title: Phase-II randomized study of preoperative IL-2 administration in radically operable gastric cancer patients.
abstract: OBJECTIVE
  Surgery has appeared to induce lymphocytopenia and this decrease in host defenses during postoperative period could promote both the proliferation of possible micrometastases and the implantation of surgically disseminated tumor cells. The aim of this study is to evaluate if the preoperative subcutaneous injection of IL-2 (interleukin-2) may be able to abrogate surgery-induced immunosuppression in radically operable gastric cancer and to assess its toxicity.
  
  
  METHODS
  This phase II study included 39 consecutive patients with histologically proven gastric adenocarcinoma (M/F 26/13; mean age 68; range 48-82) who underwent radical surgery from October 1999 to December 2000. Patients were randomized to be treated with surgery alone as controls (20 patients) or surgery plus preoperative treatment with recombinant human IL-2 (19 patients). IL-2 was administered subcutaneously, at a dose of 9,000,000 IU, for three consecutive days, followed by surgery within 36 hours from IL-2 withdrawal. 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.
  
  
  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. Among the 22 patients evaluated in the control group 13 had a decreased of CD4 under 500 cells/mm3 (65%). Instead in the IL-2 group a significant increase was observed over the control group values of total lymphocytes and CD4 cells (14th ly total and CD4: IL-2 vs. control p<0.05). Moreover in this group only 3 patients had CD4 under 500 cells/mm3 (15%). This difference in CD4 count, is significant at the 50th postoperative day too (p=0.006). No anesthesiologic or surgical complication was seen in IL-2 treated group, with low grade of toxicity (WHO grade:1): the main effect was fever (14/19) easily manageable, with no cardiovascular complications. Furthermore, IL-2 group showed lower postoperative complications (p<0.05) and higher lymphocyte/eosinophil infiltration into the tumor (p<0.002).
  
  
  CONCLUSIONS
  This phase II 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). Next randomized clinical trials could investigate the prognostic impact of IL-2 on the clinical course.
authors.affiliation: Department of Surgery, San Gerardo Hospital, II University of Milan, Bicocca, Italy. fabriziorom@hotmail.com
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Romano
authors.forename: Maria Gaia
authors.initials: MG
authors.lastname: Piacentini
authors.forename: Claudio
authors.initials: C
authors.lastname: Franciosi
authors.forename: Roberto
authors.initials: R
authors.lastname: Caprotti
authors.forename: Sergio
authors.initials: S
authors.lastname: De Fina
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cesana
authors.forename: Fabio
authors.initials: F
authors.lastname: Uggeri
authors.forename: Matteo
authors.initials: M
authors.lastname: Conti
authors.forename: Franco
authors.initials: F
authors.lastname: Uggeri
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology* / Q000601:surgery*; D000368:Aged; D018791:CD4 Lymphocyte Count; D016516:CD4-CD8 Ratio; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005743:Gastrectomy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011183:Postoperative Complications / Q000517:prevention & control; D011300:Preoperative Care / Q000379:methods; D011379:Prognosis; D012016:Reference Values; D018570:Risk Assessment; D013274:Stomach Neoplasms / Q000401:mortality / Q000473:pathology* / Q000601:surgery*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D007376:Interleukin-2