BACKGROUND: Immune tolerance seems to correlate with disease progression and T regulatory cells (Tregs) and myeloid-derived suppressor cells play a relevant role in immunosuppression. Cyclophosphamide (Cyt) and Fluorouracil (FU) seem to reduce these cell populations. METHODS AND OBJECTIVE: Establishing safety, feasibility, activity and impact on the immune system (neutrophil/lymphocyte [N/L], platelet/L [Plt/L], monocyte [M] and lymphocyte subpopulation (CD3, CD4, CD8, CD16, HLADR/CD3, Tregs, cells count), CD8/Treg and C-reactive protein (CRP). TREATMENT: 1) Cyt 300 mg/sqm ± FU 500 mg/sqm day (d) 1 and interleukin 2 (IL-2) 18 MUI/sqm intravenous (I.V.) d 4-6, 18-20 or 2) Cyt 300 mg/sqm + FU 500 mg/sqm day d 1, IL-2 4.5 MUI subcutaneous (S.C.) d 3-6, 17-20. The cycle was repeated every four weeks for 2 cycles. Stable or responding patients (pts) continued therapy for 3 cycles. RESULTS: From February 2014 to December 2016, 13/14 pre-treated pts (mean 3 lines) with solid tumors were enrolled. Male/Female: 1/1. The median age and Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 68 years and 1 respectively. Mean 2 cycles of therapy were administered. G3-4 toxicities presented as diarrhea and bleeding anemia in 2 pts and proteinuria and erhytroderma in 1pt, respectively. Regarding the hematological profile, a more reduction in Plt, less decrease of Plt/Ly, and less increase of Treg with I.V. than S.C. IL-2 administration was observed. However a transient decrease of Treg on day 7 of first cycle in the I.V. IL-2 was reported. RESPONSE: PR 3 (23%), SD 3 (23%), PD 7 (54%). The response duration was 2+ and 3 months in 2 HCC and 18+ months in the pancreatic cancer (PC). Pathological CR was reported in one HCC treated with I.V. IL-2. The median progression-free-survival (PFS) and overall survival (OS) were 1 and 7 months. CONCLUSION: Cyt-FU-IL-2 can be considered safe, feasible and moderately active in heavily pre-treated pts. Plt, Plt/Ly, CD8/Treg and a transient Tregs reduction were observed without significative difference on survival.
Lo Re, G., Lo Re, F., Doretto, P., Del Conte, A., Amadio, M., Cozzi, C., Casarotto, M. M., Maruzzi, D., Marus, W., Ubiali, P., & Sandri, P. (2019). Cyclophosphamide with or without fluorouracil followed by subcutaneous or intravenous interleukin-2 use in solid tumors: A feasibility off-label experience. Cytokine, 113, 50-60. https://doi.org/10.1016/j.cyto.2018.06.005