Biological, histological, and clinical impact of preoperative IL-2 administration in radically operable gastric cancer patients.
OBJECTIVE
Surgery induces lymphocytopenia and this decrease of host defenses, related to interleukin-2 (IL-2) endogenous imbalance during postoperative period could promote the proliferation of possible micrometastases and the implantation of surgically disseminated tumor cells. Moreover, tumor infiltrating lymphocytes (TILs), activated by endogenous IL-2 release, are linked to prognosis in cancer patients. The aim of this randomized study is to assess the biological (peripheral blood cells count, related to the grade of immunosuppression), histological (TILs), and clinical (overall and disease-free survival) impact of preoperative low doses administration of IL-2 in patients with radically operable gastric cancer.


METHODS
This prospective study enrolled 69 consecutive patients with histologically proven gastric adenocarcinoma who underwent radical surgery from October 1999 to December 2002 (M/F 39/30; mean age 66; range 42-82) who underwent radical surgery from October 1999 to December 2000. Patients were randomized to be treated with surgery alone as controls (35 patients) or surgery plus preoperative treatment with recombinant human IL-2 (34 patients). We considered the total lymphocyte count and lymphocyte subset (CD4, CD4/CD8) during the preoperative period, before IL-2 administration, and on the 14th and 50th day, peritumoral stromal (fibrosis) reaction, neutrophils, lymphocytes, and eosinophils infiltration in tumor histology, and morbidity disease free and overall survival were evaluated.


RESULTS
Two groups were well matched for type of surgery and extent of disease. All the patients underwent radical surgery plus D2 lymphadenectomy. At baseline, there were no significant differences in total lymphocyte and lymphocyte subsets between groups. The control group showed a significant decrease of total lymphocytes, CD4 cells, and CD4/CD8 ratio at the 14th postoperative day relative to the baseline value. In the control group 65% of patients had a decrease of CD4 under 500 cells/mmc. Instead it has been observed in IL-2 group a significant increase over the control group values of total lymphocytes and CD4 cells (14th total lymphocytes and CD4: IL-2 vs. control P < 0.05). Moreover in this group only 15% patients had CD4 under 500 cells/mmc. This difference, in CD4 count, is significant even at the 50th postoperative day (P = 0.006). IL-2 group showed lower postoperative complications (2/34 vs. 11/35; P < 0.05), and higher lymphocyte/eosinophil infiltration into the tumor (P < 0.0002). Median follow-up was 26 months (range 10-48) and median overall and disease-free survivals were longer, even if not significantly, in the IL-2 group than in the control arm (P = 0.07 and P = 0.06 respectively).


CONCLUSIONS
This randomized study would suggest that a preoperative immunotherapy with IL-2 is a well-tolerated treatment able to prevent surgery-induced lymphocytopenia. IL-2 seems to neutralize the immunosuppression induced by operation and so to stimulate the host reaction against tumor tissue (lymphocytes/eosinophils infiltration). Furthermore IL-2 seems to have an impact on clinical course reducing morbidity of surgery and ameliorating overall and disease-free survival.
Romano
Fabrizio
F
Department of Surgery, San Gerardo Hospital--II University of Milan--Bicocca, Italy. fabriziorom@hotmail.com
Cesana
Giovanni
G
Berselli
Mattia
M
Gaia Piacentini
Maria
M
Caprotti
Roberto
R
Bovo
Giorgio
G
Uggeri
Franco
F
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000601:surgery*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016516:CD4-CD8 Ratio; D018572:Disease-Free Survival; D005260:Female; D005743:Gastrectomy / Q000401:mortality; D006801:Humans; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D007376:Interleukin-2 / Q000008:administration & dosage*; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000637:transplantation; D008231:Lymphopenia / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D011300:Preoperative Care; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000601:surgery*
D000970:Antineoplastic Agents; D007376:Interleukin-2; D011994:Recombinant Proteins