Evaluation of CTCs Combined With Tumor Marker Detection of Efficacy of Chemotherapy in mCRC

Study Overview
=================
Brief Summary
-----------------
Evaluation of individual peripheral blood circulating tumor cells combined with tumor marker detection of efficacy of chemotherapy in patients with advanced colorectal cancer: A observational clinical trial

Detailed Description
-----------------
In 2004, based on AVF2107g clinical research, FDA has approved bevacizumab as first targeted drugs for the treatment of advanced colorectal cancer[1].So far, chemotherapy combined with target agents is currently first line standard of patients with advanced colorectal cancer. The anti-EGFR monoclonal antibodies((cetuximab and panitumumab) also have been demonstrated to be efficient in the treatment of metastatic colorectal cancer. In the CRYSTAL and OPUS studies, adding cetuximab to first-line chemotherapy (CT) improved clinical benefit in patients (pts) with KRAS wild-type (wt) mCRC [2,3]. FIRE-3 and TAILOR once again proved cetuximab combined FORFIRI or FOLFOX will improved clinical benefit[4]. Target agents are expensive, so It is necessary to explore a new evaluation criteria to avoid unnecessary economic waste. RECIST(Response Evaluation Criteria in Solid Tumors) is not suitable for the target or immunotherapy. The effect of chemotherapy not only displayed as morphology(tumor size reduction), but also as the biological activity change of tumor cells(e.g.cystic degeneration and cavity).PET-CT combined imaging of molecular function and morphology, but PET-CT was low cost -effective. The tumor markers is a rapid, easy to repeat method, but the change of the markers can not evaluation the response of tumor as an individual indicator. So we need a more sensitive effective evaluation marker. Circulating tumor cells (CTCs) are rare cancer cells released from tumors into the bloodstream that are thought to have a key role in cancer metastasis. The distant metastasis is the leading cause of death in patients with mCRC. CTCs is a method to detect the early tumor micrometastasis. CTCs is predictive of PFS and OS in lung cancer and breast cancer. CTCs is also predictive of response of tumor. CTCs is more accuracy, more sensitive way than imageology or other tumor marker to predict therapy effect and outcome. The anti-EGFR monoclonal antibody (cetuximab) target the human epidermal growth factor receptor and have been integrated into treatment regimens of mCRC. The EGFR expression is not the predicted marker of cetuximab, in patients who express EGFR, the ORR only 10%-20%[5,6].In CRYSTAL, The addition of cetuximab to FOLFIRI as first-line therapy improves PFS in patients with KRASwild-type mCRC[2]. Up to now, we know only RAS wild type patients would benefit from anti-EGFR therapy.[7] The CALGB/SWOG80405 confirmed the conclusion. Some study also found the patients with B-raf (V600e) mutation would not benefit from anti-EGFR therapy[8]. Taken together, we need a more accuracy, more sensitive method to predict the effect of cetuximab. The study is a single arm, single-center, observational study undertaken in anticipated 100 patients with histologically confirmed RAS and B-raf wild type mCRC. These patients received FOLFIRI±cetuximab therapy. Peripheral blood samples of 10 mL were collected from the patients for CTCs analysis and tumor marker in every cycle D0 and D8. The CTCs sued the integrated subtraction enrichment (SET) and immunostaining-fluorescence in situ hybridization (iFISH) platform.Tumor assessments will be performed every four cycles based on RECIST v1.1 criteria using CT/MRI scan. If the assessments are inconsistent, we will collect 10ml peripheral blood for ct DNA test, which using BEAMing, to analyze mutant gene. The correlation of the RAS status on CTCs and the mutant gene in ctDNA to the therapeutic response will be evaluated, and found the cut-off of CTCs.

Official Title
-----------------
Evaluation of Individual Peripheral Blood Circulating Tumor Cells Combined With Tumor Marker Detection of Efficacy of Chemotherapy in Patients With Advanced Colorectal Cancer: A Observational Clinical Trial

Conditions
-----------------
Colorectal Cancer Metastatic

Intervention / Treatment
-----------------
* Other: treated with FOLFIRI±cetuximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Having signed informed consent Age18-75 years old Histologically confirmed mCRC First metastatic,unresectable RAS and B-raf wild type .At least one measurable disease according to the RECIST criteria by CT/MRI Expected survival time≥12 weeks ECOG PS 0-1 Adequate bone marrow, hepatic, renal and metabolic function Exclusion Criteria: Received chemotherapy for CRC previously, except adjuvant chemotherapy end of adjuvant chemotherapy≥9m(contain irinotecan) or ≥9m(not contain irinotecan) before the study. Surgery or radiotherapy ≤30 days before the study. Received anti-EGFR,anti-VEGF or other signaling pathway inhibitor previously

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| RAS and B-raf wild type mCRC<br>patients with histologically confirmed RAS and B-raf wild type mCRC treated with FOLFIRI±cetuximab | Other: treated with FOLFIRI±cetuximab<br>* Peripheral blood samples of 10 mL were collected from the patients for CTCs analysis and tumor marker in every cycle D0 and D8. Tumor response evaluation will be performed after four cycles of chemotherapy by CT/MRI based on RECIST. Clinical data, including tumor stage, metastatic organ, objective response, progression free survival, overall survival, etc, will be collected according to study protocol.The correlation of the RAS status on CTCs and the mutant gene in ctDNA to the therapeutic response will be evaluated.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of RAS status on CTCs with clinical outcomes | To evaluate the correlation of CTCs and their RAS status to the clinical outcomes | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of mutant gene in ctDNA with cetuximab resistance. | To evaluate the correlation of mutant gene in ctDNA to the cetuximab resistance | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Metastatic colorectal cancer, Cetuximab, CTCs, ct DNA