Objective: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females worldwide. Surgery is the leading therapy, followed by adjuvant chemotherapy, yet the presence of undetected micrometastatic tumor cells at the time of surgery in advanced CRC patients, contributes to the failure of treatment, resulting in relapse and metastatic diseases.
Recently, molecular detection of circulating tumor cell free DNA (ccfDNA) has been investigated as a potential prognostic marker. If its effectiveness were to be established, it could have a major role in addressing patients to a targeted treatment and to monitor the disease progression over time.
The aim of the study is to describe changes in the presence of circulating cell free DNA (ccfDNA) in patients with resectable colon cancer who have received immediate perioperative chemotherapy right after the surgical resection, 2 weeks and 4 weeks later. The levels of ccfDNA will be compared to those of patients who will start adjuvant chemotherapy after a standard interval of time (4-6 weeks).
Methods: The study is a prospective case-control pilot study to test ccfDNA in two cohorts, one receiving perioperative chemotherapy and a control cohort.
Patients with invasive colonic adenocarcinoma will be selected and a blood sample to test ccfDNA will be taken preoperatively, on postoperative day 14 and 30 days after the resection to evaluate changes deriving from the different treatment received.
Moreover, the level on ccfDNA will be analyzed 6 weeks after surgery, to monitor variations, especially in those patients who did not receive perioperative chemotherapy; also, it will be used to evaluate relapses or metastatic spread in the long term.
This study could contribute to the increasing evidence of the liquid biopsy role in diagnostic and targeted therapy for cancer, with a specific focus on resectable colorectal cancer, making it a standard of care.
Several recent papers suggest that circulating tumor DNA in the blood should be a supplemental, or perhaps an alternative, source of DNA to identify the clinically relevant cancer mutation. This noninvasive approach could contribute the monitoring of disease progression and treatment response. Moreover, it could be useful in guiding targeted therapies based on detected mutations in patients with advanced or metastatic solid tumors.
With the widespread use of this practice, liquid biopsy could routinely be analyzed and become a marker to add in the conventional tumor description of cancer stage, such as TNM, making it more tailored on individual patient.
The current TNM criteria, provide a prediction of the treatment course and disease prognosis yet, considering the innovation in cancer genomic, it has proven to be incomplete. In fact, a disease is defined as metastatic, M1, when the metastasis is clinically evident with conventional imaging. Recent findings, thanks to the evaluation of circulating tumor cells, have proved a systemic dissemination of the disease much earlier. Therefore, the liquid biopsy should be taken into consideration as a routine diagnostic practice and an addendum to the traditional TNM. The presence of this additional indicator could be crucial in the therapeutic approach towards certain clinical situations, such as stage II colonic cancer. Those patients have a localized disease, with no nodal dissemination, but it has been proven that a certain percentage of those will relapse or have distant metastasis within years. For this reason, up to 40% of these patients, undergo adjuvant chemotherapy. Having an indicator, such as the levels of ccfDNA, could provide a solution to this medical dilemma.
Moreover, in the context of the newly proposed protocol of immediate perioperative chemotherapy for colorectal cancer, ccfDNA could represent a useful diagnostic tool in the evaluation of its effectiveness. The serial blood samples taken can provide a direct correspondence of the disease status and the effects of surgery and chemotherapy at each time point. As a secondary result, the data collected could provide information about the perioperative period, represented by the first 6 weeks after surgery, usually dedicated to the recovery of the patient from the surgical procedure and free from any oncological therapy. Yet, it has been suggested by recent studies that this delay in starting the therapy represents an independent risk factor for cancer relapse. 3 The evaluation of ccfDNA in the control group could provide an objective data and better stratify patients¿ risk of relapse.
The widespread of mini-invasive surgical techniques such as laparoscopic and robotic procedures combined with enhanced recovery after surgery (ERAS) protocol have made full recovery for patients much shorter, making it possible for selected group of patients to tolerate the side effects of immediate perioperative chemotherapy.
This innovative protocol, other than the expected benefit on oncological outcomes that are yet to the proven, has a potential for improvement in quality of life for patients by completing their overall treatment much earlier than current paradigms.
1. Lu CY, Tsai HL, Uen YH et al. Circulating Tumor cells as a surrogate marker for determining clinical outcome to mFOLFOX chemotherapy in patients with stage III colon cancer, Br J Cancer 2013; 108:791-797.
2. Mohan HM, O¿Connor DB, O¿Riordan JM, et al. Prognostic significance of detection of microscopic peritoneal disease in colorectal cancer: A systemic Review. Surg Oncol 2013; 22:e1-e6.
3. Tie J, Wang Y, Tomassetti C, et al. Circulating Tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon disease, Science Translational Medicine 2016 8: (334).
6. Kim IK, Kim BR, Kim YW, Factors Affecting Use and Delay (>8 weeks of adjuvant chemotherapy after colorectal cancer surgery and Impact of chemotherapy-use and delay on oncologic outcomes, PLos One 2015; 10(9): e0138720. Doi:10.1371/journal.pone/0138720.