Skip to main content
NCBI home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 2005 Aug 20;55(4):404–411. doi: 10.1007/s00262-005-0054-1

Efficacy of adjuvant Immunochemotherapy with polysaccharide K for patients with curatively resected colorectal cancer: a meta-analysis of centrally randomized controlled clinical trials

Junichi Sakamoto 1,✉, Satoshi Morita 2, Koji Oba 1, Takanori Matsui 3, Michiya Kobayashi 4, Hiroaki Nakazato 5, Yasuo Ohashi 6; Meta-Analysis Group of the Japanese Society for Cancer of the Colon Rectum6
PMCID: PMC11030578  PMID: 16133112

Abstract

The benefits of immunochemotherapy employing the biological response modifier polysaccharide K (PSK) for patients with curatively resected colorectal cancer was reassessed by means of a meta-analysis of data with center randomization from 1,094 patients enrolled in three clinical trials. In all three trials, patients were followed up for at least 5 years after surgery and enrollment of the last patient and outcomes for standard chemotherapy were compared with those for chemotherapy plus PSK. The endpoints were overall survival and disease-free survival; and intent-to-treat analysis was performed without patient exclusion. Data were analyzed using the weighted average of the individual log hazard ratios. The overall survival risk ratio for all eligible patients was 0.71 (95% confidence interval (CI) : 0.55–0.90; P=0.006), and the disease-free survival risk ratio was 0.72 (95% CI: 0.58–0.90; P=0.003). The results of this meta-analysis suggest that adjuvant immunochemotherapy with PSK can improve both survival and disease-free survival of patients with curatively resected colorectal cancer.

Keywords: Adjuvant immunochemotherapy, Colorectal cancer, Meta-analysis, Polysaccharide K

Introduction

Colorectal cancer is the third most common cancer in the world (9.4% of all new cancers) with two-thirds of cases occurring in developed countries [1]. In 2000, an estimated 94,500 new cases were diagnosed worldwide with 492,000 deaths (fourth highest after lung, stomach, and liver cancer). In Japan alone, the number of deaths was 80,000 in 2000; and is expected to climb to 110,000 by the year 2020.

At present, surgery and adjuvant chemotherapy with 5-FU/ Leucovorin/ Oxaliplatin have become the standard treatment for curatively resected colon cancer in Western countries [2]. In Japan, on the other hand, the efficacy of oral fluorinated pyrimidines in an adjuvant setting was demonstrated in a meta-analysis of randomized trials [3, 4]. Furthermore, the addition of immunotherapy to adjuvant chemotherapy can be expected to exert a synergistic effect [5]. One of the immunotherapy agents is polysaccharide K (PSK; Kureha Chemical Industry Co., Ltd., Tokyo, Japan), extracted from mycelia of the Coriolus versicolor strain CM-101, a member of the basidiomycetes [6]. It consists of proteins and polysaccharides, and its major glycoside portion is β-1, 4-gulcan with an average molecular weight of approximately 100 kDa. PSK is a potent inducer of gene expression for several interleukins, tumor necrosis factor, and monocyte activating factors (MCP-1). The antitumor activity of PSK is thought to be based on its regulation of the host immune response, and this nonspecific immunopotentiator is able to inhibit the immunosuppression of cancer patients. In Japan, it is widely prescribed for oral ingestion [7]. The beneficial effects of PSK have been attributed to the activation of leucocyte chemotactic locomotion and phagocytic activity [8]. Adjuvant chemotherapy with PSK and oral 5-FU, subsequent to intravenous mitomycin C (MMC), significantly increased the disease-free survival rate as compared with 5-FU alone in patients with curatively resected colorectal cancer [9]. It has been confirmed that PSK is more effective in the treatment of gastric cancer when intermittently administered followed by alternating chemotherapy [10]. However, the immunochemotherapeutic efficacy of PSK plus chemotherapeutic agents for colorectal cancer remains unclear.

The aim of the study presented here was to evaluate the combined data from published and unpublished randomized clinical trials for a comparison of the effect of adjuvant immunochemotherapy using PSK with that of chemotherapy alone for patients who had undergone curative resection of colorectal cancer.

Materials and methods

Literature search

In December 2004, a search of the MEDLINE database was performed and inquiries were made from the pharmaceutical industry regarding clinical trials published since 1980, with an abstract in either English or Japanese, of polysaccharide-K (PSK), or Krestin used for colorectal cancer patients. The collected reports were summarized independently by two of the authors using a standard form. The two resultant summaries for each report were compared to ensure there were no discrepancies. The following questions were used to decide the eligibility of the trial: (1) Was the aim of the study the evaluation of the effect of adjuvant chemotherapy with or without PSK administration? (2) Was it a randomized trial with central assignment to avoid bias? (3) Was adjuvant therapy administered after curative tumor resection? (4) Was there a control arm that received the same adjuvant chemotherapy as the therapeutic arm?

