PURPOSE: Intravenous fluorouracil and leucovorin for six to eight months is currently a standard adjuvant treatment for Stage III colon cancer; however, this regimen is complex, inconvenient, and has a high intolerability. Adjuvant chemotherapies are claimed for objective response rates with an acceptable safety profile and complexity. We investigated the benefits of oral protein-bound polysaccharide K added to oral tegafur/uracil on curatively resected Stage II or III colorectal cancer. METHODS: We prospectively randomized 207 patients to treatments of either oral 3.0 g protein-bound polysaccharide K plus 300 mg tegafur/uracil or 300 mg tegafur/uracil alone for two years following 12 mg/m2 and 8 mg/m2 mitomycin treatment on postoperative Days 1 and 2, respectively. The primary end points were disease-free and overall survival, and recurrence rates. RESULTS: Three (1.4 percent) patients were declared ineligible, and three patients did not start treatment. In total, 201 patients were analyzed. The three-year, disease-free survival rate was 80.6 percent (standard error = 3.4 percent) in the protein-bound polysaccharide K group (P = 0.02) compared with 68.7 percent (SE = 5.7 percent) in the control group after a median follow-up of 3.7 years. The estimated relative risk of recurrence in the control group was 1.87 (95 percent confidence interval, 1.10-3.20) at three years. The three-year, overall survival rate was 87.3 percent (standard error = 2.9 percent) in the protein-bound polysaccharide K group and 80.6 percent (standard error = 4.8 percent) in the control group (P = 0.24). The three-year, overall survival rate in 80 pathological TNM Stage III patients was 83.0 percent (standard error = 5.2 percent) in the protein-bound polysaccharide K group and 59.3 percent (standard error = 9.5 percent) in the control group (P = 0.02). Protein-bound polysaccharide K prevented distant metastases (P = 0.05), particularly lung metastases (P = 0.01). The incidence of adverse effects was minimal, and compliance was good. CONCLUSION: Adjuvant therapy using a combination of oral protein-bound polysaccharide K and tegafur/uracil is highly effective in preventing the recurrence of colorectal cancer in Stage II or III patients, and increases overall survival in pathological TNM Stage III. These results will be a sufficient proof to conduct a larger study to compare tegafur/uracil/protein-bound polysaccharide K with 5-fluorouracil/leucovorin.
Intravenous fluorouracil and leucovorin is the standard adjuvant treatment for stage III colon cancer. However, oral adjuvant chemotherapy is attractive because it has low toxicity and greater convenience. We investigated the benefits of oral protein-bound polysaccharide K (PSK) with tegafur/uracil (UFT) as an adjuvant in stage II and III colorectal cancer. Patients were assigned to groups that received either 3 g PSK plus 300 mg UFT, or 300 mg UFT alone orally each day for a 2-year period following intravenous mitomycin C. Of 207 registered patients, 205 with stage II (n¼123) or III (n¼82) were analysed. The 5-year disease-free survival was 73.0% (95% CI 65.6–80.4%) with PSK (n¼137) and 58.8% (95% CI 47.1–70.5%) in the controls (n¼68) (P¼0.016). POLYSACCHARIDE K reduced the recurrence by 43.6% (95% CI 4.5–66.7%) and mortality by 40.2% (95% CI _12.5 to 68.3%). The 5-year survival was 81.8% (95% CI 75.3–88.2%) in the PSK group and 72.1% (95% CI 61.4–82.7%) in the control group (P¼0.056). In stage III patients, disease-free and overall survivals in patients receiving PSK were increased significantly: 60.0% (95% CI 47.1–72.9%) and 74.6% (95% CI 63.0–86.1%) in the PSK group as compared with 32.1% (95% CI 14.8–49.4%) and 46.4% (95% CI 28.0–64.9%) in the controls (P¼0.002 and 0.003, respectively). Polysaccharide K prevented recurrence, particularly lung metastases (P¼0.02; odds ratio 0.27; 95% CI 0.09–0.77). In the models, the presence of regional metastases (relative risk, 2.973; 95% CI 1.712–5.165; Po0.001), omission of PSK (relative risk, 2.106; 95% CI 1.221–3.633; P¼0.007), and higher primary tumour (relative risk, 4.398; 95% CI 1.017–19.014; P¼0.047) were each significant indicators of recurrence. Adverse effects were mild and compliance was good. Oral PSK with UFT reduced recurrence in stage II and III colorectal cancer, and increased survival in stage III.