Although surgeical treatment is the most effective treatment for gastiric cancer, the adjuvant chemotherapy is of prime importance for the prevention of postoperative recurrence and the prolongation of survival.

Advances in surgical techniques improved the therapeutic results for gastric cancer, yet it reached its limit for the patients who had advanced disease. Radiotherapy has no effect against gastric cancer. Chemotherapy is not yet satisfactory as a treatment for advanced gastric cancer.

Reccently Immunotherapy has shown promised as another therapeutic modality by improving the survival of the patients with gastric cancer.

Levamisole was originally developed as an anthelmintic. Since Renoux et al¹⁾. reported increasd immune response of the host after receving levamisole, Levamisole has been known to have a broad range of immunmodulatory effects. It includs the enhancement of antibody production to several different antigens, augumentation of a variety of cellular immune responses, synergistic activity with T-lymphocyte mitogens and increasing those immune responses depressed by disease or immunosupressive therapy.

The ability of levamisole to restore normal functions of phagocytes and T lymphocytes in compromised hosts has suggested its potential usefulness in immunotherapy²⁾ for malignacy. Preliminary results in lung cancer and breast cancer has shown a survival gain in patients treated with levamisole^3,4). Treatment with levamisole plus 5-fluorouracil reduced recurrence of colon cancer and death rate in patients with resected stage C colon cancer⁵⁾. Furthermore, early reports indicated that side-effects were relatively uncommon and mild, leading to discontinuation of treatment in only 4.9% of 1179 colon cancer patients.

Effectiveness in the other types of tumors, including stomach cancer, has not been established.

We wish to report the results of a prospective, randomized, controlled study to determine the effectivenss of levamisole when it was added to conventional chemotherapy as an adjuvant therapy to surgery in patients with operable gastric cancer. The goals were to confirm the preliminary obervations of the disease free survival, overall survival and toxicity of levamisole.

From April 1991 to December 1992, 100 patients with gastric cancer who underwent curative resection in the Department of Surgery, University of Ulsan, Asan Medical Center, were assigned randomy to either group, one with or one without levamisole. Patient eligigibility was established at the time of the study entery.

The criteria for patients selection were as follows: 1) histologic documentation of adenocarcinoma of the stomach; 2) no privious treatment for cancer; 3)TNM stage IB or higher; 4) a potentially curative en bloc resection of tumors without gross or microcopic evidence of residual disease; 5) adequate bone marrow, renal and hepatic functions. Entry into the study was allowed no earlier than one week and no later than five weeks after surgery. All patients entered into the study gave informed consent and were randomly assigned to either chemotherapy with levamisole or chemotherapy alone. Both group had periodic evaluations. All patients were followed for total postoperative survival period. The patients attended the follow-up clinic at monthly intervals. On each visit, they were examined for evidence of recurrent tumor. Relevant investigatins were performed if tumor presence was suspected. Unless the side-effects were considered unacceptable, each treatment group received treatment for 6 months.

Hematologic testing and blood-chemistry panels were repeated every four weeks. The levamisol group received levamisole by mouth at a dose of 50mg every eight hours for a period of three days: this was repeated every two weeks for 6 months. Chemotherapy were consisted of 5-FU 1,000mg/m²/day administered as a continuous intravenous infusion for 5 days and cisplatin 60mg/m²/day as intravenous infusion for 1 day. This chemotherapy regimen repeated every 4 weeks for 6 cycles. Patients were required to have a white blood cell count (WBC) greater than 4,000/mm and a platelet counts(plateletes) greater than 150,000/mm. to receive therapy.

To receive midcycle of chemotherapy, the WBC had to be above 3,000/mm and platelets greater than 100,000/mm.

Criteria for recurrence included documentation by histologic or cytologic examination, or by evidence of metastases on the chest and bone x-ray.

