Protein-bound polysaccharide K (KRESTIN®; Kureha Chemical Industry Co., Japan), extracted from the mycelia of Coriolus versicolor, has immunomodulatory activities. It induces the production of interleukin (IL)-2 and interferon (IFN) γ, thereby stimulating lymphokine-activated killer cells (LAK) and enhancing natural killer (NK) cells (Hirose et al, 1990; Hayashida et al, 1991; Ebina and Murata, 1992; Kato et al, 1995; Yefenof et al, 1995; Algarra et al, 1997; Harada et al, 1997; Pedrinaci et al, 1999). We have reported that adjuvant therapy with PSK increases the levels of cytotoxic T cells, helper T cells, and NK cells in patients with resected colorectal cancer (Ohwada et al, 1994).

Protein-bound polysaccharide K and UFT are popularly used for adjuvant immunochemotherapy in gastric cancer patients in Japan. In a few reports, PSK and UFT have been used as adjuvant chemotherapy in colorectal cancer. A randomised, double-blind trial of stage III and IV colorectal cancers using the rules for colorectal cancer in Japan (this stage corresponds to AJCC stage III) showed that PSK provided significant benefits in improving disease-free and overall survival. The beneficial effects of PSK have been attributed to the activation of leucocyte chemotactic locomotion and phagocytic activity (Torisu et al, 1990). Adjuvant chemotherapy with PSK for over 3 years, and oral 5-FU for 2 years, following intravenous mitomycin C (MMC®), significantly increased the disease-free survival rate, as compared with 5-FU alone in patients with curatively resected colorectal cancer (Mitomi et al, 1992). These results were promising evidence of survival benefits, and encouraged us to use oral PSK together with UFT as an adjuvant immunochemotherapy.

To investigate the benefits of immunochemotherapy with oral PSK plus UFT, we conducted a randomised, controlled trial comparing PSK and UFT in combination, with UFT alone, for 2 years, in cases of curatively resected stage II and III colorectal cancer. Here, we report the results of a 5-year follow-up.

After a 5-year follow up, the rate of recurrence was 36.5% with UFT monotherapy and 23.3% with UFT/PSK, with the majority of recurrences being distant metastasis. PROTEIN-BOUND POLYSACCHARIDE K achieved a 57.5% absolute reduction in recurrence at the 5-year follow-up. The recurrence rate was 34.9–37% for stages II and III, and 33.5–39.3% for stage III with 5-FU/LV and 5-FU/levamisole treatment (QUASAR, 2000; Porschen et al, 2001), whereas the rates were 49–60% without adjuvant chemotherapy. PROTEIN-BOUND POLYSACCHARIDE K reduced the risk of recurrence by 43.6% in stages II and III, and by 63.4% in pathologic stage III, which is equivalent to the reported 33.5–41% with 5-FU/levamisole or 5-FU/LV (Moertel et al, 1990; Francini et al, 1994; IMPACT, 1995).

In curative resected stage III colon cancer, the 4-year survival estimates range from 46 to 57% (Moertel et al, 1990; Francini et al, 1994; IMPACT, 1995). Adjuvant therapy with 5-FU/levamisole increased postoperative survival to 71% at 3 years (Moertel et al, 1990). Further, adjuvant treatment with 5-FU modulated by LV increased 4-year survival to over 71–72% (Francini et al, 1994; IMPACT, 1995; QUASAR, 2000; Porschen et al, 2001). In our stage III patients, the 4-year disease-free and overall survival rates were 69.1 and 78.2% in the PSK group, as compared with 35.7 and 50% in the controls, respectively. The 5-year disease-free and overall survival rates were 60.0 and 74.6% in the PSK group, as compared with 32.1 and 46.4% in the controls, respectively. A randomised, double-blind study showed that the 5-year disease-free survival for PSK vs placebo was 38 vs 20%, and overall survival for PSK vs placebo was 50 vs 40%, respectively (Torisu et al, 1990). Survival with PSK/UFT treatment in pathologic stage III patients was comparable or superior to standard regimens of 5-FU/LV or 5-FU/levamisole (Moertel et al, 1990; Francini et al, 1994; IMPACT, 1995). However, survival with UFT monotherapy in pathologic stage III patients was worse, and was similar to that of untreated controls in standard regimen studies (Moertel et al, 1990; Francini et al, 1994; IMPACT, 1995). It is difficult to explain why survival in stage III was poor with UFT monotherapy; it might be explained by the difference in dose intensity of UFT. Tegafur/uracil was administered at a dosage of 600mgbody⁻¹ in three divided doses daily (Malik et al, 1990) or 300 or 350mgm⁻²day⁻¹ with LV (Saltz et al, 1995) in metastatic colorectal cancer. Our dose of UFT was less than that in those studies, despite the absence of LV modulation. There was a dose-dependent reduction in the odds of death for patients receiving 5-FU regimens (Zalcberg et al, 1996), while the dosage intensity was not a factor in the survival benefits (Higgins et al, 1976; Grage and Moss, 1981). Therefore, it remains speculative whether the poorer survival is explained by the difference in the dose intensity of UFT.