The adjuvant chemotherapy regimens, the number of patients in each arm, the number of deaths in each arm, and the follow-up period were recorded for each trial selected on the basis of these four questions.

Statistical methods

We used the weighted average of the individual log hazard ratios to analyze pooled estimates of the common relative risk and its confidence interval [11]. The chi-square test was used to test heterogeneity among the individual hazard ratios.

For each individual trial, the log hazard ratio and its variance were calculated from the number of observed events, the number of randomized patients, and the P-value for the log-rank test obtained with the indirect log hazard ratio and variance estimation method [11]. A relative risk of 1.0 indicated no effect of immunochemotherapy on crude mortality and recurrence of disease, whereas a ratio of less than 1.0 meant a beneficial effect of immunochemotherapy, and a ratio above 1.0 meant a harmful effect. SAS for Windows, release 8.02 (SAS Institute Inc., Cary, NC, USA) was used for all analyses.

Results

Review and evaluation of retrieved reports

The 48 papers identified as potentially relevant are summarized in Table 1, together with the reasons for exclusion. Screening of the 48 selected abstracts for relevant trials yielded 10 reports that qualified for retrieval. Of the remaining 38 abstracts, 12[12, 13, 14–26] were of preclinical studies, five [6, 27–30] of review articles, two [31] and [32] of studies using randomization with other modalities (adjuvant chemotherapy [31] or preoperative radiation [32]) than PSK administration, three [33–35] of adjuvant immunochemotherapy studies without a randomized control arm, four [36–39] of studies that examined immunologic parameters as the endpoint. In addition, one [40] was a letter commenting on an article [41], and eight articles [42–49] dealing with non-resectable cases.

Table 1.

The list of potentially relevant papers in this meta-analysis

Authors Excluded reasons
Saji et al. [33] Without a randomized control arm
Saeki et al. [42] Dealt with non-resectable cases
Nakazato et al. [53] Included (retrieved for detail evaluation)
Matsunaga et al. [14] Pre-clinical study
Yasutomi et al. [27] Review article
Nishizawa et al. [43] Dealt with non-resectable cases
Takashima et al. [64] Included (retrieved for detail evaluation)
Mitomi et al. [55] Included (retrieved for detail evaluation)
Kimura et al. [31] Randomization with other modalities
Ishigaki et al. [44] Dealt with non-resectable cases
Torisu et al. [8] Included (retrieved for detail evaluation)
Masayoshi et al. [45] Dealt with non-resectable cases
Mitomi et al. [56] Included (retrieved for detail evaluation)
Ebina et al. [12] Pre-clinical study
Nio et al. [36] Examined immunologic parameters as the endpoint
Hayashibe et al. [37] Examined immunologic parameters as the endpoint
Toshino et al. [46] Dealt with non-resectable cases
Mitomi et al. [9] Included (retrieved for detail evaluation)
Kanoh et al. [15] Pre-clinical study
Suo et al. [16] Pre-clinical study
Kaneoka et al. [47] Dealt with non-resectable cases
Noguchi et al. [17] Pre-clinical study
Ebina et al. [18] Pre-clinical study
Kobayashi et al. [6] Review article
Sugimachi et al. [38] Examined immunologic parameters as the endpoint
Sugiyama et al. [19] Pre-clinical study
Harada et al. [13] Pre-clinical study
Kamei et al. [20] Pre-clinical study
Ikeda et al. [48] Dealt with non-resectable cases
Ogihara et al. [21] Pre-clinical study
Matsunaga et al. [22] Pre-clinical study
Sakamoto et al. [28] Review article
Matsunaga et al. [23] Pre-clinical study
Kidd et al. [29] Review article
Mukai et al. [49] Dealt with non-resectable cases
Kudo et al. [50] Included (retrieved for detail evaluation)
Okuzawa et al. [44] Pre-clinical study
Fisher et al. [30] Review article
Munemoto et al. [34] Without a randomized control arm
Shibata et al. [39] Examined immunologic parameters as the endpoint
Ohwada et al. [51] Included (retrieved for detail evaluation)
Wada et al. [25] Pre-clinical study
Koda et al. [32] Randomization with other modalities
Ito et al. [52] Included (retrieved for detail evaluation)
Ohwada et al. [41] Included (retrieved for detail evaluation)
Yoshikawa et al. [26] Pre-clinical study
Munemoto et al. [25] Without a randomized control arm
Alliot et al. [40] Letter commenting
Open in a new tab

Relevant trials

The references of the ten qualifying articles were also reviewed (Table 2). The quality of the study design and the reporting of the results were evaluated, including protocol therapies of both—PSK and control arm—the method of randomization, the definition of ineligible patients, and the number of exclusions and subjects lost to follow-up. Six reports were published in English [8, 9 and 50–52], and four in Japanese [53–55 and 56]. A comparison of the number of the cases and the period of study, indicated that three articles [55, 9, 56] seemed to deal with the same study, while two [51, 41] appeared to be descriptions of the same cases. Three reports [8, 53, 54] were considered to be inadequate for this meta-analysis, because of comparison with a surgery alone group [53], with suppository usage of tegafur [54], or because it was an analysis of simple immunotherapy without combination with chemotherapy [8]. One study [50] did not seem to be randomized. Eventually, three studies [9, 51, 52] covering 1,094 patients were analyzed. In these studies, the effect of immunochemotherapy including PSK and oral fluorinated pyrimidines was compared with that of chemotherapy alone.

