Secondary prevention of cancer recurrence by interleukin-2 (IL-2) and 13-cis retinoic acid

F Recchia MD^a,b, S De Filippis MD^a, A Cesta^a, G Amiconi^a, G Saggio MD^a, A Di Blasio^a, S Rea MD^b,c

^aUnità operativa di Oncologia, Ospedale Civile di Avezzano, Fondazione “Carlo Ferri”, Monterotondo, ^bOncologia Chirurgica, Università degli studi di L’Aquila, Italy, ^c, Italy

Aim: Searching methods for secondary prevention of cancer, in a phase IB study (Clin Cancer Res 7: 1251-1257, 2001) we found the optimal biological dose of IL-2 administered subcutaneously, with oral retinoic acid (RA) in a group of patients with advanced solid tumors responding to chemotherapy. In a randomized trial we demonstrated the value of RA (Proc Am Ass Cancer Res 2002;43,914) in association with IL-2. A further phase II study confirmed the validity of this combination in a large patient population (Int J Oncol 20:1275-82,2002). Aim of this study was to evaluate the immunological parameters known to be prognostically relevant, time to progression and overall survival of 180 patients entered into these studies. Methods: One-hundred and eighty patients with advanced solid tumors (ovary 35, breast 29, lung 23, stomach 17, head and neck 16, colorectal 14, kidney 11, uterus 10, melanoma 9, lymphoma 6, other 10) with either a CR or PR after standard chemotherapy, were treated with IL-2, 1.8 M.I.U. and RA, 0.5 mg/Kg for 5 days/week for 2 consecutive cycles of 3 weeks, with a 1-week rest, for up to 1 year. A total of 1208 courses of IL-2/RA therapy were administered (median 6.7 per patient). Tumor markers, T4/T8 ratio vascular endothelial growth factor (VEGF) and NK were monitored every 2 months. Response evaluation was carried out every 4 months. Results: After a median follow-up time of 38 months there was a statistically significant improvement in the number of total lymphocytes, T4/T8 ratio,NK and a trend for VEGF decrease. Median progression-free and overall survival were not reached yet, as 59% of patients were progression-free and 77% were alive. Fifteen patients were converted from partial to complete response. Toxicity was mild with grade 2 cutaneous toxicity and fever in 29% and 13% of patients, respectively. Conclusions: These preliminary data show that after chemotherapy, the administration of low-dose subcutaneous IL-2 and oral RA is feasible and has low toxicity. A sustained increase in the immunological parameters known to be prognostically relevant was observed and a clear benefit on tumor response from immunotherapy was obtained in 8.3% of patients that were converted from partial to complete response.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 991 (Synergistic therapies).