Objective:The complexity,heterogeneity and capacity of malignant neoplastic cells and tumors for rapid change and evolution suggest that living-cell-based biological-systems approaches to cancer treatment are merited.Testing this hypothesis,the tumor marker,metabolic activity,and overall survival (OS) responses,to the use of one such system,implantable macrobeads [RENCA macrobeads (RMBs)],in phase Ⅰ and Ⅱa clinical trials in advanced,treatment-resistant metastatic colorectal cancer (mCRC) are described here.Methods:Forty-eight mCRC patients (30 females;18 males),who had failed all available,approved treatments,underwent RMB implantation (8 RMB/kg body weight) up to 4 times in phase Ⅰ and phase Ⅱa open-label trials.Physicals,labs [tumor and inflammation markers,lactate dehydrogenase (LDH)] and positron emission tomography-computed tomography (PET-CT) imaging to measure number/volume and metabolic activity of the tumors were performed pre-and 3-month-post-implantation to evaluate safety and initial efficacy (as defined by biological responses).PET-CT maximum standard uptake value (SUVmax) (baseline and d 90;SUVmax ≥2.5),LDH,and carcinoembryonic antigen (CEA) and/or cancer antigen 19-9 (CA 19-9) response (baseline,d 30 and/or d 60) were assessed and compared to OS.Results:Responses after implantation were characterized by an at least 20％ decrease in CEA and/or CA 19-9 in 75％ of patients.Fluorodeoxyglucose (FDG)-positive lesions (phase Ⅰ,39;2a,82) were detected in 37/48 evaluable patients,with 35％ stable volume and stable or decreased SUV (10) plus four with necrosis;10,increased tumor volume,SUV.LDH levels remained stable and low in Responders (R) (d 0-60,290.4-333.9),but increased steadily in Non-responders (NR) (d 0-60,382.8-1,278.5) (d 60,P=0.050).Responders to RMBs,indicated by the changes in the above markers,correlated with OS (R mean OS=10.76 months;NR mean OS=4.9 months;P=0.0006).Conclusions:The correlations of the tumor marker,tumor volume and SUV changes on PET-CT,and LDH levels themselves,and with OS,support the concept of a biological response to RMB implantation and the validity of the biological-systems approach to mCRC.A phase Ⅲ clinical trial is planned.