Table 2.

Randomized clinical trials using PSK in patients with colorectal cancer

Authors Randomization Patient accrual Treatment/control arms No. of patients Conclusion
With PSK Without PSK
Nakazato et al. [53] Envelope 1977.07–1980.06 esquinon±PSK 75 36 NS, P=0.018 in subset (Dukes’C & long(>6weeks) administration)
Takashima et al. [54] Envelope 1980.09–1983.12 MMC → tegafur supp. ±PSK 53 71 NSP<0.05 in ly (+) subset
Mitomi et al. [55] (see article no.56)
Torisu et al. [8] Double blind not described PSK only vs. placebo 56 55 P<0.05
Mitomi et al. [9] (see article no.56)
Mitomi et al. [56] Envelope 1985.03–1987.02 MMC → oral 5-FU ±PSK 221 227 P=0.0325(OS), 0.0302(DFS)
Kudo et al. [50] Not described 1995.09–1997.11 oral fluoropyrimidine ±PSK 48 10 P=0.0467 in DFS, (OS; not described)
Ohwada et al. [51] (see article no.41)
Ito et al. [52] Center 1991.02–1993.03 5-FUciv → oral 5-FU ±PSK 220 221 NS (cancer death; significant)
Ohwada et al. [41] Center 1994.10–1997.03 MMC → oral UFT ±PSK 137 68 DFS P=0.016 (OS; P=0.056)
Open in a new tab

In each of these three trials, the chemotherapy and immunochemotherapy arms were balanced with regard to the number of patients 1:1 [9, 51], 1:2 [52]. Although there were slight differences in the control chemotherapy regimen used for the three trials, chemotherapy usually consisted of induction with mitomycin C plus long-term administration of oral fluorinated pyrimidines. In all trials, the effect of immunochemotherapy including PSK was compared with that of chemotherapy alone.

Results of meta-analysis

Survival duration for all three trials was calculated starting from the date of the colorectal cancer operation. It can therefore be assumed that the combined survival odds ratio of the three trials is well synchronized and appropriate. For our meta-analysis, only the results for at least 5-year survival were used. For one trial [41], the maximum follow-up time was 7 years.

The 5-year overall survival curves are shown in Fig. 1. Survival rates were calculated based on the published results of the three trials [9, 52, 41]. After 5 years, 121 of the 578 patients allocated to the immunochemotherapy group had died (21.0%; survival rate: 79.0%) and 143 of the 516 patients allocated to chemotherapy alone had died (27.8%; survival rate: 72.2%).

Fig. 1.

Fig. 1

Open in a new tab

Five-year overall survival curves for all eligible patients in the immunochemotherapy group (solid line) and chemotherapy group (dotted line)

The survival odds ratios and 95% confidence intervals (CIs) calculated for the qualifying trials are shown in Fig. 2. The odds ratio for the immunochemotherapy group was not significantly different from that for the chemotherapy group in two of the individual trials. The test for heterogeneity of the data yielded P=0.50, thus lending strong support to the hypothesis of homogeneity. Combining the data for the trials yielded an estimated common odds ratio of 0.71 with a 95% confidence interval (CI) of 0.55–0.90, and a significant effect of PSK (P=0.006).

Fig. 2.

Fig. 2

Open in a new tab

Survival odds ratios and their 95% CIs for each trial and overall (test for treatment effect P=0.006)

The 5-year disease-free survival curves are shown in Fig. 3. After 5 years, recurrence was noted in 161 of the 578 patients allocated to the immunochemotherapy group (27.8%; survival rate: 72.2%) and 176 of the 516 patients allocated to chemotherapy alone (34.1%; survival rate: 65.9%).

Fig. 3.

Fig. 3

Open in a new tab

Five-year disease-free survival curves for all eligible patients in the immunochemotherapy group (solid line) and chemotherapy alone group (dotted line)

The disease-free survival odds ratios and 95% CIs calculated for the qualifying trials are shown in Fig. 4. The odds ratio for the immunochemotherapy group was not significantly different from that for the chemotherapy group in one of the individual trials. The test for heterogeneity of the data yielded P=0.22, i.e., similar support for the hypothesis of homogeneity as in the case of survival. Combining the data for the trials yielded an estimated common odds ratio of 0.72, with a 95% CI of 0.58–0.90, and a significant effect of PSK (P=0.003).

