Effect of interleukin-2 (IL-2) and 13-cis retinoic acid (RA) on vascular endothelial growth factor (VEGF) and durable response in patients with advanced solid tumors showing a partial response (PR) or stable disease (SD) to chemotherapy

Abstract

2521 Background: A large proportion of patients with advanced solid tumors (AST), showing response to chemotherapy, experiences relapse from resistant stem cells that form minimal residual disease (MRD). High serum levels of VEGF have been shown to be associated with MRD and with a short relapse-free survival (RFS). We have shown, that low-dose IL-2 and RA, decreased VEGF and enhanced the immune function of patients with AST responding to chemotherapy (Clin Cancer Res 2001, Anticancer Res 2005). Primary endpoint of this study was to evaluate if IL-2/RA decreased VEGF and restored the immune function in patients with AST that had a PR or SD to chemotherapy. Secondary endpoint was the evaluation of the efficacy of IL2/RA in RFS and overall survival (OS). Methods: 100 consecutive AST patients (66% PR, 34% SD), with a mean VEGF of 520 pg/mm3, were entered into the study from 01/97 to 05/04. Median age was 66 years with 57% males. Diagnosis: Lung 28, head & neck 15, kidney 13, gastric 11, ovary 10, breast 10, miscellanea 13. Therapy consisted of self-administered subcutaneous IL-2, 1.8 X 106 IU and oral RA, 0.5 mg/Kg for 5 days/week for 2 cycles of 3 weeks, with a 1-week rest, for 1 year. Therapy was continued, with intermittent schedules until progression. Immune function and tumor markers were assessed every 2 months, response every 4 months. Results: After a median follow-up time of 42 months (16–106) and 900 courses of therapy, a statistically significant decrease of VEGF (148 pg/mm3, p<0.002) and improvement of lymphocytes, NK and CD4+/CD8+ ratio, with respect to baseline values, was observed. 5-year RFS and OS were 30% and 38%, respectively. 28% of patients were converted to a complete response: Their 5-year RFS and OS were 73% and 94%, respectively. No WHO grade 3 or 4 toxicity was observed, while grade 2 cutaneous toxicity and fever occurred in 20% and 13% of patients, respectively. Conclusions: The administration of IL-2/RA determines, with a low toxicity profile, a statistically significant decrease of VEGF, an improvement of all immunological parameters known to be prognostically relevant and a durable clinical response in 28% of patients. No significant financial relationships to disclose.