Hepatic arterial infusions of interleukin-2-based immunochemotherapy in the treatment of unresectable liver metastases from colorectal cancer.

In preclinical studies, hepatic arterial infusion of interleukin-2 (IL-2) in dogs significantly induced lymphocyte proliferation and augmented antitumor killing activity in the liver. Based on these findings, a pilot study of hepatic arterial infusions of IL-2-based immunochemotherapy was conducted in 21 patients (15 men, 6 women) with unresectable liver metastases from colorectal cancer, to determine whether the addition of IL-2 improved the therapeutic efficacy of chemotherapy alone. Interleukin-2 was given to all patients as 7 to 8 x 10(5) Japanese reference units (JRU) in addition to 5-fluorouracil (5-FU) 250 mg daily and mitomycin C (MMC) 4 mg once weekly, through a subcutaneous port for 3 weeks. After completion of the initial course, patients were discharged from the hospital and continued on a modified regimen for outpatient therapy: IL-2, 2.0 to 2.1 x 10(6) JRU and 5-FU 250 mg twice weekly; MMC 4 mg once weekly. Patient response rate was 76%, and the median survival from initiation of treatment was 24 months. Toxicity of the combined regimen was minimal. Peripheral lymphocyte phenotype study showed notable decreases in CD8+, CD16+, and CD57+ cells and an increase in CD4+ cells (ie, elevation of 4:8 ratio) during therapy. Electron microscopic analysis of the resected liver of a patient receiving the IL-2-mitomycin-C/5-fluorouracil (IL-2.MF) infusion showed a pronounced accumulation of lymphocytes, penetrating from the space of Disse, around the cancer cells. The present study explores hepatic arterial infusion of IL-2-based immunochemotherapy as a new strategy, based on the activation of liver-associated immune response; this technique may provide improved response and survival for unresectable liver metastases.