Fig. 4.

Fig. 4

Open in a new tab

Disease-free survival odds ratios and their 95% CIs for each trial and overall (test for treatment effect P=0.003)

Discussion

Immunotherapy is added to adjuvant chemotherapy in an attempt to overcome the immunosuppression caused by chemotherapeutic agents as well as to exert a synergistic effect. The combination of fluorinated pyrimidines with the immunotherapeutic agent OK-432 has proved to be effective as adjuvant chemotherapy for both gastric cancer and lung cancer [57, 58]. In the case of colorectal cancer, the combination of 5-FU with levamisole (a biologic modifier) was also confirmed to be significantly more effective for Dukes’ C patients after curative resection [59].

PSK is a nonspecific immunopotentiator and exerts its immunomodulatory action by inducing the production of interleukin-2 and interferon-γ, thereby stimulating lymphokine activated killer cells (LAK) and enhancing natural killer cells [12, 13, 60–65] . PSK also has a favorable effect on the activation of leucocyte chemotactic locomotion and phagocytic activity [8].

For the meta-analysis reported here, we focused on the effect of adding PSK therapy to adjuvant chemotherapy after curative resection of colorectal cancer. In Japan, oral fluorinated pyrimidines have been developed as standard chemotherapy for colorectal cancer. Recently reported results have shown a favorable effect of oral fluorinated pyrimidine therapies, such as oral FU, which uses tegafur, tegafur-uracil (UFT), carmofur and 5’DFUR, over surgery alone, and a meta-analysis demonstrated a significant benefit of the treatment with oral fluorinated pyrimidines compared to surgery alone for resectable tumors of the colon and rectum [3, 4]. However, the same type of meta-analysis regarding the immunochemotherapeutic efficacy of PSK plus chemotherapeutic agents for colorectal cancer has not been published. Therefore, we assessed a number of randomized clinical trials designed to examine the effect of adding PSK to oral fluorinated pyrimidines.

Although a considerable number of trials have been performed to compare the effect of immunochemotherapy combined with PSK with that of chemotherapy alone, not all of these studies have been published. In an effort to broaden our search, we therefore also screened presentations made at conferences and made inquiries of doctors performing clinical trials as well as of pharmaceutical industry representatives. As a result, we succeeded in detecting a number of trials meeting our selection criteria. The final three trials were selected by checking the study procedures, especially in terms of central randomization and completeness of the data. Among the individual clinical trials performed so far, only one [9] has shown a survival advantage, while none of other trials demonstrated a significant effect of PSK.

However, combining data from the three relevant studies revealed an odds ratio of 0.71 for survival and of 0.72 for disease free survival, so that our meta-analysis indicated a significant improvement in survival as a result of immunochemotherapy with PSK (P=0.006 for survival and 0.003 for disease-free survival). This improvement may be not only statistically but also clinically significant. A reduction of the death rate by 29% and of recurrence by 28% could be substantial and may justify the inconvenience and financial burden of long-term administration of PSK.

It is difficult to explain why the combination therapy with PSK and oral fluorinated pyrimidines is more effective for curatively resected colorectal cancer. Two largescale clinical trials showed the effectiveness of levamisole plus fluorouracil as adjuvant immunochemotherapy [5, 66]. While oral fluorinated pyrimidine has already been approved as the standard adjuvant chemotherapy in Japan, an even higher efficacy as a result of the addition of immunopotentiator PSK could open new possibilities for a better therapeutic modality for colorectal cancer. Since PSK, OK-432 and levamisole all have similar immunomodulatory effects, but are not necessarily effective as monotherapy against malignancies, the effect of immunochemotherapy with PSK after curative resection of colorectal cancer may be the result of restoration of immunity in patients who show immunosuppression because of surgery and subsequent chemotherapy. Our previous findings from experimental and human studies also support this concept [67, 68].

In conclusion, the results of the meta-analysis presented here suggest that addition of PSK to the standard oral fluorinated pyrimidine based chemotherapy used in Japan offers a significant advantage over chemotherapy alone, in terms of both overall and disease-free survival for patients with curatively resected colorectal cancer. A meta-analysis of individual patient data is now in progress which is expected to provide more detailed and useful information regarding the effects of immunochemotherapy with PSK.

Acknowledgements

This work was supported in part by the EBM center of Kyoto University and by Epidemiological and Clinical Research Information Network (ECRIN), a nonprofit organization.

