Randomised trial of SIR-Spheres® plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer

Purpose: SIR-Spheres(R) are radioactive yttrium(90) microspheres (SIR-Spheres(R), Sirtex Medical Limited, Australia) used to selectively target high levels of ionising radiation to tumors within the liver. This trial was designed to measure any increased patient benefit by adding a single administration of SIR-Spheres to a regimen of regional hepatic artery chemotherapy (HAC) administered as a 12 day infusion of floxuridine and repeated at monthly intervals, vs. the same chemotherapy alone. Patients and methods: A phase III randomised clinical trial entering 74 patients was undertaken on patients with bi-lobar non-resectable liver metastases from primary adenocarcinoma of the large bowel. Patient benefit criteria assessed in the trial were tumor response, time to disease progression in the liver, overall survival, quality of life, and treatment related toxicity. Tumor response was measured by serial changes in both cross-sectional tumor areas and total tumor volumes, provided any response lasted not less than three months as well as changes in serum carcino-embryonic antigen (CEA). Results: The partial and complete response rate (PR + CR) was significantly greater for patients receiving SIR-Spheres when measured by tumor areas (44% vs. 17.6%, P = 0.01) tumor volumes (50% vs. 24%, P = 0.03) and CEA (72% vs. 47%, P= 0.004). The median time to disease progression in the liver was significantly longer for patients receiving SIR-Spheres in comparison to patients receiving HAC alone when measured by either tumor areas (9.7 vs. 15.9 months, P = 0.001), tumor volumes (7.6 vs. 12.0 months, P = 0.04) or CEA (5.7 vs. 6.7 months, P = 0.06). The one, two, three and five-year survival for patients receiving SIR-Spheres was 72%, 39%, 17% and 3.5%, compared to 68%, 29%, 6.5% and 0% for HAC alone. Cox regression analysis suggests an improvement in survival for patients treated with SIR-Spheres who survive more than 15 months (P = 0.06). There was no increase in grade 3-4 treatment related toxicity and no loss of quality of life for patients receiving SIR-Spheres in comparison to patients receiving HAC alone. Conclusion: The combination of a single injection of SIR-Spheres(R) plus HAC is substantially more effective in increasing tumor responses and progression free survival than the same regimen of HAC alone.