Abstract
Gastric adenocarcinoma is the third most common cancer and the second most common cause of death due to cancer worldwide. Surgery is still the major prognostic factor for gastric cancer. Patients who could not be resected have a poor prognosis with survival ranging from 3 to 11 months. There is evidence that surgical operations can cause a variety of immunological disturbances in man both in vivo and in vitro. The postoperative changes in the systemic immune response are proportional to the degree of surgical trauma leading to a generalized state of immunosuppression, which is implicated in the development of septic complications and provided a “fertile soil” for tumor cell metastasis. Immunotherapy may be a potentially promising alternative strategy for gastric cancer. In early clinical trials, systemic immunotherapy included both active vaccination directed against defined tumor-associated antigens expressed in gastric carcinoma cells and passive administration of IL-2 with some evidence of regression of metastatic gastric cancer. Other studies have applied immunotherapy in the adjuvant setting with equally promising results. For example, OK-432, a streptococcal preparation, demonstrated marginal improvement in survival for patients with stage III gastric cancer and a meta-analysis of centrally randomized controlled clinical trials indicated a significant survival benefit with combination OK-432 and chemotherapy compared to chemotherapy alone (p 0.05). Additional data suggesting a biological and clinical benefit of subcutaneous, preoperative administration of low-dose IL-2 in colon cancer encouraged us to evaluate low-dose IL-2 therapy in the neoadjuvant setting for patients with gastric adenocarcinoma who undergo surgery and to evaluate its effects on systemic and tumor infiltrating lymphocyte numbers. We also sought to determine if neoadjuvant low-dose IL-2 could influence the clinical outcome for patients undergoing gastric resection for cancer. We report the biological, histological and clinical results with the full accrual of patients and a median follow-up of 51 months.
Highlights
Other than characterize the peripheral blood count, such as Total peripheral WBC, neutrophils, total lymphocytes (CD3+), T helper lymphocytes (CD4+), cytotoxic lymphocytes (CD8+) and Natural Killers (NKs), we looked at the peritumoral infiltration and we graded its density according to the classification of Ropponen modified [165] and four grades were established, for both lymphocytic, eosinophylsic, and neutrophilic infiltration: negative (0: 0 cells/field ), weak (+: 1 - 30 cells/field), moderate (++: 30 - 50 cells/field), dense (+++: >50 cells/field)
According to our data low doses of IL-2 administered pre-operatively to patients with gastric cancer activate peripheral and peri-tumoral lymphocytes but did not affect prognosis and Kaplan-Meier analysis suggested no differences between cases and controls (Figure 4)
We know that only selected melanoma and renal cell carcinoma patients have a significant benefit from high-dose IL-2 therapy and for this reason we may require a much larger study to detect a benefit in patients with gastric carcinoma
Summary
A global cancer statistic made in 2002 [1] refers an incidence of gastric cancer of 8.6% worldwide (934,000 new cases per year in 2002), which poses it in fourth place behind cancers of the lung, breast, colon and rectum. It is still the second most common cause of death from cancer worldwide (700,000 deaths annually). The geographical distribution of stomach cancer has wide international variations; high-risk areas include East Asia (China, Japan), Eastern Europe, and parts of Central and South America. Survival is relatively high in North America, possibly due to early diagnosis following a greater number of endoscopic examinations performed for gastric disorders
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