References

  • 1.Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer. 2001;37(Suppl 8):S4–S66. doi: 10.1016/S0959-8049(01)00267-2. [DOI] [PubMed] [Google Scholar]
  • 2.Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–2351. doi: 10.1056/NEJMoa032709. [DOI] [PubMed] [Google Scholar]
  • 3.Sakamoto J, Hamada C, Kodaira S, et al. Adjuvant therapy with oral fluoropyrimidines as main chemotherapeutic agents after curative resection for colorectal cancer: individual patient data meta-analysis of randomized trials. Jpn J Clin Oncol. 1999;29:78–86. doi: 10.1093/jjco/29.2.78. [DOI] [PubMed] [Google Scholar]
  • 4.Meta-Analysis Group of the Japanese Society for Cancer of the Colon and Rectum and the Meta-Analysis Group in Cancer Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials. J Clin Oncol. 2004;22:484–492. doi: 10.1200/JCO.2004.04.065. [DOI] [PubMed] [Google Scholar]
  • 5.Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322:352–358. doi: 10.1056/NEJM199002083220602. [DOI] [PubMed] [Google Scholar]
  • 6.Kobayashi H, Matsunaga K, Oguchi Y. Antimetastatic effects of PSK (Krestin), a protein-bound polysaccharide obtained from basidiomycetes: an overview. Cancer Epidemiol Biomarkers Prev. 1995;4:275–281. [PubMed] [Google Scholar]
  • 7.Ikuzawa M, Matsunaga K, Nishiyama S, et al. Fate and distribution of an antitumor protein-bound polysaccharide PSK (Krestin) Int J Immunopharmacol. 1988;10:415–423. doi: 10.1016/0192-0561(88)90128-2. [DOI] [PubMed] [Google Scholar]
  • 8.Torisu M, Hayashi Y, Ishimitsu T, et al. Significant prolongation of disease-free period gained by oral polysaccharide K (PSK) administration after curative surgical operation of colorectal cancer. Cancer Immunol Immunother. 1990;31:261–268. doi: 10.1007/BF01740932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Mitomi T, Tsuchiya S, Iijima N, et al. Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. The Cooperative Study Group of Surgical Adjuvant Immunochemotherapy for Cancer of Colon and Rectum (Kanagawa) Dis Colon Rectum. 1992;35:123–130. doi: 10.1007/BF02050666. [DOI] [PubMed] [Google Scholar]
  • 10.Nakazato H, Koike A, Saji S, et al. Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Lancet. 1994;343:1122–1126. doi: 10.1016/S0140-6736(94)90233-X. [DOI] [PubMed] [Google Scholar]
  • 11.Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17:2815–2834. doi: 10.1002/(SICI)1097-0258(19981230)17:24&#x0003c;2815::AID-SIM110&#x0003e;3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
  • 12.Ebina T, Murata K. Antitumor effect of PSK at a distant site: tumor-specific immunity and combination with other chemotherapeutic agents. Jpn J Cancer Res. 1992;83:775–782. doi: 10.1111/j.1349-7006.1992.tb01979.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Harada M, Matsunaga K, Oguchi Y, et al. Oral administration of PSK can improve the impaired anti-tumor CD4+T-cell response in gut-associated lymphoid tissue (GALT) of specific-pathogen-free mice. Int J Cancer. 1997;70:362–372. doi: 10.1002/(SICI)1097-0215(19970127)70:3&#x0003c;362::AID-IJC19&#x0003e;3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  • 14.Matsunaga K, Morita I, Oguchi Y, et al. Restoration of immunologic responsiveness by PSK in tumor-bearing animals [in Japanese] Gan To Kagaku Ryoho. 1986;13:3468–3475. [PubMed] [Google Scholar]
  • 15.Kanoh T, Saito K, Matsunaga K, et al. Enhancement of the antitumor effect by the concurrent use of a monoclonal antibody and the protein-bound polysaccharide PSK in mice bearing a human cancer cell line. In Vivo. 1994;8:241–245. [PubMed] [Google Scholar]
  • 16.Suo J, Tanaka N, Hizuta A, et al. Suppression of hepatic natural killer activity by liver metastasis of cancer and restoration of killer activity by oral administration of a Basidomycetes-derived polysaccharide, PSK. Acta Med Okayama. 1994;48:237–242. doi: 10.18926/AMO/31113. [DOI] [PubMed] [Google Scholar]
  • 17.Noguchi K, Tanimura H, Yamaue H, et al. Polysaccharide preparation PSK augments the proliferation and cytotoxicity of tumor-infiltrating lymphocytes in vitro. Anticancer Res. 1995;15:255–258. [PubMed] [Google Scholar]