Studies may have shown a better tendency in overall survival, simply because the survival of pathologic stage II patients is so much better even without treatment. Another reason may be that the second-line treatments for recurrence, including chemotherapy and salvage surgical therapy, prolong the survival of these patients (Okumura et al, 1996; Goldberg et al, 1998; Saltz et al, 2000; Choti et al, 2002). All patients with recurrence received chemotherapy, trans-arterial chemotherapy, and salvage surgery (Tomizawa et al, in press). These treatments for recurrence certainly prolong overall survival and, in this era of active treatment, strategies for recurrence of disease-free survival may be more meaningful than overall survival, at least in the case of adjuvant chemotherapy for colorectal cancer.

The benefits of fluorouracil-based therapy for pathologic stage II colon cancer are unclear. While adjuvant active specific immunotherapy with BCG vaccine significantly lowered tumour recurrence in stage II colon cancer (Vermorken et al, 1999), we detected no beneficial effects of UFT/PSK with regard to the overall or disease-free survival rates in pathologic stage II cancer in this study, nor was it observed previously (Moertel et al, 1990; Mitomi et al, 1992). However, 20% of patients with pathologic stage II cancers die of recurrent disease, and lymph node micro-metastases are detected by molecular analysis in 54% of patients (Liefers et al, 1998). Molecular-based analyses would facilitate the selective use of adjuvant therapy and prevent unnecessary treatments.

Immunosuppressive acidic protein, isolated from the ascitic fluids of cancer patients, suppresses both phytohemagglutinin-induced lymphocyte blast formation and the mixed-lymphocyte reaction in vitro (Tamura et al, 1981). We expected the pre-operative IAP value to be a good predictor of PSK response, because a serum IAP value above 580μgml⁻¹, determined as an appropriate threshold value using Cox's proportional hazards model, has been reported to be a good indicator of enhanced survival in gastric cancer patients (Nakazato et al, 1994; Sakamoto et al, 1996). In Cox proportional-hazards regression models, the presence of regional metastases, omission of PSK, and higher primary tumour were each significant indicators of recurrence. Nevertheless, in this study, the pre-operative serum IAP level was not a significant predictor of survival.

The duration of adjuvant chemotherapy after colorectal cancer varies (Moertel et al, 1990; O'Connell et al, 1998; QUASAR, 2000; Porschen et al, 2001), and there is no consensus on the optimal duration of adjuvant chemotherapy. Currently, the standard adjuvant treatment for stage III colon cancer is 5-FU/LV for 6–8 months (Francini et al, 1994; IMPACT, 1995; O'Connell et al, 1998). When our study was designed, the optimal treatment duration was thought to be 2 years, because the risk of recurrence is greatest during that period and randomised controlled studies in which PSK and chemotherapy were administered for 18, 24, and over 36 months, showed a significant reduction in recurrence (Torisu et al, 1990; Mitomi et al, 1992; Nakazato et al, 1994, 1999). Indeed, in our study, 71% of cancers recurred during the first 2 years after surgery, and 85% recurred within 2 years and 6 months after surgery. The oral use of adjuvant chemotherapy with PSK and UFT has low toxicity, is simple, and does not require frequent treatment-related visits, thereby helping to ensure that patients receive treatment for 2 years.

Experimental studies have shown that PSK suppresses micro-metastases of the liver by enhancing the activities of NK cells and macrophages (Morinaga et al, 1994). It also reduces tumour cell invasiveness by downregulating several invasion-related factors, including TGF-β₁, urokinase plasminogen activator (uPA), and matrix metalloproteinases (MMPs)-2 and -9, which are produced by tumour cells (Zhang et al, 2000). PROTEIN-BOUND POLYSACCHARIDE K restores host immune functions that are suppressed by tumour or antitumour chemotherapeutic agents, thereby producing IL-2 and IFN γ, and stimulating the activities of LAK and NK cells. PROTEIN-BOUND POLYSACCHARIDE K induces IL-1, IL-6, and IL-8 in peripheral mononuclear cells, as well as tumour necrosis factor and macrophage chemotactic factor at the tumour sites (Hirose et al, 1990; Ebina and Murata, 1992), thereby activating programmed cell death (Yefenof et al, 1995; Lacour et al, 2001). Therefore, the increased disease-free survival rates and marked reduction in lung metastases seen in this study may be evidence of immunological and biochemical modulation by PSK.

The toxicity of adjuvant chemotherapy regimens needs to be considered in selecting the optimal therapy. Oral PSK and UFT have less frequent and lower grade toxicity than 5-FU/levamisole and 5-FU/LV (Moertel et al, 1990; IMPACT, 1995; O'Connell et al, 1998; QUASAR, 2000; Porschen et al, 2001). Only 6.3% of the patients in this study discontinued treatment because of adverse drug effects. Of our patients, 15.4% showed grade 1 or 2 haematological and gastrointestinal toxic effects, while none had grade 3 or 4 effects. Drug compliance was better and was confirmed by interviews and measurements of the urinary tegafur concentration, as compared with well-tolerated standard regimens (Moertel et al, 1990; IMPACT, 1995; O'Connell et al, 1998; QUASAR, 2000; Porschen et al, 2001).