Survival was the primary end point of this study. The time of the recurrence was also determined. Statistical analysis were carried out according to the procedures of the Statistical Analysis System. The survival curves were generated by the Kaplan-Meier method. The log-rank statistic was used to compare the distributions of survival times. The Cox propotional-hazards model wse used to determine the ratios of relapse and survival rates and to perform all multivariate analyses.

Levamisole has been extensively evaluated in clinical trials for various cancer therapy, particuarly in the minimal disease as a adjuvant therapy after surgical treatment. There have been many reports showing a significant improvement in duration of remission and survival by actuarial analysis in the levamisole-treated group in the cases of cancers of the lung, colon and rectum⁵⁾. The addition of levamisole to combination chemotherapy was found to increase both the response rate and survival in a randomized double-blind trial in patients with breast cancer and gastric cancer in one study⁶⁾.

Another study failed to show a beneficial effect of additional levamisole⁷⁾. In an experimental model system of KHT sarcoma in mice, the addition of levamisole did not improve local tumor control. It did not decrease the incidence of metastases^8,9). Levamisole was found to have a negative influence on survival in a multihospital randomized trial in patients with extensive lung cancer. The does-related toxicity of levamisole was also found to be significant⁷⁾. The results from a large series of 720 patients with breast cancer showed that the patients with N+M0 disease developed a significantly higher recurrence rate after total mastectomy with partially axillary lymph node biopsy when levamisole was combined with radiotherapy¹⁰⁾. In malignant melanoma, the National Cancer Institute of Canada, Clinical Trials Group, conducted a similar study and reported benefit in the groups of patients receving levamisole¹¹⁾. However, in this same study, when levamisole was combined with BCG, no advantage whatever was obtained and in a comparable melanoma’ adjuvant trial, Spittler et al found levamisole therapy to produce no advantage over placebo in either time to recurrence or survival¹²⁾. In individual experiments with Moloney virus-induced rhabdomyosarcomas in BALB/c mice, levamisole treatmment seemed to be associated with an accelerated growth of the primary tumor, but this was not significant and even counter-balanced by a greater number of animals which showed inhibited tumor growth with levamisole⁷⁾. The investigators, therefore, concluded that levamisole had no effect on the primary growth of these tumors. In an allogeneic model using L 1210 leukemia transplanted to C3H mice, an increased number of tumor takes was observed with levamisole treatment. This effect was associated with an elevated level of serum blocking activity and possible immunologic enhancement of tumor growth by levamisole. In light of the findings of Amery et al., levamisole is more effective when given prior to surgery. Japan Levamisole Research Association Group reported¹³⁾, at operable gastric cancer patients receiving 600 mg Tegafur daily were then divided into two groups according to whether levamisole was given or not. The 2-year follow-up demonstrated that in stage III patients, the levamisole group was superior to the non-levamisole group, since the former prolonged the relapse-free interval significantly. The survival rate for stage III disease was also significantly higher in the levamisole group than in the non-levamisole group.

In our study, levamisole was added to the basic combination of cisplatin and 5-FU because the combination of cisplatin and 5-FU seems to be significantly more effective than the single agent treatment. However, in our trial, a poorer survival was found for en bloc resection of gastric cancer patients treated with levamisole than for non-levamisole groups. Our current findings would indication that the adjuvant use of levamisole to conventional chemotherapy in patients with gastric cancer after surgery did not provide an additional beneficial effect on duration or survival rate; in fact, in operable gastiric cancer patients, a negative influence on survival over a 3-year follow-up period was observed. In 1980, Brincker¹⁰⁾ published his results of an interim analysis of a study very similar to ours and stated that levamisole was leading to a higher incidence of recurrences.

Our study shows no evidence of a favorable or unfavorable effect of levamisole on prognosis. The size of the study does not exclude the possibility of the existence of a small positive or negative effect. Our conclusion is that levamisole does not have any clinically significant influence on prognosis of patients with resectable gastric cancer. The both treatment arms were generally well tolerated and the toxicity profile was similar with or without levamisole.