  • 18.Ebina T, Murata K. Antitumor effect of intratumoral administration of BRM: inhibition of tumor cell invasion in vitro [in Japanese] Gan To Kagaku Ryoho. 1995;22:1626–1628. [PubMed] [Google Scholar]
  • 19.Sugiyama Y, Saji S, Miya K, et al. Locoregional therapy for liver metastases of colorectal cancer [in Japanese] Gan To Kagaku Ryoho. 1996;23:1433–1436. [PubMed] [Google Scholar]
  • 20.Kamei H, Hashimoto Y, Koide T, et al. Direct tumor growth suppressive effect of melanoidin extracted from immunomodulator-PSK. Cancer Biother Radiopharm. 1997;12:341–344. doi: 10.1089/cbr.1997.12.341. [DOI] [PubMed] [Google Scholar]
  • 21.Ogihara H, Takenoshita S, Yajima Y, et al. The efficacy of immunochemotherapy with strontium (Sr) in the 1,2-dimethylhydrazine (DMH) induced rat carcinogenetic model: ultrastructural characteristics of the mitochondria in the liver. Anticancer Res. 1998;18:159–164. [PubMed] [Google Scholar]
  • 22.Matsunaga K, Hosokawa A, Oohara M, et al. Direct action of a protein-bound polysaccharide, PSK, on transforming growth factor-beta. Immunopharmacology. 1998;40:219–230. doi: 10.1016/S0162-3109(98)00045-9. [DOI] [PubMed] [Google Scholar]
  • 23.Matsunaga K, Iijima H, Kobayashi H. Neonatal inoculation with the protein-bound polysaccharide PSK increases resistance of adult animals to challenge with syngeneic tumor cells and reduces azoxymethane-induced precancerous lesions in the colon. Cancer Epidemiol Biomarkers Prev. 2000;9:1313–1322. [PubMed] [Google Scholar]
  • 24.Okuzawa M, Shinohara H, Kobayashi T, et al. PSK, a protein-bound polysaccharide, overcomes defective maturation of dendritic cells exposed to tumor-derived factors in vitro. Int J Oncol. 2002;20:1189–1195. [PubMed] [Google Scholar]
  • 25.Wada T, Iijima H, Sekine F, et al. Effect of PSK on Th1/Th2 balance in tumor-bearing mice [in Japanese] Gan To Kagaku Ryoho. 2003;30:1798–1801. [PubMed] [Google Scholar]
  • 26.Yoshikawa R, Yanagi H, Hashimoto-Tamaoki T, et al. Gene expression in response to anti-tumor intervention by polysaccharide-K (PSK) in colorectal carcinoma cells. Oncol Rep. 2004;12:1287–1293. [PubMed] [Google Scholar]
  • 27.Yasutomi M. Surgery and adjuvant therapy of cancer of the large intestine [in Japanese] Gan To Kagaku Ryoho. 1986;13:2307–2317. [PubMed] [Google Scholar]
  • 28.Sakamoto J, Kato J, Yasue M. Surgery and multidisciplinary treatment for colorectal cancer [in Japanese] Gan To Kagaku Ryoho. 1998;25:208–215. [PubMed] [Google Scholar]
  • 29.Kidd PM. The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev. 2000;5:4–27. [PubMed] [Google Scholar]
  • 30.Fisher M, Yang LX. Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy. Anticancer Res. 2002;22:1737–1754. [PubMed] [Google Scholar]
  • 31.Kimura K, Tuchiya S, Yasutomi M, et al. Comparison of surgical therapy and combined irradiation in rectal cancer–first report, effect of irradiation on the tumor. Study Group of Surgical Therapy and Combined Irradiation in Rectal Cancer [in Japanese] Gan To Kagaku Ryoho. 1989;16:3161–3172. [PubMed] [Google Scholar]
  • 32.Koda K, Miyazaki M, Sarashina H, et al. A randomized controlled trial of postoperative adjuvant immunochemotherapy for colorectal cancer with oral medicines. Int J Oncol. 2003;23:165–172. [PubMed] [Google Scholar]
  • 33.Saji S, Kajima T, Takao H, et al. A study on postoperative long-term continuous immuno-chemotherapy with PSK and 5-FUDS for advanced gastric and colo-rectal cancers [in Japanese] Gan To Kagaku Ryoho. 1983;10:756–762. [PubMed] [Google Scholar]
  • 34.Munemoto Y, Iida Y, Abe J, et al. Significance of postoperative adjuvant immunochemotherapy after curative resection of colorectal cancers: Association between host or tumor factors and survival. Int J Oncol. 2002;20:403–411. [PubMed] [Google Scholar]
  • 35.Munemoto Y, Iida Y, Ohata K, et al. Significance of postoperative adjuvant immunochemotherapy after curative resection of colorecral cancers: identification of responders incorporating the age factor. Oncol Rep. 2004;11:623–635. [PubMed] [Google Scholar]
  • 36.Nio Y, Tsubono M, Tseng CC, et al. Immunomodulation by orally administered protein-bound polysaccharide PSK in patients with gastrointestinal cancer. Biotherapy. 1992;4:117–128. doi: 10.1007/BF02171756. [DOI] [PubMed] [Google Scholar]
