https://www.trialregister.nl/trial/6281

Postoperative circulating tumour DNA is associated with pathologic response and recurrence-free survival after resection of colorectal cancer liver metastases

“…The promising monitoring and prognostic value of ctDNA have raised major interest in ctDNA driven adjuvant trials [43] . Adjuvant systemic therapy in CRLM patients has failed to show a 5 year survival benefit [6] .…”

Recommendations for a practical implementation of circulating tumor DNA mutation testing in metastatic non-small-cell lung cancer

“…Different clinical scenarios may require different analysis strategies. 4,6,28,82,[84][85][86][87] While in some cases hotspot testing might already reveal predictive information, in other scenarios such as MRD testing and identification of recurrences only the development of patient-specific, tumor-informed assays can achieve the necessary sensitivity. In late stages larger panels for de novo mutations or shallow wholegenome sequencing to identify novel actionable target is preferable.…”

Liquid biopsies for residual disease and recurrence

“…Currently, large clinical trials, such as MEDOCC-CrEATE, 122 COBRA, 123 and DYNAMIC-II 30 are randomizing patients with stage II CRC (without an indication for adjuvant therapy) to either ctDNA testing or standard of care. Patients with ctDNA detected post-operatively are escalated to adjuvant chemotherapy.…”

“…Recent studies increasingly include outcome measures for acceptability and quality of life. 122,146 Some patients may prefer to receive results of testing to help guide their choices, 147 whereas other patients may find it anxiety-inducing, and clinicians should be mindful of the psychological impact of novel molecular diagnostics on their patients.…”