Y-Anti-Carcinoembryonic Antigen Chimeric T84.66 Radioimmunotherapy with 5-Fluorouracil in Patients with Metastatic Colorectal Cancer
نویسندگان
چکیده
Purpose: Targeted systemic radiation therapy using radiolabeled antibodies results in tumor doses sufficient to produce significant objective responses in the radiosensitive hematological malignancies. Although comparable doses to tumor are achieved with radioimmunotherapy (RIT) in solid tumors, results have been modest primarily because of their relative lack of radiosensitivity. For solid tumors, as with external beam radiotherapy, RIT should have a more important clinical role if combined with other systemic, potentially radiation-enhancing chemotherapy agents and if used as consolidative therapy in the minimal tumor burden setting. The primary objective of this trial was to evaluate the feasibility and toxicities of systemic Y-chimeric T84.66 (cT84.66) anti-carcinoembryonic antigen RIT in combination with continuous infusion 5-fluorouracil (5-FU). Experimental Design: Patients with chemotherapyrefractory metastatic colorectal cancer were entered. The study was designed for each patient to receive Y-cT84.66 anti-carcinoembryonic antigen at 16.6 mCi/m as an i.v. bolus infusion combined with 5-FU delivered as a 5-day continuous infusion initiated 4 h before antibody infusion. Cohorts of patients were entered at 5-FU dose levels of 700, 800, 900, and 1000 mg/m/day. Upon reaching the highest planned dose level of 5-FU, a final cohort received YcT84.66 at 20.6 mCi/m and 5-FU at 1000 mg/m/day. For all patients, Ca-diethylenetriaminepentaacetic acid at 125 mg/m every 12 h was administered for the first 72 h after Y-cT84.66. Patients were eligible to receive up to three cycles of Y-cT84.66/5-FU every 6 weeks. Results: Twenty-one patients were treated on this study. All had been heavily pretreated with 19 having previously received 5-FU and 16 having failed two to four chemotherapy regimens. A maximum-tolerated dose of 16.6 mCi/m 90Y-cT84.66 combined with 1000 mg/m/day 5-FU was reached. These dose levels are comparable with maximumtolerated dose levels of each agent alone. Thirteen patients received one cycle and 8 patients two cycles of therapy. Hematopoietic toxicity was dose-limiting and reversible. RIT did not appear to increase nonhematopoietic toxicities associated with 5-FU. Two of 19 patients assayed developed a human anti-chimeric antibody immune response after the first cycle of therapy, which is significantly less than that observed in a previous trial evaluating Y-cT84.66 alone. No objective responses were observed. However, 11 patients with progressive disease entering the study demonstrated radiological stable disease of 3–8 months duration and 1 patient demonstrated a mixed response. Conclusions: Results from this trial are encouraging and demonstrate the feasibility and possible advantages of combining continuous infusion 5-FU with Y-cT84.66 RIT. The addition of 5-FU does not appear to significantly enhance hematological toxicities of the radiolabeled antibody. In addition, 5-FU reduces the development of human anti-chimeric antibody response, permitting multicycle therapy in a larger number of patients. Future efforts should continue to focus on integrating radiation therapy delivered by radiolabeled antibodies into established 5-FU regimens.
منابع مشابه
A Phase I trial of 90Y-anti-carcinoembryonic antigen chimeric T84.66 radioimmunotherapy with 5-fluorouracil in patients with metastatic colorectal cancer.
PURPOSE Targeted systemic radiation therapy using radiolabeled antibodies results in tumor doses sufficient to produce significant objective responses in the radiosensitive hematological malignancies. Although comparable doses to tumor are achieved with radioimmunotherapy (RIT) in solid tumors, results have been modest primarily because of their relative lack of radiosensitivity. For solid tumo...
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