  • 37.Hayashibe A, Kito H, Taruya E, et al. Immunological competence and effect of PSK in patients with gastric cancer and colon cancer: preliminary report [in Japanese] Nippon Geka Gakkai Zasshi. 1992;93:770. [PubMed] [Google Scholar]
  • 38.Sugimachi K, Maehara Y, Kusumoto T, et al. In vitro reactivity to a protein-bound polysaccharide PSK of peripheral blood lymphocytes from patients with gastrointestinal cancer. Anticancer Res. 1995;15:2175–2179. [PubMed] [Google Scholar]
  • 39.Shibata M, Nezu T, Kanou H, et al. Immunomodulatory effects of low dose cis-Diaminedichloroplatinum (cisplatin) combined with UFT and PSK in patients with advanced colorectal cancer. Cancer Invest. 2002;20:166–173. doi: 10.1081/CNV-120001142. [DOI] [PubMed] [Google Scholar]
  • 40.Alliot C. Adjuvant immunochemotherapy with oral Tegafur/Uracil plus PSK in patients with stage II or III colorectal cancer. Br J Cancer. 2004;90:1003–1010. doi: 10.1038/sj.bjc.6601805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Ohwada S, Ikeya T, Yokomori T, et al. Adjuvant immunochemotherapy with oral Tegafur/Uracil plus PSK in patients with stage II or III colorectal cancer: a randomized controlled study. Br J Cancer. 2004;90:1003–1010. doi: 10.1038/sj.bjc.6601619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Saeki Y, Hosokawa O, Yamamichi N. Regression of adenomas in Gardner’s syndrome induced by systemic chemotherapy [in Japanese] Gan No Rinsho. 1984;30:849–854. [PubMed] [Google Scholar]
  • 43.Nishizawa R, Fukushima T, Seidou D, et al. A case report of rectal cancer with effective Krestin treatment [in Japanese] Prog Med. 1987;7:855–858. [Google Scholar]
  • 44.Ishigaki H, Satoh S, Saitoh S, et al. An autopsy case of rectal cancer receiving cisplatin at total dose of 3.250 mg and platinum concentrations in autopsy tissue samples [in Japanese] Gan To Kagaku Ryoho. 1989;16:3805–3808. [PubMed] [Google Scholar]
  • 45.Masayoshi U, Ishida H, Kiyomatsu Y, et al. A case of rectal carcinoma disappeared by the preoperative radiation [in Japanese] Nippon Geka Gakkai Zasshi. 1991;92:222–224. [PubMed] [Google Scholar]
  • 46.Toshino Y, Jojima T, Abe M, et al. Case report of lung metastasis from sigmoid colon cancer with effective combination therapy using HCFU and PSK [in Japanese] Biotherapy. 1992;6:1331–1333. [Google Scholar]
  • 47.Kaneoka S, Nakanishi M, Osawa J, et al. A case report of juvenile colon cancer with massive peritoneal dissemination effectively treated by immunochemotherapy [in Japanese] Biotherapy. 1994;8:607–609. [Google Scholar]
  • 48.Ikeda M, Shigemitsu Y, Era S, et al. A case report of a juvenile large bowel cancer [in Japanese] Iryou. 1997;51:367–370. [Google Scholar]
  • 49.Mukai M, Tokunaga N, Yasuda S, et al. Long-term survival after immunochemotherapy for juvenile colon cancer with peritoneal dissemination: a case report. Oncol Rep. 2000;7:1343–1347. doi: 10.3892/or.7.6.1343. [DOI] [PubMed] [Google Scholar]
  • 50.Kudo S, Tanaka J, Kashida H, et al. Effectiveness of immunochemotherapy with PSK, a protein-bound polysaccharide, in colorectal cancer and changes of tumor marker. Oncol Rep. 2002;9:635–638. [PubMed] [Google Scholar]
  • 51.Ohwada S, Kawate S, Ikeya T, et al. Adjuvant therapy with protein-bound polysaccharide K and tegafur uracil in patients with stage II or III colorectal cancer: randomized, controlled trial. Dis Colon Rectum. 2003;46:1060–1068. doi: 10.1007/s10350-004-7281-y. [DOI] [PubMed] [Google Scholar]
  • 52.Ito K, Nakazato H, Koike A, et al. Long-term effect of 5-fluorouracil enhanced by intermittent administration of polysaccharide K after curative resection of colon cancer. A randomized controlled trial for 7-year follow-up. Int J Colorectal Dis. 2004;19:157–164. doi: 10.1007/s00384-003-0532-x. [DOI] [PubMed] [Google Scholar]
  • 53.Nakazato H, Ichihashi H, Kondo T, et al. Clinical results of a randomized controlled trial on the effect of adjuvant immunochemotherapy using Esquinon and Krestin in patients with curatively resected gastric cancer. Cooperative Study Group of Cancer Immunochemotherapy, Tokai Gastrointestinal Oncology Group [in Japanese] Gan To Kagaku Ryoho. 1986;13:308–318. [PubMed] [Google Scholar]
  • 54.Takashima S, Kinami Y, Miyazaki I. Clinical effect of postoperative adjuvant immunochemotherapy with the FT-207 suppository and PSK in colorectal cancer patients. Colorectal Cancer Chemotherapy Group in Hokuriku [in Japanese] Gan To Kagaku Ryoho. 1988;15:2229–2236. [PubMed] [Google Scholar]
  • 55.Mitomi T, Tsuchiya S, Iijima N, et al. Randomized controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. The Cooperative Study Group of Surgical Adjuvant Immunochemotherapy for Cancer of Colon and Rectum [in Japanese] Gan To Kagaku Ryoho. 1989;16:2241–2249. [PubMed] [Google Scholar]
  • 56.Mitomi T, Tsuchiya S, Iijima N, et al. Randomized controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer [in Japanese] Nippon Gan Chiryo Gakkai Shi. 1993;28:71–83. [Google Scholar]
  • 57.Sakamoto J, Teramukai S, Nakazato H, et al. Efficacy of adjuvant immunochemotherapy with OK-432 for patients with curatively resected gastric cancer: a meta-analysis of centrally randomized controlled clinical trials. J Immunother. 2002;25:405–412. doi: 10.1097/00002371-200209000-00004. [DOI] [PubMed] [Google Scholar]
  • 58.Sakamoto J, Teramukai S, Watanabe Y, et al. Meta-analysis of adjuvant immunochemotherapy using OK-432 in patients with resected non-small-cell lung cancer. J Immunother. 2001;24:250–256. doi: 10.1097/00002371-200105000-00009. [DOI] [PubMed] [Google Scholar]
  • 59.Nakazato H, Koike A, Saji S, et al. Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Lancet. 1994;343:1122–1126. doi: 10.1016/S0140-6736(94)90233-X. [DOI] [PubMed] [Google Scholar]
  • 60.Hirose K, Zachariae CO, Oppenheim JJ, et al. Induction of gene expression and production of immunomodulating cytokines by PSK in human peripheral blood mononuclear cells. Lymphokine Res. 1990;9:475–483. [PubMed] [Google Scholar]
  • 61.Hayashida Y, Kurimoto S, Yamamoto N. Effect of lymphokine-activated killer cells on human retinoblastoma cells (Y-79) in vitro: enhancement of the activity by a polysaccharide preparation, krestin. Biochem Biophys Res Commun. 1991;174:107–114. doi: 10.1016/0006-291X(91)90492-P. [DOI] [PubMed] [Google Scholar]
  • 62.Kato M, Hirose K, Hakozaki M, et al. Induction of gene expression for immunomodulating cytokines in peripheral blood mononuclear cells in response to orally administered PSK, an immunomodulating protein-bound polysaccharide. Cancer Immunol Immunother. 1995;40:152–156. doi: 10.1007/BF01517346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Yefenof E, Gafanovitch I, Oron E, et al. Prophylactic intervention in radiation-leukemia-virus-induced murine lymphoma by the biological response modifier polysaccharide K. Cancer Immunol Immunother. 1995;41:389–396. doi: 10.1007/BF01526559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Algarra I, Collado A, Garrido F. Protein bound polysaccharide PSK abrogates more efficiently experimental metastases derived from H-2 negative than from H-2 positive fibrosarcoma tumor clones. J Exp Clin Cancer Res. 1997;16:373–380. [PubMed] [Google Scholar]
  • 65.Pedrinaci S, Algarra I, Garrido F. Protein-bound polysaccharide (PSK) induces cytotoxic activity in the NKL human natural killer cell line. Int J Clin Lab Res. 1999;29:135–140. doi: 10.1007/s005990050079. [DOI] [PubMed] [Google Scholar]
  • 66.Laurie JA, Moertel CG, Fleming TR, et al. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. J Clin Oncol. 1989;7:1447–1456. doi: 10.1200/JCO.1989.7.10.1447. [DOI] [PubMed] [Google Scholar]
  • 67.Kondo T, Sakamoto J, Nakazato H. Alternating immunochemotherapy of advanced gastric carcinoma: a randomized comparison of carbazilquinone and PSK to carbazilquinone in patients with curative gastric resection. Biotherapy. 1991;3:287–295. doi: 10.1007/BF02221321. [DOI] [PubMed] [Google Scholar]
  • 68.Sakamoto J, Teramukai S, Koike A, et al. Prognostic value of preoperative immunosuppressive acidic protein in patients with gastric carcinoma. Findings from three independent clinical trials. Tumor Marker Committee for the Study Group of Immunochemotherapy with PSK for Gastric Cancer. Cancer. 1996;77:2206–2212. doi: 10.1002/(SICI)1097-0142(19960601)77:11&#x0003c;2206::AID-CNCR4&#x0003e;3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES