Phase I-II randomized study on prehepatectomy recombinant interleukin-2 immunotherapy in patients with metastatic carcinoma of the colon and rectum

BACKGROUND. This study, which investigates prehepatectomy immunostimulation with recombinant interleukin-2 (rIL-2), had two goals: to evaluate the tolerance of rIL-2 in association with major hepatectomy, and to verify whether preoperative immunostimulation is effective (neoadjuvant immunotherapy). In animal experiments, the conjunction of shed tumor cells into the circulation during surgery and severe surgery-induced immunodepression can promote the dissemination of the disease. Perioperative immunostimulation by rIL-2 reduces the incidence of metastases in animals. STUDY DESIGN. This prospective phase I-II randomized study included 19 patients with potentially resectable hepatic metastases from adenocarcinomas of the colon and rectum. Two-thirds were randomized to the rIL-2-treated group and one-third to the control group. Preoperative rIL-2 was administered by continuous intravenous infusion over five days and stopped two days before major hepatectomy. The dose of rIL-2 was gradually increased, from 3x10⁶ IU/m²/day to 12x10⁶ IU/m²/day. At least three patients were studied at each dose level before increasing the rIL-2 dose. Nineteen patients were eligible for the study (12 in the rIL-2 group and seven in the control group). Toxicity during infusion and intraoperative and postoperative complications were evaluated. Immunological monitoring consisted of repeated determination of lymphocyte counts and phenotypic analysis of lymphocyte subpopulations. Non-major histocompatibility complex-restricted cytotoxicity was assayed against K562 and DAUDI tumor cell lines. RESULTS: Toxicity during rIL-2 infusion was acceptable, similar to that of other phase I studies, and surgery was never delayed. Morbidity and mortality rates after major hepatectomy were not different between the two groups and it appeared that prehepatectomy rIL-2 at a dose of 12x10⁶ IU/m²/day was well tolerated. During the postoperative course, the mean lymphocyte count was higher in the rIL-2 group (p<0.05), without qualitative modification of the lymphocyte subsets. Immunological modifications were dose related. High cytotoxicity against K562 and DAUDI cells was constant at the 12x10⁶ dose level. CONCLUSIONS: Preoperative five-day infusion of rIL-2 before major hepatectomy for colorectal metastases is well tolerated and reverses postoperative immunodepression.