Basal cytokines profile in metastatic renal cell carcinoma patients treated with subcutaneous IL-2-based therapy compared with that of healthy donors.
OBJECTIVE
Metastatic renal cell carcinoma (MRCC) has a poor prognosis with a median overall survival of about one year. Since only a minority of patients experienced therapeutic benefit to current treatments, several studies have attempted to identify factors that may have an impact on response and survival. Cytokines play a crucial role in the host's immune response by regulating the development and function of a lot of biological compartments. Nevertheless, available data on basal cytokine levels in MRCC are very few and no clear profile of serum cytokines has been identified yet in these patients population. Thus, determining the levels of cytokines in MRCC could not only help in understanding the biological mechanisms of the tumor growth, but also in evaluating if different cytokine profiles are correlated with particular clinical behaviors.


METHODS
In 144 healthy donors and 55 MRCC treated with subcutaneous IL-2-based regimens, we analysed a panel of basal cytokines particularly involved in the neoplastic progression (IL-1beta, IL-6, IL-8, IL-10, IL-12, alpha-TNF) and C-reactive protein (CRP) in order to compare their levels in the two groups, and to verify their impact on patient response and survival. We first compared cytokines levels in patients population and healthy donors. Than, in definite patients group, univariate and multivariate analyses were performed to evaluate the correlation existing between each factor considered and clinical outcomes. For these analyses, baseline values were included as dichotomous variables using the median values (above and below) of control group.


RESULTS
In general, higher levels of cytokines were found in patients with respect to those of healthy donors, both in term of percentage of undetectable levels or median values. The impact on response was insignificant, except for higher levels of CRP that were strongly correlated with a worse response (p < 0.001). Within the patients groups, a worse survival was associated with higher values of CRP (8 vs 31 months, p = 0.0000), IL-6 (9 vs 25 months, p = 0.0295), and IL-8 (9 vs 17 months, p = 0.0371). Conversely, higher levels of IL-12 were associated with a better survival (25 vs 15 months, months p = 0.0882). A correlation was found between CRP and IL-6 (p = 0.009) and between CRP and IL-10 (p = 0.038). After multivariate analysis only CRP (p = 0.0035) and IL-12 (p = 0.0371) maintained an independent impact on survival, while IL-6 showed a borderline value (p = 0.0792).


CONCLUSIONS
Higher cytokines levels characterize patients population with respect to healthy donors. Moreover, higher basal level of some immunosuppressive cytokines (CRP, IL-6, IL-8) result correlated with a poorer survival, whereas higher levels of IL-12, a cytokine with a potent antineoplastic activity, was associated with a better survival. A wider sample of patients is needed to better clarify if our findings are intrinsically related to patients population or if they are simply an epiphenomenon of disease progression.
Guida
Michele
M
Department of Medical Oncology, National Oncology Institute, Bari, Italy. micguida@libero.it
Casamassima
Addolorata
A
Monticelli
Giulia
G
Quaranta
Michele
M
Colucci
Giuseppe
G
D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002097:C-Reactive Protein / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000097:blood* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D016207:Cytokines / Q000097:blood*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000473:pathology; D007376:Interleukin-2 / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D009362:Neoplasm Metastasis; D012016:Reference Values; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000970:Antineoplastic Agents; D016207:Cytokines; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein